INHIBITORS OF CYSTEINE PROTEASES AND METHODS OF USE THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S.S.N. 63/036,866 filed June 9, 2020; U.S.S.N. 63/039,297 filed June 15, 2020; U.S.S.N. 63/067,669 filed August 19, 2020; U.S.S.N. 63/091,630 filed October 14, 2020; U.S.S.N. 63/129,018 filed December 22, 2020; U.S.S.N. 63/171,675 filed April 7, 2021; U.S.S.N. 63/172,478 filed April 8, 2021; U.S.S.N. 63/173,146 filed April 9, 2021; U.S.S.N. 63/179,128, filed April 23, 2021; and U.S.S.N. 63/195,460, filed June 1, 2021; the contents of each of which are incorporated herein by reference in their entirety.

BRIEF DESCRIPTION OF THE SEQUENCE LISTING

[0002] 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 June 3, 2021, is named PARB-004WO_SL.txt and is 3,285 bytes in size.

BACKGROUND

[0003] 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 21 ^st century, 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.

[0004] 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.

[0005] 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 [0006] 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.

[0007] 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.

[0008] Also disclosed herein are compounds represented by Formula II: or a pharmaceutically acceptable salt, stereoisomer, ester, or prodrug thereof, wherein:

R ^3a is 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, C ₁ -C ₈ alkoxy, oxo and a warhead A; R ^3b is selected from hydrogen and C ₁ -C ₈ alkyl; wherein R ^3a and R ^3b may 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 C ₆ -C ₁₄ aryl and a warhead A; R ^1a is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, -(C ₁ -C ₈ alkyl)-R ¹ , -(C ₁ - C ₈ alkyl)-CN, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; R ^1b is selected from hydrogen and C ₁ -C ₈ alkyl; or R ^1a and R ^1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle having a ring nitrogen, NR ^G , or a C ₃ -C ₁₀ cycloalkyl; R ¹ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C3-C 10cycloalkyl, C ₆ -C14aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from R ^A ; R ^A is independently selected for each occurrence from the group consisting of halogen, cyano, hydroxyl, oxo, SF ₅ , -CH ₂ CF ₃ , -CF ₃ , -O-CF3, -O-CHFz, -S-CH3, -S(O)z-CH ₃ , -NH ₂ , -O-phenyl, -0-(C ₁ - C ₈ alkyl)-phenyl, -NHC(O)R ^B , -NHC(O)0R ^B , -NHC(O)0-(C ₁ -C ₈ alkyl)-R ^B , -N(R ^y )2, - N(R ^y )(C ₁ -C ₈ alkyl)C(O)0-phenyl, -N(R ^y )(C ₁ -C ₈ alkyl)C(O)N(R ^y ) ₂ , -C(O)-0C(CH ₃ )3, C ₁ - C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy, C ₃ -C mcycloalkyl, - (C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), -(C ₁ -C ₈ alkyl)-(5-10 membered heteroaryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, wherein the R ^b , alkyl, heterocyclyl, heteroaryl, or aryl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, C ₁ - C ₈ alkyl, C ₁ -C ₈ alkoxy, SF ₅ , -NH ₂ , hydroxyl and oxo; R ² is selected from the group consisting of-NHC(O)R ^B , -NHC(O)N(R ^B )Z, -NHC(O)C(R ^C ) ₂ R ^b , -NHS(O) ₂ R ^b , -0-(C ₁ -C ₈ alkyl)-(C ₃ - Ciocycloalkyl), 4-10 membered heterocycle, C ₆ -C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ^B or R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ; or R ^1a and R ² may 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 NR°, or a C3-C 10cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from R ^A ; R ³ is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, C ₂ -Cioalkenyl, C ₂ -Cioalkynyl, C ₃ -C 16cycloalkyl, fluorenylmethyloxy, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; R ^c is independently selected, for each occurrence, from hydrogen, halogen and C ₁ -C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF ₅ , cyano, -O-iR^-OCH ₃ , -OCHFz, -OCF3, -O-(C ₁ -C ₈ alkyl), - C(O)0(CH ₃ ), -N(R ^y )z, -N(R ^y )C(O)R ^y , -N(R ^y )(C ₁ -C ₈ alkyl)C(O)N(R ^y ) ₂ , -N(R ^y )(C ₁ - C ₈ alkyl)C(O)OH, -(C ₁ -C ₈ alkyl)-(C3-C mcycloalkyl), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C3- Ciocycloalkyl, C ₆ -C ₁₄ aryl, -O-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; wherein two geminal C ₁ -C ₈ alkyl groups, together with the carbon to which they are attached, may be joined together to form a C ₃ -C ₆ cycloalkyl 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 C ₁ -C ₈ alkyl; R ^G is selected from the group consisting of hydrogen, C _1-6 alkyl optionally substituted by one, two or three R ^gg , -C(=O)-C _1-6 alkyl optionally substituted by one, two or three R ^hh , -C(=O)-C3- ₆ cycloalkyl, -C(O)-(C ₂ -Cioalkenyl)-(C6-Ci ₄ aryl), -C(O)-(C i-C6alkyl)-0-(C ₆ -C ₁₄ aryl), -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 R ⁸ ; R ^gg is independently selected for each occurrence from the group consisting of -C(=O), halo, cyano, -NR ^m R ^m , and -NH(C=O)R ^m ; R ^hh is independently selected for each occurrence from the group consisting of halo, cyano, - NR ^m R ^m , _NR ^m (c=O)R ^m , phenyl, cycloalkyl, heterocyclyl and C ₁ -C ₆ alkoxy; R ^jj is independently selected for each occurrence from the group consisting of halo, oxo, hydroxyl, cyano, C ₁ -C ₆ alkyl, C _1-6 haloalkyl, C _1-6 haloalkoxy, C ₁ -C ₆ alkoxy, C _3-6 cycloalkyl, SF ₅ , and NH ₂ ; R ^m is independently selected for each occurrence from the group consisting of hydrogen, C ₁ - ₃ alkyl, phenyl, -S(O)z-CH3, C _3-6 cycloalkyl, and 5-6 membered heteroaryl; wherein C ₁ -3alkyl, phenyl, and C _3-6 cycloalkyl may optionally be substituted by one, two or three halo; R ^xx is - (OCH2CH2)nn— , wherein nn is selected from 1, 2, 3, 4, 5 and 6; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, - CF3, -CH2CF3, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl), C3-C6cycloalkyl and - (C ₁ -C ₈ alkyl)COOH; A is a warhead; and X is selected from the group consisting of C(R ^xy ) and N, wherein R ^xy is selected from the group consisting of H, D, -OH, -NH ₂ , halogen, C ₁ - C ₈ alkyl, C ₁ -C ₈ haloalkyl, and C ₁ -C ₈ alkoxy.

[0009 ] In some embodiments, disclosed herein are compounds represented by Formula

I I-Α: [00010] In some embodiments, disclosed herein are compounds represented by Formula

I I-Β:

[00011] In some embodiments, disclosed herein are compounds represented by Formula n-C:

[00012] In some embodiments, disclosed herein are compounds represented by Formula

I I-D-A or Formula II-D-B:

[00013] In some embodiments, disclosed herein are compounds represented by Formula

II-E-A or Formula II-E-B:

[00014] In some embodiments, disclosed herein are compounds represented by Formula n-F: [00015] In some embodiments, disclosed herein are compounds represented by Formula n-G:

[00016] In some embodiments, disclosed herein are compounds represented by Formula

I I-Η-Α or Formula II-H-B: wherein pp is selected from 0, 1, 2, and 3.

[00017] In some embodiments, disclosed herein are compounds represented by Formula

I I-Ε: wherein ss is selected from 0, 1, 2, and 3, and mm is selected from 1, 2, and 3.

[00018] In some embodiments, disclosed herein are compounds represented by Formula

I I-Ι: or a pharmaceutically acceptable salt thereof, wherein:

R ³ is R ¹ is independently, for each occurrence, H or methyl; or each R ¹ may be taken, together with the carbon to which they are attached, to form a cyclopropyl; R ^B is selected from the group consisting of: a 9-10 membered bicyclic heteroaryl having one ring nitrogen, C ₁ -C ₆ alkyl, and Cz-Csalkenyl; wherein R ^B is optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, C ₁ -C ₈ alkoxy, NHR ^m , and phenyl (optionally substituted by one or two halogens); and R ^m is C ₁ -C ₈ alkyl or -C(O)-C ₁ -3alkyl, wherein each C ₁ -C ₈ alkyl is independently optionally substituted by one, two or three halogens.

[00019] In certain embodiments, disclosed herein are conjugates represented by Formula

I IΙ: wherein Cys145 is 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

[00020] 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

[00021 ] 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.

[00022] The term “alkyl” as used herein refers to a saturated straight or branched hydrocarbon. Exemplary alkyl groups include, but are not limited to, straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C _1-6 alkyl, C _1-4 alkyl, and C ₁ -C ₈ alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl- 1 -butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl,

3 -methyl- 1 -pentyl , 4-methyl- 1 -pentyl , 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2- pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, hexyl, etc.

[00023] 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 Cz^alkynyl, and C _3-6 alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[00024] 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 C ₁ -C ₈ alkenyl, Cz-C ₆ alkenyl, and C3-C4alkenyl, respectively. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc. [00025] 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 C ₁ -C ₈ alkoxy, C ₁ -

C ₆ alkoxy, and C2-C ₆ alkoxy, respectively. Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy, isopropoxy, etc.

[00026] 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 (“C ₆ -14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C ₆ aryl”; e.g, phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g, naphthyl such as 1 -naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C ₁₄ aryl”; 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 tetrahy dronaphthy 1.

[00027] Examples of representative substituted aryls include the following: wherein one of R ⁵⁶ and R ⁵⁷ may be hydrogen and at least one of R ⁵⁶ and R ⁵⁷ is each independently selected from halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C ₁ -C ₈ alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR ⁵⁸ COR ⁵⁹ , NR ⁵⁸ SOR ⁵⁹ NR ⁵⁸ SO _Z R ⁵⁹ , COO-alkyl, COO-aryl, CONR ⁵⁸ R ⁵⁹ , CONR ⁵⁸ OR ⁵⁹ , NR ⁵⁸ R ⁵⁹ , SOZNR ⁵⁸ R ⁵⁹ , S-alkyl, SO-alkyl, S0 ₂ .alkyl, S-aryl, SO-aryl, and S0 ₂ .aryl; or R ⁵⁶ and R ⁵⁷ may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group consisting of N, O, and S; R ⁶⁰ and R ⁶¹ are independently hydrogen, C ₁ -C ₈ alkyl, C ₁ -C4haloalkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C ₆ -C10 aryl, substituted C ₆ -C10 aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.

[00028] The term “carbonyl” as used herein refers to the radical -C(O)-.

[00029] The term “cyano” as used herein refers to the radical -CN.

[00030] 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 C _3-6 cycloalkoxy groups. Exemplary cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclohexyloxy, etc.

[00031] 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-C mcycloalkyl, C _3-6 cycloalkyl or C^cycloalkyl, respectively. Exemplary cycloalkyl groups include, but are not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutyl or cyclopropyl.

[00032] The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

[00033] 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 C _1-6 haloalkyl, C1-4 haloalkyl, and C ₁ -3haloalkyl, respectively.

[00034] 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.

[00035] 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.

[00036] Examples of representative heteroaryls include the following: wherein each Z is selected from carbonyl, N, NR ⁶⁵ , O, and S; and R ⁶⁵ is each independently hydrogen, C ₁ -C ₈ alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C ₆ -Cio aryl, and 5-10 membered heteroaryl.

[00037] 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-lH-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:

[00038] The term “heterocyclyloxy” as used herein refers to a heterocyclyl group attached to oxygen (heterocyclyl-O-).

[00039] The term “heteroaryloxy” as used herein refers to a heteroaryl group attached to oxygen (heteroaryl-O-).

[00040] The terms “hydroxy” and “hydroxyl” as used herein refers to the radical -OH.

[00041 ] The term “oxo” as used herein refers to the radical =O.

[00042] “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 Biologies standards. [00043] 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.

[00044] 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.

[00045] “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.

[00046] 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. Alteratively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect.

[00047] 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, ethane sulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,l'-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.

[00048] 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 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.

[00049] 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 symbol — denotes 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 ILJPAC 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.

[00050] 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 ILJPAC 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.”

[00051] 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 Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[00052] 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.

[00053] 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 as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ 0, ¹⁷ 0, ³¹ P, ³² P, 3 ⁵ S, ¹⁸ F, and ³⁶ C1, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.

[00054] Certain isotopically-labeled disclosed compounds (e.g., those labeled with ³ H and ¹⁴ C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e. 3H) and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ² H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the examples herein by substituting an isotopically labeled reagent for a non- isotopically labeled reagent.

[00055] 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 (Ci^)alkyl, (Cz- iz)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, l-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci.z)alkylamino(C2-3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(C ₁ -2)alkyl, N,N-di(C ₁ -2)alkylcarbamoyl-(C ₁ -2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-3)alkyl .

[00056] 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 (C _1-6 )alkylcarbonyloxymethyl, l-((C _1-6 )alkylcarbonyloxy)ethyl,

1 -methyl- 1 -((C 1-6)alkylcarbonyloxy)ethyl (C 1-6)alkoxycarbonyloxymethyl, N-(C 1- 6)alkoxycarbonylaminomethyl, succinoyl, (C _1-6 )alkylcarbonyl, a-amino(C ₁ - 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)z, -P(O)(0(C i-6)alkyl)z or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).

[00057] 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. Molecules 2008, 13, 519 and references therein.

[00058] 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.

[00059] Examples of exemplary warheads include, but not limited to, a moiety with a cyano, halomethyl, aldehyde, ketoamide, hydroxybisulfite salt, heterocycle, epoxy ketone, halomethyl ketone, hydroxymethyl ketone, electrophilic ketone, acyloxymethyl ketone, benzothiazolyl ketone or a Michael acceptor, for example:

[00060] 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 R ^13bb is selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, -N(R ^e R ^f ), and -C(O)- N(R ^e R ^f ); R ^e and R ^f are each selected from the group consisting of hydrogen and C ₁ -

C ₆ alkyl; or R ^e and R ^f may 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.

[00061] 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: and wherein R ^13bb is selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, -N(R ^e R ^f ), and -C(O)- N(R ^e R ^f ); R ^e and R ^f are each selected from the group consisting of hydrogen and C ₁ -

C ₆ alkyl; or R ^e and R ^f may 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.

[00062] In some embodiments, the warhead is a moiety with an imino-oxazolidinone moiety. Examples of exemplary imino-oxazolidinone warheads include, but not limited to:

[00063] In some embodiments, the warhead is a moiety with an iminoimidazolidinone. Examples of exemplary iminoimidazolidinone warheads include, but not limited to: [00064] wherein each R ^ccc and R ^ccc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), and C ₆ - C ₁₄ aryl. In some embodiments, the warhead is selected from the group consisting of

[00065] Other examples of exemplary warheads include, but not limited to: wherein R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₈ - C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - C ₈ alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, Cl-C ₈ alkyl, and C ₈ - C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle.

[00066] Some other examples of exemplary warheads include, but not limited to: wherein R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl.

[00067] Other examples of exemplary warheads include, but not limited to: wherein R ^c is selected from the group consisting of hydrogen, - CH ₂ C(O)0(C i -C ₈ alkyl), C ₁ -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl; , wherein X ² is selected from the group consisting of NH, O and S; X ³ is independently selected, for each occurrence, from N and CH; R ^D is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl,

R ^E is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy; p is selected from 0, 1 and 2; and q is selected from 0, 1 and 2; , wherein X ² is selected from the group consisting of NH, NR ^P , O and S, wherein R ^P is C ₁ -C ₈ alkyl; wherein R ^D is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₁ - C ₈ alkyl, and independently selected, for each occurrence, from CH and N; R ^E is independently selected, for each occurrence, from the group consisting of halogen,

-CH ₃ , -OCH3, -OCH2CH3, -OCH(CH3)Z, -CN, -CF3, -OCF3 and -SCF3; and p is selected from 0, 1 and 2; -C(O)R ^D , wherein R ^D is selected from the group consisting of hydrogen, -CH ₂ OH, -CH ₂ OR and -CH _x F _y , 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 C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-(5-10 membered aryl), C ₁ -C ₈ heteroalkyl, C ₃ -C ₆ cycloalkyl and 5-10 membered aryl; and -(CH=CH)C(O)0R ^D , wherein R ^D is C ₁ -C ₈ alkyl.

[00068] 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.

[00069] 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.

[00070] The term "inhibitor" as used herein refers to a compound that binds to and/or inhibits a target protease with measurable affinity.

[00071 ] 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.

[00072] 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

[00073] 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, Cal pain 1, and Cathepsin S. Accordingly, in various embodiments, a compound of the present disclosure (e g. a compound of Formula I I, I I-Α,

I I-Β, II-C, n-D-A, II-D-B, II-E-A, II-E-B, II-F, I I-G, I I-Η-Α, 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.

[00074] Also provided herein are compounds represented by or a pharmaceutically acceptable salt, stereoisomer, ester, or prodrug thereof, wherein:

R ^3a is 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, C ₁ -C ₈ alkoxy, oxo and a warhead A; R ^3b is selected from hydrogen and C ₁ -C ₈ alkyl; wherein R ^3a and R ^3b may 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 C ₆ -C ₁₄ aryl and a warhead A; R ^1a is selected from the group consisting of hydrogen, C ₁ - C ₈ alkyl, C ₁ -C ₈ heteroalkyl, -(C ₁ -C ₈ alkyl)-R ¹ , -(C ₁ -C ₈ alkyl)-CN, C ₃ -C ₁₀ cycloalkyl, Ce- C ₁₄ aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; R ^1b is selected from hydrogen and C ₁ -C ₈ alkyl; or R ^1a and R ^1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle having a ring nitrogen, NR ^G , or a C ₃ -C ₁₀ cycloalkyl; R ¹ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from R ^A ; R ^A is independently selected for each occurrence from the group consisting of halogen, cyano, hydroxyl, oxo, SF ₅ , -CH ₂ CF ₃ , -CF ₃ , -O-CF3, -O-CHFz, -S-CH3, -S(O)z- CH ₃ , -NHZ, -O-phenyl, -0-(C ₁ -C ₈ alkyl)-phenyl, -NHC(O)R ^B , -NHC(O)OR ^B , -NHC(O)0- (C ₁ -C ₈ alkyl)-R ^B , -N(R ^y )2, -N(R ^y )(C ₁ -C ₈ alkyl)C(O)0-phenyl, -N(R ^y )(C ₁ - C ₈ alkyl)C(O)N(R ^y ) ₂ , -C(O)-0C(CH ₃ )3, C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ - C ₈ heteroalkyl, C ₁ -C ₈ alkoxy, C3-Ciocycloalkyl, -(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), -(C ₁ - C ₈ alkyl)-(C ₆ -C ₁₄ aryl), -(C ₁ -C ₈ alkyl)-(5- 10 membered heteroaryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, wherein the R ^B , alkyl, heterocyclyl, heteroaryl, or aryl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, SF ₅ , - NH ₂ , hydroxyl and oxo; R ² is selected from the group consisting of -NHC(O)R ^B , - NHC(O)N(R ^B )2, -NHC(O)C(R ^C )2R ^b , -NHS(O)2R ^b , -0-(C ₁ -C ₈ alkyl)-(C ₃ -C 10cycloalkyl), 4- 10 membered heterocycle, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ^B or R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ; or R ^1a and R ² may 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 NR ^G , or a C3-Ciocycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from R ^A ; R ³ is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C3-C6cycloalkyl, fluorenylmethyloxy, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; R ^c is independently selected, for each occurrence, from hydrogen, halogen and C ₁ -C ₈ alkyl; R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF ₅ , cyano, -O-iR^-OCH ₃ , -OCHF2, -OCF3, -0-(C ₁ -C ₈ alkyl), - C(O)0(CH ₃ ), -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , -N(R ^y )(C ₁ -C ₈ alkyl)C(O)N(R ^y )2, -N(R ^y )(C ₁ - C ₈ alkyl)C(O)0H, -(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C3- Ciocycloalkyl, C ₆ -C ₁₄ aryl, -O-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; wherein two geminal C ₁ -C ₈ alkyl 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 C ₁ -C ₈ alkyl; R° is selected from the group consisting of hydrogen, C _1-6 alkyl optionally substituted by one, two or three R ^gg , - C(=O)-C ₁ - ₆ alkyl optionally substituted by one, two or three R ^hh , -C(=O)-C ₃ - ₆ cycloalkyl, - C(O)-(C ₂ -Cioalkenyl)-(C ₆ -Ci ₄ aryl), -C(O)-(C ₁ -C ₆ alkyl)-0-(C ₆ -Ci ₄ aryl), -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 R ⁸ ; R ^gg is independently selected for each occurrence from the group consisting of -C(=O), halo, cyano, -NR ^m R ^m , and -NH(C=O)R ^m ; R ^hh is independently selected for each occurrence from the group consisting of halo, cyano, -NR ^m R ^m , -NR ^m (C=O)R ^m , phenyl, cycloalkyl, heterocyclyl and C ₁ -C ₆ alkoxy; R ⁸ is independently selected for each occurrence from the group consisting of halo, oxo, hydroxyl, cyano, C ₁ -C ₆ alkyl, C ₁ - 6haloalkyl, C ₁ -C ₆ alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkyl, SF ₅ , and NH ₂ ; R ^m is independently selected for each occurrence from the group consisting of hydrogen, C _1-3 alkyl, phenyl, - S(O)Z-CH3, C _3-6 cycloalkyl, and 5-6 membered heteroaryl; wherein C _1-3 alkyl, phenyl, and C3- 6cycloalkyl may optionally be substituted by one, two or three halo; R ^xx is -(OCH ₂ CH ₂ )^-, wherein nn is selected from 1, 2, 3, 4, 5 and 6; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, -CF3, - CH2CF3, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl), C3-C6cycloalkyl and -(C ₁ - C ₈ alkyl)COOH; A is a warhead; and X is selected from the group consisting of C(R ^xy ) and N, wherein R ^xy is selected from the group consisting of H, D, -OH, -NH ₂ , halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, and C ₁ -C ₈ alkoxy.

[00075] In some embodiments, R ^3b is hydrogen. [00076] In certain embodiments, disclosed herein are compounds represented by Formula I I-Α:

[00077] In certain embodiments, disclosed herein are compounds represented by Formula II-B:

[00078] In various embodiments, disclosed herein are compounds represented by Formula I I-C:

[00079] In some embodiments, disclosed herein are compounds represented by Formula

I I-D-A or Formula II-D-B:

[00080] In some embodiments, disclosed herein are compounds represented by Formula II-E-A or Formula II-E-B: [00081] In some embodiments, provided herein are compounds represented by Formula

I I-F:

[00082] In some embodiments, provided herein are compounds represented by Formula

I I-G:

[00083] In some embodiments, disclosed herein are compounds represented by Formula

I I-Η-Α or Formula II-H-B: wherein pp is selected from 0, 1, 2, and 3.

[00084] In some embodiments, disclosed herein are compounds represented by Formula

I I-Ε: wherein ss is selected from 0, 1, 2, and 3, and mm is selected from 1, 2, and 3.

[00085] In other embodiments, disclosed herein are compounds represented by Formula

I I-Ε-I I: wherein ss is selected from 0, 1, 2, and 3, and mm is selected from 1, 2, and 3.

[00086] In some embodiments, disclosed herein are compounds represented by Formula

I I-Ι: or a pharmaceutically acceptable salt thereof, wherein:

R ³ is R ¹ is independently, for each occurrence, H or methyl; or each R ¹ may be taken, together with the carbon to which they are attached, to form a cyclopropyl; R ^B is selected from the group consisting of: a 9-10 membered bicyclic heteroaryl having one ring nitrogen, C ₁ -C ₆ alkyl, and C2-C3alkenyl; wherein R ^B is optionally substituted by one, two or three substituents each independently selected from the group consisting of halogen, C ₁ -C3alkoxy, NHR ^m , and phenyl (optionally substituted by one or two halogens); and R ^m is C _1-3 alkyl or -C(O)-C ₁ -3alkyl, wherein C _1-3 alkyl is independently optionally substituted by one, two or three halogens.

[00087] In certain embodiments, R ^3a is wherein R ^xy is selected from the group consisting of H, D, OH, NH ₂ , halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, and C ₁ - C ₈ alkoxy. In embodiments, R ^xy is selected from the group consisting of H, D, CH3, CH2CH3, F, and CF3. In some embodiments, R ^xy is F. In some embodiments, R ^xy is CF3. In some embodiments, CH3. In some embodiments, R ^xy is H. [00088] In various embodiments, X is selected from the group consisting of CH, CD,

C(CH ₃ ), C(CH ₂ CH ₃ ), N, CF, CC1, CBr, C(CHF ₂ ), C(CH ₂ F), and C(CF ₃ ). 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.

[00089] In some embodiments, A is selected from the group consisting of cyano, -

C(O)R ^d , -C(O)CH ₂ N(R ^b R ^c ), -C(O)CH ₂ 0C(O)R ^D , -C(O)C(O)R ^D , -(CH=CH)C(O)0R ^D , -(CH=CCN)C(O)0R ^d , -(CH=CCN)C(O)(NH)R ^d , -CH(CN)(OH), -CH(CN)(NR ^b R ^c ), wherein R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb -N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C3-C6cycloalkyl, Ce- C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, hydroxyl, and R ^E ; R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of halogen, cyano, C ₁ - C ₈ alkyl and C ₁ -C ₈ alkoxy; R ^bb is selected from the group consisting of C3-C6cycloalkyl,

C ₆ -C ₁₄ aryl, -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C3- C ₆ cycloalkyl, -(C ₁ -C ₈ alkylHC ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - C ₈ alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each independently selected from the group consisting of hydrogen, C1- C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle; R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl; and R ^b and R ^c are each selected from the group consisting of hydrogen, -CH ₂ C(O)0(C ₁ -C ₈ alkyl), - C(O)-(C ₁ -C ₈ alkyl), -S(O)z-(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)- C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, C ₆ - C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.

[00090] In embodiments, A is selected from the group consisting of -CN,

[00091] In embodiments, R ^1a is selected from the group consisting of

[00092] In embodiments, R ^1a is -(C ₁ -C ₈ alkyl)-R ¹ .

[00093] In embodiments, R ^1b is hydrogen.

[00094] In certain embodiments, R ^1a and R ^1b are joined to together to form [00095] In certain embodiments, R ^3a is a 4-10 membered heterocycle.

[00096] In some embodiments, R ^3a is selected from the group consisting of

[00097] In some embodiments, R ³ is a 4-10 membered heterocycle.

[00098] In some embodiments, R ³ is selected from some embodiments, R ³ is (for example, wherein R ^x3 are independently for each occurrence selected from the group consisting of hydrogen, halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, C ₃ -C ₆ cycloalkyl, and C ₁ -C ₈ alkoxy; and pp is selected from 0, 1, 2, and 3. In some embodiments, R ³ is In some embodiments, R ³ is In some embodiments, R ³ is In some embodiments, R ³ is In some embodiments, R ³ is or , and R ¹ is independently, for each occurrence, H or methyl; or each R ^t may be taken, together with the carbon to which they are attached, to form a cyclopropyl.

[00099] In some embodiments, R ³ is selected from the group consisting . In embodiments, R ³ is a substituted bicyclic heterocycle, substituted monocyclic heterocycle, substituted bicyclic heteroaryl or substituted monocyclic heteroaryl. [000100] In some embodiments, R ³ is selected from the group consisting of

In some embodiments, R ³ is selected from the group consisting of

[000101]

[000102] In various embodiments, R ² is -NHC(O)R ^B . In various embodiments, R ^B is a 5- 10 membered heteroaryl. In various embodiments, R ^B is a bicyclic heteroaryl (e g. 9 membered heteroaryl). In various embodiments, R ^B is substituted. In various embodiments, R ^B is unsubstituted. In various embodiments, R ^B is substituted by halogen. In various embodiments, R ^B is substituted by -OCH3. In various embodiments, R ^B is substituted by -OH. In various embodiments, R ^B is substituted by C ₁ -C ₈ alkyl. In various embodiments, R ^B is substituted by C ₁ -C ₈ alkoxy. In various embodiments, R ² is substituted. In various embodiments, R ² is unsubstituted. In various embodiments, R ² is substituted by halogen. In various embodiments, R ² is substituted by -OCH3. In various embodiments, R ² is substituted by -OH. In various embodiments, R ² is substituted by C ₁ - C ₈ alkyl. In various embodiments, R ² is substituted by C ₁ -C ₈ alkoxy.

[000103] In some embodiments, R ² is selected from the group consisting of



[000104] In some embodiments, R ^1a and R ² are joined to together to form a heterocycle selected from the group consisting of: wherein R ^1b is H. [000105] In some embodiments, R ^1a and R ² are joined to together to form a heterocycle selected from the group consisting of:

wherein R ^1b is H.

[000106] In some embodiments, R ^1a and R ² are joined to together to form a heterocycle selected from the group consisting of:

[000107] In some embodiments, R ^1a and R ² are joined to together to form a heterocycle selected from the group consisting of:

[000108] In some embodiments, R ^G is selected from the group consisting of hydrogen, C ₁ - 6alkyl optionally substituted by one, two or three R ⁸⁶ , -C(=O)-C _1-6 alkyl optionally substituted by one, two or three R ^hh , -C(=O)-C _3-6 cycloalkyl, -C(O)-(C2-Cioalkenyl)-(C6- C ₁₄ aryl), -C(O)-(C 1-C6alkyl)-0-(C ₆ -C ₁₄ aryl), -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 R ^jj . [000109] In some embodiments, R ^G is selected from the group consisting of hydrogen, C ₁ - 6alkyl optionally substituted by one, two or three R ^gg , -C(=O)-C _1-6 alkyl optionally substituted by one, two or three R ^hh , and -C(=O)-C _3-6 cycloalkyl.

[000110] In other embodiments, R ^G is selected from the group consisting of -C(O)-(Cz-

Cioalkenyl)-(C ₆ -C ₁₄ aryl), -C(O)-( C ₁ -C ₆ alkyl)-0-(C ₆ -C ₁₄ aryl), -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 R ^jj .

[000111] In some embodiments, R ^gg is independently selected for each occurrence from the group consisting of -C(=O), halo, cyano, -NR ^m R ^m , and -NH(C=O)R ^m . In other embodiments, R ^hh is independently selected for each occurrence from the group consisting of halo, cyano, -NR ^m R ^m , -NR ^m (C=O)R ^m , phenyl, cycloalkyl, heterocyclyl and C ₁ -C ₆ alkoxy. In further embodiments, R ^jj is independently selected for each occurrence from the group consisting of halo, oxo, hydroxyl, cyano, C ₁ -C ₆ alkyl, C _1-6 haloalkyl, C ₁ -

C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C _3-6 cycloalkyl, SF ₅ , and NH ₂ .

[000112] In certain embodiments, R ^m is independently selected for each occurrence from the group consisting of hydrogen, C _1-3 alkyl (optionally substituted by one, two or three F), phenyl (optionally substituted by halo), -S(O)z-CH3, C _3-6 cycloalkyl (optionally substituted by one, two, or three F), and 5-6 membered heteroaryl.

[000113] In some embodiments, R ^G is selected from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of -C(=O), halo, cyano, -NR ^m R ^m , and -NH(C=O)R ^m ) and C(=O)-C ₁ - 6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, -NR ^m R ^m , -NR ^m (C=O)R ^m , phenyl, cycloalkyl and heterocycle, wherein R ^m is selected for each occurrence from H and C ₁ - 3alkyl (optionally substituted by one, two or three halogens, e g., F), or C ₃ -C ₆ cycloalkyl (optionally substituted by one, two, or three F).

[000114] In some embodiments, R ^G is 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(R ⁵⁵ R ⁵⁶ )-NH-C(O)-R ⁵⁷ , wherein R ⁵⁵ is H and R ⁵⁶ is a straight or branched C ₁ -salkyl (optionally substituted by halo), or R ⁵⁵ and R ⁵⁶ taken together with the carbon to which they are attached form a C ₃ -scycloalkyl (optionally substituted by halo) and wherein R ⁵⁷ is C ₁ -salkyl (optionally substituted by one, two or three halo).

[000115] In some embodiments, R ^G is selected from the group consisting

[000116] In some embodiments, R ^G is

[000117] In some embodiments, a disclosed compound is represented by wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl (e g., t-butyl, propyl, cyclopropyl), phenyl and heterocyclyl; and R ^G2 is -NH(C=O)R ^m , wherein R ^m is selected for each occurrence from H, methyl and CF3.

[000118] In some embodiments, a disclosed compound is represented by , wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and heterocyclyl; and R ^G2 is - NH(C=O)R ^m , wherein R ^m is selected for each occurrence from H, methyl and CF3.

[000119] In some embodiments, a disclosed compound is represented by wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and heterocyclyl; and R ^G2 is - NH(C=O)R ^m , wherein R ^m is selected for each occurrence from H, methyl and CF3.

[000120] In some embodiments, a disclosed compound is represented by , wherein R ^G3 is selected from the group consisting of H, C ₁ - 6alkyl (optionally substituted by one, two or three C ₁ -C ₆ alkoxy), C _3-6 cycloalkyl, phenyl and heterocyclyl; and R ^G2 is selected from the group consisting of -NH(C ₁ -3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, -S(O)z-CH3, C _3-6 cycloalkyl, and 5-6 membered heteroaryl) and -NH(C=O)R ^m , wherein R ^m is selected for each occurrence from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C ₁ -C ₆ alkoxy), CHFz, CF3, and 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C ₁ -C ₆ alkoxy, CHFz, or CF3).

[000121] In some embodiments, a disclosed compound is represented by wherein R ^G3 is selected from the group consisting of H, C ₁ - 6alkyl (optionally substituted by one, two or three C ₁ -C ₆ alkoxy), C ₃ - ₆ cycloalkyl, phenyl and heterocyclyl; and R ^G2 is selected from the group consisting of -NH(C ₁ -3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, -S(O)z-CH3, C _3-6 cycloalkyl, and 5-6 membered heteroaryl) and -NH(C=O)R ^m , wherein R ^m is selected for each occurrence from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C ₁ -C ₆ alkoxy), CHFz, CF3, and 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C ₁ -C ₆ alkoxy, CHFz, or CF3).

[000122] In some embodiments, R ^G3 is selected from the group consisting of y [000123] In some embodiments, R ^G2 is selected from the group consisting of wherein R ^F is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and 5-6 membered heteroaryl, wherein R ^F may optionally be substituted by one, two or three substituents each selected from the group consisting of halo, cyano, hydroxyl and C ₁ -

C ₆ alkoxy; and X ^F is selected from the group consisting of H, halo, cyano, hydroxyl, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C ₁ -C ₆ alkoxy, and C _1-6 haloalkyl.

[000124] In some embodiments, R ^1a and R ² are joined to together to form a heterocycle selected from the group consisting of:

[000125] Further disclosed herein is a compound represented by Formula IV-A or Formula IV-B: or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R ^1a is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ - C ₈ heteroalkyl, -(C ₁ -C ₈ alkyl)-R ¹ , -(C ₁ -C ₈ alkyl)-CN, C3-Ciocycloalkyl, C ₆ -C ₁₄ aryl, 4- 10 membered heterocycle and 5-10 membered heteroaryl; R ^1b is selected from hydrogen and C ₁ -C ₈ alkyl; or R ^1a and R ^1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle having a ring nitrogen, NR ^G , or a C ₃ - Ciocycloalkyl;

R ¹ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, Cz- Cioalkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^A is independently selected for each occurrence from the group consisting of halogen, cyano, hydroxyl, oxo, SF ₅ , -CH ₂ CF ₃ , -CF ₃ , -O-CF3, -O-CHFz, -S-CH3, - S(O)Z-CH ₃ , -NHZ, -O-phenyl, -0-(C ₁ -C ₈ alkyl)-phenyl, -NHC(O)R ^B , -NHC(O)0R ^B , -NHC(O)0-(C ₁ -C ₈ alkyl)-R ^B , -N(R ^y )2, -N(R ^y )(C ₁ -C ₈ alkyl)C(O)0-phenyl, -N(R ^y )(C ₁ - C ₈ alkyl)C(O)N(R ^y ) ₂ , -C(O)-0C(CH ₃ )3, C ₁ -C ₈ alkyl, C2-C10alkenyl, C2-C10alkynyl, C ₁ - C ₈ heteroalkyl, C ₁ -C ₈ alkoxy, C3-Ciocycloalkyl, -(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), - (C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), -(C ₁ -C ₈ alkyl)-(5- 10 membered heteroaryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, wherein the R ^B , alkyl, heterocyclyl, heteroaryl, or aryl may optionally be substituted by one, two or three substituents each independently selected from the group consisting of halogen, C ₁ - C ₈ alkyl, C ₁ -C ₈ alkoxy, SF ₅ , -NH ₂ , hydroxyl and oxo; R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)0R ^B , - NHC(O)N(R ^b ) ₂ , -NHC(O)C(R ^C ) ₂ R ^b , -ΝΗ8(O)2R ^B , -0-(C ₁ -C ₈ alkyl)-(C ₃ -

Ciocycloalkyl), 4-10 membered heterocycle, C ₆ -C14aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ^B or R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ; or R ^1a and R ² may 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 NR°, or a C3-Ciocycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from R ^A ;

R ^3b is selected from hydrogen and C ₁ -C ₈ alkyl;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, C ₂ -Cioalkenyl, C ₂ -Cioalkynyl, C3-C6cycloalkyl, fluorenylmethyloxy, C ₆ - Cuaryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen, halogen and C ₁ -C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF ₅ , cyano, -0-(R ^xx )-0CH3, -OCHF ₂ , -OCF3, -0-(C ₁ - C ₈ alkyl), -C(O)0(CH ₃ ), -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , -N(R ^y )(C ₁ -C ₈ alkyl)C(O)N(R ^y ) ₂ , - N(R ^y )(C ₁ -C ₈ alkyl)C(O)OH, -(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), C ₁ -C ₈ alkyl, C ₁ - C ₈ alkoxy, C3-Ciocycloalkyl, C ₆ -C ₁₄ aryl, -O-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle; wherein two geminal C ₁ -C ₈ alkyl 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 C ₁ -C ₈ alkyl;

R ^G is selected from the group consisting of hydrogen, C _1-6 alkyl optionally substituted by one, two or three R ^gg , -C(=O)-C _1-6 alkyl optionally substituted by one, two or three R ^hh , -C(=O)-C _3-6 cycloalkyl, -C(O)-(Cz-C ioalkenyl)-(C ₆ -C ₁₄ aryl), -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 R ⁸ ;

R ^gg is independently selected for each occurrence from the group consisting of -C(=O), halo, cyano, -NR ^m R ^m , and -NH(C=O)R ^m ;

R ^hh is independently selected for each occurrence from the group consisting of halo, cyano, -NR ^m R ^m , -NR ^m (C=O)R ^m , phenyl, cycloalkyl, heterocyclyl and C ₁ - C ₆ alkoxy; R ^jj is independently selected for each occurrence from the group consisting of halo, oxo, hydroxyl, cyano, C ₁ -C ₆ alkyl, C _1-6 haloalkyl, C ₁ -C ₆ alkoxy, C _3-6 cycloalkyl, SF ₅ , and NH ₂ ;

R ^m is independently selected for each occurrence from the group consisting of hydrogen, C _1-3 alkyl, phenyl, -S(O)z-CH ₃ , C _3-6 cycloalkyl, and 5-6 membered heteroaryl; wherein C ₁ -3alkyl, phenyl, and C _3-6 cycloalkyl may optionally be substituted by one, two or three halo;

R ^xx is -(OCH ₂ CH ₂ )nn-, wherein nn is selected from 1, 2, 3, 4, 5 and 6; and

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, -CF ₃ , -CH ₂ CF ₃ , C ₁ -C ₈ alkoxy, -(C ₁ - C ₈ alkoxy)-(5-10 membered aryl), 5-10 membered heteroaryl, C ₃ -C ₆ cycloalkyl and - (C ₁ -C ₈ alkyl)COOH.

[000126] In some embodiments, a disclosed compound is selected from the group consisting of the compounds identified in Table 1 and Table 2 below: Table 1. Exemplary compounds.

Table 2. Exemplary compounds.

II. Methods [000127] 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, I I-Α, I I-Β, II-C, I I-D-A, n-D-B, I I-Ε-Α, II-E-B, I I-F, II-G, II-H-A, I I-Η-Β, I I-Ε, II-I, IV-A or IV-B.

[000128] 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 picomavirus, 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.

[000129] 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 (HAY) and foot-and-mouth disease virus (FMDV).

[000130] 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. [000131] 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.

[000132] Also provided herein, in certain embodiments, 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 to a patient suffering from the virus, and/or contacting an effective amount of a compound described herein with a virally infected cell. In some embodiments, the method further comprises administering another therapeutic. In some embodiments, the method further comprises administering an additional anti-viral therapeutic. In embodiments, the antiviral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti -caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine. In some embodiments, 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, foscamet, 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. In embodiments, the additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a YAP 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, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griflfithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine.

[000133] 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).

[000134] 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 I I, II- A, II-B, II-C, II-D-A, II-D-B, II-E-A, II-E-B, I I-F, II-G, II-H- A, II-H-B, II-E, I I-Ι, IV-Α or IV-Β as described herein) or a pharmaceutically acceptable salt thereof.

[000135] 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. [000136] Exemplary co-morbidities include lung diseases, cardiac disorders, endocrine disorders, respiratory disorders, hepatic disorders, skeletal disorders, psychiatric disorders, metabolic disorders, and reproductive disorders.

[000137] 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 picomavirus, 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.

[000138] In certain embodiments, the virus is selected from the group consisting of a retrovirus ( e.g ., human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), human T-cell lymphotropic virus (HTLV)-l, HTLV-2, HTLV-3, HTLV-4), Ebola virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, a herpes simplex virus (HSV) (e.g., HSV-1, HSV-2, varicella zoster virus, cytomegalovirus), an adenovirus, an orthomyxovirus (e.g, influenza virus A, influenza virus B, influenza virus C, influenza virus D, togavirus), a flavivirus (e.g, dengue virus, Zika virus), West Nile virus, Rift Valley fever virus, an arenavirus, Crimean-Congo hemorrhagic fever virus, an echovirus, a rhinovirus, coxsackie virus, a coronavirus (e.g, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19), a respiratory syncytial virus, a mumps virus, a rotavirus, measles virus, rubella virus, a parvovirus (e.g, an adeno-associated virus), a vaccinia virus, a variola virus, a molluscum virus, bovine leukemia virus, bovine diarrhea virus, a poliovirus, St. Louis encephalitis virus, Japanese encephalitis virus, a tick-borne encephalitis virus, Murray Valley virus, Powassan virus, Rocio virus, louping-ill virus, Banzi virus, Ilheus virus, Kokobera virus, Kunjin virus, Alfuy virus, a rabies virus, a polyomavirus (e.g, JC virus, BK virus), an alphavirus, and a rubivirus (e.g, rubella virus).

[000139] In certain embodiments, the disease or disorder is a viral infection, e.g, a disease or disorder selected from the group consisting of acquired immune deficiency syndrome (AIDS), HTLV-1 associated myelopathy /tropical spastic paraparesis, Ebola virus disease, hepatitis A, hepatitis B, hepatitis C, herpes, herpes zoster, acute varicella, mononucleosis, respiratory infections, pneumonia, influenza, dengue fever, encephalitis (e.g, Japanese encephalitis, St. Louis encephalitis, or tick-borne encephalitis such as Powassan encephalitis), West Nile fever, Rift Valley fever, Crimean-Congo hemorrhagic fever, Kyasanur Forest disease, Yellow fever, Zika fever, aseptic meningitis, myocarditis, common cold, lung infections, molloscum contagiosum, enzootic bovine leucosis, coronavirus disease 2019 (COVID-19), mumps, gastroenteritis, measles, rubella, slapped- cheek disease, smallpox, warts (e.g, genital warts), molluscum contagiosum, polio, rabies, and pityriasis rosea.

[000140] 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 DA, Holland JJ (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).

[000141] 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.

[000142] 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). FlOOOResearch, 9:72). SARS-CoV2 is the highly contagious, causative viral agent of coronavirus disease 2019 (COVID19), a global pandemic.

[000143] In some embodiments, the virus is a DNA virus (having a genome that is composed of DNA). Exemplary DNA viruses include, without limitation, parvoviruses (e.g, adeno-associated viruses), adenoviruses, asfarviruses, herpesviruses (e.g, herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV)), papillomaviruses (e.g, HPV), polyomaviruses (e.g, simian vacuolating virus 40 (SV40)), and poxviruses (e.g, vaccinia virus, cowpox virus, smallpox virus, fowlpox virus, sheeppox virus, myxoma virus). Exemplary RNA viruses include, without limitation, bunyaviruses (e.g, hantavirus), coronaviruses, flaviviruses (e.g, yellow fever virus, west Nile virus, dengue virus), hepatitis viruses (e.g, hepatitis A virus, hepatitis C virus, hepatitis E virus), influenza viruses (e.g, influenza virus type A, influenza virus type B, influenza virus type C), measles virus, mumps virus, calicivirus, noroviruses (e.g. , Norwalk virus), poliovirus, respiratory syncytial virus (RSV), retroviruses (e.g., human immunodeficiency virus- 1 (HIV-1)) and toroviruses.

[000144] 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.

[000145] 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 I I, II- A, II-B, II-C, I I-D-A, n-D-B, I I-Ε-Α, II-E-B, I I-F, II-G, II-H-A, I I-Η-Β, I I-Ε, 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.

[000146] 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 I I, II- A, II-B, II-C, I I-D-A, II-D-B, II-E-A, II-E-B, I I-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.

[000147] Compounds described herein, e g., a compound of Formula II, II- A, II-B, I I-C, n-D-A, n-D-B, I I-Ε-Α, 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, I I-Α, II-B, II-C, II- D-A, n-D-B, I I-Ε-Α, 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.

[000148] 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.

[000149] In some embodiments, the one or more additional therapeutic agents that may be administered in combination with a compound provided herein can be an antibiotic, a viral protease inhibitor, an anti-viral anti-metabolite, a lysosomotropic agent, a M2 proton channel blocker, a polymerase inhibitor (e g., EIDD-2801, which is also known as MOLNUPIRAVIR), aneuraminidase inhibitor, a reverse transcriptase inhibitor, a viral entry inhibitor, an integrase inhibitor, interferons (e g., types I, I I, and I IΙ), or a nucleoside analogue. In some embodiments, the one or more additional therapeutic agents that may be administered in combination wiht a compounds provided herein can be a steroid (e g., corticosteroids, such as bethamethasone, prednisone, prednisolone, triamcinolone, methylprednisolone, dexamethasone; mineral corticoid such as fludrocortisone; glucocorticoids, such as hydrocortisone, cortisone, ethamethasoneb, prednisone, prednisolone, triamcinolone, dexamethasone; vitamin D such as dihydrotachysterol; androgens such as apoptone, oxandrolone, oxabolone, testosterone, nandrolone (also known as anabolic steroids), oestrogens such as diethylstilbestrol, progestins such as danazol, norethindrone, medroxyprogesterone acetate, 17- Hydroxyprogesterone caproate; and progestins such as mifepristone and gestrinone) or an immunomodulator (e g., 6Mercaptopurine, 6MP, Alferon N, anakinra, Arcalyst, Avonex, AVOSTARTGRIP, Bafiertam, Berinert, Betaseron, BG-12, Cl esterase inhibitor recombinant, Cl inhibitor human, Cinryze, Copaxone, dimethyl fumarate, diroximel fumarate, ecallantide, emapalumab, emapalumab-lzsg, Extavia, fmgolimod, Firazyr, Gamifant, Gilenya, glatiramer, Glatopa, Haegarda, icatibant, Infergen, interferon alfa n3, interferon alfacon 1, interferon beta la, interferon beta lb, Kalbitor, Kineret, mercaptopurine, monomethyl fumarate, peginterferon beta- la, Plegridy, Purinethol, Purixan, Rebif, Rebif Rebidose, remestemcel-L, rilonacept, ropeginterferon alfa 2b, Ruconest, Ryoncil, siltuximab, sutimlimab, Sylvant, Tecfidera, and Vumerity). In some embodiments, the one or more additional therapeutic agent is Cathepsin L. In some embodiments, the one or more additional therapeutic agent is dehydrodidemnin B (also known as Plitidepsin or APLIDIN) or Zotatifm (eFT226).

[000150] In some embodiments, methods described herein further comprise administering an additional anti-viral therapeutic. In some embodiments, the anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine. In some embodiments, the another therapeutic is selected from the group consisting of protease inhibitors (e g., nafamostat, camostat, gabexate, epsilon-aminocapronic acid and aprotinin), fusion inhibitors (e g., BMY-27709, CL 61917, and CL 62554), M2 proton channel blockers (e g., amantadine and rimantadine), polymerase inhibitors (e g., 2-deoxy- 2'fluoroguanosides (2'-fluoroGuo), 6- endonuclease inhibitors (e g., L-735,822 and flutamide) neuraminidase inhibitors (e g., zanamivir (Relenza), oseltamivir, peramivir and ABT-675 (A-315675), reverse transcriptase inhibitor (e g., abacavir, adefovir, delavirdine, didanosine, efavirenz, emtricitabine, lamivudine, nevirapine, stavudine, tenofovir, tenofovir disoproxil, and zalcitabine), acyclovir, acyclovir, protease inhibitors (e g., amprenavir, indinavir, nelfmavir, ritonavir, and saquinavir), arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, darunavir, docosanol, edoxudine, entry inhibitors (e g., enfuvirtide and maraviroc), entecavir, famciclovir, fomivirsen, fosamprenavir, foscamet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, inosine, integrase inhibitor (e g., raltegravir), interferons (e g., types I, II, and ΙI I), lopinavir, loviride, moroxydine, nexavir, nucleoside analogues (e g., aciclovir), penciclovir, pleconaril, podophyllotoxin, ribavirin, tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine, viramidine, and zodovudine. In some embodiments, the additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a YAP 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, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griflfithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine. In some embodiments, the another therapeutic is selected from the group consisting of quinine (optionally in combination with clindamycin), chloroquine, amodiaquine, artemisinin and its derivatives (e g., artemether, artesunate, dihydroartemisinin, arteether), doxycycline, pyrimethamine, mefloquine, halofantrine, hydroxychloroquine, eflomithine, nitazoxanide, omidazole, paromomycin, pentamidine, primaquine, pyrimethamine, proguanil (optionally in combination with atovaquone), a sulfonamide (e g., sulfadoxine, sulfamethoxypyridazine), tafenoquine, tinidazole and a PPT1 inhibitor (including Lys05 and DC661). In some embodiments, the another therapeutic is an antibiotic. In some embodiments, the antibiotic is a penicillin antibiotic, a quinolone antibiotic, a tetracycline antibiotic, a macrolide antibiotic, a lincosamide antibiotic, a cephalosporin antibiotic, or an RNA synthetase inhibitor. In some embodiments, the antibiotic is selected from the group consisting of azithromycin, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, cipro, Levaquin, floxin, tequin, avelox, norflox, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem/cilastatin, meropenem, amikacin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefoxotin, and streptomycin. In some embodiments, the antibiotic is azithromycin.

[000151] In some embodiments, the one or more additional therapeutic agents that may be administered in combination with a compound provided herein can be selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine.

[000152] In some embodiments, the compounds 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, I I-F, II-G, II-H-A, II-H-B, II-E, I I-Ι, IV-A,

IV-B, etc.) and pharmaceutically acceptable salts thereof may be used in combination with one or more other agents which may be useful in the prevention or treatment of respiratory disease, inflammatory disease, autoimmune disease, for example; antihistamines, corticosteroids, (e g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e g., montelukast, zafirlukast, pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e g., beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo), DPI antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic) inhibitors or FLAP (5- lipoxygenase activating protein) inhibitors (e g., sodium 3-(3-(tert-butylthio)-l -(4-(6- ethoxypyridin-3-yl)benzyl)-5-((5-ethylpyridin-2-yl)methoxy)- l H-indol-2-yl)-2,2- dimethylpropanoate), bronchodilators (e g . muscarinic antagonists, beta-2 agonists), methotrexate, and similar agents; monoclonal antibody therapy such as anti-lgE, anti- TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapies e g. etanercept and similar agents; antigen non-specific immunotherapies (e g. interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents), suitable anti-infective agents including antibiotic agents, antifungal agents, anthelmintic agents, antimalarial agents, antiprotozoal agents and antituberculosis agents.

[000153] In some embodiments, the additional therapeutic agents can be kinase inhibitors including but not limited to erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, ponatinib, idelalisib, ibrutinib,

Loxo 292, larotrectinib, and quizartinib.

[000154] In some embodiments, the additional therapeutic agents can be therapeutic antiviral vaccines.

[000155] In some embodiments, the additional therapeutic agents can be immunomodulatory agents including but not limited to anti-PD-lor 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-lBB (anti-CD37, anti-TNFRSF9), CD40 agonist therapeutics including but not limited to SGN-40, CP-870,893 or R07009789, 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).

[000156] 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.

[000157] 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.

[000158] 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, I I-Β, II-C, I I-D-A, II-D-B, I I-Ε-Α,

I I-Ε-Β, II-F, II-G, II-H-A, II-H-B, I I-Ε, II-I, IV-A, IV-B, etc ). IIΙ. Reversible or Irreversible Conjugates

[000159] In certain embodiments, disclosed herein are conjugates represented by Formula

I IΙ:

[000160] wherein Cysws is 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.

[000161] 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.

[000162] 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 ICso of the exogenous nitrile modifier for SEQ ID NO: 1 is less than 20 micromolar.

[000163] 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.

[000164] 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 -3 CL protease does not retain the protease activity of the unmodified -3 CL or 3C protease.

[000165] In some embodiments, the engineered SARS-COV2-3CL viral protease substantially prevents viral replication of SARS-COV2. In other embodiments, the enzymatic inhibition ICso of the exogenous nitrile modifier for SEQ ID NO: 1 is less than, for example, 20 micromolar.

[000166] 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.

[000167] 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

R ¹ is C ₁ -C ₆ alkyl or -CH ₂ -C ₃ -iocycloalkyl;

R ^G is -C(O)R ^b ;

R ^B is C ₁ -C ₆ alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, -NR ^m R ^m , and -NR ^m (C=O)R ^m , wherein R ^m is selected for each occurrence from H or C _1-3 alkyl (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);

R ¹ is independently, for each occurrence, H or methyl; or each R* may be taken, together with the carbon to which they are attached, to form a cyclopropyl; R ^1a is H; or

R ¹ and R ^1a , 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 CF ₃ .

[000168] Also disclosed herein is a compound represented by or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

R ¹ is C ₁ -C ₆ alkyl or -CH ₂ -C ₃ -iocycloalkyl;

R ^G is -C(O)R ^b ;

R ^B is C ₁ -C ₆ alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, -NR ^m R ^m , and -NR ^m (C=O)R ^m , wherein R ^m is selected for each occurrence from H or C _1-3 alkyl (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); R ¹ is independently, for each occurrence, H or methyl; or each R* may be taken, together with the carbon to which they are attached, to form a cyclopropyl; R ^1a is H; or

R ¹ and R ^1a , 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

R ¹ is C ₁ -C ₆ alkyl or -CH ₂ -C ₃ -iocycloalkyl;

R ^G is -C(O)R ^b ;

R ^B is C ₁ -C ₆ alkyl or 8-10 membered bicyclic heteroaryl; wherein C ₁ -C ₆ alkyl may optionally be substituted by one, two or three R ^B1 ; and wherein the heteroaryl may optionally be substituted by one, two, or three halo;

R ^B1 is independently selected for each occurrence from the group consisting of halo, - NR ^m R ^m , and -NR ^m (C=O)R ^m ;

R ^m is independently selected for each occurrence from hydrogen or C _1-3 alkyl (optionally substituted by one, two or three halo); n is 1 or 2; R ^1a is hydrogen; or R ¹ and R ^1a , 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.

[000170] In another embodiment, disclosed herein is a compound represented by: or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

R ¹ is C ₁ -C ₆ alkyl or -CH2-C3-iocycloalkyl;

R ^G is -C(O)R ^b ;

R ^B is C ₁ -C ₆ alkyl or 8-10 membered bicyclic heteroaryl; wherein C ₁ -C ₆ alkyl may optionally be substituted by one, two or three R ^B1 ; and wherein the heteroaryl may optionally be substituted by one, two, or three halo;

R ^B1 is independently selected for each occurrence from the group consisting of halo, - NR ^m R ^m , and -NR ^m (C=O)R ^m ;

R ^m is independently selected for each occurrence from hydrogen or C ₁ -3alkyl (optionally substituted by one, two or three halo); n is 1 or 2; R ^1a is hydrogen; or

R ¹ and R ^1a , 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.

[000171] Sequence details for SEQ ID NO: 1 are indicated below.

IV. Pharmaceutical Compositions and Kits

[000172] 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.

[000173] 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.

[000174] 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 com 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.

[000175] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[000176] 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 hydroxy propyl methyl 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.

[000177] 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, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[000178] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[000179] 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.

[000180] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[000181 ] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[000182] 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.

[000183 ] 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.

[000184] Pharmaceutical compositions of this disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[000185] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants

[000186] 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. [000187] 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.

[000188] 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.

[000189] 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 comorbidities, 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

1. Contemplated Embodiment

[000190] 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:

R ¹ is selected from the group consisting of and C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, 5- 10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from

R ^a ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, -NH ₂ , C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl; R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B )z, - NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

A is a reversible or irreversible warhead;

R ³ is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; m is 1 or 2; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

2. A is a reversible or irreversible warhead selected from the group consisting of cyano, - C(O)R ^d , -C(O)CH ₂ N(R ^b R ^c ), -C(O)CH ₂ 0C(O)R ^D , -C(O)C(O)R ^D , and -(CH=CH)C(O)OR ^D , wherein

R ^D is selected from the group consisting of hydrogen, -N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ - C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ - C ₈ alkyl and C ₁ -C ₈ alkoxy; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), Cl-C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.

3. A is a reversible warhead wherein R ^c is selected from the group consisting of hydrogen, -CH ₂ C(O)0(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.

4. R ^c is wherein X ¹ is 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 , wherein

X ² is selected from the group consisting of NH, O and S;

X ³ is independently selected, for each occurrence, from N and CH;

R ^D is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl,

R ^E is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy; p is selected from 0, 1 and 2; and q is selected from 0, 1 and 2.

7. A is selected from the group consisting of

8. A is a reversible warhead , wherein X ² is selected from the group consisting of NH, NR ^P , O and S, wherein R ^P is C ₁ -C ₈ alkyl.

9. A is a reversible warhead

10. A is an irreversible warhead -C(O)CH ₂ 0C(O)R ^D , wherein

R ^D is selected from the group consisting of C ₁ -C ₈ alkyl and C3- C ₆ cycloalkyl;

X ⁴ is independently selected, for each occurrence, from CH and N;

R ^E is independently selected, for each occurrence, from the group consisting of halogen, -CN, -CH ₃ , -CH2CH3, -CH(CH ₃ ) ₂ , -OCH3, -CF ₃ , -OCF3 and -SCF ₃ ; and p is selected from 0, 1 and 2. 11. R ^D is selected from the group consisting and

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

14. A is a reversible or irreversible warhead -C(O)R ^D , wherein R ^D is selected from the group consisting of hydrogen, -CH ₂ OH, -CH ₂ OR and -CH _x F _y , wherein R is selected from the group consisting of C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-(5-10 membered aryl), C ₁ - C ₈ heteroalkyl, C ₃ -C ₆ cycloalkyl 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)0R ^D , wherein R ^D is C ₁ - C ₈ alkyl.

17. A is an irreversible warhead selected from

18. A is a reversible or irreversible warhead -C(O)CH ₂ N(R ^b R ^c ).

19. A is a reversible or irreversible warhead selected from and 20. A is a reversible or irreversible warhead wherein M is selected from Na and K.

21. A is cyano.

22. R ¹ is selected from the group consisting of

23. R ² is selected from the group consisting of and wherein denotes a bond that may be a single or double bond;

R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ⁶ is C ₁ -C ₈ alkyl; R ⁷ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )z, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

R ⁸ is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

W ¹ is selected from CH and N;

W ² is selected from the group consisting of CH ₂ , O, NH and S;

W is selected from W ¹ and W ² ; s is selected from 1 and 2; and t is selected from 0, 1, 2 and 3.

24. R ² is selected from the group consisting

25. R ³ is selected from the group consisting wherein denotes a bond that may be a single or double bond;

Y ¹ is selected from the group consisting of CH, CH ₂ , N, NH, O and S;

R ⁹ is selected from the group consisting of halogen, hydroxyl, oxo, -NH ₂ , - N(CH ₃ )Z, -N(CH ₂ CH ₃ )Z, -CH ₃ , -CHZCH ₃ , -OCH ₃ and -OCH ₂ CH ₃ .

26. R ³ is selected from the group consisting

27. The viral protease inhibitor compound is represented by wherein: R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl; and m is selected from 1 and 2.

28. R ^y is selected from the group consisting of hydrogen, and

29. The viral protease inhibitor compound is represented by wherein

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

W is CH orN; m is selected from 1 and 2; and r is selected from 0, 1, 2 and 3.

30. R ^x is -OCH ₃ .

31. A viral protease inhibitor compound selected from the group consisting of

32. A viral protease inhibitor compound represented by: wherein R ¹ is selected from the group consisting of and C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, 5- 10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from

R ^a ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, -NH ₂ , C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B )z, - NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

A is a reversible or irreversible warhead;

R ³ is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

33. A is a reversible or irreversible warhead selected from the group consisting of cyano, - C(O)R ^d , -C(O)CH ₂ N(R ^b R ^c ), -C(O)CH ₂ 0C(O)R ^D , -C(O)C(O)R ^D , and -

(CH=CH)C(O)OR ^d , wherein R ^D is selected from the group consisting of hydrogen, -N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ - C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ - C ₈ alkyl and C ₁ -C ₈ alkoxy; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), Cl-C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.

34. R ¹ is selected from the group consisting of

35. R ³ is a 5-10 membered heterocycle.

36. R ³ is selected from the group consisting

37. R ² is selected from the group consisting

38. A reversible conjugate represented by: wherein

Cysi45 is cysteine at position 145 or equivalent active site cysteine on a CL or

3 CL protease;

IR is a viral protease inhibitor;

B is selected from the group consisting of -R ^D , -C(O)R ^D , and -CH ₂ OR ⁰ , wherein

R ^D is selected from the group consisting of hydrogen, -N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ - C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl and R ^E ; R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), Cl-C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.

39. An irreversible conjugate represented by: wherein

Cysi45 is cysteine at position 145 or equivalent active site cysteine on a CL or

3 CL protease;

IR is a viral protease inhibitor;

R ^D is selected from the group consisting of hydrogen, -N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ - C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), Cl-C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 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 picomavirus, 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, foscamet, 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 YAP 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. 2. Contemplated Embodiment

[000191 ] 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:

R ¹ is selected from the group consisting of and C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, 5- 10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from

R ^a ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, -NH ₂ , C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

R ² is selected from the group consisting of -NH ₂ , -NHC(O)R ^B , - NHC(O)N(R ^B )Z, -NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C3- C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C3- C ₆ cycloalkyl;

A is a reversible or irreversible warhead;

R ³ is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; m is 1 or 2; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

2. A is a reversible or irreversible warhead selected from the group consisting of cyano, - C(O)R ^d , -C(O)CH ₂ N(R ^b R ^c ), -C(O)CH ₂ 0C(O)R ^D , -C(O)C(O)R ^D , and -

(CH=CH)C(O)0R ^d , wherein

R ^D is selected from the group consisting of hydrogen, -N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ - C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ - C ₈ alkyl and C ₁ -C ₈ alkoxy; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), Cl-C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.

3. A is a reversible warhead wherein R ^c is selected from the group consisting of hydrogen, -CH ₂ C(O)0(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.

4. R ^c is wherein X ¹ is 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 , wherein

X ² is selected from the group consisting of NH, O and S;

X ³ is independently selected, for each occurrence, from N and CH;

R ^D is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl,

R ^E is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy; p is selected from 0, 1 and 2; and q is selected from 0, 1 and 2.

7. A is selected from the group consisting

8. A is a reversible warhead wherein X ² is selected from the group consisting of NH, NR ^P , O and S, wherein R ^P is C ₁ -C ₈ alkyl.

9. A is a reversible warhead 10. A is an irreversible warhead -C(O)CH ₂ 0C(O)R ^D , wherein

R ^D is selected from the group consisting of C ₁ - alkyl and C3 - C ₆ cycloalkyl;

X ⁴ is independently selected, for each occurrence, from CH and N;

R ^E is independently selected, for each occurrence, from the group consisting of halogen, -CN, -CH ₃ , -CH2CH3, -CH(CH ₃ ) ₂ , -OCH3, -CF ₃ , -OCF3 and -SCF ₃ ; and p is selected from 0, 1 and 2.

11. R ^D is selected from the group consisting

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

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

14. A is a reversible or irreversible warhead -C(O)R ^D , wherein R ^D is selected from the group consisting of hydrogen, -CH ₂ OH, -CH ₂ OR and -CH _x F _y , wherein R is selected from the group consisting of C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-(5-10 membered aryl), C ₁ - C ₈ heteroalkyl, C ₃ -C ₆ cycloalkyl 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)0R ^D , wherein R ^D is C ₁ - C ₈ alkyl.

17. A is an irreversible warhead selected from

18. A is a reversible or irreversible warhead -C(O)CH ₂ N(R ^b R ^c ).

19. A is a reversible or irreversible warhead selected from and

20. A is a reversible or irreversible warhead wherein M is selected from Na and K.

21. A is cyano.

22. R ¹ is selected from the group consisting of 23. R ² is selected from the group consisting denotes a bond that may be a single or double bond;

R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ⁶ is C ₁ -C ₈ alkyl;

R ⁷ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )z, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl; R ⁸ is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

W ¹ is selected from CH and N;

W ² is selected from the group consisting of CH ₂ , O, NH and S;

W is selected from W ¹ and W ² ; s is selected from 1 and 2; and t is selected from 0, 1, 2 and 3.

24. R ² is selected from the group consisting

25. R ³ is selected from the group consisting wherein denotes a bond that may be a single or double bond;

Y ¹ is selected from the group consisting of CH, CH ₂ , N, NH, O and S; R ⁹ is selected from the group consisting of halogen, hydroxyl, oxo, -NH ₂ , - N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ )2, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ and -OCH ₂ CH ₃ .

26. R ³ is selected from the group consisting

27. The compound is represented by wherein:

R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl; and m is selected from 1 and 2.

28. R ^y is selected from the group consisting of hydrogen, and

29. The compound is selected from the group consisting of: 30. The compound is represented by wherein

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )z, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

W is CH orN; m is selected from 1 and 2; and r is selected from 0, 1, 2 and 3.

31. R ^x is -OCH ₃ .

32. A viral protease inhibitor compound selected from the group consisting of

33. A viral protease inhibitor compound represented by: wherein

R ¹ is selected from the group consisting of and C ₁ -C ₈ alkyl, C3-C6cycloalkyl, 5- 10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from

R ^a ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, -NH ₂ , C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy and C3-C6cycloalkyl;

R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B )z, - NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C3- C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C3- C ₆ cycloalkyl;

A is a reversible or irreversible warhead; X is selected from CH and N; R ³ is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

33. The compound is represented by: wherein

R ¹ is selected from the group consisting of and C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, 5- 10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from

R ^a ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, -NH ₂ , C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B )z, - NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C3- C ₆ cycloalkyl;

A is a reversible or irreversible warhead;

R ³ is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

34. A is a reversible or irreversible warhead selected from the group consisting of cyano, - C(O)R ^d , -C(O)CH ₂ N(R ^b R ^c ), -C(O)CH ₂ 0C(O)R ^D , -C(O)C(O)R ^D , and -

(CH=CH)C(O)0R ^d , wherein

R ^D is selected from the group consisting of hydrogen, -N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ - C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, and 5-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and 5-10 membered aryl and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ - C ₈ alkyl and C ₁ -C ₈ alkoxy; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), Cl-C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.

35. R ¹ is selected from the group consisting of

36. R ³ is a 5-10 membered heterocycle. 37. R ³ is selected from the group consisting

38. R ² is selected from the group consisting

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 picomavirus, 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 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, foscamet, 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 YAP 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.

3. Contemplated Embodiment

[000192] 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:

R ¹ is selected from the group consisting of and C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, 5- 10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from

R ^a ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -NH ₂ , C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

R ² is selected from the group consisting of -NH ₂ , -NHC(O)R ^B , - NHC(O)N(R ^B )Z, -NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

A is a warhead;

R ³ is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; m is 1 or 2; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

2. A is selected from the group consisting of cyano, -C(O)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CH ₂ 0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)OR ^d , -(CH=CCN)C(O)OR ^d , -

R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₆ - C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy;

R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;

R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - Cealkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, C 1 -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C ₃ - C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.

3. A is a warhead represented by : wherein R ^c is selected from the group consisting of hydrogen, -CH ₂ C(O)0(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl. 4. R ^c is wherein X ¹ is independently selected, for each occurrence, from N and CH.

5. A is selected from the group consisting of

6. A is wherein

X ² is selected from the group consisting of NH, O and S;

X ³ is independently selected, for each occurrence, from N and CH;

R ^D is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, R ^E is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy; p is selected from 0, 1 and 2; and q is selected from 0, 1 and 2.

7. A is selected from the group consisting

8. , wherein X ² is selected from the group consisting of NH, NR ^P , O and S, wherein R ^P is C ₁ -C ₈ alkyl.

9. A is selected from the group consisting

10. A is-C(O)CH ₂ 0C(O)R ^D , wherein R ^D is selected from the group consisting of C ₁ -C ₈ alkyl and C ₃ - C ₆ cycloalkyl;

X ⁴ is independently selected, for each occurrence, from CH and N;

R ^E is independently selected, for each occurrence, from the group consisting of halogen, -CN, -CH ₃ , -CH2CH3, -CH(CH ₃ ) ₂ , -OCH ₃ , -CF ₃ , -OCF ₃ and -SCF ₃ ; and p is selected from 0, 1 and 2.

11. R ^D is selected from the group consisting of

12. A is selected from the group consisting of

13. A is selected from the group consisting

14. A is-C(O)R ^D , wherein R ^D is selected from the group consisting of hydrogen, -CH ₂ OH, -CH ₂ OR and -CH _x Fy, wherein R is selected from the group consisting of C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-(5-10 membered aryl), C ₁ -C ₈ heteroalkyl, C ₃ -C ₆ cycloalkyl 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)0R ^d , wherein R ^D is C ₁ -C ₈ alkyl.

17. A is selected from

18. A i s-C(O)CH ₂ N(R ^b R ^c ) . 19. A is a warhead selected from

20. A is wherein Μ is selected from Na and K.

21. A is cyano.

22. R ¹ is selected from the group consisting of

23. R ² is selected from the group consisting of denotes a bond that may be a single or double bond;

R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ⁶ is C ₁ -C ₈ alkyl; R ⁷ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )2, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

R ⁸ is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

W ¹ is selected from CH and N;

W ² is selected from the group consisting of CH ₂ , O, NH and S;

W is selected from W ¹ and W ² ; s is selected from 1 and 2; and t is selected from 0, 1, 2 and 3.

24. R ² is selected from the group consisting

25. R ³ is selected from the group consisting wherein denotes a bond that may be a single or double bond;

Y ¹ is selected from the group consisting of CH, CH ₂ , N, NH, O and S;

R ⁹ is selected from the group consisting of halogen, hydroxyl, oxo, -NH ₂ , - N(CH ₃ )Z, -N(CH ₂ CH ₃ )Z, -CH ₃ , -CHZCH ₃ , -OCH ₃ and -OCH ₂ CH ₃ .

26. R ³ is selected from the group consisting

27. The compound is represented by wherein: R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl; and m is selected from 1 and 2.

28. R ^y is selected from the group consisting of hydrogen, and

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

30. The compound is represented by wherein

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )z, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

W is CH orN; m is selected from 1 and 2; and r is selected from 0, 1, 2 and 3.

31. R ^x is -OCH ₃ .

32. A protease inhibitor compound represented by: wherein

R ^3a is 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, C ₁ -C ₈ alkoxy, oxo and a warhead A;

R ^3b is selected from hydrogen and C ₁ -C ₈ alkyl; wherein R ^3a and R ^3b may 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 C ₆ -C14aryl and a warhead A; R ^1a is selected from the group consisting of C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-R ¹ , -(C ₁ - Cealkyl)-CN, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; R ^1b is selected from hydrogen and C ₁ -C ₈ alkyl; R ^1a and R ^1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C ₃ -C ₁₀ cycloalkyl; R ¹ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, Cz- Cioalkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -NH ₂ , -O-phenyl, -0-(C ₁ -C ₈ alkyl)-phenyl, -C(O)-(5-10 membered heteroaryl), -C(O)-(4-10 membered heterocycle), -C(O)-O-(4-10 membered heterocycle), -C(O)-0C(CH3)3, -C(O)-(C ₂ -C ₁₀ alkenyl)-(C6-Ci ₄ aryl) C ₁ -C ₈ alkyl, Cz- Cioalkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy, C3-Ciocycloalkyl, -(C ₁ - C ₈ alkyl)-(C ₆ -C ₁₄ aryl), -(C ₁ -C ₈ alkyl)-(5-10 membered heteroaryl), C ₆ -C ₁₄ aryl, 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, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, SF ₅ , -NH ₂ , hydroxyl or oxo;

R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B )z, - NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , 4-10 membered heterocycle, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ; R ^1a and R ² may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C ₃ -C ₁₀ cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents each selected from R ^A ;

R ³ is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl; R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF ₅ , cyano, -C(O)0(CH3), -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ - C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

A is a warhead;

X is selected from CH, C(CH3) and N; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

33. The compound is represented by:

34. The compound is represented by:

35. A is selected from the group consisting of cyano, -C(O)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CHZ0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)0R ^d , -(CH=CCN)C(O)0R ^d , - (CH=CCN)C(O)(NH)R ^d , -CH(CN)(OH), -CH(CN)(NR ^b R ^c ), and wherein

R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₆ - C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy;

R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;

R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - Cealkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, C 1 -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C ₃ - C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl. 36. A is selected from the group consisting of -CN,

37. R ^1a is selected from the group consisting

38. R ^1a is -(C ₁ -C ₈ alkyl)-R ¹ .

39. R ^1b is hydrogen.

40. R ^1a and R ^1b are joined to together to form

41. R ^3a is a 4-10 membered heterocycle substituted by A.

42. R ^3a is selected from the group consisting of

43. R ³ is a 4-10 membered heterocycle.

44. R ³ is selected from the group consisting 45. R ² is selected from the group consisting

46. R ^1a and R ² are 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 picomavirus, 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, foscamet, 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 YAP 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.

4. Contemplated Embodiment

[000193] 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:

R ^3a is 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, C ₁ -C ₈ alkoxy, oxo and a warhead A;

R ^3b is selected from hydrogen and C ₁ -C ₈ alkyl; wherein R ^3a and R ^3b may 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 C ₆ -C14aryl and a warhead A; R ^1a is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, -(C ₁ - C ₈ alkyl)-R ¹ , -(C ₁ -C ₈ alkyl)-CN, C3-C 10cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; R ^1b is selected from hydrogen and C ₁ -C ₈ alkyl; R ^1a and R ^1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C ₃ -Ciocycloalkyl;

R ¹ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, Cz- Cioalkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -CH ₂ CF ₃ , CF ₃ , -O-CF3, -O-CHFz, -S-CH3, -S(O)z-CH ₃ , -NH ₂ , -O-phenyl, -0-(C ₁ -C ₈ alkyl)-phenyl, -NHC(O)R ^B , -NHC(O)OR ^B , -NHC(O)0-(C ₁ -C ₈ alkyl)-R ^B , - N(R ^y )z, -N(R ^y )(C ₁ -C ₈ alkyl)C(O)0-phenyl, -N(R ^y )(C ₁ -C ₈ alkyl)C(O)N(R ^y )z, - NHC(O)0(C ₁ -C ₈ alkyl)R ^B , -C(O)-(5-10 membered heteroaryl), -C(O)-(4-10 membered heterocycle), -C(O)-0-(4-10 membered heterocycle), -C(O)-0C(CH3)3, - C(O)-(C ₂ -Cioalkenyl)-(C ₆ -Ci ₄ aryl), C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₁ - C ₈ heteroalkyl, C ₁ -C ₈ alkoxy, C3-Ciocycloalkyl, -(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), - (C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), -(C ₁ -C ₈ alkyl)-(5-10 membered heteroaryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the R ^B , alkyl, heterocycle, heteroaryl, or aryl may optionally be substituted by one, two or three substituents of halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, SF ₅ , -NH ₂ , hydroxyl or oxo;

R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B )z, - NHC(O)C(R ^C ) ₂ R ^b , -NHS(O) ₂ R ^b , -0-(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), 4-10 membered heterocycle, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ; R ^1a and R ² may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C3-Ciocycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents each selected from R ^A ;

R ³ is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen, halogen and C ₁ -C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF3, SF ₅ , cyano, -OCHFz, -OCF3, -0-(C ₁ -C ₈ alkyl), - C(O)0(CH ₃ ), -N(R ^y )z, -N(R ^y )C(O)R ^y , -N(R ^y )(C ₁ -C ₈ alkyl)C(O)N(R ^y )z, -N(R ^y )(C ₁ - C ₈ alkyl)C(O)OH, -(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C3- Ciocycloalkyl, C ₆ -C ₁₄ aryl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, -CH2CF3, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5- 10 membered aryl), C ₃ -C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)COOH;

A is a warhead;

X is selected from the group consisting of CH, C(CH3) and N; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

2. The compound i s represented by :

3. The compound i s represented by :

4. A is selected from the group consisting of cyano, -C(O)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CH ₂ 0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)0R ^d , -(CH=CCN)C(O)0R ^d , -

(CH=CCN)C(O)(NH)R ^d , -CH(CN)(OH), -CH(CN)(NR ^b R ^c ), and wherein R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ - C ₈ alkyl and C ₁ -C ₈ alkoxy;

R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;

R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - Cealkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, C 1 -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C ₃ - C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.

5. A is selected from the group consisting of -CN, 6. R ^1a is selected from the group consisting of

7. R ^1a is -(C ₁ -C ₈ alkyl)-R ¹ .

8. R ^1b is hydrogen.

9. R ^1a and R ^1b are joined to together to form

10. R ^3a is a 4-10 membered heterocycle substituted by A.

11. R ^3a is selected from the group consisting of

12. R ³ is a 4-10 membered heterocycle.

13. R ³ is selected from the group consisting 14. R ² is selected from the group consisting

15. R ^1a and R ² are joined to together to form the heterocycle selected from the group consisting of:

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



17. 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.

18. 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 picomavirus, 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.

19. 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.

20. The viral infection is a coronavirus infection.

21. 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).

22. The viral infection is SARS-CoV-2.

23. The viral infection is an arenavirus infection. 24. The arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.

25. The viral infection is an influenza infection.

26. The influenza is influenza H1N1, H3N2 or H5N1.

27. 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.

28. The method further comprises administering another therapeutic.

29. The method further comprises administering an additional anti-viral therapeutic.

30. The anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine.

31. 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, foscamet, 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.

32. The additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a YAP 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, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine.

33. 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.

34. The compound is administered before viral exposure.

35. The compound is administered after viral exposure.

5. Contemplated Embodiment

[000194] 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:

R ^3a is 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, C ₁ -C ₈ alkoxy, oxo and a warhead A;

R ^3b is selected from hydrogen and C ₁ -C ₈ alkyl; wherein R ^3a and R ^3b may 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 C ₆ -C14aryl and a warhead A; R ^1a is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ - C ₈ heteroalkyl, -(C ₁ -C ₈ alkyl)-R ¹ , -(C ₁ -C ₈ alkyl)-CN, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 4- 10 membered heterocycle and 5-10 membered heteroaryl; R ^1b is selected from hydrogen and C ₁ -C ₈ alkyl; R ^1a and R ^1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C ₃ -C ₁₀ cycloalkyl;

R ¹ is selected from the group consisting of C ₁ -C ₈ alkyl, C2-C10alkenyl, C2- C10alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -CH ₂ CF ₃ , CF ₃ , -O-CF3, -O-CHFz, -S-CH3, -S(O)z-CH ₃ , -NH ₂ , -O-phenyl, -0-(C ₁ -C ₈ alkyl)-phenyl, -NHC(O)R ^B , -NHC(O)OR ^B , -NHC(O)0-(C ₁ -C ₈ alkyl)-R ^B , - N(R ^y )z, -N(R ^y )(C ₁ -C ₈ alkyl)C(O)0-phenyl, -N(R ^y )(C ₁ -C ₈ alkyl)C(O)N(R ^y )z, - NHC(O)0(C ₁ -C ₈ alkyl)R ^B , -C(O)-(5-10 membered heteroaryl), -C(O)-(4-10 membered heterocycle), -C(O)-O-(4-10 membered heterocycle), -C(O)-0C(CH3)3, - C(O)-(C2-C10alkenyl)-(C ₆ -Ci ₄ aryl), C ₁ -C ₈ alkyl, C2-C10alkenyl, C2-C10alkynyl, C ₁ - C ₈ heteroalkyl, C ₁ -C ₈ alkoxy, C ₃ -C10cycloalkyl, -(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), - (C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), -(C ₁ -C ₈ alkyl)-(5- 10 membered heteroaryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the R ^B , alkyl, heterocycle, heteroaryl, or aryl may optionally be substituted by one, two or three substituents of halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, SF ₅ , -NH ₂ , hydroxyl or oxo;

R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B )z, - NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , -0-(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), 4-10 membered heterocycle, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ; R ^1a and R ² may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C ₃ -C ₁₀ cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents each selected from R ^A ;

R ³ is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen, halogen and C ₁ -C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF ₃ , SF ₅ , cyano, -OCHFz, -OCF3, -0-(C ₁ -C ₈ alkyl), - C(O)0(CH ₃ ), -N(R ^y )z, -N(R ^y )C(O)R ^y , -N(R ^y )(C ₁ -C ₈ alkyl)C(O)N(R ^y )z, -N(R ^y )(C ₁ - C ₈ alkyl)C(O)OH, -(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C3- Ciocycloalkyl, C ₆ -C ₁₄ aryl, 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 C ₁ -C ₈ alkyl; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, -CH2CF3, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5- 10 membered aryl), C ₃ -C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)COOH;

A is a warhead;

X is selected from the group consisting of C(R ^xy ) and N, wherein R ^xy is selected from the group consisting of H, D, -OH, -NH ₂ , halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, and C ₁ - C ₈ alkoxy; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

2. The compound i s represented by :

3. The compound i s represented by :

4. A is selected from the group consisting of cyano, -C(O)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CH ₂ 0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)0R ^d , -(CH=CCN)C(O)0R ^d , -

(CH=CCN)C(O (NH)R ^d , -CH(CN)(OH), -CH(CN)(NR ^b R ^c ), and wherein R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ - C ₈ alkyl and C ₁ -C ₈ alkoxy;

R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;

R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - Cealkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, Cl-C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C ₃ - C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.

5. A is selected from the group consisting of -CN, 6. R ^1a is selected from the group consisting

7. R ^1a is -(C ₁ -C ₈ alkyl)-R ¹ .

8. R ^1b is hydrogen.

9. R ^1a and R ^1b are joined to together to form

10. R ^3a is a 4-10 membered heterocycle substituted by A.

11. R ^3a is selected from the group consisting of

12. R ³ is a 4-10 membered heterocycle.

13. R ³ is selected from the group consisting 14. R ² is selected from the group consisting ,

15. R ^1a and R ² are joined to together to form the heterocycle selected from the group consisting of:

16. A compound selected from the group consisting of:  435-

17. 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.

18. 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 picomavirus, 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.

19. 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.

20. The viral infection is a coronavirus infection.

21. 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).

22. The viral infection is SARS-CoV-2.

23. The viral infection is an arenavirus infection.

24. The arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.

25. The viral infection is an influenza infection.

26. The influenza is influenza H1N1, H3N2 or H5N1.

27. 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.

28. The method further comprises administering another therapeutic.

29. The method further comprises administering an additional anti-viral therapeutic.

30. The anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti -caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine.

31. 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, foscamet, 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.

32. The additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a YAP 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, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griflfithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine.

33. 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.

34. The compound is administered before viral exposure.

35. The compound is administered after viral exposure. 6. Contemplated Embodiment

[000195] 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:

R ¹ is selected from the group consisting of and C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, 5- 10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from

R ^a ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -NH ₂ , C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

R ² is selected from the group consisting of -NH ₂ , -NHC(O)R ^B , - NHC(O)N(R ^B )Z, -NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C3- C ₆ cycloalkyl;

A is a warhead;

R ³ is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; m is 1 or 2; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

2. A is selected from the group consisting of cyano, -C(O)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CH ₂ 0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)0R ^d , -(CH=CCN)C(O)0R ^d , -

R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₆ - Cuaryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy;

R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;

R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C3- C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - C ₈ alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, C 1 -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C3- C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.

3. A is a warhead represented by : wherein R ^c is selected from the group consisting of hydrogen, -CH ₂ C(O)0(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.

4. R ^c is wherein X ¹ is independently selected, for each occurrence, from N and CH.

5. A is selected from the group consisting of

6. A is wherein

X ² is selected from the group consisting of NH, O and S;

X ³ is independently selected, for each occurrence, from N and CH;

R ^D is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl,

R ^E is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy; p is selected from 0, 1 and 2; and q is selected from 0, 1 and 2.

7. A is selected from the group consisting o

8. A is wherein X ² is selected from the group consisting of NH, NR ^P , O and S, wherein R ^P is C ₁ -C ₈ alkyl.

9. A is selected from the group consisting of and

10. A is-C(O)CH ₂ 0C(O)R ^D , wherein

R ^D is selected from the group consisting of C ₁ - alkyl and C ₃ - C ₆ cycloalkyl;

X ⁴ is independently selected, for each occurrence, from CH and N;

R ^E is independently selected, for each occurrence, from the group consisting of halogen, -CN, -CH ₃ , -CH2CH3, -CH(CH ₃ ) ₂ , -OCH ₃ , -CF ₃ , -OCF ₃ and -SCF ₃ ; and p is selected from 0, 1 and 2. 11. R ^D is selected from the group consisting of

12. A is selected from the group consisting 13. A is selected from the group consisting

14. A is-C(O)R ^D , wherein R ^D is selected from the group consisting of hydrogen, -CH ₂ OH, -CH ₂ OR and -CH _x F _y , wherein R is selected from the group consisting of C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-(5-10 membered aryl), C ₁ -C ₈ heteroalkyl, C ₃ -C ₆ cycloalkyl 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)0R ^d , wherein R ^D is C ₁ -C ₈ alkyl.

17. A is selected from

18. A is-C(O)CH ₂ N(R ^b R ^c ).

19. A is a warhead selected from

20. A is wherein M is selected from Na and K.

21. A is cyano.

22. R ¹ is selected from the group consisting of 23. R ² is selected from the group consisting of denotes a bond that may be a single or double bond;

R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ⁶ is C ₁ -C ₈ alkyl;

R ⁷ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )z, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

R ⁸ is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle; W ¹ is selected from CH and N;

W ² is selected from the group consisting of CHz, O, NH and S; W is selected from W ¹ and W ² ; s is selected from 1 and 2; and t is selected from 0, 1, 2 and 3.

24. R ² is selected from the group consisting of \

25. R ³ is selected from the group consisting wherein denotes a bond that may be a single or double bond;

Υ ¹ is selected from the group consisting of CH, CH ₂ , N, NH, 0 and S;

R ⁹ is selected from the group consisting of halogen, hydroxyl, oxo, -NH ₂ , - N(CH ₃ )Z, -N(CH ₂ CH ₃ )Z, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ and -OCH ₂ CH ₃ . 26. R ³ is selected from the group consisting

27. The compound is represented by wherein:

R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C3- C ₆ cycloalkyl; and m is selected from 1 and 2.

28. R ^y is selected from the group consisting of hydrogen, and

UO

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

30. The compound is represented by

wherein

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )z, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

W is CH orN; m is selected from 1 and 2; and r is selected from 0, 1, 2 and 3.

31. R ^x is -OCH3.

32. A protease inhibitor compound represented by: wherein R ^3a is 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, C ₁ -C ₈ alkoxy, oxo and a warhead A;

R ^3b is selected from hydrogen and C ₁ -C ₈ alkyl; wherein R ^3a and R ^3b may 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 C ₆ -C ₁₄ aryl and a warhead A; R ^1a is selected from the group consisting of C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-R ¹ , -(C ₁ - C ₈ alkyl)-CN, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; R ^1b is selected from hydrogen and C ₁ -C ₈ alkyl; or R ^1a and R ^1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C ₃ -C ₁₀ cycloalkyl;

R ¹ is selected from the group consisting of C ₁ -C ₈ alkyl, C2-Cioalkenyl, C2- Cioalkynyl, C3-Ciocycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -NH2, -O-phenyl, -0-(C ₁ -C ₈ alkyl)-phenyl, -C(O)-(5-10 membered heteroaryl), -C(O)-(4-10 membered heterocycle), -C(O)-O-(4-10 membered heterocycle), -C(O)-0C(CH3)3, -C(O)-(C ₂ -C10alkenyl)-(C6-C1 ₄ aryl), C ₁ -C ₈ alkyl, C2- Cioalkenyl, C2-C10alkynyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy, C3-Ciocycloalkyl, -(C ₁ - C ₈ alkyl)-(C ₆ -C ₁₄ aryl), -(C ₁ -C ₈ alkyl)-(5- 10 membered heteroaryl), C ₆ -C ₁₄ aryl, 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, C ₁ -C ₆ alkyl, C ₁ -C ₈ alkoxy, SF ₅ , -NH2, hydroxyl or oxo; R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B )z, - NHC(O)C(R ^c )zR ^B , -NHS(O)ZR ^b , 4-10 membered heterocycle, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ; or R ^1a and R ² may 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, NR ^G , or C ₃ -C ₁₀ cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from R ^A ;

R ³ is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^G is selected from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of -C(=O), halo, cyano, -NR ^m R ^m , and -NH(C=O)R ^m ) and C(=O)-C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, -NR ^m R ^m , -NR ^m (C=O)R ^m , phenyl, cycloalkyl and heterocycle, wherein R ^m is selected for each occurrence by H or C _1-3 alkyl (optionally substituted by one, two or three fluorines), and C ₃ -C ₆ cycloalkyl (optionally substituted by one, two, or three fluorines);

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF ₅ , cyano, -C(O)0(CH3), -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ - C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

A is a warhead;

X is selected from CH, C(CH3) and N; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

33. The compound is represented by:

34. The compound is represented by:

35. A is selected from the group consisting of cyano, -C(O)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CH ₂ 0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)0R ^d , -(CH=CCN)C(O)0R ^d , -

(CH=CCN)C(O)(NH)R ^d , -CH(CN)(OH), -CH(CN)(NR ^b R ^c ), and wherein R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₆ - C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy;

R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;

R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - Cealkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, C 1 -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C ₃ - C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.

36. A is selected from the group consisting of -CN, 37. R ^1a is selected from the group consisting

38. R ^1a is -(C ₁ -C ₈ alkyl)-R ¹ .

39. R ^1b is hydrogen.

40. R ^1a and R ^1b are joined to together to form

41. R ^3a is a 4-10 membered heterocycle substituted by A.

42. R ^3a is selected from the group consisting of

43. R ³ is a 4-10 membered heterocycle. 44. R ³ is selected from the group consisting

45. R ² is selected from the group consisting

46. R ^1a and R ² are joined to together to form the heterocycle selected from the group consisting of: and R ^1b is H.

48. The compound is represented by: wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and heterocycle; and R ^G2 is -NH(C=O)R ^m , wherein R ^m is selected for each occurrence by H, methyl or CF3.

49. The compound is represented by: wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and heterocycle; and R ^G2 is -NH(C=O)R ^m , wherein R ^m is 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 embodiment

52. 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 picomavirus, 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, foscamet, 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 YAP 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.

7. Contemplated Embodiment

[000196] 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:

R ¹ is selected from the group consisting of and C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, 5- 10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from

R ^a ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -NH ₂ , C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

R ² is selected from the group consisting of -NH ₂ , -NHC(O)R ^B , - NHC(O)N(R ^B )Z, -NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

A is a warhead;

R ³ is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; m is 1 or 2; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

2. A is selected from the group consisting of cyano, -C(O)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CH ₂ 0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)0R ^d , -(CH=CCN)C(O)0R ^d , -

R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₆ - C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy;

R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - C ₈ alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, C 1 -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C3- C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.

3. A is a warhead represented by: wherein R ^c is selected from the group consisting of hydrogen, -CH ₂ C(O)0(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, and C3-C6cycloalkyl, wherein the C ₁ -C ₈ alkyl 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. R ^c is wherein X ¹ is independently selected, for each occurrence, from

N and CH.

5. A is selected from the group consisting of

6. A is wherein

X ² is selected from the group consisting of NH, O and S;

X ³ is independently selected, for each occurrence, from N and CH;

R ^D is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl,

R ^E is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy; p is selected from 0, 1 and 2; and q is selected from 0, 1 and 2. 7. A is selected from the group consisting of

8. A is wherein X ² is selected from the group consisting of NH, NR ^P ,

O and S, wherein R ^P is C ₁ -C ₈ alkyl.

9. A is selected from the group consisting

10. A is-C(O)CH ₂ 0C(O)R ^D , wherein

R ^D is selected from the group consisting of C ₁ - alkyl and C ₃ - C ₆ cycloalkyl; X ⁴ is independently selected, for each occurrence, from CH and N;

R ^E is independently selected, for each occurrence, from the group consisting of halogen, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCH ₃ , -CF ₃ , -OCF ₃ and -SCF ₃ ; and p is selected from 0, 1 and 2.

11. R ^D is selected from the group consisting of

12. A is selected from the group consisting 13. A is selected from the group consisting

14. A is-C(O)R ^D , wherein R ^D is selected from the group consisting of hydrogen, -CH ₂ OH, -CH ₂ OR and -CH _x F _y , wherein R is selected from the group consisting of C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-(5-10 membered aryl), C ₁ -C ₈ heteroalkyl, C ₃ -C ₆ cycloalkyl 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)0R ^d , wherein R ^D is C ₁ -C ₈ alkyl.

17. A is selected from

18. A is-C(O)CH ₂ N(R ^b R ^c ).

19. A is a warhead selected from

20. A is wherein M is selected from Na and K.

21. A is cyano.

22. R ¹ is selected from the group consisting of 23. R ² is selected from the group consisting of , denotes a bond that may be a single or double bond;

R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ⁶ is C ₁ -C ₈ alkyl;

R ⁷ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )z, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

R ⁸ is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle; W ¹ is selected from CH and N;

W ² is selected from the group consisting of CH ₂ , O, NH and S; W is selected from W ¹ and W ² ; s is selected from 1 and 2; and t is selected from 0, 1, 2 and 3.

24. R ² is selected from the group consisting

25. R ³ is selected from the group consisting wherein denotes a bond that may be a single or double bond;

Y ¹ is selected from the group consisting of CH, CH ₂ , N, NH, O and S;

R ⁹ is selected from the group consisting of halogen, hydroxyl, oxo, -NH ₂ , - N(CH ₃ ) ₂ , -N(CH ₂ CH ₃ ) ₂ , -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ and -OCH ₂ CH ₃ . 26. R ³ is selected from the group consisting

27. The compound is represented by wherein:

R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C3- C ₆ cycloalkyl; and m is selected from 1 and 2.

28. R ^y is selected from the group consisting of hydrogen, 9 and

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

30. The compound is represented by

wherein

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )z, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

W is CH orN; m is selected from 1 and 2; and r is selected from 0, 1, 2 and 3.

31. R ^x is -OCH ₃ .

32. A protease inhibitor compound represented by: wherein R ^3a is 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, C ₁ -C ₈ alkoxy, oxo and a warhead A;

R ^3b is selected from hydrogen and C ₁ -C ₈ alkyl; wherein R ^3a and R ^3b may 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 C ₆ -C ₁₄ aryl and a warhead A; R ^1a is selected from the group consisting of C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-R ¹ , -(C ₁ - C ₈ alkyl)-CN, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; R ^1b is selected from hydrogen and C ₁ -C ₈ alkyl; or R ^1a and R ^1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C ₃ -C ₁₀ cycloalkyl;

R ¹ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C2- Cioalkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -NH2, -O-phenyl, -0-(C ₁ -C ₈ alkyl)-phenyl, -C(O)-(5-10 membered heteroaryl), -C(O)-(4-10 membered heterocycle), -C(O)-O-(4-10 membered heterocycle), -C(O)-0C(CH3)3, -C(O)-(C ₂ -Cmalkenyl)-(C6-Ci ₄ aryl), C ₁ -C ₈ alkyl, C2- Cioalkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy, C3-Ciocycloalkyl, -(C ₁ - C ₈ alkyl)-(C ₆ -C ₁₄ aryl), -(C ₁ -C ₈ alkyl)-(5- 10 membered heteroaryl), C ₆ -C ₁₄ aryl, 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, C ₁ -C ₆ alkyl, C ₁ -C ₈ alkoxy, SF ₅ , -NH ₂ , hydroxyl or oxo; R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B )z, - NHC(O)C(R ^c )zR ^B , -NHS(O) _Z R ^b , 4-10 membered heterocycle, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ; or R ^1a and R ² may 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, NR ^G , or C3-Ciocycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from R ^A ;

R ³ is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^G is selected from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of -C(=O), halo, cyano, -NR ^m R ^m , and -NH(C=O)R ^m ) and C(=O)-C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, -NR ^m R ^m , -NR ^m (C=O)R ^m , phenyl, cycloalkyl, heterocycle, C ₁ -C ₆ alkoxy, wherein R ^m is selected for each occurrence by H, C _1-3 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, -S(O)z-CH ₃ , C _3-6 cycloalkyl, and 5-6 membered heteroaryl ), C(=O)-C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C ₁ -C ₆ alkoxy), C(=O)-C _3-6 cycloalkyl, or C(=O)-(5-6 membered heteroaryl) (optionally substituted by halo, cyano, hydroxyl, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C ₁ -C ₆ alkoxy, and C _1-6 haloalkyl));

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF ₅ , cyano, -C(O)0(CH3), -N(R ^y )2, -N(R ^y )C(O)R ^y , C ₁ - C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

A is a warhead;

X is selected from CH, C(CH ₃ ) and N; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

33. The compound is represented by:

34. The compound is represented by:

35. A is selected from the group consisting of cyano, -C(O)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CH _Z 0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)0R ^d , -(CH=CCN)C(O)0R ^d , - and wherein

R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C3-C6cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₆ - C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy;

R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;

R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C3- C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - C ₈ alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, C 1 -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C3- C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl. 36. A is selected from the group consisting of -CN,

37. R ^1a is selected from the group consisting

38. R ^1a is -(C ₁ -C ₈ alkyl)-R ¹ .

39. R ^1b is hydrogen.

40. R ^1a and R ^1b are joined to together to form

41. R ^3a is a 4-10 membered heterocycle substituted by A.

42. R ^3a is selected from the group consisting of

43. R ³ is a 4-10 membered heterocycle.

44. R ³ is selected from the group consisting 45. R ² is selected from th e group consistin

46. R ^1a and R ² are joined to together to form the heterocycle selected from the group

; and R ^1b is H. 48. The compound is represented by: , wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and heterocycle; and R ^G2 is -NH(C=O)R ^m , wherein R ^m is selected for each occurrence by H, methyl or CF3.

49. The compound is represented by: , wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and heterocycle; and R ^G2 is -NH(C=O)R ^m , wherein R ^m is selected for each occurrence by H, methyl or CF3.

50. The compound is represented by: , wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three C ₁ -C ₆ alkoxy), C _3-6 cycloalkyl, phenyl and heterocycle; and R ^G2 is selected from the group consisting of -NH(C ₁ -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, C _3-6 cycloalkyl, and 5-6 membered heteroaryl ) and -NH(C=O)R ^m , wherein R ^m is selected for each occurrence by H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C ₁ -C ₆ alkoxy), CHF2, CF3, or 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C ₁ -C ₆ alkoxy, CHFz, and CF3). 51. The compound is represented by: , wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three C ₁ -C ₆ alkoxy), C _3-6 cycloalkyl, phenyl and heterocycle; and R ^G2 is selected from the group consisting of -NH(C ₁ -3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, -S(O)z-CH3, C _3-6 cycloalkyl, and 5-6 membered heteroaryl ) and -NH(C=O)R ^m , wherein R ^m is selected for each occurrence by H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C ₁ -C ₆ alkoxy), CHFz, CF3, or 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C ₁ -C ₆ alkoxy, CHFz, and CF3).

52. R ^G3 is selected from the group consisting of

53. R ^G2 is selected from the group consisting wherein R ^F is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and 5-6 membered heteroaryl, wherein R ^F may optionally be substituted by one, two or three substituents selected from the group consisting of halo, cyano, hydroxyl and C ₁ -C ₆ alkoxy; and X ^F is selected from the group consisting of H, halo, cyano, hydroxyl, NH ₂ , C _1-6 alkyl, C3- ecycloalkyl, C ₁ -C ₆ alkoxy, and C _1-6 haloalkyl.

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 picomavirus, 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, foscamet, 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 YAP 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.

8. Contemplated Embodiment

[000197] 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: R ¹ is selected from the group consisting of and C ₁ -C ₈ alkyl, C ₃ -C ₆ cycloalkyl, 5- 10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from

R ^a ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -NH ₂ , C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

R ² is selected from the group consisting of -NH ₂ , -NHC(O)R ^B , - NHC(O)N(R ^B )Z, -NHC(O)C(R ^C )ZR ^b , -NHS(O)ZR ^b , 5-10 membered heterocycle, 5-10 membered aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, cyano, -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

A is a warhead;

R ³ is selected from 5-10 membered heteroaryl and 5-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; m is 1 or 2; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

2. A is selected from the group consisting of cyano, -C(O)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CHZ0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)OR ^d , -(CH=CCN)C(O)OR ^d , -

R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C3-C6cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₆ - C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy;

R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;

R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C3- C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - C ₈ alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, C 1 -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C3- C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl. 3. A is a warhead represented , wherein R ^c is selected from the group consisting of hydrogen, -CH ₂ C(O)0(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, 5-10 membered aryl and 5-10 membered heteroaryl.

4. R ^c is wherein X ¹ is independently selected, for each occurrence, from N and CH.

5. A is selected from the group consisting

6. A is wherein

X ² is selected from the group consisting of NH, O and S; X ³ is independently selected, for each occurrence, from N and CH;

R ^D is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl,

R ^E is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy; p is selected from 0, 1 and 2; and q is selected from 0, 1 and 2.

7. A is selected from the group consisting

8. A is wherein X ² is selected from the group consisting of NH, NR ^P , O and S, wherein R ^P is C ₁ -C ₈ alkyl. 9. A is selected from the group consisting

10. A is-C(O)CH ₂ 0C(O)R ^D , wherein

R ^D is selected from the group consisting of C ₁ -C ₈ alkyl and C ₃ - C ₆ cycloalkyl;

X ⁴ is independently selected, for each occurrence, from CH and N;

R ^E is independently selected, for each occurrence, from the group consisting of halogen, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -OCH ₃ , -CF ₃ , -OCF ₃ and -SCF ₃ ; and p is selected from 0, 1 and 2.

11. R ^D is selected from the group consisting of 12. A is selected from the group consisting

13. A is selected from the group consisting

14. A is-C(O)R ^D , wherein R ^D is selected from the group consisting of hydrogen, -CH ₂ OH, -CH ₂ OR and -CH _x F _y , wherein R is selected from the group consisting of C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-(5-10 membered aryl), C ₁ -C ₈ heteroalkyl, C ₃ -C ₆ cycloalkyl 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)OR ^d , wherein R ^D is C ₁ -C ₈ alkyl.

17. A is selected from

18. A is-C(O)CH ₂ N(R ^b R ^c ).

19. A is a warhead selected from

20. A is wherein M is selected from Na and K.

21. A is cyano.

22. R ¹ is selected from the group consisting of

23. R ² is selected from the group consisting of denotes a bond that may be a single or double bond;

R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ⁶ is C ₁ -C ₈ alkyl;

R ⁷ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )z, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

R ⁸ is selected from the group consisting of 5-10 membered aryl, 5-10 membered heteroaryl and 5-10 membered heterocycle; W ¹ is selected from CH and N;

W ² is selected from the group consisting of CH ₂ , O, NH and S; W is selected from W ¹ and W ² ; s is selected from 1 and 2; and t is selected from 0, 1, 2 and 3.

24. R ² is selected from the group consisting

25. R ³ is selected from the group consisting wherein denotes a bond that may be a single or double bond;

Y ¹ is selected from the group consisting of CH, CH ₂ , N, NH, O and S;

R ⁹ is selected from the group consisting of halogen, hydroxyl, oxo, -NH ₂ , - N(CH ₃ )Z, -N(CH ₂ CH ₃ )Z, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ and -OCH ₂ CH ₃ . 26. R ³ is selected from the group consisting

27. The compound is represented by wherein:

R ⁵ is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y ) ₂ , -N(R ^y )C(O)R ^y , C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ - C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C3- C ₆ cycloalkyl; and m is selected from 1 and 2.

28. R ^y is selected from the group consisting of hydrogen, and

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

30. The compound is represented by

wherein

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, -N(R ^y )z, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₃ -C ₆ cycloalkyl;

W is CH orN; m is selected from 1 and 2; and r is selected from 0, 1, 2 and 3.

31. R ^x is -OCH3.

32. A protease inhibitor compound represented by: wherein R ^3a is 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, C ₁ -C ₈ alkoxy, oxo and a warhead A;

R ^3b is selected from hydrogen and C ₁ -C ₈ alkyl; wherein R ^3a and R ^3b may 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 C ₆ -C ₁₄ aryl and a warhead A; R ^1a is selected from the group consisting of C ₁ -C ₈ alkyl, -(C ₁ -C ₈ alkyl)-R ¹ , -(C ₁ - C ₈ alkyl)-CN, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle and 5-10 membered heteroaryl; R ^1b is selected from hydrogen and C ₁ -C ₈ alkyl; or R ^1a and R ^1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle or a C ₃ -C ₁₀ cycloalkyl;

R ¹ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C2- Cioalkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -NH2, -O-phenyl, -0-(C ₁ -C ₈ alkyl)-phenyl, -C(O)-(5-10 membered heteroaryl), -C(O)-(4-10 membered heterocycle), -C(O)-O-(4-10 membered heterocycle), -C(O)-0C(CH3)3, -C(O)-(C ₂ -C10alkenyl)-(C6-Ci ₄ aryl), C ₁ -C ₈ alkyl, C2- Cioalkenyl, C ₂ -C ₁₀ alkynyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy, C3-Ciocycloalkyl, -(C ₁ - C ₈ alkyl)-(C ₆ -C ₁₄ aryl), -(C ₁ -C ₈ alkyl)-(5- 10 membered heteroaryl), C ₆ -C ₁₄ aryl, 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, C ₁ -C ₆ alkyl, C ₁ -C ₈ alkoxy, SF ₅ , -NH ₂ , hydroxyl or oxo; R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B )z, - NHC(O)C(R ^c )zR ^B , -NHS(O) _Z R ^b , 4-10 membered heterocycle, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ; or R ^1a and R ² may 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, NR ^G , or C3-Ciocycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from R ^A ;

R ³ is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen and C ₁ - C ₈ alkyl;

R ^G is selected from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of -C(=O), halo, cyano, -NR ^m R ^m , and -NH(C=O)R ^m ) and C(=O)-C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, -NR ^m R ^m , -NR ^m (C=O)R ^m , phenyl, cycloalkyl, heterocycle, C ₁ -C ₆ alkoxy, wherein R ^m is selected for each occurrence by H, C _1-3 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, -S(O)z-CH ₃ , C _3-6 cycloalkyl, and 5-6 membered heteroaryl ), C(=O)-C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C ₁ -C ₆ alkoxy), C(=O)-C _3-6 cycloalkyl, or C(=O)-(5-6 membered heteroaryl) (optionally substituted by halo, cyano, hydroxyl, NH ₂ , C _1-6 alkyl, C _3-6 cycloalkyl, C ₁ -C ₆ alkoxy, and C _1-6 haloalkyl));

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, SF ₅ , cyano, -C(O)0(CH3), -N(R ^y )z, -N(R ^y )C(O)R ^y , C ₁ - C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 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 C ₁ -C ₈ alkyl;

R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5-10 membered aryl) and C ₃ - C ₆ cycloalkyl;

A is a warhead;

X is selected from CH, C(CH ₃ ) and N; and pharmaceutically acceptable salts, stereoisomers, esters, and prodrugs thereof.

33. The compound is represented by:

34. The compound is represented by:

35. A is selected from the group consisting of cyano, -C(O)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CH _Z 0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)0R ^d , -(CH=CCN)C(O)0R ^d , - (CH=CCN)C(O)(NH)R ^d , -CH(CN)(OH), -CH(CN)(NR ^b R ^c ), and wherein

R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy and C ₆ - C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ -C ₈ alkyl and C ₁ -C ₈ alkoxy;

R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;

R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - Cealkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, Cl-C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C ₃ - C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl. 36. A is selected from the group consisting of -CN,

37. R ^1a is selected from the group consisting

38. R ^1a is -(C ₁ -C ₈ alkyl)-R ¹ .

39. R ^1b is hydrogen.

40. R ^1a and R ^1b are joined to together to form

41. R ^3a is a 4-10 membered heterocycle substituted by A. 42. R ^3a is selected from the group consisting of

43. R ³ is a 4-10 membered heterocycle.

44. R ³ is selected from the group consisting 45. R ² is selected from the group consisting of

46. R ^1a and R ² are joined to together to form the heterocycle selected from the group consisting of: , ; and R ^1b is H

48. The compound is represented by: , wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and heterocycle; and R ^G2 is -NH(C=O)R ^m , wherein R ^m is selected for each occurrence by H, methyl or CF3.

49. The compound is represented by: wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and heterocycle; and R ^G2 is -NH(C=O)R ^m , wherein R ^m is selected for each occurrence by H, methyl or CF3, e g., R ^G2 is

50. The compound is represented by: wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three C ₁ -C ₆ alkoxy), C _3-6 cycloalkyl, phenyl and heterocycle; and R ^G2 is selected from the group consisting of -NH(C ₁ -3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, -S(O)z-CH3, C _3-6 cycloalkyl, and 5-6 membered heteroaryl ) and - NH(C=O)R ^m , wherein R ^m is selected for each occurrence by H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C ₁ -C ₆ alkoxy), CHFz, CF3, or 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH ₂ , Ci- ₆ alkyl, C _3-6 cycloalkyl, C ₁ -C ₆ alkoxy, CHFz, and CF3).

51. The compound is represented by: wherein R ^G3 is selected from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three C ₁ -C ₆ alkoxy), C _3-6 cycloalkyl, phenyl and heterocycle; and R ^G2 is selected from the group consisting of -NH(C ₁ -3alkyl) (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, optionally substituted phenyl, -S(O)z-CH ₃ , C _3-6 cycloalkyl, and 5-6 membered heteroaryl ) and - NH(C=O)R ^m , wherein R ^m is selected for each occurrence by H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C ₁ -C ₆ alkoxy), CHFz, CF3, or 5-6 membered heteroaryl (optionally substituted by halo, cyano, hydroxyl, NH ₂ , Ci- ₆ alkyl, C _3-6 cycloalkyl, C ₁ -C ₆ alkoxy, CHFz, and CF3). 52. R ^G3 is selected from the group consisting

53. R ^G2 is selected from the group consisting wherein R ^F is selected from the group consisting of C _1-6 alkyl, C _3-6 cycloalkyl, phenyl and 5-6 membered heteroaryl, wherein R ^F may optionally be substituted by one, two or three substituents selected from the group consisting of halo, cyano, hydroxyl and C ₁ -C ₆ alkoxy; and X ^F is selected from the group consisting of H, halo, cyano, hydroxyl, NH ₂ , C _1-6 alkyl, C ₃ - 6cycloalkyl, C ₁ -C ₆ alkoxy, and C _1-6 haloalkyl.

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 picomavirus, 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, foscamet, 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 YAP 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. 9. Contemplated Embodiment

[000198] 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:

R ^3a is 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, C ₁ -C ₈ alkoxy, oxo and a warhead A;

R ^3b is selected from hydrogen and C ₁ -C ₈ alkyl; wherein R ^3a and R ^3b may 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 C ₆ -C ₁₄ aryl and a warhead A; R ^1a is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ - C ₈ heteroalkyl, -(C ₁ -C ₈ alkyl)-R ¹ , -(C ₁ -C ₈ alkyl)-CN, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 4- 10 membered heterocycle and 5-10 membered heteroaryl; R ^1b is selected from hydrogen and C ₁ -C ₈ alkyl; or R ^1a and R ^1b may be joined together to form, together with the carbon to which they are attached, a 4-10 membered heterocycle having a ring nitrogen, NR ^G , or a C ₃ - Ciocycloalkyl;

R ¹ is selected from the group consisting of C ₁ -C ₈ alkyl, C ₂ -C ₁₀ alkenyl, Cz- Cioalkynyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ¹ may optionally be substituted by one, two, or three substituents each selected from R ^A ;

R ^A is independently selected, for each occurrence, halogen, cyano, hydroxyl, oxo, SF ₅ , -CH ₂ CF ₃ , CF ₃ , -O-CF3, -0-CHF ₂ , -S-CH3, -S(O) ₂ -CH ₃ , -NH ₂ , -O-phenyl, -0-(C ₁ -C ₈ alkyl)-phenyl, -NHC(O)R ^B , -NHC(O)0R ^B , -NHC(O)0-(C ₁ -C ₈ alkyl)-R ^B , - N(R ^y )z, -N(R ^y )(C ₁ -C ₈ alkyl)C(O)0-phenyl, -N(R ^y )(C ₁ -C ₈ alkyl)C(O)N(R ^y ) ₂ , - NHC(O)0(C ₁ -C ₈ alkyl)R ^B , -C(O)-(5-10 membered heteroaiyl), -C(O)-(4-10 membered heterocycle), -C(O)-O-(4-10 membered heterocycle), -C(O)-(4-10 membered heterocyclyloxy), -C(O)-0C(CH3)3, -C(O)-(C ₂ -C ioalkenyl)-(C ₆ -C ₁₄ aryl), C ₁ -C ₈ alkyl, C ₂ -Cioalkenyl, C ₂ -Cioalkynyl, C ₁ -C ₈ heteroalkyl, C ₁ -C ₈ alkoxy, C3- Ciocycloalkyl, -(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), -(C ₁ - C ₈ alkyl)-(5-10 membered heteroaryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein the R ^B , alkyl, heterocycle, heteroaryl, or aryl may optionally be substituted by one, two or three substituents of halogen, C ₁ -C ₈ alkyl, C ₁ - C ₈ alkoxy, SF ₅ , -NH ₂ , hydroxyl or oxo;

R ² is selected from the group consisting of -NHC(O)R ^B , -NHC(O)N(R ^B ) ₂ , - NHC(O)C(R ^C ) ₂ R ^b , -NHS(O) ₂ R ^b , -0-(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), 4-10 membered heterocycle, C ₆ -C ₁₄ aryl and 5-10 membered heteroaryl bound through the carbon or nitrogen atom, wherein R ^B or R ² may optionally be substituted by one, two, or three substituents each selected from R ^x ; or R ^1a and R ² may 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 NR ^G , or a C ₃ -C ₁₀ cycloalkyl, wherein the cycloalkyl or heterocycle may optionally be substituted by one, two or three substituents on a free carbon each selected from R ^A ;

R ³ is selected from 5-10 membered heteroaryl and 4-10 membered heterocycle, wherein R ³ may optionally be substituted by one, two, or three substituents each selected from R ^A ; R ^B is independently selected, for each occurrence, from the group consisting of C ₁ -C ₈ alkyl, C2-C10alkenyl, C2-C10alkynyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl and 4-10 membered heterocycle;

R ^c is independently selected, for each occurrence, from hydrogen, halogen and C ₁ -C ₈ alkyl;

R ^x is independently selected, for each occurrence, from the group consisting of halogen, hydroxyl, oxo, CF ₃ , SF ₅ , cyano, -O-(Rxx)-OCH ₃ , -OCHFz, -OCF3, -0-(C ₁ - C ₈ alkyl), -C(O)0(CH ₃ ), -N(R ^y )z, -N(R ^y )C(O)R ^y , -N(R ^y )(C ₁ -C ₈ alkyl)C(O)N(R ^y )z, - N(R ^y )(C ₁ -C ₈ alkyl)C(O)OH, -(C ₁ -C ₈ alkyl)-(C3-Ciocycloalkyl), C ₁ -C ₈ alkyl, C ₁ - C ₈ alkoxy, C ₃ -Ciocycloalkyl, C ₆ -C ₁₄ aryl, 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 C ₁ -C ₈ alkyl;

R ^G is selected from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of -C(=O), halo, cyano, -NR ^m R ^m , and -NH(C=O)R ^m ), and C(=O)-C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, -NR ^m R ^m , -NR ^m (C=O)R ^m , phenyl, cycloalkyl, heterocycle, C ₁ -C ₆ alkoxy, wherein R ^m is selected for each occurrence by H, C ₁ - ₃ alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo), phenyl (optionally substituted by halo), -S(O)z-CH3, C ₃ -6cycloalkyl, and 5-6 membered heteroaryl ), - C(=O)-C ₁ -6alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano and C ₁ -C ₆ alkoxy), C(=O)-C _3-6 cycloalkyl, and C(=O)-(5-6 membered heteroaryl) (optionally substituted by halo, cyano, hydroxyl, NH ₂ , C _1-6 alkyl, C ₃ -6cycloalkyl, C ₁ -C ₆ alkoxy, and C ₁ - 6haloalkyl));

R ^xx is — (OCH ₂ CH ₂ )nn- , wherein nn is selected from 1, 2, 3, 4, 5 and 6; R ^y is independently selected, for each occurrence, from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ heteroalkyl, -CH2CF3, C ₁ -C ₈ alkoxy, -(C ₁ -C ₈ alkoxy)-(5- 10 membered aryl), C ₃ -C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)COOH;

A is a warhead;

X is selected from the group consisting of C(R ^xy ) and N, wherein R ^xy is selected from the group consisting of H, D, -OH, -NH ₂ , halogen, C ₁ -C ₈ alkyl, C ₁ -C ₈ haloalkyl, and C ₁ - C ₈ alkoxy; and pharmaceutically 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: or wherein pp is selected from 0, 1, 2, and 3.

10. The compound is represented by: (Formula I I-Ε), 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)R ^D , -C(O)CH ₂ N(R ^b R ^c ), - C(O)CH ₂ 0C(O)R ^d , -C(O)C(O)R ^d , -(CH=CH)C(O)0R ^d , -(CH=CCN)C(O)0R ^d , -

(CH=CCN)C(O)(NH)R ^d , -CH(CN)(OH), -CH(CN)(NR ^b R ^c ), and wherein

R ^D is selected from the group consisting of hydrogen, hydroxyl, -OR ^bb - N(R ^b R ^c ), C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle; wherein R ^D may optionally be substituted by one, two, or three substituents each selected from the group consisting of halogen, hydroxyl, and R ^E ;

R ^E is selected from the group consisting of C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl, wherein R ^E may optionally be substituted by one, two, or three substituents each selected from halogen, cyano, C ₁ - C ₈ alkyl and C ₁ -C ₈ alkoxy; R ^bb is selected from the group consisting of C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₄ aryl, -(C ₁ - C ₈ alkyl)-C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycle;

R ^cc is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, C3- C ₆ cycloalkyl, -(C ₁ -C ₈ alkyl)-(C ₆ -C ₁₄ aryl), C ₆ -C ₁₄ aryl, 5-10 membered heteroaryl, -(C ₁ - C ₈ alkyl)-(5-10 membered heteroaryl), 5-10 membered heterocycle and -N(R ^b R ^c ), wherein R ^b and R ^c are each selected from the group consisting of hydrogen, C 1 -C ₈ alkyl, and C ₃ -C ₆ cycloalkyl, or R ^b and R ^c may be joined together to form, together with the nitrogen to which they are attached, a 5-10 membered heterocycle;

R ^cd is selected from the group consisting of hydrogen, C ₁ -C ₈ alkyl, and C3- C ₆ cycloalkyl; and

R ^b and R ^c are each selected from the group consisting of hydrogen, - CH ₂ C(O)0(C ₁ -C ₈ alkyl), -C(O)-(C ₁ -C ₈ alkyl), -S(O) ₂ -(C ₁ -C ₈ alkyl), C ₁ -C ₈ alkyl, C ₃ - C ₆ cycloalkyl and -(C ₁ -C ₈ alkyl)-C ₆ -C ₁₄ aryl, wherein the C ₁ -C ₈ alkyl may optionally be substituted by one or more substituents each selected from the group consisting of halogen, C3-C6cycloalkyl, C ₆ -C ₁₄ aryl, 4-10 membered heterocycle, and 5-10 membered heteroaryl.

12. A is selected from the group consisting of -CN,

13. R ^1a is selected from the group consisting

14. R ^1a is -(C ₁ -C ₈ alkyl)-R ¹ .

15. R ^1b is hydrogen.

16. R ^1a and R ^1b are joined to together to form

17. R ^3a is a 4-10 membered heterocycle substituted by A.

18. R ^3a is selected from the group consisting of

19. R ³ is a 4-10 membered heterocycle. 20. R ³ is selected from the group consisting

21. R ² is selected from the group consisting

22. R ^1a and R ² are joined to together to form the heterocycle selected from the group consisting of:

23. R ^G is selected from the group consisting of H, C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of - C(=O), halo, cyano, -NR ^m R ^m , and -NH(C=O)R ^m ) and C(=O)-C _1-6 alkyl (optionally substituted by one, two or three substituents each independently selected from the group consisting of halo, cyano, -NR ^m R ^m , -NR ^m (C=O)R ^m , phenyl, cycloalkyl and heterocycle, wherein R ^m is selected for each occurrence by H or C _1-3 alkyl (optionally substituted by one, two or three halogens, e g., F), or C ₃ -C ₆ cycloalkyl (optionally substituted by one, two, or three F).

24. R ^G is 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(R ⁵⁵ R ⁵⁶ )-NH-C(O)-R ⁵⁷ , wherein R ⁵⁵ is H and R ⁵⁶ is a straight or branched C ₁ -Csalkyl (optionally substituted by halo), or R ⁵⁵ and R ⁵⁶ taken together with the carbon to which they are attached form a C ₃ -C ₅ cycloalkyl (optionally substituted by halo) and wherein R ⁵⁷ is C ₁ -Csalkyl (optionally substituted by one, two or three halo).

25. R ^G is selected from the group consisting

26. A compound selected from the group consisting of: -601-

8

-641-

27. 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.

28. 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 picomavirus, 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.

29. 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.

30. The viral infection is a coronavirus infection.

31. 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).

32. The viral infection is SARS-CoV-2. 33. The viral infection is an arenavirus infection.

34. The arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus.

35. The viral infection is an influenza infection.

36. The influenza is influenza H1N1, H3N2 or H5N1.

37. 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.

38. The further comprises administering another therapeutic.

39. The method further comprises administering an additional anti-viral therapeutic.

40. The anti-viral therapeutic is selected from the group consisting of ribavirin, favipiravir, ST- 193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine.

41. 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, foscamet, 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.

42. The additional anti-viral therapeutic is selected from the group consisting of lamivudine, an interferon alpha, a YAP 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, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, ombitasvir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, ampligen, aplaviroc, anti-caprine antibody, balavir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, methisazone, MK-2048, nelfmavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR- 576, and zalcitabine.

43. A method of prophylactically treating a patient at risk of viral infection, comprising administering to the patient an effective amount of a compound of the embodiment

44. The compound is administered before viral exposure.

45. The compound is administered after viral exposure.

EXAMPLES

[000199] 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.

[000200] At least some of the compounds identified as “Intermediates” herein are contemplated as compounds of the disclosure.

[000201] ¹ H NMR spectra are recorded at ambient temperature using e g., a Varian Unity Inova (400 MHz) spectrometer with a triple resonance 5mm 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.

[000202] Abbreviations:

AcOH acetic acid

Boc tert- butoxy carbonyl protecting group

CbzCl benzyl chloroformate

DCE dichloroethane

DCM dichloromethane

DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone

DIEA N,N-diisopropylethylamine

DIPEA N,N-diisopropylethylamine

DMA dimethylacetamide

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

EA ethyl acetate

EtOAc ethyl acetate

EDCI 1 -ethyl-3- (3-dimethylaminopropyl)carbodiimide

EDTA ethylenediaminetetraacetic acid EtOH ethanol

FA formic acid

HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyr idinium 3 -oxide hexafluorophosphate

HOBt hydroxybenzotirazole

LiHMDS lithium bis(trimethylsilyl)amide

MTBA l-4-(3-Methyltriazeno)benzoic acid

MTBE methyl tert-butyl ether

MeOH methanol

MeCN acetonitrile

MS mass spectrometry

NMR nuclear magnetic resonance

PE petroleum ether

PMA phosphomolybdic acid

PMBC1 p-methoxybenzyl chloride

Pht phthaloyl

PyBOP (benzotriazol- 1 -yloxytripyrrolidinophosphonium hexafluorophosphate) t-BuLi tert-butylithium

T ₃ P propanephosphonic acid anhydride

TEA triethylamine

TFA trifluoroacetic acid

TFAA trifluoroacetic anhydride

THF tetrahydrofuran

TMSCN trimethylsilyl cyanide

General Chemistry

[000203 ] Exemplary compounds described herein are available by the general synthetic method illustrated in Scheme 1, including preparations of Intermediates and preparation of accompanying Examples.

Synthetic Scheme(s)

Scheme 1

[000204] Scheme 1 illustrates an exemplary preparation of C-l. Reacting a solution of amine A-l, and acid B-l 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-l

[000205] 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.

[000206] 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 Step 1: (2S)-2-[[(2S)-2-(lH-benzimidazole-2-carbonylamino)-4-methyl- pentanoyl]amino]-3- [ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000207] To a mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 483.81 umol, 1 eq, TFA) and 1H- benzimidazole-2-carboxylic acid (94.14 mg, 580.57 umol, 1.2 eq) in DCM (2 mL) was added EDCI (185.49 mg, 967.61 umol, 2 eq) and DMAP (118.21 mg, 967.61 umol, 2 eq). The mixture was added DMF (1 mL) and stirred at 25 °C for 4 h. The resulting mixture was diluted with H ₂ O (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM/MeOH=5/l), to give methyl (2S)-2-[[(2S)-2-(lH-benzimidazole-2-carbonylamino)-4-methyl- pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 338.22 umol) as a solid.

Step 2: N-f ( l S)-3-methyl-l-[[ ( l S)-l-(nitrosomethyl)-2-[(3S)-2-oxopyrrolidin-3- ylJethylJcarbamoylJbutylJ-lH-benzimidazole-2-carboxamide

[000208] Methyl(2S)-2-[[(2S)-2-(lH-benzimidazole-2-carbonylamino)-4-m ethyl- pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 338.22 umol, 1 eq) was added NH ₃ /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- [( 1 S)-3-methyl- 1 -[[( 1 S)- 1 -(nitrosomethyl)-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]butyl]-lH-benzimidazole-2-carboxamide (140 mg, crude) as a solid. The crude product was used directly in next step.

Step 3: N-f (1S)-1-[[(1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ] carbamoyl ]-3-methyl- butylJ-JH-benzimidazole-2-carboxamide

[000209] N-[(1S)-3-methyl-1-[[(1S)-1-(nitrosomethyl)-2-[(3S)-2-oxopyr rolidin-3- yl]ethyl]carbamoyl]butyl]-lH-benzimidazole-2-carboxamide (120.00 mg, 280.06 umol, 1 eq) in DCM (5 mL) was added Burgess reagent (150 mg, 629.45 umol, 2.25 eq). The mixture was stirred at 25 °C for 4 h. The reaction was blow-dried under N ₂ . The residue was purified by prep-HPLC (column: Waters Xb ridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water(10 mM NH4HC03 )- ACN] ;B% : 20%-40%,8 min), give N- [(1S)-1-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]ca rbamoyl]-3-methyl-butyl]- 1 H-benzimidazole-2-carboxamide (40 mg, 97.45 umol) was obtained as a solid. MS (ESI) m/z 411.1 [M+H] ⁺ , ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.11 (br s, 1H), 8.97 - 8.81 (m, 2H), 7.90 - 7.64 (m, 2H), 7.54 (br s, 1H), 7.31 (br s, 2H), 5.08 - 4.93 (m, 1H), 4.62 - 4.43 (m, 1H), 3.19 - 3.05 (m, 2H), 2.44 - 2.29 (m, 1H), 2.23 - 2.05 (m, 2H), 1.91 - 1.50 (m, 5H), 0.91 (dd, J=6.3, 8.9 Hz, 6H).

Example 2. Synthesis of viral protease inhibitor compound 105

Step 1: (2S)-2-[[(2S)-4-methyl-2-(2-naphthylsulfonylamino)pentanoyl] amino]-3-[(3S)-2- oxopyrrolidin-3-yl ]propanoate

[000210] 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 H ₂ O (20 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM/MeOH=10/l). Give methyl (2S)-2-[[(2S)-4-methyl-2-(2- naphthylsulfonylamino)pentanoyl]amino]-3-[(3S)-2-oxopyrrolid in-3-yl]propanoate (70 mg, 142.98 umol) as an oil.

Step 2: (2S)-N-[ ( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl ]-4-methyl-2- (2-naphthylsulfonylamino)pentanamide

[000211] To a mixture of methyl (2S)-2-[[(2S)-4-methyl-2-(2- naphthylsulfonylamino)pentanoyl]amino]-3-[(3S)-2-oxopyrrolid in-3-yl]propanoate (50 mg, 102.13 umol, 1 eq) was added NH ₃ /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]met hyl]ethyl]-4-methyl-2-(2- naphthylsulfonylamino)pentanamide (50 mg, crude) as an oil.

Step 3: (2S)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ]-4-methyl-2-(2- naphthylsulfonylamino)pentanamide

[000212] (2S)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-4- methyl-2-(2-naphthylsulfonylamino)pentanamide (70 mg, 147.50 umol, 1 eq) in DCM (0.5 mL) was added Burgess reagent (79.00 mg, 331.52 umol, 2.25 eq). The mixture was stirred at 25 °C for 4 h. The reaction was blow-dried under N ₂ . The residue was purified by prep-HPLC: column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water(10 mM NH4HCO3)- ACN] ;B% : 25%-55%, 8 min, give compound (2S)-N- [(1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]-4-methyl-2-(2- naphthylsulfonylamino)pentanamide (30 mg, 65.71 umol) as a solid. MS (ESI) m/z 457.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.81 (br d, J=7.5 Hz, 1H), 8.38 (s, 1H), 8.21 (br s, 1H), 8.12 - 8.03 (m, 2H), 8.00 (d,J=7.7 Hz, 1H), 7.82 - 7.72 (m, 1H), 7.71 - 7.56 (m, 3H), 4.64 (q, J=7.6 Hz, 1H), 3.78 - 3.67 (m, 1H), 3.09 - 3.01 (m, 1H), 3.00 - 2.89 (m, 1H), 2.08 - 1.96 (m, 1H), 1.90 - 1.78 (m, 1H), 1.71 - 1.60 (m, 1H), 1.58 - 1.33 (m, 4H), 1.31 - 1.19 (m, 1H), 0.78 (d, J=6.6 Hz, 3H), 0.63 (d, J=6.6 Hz, 3H).

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

Step 1: methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate [000213] 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] ⁺

Step 2: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoy l]amino]-3- [ ( 3S)-2- oxopyrrolidin-3-yl ]propanoate

[000214] 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 H ₂ O (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc=3/l to 0/1) to get the compound methyl (2S)-2-[[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl] amino]-3-[(3S)-2- oxopy rrolidin-3-yl]propanoate (250 mg, 461.36 umol) as a solid. MS (ESI) m/z 434.3 [M+H] ⁺

Step 3: benzyl N-[(lS)-l-[[(lS)-2-amino-2-oxo-l-[[(3S)-2-oxopyrrolidm-3- yl ]methyl ] ethyl ]carbamoy l ]-3-methyl-butyl ] carbamate

[000215] 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 NH ₃ /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. Step 4: benzyl N-[(lS)-l-[[(lS)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl] carbamoyl]-3- methyl-butyl] carbamate

[000216] To a mixture of benzyl N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl] carbamoyl]-3-methyl-butyl]carbamate (150 mg, 179.22 umol, 1 eq) in DCM (5 mL) was added Burgess reagent (42.71 mg, 179.22 umol, 1 eq). The mixture was stirred at 25 °C for 1 h. Once the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm* 10 um;mobile phase: [water(10 mM NH4HCO3)- ACN] ; B%: 20%-50%,8 min) to get the compound benzyl N-[( 1 S)-l -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl-butyl]carbamate (28 mg, 69.92 umol) as a solid. MS (ESI) m/z 401.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (br d, J=7.9 Hz, 1H), 7.70 (s, 1H), 7.54 (br d, J=7.8 Hz, 1H), 7.41 - 7.24 (m, 5H), 5.02 (s, 2H), 4.97 - 4.88 (m, 1H), 4.07 - 3.91 (m, 1H), 3.20 - 2.94 (m, 2H), 2.38 - 2.22 (m, 1H), 2.22 - 1.98 (m, 2H), 1.85 - 1.26 (m, 5H), 0.87 (br dd, J=6.5, 11.2 Hz, 6H)

Example 4. Synthesis of viral protease inhibitor compound 131

Step 1: (2S)-2-[[(2S)-2-(lH-imidazo[4,5-bJpyridine-2-carbonylamino)- 4-methyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000217] 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 H ₂ O (20 mL) and extracted with DCM (30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM/MeOH= 5/ 1 ) to give compound methyl (2S)-2-[[(2S)-2-(lH-imidazo[4,5-b]pyridine-2-carbonylamino)- 4- methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propano ate (100 mg, 224.98 umol) as a solid.

Step 2: N-f (1S)-1-[[(1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ] -3-methyl-butyl ]-lH-imidazo[ 4, 5-b ]pyridine-2-carboxamide [000218] To a mixture of methyl (2S)-2-[[(2S)-2-(lH-imidazo[4,5-b]pyridine-2- carbonylamino)-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrol idin-3-yl]propanoate (100 mg, 224.98 umol, 1 eq) was added NH ₃ /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-[(l S)-1-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-lH-imidazo[4,5-b] pyridine-2-carboxamide (90 mg, crude) as an oil.

Step 3: N-[(lS)-l-[[(lS)-l-cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-methyl- butyl]-lH-imidazo[4,5-b]pyridine-2-carboxamide

[000219] N-[(l S)-1-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-lH-imidazo[4,5-b] pyridine-2-carboxamide (80 mg, 186.28 umol, 1 eq) in DCM (3 mL) was added Burgess reagent (100.00 mg, 419.62 umol, 2.25 eq). The mixture was stirred at 25 °C for 4 h. The reaction was blow- dried under N ₂ . The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm* 10 um; mobile phase: [water(10 mM NH4HC03 )- ACN] ;B% : 10%-35%,8 min) to give N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl-butyl]-lH-imidazo[4,5-b]pyridin e-2-carboxamide (25 mg, 60.76 umol) as a solid. MS (ESI) m/z 412.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.58 (br s, 1H), 9.29 - 8.96 (m, 1H), 8.89 (d, 3=1.9 Hz, 1H), 8.49 (br s, 1H), 8.28 - 7.84 (m, 1H), 7.71 (s, 1H), 7.36 (dd, J=4.6, 8.2 Hz, 1H), 5.06 - 4.93 (m, 1H), 4.61 - 4.44 (m, 1H), 3.20 - 3.06 (m, 2H), 2.43 - 2.31 (m, 1H), 2.20 - 2.07 (m, 2H), 1.90 - 1.53 (m,

5H), 0.92 (dd, J=6.4, 9.5 Hz, 6H).

Example 5. Synthesis of viral protease inhibitor compound 121

Step 1: (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3- yl]propanoic acid

[000220 ] 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 H ₂ O (3 mL) was added LiOH.H ₂ O (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 HC1. 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-[(3 S)-2-oxopyrrolidin-3- yljpropaneic acid (1 g, 3.31 mmol) was obtained as an oil. MS (ESI) m/z 217.1 [M+H- 56] ⁺ .

Step 2: tert-butyl N-[(lS)-2-[methoxy(methyl)amino]-2-oxo-l-[[(3S)-2-oxopyrroli din-3- yljmethyl] ethyl] carbamate [000221] To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3- yljpropanoic 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 Ν,Ο-DIMETHYLHYDROXYL AMINE 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 H ₂ O (30 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc=5/l to 0/1) to get the compound tert-butyl N-[(1S)-2- [methoxy(methyl)amino]-2-oxo- 1 -[[(3 S)-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] ⁺

Step 3: tert-butyl N-[(JS)-2-(J,3-benzothiazol-2-yl)-2-oxo-1-[[(3S)-2-oxopyrrol idin-3- yljmethyl] ethyl] carbamate

[000222] 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 N ₂ . The mixture was stirred at -78 °C for 30 min, and then added with tert-butyl N- [( 1 S)-2-[methoxy(methyl)amino]-2-oxo- 1-[[(3 S)-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 NH4CI (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by MPLC (SiO ₂ , petroleum ether/EtOAc- MeOH=10/l to 0/1) to get the compound tert-butyl N-[(1S)-2- ( 1 ,3-benzothiazol-2-yl)-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl] methy 1 ]ethyl ]carbamate (150 mg, 346.63 umol) as a colorless oil. MS (ESI) m/z 390.1 [M+H] ⁺

Step 4: (3S)-3-[(2S)-2-amino-3-(l,3-benzothiazol-2-yl)-3-oxo-propyl] pyrrolidin-2-one

[000223] To a mixture of tert-butyl N-[( 1 S)-2-(l ,3-benzothiazol-2-yl)-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl] methy 1 ]ethy 1 ]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-(l, 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] ⁺

Step 5: N-f ( l S)-l-[[ ( l S)-2-( l, 3-benzothiazol-2-yl)-2-oxo-1-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl / ethyl ] carbamoyl ]-3-methyl-butyl ]-4-methoxy-lH-indole-2-carboxamide

[000224] To a mixture of (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoic acid (18.93 mg, 62.21 umol, 1 eq) in DMF (1 mL) was added 1- methylimidazole (25.54 mg, 311.04 umol, 24.79 uL, 5 eq) and [chloro(dimethylamino)methylene]-dimethyl-ammonium hexafluorophosphate (20.95 mg, 74.65 umol, 1.2 eq) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, and then added with (3S)-3-[(2S)-2-amino-3-(l,3-benzothiazol-2-yl)-3-oxo-propyl] pyrrolidin- 2-one (18 mg, 62.21 umol, 1 eq). The resulting mixture was stirred at 25 °C for 2 h. Once the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude was purified by neutral prep-HPLC (column: Waters Xb ridge BEH C18 100*30 mm* 10 um; mobile phase:

[water( 10mMNH4HCO3)- ACN];B%: 35%-65%,10 min) and SFC (column: DAICEL CHIRALCEL OX (250 mm*30 mm, 10 um);mobile phase: [0.1% NH3H ₂ O MEOH]; B%: 50%-50%,12 min) separation to get the compound N-[(l S)- 1 -[[( 1 S)-2-(l ,3-benzothiazol- 2-yl)-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carba moyl]-3-methyl-butyl]-4- methoxy- 1 H-indole-2-carboxamide (8 mg, 13.48 umol) as a solid. MS (ESI) m/z 576.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.69 (s, 1H), 8.75 - 8.51 (m, 2H), 8.08 (d, J=7.9 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.68 (s, 1H), 7.50 (t, J=7.4 Hz, 1H), 7.44 - 7.37 (m, 1H), 7.19 - 7.07 (m, 4H), 6.93 (d, J=8.2 Hz, 1H), 6.49 (d, J=7.7 Hz, 1H), 3.89 (s, 3H), 3.15 - 2.99 (m, 2H), 2.46 - 2.30 (m, 1H), 2.21 - 1.94 (m, 4H), 1.93 - 1.74 (m, 1H), 1.57 - 1.40 (m, 2H), 0.83 - 0.71 (m, 6H).

Example 6. Synthesis of viral protease inhibitor compound 185

Step 1: (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanamid o)-3-((S)- 2-oxopyrrolidin-3-yl)propanoate

[000225] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (170 mg, 763.47 umol, 1 eq, HC1) 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 H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO ₂ , 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] ⁺

Step 2: (S)-methyl 2-((S)-2-amino-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolid in-3- yl)propanoate

[000226] 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, HC1) was obtained as a solid and used directly next step. MS (ESI) m/z 340.1 [M+H] ⁺

Step 3: ((S)-methyl 2-((S)-3-cyclohexyl-2-(4-methoxy-lH-indole-2- carboxamido)propanamido)-3-((S)-2-oxopyrrolidin-3-yl)propano ate

[000227] A solution of 4-methoxy-lH-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, HC1) 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 H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 1 :0 to 10: 1) to get a product methyl (2S)-2-[[(2S)-3-cyclohexyl-2-[(4-methoxy-lH-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. 1H NMR (METHANOL-d ₄ , 400 MHz): δ ppm 7.26 (s, 1H), 7.09-7.20 (m, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.51 (d, J= 7.6 Hz, 1H), 4.66 (br dd, J = 9.0, 6.3 Hz, 1H), 4.52-4.58 (m, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.22-3.29 (m, 2H), 2.54-2.62 (m, 1H), 2.26-2.33 (m, 1H), 2.15-2.23 (m, 1H), 1.66-1.87 (m, 9H), 1.47-1.54 (m, 1H), 1.25-1.40 (m, 3H), 0.96-1.06 (m, 2H)

Step 4: N-( (S)-l-( ( (S) -1 -amino- l-oxo-3-( (, S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3 - cyclohexyl- 1 -oxopropan-2-yl) -4-methoxy- lH-indole-2-carboxamide

[000228] A solution of methyl (2S)-2-[[(2S)-3-cyclohexyl-2-[(4-methoxy-lH-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- lH-indole-2-carboxamide (140 mg, crude) was obtained as a solid. MS (ESI) m/z 498.2 [M+H] ^{+ 1} H NMR (METHANOL-d ₄ , 400 MHz): δ ppm 7.27-7.34 (m, 1H), 7.13-7.20 (m, 1H), 7.05 (d, J= 8.3 Hz, 1H), 6.53 (d, J= 7.7 Hz, 1H), 4.62 (t, J= 7.6 Hz, 1H), 4.42-4.51 (m, 1H), 3.95 (s, 3H), 3.22-3.30 (m, 2H), 2.53 (td, J= 9.2, 4.5 Hz, 1H), 2.33 (ddd, J= 9.2, 6.4, 3.4 Hz, 1H), 2.17 (ddd, J= 14.1, 11.4, 4.6 Hz, 1H), 1.71-1.88 (m, 9H), 1.46-1.53 (m, 1H), 1.21-1.32 (m, 3H), 0.97-1.09 (m, 2H)

Step 5: N-( (S)-l-( ( (S)-l -amino-1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3- cyclohexyl-l-oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxami de

[000229] 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-m ethoxy-lH-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- [(3 S)-2-oxopyrrolidin-3-yl]ethyl]amino]- 1 -(cyclohexylmethyl)-2-oxo-ethyl]-4-methoxy- 1 H-indole-2-carboxamide (20.02 mg, 41.75 umol) was obtained as a solid. MS (ESI) m/z 480.1 [M+H] ⁺ .

Prep-HPLC condition: column: Waters Xbridge BEH C18 100*25mm*5 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,10 min ¹ H NMR (METHANOL-d ₄ , 400 MHz): δ ppm 7.28 (s, 1H), 7.11-7.18 (m, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 5.05 (dd, J = 10.1, 5.9 Hz, 1H), 4.56-4.61 (m, 1H), 3.93 (s, 3H), 3.22-3.30 (m, 2H), 2.55-2.66 (m, 1H), 2.23-2.40 (m, 2H), 1.65-1.94 (m, 9H), 1.41-1.52 (m, 1H), 1.17-1.36 (m, 3H), 0.94-1.10 (m, 2H).

Example 7. Synthesis of viral protease inhibitor compound 101

Step 1: Methyl (2S)-2-amino-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate .hydrochloride [000230] Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (500 mg, 1.75 mmol, 1 eq) was added HCl/EtOAc (4 M, 10 mL, 22.91 eq) at 25 °C. The mixture was stirred at 25 °C for 0.5 h. The resulting mixture was concentrated under reduced pressure to give a product methyl (2S)-2-amino-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate;hydrochloride (300 mg, 1.28 mmol, 73.29% yield, 95% purity) as a solid and used directly next step. MS (ESI) m/z 187.1 [M+H] ⁺

Step 2: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoy l]amino]-3- [ ( 3S)-2- oxopyrrolidin-3-yl ]propanoate [000231 ] To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate;hydrochloride (157.89 mg, 673.65 umol, 95% purity, 1 eq) and (2S)-2- (tert-butoxycarbonylamino)-4-methyl-pentanoic acid (155.81 mg, 673.65 umol, 1 eq) in DMF (2 mL) was added EDCI (258.28 mg, 1.35 mmol, 2 eq) and DMAP (164.60 mg, 1.35 mmol, 2 eq). The mixture was added DCM (3 mL) and stirred at 25 °C for 14 h. The resulting mixture was diluted with H ₂ O (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether/EtOAc=3/l to 1/1) to get the product methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoy l]amino]-3-[(3S)- 2-oxopyrrolidin-3-yl]propanoate (250 mg, 500.65 umol, 74.32% yield, 80% purity) was obtained as a solid. MS (ESI) m/z 400.3 [M+H] ⁺

Step 3: (2S)-2-amino-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ]-4-methyl- pentanamide

[000232 ] tert-butylN-[(l S)-1-[[(l S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl-butyl] carbamate (200 mg, 491.19 umol, 90% purity, 1 eq) in DCM (5 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 13.75 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to give a product (2S)-2-amino-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl] ethyl]-4-methyl-pentanamide (120 mg, 405.50 umol, 82.55% yield, 90% purity) as an oil and used directly next step. MS (ESI) m/z 300.2 [M+H] ⁺

Step 4: methyl(2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino ]-4-methyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000233] To a mixture of 4-methoxy-lH-indole-2-carboxylic acid (120 mg, 627.67 umol,

1 eq) and methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (208.78 mg, 627.67 umol, 90% purity, 1 eq) in DCM (1 mL) was added EDCI (240.65 mg, 1.26 mmol, 2 eq) and DMAP (153.36 mg, 1.26 mmol,

2 eq). The mixture was added DMF (0.5 mL) and stirred at 25 °C for 14 h. The resulting mixture was diluted with H ₂ O (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, petroleum ether/EtOAc=3/l to 0/1) to get the compound methyl(2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino ]-4-methyl-pentanoyl] amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (160 mg, 304.74 umol, 48.55% yield, 90% purity) as a solid. MS (ESI) m/z 473.3 [M+H] ⁺

Step 5: N-f (1S)-1-[[(1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ]-3- methyl-butyl ]-4-methoxy-lH-indole-2-carboxamide [000234] methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-me thyl- pentanoy 1 ]amino] 3 - [(3S)-2-oxopyrrolidin-3-yl]propanoate (180 mg mg, 342.83 umol, 90% purity, 1 eq) was added NH ₃ /MeOH (7 M, 54.00 mL, 1102.58 eq), The mixture was stirred at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure to give a residue N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 - [[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indo le-2-carboxamide (130 mg, 255.73 umol, 74.59% yield, 90% purity) as an oil. MS (ESI) m/z 458.3 [M+H] ⁺

[000235] 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.97- 1.02 (dd, J=14.55, 6.11 Hz, 6 H) 1.74 - 1.82 (m, 5 H) 2.15 (ddd, J=14.03, 11.34, 4.58 Hz, 1 H) 2.25 - 2.37 (m, 1 H) 2.52 (ddt, J=13.82, 9.41, 4.71, 4.71 Hz, 1 H) 3.17 - 3.29 (m, 2 H) 3.90 (s, 3 H) 4.46 (dd, J=11.25, 4.16 Hz, 1 H) 4.60 (dd, J=9.66, 5.01 Hz, 1 H) 6.50 - 6.52 (d, J=7.70 Hz, 1 H) 7.02 - 7.04 (d, J=8.31 Hz, 1 H) 7.15 - 7.17 (m, 1 H) 7.28 - 7.29 (d, J=0.73 Hz, 1 H)

Step 6: N-f (1S)-1-[[(1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl] carbamoyl- 3-methyl- butyl

-4-methoxy-lH-indole-2-carboxamide

[000236] 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-methoxy-lH-indole-2-carboxamide (100 mg, 196.71 umol, 90% purity, 1 eq) in DCM (4 mL) was added Burgess reagent (93.75 mg, 393.42 umol, 2 eq). The mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC to get the product N-[( 1 S)- 1 -[[( 1 S)- 1 -cy ano-2-[(3 S)-2-oxopyrrolidin - 3-yl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2- carboxamide (23 mg, 49.50 umol, 25.16% yield, 94.59% purity) as a solid. MS (ESI) m/z 440.1 [M+H] ⁺ .

Prep-HPLC condition: column: Waters Xbridge BEH C18 100*30 mm* 10 um; mobile phase: [water(10 mM NH4HC03)-ACN];B%: 27%-57%,10 min

[000237] 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 - 0.94 (m, 6 H) 1.67 - 1.74 (m, 5 H) 2.11 - 2.13 (m, 2 H) 2.14 - 2.34 (m, 1 H) 3.09 - 3.14 (m, 2 H) 3.88 (s, 3 H) 4.36 - 4.57 (m, 1 H) 4.90 - 5.00 (m, 1 H) 6.49 - 6.51 (d, J=7.58 Hz, 1 H) 6.99 - 7.01 (m, 2 H) 7.38 (s,

1 H) 7.70 (s, 1 H) 8.45 - 8.47 (br d, J=7.70 Hz, 1 H) 8.89 - 8.91 (br d, J=7.95 Hz, 1 H) 11.57 (br s, 1 H)

Example 8. Synthesis of viral protease inhibitor compound 593

Step 1: methyl (2S)-2-amino-3-(1H-imidazol-5-yl) propanoate [000238] To the solution of (2S)-2-(tert-butoxycarbonylamino)-3-(lH-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-(lH- imidazol-5-yl) propanoate (400 mg, crude, HC1) was obtained as a solid and used directly next step. MS (ESI) m/z 170.1 [M+H] ⁺

Step 2: methyl (2S)-3-(lH-imidazol-5-yl)-2-[[(2S)-2-[(4-methoxy-lH-indole-2 - carbonyl)amino ] -4-methyl-pentanoyl ] amino ]propanoate

[000239] To a mixture of (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoic acid (741.86 mg, 1.77 mmol, 1 eq, TFA) and methyl (2S)-2-amino-3-(lH- imidazol-5-yl)propanoate (0.3 g, 1.77 mmol, 1 eq, HC1), DIPEA (1.15 g, 8.87 mmol, 1.54 mL, 5 eq) in THF (0.3 mL) and DCM (0.3 mL) was added T3P (1.69 g, 2.66 mmol, 1.58 mL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. 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 washed with brine (3 mL * 3) and dried over anhydrous sodium sulfate and concentrated to get the crude product. Methyl (2S)-3-(lH-imidazol-5-yl)-2-[[(2S)-2-[(4-methoxy-lH-indole-2 - carbonyl)amino] -4-methyl-pentanoyl]amino]propanoate (300 mg, crude) was obtained as a solid and used directly next step. MS (ESI) m/z 456.2 [M+H] ⁺

[000240] 1H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.48 (s, 1 H), 7.27 (s, 1 H), 7.11 - 7.18 (m, 1 H), 7.02 (d ,J= 8.16 Hz, 1 H), 6.85 (s, 1 H), 6.51 (d ,J= 7.72 Hz, 1 H), 4.60 - 4.71 (m, 2 H), 3.93 (s, 3 H), 3.68 (s, 3 H), 3.00 - 3.17 (m, 3 H), 1.62 - 1.78 (m, 3 H), 0.97 (dd,J= 13.78, 6.06 Hz, 6 H)

Step 3: N-[(lS)-l-[[(lS)-2-amino- J-(JH-imidazol-5-ylmethyl)-2-oxo-ethyl]carbamoyl]-3- methyl-butyl ] -4-methoxy-lH-indole-2-carboxamide

[000241] To methyl (2S)-3-(lH-imidazol-5-yl)-2-[[(2S)-2-[(4-methoxy-lH-indole-2 - carbonyl)amino]-4-methyl-pentanoyl]amino]propanoate (200 mg, 439.07 umol, 1 eq) was added NH ₃ /MeOH (7 M, 11.76 mL, 187.56 eq) in one portion at 25 °C under N ₂ . 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-[( 1 S)- 1 -[[( 1 S)-2-amino- 1 -( 1 H- imidazol-5-ylmethyl)-2-oxo-ethyl]carbamoyl]-3-methyl-butyl]- 4-methoxy-lH-indole-2- carboxamide (170 mg, 378.83 umol, 86.28% yield, 98.16% purity) was obtained as a solid and used directly next step. MS (ESI) m/z 441.2 [M+H] ⁺

Step 4: N-f ( l S)-1-[[ ( l S)-l-cyano-2-( lH-imidazol-5-yl)ethyl] carbamoyl ]-3-methyl-butyl ]-4- methoxy- lH-indole-2-carboxamide

[000242] To a mixture of N-[( 1 S)- 1 -[[( 1 S)-2-amino- 1 -( 1 H-imidazol-5-ylmethyl)-2-oxo- ethyl]carbamoyl]-3- methyl-butyl]-4-methoxy-lH-indole-2-carboxamide (140 mg, 317.82 umol, 1 eq) in DCM (2 mL) was added TFAA (133.51 mg, 635.65 umol, 88.41 uL, 2 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to get the crude product. Crude product turned into compound 593 after 36 h in storage. The residue was purified by prep-HPLC. N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-( 1 H- imidazol-5-yl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH- indole-2-carboxamide (23.89 mg, 56.31 umol, 17.72% yield, 99.581% purity) was obtained as a solid. MS (ESI) m/z 423.2 [M+H] ⁺

Prep-HPLC condition: column: Waters Xbridge BEH C18 100*25mm*5 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )- ACN] ;B% : 25%-55%,10 min

[000243] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.58 (s, 1 H), 7.30 (s, 1 H), 7.12 - 7.21 (m, 1 H), 6.99 - 7.09 (m, 2 H), 6.52 (d ,J= 7.72 Hz, 1 H), 5.05 (t ,J= 7.06 Hz, 1 H), 4.61 (br dd ,J= 9.70, 4.85 Hz, 1 H), 3.94 (s, 3 H), 3.06 - 3.21 (m, 2 H), 1.60 - 1.83 (m, 3 H), 0.99 (dd,J= 13.89, 6.17 Hz, 6 H)

Step 5: tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoate

[000244] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (5 g, 26.15 mmol, 1 eq) and tert-butyl (2S)-2-amino-4-methyl-pentanoate (5.88 g, 31.38 mmol, 1.2 eq, HC1), EDCI (6.52 g, 34.00 mmol, 1.3 eq), HOBt (4.59 g, 34.00 mmol, 1.3 eq) in DMF (30 mL) was added TEA (7.94 g, 78.46 mmol, 10.92 mL, 3 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 2 h. The reaction mixture was added water (90 mL) and extracted with EtOAc (25 mL * 3) to get the organic phase. The organic phase was washed with 5% citric acid (25 mL) and 5% aqueous solution of sodium bicarbonate (25 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to get the product. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc= 30:1 to 10:1). Tert-butyl (2S)-2-[(4-methoxy- 1 H-indole- 2-carbonyl)amino]-4-methyl- pentanoate (5.93 g, 16.45 mmol, 62.91% yield) was obtained as a solid. MS (ESI) m/z 361.2 [M+H] ⁺

[000245] ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.25 (br s, 1 H), 7.10 - 7.16 (m, 1 H), 6.93 - 7.00 (m, 2 H), 6.56 (br d,J= 8.31 Hz, 1 H), 6.44 (d ,J= 7.70 Hz, 1 H), 4.66 (td, J= 8.50, 5.14 Hz, 1 H), 3.88 (s, 3 H), 1.62 - 1.75 (m, 2 H), 1.57 - 1.62 (m, 1 H), 1.42 (s, 9 H), 0.92 (dd, J = 6.17, 3.85 Hz, 6 H).

Step 6: (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)ammo]-4-methyl-penta noic acid [000246] To a mixture of tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoate (2.00 g, 5.55 mmol, 1 eq) in DCM (8 mL) was added TFA (10.27 g, 90.04 mmol, 6.67 mL, 16.23 eq) and H ₂ O (666.67 mg, 37.01 mmol, 666.67 uL, 6.67 eq) in one portion at 0 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 4 h. The reaction mixture was concentrated to get the crude product. (2S)-2-[(4-methoxy-lH- indole-2-carbonyl)amino]-4-methyl-pentanoic acid (2.24 g, 5.35 mmol, 96.50% yield, TFA) was obtained as a solid and used directly next step. MS (ESI) m/z 305.1 [M+H] ⁺

Example 9. Synthesis of viral protease inhibitor compounds 135, 595 and 136

Step 1: N-[ (1S)-1-[[(1 S)-l-(hydroxymethyl)-2-[(3S)-2-oxopyrrolidin-3-yl ] ethyl ] carbamoyl ]-

3-methyl -butyl ]-4-methoxy-lH-indole-2-carboxamide

[000247] To a mixture of methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4-methyl- pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.5 g, 2.86 mmol, 90% purity, 1 eq) in THF (20 mL) was added L1BH4 (124.45 mg, 5.71 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Once the reaction was completed, the reaction mixture was quenched by addition H ₂ O (10 mL) at 0 °C, and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue compound N-[(l S)-1-[[(l S)-1-(hydroxymethyl)-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3- methyl- butyl ]-4-methoxy- 1 H-indole-2-carboxamide (1.0 g, 2.25 mmol, 78.74% yield) was obtained as a solid. MS (ESI) m/z 445.1 [M+H] ⁺ . ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.27 (s, 1H), 7.19 - 7.10 (m, 1H), 7.02 (d, J=8.3 Hz,

1H), 6.51 (d, J=7.7 Hz, 1H), 4.65 - 4.53 (m, 1H), 4.05 - 3.97 (m, 1H), 3.93 (s, 3H), 3.60 - 3.43 (m, 2H), 3.27 - 3.10 (m, 2H), 2.59 - 2.43 (m, 1H), 2.39 - 2.19 (m, 1H), 2.08 - 1.89 (m, 1H), 1.85 - 1.63 (m, 4H), 1.60 - 1.46 (m, 1H), 1.00 (dd,J=6.1, 12.5 Hz, 6H).

Step 2: N-f (1S)-1-[[(1 S)-l -formyl-2- f(3S)-2-oxopyrrolidin-3-yl ] ethyl] carbamoyl ] -3-methyl- butyl ]-4- methoxy-lH-indole-2-carboxamide

[000248] To a mixture of N-[(1S)-1-[[(1S)-1-(hydroxymethyl)-2-[(3S)-2-oxopyrrolidin-3 - yl]ethyl]carbamoyl] -3-methyl-butyl]-4-methoxy-lH-indole-2-carboxamide (674 mg,

1.52 mmol, 1 eq) in DMSO (25 mL) was added IBX (849.14 mg, 3.03 mmol, 2 eq). The mixture was stirred at 25 °C for 15 h. Once the reaction was completed, the reaction mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (30 mL * 2). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was added ethyl acetate (10 mL) and filtered to give the product N-[(1S)-1-[[(1S)-1-formyl-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl] carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2- carboxamide (420 mg, 759.31 umol, 50.08% yield, 80% purity) as a solid. MS (ESI) m/z 443.1 [M+H] ⁺ . ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.27 (s, 1H), 7.20 - 7.09 (m, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.51 (d, J=7.7 Hz, 1H), 4.60 (dt, J=5.5, 9.9 Hz, 1.5H), 4.47 (dd,J=1.4, 4.1 Hz, 0.5H), 4.02 - 3.94 (m, 1H), 3.93 (s, 3H), 3.28 - 3.15 (m, 2H), 2.54 - 2.39 (m, 1H), 2.37 - 2.21 (m, 1H), 2.10 - 1.93 (m, 1H), 1.89 - 1.49 (m, 5H), 1.17 - 0.91 (m, 6H).

Step 3: N-f ( l S)-1-[[ ( l S)-2-cyano-2-hydroxy-l-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ] -3-methyl-butyl ]-4-methoxy-lH-indole-2-carboxamide

[0H0249] To a mixture of N-[(1S)-1-[[(1S)-1-formyl-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl -butyl]-4-methoxy-lH-indole-2-carboxamide (400 mg, 723.15 umol, 80% purity, 1 eq) in DCM (10 mL) was added saturated NaHSCh (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-l eq) in H ₂ O (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 Na ₂ SO ₄ , 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 HC1 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- 1 H-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-lH-indo le-2-carboxamide (64 mg, 131.75 umol, 18.22% yield, 96.66% purity) as a solid. MS (ESI) m/z 470.2[M+H] ⁺ . prep-HPLC condition: column: Phenomenex luna C1880*40 mm*3 um ;mobile phase: [water (0.04% HC1) - ACN];B%: 26%-50%,7min

SFC condition: column: REGIS (R,R) WHELK-01(25 0mm*25mm, 10 um);mobile phase: [Neu-IPA]; B%: 35%-35%,ll min

[000250] Compound 134 Isomer 1 : ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.57 (d, J=1.8 Hz, 1H), 8.40 (d, J=7.9 Hz, 1H), 8.13 (d, J=9.3 Hz, 1H), 7.57 (s, 1H), 7.36 (d, J=1.5 Hz, 1H), 7.13 - 7.06 (m, 1H), 7.03 - 6.97 (m, 1H), 6.69 (d, J=7.3 Hz, 1H), 6.50 (d, J=7.7 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.33 (t, J=7.8 Hz, 1H), 4.10 - 3.97 (m, 1H), 3.88 (s, 3H), 3.16 - 2.98 (m, 2H), 2.39 - 2.26 (m, 1H), 2.15 - 2.01 (m, 1H), 1.92 - 1.80 (m, 1H), 1.80 - 1.63 (m, 2H), 1.62 - 1.40 (m, 3H), 0.90 (dd, J=6.3, 15.5 Hz, 6H).

[000251] Compound 134 Isomer 2: ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.55 (br d, J=1.5 Hz, 1H), 8.35 (d, J=7.9 Hz, 1H), 8.21 (d, J=8.6 Hz, 1H), 7.60 (s, 1H), 7.34 (d, J=1.8 Hz, 1H), 7.12 - 7.06 (m, 1H), 7.03 - 6.97 (m, 1H), 6.64 (d, J=6.0 Hz, 1H), 6.50 (d, J=7.5 Hz, 1H), 4.60 - 4.49 (m, 2H), 4.12 - 3.96 (m, 1H), 3.88 (s, 3H), 3.19 - 2.98 (m, 2H), 2.41 - 2.26 (m, 1H), 2.16 - 1.95 (m, 2H), 1.92 - 1.35 (m, 5H), 0.98 - 0.82 (m, 6H).

Step 4: [(2S)-l-hydroxy-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl) amino]-4-methyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ] propyl ]sulfonyloxysodium

[000252] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- y 1 ]ethy 1 ]carbamoy 1 ]-3 -methyl- butyl]-4-methoxy-lH-indole-2-carboxamide (50 mg,

112.99 umol, 1 eq) in EtOH (0.4 mL), EtOAc (0.2 mL) and H ₂ O (0.1 mL) was added NaHSO3 (11.76 mg, 112.99 umol, 7.94 uL, 1 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. The residue was added DCM (3 mL) and ACN (3 mL), filtered to get the compound [(2S)-1-hydroxy-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4- methyl-pentanoyl] amino]-3-[(3 S)-2-oxopyrrolidin-3- yl]propyl]sulfonyloxysodium (5 mg, 5.26 umol, 4.66% yield, 57.5% purity) as a solid. (ESI) m/z 525.1 [M+H] ⁺

[000253] ¹ H NMR (400MHz, DMSO-d6) δ = 11.67 - 11.44 (m, 1H), 9.42 (s, 0.02H), 8.52 - 8.27 (m, 1H), 7.74 - 7.59 (m, 1H), 7.43 (s, 1H), 7.32 (dd, J=1.8, 4.9 Hz, 1H), 7.15 - 6.93 (m, 2H), 6.50 (d, J=7.7 Hz, 1H), 5.40 - 5.24 (m, 1H), 4.61 - 4.33 (m, 1H), 4.31 - 4.15 (m, 0.5H), 4.11 - 3.96 (m, 0.5H), 3.94 (dd,J=2.4, 5.7 Hz, 0.5H), 3.88 (s, 3H), 3.85 - 3.81 (m, 0.5H), 3.19 - 2.94 (m, 2H), 2.27 - 1.87 (m, 3H), 1.85 - 1.42 (m, 5H), 0.99 - 0.79 (m, 6H)

Step 5: 4-methoxy-N-[ ( l S)-3-methyl-l-[[(E, lS)-3-methylsulfonyl-l-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl / allyl ] carbamoyl ] butyl /- lH-indole-2-carboxamide

[000254] To a mixture of l-[ethoxy(methylsulfonylmethyl)phosphoryl]oxyethane (130.06 mg, 564.96 umol, 5 eq) in THF (2 mL) was added n-BuLi (2.5 M, 180.79 uL, 4 eq) at 0 °C under N ₂ . The mixture was stirred at -75 °C for 30 min, then added N-[(1S)-1- [[(1S)-1-formyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl] carbamoyl]-3-methyl-butyl]-4- methoxy-lH-indole-2-carboxamide (50 mg, 112.99 umol, 1 eq). The mixture was stirred at -75 °C for 2 h. Once the reaction was completed, the reaction mixture was quenched by addition H ₂ O (10 mL) at 0 °C, and then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to get the compound 4-methoxy-N- [(1S)-3 -methyl -1-[[(E,1S)-3-methylsulfonyl-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]allyl]carbamoyl]butyl]-lH-indole-2-carboxamide (15 mg, 28.82 umol, 25.50% yield, 99.638% purity) as a solid. (ESI) m/z 519.1 [M+H] ⁺ column: Phenomenex luna C18 80*40mm*3 um;mobile phase: [water(0.04%HCl)-ACN];B%: 26%-52%,7min

[000255] ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.33 - 7.26 (m, 1H), 7.20 - 7.10 (m, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.85 (dd,J=4.8, 15.3 Hz, 1H), 6.68 (dd,J=1.6, 15.3 Hz, 1H), 6.52 (d, J=7.7 Hz, 1H), 4.77 - 4.67 (m, 1H), 4.61 - 4.50 (m, 1H), 3.99 - 3.83 (m, 3H), 3.28 - 3.18 (m, 2H), 3.01 - 2.88 (m, 3H), 2.65 - 2.50 (m, 1H), 2.39 - 2.22 (m, 1H), 2.15 - 1.97 (m, 1H), 1.91 - 1.62 (m, 5H), 1.09 - 0.92 (m, 6H) Example 10. Synthesis of viral protease inhibitor compound 740 and 741

Step 7: tert-butyl ((S)-4-chloro-3-oxo-l-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)c arbamate [000256] 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. NaHCO ₃ (30 mL). The organic layers were washed dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc= 2: 1 to 0: 1) and then triturated with methyl tertiary butyl etherpetroleum ether = 4:1 (3 mL) to give tert-butyl N-[(1S)-3-chloro-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- y 1 ]methy 1 ]propy 1 ]carbamate (0.35 g, 1.03 mmol, 49.32% yield, 90% purity) as a solid.

MS (ESI) m/z 308.0 [M+H] ⁺ .

[000257] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.66 (br s, IH), 7.53 (br d,J= 7.7 Hz, IH), 4.61 (d, J= 2.2 Hz, 2H), 4.22 - 4.10 (m, IH), 3.21 - 3.11 (m, 2H), 2.34 - 2.06 (m, 2H), 1.93 - 1.80 (m, IH), 1.73 - 1.54 (m, 2H), 1.39 (s, 9H). Step 2: (S)-3-((S)-2-amino-4-chloro-3-oxobutyl)pyrrolidin-2-one

[000258] A solution of tert-butyl N-[(l S)-3-chloro-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]propyl]carbamate (0.33 g, 1.08 mmol, 1 eq) in HCl/EtOAc (4 M, 5 mL, 18.47 eq) was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (3S)-3-[(2S)-2-amino-4-chloro-3-oxo-butyl]pyrrolidin-2- one (0.3 g, crude, HC1) as an oil. MS (ESI) m/z 205.0 [M+H] ⁺ .

[000259] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.75 (br s, 3H), 7.97 (br s, 1H), 4.96 - 4.91 (m, 1H), 4.77 (s, 1H), 4.37 - 4.23 (m, 1H), 3.26 - 3.07 (m, 2H), 2.60 (br d , J= 8.6 Hz, 1H), 2.37 - 2.27 (m, 1H), 1.96 - 1.90 (m, 1H), 1.79 - 1.66 (m, 1H).

Step 3: N-((S)-l-(((S)-4-chloro-3-oxo-l-((S)-2-oxopyrrolidin-3-yl)bu tan-2-yl)amino)-4- methyl- 1 -oxopentan-2-yl)-4-methoxy- lH-indole-2-carboxamide

[000260| A solution of (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoic acid (416.53 mg, 1.37 mmol, 1.1 eq) in DMF (5 mL) was added HATU (946.18 mg, 2.49 mmol, 2 eq) and NMM (251.71 mg, 2.49 mmol, 273.59 uL, 2 eq), the solution was stirred at 0 °C for 0.5 h. Then a solution of (3S)-3-[(2S)-2-amino-4-chloro-3-oxo- butyl]pyrrolidin-2-one (0.3 g, 1.24 mmol, 1 eq, HC1) in DMF (5 mL) was added drop- wise at 0 °C. The reaction was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was diluted with water (50 mL) at 0 °C drop-wise and extracted with EtOAc (20 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc= 2:1 to 0:1). TogiveN-[(1S)-1-[[(1S)-3- chloro-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]car bamoyl]-3-methyl-butyl]- 4-methoxy-lH-indole-2-carboxamide (0.3 g, 549.92 umol, 44.20% yield, 90% purity) as a solid. MS (ESI) m/z 491.1 [M+H] ⁺ .

[000261 ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.58 (br s, 1H), 8.74 - 8.57 (m, 1H), 8.44 (br d,J= 5.0 Hz, 1H), 7.65 (br d, J= 4.5 Hz, 1H), 7.37 (br s, 1H), 7.15 - 7.06 (m, 1H), 7.01 (br d,J= 8.1 Hz, 1H), 6.50 (br d, J= 7.6 Hz, 1H), 4.75 - 4.60 (m, 1H), 4.59 - 4.55 (m, 1H), 4.44 (br d, J= 9.2 Hz, 2H), 3.88 (s, 3H), 3.13 - 3.01 (m, 2H), 2.34 - 2.18 (m, 1H), 2.09 (br dd,J= 2.5, 3.9 Hz, 1H), 1.99 - 1.90 (m, 1H), 1.78 - 1.49 (m, 5H), 0.97 - 0.81 (m, 6H). Step 4: (S)-3-( (S)-2-( 4-methoxy-lH-indole-2-carboxamido)-4-methylpentanamido)-2-ox o-4- ( (S)-2-oxopyrrolidin-3-yl)butyl 2-oxo-2-phenylacetate

[000262] To a solution of N-[( 1 S)- 1 -[[( 1 S)-3 -chloro-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]propyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-ind ole-2-carboxamide (0.25 g, 509.19 umol, 1 eq) in DMF (6 mL) was added benzoylformic acid (99.38 mg, 661.94 umol, 1.3 eq) and CsF (177.89 mg, 1.17 mmol, 43.18 uL, 2.3 eq). The reaction was stirred at 65 °C for 4 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give [(3S)-3- [[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl-pe ntanoyl]amino]-2-oxo-4- [(3S)-2-oxopyrrolidin-3-yl]butyl] 2-oxo-2-phenyl-acetate (0.3 g, crude) as an oil. MS (ESI) m/z 605.2 [M+H] ⁺ .

Step 5&6: N-[ (JR)-1-[[(JS) -3-hydroxy-2-oxo- 1-[[(3S) -2-oxopyrrolidin-3- yl ]methyl Ipropyl ] carbamoyl / -3-methyl-butyl ]-4-methoxy-lH-indole-2-carboxamide N-[ ( IS ')- 1-[[(1 S)-3-hydroxy-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ]propyl ] carbamoyl] -3- methyl-butyl]-4-methoxy-lH-indole-2-carboxamide

[000263] To a solution of [(3S)-3-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoyl]amino]-2-oxo-4-[(3S)-2-oxopyrrolidin-3-yl]b utyl] 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 (SiO ₂ , DCM:MeOH = 10:1) to give the product.

[000264] ¹ H NMR (400 MHz, DMSO-d6) δ = 11.58 (s, 1H), 8.50 (d ,J= 7.8 Hz, 1H), 8.41 (d,J= 7.9 Hz, 1H), 7.63 (s, 1H), 7.35 (d, J= 1.5 Hz, 1H), 7.14 - 7.05 (m, 1H), 7.04 - 6.94 (m, 1H), 6.50 (d ,J= 7.7 Hz, 1H), 5.05 - 4.98 (m, 1H), 4.57 - 4.46 (m, 1H), 4.41 (ddd, J = 4.0, 7.7, 11.2 Hz, 1H), 4.34 - 4.25 (m, 1H), 4.22 - 4.13 (m, 1H), 3.88 (s, 3H), 3.18 - 3.01 (m, 2H), 2.25 - 2.14 (m, 1H), 2.13 - 2.04 (m, 1H), 1.99 - 1.84 (m, 1H), 1.77 - 1.48 (m, 5H), 0.93 (br d ,J= 6.2 Hz, 3H), 0.89 (br d ,J= 6.4 Hz, 3H).

[000265] To give N-[(l S)-1-[[(l S)-3-hydroxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]propyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-ind ole-2-carboxamide (23.86 mg, 49.08 umol, 9.89% yield, 97.2% purity) as a solid. MS (ESI) m/z 473.2 [M+H] ⁺ . The product was separated by chiral-SFC (column: DAICEL CHIRALCEL OJ(250mm*30mm,10um);mobile phase: [Neu-MeOH];B%: 20%-20%, 15min) to give N- [( 1 R)- 1 -[[( 1 S)-3-hydroxy -2-oxo- 1-[[(3 S)-2-oxopyrrolidin-3- yl]methyl]propyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-ind ole-2-carboxamide (15.43 mg, 31.22 umol, 6.29% yield, 95.6% purity) as a solid. MS (ESI) m/z 473.2 [M+H] ⁺ .

[000266] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.57 (s, 1H), 8.45 (br d, J = 8.1 Hz, 1H), 8.41 (br d, J= 7.8 Hz, 1H), 7.62 (s, 1H), 7.36 (d, J= 1.3 Hz, 1H), 7.14 - 7.05 (m, 1H), 7.04 - 6.97 (m, 1H), 6.50 (d ,J= 7.6 Hz, 1H), 5.06 (br s, 1H), 4.62 - 4.38 (m, 2H), 4.30 - 4.19 (m, 1H), 4.19 - 4.09 (m, 1H), 3.88 (s, 3H), 3.19 - 3.01 (m, 2H), 2.37 - 2.22 (m, 1H), 2.09 (br dd,J = 3.2, 6.2 Hz, 1H), 1.99 - 1.86 (m, 1H), 1.80 - 1.43 (m, 5H), 0.94 (d, J= 6.2 Hz, 3H), 0.89 (d ,J= 6.2 Hz, 3H).

Example 11. Synthesis of viral protease inhibitor compound 143

Step J: methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)-2-ox opyrrolidin-3- yljpropanoate

[000267] 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-oxopyrrol idin-3-yl]propanoate (230 mg, crude) as an oil. MS (ESI) m/z 300.0 [M+H] ⁺ .

Step 2: methyl (2S)-2-[[(2S)-4-methyl-2-[[(E)-3-phenylprop-2-enoyl ] amino] pentanoyl ]amino J-3-[( 3S)-2-oxopyrrolidin-3-yl ]propanoate [000268] A mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)- 2-oxopyrrolidin-3-yl]propanoate (230 mg, 684.88 umol, 1 eq, HC1) and (E)-3- phenylprop-2-enoic acid (202.94 mg, 1.37 mmol, 162.35 uL, 2 eq) in DMF (2 mL) and DCM (4 mL), and added EDCI (262.59 mg, 1.37 mmol, 2 eq) and DMAP (167.34 mg, 1.37 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO ₂ , petroleum ether :EtOAc= 1 : 1) to get a product methyl (2S)-2-[[(2S)-4-methyl-2-[[(E)-3-phenylprop-2-enoyl]amino]pe ntanoyl]amino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (200 mg, 465.65 umol, 67.99% yield) as an oil. MS (ESI) m/z 430.1 [M+H] ⁺ .

Step 3: (2S)-N-[ ( l S)-2-amino-2-oxo-l-[[ ( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl ]-4-methyl-2- [[(E)-3-phenylprop-2-enoyl]amino]pentanamide

[000269] A mixture of methyl (2S)-2-[[(2S)-4-methyl-2-[[(E)-3-phenylprop-2- enoyl]amino]pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]pr opanoate (200 mg, 465.65 umol, 1 eq) in NH ₃ /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-phenylpr op-2- enoyl]amino]pentanamide (200 mg, crude) as an oil. MS (ESI) m/z 415.1 [M+H] ⁺ .

Step 4: (2S)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ]-4-methyl-2-[[(E)-3- phenylprop-2-enoyl ] amino ]pentanamide

[000270] A mixture of (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, 482.51 umol, 1 eq) in DCM (2 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (574.93 mg, 2.41 mmol, 5 eq), the mixture 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-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water(10 mM NH4HCO3)- ACN]; B%: 25% - 55%, 8min) to give a product (2S)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-4-methyl-2-[[(E)-3-phenylprop-2-en oyl]amino]pentanamide (23.1 mg, 58.26 umol, 12.07% yield, 100% purity) as a solid. MS (ESI) m/z 397.2 [M+H] ⁺ .

[000271] ¹ H NMR (400MHz, CDCl ₃ ) = 8.70 (br d, J=6.6 Hz, 1H), 7.66 - 7.55 (m, 1H), 7.54 - 7.44 (m, 2H), 7.35 (br s, 3H), 6.72 - 6.52 (m, 2H), 6.47 (d, J=15.7 Hz, 1H), 5.02 - 4.67 (m, 2H), 3.49 - 3.22 (m, 2H), 2.56 - 2.27 (m, 3H), 2.02 - 1.88 (m, 1H), 1.88 - 1.80 (m, 1H), 1.75 - 1.61 (m, 3H), 1.07 - 0.87 (m, 6H)

Example 12. Synthesis of viral protease inhibitor compound 598

Step 1: methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl ]amino]-3-[ ( 3S)-2-oxopyrrolidin-3- yljpropanoate

[000272] A mixture 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) was added HCl/EtOAc (4 M, 6 mL, 31.96 eq) at 25 °C for 1 h. Upon completion, the product blow-dried directly with N ₂ to get the product methyl (2S)-2-[[(2S)-2-amino-4- methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propano ate (260 mg, crude) as an oil. MS (ESI) m/z 300.1 [M+H] ⁺ .

Step 2: methyl (2S)-2-[[(2S)-2-[[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-eno yl]amino]-4-met hyl-pentanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000273] A mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)- 2-oxopyrrolidin-3-yl]propanoate (250 mg, 744.43 umol, 1 eq, HC1) and (E)-3-(4-chloro- 2-fluoro-phenyl)prop-2-enoic acid (298.66 mg, 1.49 mmol, 81.96 uL, 2 eq) in DMF (2 mL) and DCM (4 mL) was added EDCI (285.42 mg, 1.49 mmol, 2 eq) and DMAP (181.89 mg, 1.49 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO ₂ , petroleum ether :EtOAc= 0:1) to get a product methyl (2 S)-2-[[(2 S)-2-[ [(E)-3 -(4-chloro-2-fluoro-phenyl )prop-2-enoy 1 ]amino]- 4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propa noate (80 mg, 165.99 umol, 22.30% yield) as an oil. MS (ESI) m/z 482.1 [M+H] ⁺ .

Step 3: (2S)-N-[ ( l S)-2-amino-2-oxo-l-[[ ( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl ]-2-[[(E)-3-(4 -chloro-2-fluoro-phenyl)prop-2-enoyl]amino]-4-methyl-pentana mide

[000274] A mixture of methyl (2S)-2-[[(2S)-2-[[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2- enoyl]amino]-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolid in-3-yl]propanoate (70 mg, 145.25 umol, 1 eq) in NH ₃ /MeOH (7 M, 6 mL, 97% purity, 289.17 eq) was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product (2S)-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]amino]-4-methyl- pentanamide (70 mg, crude) as an oil. MS (ESI) m/z 467.1 [M+H] ⁺ .

Step 4: (2S)-2-[[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]amino] -N-[(lS)-l-cyano-2-[( 3S)-2-oxopyrrolidin-3-yl ] ethyl ]-4-methyl-pentanamide

[000275] A mixture of (2S)-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]amino]-4-methyl- pentanamide (70 mg, 149.91 umol, 1 eq) in DCM (1.5 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (160.77 mg, 674.62 umol, 4.5 eq), the mixture 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-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water(10 mM NH4HCO3)- ACN] ; B%: 30%-60%, 8min) to get product (2S)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-4-methyl-2-[[(E)-3-phenylprop-2-en oyl]amino]pentanamide (13.4 mg, 58.26 umol, 12.07% yield, 100% purity) as a solid. MS (ESI) m/z 449.1 [M+H] ⁺ . [000276] ¹ H NMR (400MHz, CDCl ₃ ) δ = 8.67 (br d, J=5.7 Hz, 1H), 7.63 (d, J=15.7 Hz, 1H), 7.42 (t, J=8.3 Hz, 1H), 7.19 - 7.06 (m, 2H), 6.55 (d, J=15.7 Hz, 1H), 6.34 (br s, 1H), 6.19 (br s, 1H), 4.83 - 4.67 (m, 2H), 3.47 - 3.33 (m, 2H), 2.58 - 2.28 (m, 3H), 2.04 (br s, 1H), 1.95 - 1.82 (m, 1H), 1.81 - 1.62 (m, 3H), 0.99 (d, J=6.0 Hz, 6H)

Example 13. Synthesis of viral protease inhibitor compound 149

Step J: methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate [000277] 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] ⁺

Step 2: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-2-indan-2-yl-acet yl]amino]-3- [ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate [000278] To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (190 mg, 1.02 mmol, 1 eq) and (2S)-2-(tert-butoxycarbonylamino)-2-indan-2-yl-acetic acid (297.27 mg, 1.02 mmol, 1 eq) in DCM (9 mL) and DMF (3 mL) was added DMAP (249.31 mg, 2.04 mmol, 2 eq) and EDCI (391.21 mg, 2.04 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Once the reaction was completed, the reaction was poured into ice-water (30 mL) and extracted with EtOAc (20 mL*3). The combined organic phase was dried with anhydrous Na ₂ SO ₄ filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100- 200 mesh silica gel, petroleum ether/EtOAc=l/l, 0/1) to give methyl (2S)-2-[[(2S)-2- (tert-butoxycarbonylamino)-2-indan-2-yl-acetyl]amino]-3-[(3S )-2-oxopyrrolidin-3- yl]propanoate (300 mg, 522.27 umol, 51.18% yield, 80% purity) (solid). MS (ESI) m/z 460.3 [M+H] ⁺

Step 3: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-2-indan-2-yl-acet yl]amino]-3- [ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000279] 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-ox opyrrolidin-3- yl Jpropanoate (330 mg, crude) was obtained as an oil and used directly next step. MS (ESI) m/z 360.2 [M+H] ⁺

Step 4: methyl (2S)-2-[[(2S)-2-amino-2-indan-2-yl-acetyl ]amino]-3-[ ( 3S)-2-oxopyrrolidin-3- yljpropanoate

[000280] To a mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-2-indan-2- yl-acetyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 652.84 umol, 1 eq) and 4-methoxy- 1 H-indole-2-carboxylic acid (149.77 mg, 783.40 umol, 1.2 eq) in DCM (6 mL) and DMF (2 mL) was added DMAP (159.51 mg, 1.31 mmol, 2 eq) and EDCI (250.30 mg, 1.31 mmol, 2 eq). The mixture was stirred at 25 °C and stirred for 2 h. Once the reaction was completed, the reaction was poured into ice-water (30 mL) and extracted with ethyl acetate (20 mL*3). The combined organic phase was dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether/ethyl acetate=l/l, 0/1) to give methyl (2S)-2-[[(2S)-2-amino-2-indan-2- yl-acetyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 506.96 umol, 77.66% yield, 90% purity) (solid). MS (ESI) m/z 533.2 [M+H] ⁺

Step 5: N-f (lS)-l-[[( IS)- 2-amino-1-[(3-methylimidazol-4-yl)methyl]-2-oxo- ethyl ] carbamoyl ]-3- methyl-butyl ]-4-methoxy-lH-indole-2-carboxamide

[000281] To a mixture of (S)-methyl 2-((S)-2-(2,3-dihydro-lH-inden-2-yl)-2-(4-methoxy- lH-indole-2-carboxamido)acetamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (100 mg, 187.76 umol, 1 eq) was added ammonia (3.20 mg, 187.76 umol, 3.13 uL, 1 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 N-((S)-2-(((S)-l -amino- l-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)amino)-1-(2,3-dihydro-lH-inde n-2-yl)-2-oxoethyl)-4- methoxy- 1 H-indole-2-carboxamide (70 mg, 108.20 umol, 57.62% yield, 80% purity) as a solid. Crude product was used directly without further purification. MS (ESI) m/z 518.2 [M+H] ⁺

Step 6: N-f ( l S)-2-[[( 1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl] amino] -l-indan-2-yl-2- oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide

[000282] To a mixture of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-indan-2-yl-2-oxo-ethyl]-4-methoxy-l H-indole-2-carboxamide (60 mg, 115.93 umol, 1 eq) and methoxycarbonyl-(triethylammonio)sulfonyl-azanide (55.25 mg, 231.85 umol, 2 eq) in DCM (0.5 mL). The mixture was stirred at 25 °C and stirred for 2 h. Once the reaction was completed, the reaction was poured into ice-water (30 mL) and extracted with DCM (20 mL*3). The combined organic phase was dried with anhydrous Na ₂ SO ₄ filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [water(10Mm NH ₄ HCO ₃ )-ACN];B%: 20%-50%,8min) to give N-[(1S)-2-[[(1S)-1-cyano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-indan-2-yl-2-oxo -ethyl]-4-methoxy-lH- indole-2-carboxamide (23.83 mg, 47.70 umol, 41.15% yield, 100% purity) (solid). MS (ESI) m/z 500.3 [M+H] ⁺ .

[000283] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.26 (s, 1 H), 7.13- 7.17 (m, 2 H), 7.11- 7.12 (m, 3 H), 7.03 (s, 1 H), 6.55- 6.52 (d, J=12.4 Hz, 1 H), 5.05- 5.01 (m, 1 H), 4.85- 5.00 (m, 1 H), 3.92 (s, 3 H), 3.25- 3.26 (m, 3 H), 3.21- 3.24 (m, 2 H), 2.90- 3.01 (m, 2 H), 2.88- 2.89 (m, 1 H), 2.31- 3.33 (m, 2 H), 1.81- 1.92 (m, 2 H)

Example 14. Synthesis of viral protease inhibitor compound 165

Step 1: methyl (2S)-2-amino-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate; hydrochloride [000284] 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.

Step 2:

(2S,4R)-(9H-fluoren-9-yl)methyl-4-(tert-butoxy)-2-(((S)-l -methoxy-l-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)pyrrolidine-l-carbo xylate

[000285] A mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (190 mg, 853.29 umol, 1 eq, HC1), (2S,4R)-4-tert-butoxy-1-(9H-fluoren-9- ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid (349.40 mg, 853.29 umol, 1 eq), EDCI (327.15 mg, 1.71 mmol, 2 eq), DMAP (208.49 mg, 1.71 mmol, 2 eq), DMF (3 mL) and DCM (6 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc= 0/1) to get the product (2S,4R)-(9H-fluoren-9-yl)methyl-4-(tert-butoxy)-2- (((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-y l)carbamoyl)pyrrolidine-1- carboxylate (230 mg, 319.96 umol, 37.50% yield, 80.36% purity), as an oil. MS (ESI) m/z 578.2 [M+H] ⁺

Step 3: (S)-methyl-2-((2S, 4R)-4-(tert-butoxy)pyrrolidine-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate

[000286] A mixture of (2S,4R)-(9H-fluoren-9-yl)methyl-4-(tert-butoxy)-2-(((S)-1- methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbam oyl)pyrrolidine-1- carboxylate (170 mg, 294.29 umol, 1 eq), piperidine (3.76 g, 8.83 mmol, 4.36 mL, 20% purity, 30 eq), DMF (1 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (DCM/MeOH = 10/1) to get the product (S)-methyl-2-((2S,4R)-4-(tert- butoxy)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-y l)propanoate (40 mg,

112.54 umol, 38.24% yield) as an oil.

Step 4: (S)-methyl-2-((2S, 4R)-4-(tert-butoxy)-l-(4-methoxy-lH-indole-2- carbonyl)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3 -yl)propanoate

[000287] A mixture of (S)-methyl-2-((2S,4R)-4-(tert-butoxy)pyrrolidine-2-carboxami do)- 3-((S)-2-oxopyrrolidin-3-yl)propanoate (40 mg, 112.54 umol, 1 eq), 4-methoxy-lH- indole-2-carboxylic acid (21.52 mg, 112.54 umol, 1 eq), EDCI (43.15 mg, 225.08 umol, 2 eq), DMAP (27.50 mg, 225.08 umol, 2 eq), DMF (0.5 mL) and DCM (1 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc= 0/1) to get the compound (S)-methyl-2-((2S,4R)-4-(tert-butoxy)- 1 -(4-methoxy- 1 H-indole-2- carbonyl)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3 -yl)propanoate (30 mg, 22.33 umol, 19.84% yield), as an oil. Step 5: (2S, 4R)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-4-(tert- butoxy)-l-(4-methoxy-lH-indole-2-carbonyl)pyrrolidine-2-carb oxamide [000288] A mixture of (S)-methyl-2-((2S,4R)-4-(tert-butoxy)- 1 -(4-methoxy- 1 H-indole-2- carbonyl)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3 -yl)propanoate (27 mg, 20.10 umol, 39.35% purity, 1 eq) and NH ₃ /MeOH (7 M, 3 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a product (2S,4R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)pro pan-2-yl)-4-(tert-butoxy)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)py rrolidine-2-carboxamide (22 mg, crude) as a solid. MS (ESI) m/z 514.2 [M+H] ⁺

Step 6: (2S,4R)-4-(tert-butoxy)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidi n-3-yl)ethyl)-l-(4- methoxy-lH-indole-2-carbonyl)pyrrolidine-2-carboxamide

[000289] A mixture of (2S,4R)-N-((S)- 1 -amino-1 -oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-4-(tert-butoxy)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)pyrrolidine-2- carboxamide (20 mg, 38.94 umol, 1 eq), Burgess reagent (27.84 mg, 116.83 umol, 3 eq) and DCM (1 mL) 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 (column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(0.05%NH3H ₂ 0+ 1 OmM NH4HCO3)- ACN] ;B% : 20%-40%,8min) to get the product (2S,4R)-4-(tert-butoxy)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidi n-3-yl)ethyl)-1-(4-methoxy- lH-indole-2-carbonyl)pyrrolidine-2-carboxamide (5 mg, 10.09 umol, 25.91% yield,

100% purity), as a solid. MS (ESI) m/z 496.3 [M+H] ⁺ .

[000290] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.73 - 11.43 (m, 1H), 9.26 - 8.84 (m, 1H), 7.84 - 7.49 (m, 1H), 7.19 - 7.07 (m, 1H), 7.05 - 6.96 (m, 1H), 6.94 - 6.65 (m, 1H), 6.57 - 6.41 (m, 1H), 5.08 - 4.92 (m, 1H), 4.85 - 4.40 (m, 2H), 4.34 - 4.08 (m, 1H), 3.98 - 3.75 (m, 3H), 3.74 - 3.50 (m, 1H), 3.22 - 2.80 (m, 2H), 2.47 - 2.37 (m, 1H), 2.27 - 2.04 (m, 3H), 2.03 - 1.87 (m, 1H), 1.86 - 1.36 (m, 2H), 1.15 (s, 9H)

Example 15. Synthesis of viral protease inhibitor compound 167

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000291 ] Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (300 mg, 1.05 mmol, 1 eq) in HCl/EtOAc (4 M, 5 mL, 19.09 eq) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressure affording the product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (HC1 salt, 210 mg, crude) as a solid.

Step 2: (2S,4S)-(9H-fluoren-9-yl)methyl4-cyclohexyl-2-(((S)-l-methox y-l-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)pyrrolidine-l-carbo xylate [000292] Methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 1.07 mmol, 1 eq) and (2S,4S)-4-cyclohexyl-1-(9Hfluoren-9-ylmethoxycarbonyl)pyrrol idine-2- carboxylic acid (450.58 mg, 1.07 mmol, 1 eq) in DMF (1 mL) and DCM (2 mL) was added DMAP (262.43 mg, 2.15 mmol, 2 eq) and EDCI (411.80 mg, 2.15 mmol, 2 eq). The mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (10 mL), and then extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc= 5:1 to 1:1) affording the product 9H-fluoren-9-ylmethyl (2S,4S)-4-cyclohexyl-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)- 2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]pyrrolidine-1-ca rboxylate (500 mg, 850.77 umol, 79.21% yield) as a solid. MS (ESI) m/z 588.3 [M+H] ⁺

Step 3: (S)-methyl2-((2S, 4S)-4-cyclohexylpyrrolidine-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate

[000293] 9H-fluoren-9-ylmethyl (2S,4S)-4-cyclohexyl-2-[[( 1S)-2-methoxy-2-oxo- 1 - [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]pyrrolidi ne-1-carboxylate (480 mg, 816.74 umol, 1 eq) in DMF (4 mL) and PIPERIDINE (862.20 mg, 10.13 mmol, 1 mL, 12.40 eq) was stirred at 25 °C for 0.5 h. Upon completion, the mixture was drying with N ₂ and then diluted with DCM (10 mL), concentrated under the reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) affording the product methyl (2S)-2-[[(2S,4S)-4-cyclohexylpyrrolidine-2-carbonyl]amino]-3 - [(3 S)- 2-oxopyrrolidin-3-yl]propanoate (210 mg, 574.61 umol, 70.35% yield) as a solid.

Step 4: (S)-methyl2-((2S, 4S)-4-cyclohexyl-l -(4-methoxy- lH-indole-2-carbonyl)pyrrolidine-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000294] Methyl(2S)-2-[[(2S,4S)-4-cyclohexylpyrrolidine-2-carbonyl]am ino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (200 mg, 547.25 umol, 1 eq) and 4-methoxy- 1H-indole-2- carboxylic acid (104.62 mg, 547.25 umol, 1 eq) in DMF (2 mL) and DCM (3 mL) was added DMAP (133.71 mg, 1.09 mmol, 2 eq) and EDCI (209.82 mg, 1.09 mmol, 2 eq).

The mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (10 mL), and then extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether:EtOAc= 0:1) affording the product methyl(2S)-2- [[(2S,4S)-4-cyclohexyl- 1 -(4-methoxy- 1H-indole-2 -carbonyl)pyrrolidine-2- carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (210 mg, 389.88 umol, 71.24% yield) as a solid. MS (ESI) m/z 539.2 [M+H] ⁺

Step 5: (2S,4S)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)pro pan-2-yl)-4-cyclohexyl- 1 -(4-methoxy- lH-indole-2-carbonyl)pyrrolidine-2-carboxamide

[000295] Methyl(2S)-2-[[(2S,4S)-4-cyclohexyl- 1 -(4-methoxy-/H-indole-2- carbonyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxopyrrolid in-3-yl]propanoate (200 mg, 371.31 umol, 1 eq) was in NH ₃ /MeOH (7 M, 10 mL, 188.52 eq). The mixture was stirred at 80 °C for 16 h. Upon completion, the mixture was concentrated under the reduced pressure affording the product (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]-4-cyclohexyl- 1 -(4-methoxy- l/fmdole-2- carbonyl)pyrrolidine-2-carboxamide (110 mg, crude) as a solid. MS (ESI) m/z 524.2 [M+H] ⁺

Step 6: (2S,4S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-4- cyclohexyl-l -(4-methoxy- lH-indole-2-carbonyl)pyrrolidine-2-carboxamide

[000296] (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl] methyl]ethyl]-4- cyclohexyl-1 -(4-methoxy- 1H-indole-2-carbonyl)pyrrolidine-2-carboxamide (100 mg, 190.98 umol, 1 eq) in DCM (1 mL) was added methoxy carbonyl - (triethylammonio)sulfonyl-azanide (227.55 mg, 954.89 umol, 5 eq). The mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (lOmM NH4HCO3) - ACN]; B%: 30% - 60%, lOmin) affording the product (2S,4S)-N-[( 1 S)- 1 -cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-4-cyclohexyl-1-(4-methoxy -1H-indole-2-carbonyl)pyrrolidine- 2-carboxamide (30.7 mg, 60.17 umol, 31.51% yield, 99.1% purity) as a solid. MS (ESI) m/z 506.3 [M+H] ⁺

[000297] 1 H NMR (400 MHz, MeOD-d ₄ ) δ = 7.23 - 6.82 (m, 3H), 6.60 - 6.36 (m, 1H), 5.21 - 4.96 (m, 1H), 4.72 - 4.56 (m, 1H), 4.34 - 4.07 (m, 1H), 4.00 - 3.80 (m, 3H), 3.57 (br t ,J= 9.4 Hz, 1H), 3.02 - 2.54 (m, 1H), 2.46 - 0.92 (m, 20H)

Example 16. Synthesis of viral protease inhibitor compound 209

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate [000298] A mixture of methyl (2 S)-2-(tert-butoxy carbonyl amino)-3 -[(3 S)-2- oxopyrrolidin-3-yl]propanoate (0.55 g, 1.92 mmol, 1 eq) and HCl/EtOAc (4 M, 10 mL, 20.82 eq) was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin- 3-yl)propanoate (0.35 g, crude) as an oil.

Step 2: (2S,4S)-tert-butyl 2-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 - yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate

[000299] A mixture of (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (0.15 g, 805.55 umol, 1 eq), (2S,4S)-1-tert-butoxycarbonyl-4-phenyl-pyrrolidine-2-carboxy lic acid (234.69 mg, 805.55 umol, 1 eq), DMAP (196.83 mg, 1.61 mmol, 2 eq), EDCI (308.85 mg, 1.61 mmol, 2 eq) in DMF (1 mL) and DCM (2 mL) was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc= 2: 1 to 0: 1) to give (2S,4S)-tert-butyl 2-[[(l S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-4-phenyl-pyrrolidine-1-carboxylat e (0.25 g, 500.51 umol, 62.13% yield, 92% purity) as a colorless oil. MS (ESI) m/z 460.1 [M+H] ⁺ .

Step 3: (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((2S,4S)-4-phenylpyrrolidine- 2- carboxamido)propanoate [000300] A mixture of tert-butyl (2S,4S)-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-4-phenyl-pyrrolid ine- 1 -carboxylate (0.25 g, 544.03 umol, 1 eq) and HCl/EtOAc (4 M, 10 mL, 73.53 eq) was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2S)-3-[(3S)-2-oxopyrrolidin-3-yl]-2-[[(2S,4S)-4-phenylpyrro lidine-2- carbonyl]amino]propanoate (0.2 g, crude) as an oil. MS (ESI) m/z 360.1 [M+H] ⁺ .

Step 4: (S)-methyl 2-((2S,4S)-l-((E)-3-(4-chloro-2-fluorophenyl)acryloyl)-4- phenylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl )propanoate [000301] A mixture of methyl (2S)-3-[(3 S)-2-oxopyrrolidin-3-yl]-2-[[(2S,4S)-4- phenylpyrrolidine-2-carbonyl]amino]propanoate (0.17 g, 472.99 umol, 1 eq), (E)-3-(4- chloro-2-fluoro-phenyl)prop-2-enoic acid (94.88 mg, 472.99 umol, 1 eq), T3P (451.48 mg, 709.48 umol, 421.95 uL, 50% purity, 1.5 eq), TEA (143.58 mg, 1.42 mmol, 197.50 uL, 3 eq) in DMF (4 mL) was degassed stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc= 2:1 to 0:1) to give 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 (0.11 g, 162.36 umol, 34.33% yield, 80% purity) as a solid. MS (ESI) m/z 542.1 [M+H] ⁺ .

Step 5: (2S, 4S)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-l-((E)-3-(4- chloro-2-fluorophenyl)acryloyl)-4-phenylpyrrolidine-2-carbox amide

[000302] 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-ox opyrrolidin-3- yl]propanoate (0.1 g, 184.50 umol, 1 eq) in NH ₃ /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-e noyl]-4-phenyl-pyrrolidine- 2-carboxamide (0.09 g, crude) as a yellow oil. MS (ESI) m/z 527.0 [M+H] ⁺ .

Step 6: (2S, 4S)-1-( (E)-3-( 4-chloro-2-fluorophenyl)acryloyl)-N-( (S)-l-cyano-2-( (, S)-2 - oxopyrrolidin-3-yl)ethyl)-4-phenylpyrrolidine-2-carboxamide [000303] To a solution of (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-e noyl]-4-phenyl-pyrrolidine- 2-carboxamide (0.09 g, 170.78 umol, 1 eq) in DCM (1 mL) was added Burgess reagent (203.50 mg, 853.91 umol, 5 eq), the solution 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-HPLC (column: Waters Xbridge BEH C18 100*25mm*5um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,10min) to give (2S,4S)-1-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]-N-[ (l S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-phenyl-pyrrolidine-2-car boxamide (29.73 mg, 56.89 umol, 33.31% yield, 97.4% purity) as a solid. MS (ESI) m/z 509.1 [M+H] ⁺ .

[000304] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.17 - 8.86 (m, 1H), 8.07 - 7.75 (m, 1H), 7.75 - 7.65 (m, 1H), 7.62 - 7.49 (m, 2H), 7.48 - 7.30 (m, 5H), 7.26 (tt, J= 3.0, 5.6 Hz, 1H), 7.22 - 6.73 (m, 1H), 5.09 - 4.83 (m, 1H), 4.69 - 4.47 (m, 1H), 4.40 - 4.01 (m, 1H), 3.77 - 3.50 (m, 3H), 3.19 - 3.04 (m, 2H), 2.44 - 2.31 (m, 2H), 2.22 - 2.09 (m, 2H), 1.88 - 1.59 (m, 2H).

Example 17. Synthesis of viral protease inhibitor compound 183

Step 1: methyl (2S)-2-amino-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate; hydrochloride [000305] Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3- yl Jpropanoate (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 Jpropanoate: HCI (230 mg, crude) as an oil and used directly for next step.

Step 2:

(S)-tert-butyl 5-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 -yl)carbamoyl)- 6-azaspiro[ 2.5 ]octane-6-carboxylate [ [000000330066]] A mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (230 mg, 1.03 mmol, 1 eq, HCI), (7S)-6-tert-butoxycarbonyl-6-azaspiro[2.5]octane-7- carboxylic acid (263.72 mg, 1.03 mmol, 1 eq), T3P (657.31 mg, 2.07 mmol, 614.31 uL, 2 eq), EtsN (522.60 mg, 5.16 mmol, 718.85 uL, 5 eq) and DMF (5 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc= 0/1) to get the product (S)-tert-butyl 5-(((S)- 1 -methoxy- 1 -oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (300 mg, 708.38 umol, 68.58% yield), as yellow oil. MS (ESI) m/z 424.1 [M+H] ⁺

Step 3: (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-6-azaspiro[2.5]octane-5- carboxamido)propanoate [000307] A mixture of (S)-tert-butyl 5-(((S)-l -methoxy- 1 -oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylat e (290 mg, 684.77 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 3-((S)-2-oxopyrrolidin- 3-yl)-2-((S)-6-azaspiro[2.5]octane-5-carboxamido)propanoate (240 mg, crude, HC1) as a an oil and used directly for next step.

Step 4: (S)-methyl 2-((S)-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspiro[2.5]oct ane-5- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000308] A mixture of (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-6- azaspiro[2.5]octane-5-carboxamido)propanoate (240 mg, 666.95 umol, 1 eq, HC1), 4- methoxy-lH-indole-2-carboxylic acid (127.51 mg, 666.95 umol, 1 eq), DMAP (162.96 mg, 1.33 mmol, 2 eq), EDCI (255.71 mg, 1.33 mmol, 2 eq), DMF (2 mL) and DCM (4 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc= 0/1) to get the compound (S)-methyl 2-((S)-6-(4-methoxy-lH-indole-2- carbonyl)-6-azaspiro[2.5]octane-5-carboxamido)-3-((S)-2-oxop yrrolidin-3-yl)propanoate (150 mg, 275.74 umol, 41.34% yield, 91.28% purity) as an oil. MS (ESI) m/z 495.2 [M-

H] ^"

Step 5: (S)-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspiro[2.5]octane -5-carboxylic acid [000309] A mixture of (S)-methyl 2-((S)-6-(4-methoxy-lH-indole-2-carbonyl)-6- azaspiro[2.5]octane-5-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate, LiOH (24.12 mg, 1.01 mmol, 5 eq), H ₂ O (1 mL) and THF (4 mL) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a product (S)-6-(4- methoxy- 1 H-indole-2-carbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid (65 mg, crude) as a solid. MS (ESI) m/z 327.1 [M-H] ^"

Step 6: tert-butyl ((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidm-3-yl)propan-2-yl)ca rbamate [000310] A mixture of methyl (2 S)-2-(tert-butoxy carbonyl amino)-3 -[(3 S)-2- oxopyrrolidin-3-yl]propanoate (400 mg, 1.40 mmol, 1 eq) and NH ₃ /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)-l -amino- l-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamate (380 mg, crude) as a solid.

Step 7: (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide

[000311] 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.

Step 8: (S)-N-( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6-( 4-methoxy-lH- indole-2-carbonyl)-6-azaspiro[2.5Joctane-5-carboxamide

[000312] A solution of (S)-6-(4-m ethoxy- 1 H-indole-2-carbonyl)-6-azaspiro[2.5]octane-5- carboxylic acid (65 mg, 197.95 umol, 1 eq), (S)-2-amino-3-((S)-2-oxopyrrolidin-3- yl)propanamide (33.89 mg, 197.95 umol, 1 eq), DMAP (48.37 mg, 395.91 umol, 2 eq), EDCI (75.90 mg, 395.91 umol, 2 eq), DMF (1 mL) and DCM (3 mL) was stirred at 25 °C for 16 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini -NX C18 75*30mm*3um;mobile phase: [water(0.05%NH3H ₂ O+ 1 OmM NH ₄ HCO3)- ACN] ;B% : 10%-40%,8min) to get the compound (S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin- 3-yl)propan-2-yl)-6-(4-methoxy-lH-indole-2-carbonyl)-6-azasp iro[2.5]octane-5- carboxamide (45 mg, 79.43 umol, 40.13% yield, 85% purity) as a solid. MS (ESI) m/z 480.2 [M-H ]- Step 9: (S)-N-( ( S)-l-cyano-2-( (S)-2-oxopyrrolidin-3-yl)ethyl)-6-( 4-methoxy- lH-indole-2- carbonyl)-6-azaspiro[2.5]octane-5-carboxamide

[000313] A mixture of (S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2- yl)-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspiro[2.5]octane -5-carboxamide (40 mg, 83.07 umol, 1 eq), Burgess reagent (237.55 mg, 996.80 umol, 12 eq) and DCM (20 mL) was stirred at 25 °C for 8 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [ water(0.05%NH3H ₂ O+ 1 OmM NH4HCO3)- ACN] ;B% : 20%-40%,8min) to get the product (S)-N-((S)-1-cyano-2-((S)-2- oxopyrrolidin-3-yl)ethyl)-6-(4-methoxy-lH-indole-2-carbonyl) -6-azaspiro[2.5]octane-5- carboxamide (17 mg, 34.79 umol, 41.89% yield, 94.87% purity), as a solid. MS (ESI) m/z 462.2 [M-H ]·.

[000314] ¹ H NMR (400MHz, DMSO-4) δ = 11.64 (s, 1H), 9.26 - 8.52 (m, 1H), 7.87 - 7.61 (m, 1H), 7.18 - 7.07 (m, 1H), 7.06 - 6.96 (m, 1H), 6.85 - 6.60 (m, 1H), 6.51 (d, 1H), 5.30 - 4.93 (m, 2H), 4.61 - 4.41 (m, 1H), 3.85 (s, 3H), 3.21 - 2.96 (m, 2H), 2.39 - 2.03 (m, 5H), 1.96 - 1.56 (m, 4H), 0.99 (d, 1H), 0.45 - 0.15 (m, 4H)

Example 18. Synthesis of viral protease inhibitor compound 185

Step 1: (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropcmamid o)-3-((S)- 2-oxopyrrolidin-3-yl)propanoate

[000315] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (170 mg, 763.47 umol, 1 eq, HC1) 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. The reaction mixture was quenched by addition H ₂ O (30 mL) at 0 °C, and then extracted with DCM (20 mL * 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , 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] ⁺

Step 2: (S)-methyl 2-((S)-2-amino-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolid in-3- yl)propanoate

[000316] 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, HC1) was obtained as a solid and used directly next step. MS (ESI) m/z 340.1 [M+H] ⁺

Step 3: ((S)-methyl 2-((S)-3-cyclohexyl-2-(4-methoxy-lH-indole-2- carboxamido)propanamido)-3-((S)-2-oxopyrrolidin-3-yl)propano ate

[000317] A solution of 4-methoxy-lH-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, HC1) 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 H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 1 :0 to 10: 1) to get a product methyl (2S)-2-[[(2S)-3-cyclohexyl-2-[(4-methoxy-lH-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.

[000318] ¹ H NMR (METHANOL-d ₄ , 400 MHz): δ ppm 7.26 (s, 1H), 7.09-7.20 (m, 1H),

7.02 (d,J= 8.3 Hz, 1H), 6.51 (d, J= 7.6 Hz, 1H), 4.66 (br dd, J = 9.0, 6.3 Hz, 1H), 4.52- 4.58 (m, 1H), 3.93 (s, 3H), 3.72 (s, 3H), 3.22-3.29 (m, 2H), 2.54-2.62 (m, 1H), 2.26-2.33 (m, 1H), 2.15-2.23 (m, 1H), 1.66-1.87 (m, 9H), 1.47-1.54 (m, 1H), 1.25-1.40 (m, 3H), 0.96-1.06 (m, 2H)

Step 4: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3- cyclohexyl-l-oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxami de

[000319] To a solution of methyl (2S)-2-[[(2S)-3-cyclohexyl-2-[(4-methoxy-lH-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- lH-indole-2-carboxamide (140 mg, crude) was obtained as a solid. MS (ESI) m/z 498.2 [M+H] ⁺

[000320] ¹ H NMR (METHANOL-d ₄ , 400 MHz): δ ppm 7.27-7.34 (m, 1H), 7.13-7.20 (m, 1H), 7.05 (d,J= 8.3 Hz, 1H), 6.53 (d, J= 7.7 Hz, 1H), 4.62 (t, J= 7.6 Hz, 1H), 4.42-4.51 (m, 1H), 3.95 (s, 3H), 3.22-3.30 (m, 2H), 2.53 (td, J= 9.2, 4.5 Hz, 1H), 2.33 (ddd, J=

9.2, 6.4, 3.4 Hz, 1H), 2.17 (ddd, J= 14.1, 11.4, 4.6 Hz, 1H), 1.71-1.88 (m, 9H), 1.46-1.53 (m, 1H), 1.21-1.32 (m, 3H), 0.97-1.09 (m, 2H)

Step 5: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)ammo)-3- cyclohexyl-l-oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxami de

[000321] 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-m ethoxy-lH-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-e thyl]-4-methoxy-lH- 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] ⁺ .

Prep-HPLC condition: column: Waters Xbridge BEH C18 100*25mm*5um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,10min

[000322] ¹ H NMR (METHANOL-d ₄ , 400 MHz): δ ppm 7.28 (s, 1H), 7.11-7.18 (m, 1H),

7.02 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 5.05 (dd, J = 10.1, 5.9 Hz, 1H), 4.56- 4.61 (m, 1H), 3.93 (s, 3H), 3.22-3.30 (m, 2H), 2.55-2.66 (m, 1H), 2.23-2.40 (m, 2H), 1.65-1.94 (m, 9H), 1.41-1.52 (m, 1H), 1.17-1.36 (m, 3H), 0.94-1.10 (m, 2H).

Example 19. Synthesis of viral protease inhibitor compound 197

Step 1: methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate

[000323] 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] ⁺

Step 2: tert-butyl (2S, 5S)-2-[[( JS)-2-methoxy-2-oxo-1-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ]-6, 6-dimethyl-3-azabicyclo[ 3.1.0 ] hexane- 3-car boxy late

[000324] To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (230 mg, 1.24 mmol, 1 eq) and (2S,5S)-3-tert-butoxy carbonyl-6, 6-dimethyl-3- azabicyclo[3.1 0]hexane-2-carboxylic acid (315.35 mg, 1.24 mmol, 1 eq) in DCM (4.5 mL) and DMF (1.5 mL) was added EDCI (473.57 mg, 2.47 mmol, 2 eq) and DMAP (301.80 mg, 2.47 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Once the reaction was completed, the reaction was concentrated and purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(10mM NH4HCO3)- ACN];B%: 25%-55%,10min) to give tert-butyl (2 S, 5 S)-2-[ [( 1 S)-2-methoxy-2-oxo- 1 - [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6,6-dime thyl-3- azabicyclo[3.1 0]hexane-3-carboxylate (200 mg, 425.03 umol, 34.41% yield, 90% purity) (solid). MS (ESI) m/z 424.1 [M+H] ⁺

Step 3: (S)-methyl 2-((lS,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbo xamido)-3- ((S)-2-oxopyrrolidin-3-yl)propanoate

[000325] To a mixture of (1 S,2S,5S)-tert-butyl 2-(((S)- 1 -m ethoxy- 1 -oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-aza bicyclo[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-((lS,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1 ,0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propano ate ( 150 mg, crude, an oil). Crude product was used directly without further purification. MS (ESI) m/z 324.1 [M+H] ⁺

Step 4: methyl (2S)-2-[[(2S,5S)-3-(4-methoxy-lH-indole-2-carbonyl)-6,6-dime thyl-3- azabicyclo[ 3.1.0 ]hexane-2-carbonyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate [000326] To a mixture of (S)-methyl 2-((lS,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1 ,0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propano ate ( 150 mg, 463.84 umol, 1 eq) and 4-methoxy- 1 H-indole-2-carboxylic acid (88.68 mg, 463.84 umol, 1 eq) in DCM (3 mL) and DMF (1 mL) was added EDCI (177.84 mg, 927.68 umol, 2 eq) and DMAP (113.33 mg, 927.68 umol, 2 eq). The mixture was stirred at 25 °C and stirred for 14 h. Once the reaction was completed, the mixture was poured into water (50 mL) and extracted with DCM (20 mL*3).The combined organic phase was washed with brine (60 mL*3), dried with anhydrous Na ₂ SO ₄ filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter:

100 mm, 100-200 mesh silica gel, petroleum ether/ethyl acetate=l/l, 0/1) to afford methyl (2S)-2-[[(2S,5S)-3-(4-methoxy-lH-indole-2-carbonyl)-6,6-dime thyl-3- azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-[(3S)-2-oxopyrro lidin-3-yl]propanoate (50 mg, 80.56 umol, 17.37% yield, 80% purity) as solid. MS (ESI) m/z 497.2 [M+H] ⁺

Step 5: (2S,5S)-N-[ ( 1 S)-2-amino-2-oxo-1-[[( 3S)-2-oxopyrrolidin-3-yl ] methyl ] ethyl ]-3-(4- methoxy-lH-indole-2-carbonyl)-6, 6-dimethyl-3-azabicyclo[ 3.1.0 ]hexane-2-carboxamide

[000327] To a mixture of methyl (2S)-2-[[(2S,5S)-3-(4-methoxy-lH-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 -lH-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] ⁺

Step 6: (2S,5S)-N-[ ( 1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ]-3-(4-methoxy-lH- indole -2-carbonyl) -6, 6-dimethyl-3-azabicyclo[ 3.1.0 ]hexane-2-carboxamide

[000328] To a mixture of (2S,5S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-3-(4-methoxy-lH-indole-2-carbonyl)-6,6-dime thyl-3- azabicyclo[3.1 0]hexane-2-carboxamide (50 mg, 103.83 umol, 1 eq) in DCM (3 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (49.49 mg, 207.67 umol, 2 eq). The mixture was stirred at 25 °C for 2 h. Once the reaction was completed, the reaction was concentrated and purified by prep-HPLC (column: Phenomenex Gemini -NX 80*40mm*3um;mobile phase: [water(10mM NH4HC03 )- ACN] ;B% : 20%-40%,8min) to give (2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]- 3-(4-methoxy-lH- indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxamide (14.44 mg, 31.15 umol, 30.00% yield, 100% purity) as a solid. MS (ESI) m/z 464.2[M+H]+. [000329] 1H NMR (400 MHz, METHANOL-d4) : δ ppm 7.16 - 7.18 (m, 1 H), 7.11- 7.14 (m, 2 H), 6.4 - 6.88 (m, 1 H), 5.05- 5.08 (m, 0.5 H), 4.06 (s, 2 H), 3.94- 3.98 (m, 0.5 H), 3.77 - 3.86 (m, 4 H), 3.28 (s, 2 H), 2.61- 3.69 (m, 1 H), 2.27- 2.32 (m, 1 H), 2.25- 2.26 (m, 1 H), 1.78 - 2.00 (m, 1 H), 1.74- 1.75 (m, 1 H) 1.35- 1.64 (m, 2 H), 0.97- 1.15 (m, 6

H)

Example 20. Synthesis of viral protease inhibitor compound 213

Step 1: (S)-Methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000330 ] 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. 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.

Step 2: (S)-benzyl 3-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 - yl)carbamoyl)tetrahydropyridazine-l(2H)-carboxylate

[000331] Methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (295.93 mg, 1.59 mmol, 1.4 eq) and (3S)-1-benzyloxycarbonylhexahydropyridazine-3-carboxylic acid (300 mg, 1.14 mmol, 1 eq) in DCM (2 mL)/THF (2 mL) was cooled to 0 °C, then the T3P (1.08 g, 1.70 mmol, 1.01 mL, 50% purity, 1.5 eq) and DIEA (440.14 mg, 3.41 mmol, 593.18 uL, 3 eq) was added and the solution was stirred at 25 °C for 13 h. Upon completion, the solution was diluted with H ₂ O (20 mL), extracted with Ethyl acetate (30 mL*3), the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The crude was used to next step directly and without further purification. Benzyl (3 S)-3-[[(l S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl] methyl] ethyl] carbamoyl] hexahydropy ridazine- 1 -carboxylate (455 mg, crude) was obtained as yellow oil. MS (ESI) m/z 433.1 [M+H] ⁺ .

Step 3: (S)-benzyl 2-((E)-3-(4-chloro-2-fluorophenyl)acryloyl)-3-(((S)-l-methox y-l-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)tetrahydropy ridazine-l(2H)-carboxylate

[000332] Benzyl (3S)-3-[[(l S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]hexahydropyridazine- 1 -carboxylate (200 mg, 462.46 umol, 1 eq) in DCM (2 mL) was added the DIEA (119.54 mg, 924.92 umol, 161.10 uL, 2 eq), (E)- 3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl chloride (121.56 mg, 554.95 umol, 1.2 eq) was added and the solution was stirred at 25 °C for 1 h. Upon completion, the solution was diluted with H ₂ O (10 mL), extracted with DCM (20 mL*3), the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10:1). Benzyl (3 S)-2-[(E)-3-(4-chloro-2- fluoro-phenyl) prop-2-enoyl]-3-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl] methyl] ethyl] carbamoyl] hexahydropyridazine- 1 -carboxylate (160 mg, 248.88 umol, 53.82% yield, 95.67% purity) was obtained as yellow oil. MS (ESI) m/z 433.1 [M+H] ⁺ .

Step 4: (S)-methyl 2-((S)-2-((E)-3-(4-chloro-2-fluorophenyl)acryloyl)hexahydrop yridazine-3- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000333] Benzyl (3S)-2-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]-3-[[(1 S)-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 ofNaHCOs, extracted with EtOAc (20 mL*3), the combined organic phase was dried over Na ₂ SO ₄ , 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] ⁺ .

Step5: (S)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-2-((E)-3-(4- chloro-2-fluorophenyl)acryloyl)hexahydropyridazine-3-carboxa mide [000334] Methyl (2S)-2-[[(3S)-2-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2- enoyl]hexahydropyridazine-3-carbonyl]amino]-3-[(3S)-2-oxopyr rolidin-3-yl]propanoate (80 mg, 166.35 umol, 1 eq) in NH ₃ /MeOH (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 to 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] ⁺ .

Step 6: (S)-2-((E)-3-(4-chloro-2-fluorophenyl)acryloyl)-N-((S)-l-cya no-2-((S)-2- oxopyrrolidin-3-yl)ethyl)hexahydropyridazine-3-carboxamide

[000335] (3 S)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-2- [(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]hexahydropyrid azine-3-carboxamide (75 mg, 160.98 umol, 1 eq) in DCM (0.5 mL) was added the Burgess reagent (76.72 mg, 321.95 umol, 2 eq) and the solution was stirred at 25 °C for 2 h. Upon completion, the solution was concentrated to remove the DCM. The residue was purified by prep-HPLC (neutral condition). Column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [water (lOmM NH4HC03)-ACN]; B%: 25%-45%, 8min. (3S)-2-[(E)-3-(4-chloro-2- fluoro-phenyl)prop-2-enoyl]-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]hexahydropyridazine-3-carboxamide (20 mg, 44.65 umol, 27.74% yield, 100% purity) was obtained as a solid. ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.79 - 7.60 (m, 3H), 7.32 - 7.22 (m, 2H), 5.17 (dd, J=2.2, 6.0 Hz, 1H), 5.07 (dd, J=6.4, 9.7 Hz, 1H), 3.38 - 3.32 (m, 2H), 3.12 (br d, J=13.7 Hz, 1H), 2.90 - 2.74 (m, 1H), 2.56 (dq, J=5.8, 9.0 Hz, 1H), 2.44 - 2.14 (m, 3H), 2.08 - 1.79 (m, 3H), 1.75 - 1.53 (m, 2H). MS (ESI) m/z 448.2 [M+H] ⁺ .

Step 7: (E)-3-(4-chloro-2-fluorophenyl)acryloyl chloride

[000336] (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)z (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

Step 1: methyl (2S)-2-amino-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate; hydrochloride [000337] Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3- yl Jpropanoate (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.

Step 2: (S)-methyl-2-((S)-2-((tert-butoxycarbonyl)amino)pent-4-ynami do)-3-((S)-2- oxopyrrolidin-3-yl)propanoate

[000338] A mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate;hydrochloride (180 mg, 808.38 umol, 1 eq), (2S)-2-(tert- butoxycarbonylamino)pent-4-ynoic acid (172.37 mg, 808.38 umol, 1 eq), TEA (572.59 mg, 5.66 mmol, 787.61 uL, 7 eq), T3P (1.03 g, 1.62 mmol, 961.53 uL, 50% purity, 2 eq) and DMF (3 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc= 0/1) to afford the product (S)-methyl-2-((S)-2-((tert- butoxycarbonyl)amino)pent-4-ynamido)-3-((S)-2-oxopyrrolidin- 3-yl)propanoate ( 150 mg, 393.26 umol, 48.65% yield), as an oil. MS (ESI) m/z 382.1 [M+H] ⁺

Step 3: (S)-methyl 2-((S)-2-aminopent-4-ynamido)-3-((S)-2-oxopyrrolidin-3-yl)pr opanoate [000339] 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, HC1) as an oil and used directly for next step.

Step 4: (S)-methyl-2-((S)-2-(4-methoxy-lH-indole-2-carboxamido)pent- 4-ynamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate

[000340] A mixture of (S)-methyl 2-((S)-2-aminopent-4-ynamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate (120 mg, 377.63 umol, 1 eq, HC1), 4-methoxy- 1 H-indole- 2-carboxylic acid (72.20 mg, 377.63 umol, 1 eq), EDCI (144.78 mg, 755.27 umol, 2 eq), DMAP (92.27 mg, 755.27 umol, 2 eq), DMF (2 mL) and DCM (4 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc= 0/1) to get the compound (S)-methyl-2-((S)-2-(4-methoxy-lH-indole-2-carboxamido)pent- 4- ynamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (90 mg, 160.56 umol, 42.52% yield, 81.08% purity), as an oil. MS (ESI) m/z 455.1 [M+H] ⁺

Step 5: N-( (S)-l-( ( (S)-l -amino-1 -oxo-3-( (, S)-2-oxopyrrolidin-3-yl)propan-2-yl)ammo)-l - oxopent-4-yn-2-yl)-4-methoxy-lH-indole-2-carboxamide

[000341] A mixture of (S)-methyl-2-((S)-2-(4-methoxy- 1 H-indole-2-carboxamido)pent-4- ynamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (85 mg, 187.03 umol, 1 eq) and NH ₃ /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 N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopent-4-yn- 2-yl)-4-methoxy-lH- indole-2-carboxamide (85 mg, crude) as a solid. MS (ESI) m/z 440.2 [M+H] ⁺

Step 6: N-( (S)-l-( ( (S)-l-cyano-2-( ( S)-2-oxopyrrolidin-3-yl)ethyl)ammo)-l-oxopent-4-yn-2 - yl)-4-methoxy-lH-indole-2-carboxamide

[000342] A mixture of N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)amino)- 1 -oxopent-4-yn-2-yl)-4-methoxy- 1 H-indole-2-carboxamide (80 mg, 182.04 umol, 1 eq), Burgess reagent (216.91 mg, 910.20 umol, 5 eq) and DCM (5 mL) 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 (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(0.04%NH3H ₂ O+10mM NH4HCO3)- ACN];B%: 20%-50%,10min) to get the product N-((S)-1-(((S)-1-cyano-2-((S)-2- oxopyrrolidin-3-yl)ethyl)amino)-1-oxopent-4-yn-2-yl)-4-metho xy-lH-indole-2- carboxamide (20 mg, 47.46 umol, 26.07% yield, 100% purity), as solid. MS (ESI) m/z 422.2 [M+H] ⁺ .

[000343] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.61 (d, J=1.8 Hz, 1H), 9.18 - 8.93 (m,

1H), 8.74 - 8.58 (m, 1H), 7.78 - 7.62 (m, 1H), 7.37 - 7.29 (m, 1H), 7.15 - 7.07 (m, 1H), 7.05 - 6.97 (m, 1H), 6.51 (d, J=7.5 Hz, 1H), 5.03 - 4.91 (m, 1H), 4.65 - 4.50 (m, 1H), 3.89 (s, 3H), 3.20 - 3.05 (m, 2H), 2.91-2.85 (m, 1H), 2.78 - 2.59 (m, 2H), 2.43 - 2.29 (m, 1H), 2.21 - 2.06 (m, 2H), 1.88 - 1.59 (m, 2H)

Example 22. Synthesis of viral protease inhibitor compound 205

Step 1: (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid

[000344] To a solution of (2S)-2-amino-3-cydopropyl-propanoic acid (1 g, 7.74 mmol, 1 eq) in THF (5 mL) and H ₂ O (5 mL), was added K2CO3 (3.75 g, 27.10 mmol, 3.5 eq) and (Boc) ₂ O (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 IN aqueous citric acid (30 mL). The solution was extracted with DCM (30 mL * 3) and was concentrated in vacuum to afford (S)-2-((tert-butoxy carbonyl) amino)-3-cyclopropyl propanoic acid (1.8 g, crude) as an oil.

Step 2: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidm-3-yl)propanoate

[000345] (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, HCI, crude) as a yellow gum and used to next step directly.

Step 3: (S)-methyl2-((S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropy lpropanamido)-3-((S)- 2-oxopyrrolidin-3-yl)propanoate [000346] To a mixture of (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl) propanoate

(250 mg, 1.12 mmol, 1 eq, HC1) and (S)-2-((tert-butoxy carbonyl) amino)-3-cyclopropyl propanoic acid (386.12 mg, 1.68 mmol, 1.5 eq) in DCM (5 mL) was added TEA (568.05 mg, 5.61 mmol, 781.36 uL, 5 eq) at 0°C, the mixture was added T3P (2.14 g, 3.37 mmol, 2.00 mL, 50% purity, 3 eq) at 0°C, then the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by water (10 mL) and was extracted with DCM (5 mL * 3). The resulting solution was dried with Na ₂ SO ₄ , filtered and concentration in vacuum to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether:EtOAc= 1 :0 to 0: 1) to afford the product (S)-methyl 2-((S)-2-((tert- butoxycarbonyl)amino)-3-cyclopropylpropanamido)-3-((S)-2-oxo pyrrolidin-3- yl)propanoate (400 mg, 905.74 umol, 80.67% yield, 90% purity) was obtained as a gum.

[000347] ¹ H NMR (400MHz, CDCl ₃ ) δ ppm 7.60 (d ,J= 5.6 Hz, 1H), 5.96 (s, 1H), 5.24 (d ,J= 7.5 Hz, 1H), 4.65 - 4.47 (m, 1H), 4.24 (d , J= 6.6 Hz, 1H), 3.73 (s, 3H), 3.44 - 3.27 (m, 2H), 2.51 - 2.36 (m, 2H), 2.25 - 2.13 (m, 1H), 1.98 - 1.82 (m, 1H), 1.66 - 1.58 (m,

1H), 1.44 (s, 9H), 1.30 - 1.21 (m, 1H), 0.86 - 0.71 (m, 1H), 0.49 (d ,J= 7.9 Hz, 2H), 0.13 (d,J= 4.4 Hz, 2H).

Step 4: (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((S)-2-oxopyrroli din-3- yl)propanoate

[000348] A solution of (S)-methyl2-((S)-2-((tert-butoxycarbonyl)amino)-3- cyclopropylpropanamido)-3- ((S)-2- oxopyrrolidin-3-yl)propanoate in HCl/EtOAc (4 M, 4 mL), 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-((S)-2-amino-3- cyclopropylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl) propanoate (330 mg, crude, HC1) as a yellow gum and used directly next step.

[000349] 1H NMR (400 MHz, MeOD-d4) δ ppm 4.57 (dd, J = 4.1, 11.0 Hz, 1H), 3.94 (t, J = 6.7 Hz, 1H), 3.73 (s, 3H), 3.40 - 3.33 (m, 2H), 2.55 - 2.33 (m, 2H), 2.19 - 2.07 (m, 1H), 2.03 - 2.00 (m, 1H), 1.93 - 1.84 (m, 2H), 1.24 (t ,J= 7.1 Hz, 1H), 0.89 - 0.79 (m, 1H),

0.59 (dd, J = 4.5, 7.9 Hz, 2H), 0.26 - 0.17 (m, 2H).

Step 5: (S)-methyl2-((S)-3-cyclopropyl-2-(4-methoxy-lH-indole-2- carboxamido)propanamido)-3-((S)-2-oxopyrrolidin-3-yl)propano ate [000350] To a mixture of 4-methoxy-1H-indole-2-carboxylic acid (257.73 mg, 1.35 mmol, 1.5 eq) and (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((S)-2- oxopyrrolidin-3-yl) propanoate (300 mg, 898.71 umol, 1 eq, HC1) in DCM (8 mL) was added EDCI (861.43 mg, 4.49 mmol, 5 eq) and DMAP (329.38 mg, 2.70 mmol, 3 eq), then the mixture was stirred at 25 °C for 2 h. The combined organic layers were quenched with water (10 mL) and were extracted with DCM (4 mL * 3). The resulting solution was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

The residue was purified by column chromatography (SiO ₂ , EtOAc) to get the compound (S)-methyl2-((S)-3-cyclopropyl-2-(4-methoxy-1H-indole-2-carb oxamido)propanamido)- 3-((S)-2-oxopyrrolidin-3-yl)propanoate (250 mg, 425.06 umol, 47.30% yield, 80% purity) as yellow oil. MS (ESI) m/z 471.1 [M+H] ⁺

Step 6: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (, S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3 - cyclopropyl- l-oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxamide [000351] (S)-Methyl2-((S)-3 -cy cl opropyl-2-(4-m ethoxy- 1H-indole-2- carboxamido)propanamido)-3-((S)-2-oxopyrrolidin-3-yl)propano ate (250 mg, 531.33 umol, 1 eq) was added with NH ₃ /MeOH (7 M, 6.00 mL). The mixture was stirred at 80 °C for 16 h. The resulting mixture was concentrated under reduced pressure to give a residue 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-lH-indole-2-carboxam ide (200 mg, crude) as a solid. MS (ESI) m/z 456.1 [M+H] ⁺

Step 7: N-( (S)-l-( ( (S)-l-cyano-2-( ( S)-2-oxopyrrolidin-3-yl)ethyl)ammo)-3-cyclopropyl-l - oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxamide

[000352] 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-lH-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 N ₂ . 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] ⁺ . prep-HPLC condition: column: Waters Xbridge BEH C18 100 * 25mm * 5 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )- ACN] ; B%: 20%-50%, 10 min .

[000353] 1 H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (d ,J= 1.8 Hz, 1H), 8.90 (d, J =

8.2 Hz, 1H), 8.50 (d,J= 7.5 Hz, 1H), 7.78 - 7.65 (m, 1H), 7.36 (d,J= 1.5 Hz, 1H), 7.13 - 7.04 (m, 1H), 7.03 - 6.96 (m, 1H), 6.50 (d, J= 7.8 Hz, 1H), 5.04 - 4.94 (m, 1H), 4.54 - 4.38 (m, 1H), 3.89 (s, 3H), 3.19 - 3.06 (m, 2H), 2.44 - 2.33 (m, 1H), 2.22 - 2.07 (m, 2H), 1.90 - 1.75 (m, 2H), 1.74 - 1.63 (m, 1H), 1.54 - 1.41 (m, 1H), 0.87 - 0.73 (m, 1H), 0.47 - 0.34 (m, 2H), 0.25 - 0.15 (m, 1H), 0.14 - 0.04 (m, 1H).

Example 23. Synthesis of viral protease inhibitor compound 401

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000354] Methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (400 mg, 1.40 mmol, 1 eq) in HCl/EtOAc (4 M, 10 mL, 28.63 eq) was stirred at 25 °C for 0.5 h. Upon completion, the mixture was concentrated under the reduced pressure affording the product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (300 mg, crude, HC1) as a solid. Step 2: (S)-tert-butyl3-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin -3-yl)propan-2- yl) carbamoyl) -2-azaspiro[ 4.4 ]nonane-2-carboxylate

[000355] Methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 1.35 mmol, 1 eq, HC1) and (3S)-2-tertbutoxycarbonyl-2-azaspiro[4.4]nonane-3-carboxylic acid (362.87 mg, 1.35 mmol, 1 eq) in DMF (2 mL) and DCM (5 mL) was added DMAP (329.19 mg, 2.69 mmol, 2 eq) and EDCI (516.56 mg, 2.69 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (10 mL), and then extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc= 5:1 to 0:1) affording the product tert-butyl(3S)-3-[[(1S)- 2-methoxy-2-oxo- 1 - [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-2- azaspiro[4.4]nonane-2-carboxylate (340 mg, 777.09 umol, 57.68% yield) as an oil.

Step 3: (S)-methyl3-( (, S)-2-oxopyrrolidin-3-yl)-2-( ( S)-2-azaspiro[ 4.4 ]nonane-3- carboxamido)propanoate

[000356] tert-Butyl(3S)-3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrol idin-3- yl]methyl]ethyl]carbamoyl]-2-azaspiro[4.4]nonane-2-carboxyla te (340 mg, 777.09 umol, 1 eq) in HCl/EtOAc (4 M, 10 mL, 51.47 eq) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressured affording the product methyl(2S)-2-[[(3S)-2-azaspiro[4.4]nonane-3-carbonyl]amino] -3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (250 mg, crude, HC1) as an oil.

Step 4: (S)-methyl2-((S)-2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspi ro[4.4]nonane-3- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000357] Methyl(2S)-2-[[(3S)-2-azaspiro[4.4]nonane-3-carbonyl]amino]- 3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (250 mg, 668.67 umol, 1 eq, HC1) and 4-methoxy-1H- indole-2-carboxylic acid (127.84 mg, 668.67 umol, 1 eq) in DMF (2 mL) and DCM (6 mL) was added DMAP (163.38 mg, 1.34 mmol, 2 eq) and EDCI (256.37 mg, 1.34 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (10 mL), and then extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether:EtOAc= 0: 1) affording the product methyl(2S)-2-[[(3S)- 2-(4-methoxy-1H-indole-2-carbonyl)-2 -azaspiro[4.4]nonane-3-carbonyl]amino]-3-[(3S)- 2-oxopyrrolidin-3-yl]propanoate (180 mg, 352.54 umol, 52.72% yield) as an oil. MS (ESI) m/z 511.2 [M+H] ⁺

Step 5: (S)-N-( (S)-l -amino-1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-( 4-methoxy-lH- indole-2-carbonyl) -2-azaspiro[ 4.4 ]nonane-3-carboxamide

[000358 ] Methyl(2S)-2-[[(3S)-2-(4-methoxy-1H-indole-2-carbonyl)-2- azaspiro[4.4]nonane-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidi n-3-yl]propanoate ( 180 mg, 352.54 umol, 1 eq) in ammonia (7 M, 20 mL, 397.12 eq) was stirred at 80 °C for 16 h. Upon completion, the mixture was concentrated under the reduced pressure affording the product (3S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl] methyl]ethyl]-2- (4-methoxy- 1H-indole-2- carbonyl)-2-azaspiro[4.4]nonane-3-carboxamide (170 mg, crude) as an oil.

Step 6: (S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-m ethoxy-lH-indole-2- carbonyl)-2-azaspiro[ 4.4 ]nonane-3-carboxamide

[000359] (3S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]met hyl]ethyl]-2-(4- methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.4]nonane-3-carbox amide (170 mg, 343.04 umol, 1 eq) in DCM (3 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl- azanide (408.74 mg, 1.72 mmol, 5 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xb ridge BEH Cl 8 100*25mm*5 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30% - 60%, 10 min) affording the product (3S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]- 2-(4-methoxy-1H-indole-2 -carbonyl)-2-azaspiro[4.4]nonane-3-carboxamide (25 mg, 51.09 umol, 14.89% yield, 97.6% purity) as a solid. MS (ESI) m/z 478.2 [M+H] ⁺

[000360] ¹ H NMR (400 MHz, MMeOD-d ₄ ) δ = 7.22 - 7.12 (m, 1H), 7.11 - 6.98 (m, 2H), 6.58 - 6.45 (m, 1H), 5.11 - 4.95 (m, 1H), 4.65 - 4.52 (m, 1H), 3.94 (s, 3H), 3.93 - 3.80 (m, 2H), 3.28 - 3.18 (m, 1H), 2.54 - 2.02 (m, 4H), 2.01 - 1.48 (m, 12 H).

Example 24. Synthesis of viral protease inhibitor compound 225

Step 1: methyl (2S)-2-amino-3-(3-methylimidazol-4-yl)propanoate

[000361 ] 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 (2 S)-2-amino-3 -(3 - methylimidazol-4-yl)propanoate (250 mg, crude, HC1) was obtained as a solid and used directly next step. MS (ESI) m/z 183.2 [M+H] ⁺

[000362] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.94 (s, 1 H), 7.56 (s, 1 H), 4.51 (t, J=7.17 Hz, 1 H), 3.93 (s, 3 H), 3.87 (s, 3 H), 3.46 - 3.55 (m, 1 H), 3.32 - 3.42 (m, 1 H).

Step 2: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoy l]amino]-3-(3- methyli midazol-4-yl)propanoate

[000363] To a mixture of methyl (2S)-2-amino-3-(3-methylimidazol-4-yl)propanoate (250 mg, 1.14 mmol, 1 eq, HC1) and (2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoic acid (263.22 mg, 1.14 mmol, 1 eq) in THF (1 mL) and DCM (1 mL) and DIPEA (441.26 mg, 3.41 mmol, 594.69 uL, 3 eq) was added T3P (1.09 g, 1.71 mmol, 1.02 mL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 10 h. LCMS showed the reaction mixture was completed. The reaction mixture was added saturated sodium bicarbonate solution (10 mL) and extracted with DCM (10 mL x 2) to get the organic phase. The organic phase was washed with brine (3 mL x 3), dried over anhydrous sodium sulfate and concentrated to get the crude product. Methyl (2S)-2- [ [(2 S)-2-(tert-butoxy carbonyl amino)-4-methyl-pentanoyl]amino]-3-(3-methylimidazol- 4-yl)propanoate (360 mg, crude) was obtained as an oil and used directly next step. MS (ESI) m/z 397.3 [M+H] ⁺

Step 3: methyl(2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]ammo]-3-(3-me thylimidazol-4- yl)propanoate

[000364] 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 N ₂ . 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] ⁺

Step 4: methyl (2S)-2-[[(2S)-2-[(4-methoxy- lH-indole-2-carbonyl)ammo]-4-methyl- pentanoyl ] amino ] -3-( 3-methylimidazol-4-yl)propanoate

[000365] 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-lH- 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 N ₂ . 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 (Si 02, petroleum ether/EtOAc=2/l to EtOAc/Methanol = 10/1). Methyl (2S)-2-[[(2S)-2-[(4-methoxy- lH-indole-2- carbonyl)amino]-4-methyl-pentanoyl]amino]-3-(3-methylimidazo l-4-yl)propanoate (270 mg, crude) was obtained as an oil. MS (ESI) m/z 469.5 [M+H] ⁺

Step 5: N-[ (lS)-l-[[( IS)- 2-amino-1-[(3-methylimidazol-4-yl)methylJ-2-oxo- ethyl ] carbamoyl ]-3- methyl-butyl ]-4-methoxy-lH-indole-2-carboxamide

[000366] To methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-me thyl- pentanoyl]amino]- 3-(3-methylimidazol-4-yl)propanoate (235.00 mg, 500.50 umol, 1 eq) was added NH ₃ /MeOH (7 M, 1.94 mL, 27.14 eq) in one portion at 25 °C under N ₂ . 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-lH- indole-2-carboxamide (170 mg, crude) was obtained as a solid. MS (ESI) m/z 455.3 [M+H] ⁺

Step 6: N-f (IS)- 1 -[[(l S)-l-cyano-2-( 3-methylimidazol-4-yl)ethyl ] carbamoyl /-3-methyl- butyl ]-4- methoxy-lH-indole-2-carboxamide

[000367] To a mixture of N-[(l S)-1-[[(l S)-2-amino-1-[(3-methylimidazol-4-yl)methyl]-2- oxo-ethyl]carb amoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2-carboxamide (140 mg, 308.02 umol, 1 eq) in DCM (2 mL) was added Burgess reagent (293.61 mg, 1.23 mmol, 4 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 12 h, and then concentrated to get the crude product. The crude product was purified by pre-HPLC. N-[(l S)-1- [[(1S)-1-cyano-2-(3-methylimidazol-4-yl)ethyl]carbamoyl]-3-m ethyl-butyl]-4- methoxy- 1 H-indole-2-carboxamide (10.59 mg, 23.82 umol, 7.73% yield, 98.2% purity) was obtained as a solid. MS (ESI) m/z 437.2 [M+H] ⁺ .

Prep-HPLC condition: column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(10mM NH4HCO3) -ACN];B%: 25%-50%,6min column: Waters Xbridge BEH C 18 100*30mm* 10um;mobile phase: [water( 1 OmM NH ₄ HCO3) -ACN];B%: 20%-45%,8min

[000368] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.52 - 7.57 (m, 1 H), 7.28 (s, 1 H), 7.12 - 7.18 (m, 1 H), 7.03 (d, J=8.38 Hz, 1 H), 6.85 - 6.96 (m, 1 H), 6.52 (d, J=7.72 Hz, 1 H), 5.05 - 5.13 (m, 1 H), 4.55 - 4.62 (m, 1 H), 3.86 - 3.99 (m, 3 H), 3.68 (s, 3 H), 3.21 (tt, J=15.24, 7.80 Hz, 2 H), 1.55 - 1.81 (m, 3 H), 0.86 - 1.07 (m, 6 H)

Example 25. Synthesis of viral protease inhibitor compound 227

Step 1: methyl (2S)-2-amino-3- (l-methylimidazol-4-yl)propanoate

[000369] 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 N ₂ . 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, HC1) was obtained as a solid and used directly next step. MS (ESI) m/z 184.1 [M+H] ⁺

Step 2: methyl (2S)-2-[[(2S)-2-[(4-methoxy -JH-indole-2-carbonyl)aminoJ-4-methyl- pentanoyl ] amino ] -3-(l -methylimidazol-4-yl)propanoate

[000370] To a mixture of (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoic acid (498.76 mg, 1.64 mmol, 1.2 eq) and methyl (2 S)-2-amino-3 -( 1 - methylimidazol-4-yl)propanoate (0.3 g, 1.37 mmol, 1 eq, HC1), DIPEA (882.53 mg, 6.83 mmol, 1.19 mL, 5 eq) in THF (0.9 mL) and DCM (0.9 mL) was added T3P (1.30 g, 2.05 mmol, 1.22 mL, 50% purity, 1.5 eq) si 0 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. The reaction mixture was added to saturated sodium bicarbonate solution (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 prep-HPLC. Methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-me thyl-pentanoyl]amino]- 3-(l-methylimidazol-4-yl)propanoate (100 mg, 202.97 umol, 14.86% yield, 95.3% purity) was obtained as a solid. MS (ESI) m/z 470.2 [M+H] ⁺

Prep-HPLC condition: column: Kromasil C18 (250*50mm*10 um);mobile phase: [water(10mM NH4HCO3)- ACN];B%: 25% - 50%,10min

Step 3: N-f ( l S)-l-[[( IS) -2 -amino- 1 -[ ( l -methylimidazol-4-yl)methyl]-2-oxo- ethyl ] carbamoyl ]-3-methyl -butyl ]-4-methoxy-lH-indole-2-carboxamide

[000371] To methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-me thyl- pentanoyl]amino] -3 -( 1 -methylimidazol-4-yl)propanoate (100 mg, 212.98 umol, 1 eq) was added NH ₃ /MeOH (7 M, 10.00 mL, 328.67 eq) in one portion at 25 °C under N ₂ . 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- [[( 1 S)-2-amino- 1 -[( 1 -methylimidazol-4- yl)methyl]-2-oxo-ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy- lH-indole-2- carboxamide (95.5 mg, 190.57 umol, 89.48% yield, 90.7% purity) was obtained as a solid and used directly next step. MS (ESI) m/z 455.2 [M+H] ⁺

Step 4: N-[(lS)-l-[[(lS)-l-cyano-2-(l-methylimidazol-4-yl)ethyl] carbamoyl] -3-methyl- butyl] -4- methoxy- lH-indole-2-carboxamide

[000372] To a mixture of N-[( 1 S)- 1 -[[( 1 S)-2-amino- 1 -[( 1 -methylimidazol-4-yl)methyl]-2- oxo-ethyl]carba moyl]-3-methyl-butyl]-4-methoxy-lH-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 N ₂ . 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-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-( 1 -methylimidazol-4-yl)ethyl] carbamoyl]-3- methyl-butyl]-4-methoxy-lH-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] ⁺

Prep-HPLC condition: column: Waters Xbridge BEH ClS 100*25mm*5um;mobile phase: [water(10mM NH4HCO3) -ACN] ;B%: 25%-55%,10min

[000373] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.35 (s, 1 H), 7.28 (s, 1 H), 7.12 - 7.20 (m, 1 H), 7.05 (d ,J= 8.38 Hz, 1 H), 6.91 - 6.98 (m, 1 H), 6.53 (d ,J= 7.72 Hz, 1 H), 5.01 (t ,J = 7.06 Hz, 1 H), 4.63 (br dd, J = 9.59, 4.96 Hz, 1 H), 3.94 (s, 3 H), 3.46 - 3.59 (m, 3 H), 3.00 - 3.13 (m, 2 H), 1.61 - 1.81 (m, 3 H), 0.89 - 1.07 (m, 6 H)

Step 5: tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoate

[000374] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (5 g, 26.15 mmol, 1 eq) and tert-butyl (2S)-2-amino-4-methyl-pentanoate (5.88 g, 31.38 mmol, 1.2 eq, HC1), EDCI (6.52 g, 34.00 mmol, 1.3 eq), HOBt (4.59 g, 34.00 mmol, 1.3 eq) in DMF (30 mL) was added TEA (7.94 g, 78.46 mmol, 10.92 mL, 3 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 2 h. The reaction mixture was added water (90 mL) and extracted with EtOAc (25 mL * 3) to get the organic phase. The organic phase was washed with 5% citric acid (25 mL) and 5% aqueous solution of sodium bicarbonate (25 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to get the product. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc= 30:1 to 10:1). Tert-butyl (2S)-2-[(4-methoxy- 1 H-indole- 2-carbonyl)amino]-4-methyl- pentanoate (5.93 g, 16.45 mmol, 62.91% yield) was obtained as solid. MS (ESI) m/z 361.2 [M+H] ⁺

[000375] ¹ H NMR (400 MHz, CHLOROFORM-*/) δ ppm 9.25 (br s, 1 H), 7.10 - 7.16 (m, 1 H), 6.93 - 7.00 (m, 2 H), 6.56 (br d,J= 8.31 Hz, 1 H), 6.44 (d ,J= 7.70 Hz, 1 H), 4.66 (td, J= 8.50, 5.14 Hz, 1 H), 3.88 (s, 3 H), 1.62 - 1.75 (m, 2 H), 1.57 - 1.62 (m, 1 H), 1.42 (s, 9 H), 0.92 (dd, J = 6.17, 3.85 Hz, 6 H).

Step 6: (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)ammo]-4-methyl-penta noic acid

[000376] To a mixture of tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoate (2.00 g, 5.55 mmol, 1 eq) in DCM (8 mL) was added TEA (10.27 g, 90.04 mmol, 6.67 mL, 16.23 eq) and H ₂ O (666.67 mg, 37.01 mmol, 666.67 uL, 6.67 eq) in one portion at 0 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 4 h. The reaction mixture was concentrated to get the crude product. (2 S)-2-[(4-methoxy- 1 H- indole-2-carbonyl)amino]-4-methyl-pentanoic acid (2.24 g, 5.35 mmol, 96.50% yield, TFA) was obtained as a solid and used directly next step. MS (ESI) m/z 305.1 [M+H] ⁺

Example 26. Synthesis of viral protease inhibitor compound 231

Step 1: (S)-methyl 2-amino-3-(pyridin-3-yl)propanoate hydrochloride [000377] 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 N ₂ . The mixture was stirred at 25 °C and stirred for 12 h. Upon completion, the reaction mixture was concentrated to get methyl (2 S)-2-amino-3 -(3 - pyridyl)propanoate (400 mg, crude, HC1) as an oil and used directly for the next step. MS (ESI) m/z 181.1 [M+H] ⁺

Step 2: (S)-methyl 2-((S)-2-(4-methoxy-lH-indole-2-carboxamido)-4-methylpentana mido)-3- (pyridine -3-yl)propanoate

[000378] To a mixture of methyl (2S)-2-amino-3-(3-pyridyl)propanoate (0.3 g, 1.66 mmol, 1 eq, HC1) and (2S)-2-[(4-methoxy-lH-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 N ₂ . 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- [ [(2 S)-2-[(4-methoxy -lH-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] ⁺ Step 3: N-( (S)-l-( ( (S)-l -amino- l-oxo-3-(pyridin-3-yl)propan-2-yl)amino)-4-methyl-l- oxopentan-2-yl) -4-methoxy-lH-indole-2-carboxamide

[000379] To a mixture of methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4-methyl -pentanoyl]amino]-3-(3-pyridyl)propanoate (200.00 mg, 428.70 umol, 1 eq) was added NH ₃ /MeOH (7 M, 5 mL, 81.64 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 80 °C for 4 h. Upon completion, the reaction mixture was cooled to 25 °C and concentrated to get N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-(3- pyridylmethyl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH- indole-2-carboxamide (0.18 g, 339.65 umol, 79.23% yield, 85.2% purity) as a solid and used directly next step. MS (ESI) m/z 452.2 [M+H] ⁺

Step 3: N-( (S)-l-( ( (S)-l-cyano-2-(pyridin-3-yl)ethyl)amino)-4-methyl-l-oxopenta n-2-yl)-4- methoxy-lH -indole-2-carboxamide

[000380] To a mixture of N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -(3- pyridylmethyl)ethyl]carbamoyl]-3-methyl -butyl]-4-methoxy-lH-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 N ₂ . 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-met hyl- butyl]-4-methoxy- 1 H-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] ⁺

Prep-HPLC condition: column: Waters Xbridge BEH C 18 100*25mm*5um;mobile phase: [water( 1 OmM NH ₄ HCO3)- ACN];B%: 30%-60%,10min

[000381] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.47 - 8.52 (m, 1 H), 8.34 - 8.45 (m, 1 H), 7.77 - 7.84 (m, 1 H), 7.28 - 7.38 (m, 1 H), 7.23 - 7.28 (m, 1 H), 7.12 - 7.19 (m, 1 H), 6.99 - 7.07 (m, 1 H), 6.52 (d, J = 7.63 Hz, 1 H), 5.08 - 5.18 (m, 1 H), 4.48 - 4.61 (m, 1 H), 3.94 (s, 3 H), 3.12 - 3.29 (m, 2 H), 1.41 - 1.76 (m, 3 H), 0.87 - 1.03 (m, 6 H).

Step 5: (S)-tert-butyl 2-(4-methoxy-lH-indole-2-carboxamido)-4-methylpentanoate [000382] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (5 g, 26.15 mmol, 1 eq) and tert-butyl (2S)-2-amino-4-methyl-pentanoate (5.88 g, 31.38 mmol, 1.2 eq, HC1), EDCI (6.52 g, 34.00 mmol, 1.3 eq), HOBt (4.59 g, 34.00 mmol, 1.3 eq) in DMF (30 mL) was added TEA (7.94 g, 78.46 mmol, 10.92 mL, 3 eq) in one portion at 25 °C under N ₂ .

The mixture was stirred at 25 °C and stirred for 2 h. Upon completion, the reaction mixture was added water (90 mL) and extracted with ethyl acetate (25 mL * 3) to get the organic phase. The organic phase was washed with 5% citric acid (25 mL) and 5% aqueous solution of sodium bicarbonate (25 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to get the crude product. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc= 30: 1 to 10: 1) to give tert-butyl (2S)-2-[(4-methoxy-lH-indole- 2-carbonyl)amino]-4-methyl-pentanoate (5.93 g, 16.45 mmol, 62.91% yield) as a solid. MS (ESI) m/z 361.2 [M+H] ⁺

[000383] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.25 (br s, 1 H), 7.10 - 7.16 (m, 1 H), 6.93 - 7.00 (m, 2 H), 6.56 (br d, J= 8.31 Hz, 1 H), 6.44 (d, J= 7.70 Hz, 1 H), 4.66 (td, ./ = 8.50, 5.14 Hz, 1 H), 3.88 (s, 3 H), 1.62 - 1.75 (m, 2 H), 1.57 - 1.62 (m, 1 H), 1.42 (s, 9 H), 0.92 (dd, J= 6.17, 3.85 Hz, 6 H).

Step 6: (S)-2-(4-methoxy-lH-indole-2-carboxamido)-4-methylpentanoic acid

[000384] To a mixture of tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoate (0.5 g, 1.39 mmol, 1 eq) in DCM (0.33 mL) was added TFA (2.57 g, 22.51 mmol, 1.67 mL, 16.23 eq) and H ₂ O (166.71 mg, 9.25 mmol, 166.71 uL, 6.67 eq) in one portion at 0 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 2 h. Upon completion, the reaction mixture was concentrated to give (S)-2-(4-methoxy-lH-indole-2- carboxamido)-4-methylpentanoic acid (400 mg, crude, TFA) as a solid and used directly next step. MS (ESI) m/z 305.1 [M+H] ⁺

Example 27. Synthesis of viral protease inhibitor compound 599

Step 1: tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoate [000385] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (5 g, 26.15 mmol, 1 eq) and tert-butyl (2S)-2-amino-4-methyl-pentanoate (5.88 g, 31.38 mmol, 1.2 eq, HC1),

EDCI (6.52 g, 34.00 mmol, 1.3 eq), HOBt (4.59 g, 34.00 mmol, 1.3 eq) in DMF (30 mL) was added TEA (7.94 g, 78.46 mmol, 10.92 mL, 3 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 2 h. The reaction mixture was added with water (90 mL) and extracted with EtOAc (25 mL * 3) to get the organic phase. The organic phase was washed with 5% citric acid (25 mL) and 5% aqueous solution of sodium bicarbonate (25 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to get the product. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc= 30:1 to 10:1). Tert-butyl (2S)-2-[(4-methoxy- 1 H-indole- 2-carbonyl)amino]-4-methyl- pentanoate (5.93 g, 16.45 mmol, 62.91% yield) was obtained as a solid. MS (ESI) m/z 361.2 [M+H] ⁺

[000386] 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.25 (br s, 1 H), 7.10 - 7.16 (m, 1 H), 6.93 - 7.00 (m, 2 H), 6.56 (br d,J= 8.31 Hz, 1 H), 6.44 (d ,J= 7.70 Hz, 1 H), 4.66 (td, J= 8.50, 5.14 Hz, 1 H), 3.88 (s, 3 H), 1.62 - 1.75 (m, 2 H), 1.57 - 1.62 (m, 1 H), 1.42 (s, 9 H), 0.92 (dd, J = 6.17, 3.85 Hz, 6 H).

Step 2: (2S)-2-[(4-methoxy-lH-mdole-2-carbonyl)ammo]-4-methyl-pentan oic acid [000387] To a mixture of tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoate (2.00 g, 5.55 mmol, 1 eq) in DCM (8 mL) was added TFA (10.27 g, 90.04 mmol, 6.67 mL, 16.23 eq) and H ₂ O (666.67 mg, 37.01 mmol, 666.67 uL, 6.67 eq) in one portion at 0 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 4 h. The reaction mixture was concentrated to get the crude product. (2 S)-2-[(4-methoxy- 1 H- indole-2-carbonyl)amino]-4-methyl-pentanoic acid (2.24 g, 5.35 mmol, 96.50% yield, TFA) was obtained as a solid and used directly next step. MS (ESI) m/z 305.1 [M+H] ⁺

Step 3: methyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoyl]amino]-3- (2-oxo-lH-quinolin-4-yl)propanoate

[000388] To a mixture of (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoic acid (568.23 mg, 1.36 mmol, 1.2 eq, TFA) and methyl 2-amino-3-(2-oxo-lH- quinolin-4-yl)propanoate (320 mg, 1.13 mmol, 1 eq, HC1), DIPEA (731.40 mg, 5.66 mmol, 985.72 uL, 5 eq) in THF (1 mL) and DCM (1 mL) was added T3P (1.08 g, 1.70 mmol, 1.01 mL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. The reaction mixture was added with 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 prep-HPLC. Methyl 2-[[(2S)-2-[(4-methoxy -lH-indole-2-carbonyl)amino]-4-methyl- pentanoyl]amino]-3 -(2-oxo- lH-quinolin-4-yl)propanoate (0.2 g, 375.53 umol, 33.18% yield) was obtained as a solid. MS (ESI) m/z 533.2 [M+H] ⁺

[000389] Prep-HPLC condition: column: Kromasil C18 (250*50mm*10 um);mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN];B%: 30%-60%,10min

Step 4: N-[(lS)-l-[[2-amino-2-oxo-l-[(2-oxo-lH-quinolm-4-yl)methyl]e thyl]carbamoyl]-3- methyl- butyl ]-4-methoxy-JH-indole -2-carboxamide

[000390] To a mixture ofmethyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoyl] amino]-3-(2-oxo-lH-quinolin-4-yl)propanoate (200.00 mg, 375.53 umol, 1 eq) was added NH ₃ /MeOH (7 M, 10.00 mL, 186.41 eq) in one portion at 25 °C under N ₂ . 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-[(l S)-1-[[2-amino-2-oxo-1-[(2-oxo-lH- quinolin-4-yl)methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-meth oxy-lH-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] ⁺

Step 5: N-f (1S)-1-[[1 -cyano-2-(2-oxo-lH-quinolin-4-yl)ethyl ] carbamoyl ]-3-methyl-butyl ]-4- methoxy- lH-indole-2-carboxamide [000391] To a mixture of N-[( 1 S)- 1 -[[2-amino-2-oxo- 1 -[(2-oxo- 1 H-quinolin-4- yl)methyl]ethyl]carbamoyl]-3- methyl-butyl]-4-methoxy-lH-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 N ₂ . The mixture was stirred at 25 °C for 12 h, and then concentrated to get the crude product.

[000392] The residue was purified by prep-HPLC. N-[(1S)-1-[[l-cyano-2-(2-oxo-lH- quinolin-4-yl)ethyl] carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2-carboxamide (20.74 mg, 41.13 umol, 23.66% yield, 99.079% purity) was obtained as a solid. MS (ESI) m/z 500.2 [M+H] ⁺

[000393] Prep-HPLC condition: column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water(10 mM NH4HCO ₃ )-ACN];B%: 30%-65%, 10 min

[000394] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.93 (br d, J = 8.16 Hz, 1 H), 7.50 - 7.58 (m, 1 H), 7.28 - 7.40 (m, 2 H), 7.26 (dd, J= 11.47, 0.66 Hz, 1 H), 7.11 - 7.19 (m, 1 H), 7.04 (dd, J= 8.27, 4.08 Hz, 1 H), 6.59 - 6.70 (m, 1 H), 6.46 - 6.56 (m, 1 H), 5.24 - 5.34 (m, 1 H), 4.53 (td, J= 10.31, 5.18 Hz, 1 H), 3.93 (d, J= 4.41 Hz, 3 H), 3.40 - 3.59 (m, 3 H), 1.72 (ddd, J= 15.16, 9.87, 5.18 Hz, 1 H), 1.53 - 1.66 (m, 2 H), 1.40 - 1.50 (m, 1 H), 0.87 - 1.01 (m, 5 H)

Step 6: methyl 2-amino-3-(2-oxo-lH-quinolin-4-yl)propanoate

[000395] To 2-amino-3-(2-oxo-lH-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 N ₂ . 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-lH-quinolin-4-yl)propanoate (370 mg, crude, HC1) was obtained as a solid and used directly next step.

Example 28. Synthesis of viral protease inhibitor compound 249

Step 1: 2-amino-3-(2-oxo-3, 4-dihydro- lH-quinolin-4-yl)propanoic acid

[000396 ] To a solution of 2-amino-3-(2-oxo-lH-quinolin-4-yl)propanoic acid (200 mg,

861.20 umol, 1 eq) in H ₂ O (1 mL) was added Pd/C (20 mg, 861.20 umol, 10% purity) at

25 °C under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (861.20 umol) (15psi) 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-lH- 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] ⁺

[000397] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.92 - 2.03 (m, 1 H) 2.06 - 2.21 (m, 1 H) 2.45 - 2.62 (m, 1 H) 2.86 (dd,J= 16.43, 6.06 Hz, 1 H) 3.32 - 3.40 (m, 1 H) 3.83 (br dd ,J= 8.49, 5.84 Hz, 1 H) 3.93 (br t, J = 6.95 Hz, 1 H) 6.93 (d, J= 7.72 Hz, 1 H) 7.01 - 7.10 (m, 1 H) 7.24 (br t ,J= 7.72 Hz, 1 H) 7.36 (d, J=7.06 Hz, 1 H)

Step 2: methyl 2-amino-3-(2-oxo-3,4-dihydro-lH-quinolin-4-yl)propanoate

[000398] To 2-amino-3-(2-oxo-3,4-dihydro-lH-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 N ₂ . 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- 1 H- quinolin-4-yl)propanoate (260 mg, crude, HC1) was obtained as the yellow oil and used directly next step. MS (ESI) m/z 249.1 [M+H] ⁺

Step 3: methyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoyl]amino]-3- (2-oxo-3,4-dihydro-lH-quinolin-4-yl)propanoate [000399] To a mixture of methyl 2-amino-3-(2-oxo-3,4-dihydro-lH-quinolin-4- yl)propanoate (260 mg, 913.12 umol, 1 eq, HC1) and (2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4-methyl-pentanoic acid (277.90 mg, 913.12 umol, 1 eq), DIPEA (590.07 mg, 4.57 mmol, 795.24 uL, 5 eq) in THF (0.6 mL) and DCM (0.6 mL) was added T3P (871.61 mg, 1.37 mmol, 814.59 uL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. 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 pre-HPLC. Methyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoyl]amino]-3-(2-oxo -3 ,4-dihydro- lH-quinolin-4-yl)propanoate (85 mg, 151.05 umol, 16.54% yield, 95% purity) was obtained as a solid. MS (ESI) m/z 535.2 [M+H] ⁺

[000400] ^Prep-HPLC condition: column: Phenomenex Gemini-NX 80*40 mm*3 um;mobile phase: [water(10 mMNH4HC03)- ACN];B%: 27%-47%,8 min

Step 4: N-[(JS)-1-[[2-amino-2-oxo-1-[(2-oxo-3, 4-dihydro- JH-quinolin-4- yl)methyl ] ethyl ] carbamoyl ] -3-methyl-butyl ]-4-methoxy-lH-indole-2-carboxamide

[000401] To a mixture of methyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoyl] amino]-3-(2-oxo-3,4-dihydro-lH-quinolin-4-yl)propanoate (55 mg, 102.88 umol, 1 eq) was added NH ₃ /MeOH (7 M, 1.83 mL, 124.74 eq) in one portion at 25 °C under N ₂ . 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-lH-quinolin-4-yl)methyl]ethyl]carbamoyl] -3-methyl-butyl]-4- methoxy-lH-indole-2-carboxamide (55 mg, crude) was obtained as a solid and used directly next step. MS (ESI) m/z 518.2 [M+H] ⁺

Step 5: N-f (1S)-1-[[1 -cyano-2-(2-oxo-lH-quinolin-4-yl)ethyl ] carbamoyl ]-3-methyl-butyl ]-4- methoxy- lH-indole-2-carboxamide

[000402] To a mixture of N-[(1S)-1-[[2-amino-2-oxo-1-[(2-oxo-3,4-dihydro-lH-quinolin- 4-yl)methyl]ethyl] carbamoyl]-3-methyl-butyl]-4-methoxy-lH-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 N ₂ . 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-[( 1 S)- 1 -[[ 1 -cyano-2-(2-oxo-3 ,4-dihydro- 1 H- quinolin-4-yl) ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2-carbo xamide (26.51 mg, 52.85 umol, 36.62% yield, 100% purity) was obtained as a solid. MS (ESI) m/z 502.2 [M+H] ⁺

[000403] Prep-HPLC condition: column: Waters Xbridge BEH C18 100*25mm*5 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,10 min

[000404] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.51 - 11.61 (m, 1 H), 10.14 - 10.20 (m, 1 H), 8.84 - 9.01 (m, 1 H), 8.42 - 8.59 (m, 1 H), 7.32 - 7.42 (m, 1 H), 7.05 - 7.22 (m, 3 H), 6.81 - 7.04 (m, 3 H), 6.50 (dd, J = 7.64, 3.85 Hz, 1 H), 4.37 - 4.66 (m, 2 H), 3.83 - 3.95 (m, 3 H), 2.95 - 3.12 (m, 1 H), 2.63 - 2.82 (m, 1 H), 2.26 - 2.42 (m, 1 H), 1.88 - 2.08 (m, 2 H), 1.45 - 1.82 (m, 3 H), 0.81 - 1.02 (m, 6 H)

Step 6: (S)-tert-butyl 2-(4-methoxy-lH-indole-2-carboxamido)-4-methylpentanoate [000405] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (15 g, 78.46 mmol, 1 eq) and tert-butyl (2S)-2-amino-4-methyl-pentanoate (21.07 g, 94.15 mmol, 1.2 eq, HC1) in DMF (150 mL) was added EDCI (19.55 g, 102.00 mmol, 1.3 eq), HOBt (13.78 g, 102.00 mmol, 1.3 eq), TEA (23.82 g, 235.38 mmol, 32.76 mL, 3 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 2 h. The reaction mixture was added water (450 mL) and extracted with EtOAc (250 mL * 3) to get the organic phase. The organic phase was washed with 5% citric acid (300 mL) and 5% aqueous solution of sodium bicarbonate (300 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to get the product. The residue was purified by column chromatography (SiO ₂ , petroleum ether: EtOAc=30:l to 10:1). tert-butyl (2S)-2-[(4-methoxy- 1 H-indole- 2-carbonyl)amino]-4-methyl- pentanoate (24 g, 66.58 mmol, 84.87% yield) was obtained as a solid. MS (ESI) m/z 361.2 [M+H] ⁺

Step 7: (S)-2-(4-methoxy-lH-indole-2-carboxamido)-4-methylpentanoic acid

[000406] To a mixture of tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoate (10 g, 27.74 mmol, 1 eq) in DCM (30 mL) was added TEA (61.60 g, 540.26 mmol, 40 mL, 19.47 eq) and H ₂ O (4.00 g, 221.98 mmol, 4.00 mL, 8.00 eq) in one portion at 0 °C under N ₂ . The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to get the crude product. The crude product was purified with petroleum ether: ethyl acetate = 10: 1(20 mL) and filtered to get the product. (2S)-2-[(4- methoxy- 1 H-indole-2-carbonyl)amino]-4-methyl-pentanoic acid (6 g, 19.22 mmol, 69.27% yield, 97.48% purity) was obtained as a solid. MS (ESI) m/z 305.1 [M+H] ⁺

Example 29. Synthesis of viral protease inhibitor compound 600

Step 1: methyl 2-amino-3-(2-oxo-l,2-dihydropyridin-3-yl)propanoate [000407] A mixture of 2-amino-3-(2-oxo-lH-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, HCI) as a yellow oil and used directly for next step. MS (ESI) m/z 197.0 [M+H] ⁺

Step 2: methyl-2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentana mido)-3-(2-oxo-l,2- dihydropyridin-3-yl)propanoate

[000408] A mixture of methyl 2-amino-3-(2-oxo-lH-pyridin-3-yl)propanoate (650 mg, 2.79 mmol, 1 eq, HCI), (2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoic acid (646.16 mg, 2.79 mmol, 1 eq), EDCI (1.07 g, 5.59 mmol, 2 eq), DMAP (682.62 mg, 5.59 mmol, 2 eq), DMF (2 mL) and DCM (4 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc= 0/1) to get the product methyl-2- ((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-( 2-oxo-l,2-dihydropyridin- 3-yl)propanoate (900 mg, 1.89 mmol, 67.68% yield, 86.02% purity), as a solid. MS (ESI) m/z 410.1 [M+H] ⁺

Step 3: methyl 2-((S)-2-amino-4-methylpentanamido)-3-(2-oxo-l,2-dihydropyri din-3- yl)propanoate

[000409] A mixture of methyl-2-((S)-2-((tert-butoxycarbonyl)amino)-4- methylpentanamido)-3-(2-oxo-l,2-dihydropyridin-3-yl)propanoa te (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-l,2-dihydropyridin-3-yl) propanoate (170 mg, crude, HC1) as a solid and used directly for next step.

Step 4: methyl 2-((S)-2-(4-methoxy-lH-indole-2-carboxamido)-4-methylpentana mido)-3-(2- oxo-1, 2-dihydropyridin-3-yl)propanoate

[000410] A mixture of methyl 2-((S)-2-amino-4-methylpentanamido)-3-(2-oxo-l,2- dihydropyridin-3-yl)propanoate (170 mg, 491.58 umol, 1 eq, HC1), 4-methoxy-lH- indole-2-carboxylic acid (93.98 mg, 491.58 umol, 1 eq), EDCI (188.47 mg, 983.17 umol, 2 eq), DMAP (120.11 mg, 983.17 umol, 2 eq), DMF (2 mL) and DCM (4 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc= 0/1) to get the compound methyl 2-((S)-2-(4-methoxy-lH-indole-2-carboxamido)-4- methylpentanamido)-3-(2-oxo-l,2-dihydropyridin-3-yl)propanoa te (130 mg, 269.41 umol, 54.81% yield), as a solid. MS (ESI) m/z 483.1 [M+H] ⁺

Step 5: N-( (2S)-l-( ( 1 -amino- 1 -oxo-3 -( 2-oxo-l, 2-dihydropyridin-3-yl)propan-2-yl)ammo)-4- methyl-l-oxopentan-2-yl)-4-methoxy-lH-indole-2-carboxamide

[000411 ] A mixture of methyl 2-((S)-2-(4-methoxy-lH-indole-2-carboxamido)-4- methylpentanamido)-3-(2-oxo-l,2-dihydropyridin-3-yl)propanoa te (190 mg, 393.76 umol, 1 eq), NH ₃ /MeOH (7 M, 10 mL) was stirred at 80 °C for 15 h. The reaction mixture was concentrated under reduced pressure to give N-((2 S)- 1 -(( 1 -amino- 1 -oxo-3 -(2-oxo- l,2-dihydropyridin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopen tan-2-yl)-4-methoxy-lH- indole-2-carboxamide (190 mg, crude) as a solid. MS (ESI) m/z 468.2 [M+H] ⁺

Step 6: N-( (2S)-l-( ( l -cyano-2-(2-oxo-J, 2-dihydropyridin-3-yl)ethyl)amino)-4-methyl-1- oxopentan-2-yl)-4-methoxy-1H-indole-2-carboxamide

[000412] A mixture of N-((2S)- 1 -(( 1 -amino- 1 -oxo-3-(2-oxo- 1 ,2-dihydropyridin-3- yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-4-methoxy-l H-indole-2-carboxamide (180 mg, 385.01 umol, 1 eq), Burgess reagent (917.53 mg, 3.85 mmol, 10 eq) and DCM (30 mL) was stirred at 25 °C for 8 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um;mobile phase:

[water(0.05%NH ₃ H ₂ 0+10mM NH4HCO ₃ )-ACN];B%: 25%-45%,8min) to get the product N-((2S)- 1 -(( 1 -cyano-2-(2-oxo- 1 ,2-dihydropyridin-3-yl)ethyl)amino)-4-methyl- 1 - oxopentan-2-yl)-4-methoxy-lH-indole-2-carboxamide (24 mg, 52.18 umol, 13.55% yield, 97.73% purity), as a solid. MS (ESI) m/z 450.2 [M+H] ⁺ .

[000413] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.90-11.40 (m, 2H), 9.08 - 8.85 (m, 1H), 8.55 - 8.35 (m, 1H), 7.51 - 7.26 (m, 3H), 7.16 - 7.05 (m, 1H), 7.04 - 6.94 (m, 1H), 6.51 (d, J=7.5 Hz, 1H), 6.15 (t, J=6.6 Hz, 1H), 5.19 - 5.01 (m, 1H), 4.55 - 4.33 (m, 1H), 3.89 (s, 3H), 3.02 - 2.78 (m, 2H), 1.75 - 1.33 (m, 3H), 0.98 - 0.72 (m, 6H)

Example 30. Synthesis of viral protease inhibitor compounds 344C, 344D, 507 and 511 Step for compound 344C: N-[(lS)-l-[[(lS)-2-amino-2-cyano-l-[[(3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ]-3- methyl-butyl ]-4-methoxy-lH-indole-2-carboxamide

[000414] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- y 1 ]ethy 1 ]carbamoy 1 ]-3 -methyl- butyl]-4-methoxy-lH-indole-2-carboxamide (100 mg, 180.79 umol, 80% purity, 1 eq) in DCM (10 mL) was added NH3.H ₂ O (46.93 mg, 361.58 umol, 51.57 uL, 27% purity, 2 eq) and NH4CI (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 H ₂ O (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 H ₂ O (10 mL) at 0 °C, and then diluted with H ₂ O (10 mL) and extracted with EtOAc (30 mL * 2). The combined organic layers were washed with brine (30 mL), dried over Na ₂ S0 ₄ , 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 HC1 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-lH-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] ⁺ prep-HPLC condition: column: Phenomenex luna C 1880*40mm*3 um;mobile phase: [water(0.04%HC1)- ACN] ; B%:

15% - 40%,7min

[000415] ¹ H NMR (400MHz, DMSO-d6) δ = 11.59 (dd, J=1.9, 5.0 Hz, 1H), 9.16 - 8.58 (m, 2H), 8.54 - 8.26 (m, 2H), 7.66 (d, J=9.0 Hz, 1H), 7.37 (dd, J=2.0, 4.2 Hz, 1H), 7.14 - 7.06 (m, 1H), 7.04 - 6.97 (m, 1H), 6.51 (d, J=7.5 Hz, 1H), 4.61 - 4.42 (m, 2H), 4.39 - 4.21 (m, 1H), 3.88 (s, 3H), 3.20 - 2.98 (m, 2H), 2.48 - 2.34 (m, 1H), 2.14 - 1.88 (m, 2H), 1.82 - 1.47 (m, 5H), 0.92 (dd, J=6.0, 14.8 Hz, 6H)

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

[000416] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- y 1 ]ethy 1 ]carbamoy 1 ]-3 -methyl- butyl]-4-methoxy-lH-indole-2-carboxamide (80 mg, 108.47 umol, 60% purity, 1 eq) in DCM (5 mL) was added PdCh (3.85 mg, 21.69 umol, 0.2 eq), Na2SO4 (53.93 mg, 379.66 umol, 38.52 uL, 3.5 eq), and ethanamine (9.78 mg, 216.95 umol, 14.19 uL, 2 eq). The resulting mixture was stirred at 25 °C for 30 min, and then added with TMSCN (21.52 mg, 216.95 umol, 27.14 uL, 2 eq). The resulting mixture was stirred at 25 °C for 1 h. Once the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by HC1 prep-HPLC to yield 70 mg of the mixture. The mixture was purified by SFC to get the N-[(l S)-1-[[(l S)-2-cyano-2-(ethylamino)-1-[[(3S)-2-oxo pyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indo le-2-carboxamide (16 mg, 28.20 umol, 26.00% yield, 87.525% purity) as an oil and N-[(1S)-1-[[(1S) -2-cyano- 2-(ethylamino)- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-but yl]- 4-methoxy- 1 H-indole-2-carboxamide (16 mg, 31.44 umol, 28.98% yield, 97.569% purity) as a solid. MS (ESI) m/z 497.3 [M+H] ⁺

Prep-HPLC condition: column: Phenomenex lunaCIS 80*40mm*3 um;mobile phase: [water(0.04%HCl)-ACN];B%:

25%-40%,7min

SFC condition: column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [Neu-ET OH] ;B% :

38% - 38%, 9min

[000417] Compound 511 Isomer 1 : ¹ H NMR (400MHz, DMSO-i/6) δ = 11.56 (br s, 1H),

8.37 (br d, J=7.7 Hz, 1H), 8.29 - 8.20 (m, 1H), 7.80 - 7.48 (m, 3H), 7.35 (br d, J=2.0 Hz, 1H), 7.17 - 6.96 (m, 2H), 6.50 (d, 3=1.1 Hz, 1H), 4.53 - 4.40 (m, 1H), 4.05 (td, J=3.9, 7.7 Hz, 1H), 3.88 (s, 3H), 3.77 (br dd,J=4.9, 10.1 Hz, 1H), 3.18 - 2.97 (m, 2H), 2.88 - 2.63 (m, 2H), 2.40 - 2.24 (m, 1H), 2.14 - 2.06 (m, 2H), 1.82 - 1.31 (m, 5H), 1.09 - 0.98 (m, 3H), 0.91 (br dd, J=6.2, 16.1 Hz, 6H)

[000418] Compound 511 Isomer 2 : ¹ H NMR (400MHz, DMSO-J6) δ = 11.58 (d, J=1.5 Hz, 1H), 8.41 (br d, J=7.9 Hz, 1H), 8.17 (br s, 1H), 7.63 - 7.50 (m, 1H), 7.37 (d, J=1.8 Hz, 1H), 7.14 - 7.05 (m, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.50 (d, J=7.5 Hz, 1H), 4.58 - 4.37 (m, 1H), 4.25 - 3.99 (m, 1H), 3.88 (s, 3H), 3.81 - 3.51 (m, 1H), 3.16 - 2.96 (m, 2H), 2.89 - 2.54 (m, 2H), 2.43 - 2.23 (m, 1H), 2.20 - 1.99 (m, 1H), 1.95 - 1.43 (m, 6H), 1.10 - 0.98 (m, 3H), 0.91 (dd, J=6.4, 15.2 Hz, 6H)

Step for compound 507: N-[(lS)-l-[[(lS)-2-(benzylamino)-2-cyano-l-[[(3S)-2-oxopyrro lidin- 3-yl ]methyl ] ethyl ] carbamoyl ] -3-methyl-butyl ]-4-methoxy-lH-indole-2 -carboxamide [000419] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl- butyl]-4-methoxy-lH-indole-2-carboxamide (150 mg, 271.18 umol, 80% purity, 1 eq) in DCM (15 mL) was added PdCl2 (9.62 mg, 54.24 umol, 0.2 eq), Na ₂ S0 ₄ (134.82 mg, 949.14 umol, 96.30 uL, 3.5 eq) and BnNH ₂ (58.11 mg, 542.36 umol, 59.12 uL, 2 eq). The mixture was stirred at 25 °C for 30 min, then added with TMSCN (53.81 mg, 542.36 umol, 67.85 uL, 2 eq). The mixture was stirred at 25 °C for 2 hours. Once the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by HC1 prep-HPLC to get the compound N-[(1S)-1-[[(1S)-2-(benzylamino)-2-cyano-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4 -methoxy-lH-indole-2- carboxamide (30 mg, 51.71 umol, 19.07% yield, 96.291% purity) and N-[(1S)-1-[[(1S)-2- (benzylamino)-2-cyano-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]e thyl] carbamoyl]-3- methyl-butyl]-4-methoxy-lH-indole-2-carboxamide (18 mg, 31.04 umol, 11.44% yield, 96.329% purity) as a solid. MS (ESI) m/z 559.3 [M+H] ⁺

Prep-HPLC condition: column: Phenomenex luna C1880*40mm*3 um;mobile phase: [water(0.04%HCl)-ACN];B%: 38%-62%,7min

[000420] Compound 507 Isomer 1 : ¹ H NMR: (400MHz, DMSO-d6) δ = 11.58 (d, J=1.8 Hz, 1H), 8.48 - 8.34 (m, 1H), 8.23 (br d, J=9.5 Hz, 1H), 7.69 - 7.53 (m, 1H), 7.51 - 7.23 (m, 5H), 7.14 - 7.05 (m, 1H), 7.02 - 6.97 (m, 1H), 6.50 (d, J=7.7 Hz, 1H), 4.56 - 4.37 (m, 1H), 4.23 (br d, J=9.3 Hz, 1H), 4.13 - 3.91 (m, 2H), 3.88 (s, 3H), 3.84 (br d, J=13.2 Hz, 1H), 3.17 - 2.95 (m, 2H), 2.42 - 2.24 (m, 1H), 2.16 - 1.98 (m, 1H), 1.93 - 1.44 (m, 6H), 0.90 (dd, J=6.3, 16.2 Hz, 6H)

[000421] Compound 507 Isomer 2: ¹ H NMR (400MHz, DMSO-d6) δ = 11.56 (br d, J=1.5 Hz, 1H), 8.52 - 8.14 (m, 2H), 7.69 - 7.55 (m, 1H), 7.49 - 7.22 (m, 6H), 7.13 - 7.05 (m, 1H), 7.00 (d, J=8.4 Hz, 1H), 6.50 (d, J=7.5 Hz, 1H), 4.56 - 4.41 (m, 1H), 4.21 (br s, 1H), 4.06 - 3.94 (m, 2H), 3.88 (s, 3H), 3.83 (br d, J=12.8 Hz, 1H), 3.17 - 2.97 (m, 2H), 2.42 - 2.29 (m, 1H), 2.17 - 2.00 (m, 2H), 1.83 - 1.44 (m, 5H), 0.90 (dd, J=6.3, 17.8 Hz, 6H)

Example 31. Synthesis of viral protease inhibitor compound 129

Step 1. 2-(trichloromethyl)-3H-imidazo[4,5-c]pyridine

[000422] 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 H ₂ O (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] ⁺

Step 2: N-f ( l S)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ]cmtmo]-l- (cyclopropylmethyl)-2-oxo-ethyl]-3H-imidazo[4,5-c]pyridine-2 -carboxamide

[000423] To a solution of 2-(trichloromethyl)-3H-imidazo[4,5-c]pyridine (150 mg, 634.29 umol, 1 eq) and (2S)-2-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]et hyl]-3- cyclopropyl-propanamide( 167.66 mg, 634.29 umol, 1 eq) in THF (5 mL) and H ₂ O (2.5 mL) was added Na ₂ CO ₃ (201.68 mg, 1.90 mmol, 3 eq). The solution was stirred for 1 h at 20 °C. The solution was added with H ₂ O (20 mL), extracted with ethyl acetate (40 mL *

3) and concentrated to give crude. The crude was purified by pre-HPLC(Column : Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (lOmM NH ₄ HC03)-ACN]; B%: l%-23%, 8min) to give 70% purity product and then continue purified by pre- HPLC(Column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.2%FA)-ACN]; B%: l%-30%, 8min) to give product N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)- 2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-ox o-ethyl]-3H-imidazo[4,5- c]pyridine-2-carboxamide (3 mg, 6.96 umol, 1.10% yield, 95% purity) was obtained as a solid. MS (ESI) m/z 410.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.89 - 8.81 (m, 2H), 8.77 (d, J=7.9 Hz, 1H), 8.21 (d, J=5.4 Hz, 2H), 7.54 (s, 1H), 7.43 (br d, J=5.4 Hz, 1H), 4.91 - 4.76 (m, 1H), 4.44 - 4.32 (m, 1H), 3.02 - 2.92 (m, 2H), 2.25 - 2.16 (m, 1H), 2.03 - 1.91 (m, 2H), 1.78 - 1.38 (m, 4H), 0.59 (br s, 1H), 0.25 (br d, J=7.9 Hz, 2H), 0.05 - 0.11 (m, 2H).

Example 32. Synthesis of viral protease inhibitor compound 389A and 389B

Step 1: (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide

[000424] tert- Butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamate (2 g, 7.37 mmol, 1 eq) in HCl/EtOAc (4 M, 50 mL, 27.13 eq) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressure affording the product (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanamide (1.2 g, crude) as a solid.

Step 2: Methyl 2-azaspiro[4.5]decane-3-carboxylate

[000425] 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.

Step 3: Methyl 2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-c arboxylate [000426] To a solution of methyl 2-azaspiro[4.5]decane-3-carboxylate (2 g, 10.14 mmol,

1 eq) and 4-methoxy-1H-indole-2-carboxylic acid (2.33 g, 12.17 mmol, 1.2 eq) in DCM (30 mL) and DMF (5 mL) was added T3P (12.90 g, 20.28 mmol, 12.06 mL, 50% purity, 2 eq) and DIEA (3.93 g, 30.41 mmol, 5.30 mL, 3 eq). The mixture was stirred at 25 °C for

2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (100 mL), and extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ethenEthyl acetate = 10: 1 to 0: 1) to afford the product methyl 2-(4-methoxy- 1H-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxylate (3 g, 8.10 mmol, 79.88% yield) as a solid. MS (ESI) m/z 371.1 [M+H] ⁺

Step 4: 2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-c arboxylic acid

[000427] 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 H ₂ O (15 mL) was added LiOH.H ₂ O (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 H ₂ O (50 mL), and then added aq. HC1 (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 Na ₂ SO ₄ , 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] ⁺

Step 5: N-( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-( 4-methoxy-lH- indole-2-carbonyl)-2-azaspiro[4.5Jdecane-3-carboxamide

[000428] To a solution of 2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3- carboxylic acid (1 g, 2.81 mmol, 1 eq) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yljpropanamide (720.49 mg, 4.21 mmol, 1.5 eq) in DCM (30 mL) was added T3P (3.57 g, 5.61 mmol, 3.34 mL, 50% purity, 2 eq) and DIEA (1.09 g, 8.42 mmol, 1.47 mL, 3 eq) at

0 °C. The mixture was stirred at 30 °C for 1 h. Upon completion, the mixture was quenched by addition H ₂ O (100 mL), and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, DCM:MeOH = 1 :0 to 10: 1) affording the product N- [(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]eth yl]-2-(4-methoxy-1H- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (700 mg, 1.37 mmol, 48.96% yield) as a white solid. MS (ESI) m/z 510.3 [M+H] ⁺

Step 6: N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-metho xy-lH-indole-2- carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[000429] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspi ro[4.5]decane-3- carboxamide (700 mg, 1.37 mmol, 1 eq) in DCM (10 mL) was added Burgess reagent (982.03 mg, 4.12 mmol, 3 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Kromasil C18 (250 * 50 mm * 10 um); mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30% - 60%, 10 min) affording the product N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-met hoxy-1H-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (500 mg, 1.02 mmol, 74.05% yield) as a white solid. MS (ESI) m/z 492.3 [M+H] ⁺

Step 7: N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-metho xy-lH-indole-2- carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[000430] N-[(1S)-1-cyano-2-[(3S)-2-oxopyirolidin-3-yl]ethyl]-2-(4-met hoxy-1H-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (500 mg, 1.02 mmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase:

[0.1% NH ₃ H ₂ O IP A]; B%: 55% - 55%, 9 min) to afford the product N-[(1S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-methoxy-1H-indole-2-c arbonyl)-2- azaspiro[4.5]decane-3-carboxamide, Isomer 1 (264 mg, 537.04 umol, 52.80% yield) as a solid. MS (ESI) m/z 492.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.28 - 6.76 (m, 3H), 6.60 - 6.38 (m, 1H), 5.05 (br dd, J= 5.2, 10.2 Hz, 1H), 4.63 - 4.60 (m, 1H), 4.03 - 3.85 (m, 5H), 3.74 - 3.28 (m, 1H), 2.73 (br dd, J= 5.0, 8.6 Hz, 1H), 2.51 - 2.28 (m, 2H), 2.27 - 2.08 (m, 1H), 1.96 - 1.72 (m, 2H), 1.69 - 1.38 (m, 11H), 1.37 - 1.09 (m, 1H); and [000431 ] N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-met hoxy-1H-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide, Isomer 2 (140 mg, 284.51 umol, 27.97% yield) as a solid. MS (ESI) m/z 492.3 [M+H] ⁺ ; ¹ H NMR (400 MHz, METHANOL-d4) δ = 7.30 - 6.81 (m, 3H), 6.53 (br d,J= 2.0 Hz, 1H), 5.12 - 4.95 (m, 2H), 4.70 - 4.55 (m, 2H), 4.08 - 3.86 (m, 4H), 3.84 - 3.72 (m, 1H), 2.62 - 2.40 (m, 1H), 2.36 - 2.18 (m, 2H), 1.94 - 1.69 (m, 3H), 1.68 - 1.34 (m, 11H).

Example 33. Synthesis of viral protease inhibitor compound 399

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride

[000432] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (130 mg, 454.03 umol, 1 eq) in HCl/dioxane (4 M, 2.27 mL, 20 eq) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to get the product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (173.4 mg, 451.67 umol, 99.48% yield, HC1) was obtained as yellow liquid.

Step 2: (S)-tert-butyl 7-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 - yl) carbamoyl) -6-azaspiro[ 3.4 ]octane-6-carboxylate

[000433] To a solution of (7S)-6-tert-butoxycarbonyl-6-azaspiro[3 ,4]octane-7-carboxylic acid (105.34 mg, 412.59 umol, 1 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (158.4 mg, 412.59 umol, 1 eq, HC1) in DCM (1.2 mL) and DMF (0.4 mL) was added DMAP (100.81 mg, 825.19 umol, 2 eq) and EDCI (158.19 mg, 825.19 umol, 2 eq). The reaction mixture was stirred at 25 °C for 1 h. The residue was diluted with H ₂ O (6 mL) and extracted with ethyl acetate (3 mL). The combined organic layers were washed with ethyl acetate (3 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether/ethyl acetate=0/l) to get the product tert-butyl (7S)-7-[[(l S)-2-methoxy- 2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6-azaspiro[3 ,4]octane-6- carboxylate (66.3 mg, 156.55 umol, 37.94% yield) was obtained as a liquid. MS (ESI) m/z 424.0 [M+H] ⁺

Step 3: (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-6-azaspiro[3.4]octane-7- carboxamido)propanoate

[000434] A solution of tert-butyl (7S)-7-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6-azaspiro[3.4]oc tane-6-carboxylate (66.3 mg, 156.55 umol, 1 eq) in HCl/MeOH (4 M, 782.76 uL, 20 eq) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to get the product methyl (2S)-2-[[(7S)-6-azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S )-2-oxopyrrolidin- 3-yl]propanoate (71.1 mg, 156.09 umol, 99.71% yield, 79% purity, HC1) was obtained as a yellow liquid.

Step 4: (S)-methyl 2-((S)-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspiro[3.4]oct ane-7- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000435] To a solution of methyl (2S)-2-[[(7S)-6-azaspiro[3.4]octane-7-carbonyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (62.8 mg, 137.87 umol, 1 eq, HC1) and 4- methoxy- 1 H-indole-2-carboxylic acid (26.36 mg, 137.87 umol, 1 eq) in DCM (1.2 mL) and DMF (0.4 mL) was added DMAP (33.69 mg, 275.74 umol, 2 eq) and EDCI (52.86 mg, 275.74 umol, 2 eq) at 25 °C for 1 h. The residue was diluted with brine (6 mL) and extracted with ethyl acetate (3 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether/ethyl acetate=0/l) to get the product methyl (2S)-2-[[(7S)-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspiro[ 3.4]octane-7- carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (33.2 mg, 66.86 umol, 48.50% yield) was obtained as a white solid. MS (ESI) m/z 497.1 [M+H] ⁺ Step 5: (S)-N-( (S)-l -amino- l-oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6-( 4-methoxy-JH- indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000436] A mixture of methyl (2S)-2-[[(7S)-6-(4-methoxy-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-oxopyrrolidi n-3-yl]propanoate (23.0 mg, 46.32 umol, 1 eq) and ammonia (7 M, 4 mL, 604.50 eq) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to get the product (7S)-N- [(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]eth yl]-6-(4-methoxy-lH- indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide (15 mg, crude) was obtained as a yellow solid. MS (ESI) m/z 482.2 [M+H] ⁺

Step 6: (S)-N-( (S)-l-cyano-2-( (S)-2-oxopyrrolidin-3-yl)ethyl)-6-( 4-methoxy- lH-indole-2- carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000437] A solution of (7S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspi ro[3.4]octane-7- carboxamide (15 mg, 28.66 umol, 1 eq) and Burgess reagent (13.66 mg, 57.32 umol, 2 eq) was stirred at 25 °C for 24 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 30mm * lOum; mobile phase: [water(10 mM NH4HCO3)- ACN] ; B%: 20% - 45%, 8min) to get the product (7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspiro[3. 4]octane-7-carboxamide (3.01 mg, 6.49 umol, 22.66% yield) was obtained as a solid. MS (ESI) m/z 464.3 [M+H] ^{+ 1} H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 6.95 - 7.24 (m, 3 H) 6.47 - 6.58 (m, 1 H) 5.01 (br dd, J=10.67, 5.19 Hz, 1 H) 4.58 (t, J=7.09 Hz, 1 H) 3.82 - 4.19 (m, 5 H) 3.19 (br t, J=8.52 Hz, 1 H) 2.93 - 3.07 (m, 1 H) 2.28 - 2.56 (m, 3 H) 2.16 - 2.27 (m, 2 H) 1.94 - 2.14 (m, 6 H) 1.47 - 1.86 (m, 2 H).

Example 34. Synthesis of viral protease inhibitor compound 405

Step 1: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pent anoyl]amino]-3- [ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000438] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (225 mg, 1.21 mmol, 1 eq) in DMF (2 mL) and DCM (4 mL) was added TEA (733.62 mg, 7.25 mmol, 1.01 mL, 6 eq) and T3P (1.15 g, 3.62 mmol, 1.08 mL, 3 eq) and (2S)-2- (tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (296.42 mg, 1.21 mmol, 1 eq). The solution was stirred for 1 h at 25 °C. The reaction was added with H ₂ O (40 mL) and extracted with ethyl acetate (50 mL* 3) and the organic layer was cautiously concentrated to give crude compound methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4- dimethyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propa noate (440 mg, crude) as a solid used directly for the next step. MS (ESI) m/z 414.1 [M+H] ⁺

Step 2: methyl (2S)-2-[[(2S)-2-amino-4, 4-dimethyl-pentanoyl ]amino]-3-[ ( 3S)-2- oxopyrrolidin-3-yl ]propanoate

[000439] 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] ⁺

Step 3: methyl (2S)-2-[[(2S)-2-[(4-methoxy-JH-indole-2-carbonyl)amino]-4,4- dimethyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000440] To a solution of methyl (2 S)-2-[ [(2 S)-2-amino-4,4-dimethy 1-pentanoy 1 ]ami no]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (310 mg, 989.18 umol, 1 eq) in DMF (4 mL) and DCM (4 mL) was added EDCI (379.25 mg, 1.98 mmol, 2 eq) and DMAP (241.70 mg, 1.98 mmol, 2 eq) and 4-methoxy- 1 H-indole-2-carboxylic acid (189.11 mg, 989.18 umol, 1 eq) was added. The solution was stirred for 3 h at 25 °C. The reaction was added with H ₂ O (40 mL) and extracted with ethyl acetate (80 mL* 3) and the organic layer was cautiously concentrated to give crude. The crude was purified by pre-TLC(SiO ₂ , ethyl acetate:MeOH=10: 1) to afford methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxop yrrolidin-3- yl]propanoate (200 mg, 411.05 umol, 41.55% yield). MS (ESI) m/z 487.2 [M-H] ⁺

Step 4: N-f (1S)-1-[[(1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ]-3, 3-dimethyl-butyl / -4-methoxy- lH-indole-2-carboxamide

[000441] A solution of methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxop yrrolidin-3- yl]propanoate (135 mg, 277.46 umol, 1 eq) in NH ₃ /MeOH (7 M, 8 mL, 201.83 eq) was stirred for 16 h at 65 °C. The reaction was cautiously concentrated to give crude. Compound N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-methoxy-lH- indole-2-carboxamide (130 mg, crude) as a solid used directly for the next step. MS (ESI) m/z 472.3 [M+H] ⁺ ; Prep-HPLC condition: column: Phenomenex Gemini -NX C18 75*30 mm*3 um; mobile phase: [water(0.05% NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ )-ACN];B%: 35%-55%, 8min

Step 5: N-f (1S)-1-[[(1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ] carbamoyl ]-3, 3- dimethyl-butyl] -4-methoxy- lH-indole-2-carboxamide [000442] To a solution of N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-methoxy-lH- indole-2-carboxamide (130 mg, 275.69 umol, 1 eq) in DCM (7 mL) was added Burgess reagent (197.09 mg, 827.06 umol, 3 eq) The solution was stirred for 1 h at 25 °C. The reaction was cautiously concentrated to give crude. The crude was purified by pre-HPLC(TFA) to afford N-[(1S)- 1 -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3,3-dimethyl-butyl] -4- methoxy-lH-indole-2-carboxamide (36 mg, 75.41 umol, 27.35% yield, 95% purity) as a solid. MS (ESI) m/z 454.1 [M+H] ⁺ . Prep-HPLC condition: column: Phenomenex luna C18 80*40 mm*3 um; mobile phase: [water(0.04% HC1)-ACN];B%: 30%-55%,7 min; ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.02 (s, 9 H) 1.74 - 1.94 (m, 4 H) 2.21 - 2.37 (m, 2 H) 2.52 - 2.63 (m, 1 H) 3.16 - 3.26 (m, 2 H) 3.92 (s, 3 H) 4.63 (dd, J=8.49, 4.30 Hz, 1 H) 4.98 - 5.06 (m, 1 H) 6.50 (d, J=7.72 Hz, 1 H) 7.02 (d, J=8.38 Hz, 1 H) 7.10 - 7.16 (m, 1 H) 7.23 (d, J=0.88 Hz, 1 H).

Example 35. Synthesis of viral protease inhibitor compound 491 and 491A

Step 1: Methyl (2S)-2-[[3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000443] To the mixture of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (1 g, 4.22 mmol, 1 e#,HCl),3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoic acid (1.5 g, 5.06 mmol, 1.2 eq, HC1) and TEA (1.7 g, 16.88 mmol, 2.35 mL, 4 eq) in DMF (5 mL) was added T3P (5.3 g, 8.44 mmol, 5.02 mL, 50% purity, 2 eq) at 25°C. The mixture was stirred at 25°C for 16 h. TLC (DCM:MeOH =10: l/UV254nm) showed new spot was detected. The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ S0 ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 100-25% Ethyl acetate/MeOH@ 30 mL/min). Compound methyl (2S)-2-[[3-cyclopropyl-2-[(4- methoxy-lH-indole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)- 2-oxo-3- piperidyl]propanoate (1.9 g, 3.84 mmol, 91.0% yield) was obtained as a solid. Methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (50 mg, 0.10 mmol, 1 eq) was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water(0.05%NH ₃ H ₂ 0+10 mMNH ₄ HCO ₃ )-ACN];B%: 20%-50%,9.5 min). Compound methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (50 mg, 0.10 mmol, 1 eq) was obtained as a solid.

Step 2: N-[2-[[( 1 S)-2-amino-2-oxo-l-[[(3S)-2-oxo-3-piperidyl ]methyl ] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide

[000444] The mixture of methyl (2S)-2-[[3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (1.00 g, 1.73 mmol, 84% purity, 1 eq) in NH ₃ (7 M, 24.77 mL, 100 eq) (7M in MeOH) was stirred at 80 °C for 36 h. Then, the reaction mixture was concentrated in vacuum. Compound N- [2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]et hyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide (813 mg, crude) was obtained as yellow solid.

[000445] N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3 - piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-methoxy-lH- indole-2-carboxamide (50 mg, 0.10 mmol, 1 eq) was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3um; mobile phase: [water(0.05% NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ )-ACN];B%: 23%-53%,7.8 min). Compound N-[(1S)-2-[[(l S)-2-amino-2- oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclop ropylmethyl)-2-oxo- ethyl]-4-methoxy-lH-indole-2-carboxamide (20.3 mg, 42.5 umol, 39.9% yield, 98.4% purity) was obtained as white solid. Step 3: N-[2-[[( lS)-l-cyano-2-[ ( 3S)-2-oxo-3-piperidyl ] ethyl ] amino ]-l-(cyclopropylmethyl)- 2-oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide

[000446] A mixture of N-[2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-methoxy-lH- indole-2-carboxamide (663.0 mg, 1.41 mmol, 1 eq) and methoxycarbonyl- (triethylammonio)sulfonyl-azanide (673.0 mg, 2.82 mmol, 2 eq) in DCM (8 mL) was stirred at 25 °C for 16 h. Then, methoxycarbonyl-(triethylammonio)sulfonyl-azanide (336.5 mg, 1.41 mmol, 1 eq) was added at the mixture and the mixture was stirred at 25°C for 16 hr. LC-MS showed that the desired compound was detected. TLC (petroleum ether: ethyl acetate =0: 1/I2) showed new spots were detected. The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water (0.05% NH3H ₂ O+IO mMNH ₄ HC0 ₃ )-ACN]; B%: 23%-53%, 9.5 min). Compound N-[2-[[(1S)-1- cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylm ethyl)-2-oxo-ethyl]-4- methoxy- 1 H-indole-2-carboxamide (450 mg, 0.98 mmol, 69.9% yield) was obtained as yellow solid.

Step 4: N-f ( l S)-2-[[ ( l S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide

[000447] N-[2-[[ 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)- 2-oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide (550.0 mg, 1.22 mmol, 1 eq) was purified by SFC(column: DAICEL CHIRALPAK AD(250 mm*30 mm, 10 um);mobile phase: [0.1% NH3H ₂ O ETOH];B%: 55%-55%, min). Compound N-[(1S)-2-[[(1S)-1- cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylm ethyl)-2-oxo-ethyl]-4- methoxy- 1 H-indole-2-carboxamide, Isomer 1(147.1 mg, 0.25 mmol, 22.1% yield) was obtained as a solid. LCMS: Rt = 0.756 min; for C24H29N5O4 MS Calcd: 451.22, MS Found:452.1 [M+H ⁺ ], ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.56 (br s, 1H), 8.90 (br d ,J= 8.0 Hz, 1H), 8.49 (br d ,J= 7.4 Hz, 1H), 7.52 (br s, 1H), 7.36 (s, 1H), 7.12 - 7.06 (m, 1H), 7.03 - 6.98 (m, 1H), 6.50 (d, J= 7.6 Hz, 1H), 5.17 - 4.96 (m, 1H), 4.56 - 4.33 (m, 1H), 3.88 (s, 3H), 3.09 (br s, 2H), 2.33 - 2.19 (m, 2H), 1.88 - 1.76 (m, 3H), 1.70 (br dd, J= 3.8, 8.3 Hz, 1H), 1.57 (br s, 1H), 1.50 - 1.35 (m, 2H), 0.80 (br s, 1H), 0.41 (br d, J= 6.6 Hz, 2H), 0.25 - 0.03 (m, 2H); and

[000448] N-[(1R)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy- 1H-indole-2-carboxamidem, Isomer 2 (113.1 mg, 0.32mmol, 28.8% yield, 100% purity) was obtained as a solid. LCMS: Rt = 0.761min; for C24H29N5O4MS Calcd: 451.22, MS Found:452.0 [M+H ⁺ ], ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.57 (s, 1H), 8.89 (br d, J= 8.0 Hz, 1H), 8.49 (br d, J= 7.6 Hz, 1H), 7.51 (br s, 1H), 7.36 (d, J= 1.6 Hz, 1H), 7.13 - 7.06 (m, 1H), 7.03 - 6.97 (m, 1H), 6.50 (d, J= 7.5 Hz, 1H), 5.08 - 4.99 (m, 1H), 4.52 - 4.42 (m, 1H), 3.88 (s, 3H), 3.08 (br s, 2H), 2.23 - 2.13 (m, 2H), 1.90 - 1.68 (m, 4H), 1.64 - 1.36 (m, 3H), 0.85 - 0.70 (m, 1H), 0.45 - 0.33 (m, 2H), 0.24 - 0.11 (m, 1H), 0.13 - 0.03 (m, 1H).

Example 36. Synthesis of viral protease inhibitor compound 531

Step 1: methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]-3-cyc lopropyl- propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000449] To a mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (500 mg, 1.68 mmol, 1 eq) in DCM (10 mL) and DMF (2.5 mL), was added DMAP (616.30 mg, 5.04 mmol, 3 eq) in one portion at 25 °C. The mixture was added 7-chloro-lH-indole-2-carboxylic acid (394.69 mg, 2.02 mmol,

1.2 eq) and EDCI (967.04 mg, 5.04 mmol, 3 eq). The resulting mixture was stirred at 25 °C for 2 h. Then, the mixture was concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1 to 0/1) to give methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo pyrrolidin-3- yl]propanoate (550 mg, 1.16 mmol, 68.87% yield) as a white solid. MS (ESI) m/z 475.1 [M+H] ⁺

Step 2: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl]amino]~ l-(cyclopropylmethyl)-2-oxo-ethylJ-7-chloro-lH-indole-2-carb oxamide

[000450] A mixture of methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]-3- cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]pr opanoate (500 mg, 1.05 mmol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 66.49 eq) was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-[[(1S)-2- amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]- 1 -(cyclopropylmethyl)- 2-oxo-ethyl]-7-chloro- 1 H-indole-2-carboxamide (440 mg, 956.68 umol, 90.87% yield) as a solid. MS (ESI) m/z 460.3 [M+H] ⁺

Step 3: 7-chloro-N-[ ( l S)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[000451 ] 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]-7- chloro-lH-indole-2- carboxamide (430 mg, 934.94 umol, 1 eq) in DCM (6 mL) was added Burgess reagent (445.61 mg, 1.87 mmol, 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 the crude product. The crude was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 um; mobile phase: [water(0.05% NH3H ₂ O+IO mM NH4HCO3 ₎ - ACN] ;B% : 30%-60%,8 min) to give 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]- 1 H-indole-2-carboxamide ( 180 mg, 407.32 umol, 43.57% yield) as a solid. MS (ESI) m/z 442.2 [M+H] ⁺ ; ¹ H NMR (400 MHz,

DMSO-d ₆ ) δ = 11.71 (br s, 1H), 9.01 (d, J=7.9 Hz, 1H), 8.72 (d, J=7.5 Hz, 1H), 7.71 (s,

1H), 7.63 (dd, J=0.7, 7.9 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.07 (t, J=7.8 Hz, 1H), 5.00 (q, J=7.9 Hz, 1H), 4.58 - 4.49 (m, 1H), 3.13 (quin, J=9.2 Hz, 2H), 2.42 - 2.31 (m, 1H), 2.22 - 2.05 (m, 2H), 1.89 - 1.64 (m, 3H), 1.57 - 1.46 (m, 1H), 0.89 - 0.75 (m, 1H), 0.50 - 0.37 (m, 2H), 0.25 - 0.07 (m, 2H).

Example 37. Synthesis of viral protease inhibitor compound 635

Step 1 : (2S)-2-amino-N-[ ( l S)-2-amino-2-oxo-l-[ [ ( 3S)-2-oxo-3-piperidyl ] methyl ] ethyl ]-3- cyclopropyl-propanamide

[000452] To a solution of benzyl N-[( 1 S)-2-[ [( 1 S)-2-amino-2-oxo- 1 -[ [(3S)-2-oxo-3 - piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]carbamate (400 mg, 0.92 mmol, 1 eq) in MeOH (5 mL) was added Pd (200 mg, 10% purity) and H ₂ (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.

Step 2: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-lH-indole-2-carbox amide

[000453] To a solution of (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (137 mg, 0.46 mmol, 1 eq) and 6- chloro-1H-indole-2-carboxylic acid (90.4 mg, 0.46 mmol, 1 eq) in DMF (2 mL) was added DIPEA (119.4 mg, 0.92 mmol, 0.16 mL, 2 eq) and HATU (210.9 mg, 0.55 mmol,

1.2 eq). The mixture was stirred at 25 °C for 1 hr. LCMS showed one peak with desired MS was detected. The mixture was 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 Compound N-[(1S)-2- [[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl ]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-1H-indole-2-carbox amide (200 mg, 89.0% yield) as a solid. LCMS: Rt = 0.780 min; for C23H28CIN5O4 MS Calcd. : 473.18; MS Found: 474.1 [M+H ⁺ ],

Step 3: 6-Chloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[000454] 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-et hyl]-6-chloro-1H-indole- 2-carboxamide (47.5 mg, 0.1 mmol, 1 eq) in DCM (1 mL) was added Burgess reagent (71.6 mg, 0.3 mmol, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hr. The mixture was 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% NH3H ₂ O+IO mM NH4HCO3)- ACN] ;B% : 31%-61%,7.8 min) to give compound 6-chloro- N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1-(cyclopropylmethyl)- 2-oxo-ethyl]-1H-indole-2-carboxamide(64.33 mg, 34.7% yield) as a solid. LCMS: Rt = 0.832 min; for C23H26CIN5O3; MS Calcd.:455.17; MS Found: 456.1 [M+H ⁺ ], ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.73 (br s, 1H), 8.95 (br d, J=8.0 Hz, 1H), 8.66 (br d, J=7.5 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.53 (br s, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 7.05 (dd, J=1.8,

8.5 Hz, 1H), 5.11 - 4.96 (m, 1H), 4.52 - 4.42 (m, 1H), 3.09 (br s, 2H), 2.34 - 2.21 (m, 2H), 1.89 - 1.75 (m, 3H), 1.74 - 1.65 (m, 1H), 1.56 (br s, 1H), 1.51 - 1.29 (m, 2H), 0.79 (br s, 1H), 0.42 (br d, J=7.0 Hz, 2H), 0.23 - 0.01 (m, 2H)

Example 38. Synthesis of viral protease inhibitor compound 637

Step 1: 4, 7-Dichloro-2-(trichloromethyl)-lH-benzimidazole [000455] To a solution of 3, 6-di chlorobenzene- 1,2-diamine (0.3 g, 1.69 mmol, 1 eq) in

AcOH (12.57 g, 209.2 mmol, 11.97 mL, 123.8 eq) was added methyl 2,2,2- trichloroacetimidate (313.0 mg, 1.77 mmol, 0.21 mL, 1.05 eq) at 0°C. The mixture was stirred at 25 °C for 16 hr. The resulting mixture was diluted with H ₂ O (40 mL) and filtered to give 4,7-dichloro-2-(trichloromethyl)-lH-benzo[d]imidazole (300 mg, crude) as a solid.

Step 2: 4, 7-Dichloro-lH-benzimidazole-2-carboxylic acid

[000456] To a solution ofNaOH (0.8 g, 20.0 mmol, 20.2 eq) in H ₂ O (10 mL) was added 4,7-dichloro-2-(trichloromethyl)-lH-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 HC1 (2 M) to pH = 2-3 and then the mixture was filtered to give 4,7-dichloro-lH- benzo[d]imidazole-2-carboxylic acid (0.2 g, crude) as a solid.

Step 3: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4,6-dichloro-lH-benzimidazo le-2-carboxamide

[000457] To a solution of (S)-2-amino-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)-3-cyclopropylpropanamide (130 mg, 0.43 mmol, 1 eq) and 4,7-dichloro- lH-benzo[d]imidazole-2-carboxylic acid (101.3 mg, 0.43 mmol, 1.0 eq) in DMF (3 mL) was added HATU (250.1 mg, 0.65 mmol, 1.5 eq) and DIPEA (113.3 mg, 0.87 mmol, 0.15 mL, 2.0 eq). The mixture was stirred at 25 °C for 1 hr. TLC (Dichloromethane: Methanol=10/1) indicated 4,7-dichloro-lH-benzo[d]imidazole-2-carboxylic acid was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate= 100/1 to 10/1) to give N-((S)-1- (((S)-l -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3-cyclopr opyl- 1 - oxopropan-2-yl)-4,7-dichloro-lH-benzo[d]imidazole-2-carboxam ide (0.2 g, 0.39 mmol, 89% yield) as a solid.

Step 4: 4, 7-dichloro-N-[ ( l S)-2-[[( l S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-benzimidazole-2-carboxam ide [000458] To a solution of N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperi din-3 - yl)propan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4,7-di chloro-lH- benzo[d]imidazole-2-carboxamide (100.00 mg, 0.19 mmol, 1 eq) in DCM (3.0 mL) was added Burgess Reagent (140.3 mg, 0.58 mmol, 3.0 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Gemini -NX 80*40mm*3um; mobile phase: [water (0.05% NH3H2O+10 mM NH4HC03)-ACN]; B%: 20%-50%, 7.8 min) to give the product (22.11 mg, 22% yield) as a solid. LCMS : Rt = 0.824 min; for C22H24CI2N6O3 MS Calcd.: 490.13; MS Found: 491.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 7.30 (s, 2H), 5.22 - 5.09 (m, 1H), 4.60 (t, J= 7.1 Hz, 1H), 3.27 - 3.19 (m, 2H), 2.56 - 2.37 (m, 2H), 2.06 - 1.88 (m, 3H), 1.87 - 1.79 (m, 1H), 1.73 (td, J= 7.2, 14.0 Hz, 2H), 1.60 - 1.44 (m, 1H), 0.96 - 0.75 (m, 1H), 0.54 (d, J= 6.9 Hz, 2H), 0.21 (dd, J= 4.8, 10.4 Hz, 2H).

Example 39. Synthesis of viral protease inhibitor compound 639 and 639A

Step 1: Methyl ( 2S) -2-[[( 2S) -2-(tert-butoxycarbonylamino) -3-cyclopropyl-propanoyl ] amino ]- 3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate [000459] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (1.07 g, 4.65 mmol, 1.1 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3- piperidyljpropanoate (1 g, 4.22 mmol, 1 eq, HC1) in DCM (10 mL) was added DMAP (1.55 g, 12.67 mmol, 3 eq) and EDCI (1.62 g, 8.45 mmol, 2 eq). The resulting mixture was stirred at 25 °C for 1 h. Upon completion, the solution was added with H ₂ O (30 mL), and then extracted with ethyl acetate (30 mL * 3). The combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated. The residue was purified by column chromatography (S1O2, DCM/MeOH = 30/1 to 10/1) to give methyl (2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[(3S)- 2-oxo-3-piperidyl] propanoate (1.2 g, 2.92 mmol, 68.97% yield, 100% purity) was obtained as yellow oil.

MS (ESI) m/z 412.3 [M+H] ⁺ .

Step 2: (2R)-N-(4-(tert-butyl)phenyl)-N-(2-oxo-l-(pyridin-3-yl)-2-(( pyridin-4- ylmethyl)amino)ethyl)pyrrolidine-2-carboxamide

[000460] Methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (600 mg, 1.46 mmol, 1 eq) in ammonia (7 M, 7.2 mL, 8.30 eq) was stirred at 50 °C for 14 h. Upon completion, the solution was concentrated to give 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 (580 mg, crude) as yellow oil. MS (ESI) m/z 397.3 [M+H] ⁺ .

Step 3: (2S)-2-amino-N-[ ( l S)-2-amino-2-oxo-l-[ [ ( 3S)-2-oxo-3-piperidyl ] methyl ] ethyl ]-3- cyclopropyl-propanamide

[000461 ] T ert-buty 1 N-[( 1 S)-2-[ [( 1 S)-2-amino-2-oxo- 1-[[(3 S)-2-oxo-3 - piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]carbamate (580 mg, 1.46 mmol, 1 eq) in HCl/MeOH (4 M, 10.00 mL, 7.93 eq) was stirred at 25 °C for 1 h. Upon completion, the solution was concentrated to give (2S)-2-amino-N-[(l S)-2-amino- 2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (380 mg, crude) was obtained as yellow oil. MS (ESI) m/z 297.2 [M+H] ⁺ .

Step 4: ( 2S) -2-amino-N-[ ( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl]methyl]ethyl ]-3- cyclopropyl-propanamide [000462] To a solution of (2S)-2-amino-N-[(l S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (380 mg, 1.28 mmol, 1 eq) in DCM (3 mL) was added 7-chloro-lH-indole-2-carboxylic acid (275.88 mg, 1.41 mmol, 1.1 eq), T3P (1.22 g, 1.93 mmol, 1.14 mL, 50% purity, 1.5 eq), and DIEA (331.44 mg, 2.56 mmol, 446.68 uL, 2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the solution was diluted with H ₂ O (20 mL), extracted with DCM (30 mL * 3), the combined organic phase was dried over Na ₂ S0 ₄ , filtrated and concentrated. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)- 2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)- 2-oxo-ethyl]-7-chloro-lH- indole-2-carboxamide (350 mg, 738.47 umol, 57.59% yield, 100% purity) as yellow oil. MS (ESI) m/z 474.3 [M+H] ⁺ .

Step 5: 7-chloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[000463] 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-et hyl]-7-chloro-lH-indole- 2-carboxamide (350 mg, 738.47 umol, 1 eq) in DCM (4 mL) was added Burgess reagent (527.94 mg, 2.22 mmol, 3 eq), and the solution was stirred at 25 °C for 6 h. Upon completion, DCM was removed using blow dry. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(0.05%NH ₃ H ₂ 0+ 1 OmM NH4HCO ₃ )-ACN];B%: 25%-55%,8min) to afford the product as a solid, which was further separated by SFC (column: DAICEL CHIRALPAK AS(250mm*30mm,10um); mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 33%-33%,8min) to give:

[000464] 7-chloro-N-[(l S)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]-l - (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide (250 mg, 530.89 umol, 74.25% yield, 96.82% purity) as a solid. MS (ESI) m/z 456.2 [M+H] ⁺ . ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.58 (d, J=7.9 Hz, 1H), 7.35 - 7.20 (m, 2H), 7.06 (t, J=7.8 Hz, 1H), 5.22 - 5.05 (m, 1H), 4.57 (t,J=7.5 Hz, 1H), 3.27 - 3.14 (m, 2H), 2.61 - 2.34 (m, 2H), 2.09 - 1.61 (m, 6H), 1.59 - 1.43 (m, 1H), 0.98 - 0.76 (m, 1H), 0.55 (dd, J=1.3, 8.2 Hz, 2H), 0.31 - 0.09 (m, 2H); and [000465] 7-chloro-N-[(lR)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide (45 mg, 98.70 umol, 13.37% yield, 100% purity) as a solid. MS (ESI) m/z 456.2 [M+H] ⁺ . ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.59 (dd, J=0.9, 7.9 Hz, 1H), 7.32 - 7.21 (m, 2H), 7.07 (t, J=7.8 Hz, 1H), 5.12 - 5.02 (m, 1H), 4.59 (dd, J=6.4, 7.9 Hz, 1H), 3.21 (dd,J=4.6, 7.7 Hz, 2H), 2.44 - 2.23 (m, 2H), 2.09 - 1.62 (m, 6H), 1.60 - 1.47 (m, 1H), 0.94 - 0.78 (m, 1H), 0.62 - 0.43 (m, 2H), 0.27 - 0.11 (m, 2H).

Example 40. Synthesis of viral protease inhibitor compound 643

Step 1: Methyl ( 2S) -2-[[( 2S) -2-(tert-butoxycarbonylamino)-4, 4-dimethyl-pentanoyl ] amino ]- 3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000466] T3P (2.69 g, 4.22 mmol, 2.51 mL, 50% purity, 2 eq) was added to a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (500 mg, 2.11 mmol, 1 eq, HC1), (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (570.0 mg, 2.32 mmol, 1.1 eq) and TEA (855.0 mg, 8.45 mmol, 1.18 mL, 4 eq) in DMF (5 mL). The resulting mixture was stirred at 70°C for 16hr. TLC (petroleum ether: ethyl acetate =0: 1/PMA) showed new spots were detected. The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®;20 g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ethergradient @30 mL/min). Compound methyl (2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2 -oxo-3- piperidyl]propanoate (436 mg, 0.99 mmol, 47.2% yield, 97.9% purity) was obtained as a solid.

Step 2: Methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoylJaminoJ-3-[(3S)- 2-oxo-3- piperidyl ]propanoate

[000467] Methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (300 mg, 0.70 mmol, 1 eq) in HCl/dioxane (4 M, 175.42 uL, 1 eq) was stirred at 25°C for 2hr. Compound methyl (2S)- 2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo -3-piperidyl]propanoate (250 mg, crude, HC1) was obtained as a solid and was used into next step without further purification.

Step 3: Methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)aminoJ-4,4- dimethyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000468] A mixture of methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (310 mg, 0.85 mmol, 1 eq, HC1), 4-methoxy-lH- indole-2-carboxylic acid (179.1 mg, 0.93 mmol, 1.1 eq), HATU (647.8 mg, 1.70 mmol, 2 eq) and DIPEA (440.4 mg, 3.41 mmol, 0.60 mL, 4 eq) in DCM (4 mL) was stirred at 25°C for 2hr. TLC (petroleum ether/ethyl acetate =0: 1/UV 254nm) showed new spots were detected. The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0-100% Ethyl acetate/Petroleum ethergradient @ 30mL/min). Compound methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo- 3-piperidyl]propanoate (451 mg, 0.68 mmol, 80.1% yield) was obtained as an oil and confirmed by LC-MS.

Step 4: N-[(lS)-l-[[(lS)-2-amino-2-oxo-l-[[(3S)-2-oxo-3- piperidyl ] methyl ] ethyl ] carbamoyl ]-3, 3-dimethyl-butyl ]-4-methoxy-lH-indole-2-carboxamide [000469] ΝΗ ₃ (7 Μ, 11.42 mL, 100 eq) was added to a mixture of methyl (2S)-2-[[(2S)-2- [(4-methoxy-lH-indole-2-carbonyl)amino]-4,4-dimethyl-pentano yl]amino]-3-[(3S)-2- oxo-3-piperidyl]propanoate (400 mg, 0.79 mmol, 1 eq) in MeOH. Then, the mixture was stirred at 80°C for 16hr. TLC (DCM:MeOH=10: 1/UV 254nm) showed new spot was detected. The reaction mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®;12g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/MeOH @30 mL/min). Compound N-[(1S)-1-[[(1S)-2-amino-2-oxo- l-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-3,3-dimet hyl-butyl]-4-methoxy-lH- indole-2-carboxamide (295 mg, 0.60 mmol, 75.1% yield, 98.9% purity) was obtained as a solid.

Step 5: N-f (IS)- 1-[[(1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl ] carbamoyl ]-3, 3-dimethyl- butyl]-4-methoxy-lH-indole-2-carboxamide

[000470] Methoxycarbonyl-(triethylammonio)sulfonyl-azanide (284.6 mg, 1.19 mmol, 2 eq) was added at the mixture of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-meth oxy-lH-indole-2- carboxamide (290 mg, 0.59 mmol, 1 eq) in DCM (3 mL) at 25°C. Then the mixture was stirred at 25°C for 16hr. Then methoxycarbonyl-(triethylammonio)sulfonyl-azanide (142.3 mg, 0.59 mmol, 1 eq) was added to the mixture and the mixture was stirred at 25°C for anther 16hr. The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water (0.05% ammonia hydroxide v/v)-MeOH];B%:

55%-85%, 9.5min) . Compound N-[(1S)-1-[[(1S)-1 -cy ano-2-[(3 S)-2-oxo-3 - piperidyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-methoxy-lH- indole-2-carboxamide (28.1 mg, 59.3 umol, 9.9% yield, 98.7% purity) was obtained as a solid. Rt = 0.832 min; for CZ5H33N5O4MS Calcd.: 467.25, MS Found: 468.2 [M+H ⁺ ], ¹ H NMR (400MHz, CD3OD) δ 7.26 - 7.22 (m, 1H), 7.18 - 7.12 (m, 1H), 7.05 - 7.00 (m, 1H), 6.51 (d, J= 7.5 Hz, 1H), 5.08 (dd, J= 6.3, 9.8 Hz, 1H), 4.67 - 4.63 (m, 1H), 3.93 (s, 3H), 3.21 - 3.15 (m, 2H), 2.47 - 2.38 (m, 2H), 1.98 - 1.72 (m, 6H), 1.70 - 1.58 (m, 1H), 1.54 - 1.43 (m, 1H), 1.02 (s, 8H), 1.04 - 1.01 (m, 2H). Example 41. Synthesis of viral protease inhibitor compound 681

Step 1: (2S)-methyl 2-(2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane- 3- carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000471] To a solution of methyl (2 S)-2-amino-3 -[(3 S)-2-oxo-3 -piperidy 1 ]propanoate (500 mg, 2.11 mmol, 1.1 eq, HC1) and 2-(4-methoxy- 1 H-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carboxylic acid (684.45 mg, 1.92 mmol, 1 eq) in DMF (15 mL) was added N,N-diisopropylethylamine (DIEA) (744.57 mg, 5.76 mmol, 1.00 mL, 3 eq) and (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyr idinium 3-oxide hexafluorophosphate (HATU) (730.19 mg, 1.92 mmol, 1 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the two batch reaction mixture was quenched by addition H ₂ O (80 mL), and extracted with ethyl acetate (40 mL * 3). The combined organic layers were washed with brine 40 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get the product methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)- 2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-pipe ridyl]propanoate (1.35 g, crude) was obtained as white solid. MS (ESI) m/z 539.3 [M+H] ⁺ .

Step 2: N-( (S)-l -amino- l-oxo-3-( (, S)-2-oxopiperidin-3-yl)propan-2-yl)-2-( 4-methoxy-lH- indole-2-carbonyl)-2-azaspiro[4.5Jdecane-3-carboxamide

[000472] A solution of methyl (2 S)-2-[ [2-(4-methoxy- 1 H-i ndole-2-carbony 1 )-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (650 mg, 1.21 mmol, 1 eq) in NH ₃ /MeOH (7 M, 3.45 mL, 20 eq) was stirred at 65 °C for 17 h. Upon completion, the two batch reaction mixture was concentrated under reduced pressure to get the product N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)-2 -azaspiro[4.5]decane-3- carboxamide (1.22 g, crude) as colorless oil. MS (ESI) m/z 524.3 [M+H] ⁺ .

Step 3: N-((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2-(4-methox y-JH-indole-2- carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[000473] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)-2 -azaspiro[4.5]decane-3- carboxamide (1.22 g, 2.33 mmol, 1 eq) in DCM (20 mL) was added Burgess reagent (1.39 g, 5.82 mmol, 2.5 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by the addition of H ₂ O (3 mL) and then concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Agela DuraShell C18250*70mm*10um;mobile phase: [water(10mM NH4HCO ₃ )-ACN]; B%: 43%-63%,20min) to give desired compound (490 mg) as a solid, which was further separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um); mobile phase: [0.1%NH ₃ H ₂ O IPA];B%: 58%-58%,10min) to afford the product N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-(4-methox y-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide, Isomer 1 (201.77 mg, 394.36 umol, 16.93% yield) was obtained as white solid. MS (ESI) m/z 506.3[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.26 (br s, 1 H) 8.50 - 8.85 (m, 1 H) 7.23 (br s, 1 H) 7.00 - 7.16 (m, 2 H) 6.89 (br s, 1 H) 6.52 (br d, J= 7.46 Hz, 1 H) 4.86 - 5.06 (m, 1 H) 4.48 - 4.79 (m, 1 H) 3.80 - 3.98 (m, 4 H) 3.59 (br d, J= 4.65 Hz, 1 H) 3.09 (br s, 2 H) 2.15 - 2.31 (m, 3 H) 1.73 - 2.01 (m, 2 H) 1.67 (br dd, J= 12.17, 8.62 Hz, 2 H) 1.33 - 1.61 (m, 12 H); and

[000474] N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-(4-methox y-lH-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxamide, Isomer 2 (200.95 mg, 394.35 umol, 16.93% yield) was obtained as white solid. MS (ESI) m/z 506.3[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.27 (br s, 1 H) 8.61 (br d, J= 1.22 Hz, 1 H) 7.02 - 7.26 (m, 3 H) 6.91 (br s, 1 H) 6.53 (d, J=7.46 Hz, 1 H) 4.91 - 5.06 (m, 1 H) 4.62 (br s, 1 H) 3.82 - 3.98 (m, 4 H) 3.52 - 3.75 (m, 1 H) 3.09 (br s, 2 H) 2.09 - 2.28 (m, 3 H) 1.63 - 1.92 (m, 4 H) 1.33 - 1.62 (m, 12 H).

Example 42. Synthesis of viral protease inhibitor compound 721

Step 1: (S)-methyl2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethyl pentanamido)-3-((S)-2- oxopiperidin-3-yl)propanoate

[000475] To a solution of (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid

(2.49 g, 10.14 mmol, 1.2 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl] propanoate (2 g, 8.45 mmol, 1 eq, HCI) in DCM (60 mL) was added DMAP (3.10 g, 25.35 mmol, 3 eq). Then, EDCI (3.24 g, 16.90 mmol, 2 eq) was added, and the resulting mixture was stirred at 25 °C for 1 h. Upon the reaction completement, the mixture was quenched by water (400 mL), extracted with DCM (150 mL * 3), and then was dried by sat. NaCl (50 mL). The resulting solution was concentrated in vacuum and was purified by column (SiO ₂ , petroleum ether: ethyl acetate = 2:1 to 0:1). The resulting residue was washed with HC1 (1 M, 150 mL), extracted with DCM (50 mL * 3), and then the pH of the solution was adjust pH= ~8 with sat. NaHCO3 (30 mL). The resulting mixture was extracted with DCM (100 mL), and then concentrated under vacuum to afford (S)-methyl

2-((S)-2-((tert-butoxycarbonyl)amino)-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin-

3-yl) propanoate (3 g, 6.32 mmol, 74.74% yield) as a solid. ¹ H NMR (400MHz, CDCl ₃ -d) δ ppm 7.61 (d ,J= 7.0 Hz, IH), 6.85 - 6.51 (m, IH), 6.22 (s, IH), 5.06 - 4.85 (m, IH),

4.63 - 4.47 (m, IH), 4.30 - 4.02 (m, IH), 3.79 - 3.66 (m, 3H), 3.35 - 3.25 (m, 2H), 2.42 - 2.24 (m, 1H), 2.14 - 2.05 (m, 1H), 1.96 - 1.66 (m, 4H), 1.63 - 1.52 (m, 1H), 1.43 (s, 9H), 1.03 - 0.90 (m, 9H).

Step 2: (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((S)-2-oxopiperidi n-3- yl)propanoate

[000476] A solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl) amino)-4,4- dimethylpentanamido) -3-((S)-2-oxopiperidin-3-yl) propanoate (1.5 g, 3.51 mmol, 1 eq) in HCl/MeOH (4 M, 20 mL) was stirred at 25 °C for 1 h. Upon the reaction completement, the mixture was concentrated under vacuum to obtain (S)-methyl 2-((S)-2- amino-4,4-dimethylpentanamido)-3-((S)-2-oxopiperidin -3-yl)propanoate (1.1 g, crude, HC1) as a solid. ¹ H NMR (400MHz, D ₂ 0) δ ppm 4.57 (dd, J= 4.8, 10.3 Hz, 1H), 3.98 (dd,J= 5.2, 7.8 Hz, 1H), 3.78 - 3.65 (m, 3H), 3.29 - 3.14 (m, 2H), 2.75 - 2.33 (m, 1H), 2.24 - 1.47 (m, 8H), 1.04 - 0.86 (m, 9H).

Step 3: (S)-methyl2-((S)-2-(7-chloro-lH-indole-2-carboxamido)-4, 4-dimethylpentanamido)- 3-((S)-2-oxopiperidin-3-yl)propanoate

[000477] To a solution of (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((S)-2- oxopiperidin -3-yl)propanoate (550 mg * 2, HC1 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). EDCI (644.05 mg, 3.36 mmol, 2 eq) was added to the mixture at 25 °C, and the mixture was stirred at 25 °C for 1 h. Upon the reaction completement, the mixture was quenched by water (200 mL), extracted with DCM (70 mL * 3), and then concentrated under vacuum. The resulting residue was purified by column (SiO ₂ , petroleum ether: ethyl acetate = 1:1 to 0:1), concentrated in vacuum, and then was washed with 1M HC1 (100 mL) and extracted with DCM (30 mL * 3). The organic phase was adjusted to pH= ~7 with sat. NaHCOs (30 mL), and then 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) as a solid. MS (ESI) m/z 505.2 [M+H] ⁺ ; ¹ H NMR (400MHz, MeOD-d ₄ ) δ ppm 7.58 (d ,J= 7.8 Hz, 1H), 7.32 - 7.17 (m, 2H), 7.06 (t ,J= 7.8 Hz, 1H), 4.73 (dd,J= 3.8, 8.6 Hz, 1H), 4.55 (dd, J = 4.0, 11.7 Hz, 1H), 3.71 (s, 3H), 3.35 (s, 1H), 3.24 - 3.01 (m, 2H), 2.49 - 2.22 (m, 2H), 2.02 - 1.40 (m, 8H), 1.08 - 0.96 (m, 9H). Step 4: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-4, 4- dimethyl-1-oxopentan-2-yl)-7-chloro-JH-indole-2-carboxamide

[000478] A solution of (S)-methyl 2-((S)-2-(7-chloro-1H-indole-2-carboxamido)-4,4- dimethylpentanamido) -3 -((S)-2-oxopi peri din-3 -yl)propanoate (650 mg, 1.29 mmol, 1 eq) in NH ₃ /MeOH (7M, 10 mL) was stirred at 50 °C for 16 h. Upon the reaction completement, 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)-4,4- dimethyl- 1 -oxopentan-2-yl)- 7-chloro-1H-indole-2-carboxamide (450 mg, crude) as a light yellow solid. MS (ESI) m/z 490.3 [M+H] ⁺

Step 5: 7-chloro-N-((S)-l-(((S)-l-cyano-2-((S)-2-oxopiperidin-3-yl)e thyl)ammo)-4,4- dimethyl-l-oxopentan-2-yl)-lH-indole-2-carboxamide

[000479] To a solution of N-((S)- 1 -(((S)- 1 -amino-1 -oxo-3-((S)-2-oxopiperidin-3-yl) propan-2-yl) amino)-4,4- dimethyl- 1 -oxopentan-2-yl)-7-chloro- 1H-indole-2-carboxamide (430 mg, 877.56 umol, 1 eq) in DCM (10 mL) was added Burgess reagent (627.38 mg, 2.63 mmol, 3 eq). The reaction mixture was stirred at 25 °C for 4 h. Upon the reaction completement, the mixture was quenched by water (10 mL), dried with a stream ofN ₂ and purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 um); mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 35%-65%, lOmin) to obtain 7-chloro-N-((S)-1- (((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)- 1H-indole-2-carboxamide (205 mg, 424.79 umol, 48.41% yield) as a white solid. MS (ESI) m/z 472.2 [M+H] ⁺ ; 1H NMR (400MHz, DMSO-d ₆ ) δ ppm 11.70 (s, 1H), 9.02 (d, J = 8.0 Hz, 1H), 8.71 (d, J= 8.0 Hz, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.52 (s, 1H), 7.34 - 7.23 (m, 2H), 7.07 (t ,J= 7.8 Hz, 1H), 5.05 (q, J= 8.2 Hz, 1H), 4.63 - 4.54 (m, 1H), 3.07 (s, 2H), 2.30 - 2.18 (m, 2H), 1.88 - 1.32 (m, 7H), 0.95 (s, 9H).

Example 43. Synthesis of viral protease inhibitor compound 133

Step 1: 7-chloro-JH-benzo[dJimidazole-2-carboxylic acid

[000480] 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 H ₂ O 10 mL at 0 °C, and the resultant precipitate was collected. The solid was washed with H ₂ O (2 * 10 mL) and dried under vacuum to get the product 7-chloro- lH-benzimidazole-2-carboxylic acid (500 mg, crude) was obtained as a solid. MS (ESI) m/z 195.1 [M-H] ⁺

Step 2: (S)-methyl 2-((S)-2-amino-4-methylpentanamido)-3-((S)-2-oxopyrrolidm-3- yl)propanoate hydrochloride

[000481] 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 (2 S)-2-[ [(2 S)-2-amino-4-methy 1- pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, crude, HC1) was obtained as a solid.

Step 3: (S)-methyl 2-((S)-2-(7-chloro-lH-benzo[d]imidazole-2-carboxamido)-4- methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000482] To a solution of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 744.43 umol, 1.0 eq, HC1) and 7-chloro- lH-benzimidazole-2-carboxylic acid (243.91 mg, 744.43 umol, 60% purity, 1 eq) in DMF (3 mL) was added EDCI (285.42 mg, 1.49 mmol, 2.0 eq), DMAP (181.89 mg, 1.49 mmol, 2.0 eq). After the addition of DCM (9 mL), the reaction was stirred at 25 °C for 12 h. The reaction mixture was quenched by addition H ₂ O (40 mL) at 0°C, and then extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=l/0 to 0/1) to get a product methyl (2S)-2-[[(2S)-2-[(7-chloro-lH- benzimidazole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3- yl]propanoate (220 mg, 327.28 umol, 43.96% yield, 71.1% purity) was obtained as a yellow solid. MS (ESI) m/z 478.0 [M+H] ⁺

Step 4: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4- methyl-l-oxopentan-2-yl)-7-chloro-lH-benzo[d]imidazole-2-car boxamide

[000483] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-benzimidazole-2- carbonyl)amino]-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrro lidin-3-yl]propanoate (200 mg, 418.46 umol, 1 eq) in ammonia (7 M, 20 mL, 334.56 eq) was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get a product N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1-[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]- 3-methyl-butyl]-7-chloro-lH-benzimidazole-2-carboxamide (160 mg, crude) was obtained as a yellow solid. MS (ESI) m/z 463.2 [M+H] ⁺

Step 5: 7-chloro-N-((S)-l-(((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl) ethyl)amino)-4-methyl-l- oxopentan-2-yl)-lH-benzo[d]imidazole-2-carboxamide

[000484] To a solution of N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-7-chloro-lH-benzi midazole-2-carboxamide (80 mg, 108.87 umol, 63% purity, 1 eq) in DCM (4 mL) was added methoxy carbonyl - (triethylammonio)sulfonyl-azanide (129.73 mg, 544.36 umol, 5.0 eq), and then the mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 25mm * 5um;mobile phase: [water(10mM NH4HCO3)- ACN]; B%: 20% - 50%, 10 min) and by prep-HPLC (column: Phenomenex Luna C 1875 * 30mm * 3 um;mobile phase: [water(0.2% FA) - ACN]; B%: 10% - 60%, 8min) to afford 7-chloro-N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]- 3-methyl-butyl]-lH-benzimidazole-2-carboxamide (13.28 mg, 29.85 umol, 27.42% yield, 100% purity) as a white solid. MS (ESI) m/z 445.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.64 (br s, 1H), 8.76 - 9.00 (m, 2H), 7.70 (s, 1H), 7.51 (br d, J= 6.2 Hz, 1H), 7.25 - 7.42 (m, 2H), 4.90 - 5.06 (m, 1H), 4.55 (brt,J= 7.4 Hz, 1H), 3.05 - 3.18 (m, 2H), 2.33 - 2.42 (m, 1H), 2.05 - 2.23 (m, 2H), 1.54 - 1.90 (m, 5H), 0.92 (br dd ,J =

8.5, 6.3 Hz, 6H).

Example 44. Synthesis of viral protease inhibitor compound 145

Step 1: 3-methoxybenzene-l, 2-diamine:

[000485] To a mixture of 2-methoxy-6-nitro-aniline (1 g, 5.95 mmol, 1.00 mL, 1 eq) in

EtOH (12 mL) and H ₂ O (4 mL) was added NH ₄ CI (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 H ₂ O (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 Na ₂ S0 ₄ , and filtered and concentrated under reduced pressure to give 3-methoxybenzene-l, 2-diamine (770 mg, 5.02 mmol, 84.34% yield, 90% purity) as a black oil. MS (ESI) m/z 139.1 [M+H] ⁺

Step 2: 7-methoxy-lH-benzimidazole-2-carboxylic acid:

[000486] A mixture of 3-methoxybenzene-l, 2-diamine (750 mg, 5.43 mmol, 1 eq) and methyl 2,2,2-trichloroethanimidate (1.15 g, 6.51 mmol, 803.66 uL, 1.2 eq) in AcOH (8 mL) was added in one portion at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was adjusted to neutral by Na2CO ₃ solution, and then diluted with H ₂ O (5 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic layers were washed with brine (10 mL * 1) and concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (TFA condition;) to give 7-methoxy-lH- benzimidazole-2-carboxylic acid (300 mg, 1.56 mmol, 28.76% yield) as a yellow solid. MS (ESI) m/z 193.1 [M+H] ⁺ column: Phenomenex luna C18 100*40 mm*5 um; mobile phase: [water(0.1% TFA)-ACN];B%: 20%-55%,8 min

Step 3: N-f ( l S)-2-[[( 1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl]amino]-l- (cyclopropylmethyl)-2- oxo-ethyl /- 7-methoxy-lH-benzimidazole-2-carboxamide

[000487] To a mixture of 7-methoxy- 1 H-benzimidazole-2-carboxylic acid (150 mg,

780.55 umol, 1 eq) and (2S)-2-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-3-cyclopropyl-propanamide (711.44 mg, 780.55 umol, 29% purity, 1 eq) in DCM (3 mL) was added DIEA (302.64 mg, 2.34 mmol, 407.88 uL, 3 eq) and T3P (745.07 mg, 1.17 mmol, 696.33 uL, 50% purity, 1.5 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with H ₂ O (5 mL) and then extracted with DCM (5 mL * 3). The combined organic layers were washed with brine (8 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition) to give N-[(1S)- 2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2- oxo-ethyl]-7-methoxy-lH-benzimidazole-2-carboxamide (48 mg, 109.47 umol, 14.02% yield) as a white solid. MS (ESI) m/z 439.2 [M+H] ⁺ . column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water(10 mM NH4HCO3)- ACN] ;B% : 20%-40%, 8 min.

[000488] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.29 (br s, 1H), 9.09 - 8.90 (m, 1H), 8.80 - 8.66 (m, 1H), 7.79 - 7.67 (m, 1H), 7.27 - 7.17 (m, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 5.06 - 4.83 (m, 1H), 4.61 - 4.48 (m, 1H), 3.98 - 3.88 (m, 3H), 3.20 - 3.05 (m, 2H), 2.44 - 2.30 (m, 1H), 2.27 - 2.06 (m, 2H), 1.96 - 1.84 (m, 1H), 1.83 - 1.66 (m, 2H), 1.65 - 1.55 (m, 1H), 0.74 (br s, 1H), 0.40 (br d, J=8.2 Hz, 2H), 0.23 - -0.01 (m, 2H)

Example 45. Synthesis of viral protease inhibitor compound 163

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000489] A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl] propanoate (500 mg, 1.75 mmol, 1 eq) in HCl/EtOAc (3 mL) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated in vacuum to afford (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl) propanoate (350 mg, crude, HC1) as a yellow gum.

Step 2: (2S,3R)-tert-butyl2-(((S)-l -methoxy- l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamoyl)-3-phenylpyrrolidine-l-carboxylate

[000490] To a solution of methyl (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl) propanoate (320 mg, 1.44 mmol, 1 eq, HC1) and (2S,3R)-1-tert-butoxycarbonyl-3-phenyl- pyrrolidine-2-carboxylic acid (502.43 mg, 1.72 mmol, 1.2 eq) in DCM (15 mL) was added DMAP (526.70 mg, 4.31 mmol, 3 eq) and EDCI (1.38 g, 7.19 mmol, 5 eq), and then the mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was poured into water (45 mL) and was extracted with DCM (20 mL * 3), then was concentrated in vacuum and was purified by column (SiO ₂ , PE:EA = 1:1 to 0:1 and then DCM:MeOH = 10:1 to 5:1) to afford (2S, 3R)-tert-butyl2-(((S)-1-methoxy- 1 -oxo-3 -((S)-2- oxopyrrolidin- 3-yl)propan-2-yl)carbamoyl)-3-phenylpyrrolidine- 1 -carboxylate (500 mg, 544.03 umol, 37.86% yield, 50% purity) as a white solid. MS (ESI) m/z 460.3 [M+H] ⁺

Step 3: (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((2S,3R)-3-phenylpyrrolidine- 2- carboxamido)propanoate

[000491] A solution of (2S,3R)-tert-butyl2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrol idin- 3-yl)propan-2-yl) carbamoyl)-3-phenylpyrrolidine-1-carboxylate (500 mg, 1.09 mmol, 1 eq) in HCl/MeOH (4 M, 5 mL) was stirred at 25 °C for 1 h. Upon reaction completion, the mixture was concentrated in vacuum to afford (S)-methyl 3-((S)-2-oxopyrrolidin-3- yl)-2-((2S,3R)-3-phenylpyrrolidine-2-carboxamido) propanoate (340 mg, crude, HC1) as a light yellow solid.

Step 4: (S)-methyl2-((2S, 3R)-1-(4-methoxy-JH-indole-2-carbonyl)-3-phenylpyrrolidine-2 - carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000492] To a solution of (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((2S,3R)-3- phenylpyrrolidine-2-carboxamido) propanoate (200 mg, 278.23 umol, 50% purity, 1 eq) and 4-methoxy-1H-indole-2-carboxylic acid (63.83 mg, 333.87 umol, 1.2 eq) in DCM (5 mL) was added DMAP (101.97 mg, 834.68 umol, 3 eq) and EDCI (106.67 mg, 556.45 umol, 2 eq), and then the mixture was stirred at 25 °C for 1 h. Upon the reaction completion, the mixture was quenched by water (30 mL) and was extracted with DCM (10 mL * 3). The resultant was concentrated in vacuum and was purified by prep-TLC (SiO ₂ , ethyl acetate = 1) to afford (S)-methyl 2-((2S,3R)- 1 -(4-methoxy- 1H-indole-2- carbonyl)-3-phenylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyi Tolidin-3-yl)propanoate (130 mg, 216.51 umol, 77.82% yield, 88.7% purity) as a white solid. MS (ESI) m/z 533.3 [M+H] ⁺

Step 5: (2S, 3R)-N-( (S)-l -amino- 1 -oxo-3 -( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)-l-( 4- methoxy-lH-indole-2-carbonyl)-3-phenylpyrrolidine-2-carboxam ide

[000493] A solution of (S)-methyl 2-((2S,3R)-1-(4-methoxy-1H-indole-2-carbonyl)-3- phenylpyrrolidine-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (180 mg, 337.97 umol, 1 eq) in NH ₃ /MeOH (7M, 7.00 mL) was stirred at 25 °C for 24 h. Upon the reaction completion, the mixture was concentrated in vacuum to afford (2S,3R)-N-((S)-\- amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl)- 1 -(4-methoxy- 1H-indole-2- carbonyl)-3-phenylpyrrolidine-2-carboxamide (160 mg, crude) as a white solid. MS (ESI) m/z 518.3 [M+H] ⁺

Step 6: (2S, 3R)-N-( ( S)-l-cyano-2-( (, S)-2-oxopyrrolidin-3-yl)ethyl)-1-( 4-methoxy- lH-indole-2- carbonyl)-3-phenylpyrrolidine-2-carboxamide

[000494] To a solution of (2S,3R)-N-((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-1-(4- methoxy-1H-indole-2-carbonyl)-3-phenylpyrrolidine-2- carboxamide (160 mg, 309.13 umol, 1 eq) in DCM (5 mL) was added Burgess reagent (294.67 mg, 1.24 mmol, 4 eq), and then the mixture was stirred at 45 °C for 4 h. Upon the reaction completion, the mixture was quenched by water (3 mL) and was dried by blowing N ₂ and was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 25mm * Sum; mobile phase: [water (lOmM NH4HCO ₃ )-ACN]; B%: 25%-55%, 10 min) to afford (2S,3R)-N-((S)- 1 -cyano-2-((S)-2-oxopy rrolidin-3-yl)ethyl)- 1 -(4-methoxy- 1 H- indole-2-carbonyl)-3-phenylpyrrolidine-2-carboxamide (45 mg, 89.18 umol, 28.85% yield, 99% purity) as a white solid. MS (ESI) m/z 500.2 [M+H] ⁺ .

[000495] ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 11.69 - 11.50 (m, 1H), 9.21 - 8.79 (m, 1H), 7.76 - 7.49 (m, 1H), 7.42 - 7.20 (m, 5H), 7.17 - 6.72 (m, 3H), 6.57 - 6.39 (m, 1H), 5.00 - 4.76 (m, 1H), 4.47 (d, J= 6.8 Hz, 1H), 4.17 - 3.72 (m, 5H), 3.55 - 3.38 (m, 1H), 3.17 - 2.77 (m, 2H), 2.46 - 2.34 (m, 2H), 2.30 - 2.01 (m, 3H), 1.79 - 1.31 (m, 2H).

[000496] ¹ H NMR (400MHz, DMSO-d ₆ , 273+80K) δ ppm 11.33 (s, 1H), 8.75 (br s, 1H), 7.43 - 7.22 (m, 6H), 7.17 - 7.03 (m, 2H), 6.96 (s, 1H), 6.52 (d, J= 7.3 Hz, 1H), 4.99 - 4.87 (m, 1H), 4.63 (s, 1H), 4.08 (s, 2H), 3.90 (s, 3H), 3.50 (q, J= 6.8 Hz, 1H), 3.17 - 3.06 (m, 2H), 2.42 (s, 2H), 2.25 - 2.03 (m, 3H), 1.84 - 1.57 (m, 2H).

Example 46. Synthesis of viral protease inhibitor compound 191

Step 1: methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate

[000497] A mixture of methyl (2 S)-2-(tert-butoxy carbonyl amino)-3 -[(3 S)-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] ⁺ .

Step 2: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-(3-pyridyl)prop anoyl]amino]-3- [ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000498] A mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (320 mg, 1.44 mmol, 1.2 eq, HC1) in DCM (4 mL) and DMF (1 mL) added (2S)-2-(tert- butoxycarbonylamino)-3-(3-pyridyl)propanoic acid (318.91 mg, 1.20 mmol, 1 eq), TEA (727.10 mg, 7.19 mmol, 1.00 mL, 6 eq) and T3P (1.14 g, 1.80 mmol, 1.07 mL, 50% purity, 1.5 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (3 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO ₂ , DCM:MeOH =

9: 1) and TLC (SiO ₂ , DCM:MeOH = 10: 1) to get the product methyl (2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-3-(3-pyridyl)propanoyl]amino]-3-[(3S)-2 -oxopyrrolidin-3- yl]propanoate (490 mg, 1.13 mmol, 94.17% yield) as a yellow oil. MS (ESI) m/z 435.3 [M+H] ⁺ .

Step 3: methyl (2S)-2-[[(2S)-2-amino-3-( 3-pyridyl)propanoyl ]amino]-3-[ ( 3S)-2- oxopyrrolidin-3-yl ]propanoate

[000499] A mixture of methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbony lamino)-3 -(3- pyridyl)propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propan oate (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 Jpropanoate (340 mg, crude) as white oil. MS (ESI) m/z 335.1 [M+H] ⁺ .

Step 4: methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-3-(3 - pyridyl)propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000500 ] A mixture of methyl (2S)-2-[[(2S)-2-amino-3-(3-pyridyl)propanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (340 mg, 916.86 umol, 1 eq, HC1) in DCM (2 mL) and DMF (2 mL) then added 4-methoxy- 1 H-indole-2-carboxylic acid (210.35 mg, 1.10 mmol, 1.2 eq), TEA (556.66 mg, 5.50 mmol, 765.70 uL, 6 eq) and T3P (875.18 mg, 1.38 mmol, 817.93 uL, 50% purity, 1.5 eq) was stirred at 25 °C for 1.5 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (3 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10:1) and TLC (SiO ₂ , DCM:MeOH = 10:1) to get the product methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-3-(3 - pyridyl)propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propan oate (180 mg, 354.65 umol, 38.68% yield) as yellow solid. MS (ESI) m/z 508.2 [M+H] ⁺ .

Step 5: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl]amino]~ 2-oxo-l-(3-pyridylmethyl)ethyl]-4-methoxy-lH-indole-2-carbox amide [000501 ] A mixture of methyl (2 S)-2-[ [(2 S)-2-[(4-methoxy- 1 H-indole-2- carbonyl)amino]-3-(3-pyridyl)propanoyl]amino]-3-[(3S)-2-oxop yrrolidin-3-yl]propanoate (165 mg, 325.10 umol, 1 eq ) in NH ₃ /MeOH (7 M, 5 mL, 107.66 eq) was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to get the product N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-2-oxo-1-(3-pyridylmethyl)ethyl]-4-met hoxy-lH-indole-2- carboxamide (150 mg, crude) as yellow solid. MS (ESI) m/z 493.2 [M+H] ⁺ .

Step 6: N-f ( l S)-2-[[( 1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ]amino]-2-oxo-l-(3- pyridylmethyl)ethyl]-4-methoxy-lH-indole-2-carboxamide

[000502] To a mixture of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-2-oxo-1-(3-pyridylmethyl)ethyl]-4-met hoxy-lH-indole-2- carboxamide (126 mg, 255.82 umol, 1 eq) in DCM (3 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (243.86 mg, 1.02 mmol, 4 eq), and the reaction was stirred at 40 °C for 2 h. Upon completion, the mixture were quenched with water (1 mL) and blow-dried with N ₂ . The residue was purified by prep-HPLC (column: Waters X bridge BEH C18 100 * 25 mm * 5 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 15% - 45%, 10 min) to afford N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]-2-oxo-1-(3-pyridylmethyl)ethyl]-4-methoxy-lH -indole-2-carboxamide (30.52 mg, 64.32 umol, 25.14% yield, 100% purity) as a white solid. MS (ESI) m/z 475.2 [M+H] ⁺ . ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.50 (d, J=1.5 Hz, 1H), 8.41 - 8.34 (m, 1H), 7.80 (br d, J=7.9 Hz, 1H), 7.37 (dd, J=4.9, 7.8 Hz, 1H), 7.21 (s, 1H), 7.13 (d, J=7.7 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.50 (d, J=7.7 Hz, 1H), 5.03 (dd, J=6.0, 10.0 Hz, 1H), 4.76 (s, 1H), 3.92 (s, 3H), 3.30 - 3.21 (m, 3H), 3.17 (dd,J=8.8, 13.9 Hz, 1H), 2.56 (dq,J=5.5, 9.3 Hz, 1H), 2.36 - 2.21 (m, 2H), 1.96 - 1.73 (m, 2H).

Example 47. Synthesis of viral protease inhibitor compound 213

Step 1: (S)-methyl 2-ammo-3-((S)-2-oxopyrrolidm-3-yl)propanoate

[000503] 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 HC1/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.

Step 2: (S)-benzyl 3-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 - yl)carbamoyl)tetrahydropyridazine-l(2H)-carboxylate

[000504] A solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (295.93 mg, 1.59 mmol, 1.4 eq) and (3S)-1-benzyloxycarbonylhexahydropyridazine-3- carboxylic acid (300 mg, 1.14 mmol, 1 eq) in DCM (2 mL)/THF (2 mL) was cooled to 0 °C, and then the T3P (1.08 g, 1.70 mmol, 1.01 mL, 50% purity, 1.5 eq) and DIEA (440.14 mg, 3.41 mmol, 593.18 uL, 3 eq) were added. After stirring at 25 °C for 13 h, the solution was diluted with H ₂ O (20 mL) and extracted with ethyl acetate (30 mL*3). The combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The crude was used to next step directly and without further purification. Benzyl (3S)-3-[[( 1 S)-2-methoxy -2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl] methyl] ethyl] carbamoyl] hexahydropyridazine- 1 -carboxylate (455 mg, crude) was obtained as yellow oil. MS (ESI) m/z 433.1 [M+H] ⁺ . Step 3: (S)-bertzyl 2-((E)-3-(4-chloro-2-fluorophenyl)acryloyl)-3-(((S)-l-methox y-l-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)tetrahydropy ridazine-l(2H)-carboxylate

[000505] To a solution of benzyl (3 S)-3-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]hexahydropyridazin e- 1 -carboxylate (200 mg, 462.46 umol, 1 eq) in DCM (2 mL) was added the DIEA (119.54 mg, 924.92 umol,

161.10 uL, 2 eq), (E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl chloride (121.56 mg, 554.95 umol, 1.2 eq), and then the solution was stirred at 25 °C for 1 h. Upon completion, the solution was diluted with H ₂ O (10 mL), extracted with DCM (20 mL*3), the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10: 1). 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, 248.88 umol, 53.82% yield, 95.67% purity) was obtained as yellow oil. MS (ESI) m/z 433.1 [M+H] ⁺ .

Step 4: (S)-methyl 2-((S)-2-((E)-3-(4-chloro-2-fluorophenyl)acryloyl)hexahydrop yridazine-3- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000506] Benzyl (3S)-2-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]-3-[[(1 S)-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 ofNaHCOs, and extracted with ethyl acetate (20 mL*3). The combined organic phase was dried over Na ₂ SO ₄ , 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] ⁺ .

Step 5: (S)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-2-((E)-3-(4- chloro-2-fluorophenyl)acryloyl)hexahydropyridazine-3-carboxa mide [000507] Methyl (2S)-2-[[(3S)-2-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2- enoyl]hexahydropyridazine-3-carbonyl]amino]-3-[(3S)-2-oxopyr rolidin-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] ⁺ .

Step 6: (S)-2-((E)-3-(4-chloro-2-fluorophenyl)acryloyl)-N-((S)-l-cya no-2-((S)-2- oxopyrrolidin-3-yl)ethyl)hexahydropyridazine-3-carboxamide

[000508] To a solution of (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-e noyl]hexahydropyridazine- 3-carboxamide (75 mg, 160.98 umol, 1 eq) in DCM (0.5 mL) was added the Burgess reagent (76.72 mg, 321.95 umol, 2 eq) and the solution was stirred at 25 °C for 2 h. Upon completion, the solution was concentrated to remove the DCM. The residue was purified by prep-HPLC (neutral condition). Column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 25%-45%, 8min. (3S)-2-[(E)-3-(4- chloro-2-fluoro-phenyl)prop-2-enoyl]-N-[(1S)-1-cyano-2-[(3S) -2-oxopyrrolidin-3- yl]ethyl]hexahydropyridazine-3-carboxamide (20 mg, 44.65 umol, 27.74% yield, 100% purity) was obtained as a white solid. ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.79 - 7.60 (m, 3H), 7.32 - 7.22 (m, 2H), 5.17 (dd, J=2.2, 6.0 Hz, 1H), 5.07 (dd, J=6.4, 9.7 Hz, 1H), 3.38 - 3.32 (m, 2H), 3.12 (br d, J=13.7 Hz, 1H), 2.90 - 2.74 (m, 1H), 2.56 (dq, J=5.8, 9.0 Hz, 1H), 2.44 - 2.14 (m, 3H), 2.08 - 1.79 (m, 3H), 1.75 - 1.53 (m, 2H). MS (ESI) m/z 448.2 [M+H] ⁺ .

Step 7: (E)-3-(4-chloro-2-fluorophenyl)acryloyl chloride

[000509] 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)z (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 furtehr 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

Step 1: (S)-methyl 2-ammo-3-((S)-2-oxopyrrolidm-3-yl)propanoate

[000510] A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2- oxopyrrolidin-3-yl)propanoate (600 mg, 2.10 mmol, 1 eq) in HCl/EtOAc (20 mL) 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 (530 mg, crude) as yellow solid. MS (ESI) m/z 187.1 [M+H] ⁺

Step 2:(S)-methyl2-((S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-4 -methylpentanamido)-3- ((S)-2-oxopyrrolidin-3-yl)propanoate

[000511] To a solution of methyl (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3- yl)propanoate (530 mg, 2.85 mmol, 1 eq) in DMF (1 mL) and DCM (10 mL) was added (S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-4-methylpentanoi c acid (710.44 mg, 2.85 mmol, 1 eq), T3P (2.36 g, 3.71 mmol, 2.20 mL, 50% purity, 1.3 eq) and TEA (865.17 mg, 8.55 mmol, 1.19 mL, 3 eq), and the mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was quenched by addition H ₂ O (50 mL) and then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue and was purified by column chromatography (S1O2, petroleum ether: ethyl acetate = 0: 1) to give the crude product (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-4- methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (730 mg, 1.57 mmol, 55.19% yield, 89.95% purity) was yellow oil. MS (ESI) m/z 418.2 [M+H] ⁺

Step 3: (S)-methyl2-( (, S)-2-amino-4-fluoro-4-methylpentanamido)-3-( ( S)-2-oxopyrrolidin-3 - yl)propanoate

[000512] A solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-4- methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (530.00 mg, 1.27 mmol, 1 eq) in HCl/MeOH (20 mL) was stirred at 25 °C for 1 h. Upon completion, the reaction was concentrated in the vacuum to give the crude product (S)-methyl 2-((S)-2-amino-4- fluoro-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)prop anoate (500 mg, crude) was yellow solid. MS (ESI) m/z 318.2 [M+H] ⁺

Step 4: (S)-methyl2-((S)-4-fluoro-2-(4-methoxy-lH-indole-2-carboxami do)-4- methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000513] To a solution of (S)-methyl 2-((S)-2-amino-4-fluoro-4-methylpentanamido)-3-

((S)-2-oxopyrrolidin-3-yl)propanoate (500.00 mg, 1.58 mmol, 1 eq) in ACN (20 mL) was added 4-methoxy-1H-indole-2-carboxylic acid (301.21 mg, 1.58 mmol, 1 eq), DMAP (384.96 mg, 3.15 mmol, 2 eq), EDCI (604.06 mg, 3.15 mmol, 2 eq) and the mixture was stirred at 25 °C for 1 h. Upon completion, the residue was poured into H ₂ O (50 mL) and was extracted with EtOAc (20 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with Na ₂ SO ₄ filtered and concentrated in vacuum and was purified by column chromatography (S1O2, petroleum ether: ethyl acetate = 0:1) to give product (S)-m ethyl 2-((S)-4-fl uoro-2 -(4-methoxy - 1 H-indole-2-carboxamido)-4- methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (340 mg, 652.80 umol, 41.43% yield, 94.18% purity). MS (ESI) m/z 491.2 [M+H] ⁺ Step5: N-((S)-1-(((S)-1 -amino-1 -oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4- fluoro-4-methyl-l-oxopentan-2-yl)-4-methoxy-lH-indole-2-carb oxamide

[000514] A solution of (S)-methyl 2-((S)-4-fluoro-2-(4-methoxy- 1 H-indole-2- carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-y l)propanoate (330 mg, 672.75 umol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 104.05 eq) was stirred at 25 °C for 10 h. Upon, completion, the mixture was concentrated in the vacuum, to give crude product N- ((S)- 1 -(((S)- 1 -amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)- 4-fluoro-4- methyl- 1 -oxopentan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide (280 mg, crude) as a yellow solid. MS (ESI) m/z 476.2 [M+H] ⁺

Step6: N-((S)-l-(((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)amm o)-4-fluoro-4-methyl-l- oxopentan-2-yl)-4-methoxy-lH-indole-2-carboxamide

[000515] To a solution of N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)amino)-4-fluoro-4-methyl- 1 -oxopentan-2-yl)-4-methoxy- 1H-indole-2- carboxamide (220 mg, 462.66 umol, 1 eq) in DCM (10 mL) was added Burgess reagent (1.10 g, 4.63 mmol, 10 eq) and the mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated in the vacuum and was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875 * 30mm * 3um;mobile phase:

[water(0.05%NH ₃ H ₂ 0+ 1 OmM NH ₄ HCO ₃ )-ACN];B%: 20%-50%,8min) to give product N-((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)amino)-4-fluoro-4-m ethyl-l - oxopentan-2-yl)-4-methoxy-1H-indole-2-carboxamide (10 mg, 21.86 umol, 4.72% yield, 100% purity). MS (ESI) m/z 458.2 [M+H] ^{+ 1} H NMR (400MHz, MeOD-d ₄ ) δ = 7.22 (s, 1H), 7.18 - 7.12 (m, 1H), 7.03 - 7.02 (m, 1H), 6.52 - 6.50 (m, 1H), 5.06 - 5.03 (m, 1H), 4.74 - 4.72 (m, 1H), 3.93 (s, 3H), 3.29 - 3.19 (m, 2H), 2.32 - 2.31 (m, 1H), 2.36 - 2.25 (m, 3H), 2.24 - 2.14 (m, 1H), 1.93 - 1.76 (m, 2H), 1.48 - 1.46 (m, 3H), 1.43 - 1.41 (m, 3H)

Example 49. Synthesis of viral protease inhibitor compound 223

Step 1: methyl (2S)-2-amino-3-(lH-imidazol-5-yl) propanoate

[000516] To the solution of (2S)-2-(tert-butoxycarbonylamino)-3-(lH-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 afford methyl (2S)-2-amino-3-(lH-imidazol-5-yl) propanoate (400 mg, crude, HC1) as white solid, which was used directly next step. MS (ESI) m/z 170.1 [M+H] ⁺

Step 2: methyl (2S)-3-(lH-imidazol-5-yl)-2-[[(2S)-2-[(4-methoxy-lH-indole-2 - carbonyl)amino ] -4-methyl-pentanoyl ] amino ]propanoate

[000517] To a mixture of (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoic acid (741.86 mg, 1.77 mmol, 1 eq, TFA) and methyl (2 S)-2-amino-3 -( 1 H- imidazol-5-yl)propanoate (0.3 g, 1.77 mmol, 1 eq, HC1), DIPEA (1.15 g, 8.87 mmol, 1.54 mL, 5 eq) in THF (0.3 mL) and DCM (0.3 mL) was added T3P (1.69 g, 2.66 mmol, 1.58 mL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. 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 washed with brine (3 mL * 3) and dried over anhydrous sodium sulfate and concentrated to get the crude product. Methyl (2S)-3-(lH-imidazol-5-yl)-2-[[(2S)-2-[(4-methoxy-lH-indole-2 - carbonyl)amino] -4-methyl-pentanoyl]amino]propanoate (300 mg, crude) was obtained as the white solid and used directly next step. MS (ESI) m/z 456.2 [M+H] ⁺ 1H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.48 (s, 1 H), 7.27 (s, 1 H), 7.11 - 7.18 (m, 1 H), 7.02 (d, J = 8.16 Hz, 1 H), 6.85 (s, 1 H), 6.51 (d , J= 7.72 Hz, 1 H), 4.60 - 4.71 (m, 2 H), 3.93 (s, 3 H), 3.68 (s, 3 H), 3.00 - 3.17 (m, 3 H), 1.62 - 1.78 (m, 3 H), 0.97 (dd, J = 13.78, 6.06 Hz,

6 H)

Step 3: N-[(lS)-l-[[(lS)-2-amino- J-(JH-imidazol-5-ylmethyl)-2-oxo-ethyl]carbamoyl]-3- methyl-butyl ] -4-methoxy-lH-indole-2-carboxamide

[000518] To methyl (2S)-3-(lH-imidazol-5-yl)-2-[[(2S)-2-[(4-methoxy-lH-indole-2 - carbonyl)amino]-4-met hyl-pentanoyl]amino]propanoate (200 mg, 439.07 umol, 1 eq) was added NH ₃ /MeOH (7 M, 11.76 mL, 187.56 eq) in one portion at 25 °C under N ₂ .

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-[( 1 S)- 1 -[[( 1 S)-2-amino- 1 -( 1 H- imidazol-5-ylmethyl)-2-oxo-ethyl]carbamoyl]-3-methyl-butyl]- 4-methoxy-lH-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] ⁺

Step 4: N-f (1S)-1-[[(1 S)-l-cyano-2-( lH-imidazol-5-yl)ethyl] carbamoyl ]-3-methyl-butyl ]-4- methoxy- lH-indole-2-carboxamide

[000519] To a mixture of N-[( 1 S)- 1 -[[( 1 S)-2-amino- 1 -( 1 H-imidazol-5-ylmethyl)-2-oxo- ethyl]carbamoyl]-3- methyl-butyl]-4-methoxy-lH-indole-2-carboxamide (140 mg, 317.82 umol, 1 eq) in DCM (2 mL) was added TFAA (133.51 mg, 635.65 umol, 88.41 uL, 2 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to get the crude product, which turned into N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-( 1 H- imidazol-5-yl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH- indole-2-carboxamide after 36 h in storage. The residue was purified by prep-HPLC to afford N-[(1S)-1-[[(1S)- l-cyano-2-(lH-imidazol-5-yl)ethyl]carbamoyl]-3-methyl-butyl] -4-methoxy-lH-indole-2- carboxamide (23.89 mg, 56.31 umol, 17.72% yield, 99.581% purity) as a white solid. MS (ESI) m/z 423.2 [M+H] ⁺ [000520] Prep-HPLC condition: column: Waters Xbridge BEH C18

100*25mm*5um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 25%-55%,10min; 1H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.58 (s, 1 H), 7.30 (s, 1 H), 7.12 - 7.21 (m, 1 H), 6.99 - 7.09 (m, 2 H), 6.52 (d ,J= 7.72 Hz, 1 H), 5.05 (t ,J= 7.06 Hz, 1 H), 4.61 (br dd ,J= 9.70, 4.85 Hz, 1 H), 3.94 (s, 3 H), 3.06 - 3.21 (m, 2 H), 1.60 - 1.83 (m, 3 H), 0.99 (dd,J= 13.89, 6.17 Hz, 6 H)

Step 5: tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoate

[000521] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (5 g, 26.15 mmol, 1 eq) and tert-butyl (2S)-2-amino-4-methyl-pentanoate (5.88 g, 31.38 mmol, 1.2 eq, HC1), EDCI (6.52 g, 34.00 mmol, 1.3 eq), HOBt (4.59 g, 34.00 mmol, 1.3 eq) in DMF (30 mL) was added TEA (7.94 g, 78.46 mmol, 10.92 mL, 3 eq) in one portion at 25 °C under N ₂ .

The mixture was stirred at 25 °C and stirred for 2 h. The reaction mixture was added water (90 mL) and extracted with ethyl acetate (25 mL * 3) to get the organic phase. The organic phase was washed with 5% citric acid (25 mL) and 5% aqueous solution of sodium bicarbonate (25 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to get the product. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 30:1 to 10:1). Tert-butyl (2S)-2-[(4-methoxy- 1 H- indole-2-carbonyl)amino]-4-methyl- pentanoate (5.93 g, 16.45 mmol, 62.91% yield) was obtained as light yellow solid. MS (ESI) m/z 361.2 [M+H] ^{+ 1} H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.25 (br s, 1 H), 7.10 - 7.16 (m, 1 H), 6.93 - 7.00 (m, 2 H), 6.56 (br d, J= 8.31 Hz, 1 H), 6.44 (d, J= 7.70 Hz, 1 H), 4.66 (td, J= 8.50, 5.14 Hz, 1 H), 3.88 (s, 3 H), 1.62 - 1.75 (m, 2 H), 1.57 - 1.62 (m, 1 H), 1.42 (s, 9 H), 0.92 (dd,J= 6.17, 3.85 Hz, 6 H).

Step 6: (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl-pent anoic acid

[000522] To a mixture of tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoate (2.00 g, 5.55 mmol, 1 eq) in DCM (8 mL) was added TFA (10.27 g, 90.04 mmol, 6.67 mL, 16.23 eq) and H ₂ O (666.67 mg, 37.01 mmol, 666.67 uL, 6.67 eq) in one portion atO °C under N ₂ . The mixture was stirred at 25 °C and stirred for 4 h. The reaction mixture was concentrated to get the crude product. (2S)-2-[(4-methoxy- 1 H- indole-2-carbonyl)amino]-4-methyl-pentanoic acid (2.24 g, 5.35 mmol, 96.50% yield, TFA) was obtained as the yellow solid and used directly next step. MS (ESI) m/z 305.1 [M+H] ⁺

Example 50. Synthesis of viral protease inhibitor compound 237

Step 1: tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoate

[000523] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (5 g, 26.15 mmol, 1 eq) and tert-butyl (2S)-2-amino-4-methyl-pentanoate (5.88 g, 31.38 mmol, 1.2 eq, HC1), EDCI (6.52 g, 34.00 mmol, 1.3 eq), HOBt (4.59 g, 34.00 mmol, 1.3 eq) in DMF (30 mL) was added TEA (7.94 g, 78.46 mmol, 10.92 mL, 3 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 2 h. The reaction mixture was added water (90 mL) and extracted with ethyl acetate (25 mL * 3) to get the organic phase. The organic phase was washed with 5% citric acid (25 mL) and 5% aqueous solution of sodium bicarbonate (25 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to get the product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 30:1 to 10:1). Tert-butyl (2 S)-2-[(4-methoxy- 1 H- indole-2-carbonyl)amino]-4-methyl- pentanoate (5.93 g, 16.45 mmol, 62.91% yield) was obtained as light yellow solid. MS (ESI) m/z 361.2 [M+H] ⁺

[000524] ¹ H NMR (400 MHz, CHLOROFORM-*/) δ ppm 9.25 (br s, 1 H), 7.10 - 7.16 (m, 1 H), 6.93 - 7.00 (m, 2 H), 6.56 (br d,J= 8.31 Hz, 1 H), 6.44 (d ,J= 7.70 Hz, 1 H), 4.66 (td, J= 8.50, 5.14 Hz, 1 H), 3.88 (s, 3 H), 1.62 - 1.75 (m, 2 H), 1.57 - 1.62 (m, 1 H), 1.42 (s, 9 H), 0.92 (dd, J = 6.17, 3.85 Hz, 6 H).

Step 2: (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)ammo]-4-methyl-penta noic acid [000525] To a mixture of tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoate (2.00 g, 5.55 mmol, 1 eq) in DCM (8 mL) was added TFA (10.27 g, 90.04 mmol, 6.67 mL, 16.23 eq) and H ₂ O (666.67 mg, 37.01 mmol, 666.67 uL, 6.67 eq) in one portion at 0 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 4 h. The reaction mixture was concentrated to afford (2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4-methyl-pentanoic acid (2.24 g, 5.35 mmol, 96.50% yield, TFA) as the yellow solid, which was used directly next step. MS (ESI) m/z 305.1 [M+H] ⁺

Step 3: methyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoyl]amino]-3- (2-oxo-lH-quinolin-4-yl)propanoate

[000526] To a mixture of (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoic acid (568.23 mg, 1.36 mmol, 1.2 eq, TFA) and methyl 2-ami no-3 -(2-oxo- 1 H- quinolin-4-yl)propanoate (320 mg, 1.13 mmol, 1 eq, HC1), DIPEA (731.40 mg, 5.66 mmol, 985.72 uL, 5 eq) in THF (1 mL) and DCM (1 mL) was added T3P (1.08 g, 1.70 mmol, 1.01 mL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. The reaction mixture was added with 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 prep-HPLC. Methyl 2-[[(2S)-2-[(4-methoxy -lH-indole-2-carbonyl)amino]-4-methyl- pentanoyl]amino]-3 -(2-oxo- 1 H-quinolin-4-yl)propanoate (0.2 g, 375.53 umol, 33.18% yield) was obtained as the white solid. MS (ESI) m/z 533.2 [M+H] ⁺

[000527] Prep-HPLC condition: column: Kromasil C18 (250*50mm*10 um);mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN];B%: 30%-60%,10min

Step 4: N-[(lS)-l-[[2-amino-2-oxo-l-[(2-oxo-lH-quinolm-4-yl)methyl]e thyl]carbamoyl]-3- methyl- butyl ]-4-methoxy-JH-indole -2-carboxamide

[000528] To a mixture of methyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methy 1-pentanoy 1 ] amino]-3-(2-oxo-lH-quinolin-4-yl)propanoate (200.00 mg, 375.53 umol, 1 eq) was added NH ₃ /MeOH (7 M, 10.00 mL, 186.41 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to 25 °C and concentrated to afford N-[( 1 S)- 1 -[[2-amino-2-oxo- 1 -[(2-oxo- 1 H-quinolin-4- yl)methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indo le-2-carboxamide (180 mg, 326.21 umol, 86.87% yield, 93.8% purity) as the light yellow solid and used directly next step. MS (ESI) m/z 518.2 [M+H] ⁺

Step 5: N-f (1S)-1-[[1 -cyano-2-(2-oxo-lH-quinolin-4-yl)ethyl ] carbamoyl ]-3-methyl-butyl ]-4- methoxy- lH-indole-2-carboxamide

[000529] To a mixture of N-[(l S)-1-[[2-amino-2-oxo-l -[(2-oxo- lH-quinolin-4- yl)methyl]ethyl]carbamoyl]-3- methyl-butyl]-4-methoxy-lH-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 N ₂ . The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated and purified by prep-HPLC. N-[(1S)-1-[[l-cyano- 2-(2-oxo-lH-quinolin-4-yl)ethyl] carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2- carboxamide (20.74 mg, 41.13 umol, 23.66% yield, 99.079% purity) was obtained as the white solid. MS (ESI) m/z 500.2 [M+H] ⁺

[000530] Prep-HPLC condition: column: Waters Xbridge BEH C18

100*25mm*5um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 30%-65%,10min

[000531] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.93 (br d, J = 8.16 Hz, 1 H), 7.50 - 7.58 (m, 1 H), 7.28 - 7.40 (m, 2 H), 7.26 (dd, J= 11.47, 0.66 Hz, 1 H), 7.11 - 7.19 (m, 1 H), 7.04 (dd, J= 8.27, 4.08 Hz, 1 H), 6.59 - 6.70 (m, 1 H), 6.46 - 6.56 (m, 1 H), 5.24 - 5.34 (m, 1 H), 4.53 (td, J= 10.31, 5.18 Hz, 1 H), 3.93 (d, J= 4.41 Hz, 3 H), 3.40 - 3.59 (m, 3 H), 1.72 (ddd, J= 15.16, 9.87, 5.18 Hz, 1 H), 1.53 - 1.66 (m, 2 H), 1.40 - 1.50 (m, 1 H), 0.87 - 1.01 (m, 5 H)

Step 6: methyl 2-amino-3-(2-oxo-JH-quinolin-4-yl)propanoate

[000532] To 2-amino-3-(2-oxo-lH-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 N ₂ . 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-lH-quinolin-4-yl)propanoate (370 mg, crude, HC1) was obtained as the white solid and used directly next step. Example 51. Synthesis of viral protease inhibitor compound 241

Step 1: methyl 2-amino-3-(lH-pyrazol-3-yl)propanoate

[000533] To 2-amino-3-(lH-pyrazol-3-yl)propanoic acid (0.5 g, 2.19 mmol, 1 eq, 2HC1) was added HCl/MeOH (4 M, 17.01 mL, 31.03 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to get the crude product. Methyl 2-amino-3-(lH-pyrazol-3-yl)propanoate (530 mg, crude, 2HC1) was obtained as the yellow solid and used directly next step. MS (ESI) m/z 170.1 [M+H] ⁺

Step 2: methyl 2-[[(2S)-2- [(4-methoxy-lH-indole-2-carbonyl)ammo]-4-methyl- pentanoyl ] amino ]-3- ( lH-pyrazol-3-yl)propanoate

[000534] To a mixture of (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoic acid (377.12 mg, 1.24 mmol, 1 eq) and methyl 2-amino-3-(lH-pyrazol-3- yl)propanoate (300 mg, 1.24 mmol, 1 eq, 2HC1), DIPEA (800.75 mg, 6.20 mmol, 1.08 mL, 5 eq) in THF (0.9 mL) and DCM (0.9 mL) was added T3P (1.18 g, 1.86 mmol, 1.11 mL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 12 h. 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 pre-HPLC. Methyl 2- [[(2S)-2- [(4-m ethoxy- lH-indole-2-carbonyl)amino]-4-methyl-pentanoyl]amino]-3-(lH- pyrazol-3-yl)propanoate (130 mg, 285.40 umol, 23.03% yield) was obtained as the white solid. MS (ESI) m/z 456.2 [M+H] ⁺

[000535 ] Prep-HPLC condition: column: Phenomenex Gemini-NX

80*40mm*3um;mobile phase: [water(10mM NH ₄ HCO3)- ACN] ;B% : 25%-45%,8min

Step 3: N-f ( l S)-l-[[2-amino-2-oxo-l-(lH-pyrazol-3-ylmethyl)ethyl ] carbamoyl ] -3-methyl- butyl ]-4- methoxy-lH-indole-2-carboxamide

[000536] To a mixture of methyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoyl] amino]-3-(lH-pyrazol-3-yl)propanoate (100 mg, 219.54 umol, 1 eq) was added NH ₃ /MeOH (7 M, 3.33 mL, 106.28 eq) in one portion at 25 °C under N ₂ . 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-[( 1 S)- 1 -[[2-amino -2-oxo- 1 -( 1 H-py razol -3 - ylmethyl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indol e-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] ⁺

Step 4: N-[(JS)-1-[[1-cyano-2-(JH-pyrazol-3-yl)ethyl]carbamoyl]-3-me thyl-butyl]-4- methoxy-lH- indole-2-carboxamide

[000537] To a mixture of N-[( 1 S)- 1 -[[2-amino-2-oxo- 1 -( 1 H-pyrazol-3- ylmethyl)ethyl]carbamoyl]-3-methyl- butyl ]-4-methoxy- lH-indole-2-carboxamide (95 mg, 215.67 umol, 1 eq) TEA (43.65 mg, 431.33 umol, 60.04 uL, 2 eq) in DCM (0.1 mL) was added TFAA (90.59 mg, 431.33 umol, 60.00 uL, 2 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to get the crude product. The crude product was purified by pre-HPLC. N-[( 1 S)- 1 -[[ 1 -cyano-2- (1H- pyrazol-3-yl)ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-i ndole-2- carboxamide (23.35 mg, 54.93 umol, 25.47% yield, 99.384% purity) was obtained as the white solid MS (ESI) m/z 423.2 [M+H] ⁺

[000538] Prep-HPLC condition: column: Waters Xbridge Prep OBD C18

150*40mm* 10um;mobile phase: [water(10mM NH4HC03 )- ACN] ;B% : 25%-55%,8min

[000539 ] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.55 (br d, J = 11.25 Hz, 1 H), 7.30 (s, 1 H), 7.13 - 7.22 (m, 1 H), 7.05 (d, J=7.95 Hz, 1 H), 6.54 (d, J= 7.70 Hz, 1 H), 6.31 (dd,J = 10.58, 2.14 Hz, 1 H), 5.04 - 5.17 (m, 1 H), 4.56 - 4.64 (m, 1 H), 3.95 (s, 3 H), 3.13 - 3.30 (m, 2 H), 1.52 - 1.83 (m, 3 H), 0.90 - 1.08 (m, 6 H)

Step 6: (S)-tert-butyl 2-(4-methoxy-lH-indole-2-carboxamido)-4-methylpentanoate [000540] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (15 g, 78.46 mmol, 1 eq) and tert-butyl (2S)-2-amino-4-methyl-pentanoate (21.07 g, 94.15 mmol, 1.2 eq, HC1) in DMF (150 mL) was added EDCI (19.55 g, 102.00 mmol, 1.3 eq), HOBt (13.78 g, 102.00 mmol, 1.3 eq), TEA (23.82 g, 235.38 mmol, 32.76 mL, 3 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 2 h. The reaction mixture was added water (450 mL) and extracted with ethyl acetate (250 mL * 3) to get the organic phase. The organic phase was washed with 5% citric acid (300 mL) and 5% aqueous solution of sodium bicarbonate (300 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to get the product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate=30:l to 10:1). tert-butyl (2 S)-2-[(4-methoxy- 1 H- indole-2-carbonyl)amino]-4-methyl- pentanoate (24 g, 66.58 mmol, 84.87% yield) was obtained as light yellow solid. MS (ESI) m/z 361.2 [M+H] ⁺

Step 7: (S)-2-(4-methoxy-JH-indole-2-carboxamido)-4-methylpentanoic acid

[000541] To a mixture of tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoate (10 g, 27.74 mmol, 1 eq) in DCM (30 mL) was added TFA (61.60 g, 540.26 mmol, 40 mL, 19.47 eq) and H ₂ O (4.00 g, 221.98 mmol, 4.00 mL, 8.00 eq) in one portion at 0 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 2 h. The reaction mixture was concentrated to get the crude product. The crude product was purified by petroleum ether: Ethyl acetate = 10: 1(20 mL) and filtered to get the product. (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl-pent anoic acid (6 g, 19.22 mmol, 69.27% yield, 97.48% purity) was obtained as the light yellow solid. MS (ESI) m/z 305.1 [M+H] ⁺

Example 52. Synthesis of viral protease inhibitor compound 245

Step 1: methyl 2-amino-3-(lH-mdazol-3-yl)propanoate

[000542] To a mixture of 2-amino-3-(lH-indazol-3-yl) propanoic acid (200 mg, 827.56 umol, 1 eq, HCI) was added HCl/MeOH (4 M, 2 mL, 9.67 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated to get the crude product. Methyl 2-amino-3-( 1 H-indazol -3-yl) propanoate (200 mg, crude, HCI) was obtained as the light yellow solid and used directly next step. MS (ESI) m/z 220.1 [M+H] ⁺

Step 2: methyl 2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoyl]ami no]-3-(lH- indazol-3-yl) propanoate

[000543] To a mixture of methyl 2-amino-3-( 1 H-indazol-3 -yl)propanoate (150 mg,

586.62 umol, 1 eq, HCI) and (2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoic acid (203.52 mg, 879.94 umol, 1.5 eq), DIPEA (379.09 mg, 2.93 mmol, 510.90 uL, 5 eq) in DCM (1.5 mL) and THF (1.5 mL) was added T3P (559.96 mg, 879.94 umol, 523.33 uL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. The reaction mixture was added with saturated sodium bicarbonate solution (10 mL) and extracted with DCM (10 mL * 2). The organic phase was concentrated to afford methyl 2- [[(2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoyl]amino ] -3-(lH-indazol-3- yl)propanoate (180 mg, crude) as a light yellow solid. MS (ESI) m/z 433.2 [M+H] ⁺

Step 3: methyl 2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-(lH-indazol-3-y l)propanoate

[000544] To a mixture of methyl 2-[[(2S)-2-(tert-butoxycarbonylamino)-4-methyl- pentanoyl]amino]-3- ( 1 H-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 N ₂ . 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-(lH-indazol-3-yl) propanoate (160 mg, crude, HC1) as light yellow oil and used directly next step. MS (ESI) m/z 333.2 [M+H] ⁺

Step 4: methyl 3-(lH-indazol-3-yl)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbo nyl)amino]-4- methyl- pentanoyl ] amino ]propanoate

[000545] To a mixture of methyl 2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-(lH- indazol-3-yl) propanoate (160 mg, 433.77 umol, 1 eq, HC1) and 4-methoxy- lH-indole-2- carboxylic acid (99.52 mg, 520.53 umol, 1.2 eq), DIPEA (280.31 mg, 2.17 mmol, 377.78 uL, 5 eq) in DCM (1 mL) and THF (1 mL) was added T3P (414.05 mg, 650.66 umol, 386.97 uL, 50% purity, 1.5 eq) in one portion at 0 °C under N ₂ . The mixture was stirred at 25 °C for 4 h. The reaction mixture was added with saturated sodium bicarbonate solution (10 mL) and extracted with DCM (10 mL * 2). The organic phase was concentrated to get the crude product. The residue was purified by pre-HPLC. Methyl 3- (lH-indazol-3-yl) -2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino] -4-methyl- pentanoyl] amino]propanoate (80 mg, crude) was obtained as the light yellow solid. MS (ESI) m/z 506.2 [M+H] ⁺

[000546] Prep-HPLC condition: column: Phenomenex Gemini-NX

80*40mm*3um;mobile phase: [water(10mM NH4HCO ₃ )-ACN];B%: 35%-65%,8min

Step 5: N-f (1S)-1-[[1~( lH-indazol-3-ylmethyl)-2-nitroso-ethyl j carbamoyl] -3-methyl-butyl /- 4-methoxy -lH-indole-2-carboxamide

[000547] To a mixture of methyl 3-(lH-indazol-3-yl)-2-[[(2S)-2-[(4-methoxy-lH-indole- 2-carbonyl)amino] -4-methyl-pentanoyl]amino]propanoate (80 mg, 158.24 umol, 1 eq) was added NH ₃ /MeOH (7 M, 1 mL, 44.24 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to 25 °C and concentrated. N-[(1S)-1-[[l-(lH-indazol-3-ylmethyl)-2-nitroso-ethyl]carbam oyl]-3- methyl -butyl]-4-methoxy-lH-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] ⁺ Step 6: N-f (1S)-1-[[1 -cyano-2-( lH-indazol-3-yl)ethyl ] carbamoyl ] -3-methyl-butyl] -4- methoxy-lH- indole-2-carboxamide

[000548] To a mixture of N-[( 1 S)- 1 -[[ 1 -( 1 H-indazol-3-ylmethyl)-2-nitroso- ethyl]carbamoyl]-3-methyl-butyl] -4-methoxy- 1 H-indole-2-carboxamide (75 mg, 152.89 umol, 1 eq) in DCM (0.5 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl- azanide (75.00 mg, 314.72 umol, 2.06 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated and purified by pre-HPLC. N- [( 1 S)- 1 -[ [ 1 -cy ano-2-( 1 H- indazol-3 -y l)ethy 1 Jcarbamoy 1 ]-3 -methyl-butyl ]-4-methoxy- 1 H- indole-2-carboxamide (12.0 mg, 25.39 umol, 16.61% yield) was obtained as a white solid. MS (ESI) m/z 473.2 [M+H] ⁺

[000549] Prep-HPLC condition: column: Waters Xbridge BEH C 18

100*30mm*10um;mobile phase: [water(10Mm NH ₄ HC03)-ACN]; B%: 28%-58%,10min

[000550] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.95 (br d,J= 8.82 Hz, 1 H), 11.59 (br dd,J= 6.50, 1.87 Hz, 1 H), 9.02 (br dd , J= 14.11, 7.94 Hz, 1 H), 8.39 - 8.51 (m, 1 H), 7.82 (dd, J= 11.14, 8.27 Hz, 1 H), 7.48 - 7.55 (m, 1 H), 7.31 - 7.41 (m, 1 H), 7.07 - 7.16 (m, 2 H), 6.99 - 7.05 (m, 1 H), 6.49 - 6.56 (m, 1 H), 5.24 (quin, J= 111 Hz, 1 H), 4.39 - 4.57 (m, 1 H), 3.90 (d,J = 3.97 Hz, 3 H), 3.37 - 3.62 (m, 2 H), 1.60 - 1.73 (m, 1 H), 1.43 - 1.53 (m, 1 H), 1.15 - 1.28 (m, 1 H), 0.84 - 0.98 (m, 3 H), 0.80 (d, J= 6.39 Hz, 2 H)

Example 53. Synthesis of viral protease inhibitor compound 1045

Step 1: methyl (2S)-2-[[( 2S) -2 -amino- 3 -cyclopropyl-propanoyl ] amino ]-3-[(3S)-2- oxopyrrolidin-3-yl ]propanoate [000551] 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 (10 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give crude methyl (2S)-2-[[(2S)-2-amino-3- cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]pr opanoate (900 mg, 3.03 mmol, 92.54% yield) as a yellow oil.

Step 2: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-propoxy-lH-indole-2- carbonyl)amino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000552] 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-lH- 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 DMAP (552.19 mg, 4.52 mmol, 3 eq) and stirred at 25 °C for 2 h.

The reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (10 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/l to 0/1) to afford methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-propoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3 S)-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] ⁺

Step 3: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-1-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl]aminof- l-(cyclopropylmethyl)-2-oxo-ethyl]-4-propoxy-lH-indole-2-car boxamide

[000553] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-propoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (480 mg,

962.75 umol, 1 eq) in NH ₃ /MeOH (7M) (3 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude N-[(1S)-2- [[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]et hyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-propoxy-lH-indole-2-carbo xamide (380 mg, 785.84 umol, 81.62% yield) as a white solid. MS (ESI) m/z 484.3 [M+H] ⁺

Step 4: N-f ( l S)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-propoxy-lH-indole-2-carbo xamide [000554] To a mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4- propoxy-lH-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-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-4- propoxy-lH-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] ⁺

[000555] column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,8min

[000556] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.55 (br d, J=1.7 Hz, 1H), 9.07 - 8.85 (m, 1H), 8.57 (d, J=7.6 Hz, 1H), 7.83 - 7.61 (m, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.14 - 6.90 (m, 2H), 6.48 (d, J=7.6 Hz, 1H), 5.09 - 4.86 (m, 1H), 4.60 - 4.28 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.22 - 3.01 (m, 2H), 2.45 - 2.03 (m, 3H), 1.94 - 1.59 (m, 5H), 1.58 - 1.34 (m, 1H), 1.06 (t, J=7.4 Hz, 3H), 0.95 - 0.69 (m, 1H), 0.55 - 0.30 (m, 2H), 0.28 - -0.02 (m, 2H)

Example 54. Synthesis of viral protease inhibitor compound 147

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate [000557] A solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-((S)-2- oxopyrrolidin-3-yl)propanoate (100 mg, 349.26 umol, 1 eq) in HCl/MeOH (4 M, 2 mL, 22.9 leg) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated to give the crude product (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (65 mg, crude) as white solid. MS (ESI) m/z 187.1 [M+H] ⁺

Step 2: (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)ammo)-2-((S)-2,3-dihydrobenzo furan-2- yl)acetamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000558] To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-((S)-2,3- dihydrobenzofuran-2-yl)acetic acid (100 mg, 340.93 umol, 1 eq) and (S)-methyl 2-amino- 3-((S)-2-oxopyrrolidin-3-yl)propanoate (65 mg, 349.07 umol, 1.02 eq) in DMF (3 mL) was added TEA (206.99 mg, 2.05 mmol, 284.72 uL, 6 eq) and T3P (325.43 mg, 511.40 umol, 304.14 uL, 50% purity, 1.5 eq). The reaction was stirred at 25 °C for 1 h, and then diluted with H ₂ O (20 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (S)-methyl 2-((S)-2-((tert- butoxycarbonyl)amino)-2-((S)-2,3-dihydrobenzofuran-2-yl)acet amido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate (110 mg, crude) as white solid. MS (ESI) m/z 462.2 [M+H] ⁺

Step 3: (S)-methyl 2-((S)-2-amino-2-((S)-2,3-dihydrobenzqfuran-2-yl)acetamido)- 3-((S)-2- oxopyrrolidin-3-yl)propanoate

[000559] A solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-2-((S)-2,3- dihydrobenzofuran-2-yl)acetamido)-3-((S)-2-oxopyrrolidin-3-y l)propanoate (110 mg, 238.35 umol, 1 eq) in HCl/dioxane (2 mL) was stirred at 25°C for 1 h. The residue was concentrated in vacuum to afford (S)-methyl 2-((S)-2-amino-2-((S)-2,3- dihydrobenzofuran-2-yl)acetamido)-3-((S)-2-oxopyrrolidin-3-y l)propanoate (95 mg, crude, HC1) as white solid. MS (ESI) m/z 362.2 [M+H] ⁺

Step 4: (S)-methyl 2-((S)-2-((S)-2,3-dihydrobenzqfuran-2-yl)-2-(4-methoxy-lH-in dole-2- carboxamido)acetamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoat e

[000560] To a solution of (S)-methyl 2-((S)-2-amino-2-((S)-2,3-dihydrobenzofuran-2- yl)acetamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (95 mg, 238.78 umol, 1 eq, HC1) and 4-methoxy- 1 H-indole-2-carboxylic acid (45.65 mg, 238.78 umol, 1 eq) in DMF (3 mL) was added EDCI (91.55 mg, 477.56 umol, 2 eq) and DMAP (58.34 mg, 477.56 umol, 2 eq) then was stirred at 25 °C for 1 h. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL*3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep- HPLC column: Waters Xbridge BEH C18 100*25 mm*5 um; mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN]; B%: 20%-50%,10 min to give (S)-methyl 2-((S)-2-((S)-2,3-dihydrobenzofuran-2-yl)-2- (4-methoxy-lH-indole-2-carboxamido)acetamido)-3-((S)-2-oxopy rrolidin-3- yl)propanoate (21 mg, 39.28 umol, 16.45% yield) as light yellow solid. MS (ESI) m/z 535.2 [M+H] ⁺

Step 5: -((S)-2-(((S)~ 1 -amino- 1 -oxo-3-((S)-2-oxopyrr olidin-3-yl)propan-2-yl)amino)- 1-((S)~ 2,3-dihydrobenzqfuran-2-yl)-2-oxoethyl)-4-methoxy-lH-indole- 2-carboxamide

[000561] A solution of (S)-methyl 2-((S)-2-((S)-2,3-dihydrobenzofuran-2-yl)-2-(4- methoxy-lH-indole-2-carboxamido)acetamido)-3-((S)-2-oxopyrro lidin-3-yl)propanoate (19 mg, 35.54 umol, 1 eq) in NH ₃ .MeOH (7 M, 5 mL, 984.71 eq) was stirred at 25 °C for 12 h. The reaction was concentrated to afford N-((S)-2-(((S)-1-amino-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)amino)-1-((S)-2,3-dihydrobenz ofuran-2-yl)-2-oxoethyl)- 4-methoxy-lH-indole-2-carboxamide (19 mg, crude) as white solid. MS (ESI) m/z 520.1 [M+H] ⁺

Step 6: N-( (S)-2-( ( (S)-l-cyano-2-( (S)-2-oxopyrrolidin-3-yl)ethyl)amino)-l-( (S)-2, 3- dihydrobenzqfuran-2-yl)-2-oxoethyl)-4-methoxy-lH-indole-2-ca rboxamide

[000562] A mixture of N-((S)-2-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)pro pan- 2-yl)amino)-1-((S)-2,3-dihydrobenzofuran-2-yl)-2-oxoethyl)-4 -methoxy-lH-indole-2- carboxamide (19 mg, 36.57 umol, 1 eq), methoxycarbonyl-(triethylammonio)sulfonyl- azanide (26.14 mg, 109.71 umol, 3 eq) in DCM (2 mL) was stirred at 25 °C for 3 h. The reaction mixture was concentrated and purified by prep- HPLC column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water (lOmM NH4HCO ₃ )-ACN];

B%: 20%-50%, 8 min togiveN-((S)-2-(((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)amino)-1-((S)-2,3-dihydrobenzofuran-2-yl)-2-oxoethy l)-4-methoxy-lH-indole-2- carboxamide (2.13 mg, 3.74 umol, 10.22% yield, 88% purity) as white solid. MS (ESI) m/z 502.2 [M+H] ⁺ .

[000563] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.29 - 7.32 (m, 1 H) 7.19 - 7.25 (m, 1 H) 7.17 (d, J=8.07 Hz, 1 H) 7.08 - 7.14 (m, 1 H) 7.05 (d, J=8.31 Hz, 1 H) 6.87 (t, J=7.40 Hz, 1 H) 6.74 (d, J=7.95 Hz, 1 H) 6.54 (d, J=7.70 Hz, 1 H) 5.04 - 5.24 (m, 2 H) 4.71 - 4.78 (m, 1 H) 4.63 (s, 1 H) 3.96 (s, 3 H) 3.35 - 3.51 (m, 2 H) 3.06 - 3.30 (m, 2 H) 2.68 (ddt, J=14.09, 9.63, 4.83, 4.83 Hz, 0.4 H) 2.24 - 2.45 (m, 2 H) 2.13 - 2.22 (m, 0.6 H) 1.70 - 1.94 (m, 2 H)

Example 55. Synthesis of viral protease inhibitor compound 491

Step 1: methyl (2S)-2-[[3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000564] To the mixture of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (240 mg, 1.01 mmol, 1 eq, HC1), (2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoic acid (412.2 mg, 1.22 mmol, 1.2 eq, HC1) and TEA (410.4 mg, 4.06 mmol, 0.56 mL, 4 eq) in DMF (3 mL) was added T3P (1.2 g, 2.03 mmol, 1.21 mL, 50% purity, 2 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. TLC (DCM:MeOH =10: l/UV254nm) showed new spot was detected. The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 100-25% Ethyl acetate/MeOH@ 30 mL/min). Compound methyl (2S)-2-[[(2S)-3-cyclopropyl-2- [(4-methoxy-lH-indole-2-carbonyl)amino]propanoyl]amino]-3-[( 3S)-2-oxo-3- piperidyl]propanoate (256 mg, 0.48 mmol, 48.2% yield, 92.5% purity) was obtained as yellow solid.

Step 2: N-[2-[[( 1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ] methyl ] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide

[000565] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (246.3 mg, 0.47 mmol, 92.5% purity, 1 eq) in NH ₃ (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-(cyclop ropylmethyl)-2-oxo- ethyl]-4-methoxy-lH-indole-2-carboxamide (220 mg, crude) was obtained as yellow solid, which was used into the next step without further purification.

Step 3: N-[2-[[(lS)-l-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-l -(cyclopropylmethyl)- 2-oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide

[000566] A mixture of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-methoxy-lH- indole-2-carboxamide (250 mg, 0.53 mmol, 1 eq) and methoxycarbonyl- (triethylammonio)sulfonyl-azanide (444.0 mg, 1.86 mmol, 3.5 eq) in DCM (3 mL) was stirred at 25 °C for 16 h. The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water (0.05% NH ₃ H ₂ O+lO mM NH ₄ HCO ₃ )-ACN]; B%: 23%-53%, 9.5 min). Compound N-[(1S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4- methoxy-lH-indole-2- carboxamide (83 mg, 0.18 mmol, 34.2% yield, 99.0% purity) was obtained as white solid.

[000567] Isomer 1 : N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1-

(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-ca rboxamide

[000568] Isomer 2 : N-[( 1S)-2-[[( 1R)- 1 -cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-

(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-ca rboxamide [000569] Isomer 3 : N-[(1R)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1-

(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-ca rboxamide

[000570] Isomer 4: N-[(1R)-2-[[(1R)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1-

(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-ca rboxamide

[000571] N-[2-[[ 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)- 2-oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide (50 mg, 0.1 lmmol, 1 eq) was purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH3HZO ETOH];B%: 55%-55%,min) to get three fragments.

[000572] Isomer 1 : N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy- 1H-indole-2-carboxamide. Compound N- [(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino ]-1-(cyclopropylmethyl)-2- oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide (28.1 mg, 62.2 umol, 56.2% yield,

100% purity) was obtained as white solid. LCMS: Rt = 0.755min; for C ₂₄ H ₂ 9N5O ₄ MS Calcd. : 451.22, MS Found: 452.2 [M+H ⁺ ],

[000573] 1 H NMR (400 MHz, DMSO-d ₆ ) δ 11.57 (s, 1H), 8.91 (br d ,J= 8.0 Hz, 1H), 8.50 (br d,J= 7.5 Hz, 1H), 7.53 (br s, 1H), 7.37 (d, J= 1.4 Hz, 1H), 7.15 - 7.06 (m, 1H), 7.04 - 6.97 (m, 1H), 6.51 (d, J= 7.6 Hz, 1H), 5.07 (q, J= 8.2 Hz, 1H), 4.49 - 4.40 (m, 1H), 3.89 (s, 3H), 3.15 - 3.01 (m, 2H), 2.34 - 2.20 (m, 2H), 1.91 - 1.76 (m, 3H), 1.70 (br dd, J= 4.4, 8.7 Hz, 1H), 1.64 - 1.53 (m, 1H), 1.35 (br s, 1H), 0.86 - 0.76 (m, 1H), 0.48 - 0.35 (m, 2H), 0.25 - 0.04 (m, 2H).

[000574] Isomer 4: N-[(lR)-2-[[(lR)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy- 1H-indole-2-carboxamide. Compound N- [( lR)-2-[[( 1R)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2- oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide (6.1 mg, 13.5 umol, 12.2% yield, 100% purity) was obtained as white solid. LCMS: Rt = 0.752min; for C24H29N5O4 MS Calcd. : 451.22, MS Found: 452.2 [M+H ⁺ ],

[000575] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.27 (s, 1H), 7.18 - 7.12 (m, 1H), 7.03 (d ,J = 8.4 Hz, 1H), 6.51 (d, J= 7.6 Hz, 1H), 5.12 (dd, J= 6.4, 7.7 Hz, 1H), 4.85 (br s, 1H), 3.93 (s, 3H), 3.24 - 3.16 (m, 2H), 2.50 - 2.32 (m, 2H), 2.06 - 1.92 (m, 2H), 1.92 - 1.82 (m, 2H), 1.70 (dt, J= 7.0, 14.2 Hz, 2H), 1.63 - 1.54 (m, 1H), 1.31 - 1.31 (m, 1H), 1.41 - 1.27 (m, 1H), 0.91 - 0.80 (m, 1H), 0.53 (br d ,J= 8.0 Hz, 2H), 0.25 - 0.14 (m, 2H).

[000576] The mixture of Isomer 2 & Isomer 3 (20.0 mg, 44.3 umol, 1 eq) was purified by SFC (column: DAICEL CHIRALCEL OD-H(250mm * 30mm, 5um);mobile phase: [0.1%NH3HZO ETOH];B%: 45%-45%,min) to get two fragments.

[000577] Isomer 3 : N-[(lR)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide. Compound N- [(lR)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2- oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide (5.1 mg, 11.3 umol, 25.6% yield, 100% purity) was obtained as white solid. LCMS: Rt = 0.754min; for C24H29N5O4 MS Calcd: 451.22, MS Found: 452.1 [M+H ⁺ ],

[000578] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.28 (s, 1H), 7.18 - 7.12 (m, 1H), 7.03 (d ,J = 8.3 Hz, 1H), 6.52 (d, J= 7.5 Hz, 1H), 5.06 (dd, J= 6.5, 9.8 Hz, 1H), 4.81 (br s, 1H), 3.93 (s, 3H), 3.18 (br s, 2H), 2.43 - 2.35 (m, 1H), 2.45 - 2.27 (m, 1H), 2.31 (br s, 1H), 2.06 - 1.95 (m, 1H), 1.94 - 1.78 (m, 3H), 1.76 - 1.59 (m, 2H), 1.58 - 1.45 (m, 1H), 1.40 (s, 1H), 1.29 (s, 1H), 0.92 - 0.79 (m, 1H), 0.58 - 0.44 (m, 2H), 0.26 - 0.12 (m, 2H).

[000579] Isomer 2 : N-[(1S)-2-[[( 1R)- 1 -cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-l - (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy- 1H-indole-2-carboxamide. Compound N- [(1S)-2-[[(lR)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino ]-1-(cyclopropylmethyl)-2- oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide (6.3 mg, 14.0 umol, 31.6% yield, 100% purity) was obtained white solid. LCMS: Rt = 0.754min; for C24H29N5O4 MS Calcd: 451.22, MS Found: 452.1 [M+H ⁺ ],

[000580] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.12 (s, 1H), 7.01 - 6.96 (m, 1H), 6.87 (d ,J = 8.3 Hz, 1H), 6.35 (d ,J= 7.8 Hz, 1H), 4.89 (t , J= 7.2 Hz, 1H), 4.43 (dd, J= 6.3, 8.3 Hz, 2H), 3.77 (s, 3H), 3.08 - 3.00 (m, 2H), 2.32 - 2.22 (m, 1H), 2.20 - 2.10 (m, 1H), 2.27 - 2.07 (m, 1H), 1.84 - 1.73 (m, 2H), 1.72 - 1.62 (m, 2H), 1.60 - 1.50 (m, 2H), 1.43 - 1.34 (m, 1H), 0.75 - 0.62 (m, 1H), 0.40 - 0.27 (m, 2H), 0.08 -0.04 (m, 2H).

Example 56. Synthesis of viral protease inhibitor compound 247

Step 1: (2S)-2-(benzyloxycarbonylamino)-3-(lH-mdol-3-yl)propanoic acid [000581] (2S)-2-amino-3-(lH-indol-3-yl)propanoic acid (3 g, 14.69 mmol, 1 eq) was dissolved in NaOH (1 M, 14.65 mL) and stirred at 0 °C. CbzCl (2.51 g, 14.73 mmol, 2.09 mL, 1 eq) and NaOH (1 M, 14.65 mL) were then simultaneously added drop-wise. The mixture was stirred for 17 h at 20 °C. Upon completion, the solution was acidified with 6 M HC1 to pH = 1 after which the product was extracted with EtOAc (80 mL * 3). The organic layers were combined, dried by NazSO ₄ and evaporated. The crude product was purified by silica gel chromatography (SiO ₂ , DCM:MeOH = 7:1) and re-purified by prep- HPLC (HPLC:ET40319-84-P1D; column: Xtimate C18 lOu 250mm*80mm;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 5%-35%,25min) to give (2S)-2- (benzyloxycarbonylamino)-3-(lH-indol-3-yl)propanoic acid (1.6 g, 4.63 mmol, 31.55% yield, 98% purity) as light yellow solid. MS (ESI) m/z 339.1 [M+H] ⁺

[000582] ¹ H NMR (400MHz, DMSO-d6) δ = 10.79 (br s, 1H), 7.57 - 7.44 (m, 1H), 7.35 - 7.23 (m, 5H), 7.21 - 7.13 (m, 1H), 7.10 (d, J=2.1 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.98 - 6.88 (m, 2H), 6.98 - 6.88 (m, 1H), 4.97 (s, 2H), 4.09 (dt, J=4.6, 7.7 Hz, 1H), 3.22 (dd, J=4.3, 14.4 Hz, 1H), 3.00 (dd, J=8.0, 14.5 Hz, 1H).

Step 2: (2S)-2-(benzyloxycarbonylamino)-3-(2-oxoindolm-3-yl)propanoi c acid

[000583] A mixture of (2S)-2-(benzyloxycarbonylamino)-3-(lH-indol-3-yl)propanoic acid (1.5 g, 4.00 mmol, 1 eq, HC1) in AcOH (60 mL) was added DMSO (469.01 mg, 6.00 mmol, 469.01 uL, 1.5 eq) and HC1 (12 M, 1.33 mL, 4 eq) at 25 °C, and the mixture was stirred at 25 °C for 3 h under N ₂ . Upon completion, the mixture was quenched with water (100 mL), extracted with ethyl acetate (60 mL * 3), the combined organic layer washed with brine (200 mL), dried with Na ₂ SO ₄ , filtered and concentrated in reduced pressure at 40 °C. The mixture was purified by prep-HPLC (column: Welch Xtimate C18 250*70mm#10um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 7%-37%,20min) to give (2S)-2-(benzyloxycarbonylamino)-3-(2-oxoindolin-3-yl)propano ic acid (800 mg, 2.03 mmol, 50.77% yield, 90% purity) as white solid. MS (ESI) m/z 337.0 [M+H] ⁺

Step 3: benzyl N-[(lS)-2-amino-2-oxo-l-[(2-oxomdolm-3-yl)methyl] ethyl] carbamate

[000584] A mixture of (2S)-2-(benzyloxycarbonylamino)-3-(2-oxoindolin-3-yl)propano ic acid (600 mg, 1.54 mmol, 1 eq, HC1) in DMF (20 mL) was added 1 -hydroxybenzotriazole (207.45 mg, 1.54 mmol, 1 eq) and EDCI (323.74 mg, 1.69 mmol, 1.1 eq) at 20 °C. After the mixture was stirred at 20 °C for 2 h under N ₂ , NH ₃ .H ₂ O (1.01 g, 7.22 mmol, 1.11 mL, 25% purity, 4.7 eq) was added drop-wise. The mixture was stirred at 20 °C for 16 h.

Upon completion, the mixture quenched with water (30 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers washed with brine (100 mL), dried with Na ₂ SO ₄ , filtered and concentrated in reduced pressure at 40 °C to give benzyl N- [(1S)-2-amino-2-oxo-1-[(2-oxoindolin-3-yl)methyl]ethyl]carba mate (500 mg, crude) as white solid which was used for next step without further purification. MS (ESI) m/z 354.1 [M+H] ⁺

Step 4: (2S)-2-amino-3-(2-oxoindolin-3-yl)propanamide

[000585] To a solution of benzyl N-[(1S)-2-amino-2-oxo-1-[(2-oxoindolin-3- yl)methyl]ethyl]carbamate (500 mg, 1.41 mmol, 1 eq) in i-PrOH (100 mL) was added Pd/C (339.59 mg, 282.99 umol, 10% purity, 0.2 eq) and HC1 (12 M, 1.30 mL, 11 eq) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 50 °C for 16 h. Upon completion, the reaction mixture was filtered and the filter was concentrated. The crude product was purified by prep-HPLC (HPLC: ET40319-96-P1C; column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN];B%: 1%- 20%,8min) to give (2S)-2-amino-3-(2-oxoindolin-3-yl)propanamide (130 mg, 549.67 umol, 38.85% yield, 92.7% purity) as white solid. MS (ESI) m/z 220.1 [M+H] ⁺ Step 5: N-f ( l S)-2-[[ ( l S)-2-amino-2-oxo-l-[(2-oxoindolin-3-yl)methyl ]ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide

[000586] To a mixture of (2S)-2-amino-3-(2-oxoindolin-3-yl)propanamide (60 mg,

273.67 umol, 1 eq), (2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoic acid (99.29 mg, 328.41 umol, 1.2 eq) and EtsN (166.16 mg, 1.64 mmol, 228.55 uL, 6 eq) in DCM (10 mL) was added T3P (522.46 mg, 821.02 umol, 488.28 uL, 50% purity, 3 eq) drop-wise at 0 °C. The solution was stirred at 25 °C for 1 h under N ₂ . Upon completion, the mixture was quenched with water (20 mL) and extracted with DCM:MeOH = 7:1 (15 mL * 2). The combined organic layers washed with brine (30 mL), dried with Na ₂ SO ₄ , filtered and concentrated in reduced pressure at 40 °C. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give N-[(1S)-2-[[(1S)- 2-amino-2-oxo-1-[(2-oxoindolin-3-yl)methyl]ethyl]amino]-1-(c yclopropylmethyl)-2-oxo- ethyl]-4-methoxy- 1 H-indole-2-carboxamide (40 mg, 55.61 umol, 20.32% yield, 70% purity) as colorless oil. MS (ESI) m/z 504.3 [M+H] ⁺

Step 6: N-[ ( l S)-2-[[ ( l S)-1-cyano-2-(2-oxoindolin-3-yl)ethyl ] amino] -l-(cyclopropylmethyl)- 2-oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide

[000587] To a mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[(2-oxoindolin-3- yl)methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4- methoxy-lH-indole-2- carboxamide (35 mg, 69.51 umol, 1 eq) in DCM (6 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (49.69 mg, 208.52 umol, 3 eq) in one portion at 20 °C and stirred at 20 °C for 2 h. Methoxycarbonyl-(triethylammonio)sulfonyl-azanide (82.82 mg, 347.53 umol, 5 eq) was added at 20 °C and stirred at 20 °C for 4 h. Upon completion, the crude was dried by N ₂ and purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HCC>3)-ACN];B%: 30%- 60%,8min) and re-purified by prep-HPLC (column: Phenomenex Luna C 18 75*30mm*3um;mobile phase: [ water(0.2%F A)- ACN] ;B% : 30%-70%,8min) to afford N- [(1S)-2-[[(1S)-1-cyano-2-(2-oxoindolin-3-yl)ethyl]amino]-1-( cyclopropylmethyl)-2-oxo- ethyl]-4-methoxy-lH-indole-2-carboxamide (5 mg, 10.23 umol, 14.72% yield, 99.36% purity, 99.36% purity) as white solid. MS (ESI) m/z 486.2 [M+H] ⁺

[000588] ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.39 - 7.09 (m, 4H), 7.07 - 6.95 (m, 2H), 6.92 - 6.80 (m, 1H), 6.51 (dd, J=3.1, 7.5 Hz, 1H), 5.37 - 5.14 (m, 1H), 4.65 - 4.47 (m, 1H), 3.93 (dd, J=1.4, 3.4 Hz, 3H), 3.70 - 3.52 (m, 1H), 2.63 - 2.27 (m, 2H), 1.92 - 1.60 (m, 2H), 0.84 (br s, 1H), 0.59 - 0.43 (m, 2H), 0.27 - 0.10 (m, 2H)

Example 57. Synthesis of viral protease inhibitor compound 331

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

[000589] To a mixture of N-[(1S)-1-[[(1S)-1-formyl-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl] -3-methyl-butyl]-4-methoxy-lH-indole-2-carboxamide (700 mg,

1.27 mmol, 80% purity, 1 eq) in EtOH (10 mL) was added pyrrolidine (180.01 mg, 2.53 mmol, 211.28 uL, 2 eq) and ZnC12 (1 M, 12.66 uL, 0.01 eq). The mixture was stirred at 25 °C for 30 min, and then added TMSCN (251.10 mg, 2.53 mmol, 316.65 uL, 2 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC to get the compound N-[(1S)-1-[[(1S)-2-cyano-1-[[(3S)-2-oxopyrrolidin-3-yl]methy l]-2- pyrrolidin-1-yl-ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-l H-indole-2-carboxamide (110 mg, 199.95 umol, 15.80% yield, 95% purity) and N-[(1S)-1-[[(1S)-2-cyano-1-[[(3S)- 2-oxopyrrolidin-3-yl]methyl]-2-pyrrolidin-1-yl-ethyl] carbamoyl]-3-methyl-butyl]-4- methoxy-lH-indole-2-carboxamide (110 mg, 199.95 umol, 15.80% yield, 95% purity) as white solid. MS (ESI) m/z 523.4 [M+H] ⁺

[000590] column: Phenomenex luna CN 5u 100*30mm;mobile phase: [Hexane-IPA];B%: 5%-40%,20min

[000591] Isomer 1 : ¹ H NMR (400MHz, DMSO-d6) δ = 11.58 (s, 1H), 8.43 (d, J=7.7 Hz, 1H), 8.20 (d, J=9.4 Hz, 1H), 7.68 - 7.49 (m, 1H), 7.38 (d, J=1.2 Hz, 1H), 7.18 - 6.93 (m, 2H), 6.50 (d, J=7.6 Hz, 1H), 4.57 - 3.99 (m, 3H), 3.88 (s, 3H), 3.19 - 2.95 (m, 2H), 2.64 - 2.53 (m, 4H), 2.38 - 2.27 (m, 1H), 2.15 - 2.01 (m, 1H), 1.85 - 1.44 (m, 10H), 0.91 (dd, J=6.4, 16.3 Hz, 6H) [000592] Isomer 2: ¹ H NMR (400MHz, DMS0-d6) δ = 11.59 (br s, 1H), 8.39 (br d, J=7.6 Hz, 1H), 8.01 (br d, J=9.1 Hz, 1H), 7.69 - 7.49 (m, 1H), 7.43 - 7.28 (m, 1H), 7.16 - 6.86 (m, 2H), 6.50 (d, J=7.6 Hz, 1H), 4.59 - 4.24 (m, 3H), 3.88 (s, 3H), 3.19 - 2.94 (m, 2H), 2.71 - 2.57 (m, 2H), 2.49 - 2.32 (m, 3H), 2.18 - 2.08 (m, 1H), 2.06 - 1.93 (m, 1H), 1.83 - 1.37 (m, 9H), 0.90 (dd, J=6.5, 15.2 Hz, 6H)

Example 58. Synthesis of viral protease inhibitor compound 389

Step 1: (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide

[000593] tert- butyl N-[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamate (2 g, 7.37 mmol, 1 eq) in HCl/EtOAc (4 M, 50 mL, 27.13 eq) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressure to afford (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (1.2 g, crude) as a white solid.

Step 2: methyl 2-azaspiro[4.5]decane-3-carboxylate

[000594] 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). The mixture 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 -carboxyl ate (2 g, crude) as a yellow oil.

Step 3: methyl 2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-c arboxylate [000595] To a solution of methyl 2-azaspiro[4.5]decane-3-carboxylate (2 g, 10.14 mmol,

1 eq) and 4-methoxy-1H-indole-2-carboxylic acid (2.33 g, 12.17 mmol, 1.2 eq) in DCM (30 mL) and DMF (5 mL) was added T3P (12.90 g, 20.28 mmol, 12.06 mL, 50% purity, 2 eq) and DIEA (3.93 g, 30.41 mmol, 5.30 mL, 3 eq). The mixture was stirred at 25 °C for

2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (100 mL) and extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum etherEthyl acetate = 10: 1 to 0: 1) affording the product methyl 2-(4-methoxy-1H-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carboxylate (3 g, 8.10 mmol, 79.88% yield) as a white solid. MS (ESI) m/z 371.1 [M+H] ⁺

Step 4: 2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-c arboxylic acid

[000596] 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 H ₂ O (15 mL) was added LiOH.H ₂ O (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 H ₂ O (50 mL), and then added aq. HC1 (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure affording the product 2-(4-methoxy- \H- 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] ⁺

Step 5: N-((S)-1-amino- J-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-(4-methoxy- JH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide

[000597] To a solution of 2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3- carboxylic acid (1 g, 2.81 mmol, 1 eq) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yljpropanamide (720.49 mg, 4.21 mmol, 1.5 eq) in DCM (30 mL) was added T3P (3.57 g, 5.61 mmol, 3.34 mL, 50% purity, 2 eq) and DIEA (1.09 g, 8.42 mmol, 1.47 mL, 3 eq) at 0 °C. The mixture was stirred at 30 °C for 1 h. Upon completion, the mixture was quenched by the addition ofH ₂ O (100 mL), and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 1:0 to 10: 1) affording the product N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]e thyl]-2-(4- methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbox amide (700 mg, 1.37 mmol, 48.96% yield) as a white solid. MS (ESI) m/z 510.3 [M+H] ⁺

Step 6: N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-metho xy-lH-indole-2- carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[000598] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspi ro[4.5]decane-3- carboxamide (700 mg, 1.37 mmol, 1 eq) in DCM (10 mL) was added Burgess reagent (982.03 mg, 4.12 mmol, 3 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Kromasil C18 (250 * 50 mm * 10 um); mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30% - 60%, 10 min) affording the product N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-met hoxy-l/7-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (500 mg, 1.02 mmol, 74.05% yield) as a white solid. MS (ESI) m/z 492.3 [M+H] ⁺

Step 7: N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-metho xy-lH-indole-2- carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[000599] N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-met hoxy-1H-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (500 mg, 1.02 mmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: [0.1% NH ₃ H ₂ O IP A]; B%: 55% - 55%, 9 min) affording the product N-[( IS)- l-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-methoxy-lH-indole-2-c arbonyl)-2- azaspiro[4.5]decane-3-carboxamide Isomer 1 (264 mg, 537.04 umol, 52.80% yield, 100% purity) as a white solid. MS (ESI) m/z 492.3 [M+H] ⁺

[000600] ¹ H NMR (400 MHz, METHANOL-d4) δ = 7.28 - 6.76 (m, 3H), 6.60 - 6.38 (m, 1H), 5.05 (br dd ,J= 5.2, 10.2 Hz, 1H), 4.63 - 4.60 (m, 1H), 4.03 - 3.85 (m, 5H), 3.74 - 3.28 (m, 1H), 2.73 (br dd,J= 5.0, 8.6 Hz, 1H), 2.51 - 2.28 (m, 2H), 2.27 - 2.08 (m, 1H), 1.96 - 1.72 (m, 2H), 1.69 - 1.38 (m, 11H), 1.37 - 1.09 (m, 1H).

[000601] N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-met hoxy-1H-indole-

2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide Isomer 2 (140 mg, 284.51 umol, 27.97% yield, 99.9% purity) as a white solid. MS (ESI) m/z 492.3 [M+H] ⁺

[000602] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.30 - 6.81 (m, 3H), 6.53 (br d ,J = 2.0 Hz, IH), 5.12 - 4.95 (m, 2H), 4.70 - 4.55 (m, 2H), 4.08 - 3.86 (m, 4H), 3.84 - 3.72 (m, IH), 2.62 - 2.40 (m, IH), 2.36 - 2.18 (m, 2H), 1.94 - 1.69 (m, 3H), 1.68 - 1.34 (m, 11H).

Example 59. Synthesis of viral protease inhibitor compound 513

Step 1: O1-tert-butyl 02-methyl 4-methoxyindoline-l,2-dicarboxylate [000603] A mixture of l-tert-butoxycarbonyl-4-hydroxy-indoline-2-carboxylic acid (300 mg, 1.07 mmol, 1 eq) in DMF (4 mL) was added K2CO3 (445.37 mg, 3.22 mmol, 3 eq), and the mixture was added with Mel (381.16 mg, 2.69 mmol, 167.18 uL, 2.5 eq) at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (10 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=10/l to 5/1) to give Ol-tert-butyl 02-methyl 4- methoxyindoline- 1 ,2-dicarboxylate (220 mg, 715.82 umol, 66.64% yield) as a yellow solid. MS (ESI) m/z 208.0 [M+H-Boc] ⁺

Step 2: l-tert-butoxycarbonyl-4-methoxy-indoline-2-carboxylic acid [000604] A mixture of Ol-tert-butyl 02-methyl 4-methoxyindoline- 1 ,2-dicarboxylate (200 mg, 650.74 umol, 1 eq) in THF (1 mL) and H ₂ O (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 HCI solution and extracted with ethyl acetate (2 mL * 3). The combined organic layers were washed with brine (5 mL * 1), dried over Na ₂ SO ₄ , 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] ⁺

Step 3: 4-methoxyindoline-2-carboxylic acid

[000605] To a mixture of l-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, HCI) as yellow oil. MS (ESI) m/z 194.1 [M+H] ⁺

Step 4: N-f ( l S)-2-[[( 1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ]ammo]-l- (cyclopropylmethyl)-2 -oxo-ethyl]-4-methoxy-indolme-2-carboxamide

[000606] To a mixture of 4-methoxyindoline-2-carboxylic acid (110 mg, 478.97 umol, 1 eq, HCI) and (2S)-2-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]et hyl]-3- cyclopropyl-propanamide (316.51 mg, 478.97 umol, 40% purity, 1 eq) in DCM (8 mL) was added DIEA (123.81 mg, 957.94 umol, 166.86 uL, 2 eq) and T ₃ P (457.20 mg, 718.45 umol, 427.29 uL, 50% purity, 1.5 eq) at 0°C. The mixture was stirred at 0 °C for 1 h. The mixture was stirred with EDTA (10 mL) at 25 °C, The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 2). The combined organic layer was concentrated under reduced pressure to give a residue. The residue was purified with neutral prep-HPLC to get the compound N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo- ethyl]-4-methoxy- indoline-2-carboxamide (29 mg, 63.81 umol, 13.32% yield, 96.7% purity) and N-[(1S)-2- [[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-( cyclopropylmethyl)-2-oxo- ethyl]-4-methoxy-indoline-2-carboxamide (26 mg, 55.61 umol, 11.61% yield, 94% purity) as a white solid. MS (ESI) m/z 440.2 [M+H] ⁺ [000607] column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(10mM NH4HC03)-ACN];B%: 20%-50%,10min

[000608] ¹ H NMR (400MHz, DMSO-d6) δ = 8.99 - 8.83 (m, 1H), 8.08 - 7.89 (m, 1H), 7.71 (s, 1H), 6.92 (t, J=8.0 Hz, 1H), 6.25 (dd, J=4.4, 7.9 Hz, 2H), 5.91 (d, J=3.5 Hz, 1H), 5.05 - 4.85 (m, 1H), 4.42 - 4.14 (m, 2H), 3.70 (s, 3H), 3.28 - 2.97 (m, 3H), 2.90 - 2.76 (m, 1H), 2.43 - 2.26 (m, 1H), 2.19 - 1.98 (m, 2H), 1.87 - 1.54 (m, 3H), 1.50 - 1.31 (m, 1H), 0.79 - 0.54 (m, 1H), 0.47 - 0.26 (m, 2H), 0.20 -0.10 (m, 2H)

[000609] ¹ H NMR (400MHz, DMSO-d6) δ = 8.88 (d, J=7.9 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 6.93 (t, J=8.0 Hz, 1H), 6.26 (dd, J=4.5, 7.9 Hz, 2H), 5.92 (d, J=3.6 Hz, 1H), 5.08 - 4.84 (m, 1H), 4.50 - 4.17 (m, 2H), 3.70 (s, 3H), 3.27 - 2.99 (m, 3H), 2.88 - 2.72 (m, 1H), 2.40 - 2.25 (m, 1H), 2.17 - 2.02 (m, 2H), 1.87 - 1.57 (m, 3H), 1.51 - 1.39 (m, 1H), 0.70 (br s, 1H), 0.49 - 0.26 (m, 2H), 0.21 -0.14 (m, 2H)

Example 60. Synthesis of viral protease inhibitor compound 515

Step 1: 4-hydroxy- 1H-indole-2-carboxylic acid

[000610] To a mixture of 4-methoxy- 1 H-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 H ₂ O (30 mL) and extracted with DCM (30 mL * 2). The combined organic layers were washed with brine 20 mL, dried over Na ₂ SO ₄ , 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] ⁺ Step 2: methyl 4-hydroxy- lH-indole-2-carboxylate

[000611] 4-hydroxy- 1 H-indole-2-carboxylic acid (200 mg, 1.13 mmol, 1 eq) was added with HCl/MeOH (4 M, 10 mL, 35.43 eq), and the mixture was stirred at 70 °C for 5 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=9/l to 8/1) to give methyl 4-hydroxy- 1 H-indole-2-carboxylate (170 mg, 800.28 umol, 70.89% yield, 90% purity) as a yellow solid. MS (ESI) m/z 190.1 [M-H] ⁺

Step 3: methyl 4-(2-morpholinoethoxy)-lH-indole-2-carboxylate

[000612] To a mixture of methyl 4-hydroxy- 1 H-indole-2-carboxylate (300 mg, 1.57 mmol, 1 eq) and 2-morpholinoethanol (205.83 mg, 1.57 mmol, 192.37 uL, 1 eq) in THF (4 mL) was added PPhs (452.73 mg, 1.73 mmol, 1.1 eq), DIAD (317.30 mg, 1.57 mmol, 305.10 uL, 1 eq) was added at 0 °C under N ₂ . The mixture was stirred at 25 °C for 60 min. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 2). The combined organic layers were washed with brine (20 mL), filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC(PE:EA=0: 1) to give methyl 4-(2-morpholinoethoxy)- 1 H-indole-2-carboxylate (200 mg, 591.44 umol, 37.69% yield, 90% purity) as a yellow solid. MS (ESI) m/z 304.9 [M+H] ⁺

Step 4: 4-(2-morpholinoethoxy)-lH-indole-2-carboxylic acid

[000613] To a mixture of methyl 4-(2-morpholinoethoxy)- 1 H-indole-2-carboxylate (200 mg, 657.16 umol, 1 eq) in THF (2 mL) and H ₂ O (1 mL) was added LiOH.H ₂ O (41.37 mg, 985.74 umol, 1.5 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was purified by HC1 prep-HPLC to give 4-(2-morpholinoethoxy)-lH-indole-2-carboxylic acid (80 mg, 261.79 umol, 39.84% yield, 95% purity) as a white solid. MS (ESI) m/z 289.2 [M-H] ⁺

[000614] column: Phenomenex luna C1880*40mm*3 um;mobile phase: [water(0.04%HCl)-ACN];B%: l%-32%,6.5min

Step 5: N-f ( l S)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-(2-morpholinoethoxy)-lH-i ndole-2-carboxamide [000615] To a mixture of 4-(2-morpholinoethoxy)- 1 H-indole-2-carboxylic acid (70 mg,

241.12 umol, 1 eq) and (2S)-2-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-3-cyclopropyl-propanamide (159.33 mg, 241.12 umol, 40% purity, 1 eq) in DCM (2 mL) was added DIEA (93.49 mg, 723.36 umol, 125.99 uL, 3 eq) and T ₃ P (230.16 mg, 361.68 umol, 215.10 uL, 50% purity, 1.5 eq) in one portion at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction mixture was added with EDTA solution (2 mL) and stirred at 25 °C for 10 min, and then extracted with DCM (2 mL * 3). The combined organic layers were washed with brine (5 mL * 1), and 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-(2-morpholinoethoxy)-lH-i ndole-2-carboxamide (13 mg, 24.23 umol, 10.05% yield) as a white solid. MS (ESI) m/z 537.3 [M+H] ⁺

[000616] column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase:

[water(10mM NH ₄ HCO ₃ )-ACN];B%: 20%-50%,8min

[000617] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.57 (s, 1H), 8.92 (d, J=7.9 Hz, 1H), 8.60 (br d,J=7.5 Hz, 1H), 7.79 - 7.68 (m, 1H), 7.35 (d, J=1.5 Hz, 1H), 7.14 - 6.93 (m, 2H), 6.51 (d, J=7.5 Hz, 1H), 4.98 (q, J=7.9 Hz, 1H), 4.54 - 4.38 (m, 1H), 4.21 (br d, J=3.5 Hz, 2H), 3.59 (t, J=4.5 Hz, 4H), 3.20 - 3.05 (m, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.60 - 2.52 (m, 4H), 2.43 - 2.28 (m, 1H), 2.23 - 2.04 (m, 2H), 1.92 - 1.60 (m, 3H), 1.56 - 1.38 (m, 1H), 0.80 (br d, J=5.3 Hz, 1H), 0.51 - 0.30 (m, 2H), 0.25 - 0.05 (m, 2H)

[000618] ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.34 - 7.28 (m, 1H), 7.18 - 7.11 (m, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H), 5.08 (dd, J=5.8, 10.3 Hz, 1H), 4.54 (t, J=7.4 Hz, 1H), 4.30 (t, J=5.3 Hz, 2H), 3.77 - 3.72 (m, 4H), 3.30 - 3.27 (m, 2H), 2.92 (t, J=5.3 Hz, 2H), 2.75 - 2.59 (m, 5H), 2.40 - 2.26 (m, 2H), 1.99 - 1.79 (m, 3H), 1.78 - 1.60 (m, 1H), 0.93 - 0.76 (m, 1H), 0.58 - 0.52 (m, 2H), 0.20 (br dd, J=5.0, 11.6 Hz, 2H)

Example 61. Synthesis of viral protease inhibitor compound 525

Step 1: 4,6-dichloro-2-(trichloromethyl)-lH-benzimidazole

[000619] A mixture of 3, 5-di chlorobenzene- 1,2-diamine (640.64 mg, 3.62 mmol, 1 eq) and methyl 2,2,2-trichloroethanimidate (766.16 mg, 4.34 mmol, 535.78 uL, 1.2 eq) in AcOH (5 mL) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (10 mL) and filtered to afford 4,6-dichloro-2-(trichloromethyl)-lH- benzimidazole (860 mg, 2.83 mmol, 78.07% yield) as a brown solid. MS (ESI) m/z 304.5 [M+2H] ⁺

Step 2: methyl 4,6-dichloro-lH-benzimidazole-2-carboxylate

[000620] A mixture of 4,6-dichloro-2-(trichloromethyl)-lH-benzimidazole (420 mg, 1.38 mmol, 1 eq) in MeOH (5 mL) was added Na2CO ₃ (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 HC1 (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 Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give methyl 4,6-dichloro-lH-benzimidazole-2-carboxylate (330 mg, 1.35 mmol, 97.59% yield) as a brown solid. MS (ESI) m/z 245.0 [M+H] ⁺

Step 3: 4,6-dichloro-lH-benzimidazole-2-carboxylic acid

[000621] To a mixture of methyl 4,6-dichloro-lH-benzimidazole-2-carboxylate (330 mg, 1.35 mmol, 1 eq) in THF (2 mL) and H ₂ O (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 HC1 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 4,6-dichloro-lH-benzimidazole-2-carboxylic acid (200 mg, 865.67 umol, 64.29% yield) as a brown solid. MS (ESI) m/z 229.0 [M-H] ⁺

Step 4: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,6-dichloro-lH-benzimidazol e-2- carbonyl)amino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000622] To a mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (140 mg, 470.83 umol, 1 eq) and 4,6-dichloro- lH-benzimidazole-2-carboxylic acid (197.78 mg, 470.83 umol, 55% purity, 1 eq) in DCM (3 mL) and DMF (1 mL) was added DMAP (172.56 mg, 1.41 mmol, 3 eq) in one portion at 25 °C. The mixture was added EDCI (270.78 mg, 1.41 mmol, 3 eq) and stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O (4 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic layers were washed with brine (8 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (basic condition, column: Phenomenex Gemini-NX C1875*30 mm*3 um; mobile phase: [water(0.05% NH ₃ H ₂ O+lO mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%, 8 min) to give methyl (2S)-2-[[(2S)- 3-cyclopropyl-2-[(4,6-dichloro-lH-benzimidazole-2-carbonyl)a mino]propanoyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (70 mg, 137.16 umol, 29.13% yield) as a white solid. MS (ESI) m/z 510.2 [M+H] ⁺

Step 5: N-f ( l S)-2-[[ ( l S)-2-amino-2-oxo-l-[ [ ( 3S)-2-oxopyrrolidin-3-yl ]methyl ] ethyl ]amino ]- l-(cyclopropylmethyl)-2-oxo-ethyl]-4,6-dichloro-lH-benzimida zole-2-carboxamide [000623] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,6-dichloro-lH- benzimidazole-2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-ox opyrrolidin-3- yl jpropanoate (60 mg, 117.56 umol, 1 eq) in NLh/MeOH (7 M, 8 mL, 476.34 eq) was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4, 6-dichloro-lH- benzimidazole-2-carboxamide (58 mg, 117.09 umol, 99.60% yield) as a white solid. MS (ESI) m/z 495.2 [M+H] ⁺ Step 6: 4, 6-dichloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-2-yl ]ethyl ]aminoJ-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-benzimidazole-2-carboxam ide

[000624] To a mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4, 6-dichloro-lH- benzimidazole-2-carboxamide (50 mg, 100.94 umol, 1 eq) in DCM (1 mL) was added Burgess reagent (48.11 mg, 201.87 umol, 2 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (basic condition, column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(0.05%NH ₃ H ₂ 0+ 1 OmM NH ₄ HCO ₃ )-ACN];B%: 15%-45%,8min) to give 4,6- dichloro-N-[( 1 S)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-benzimidazole-2-carboxam ide (13 mg, 27.23 umol, 26.98% yield) as a white solid. MS (ESI) m/z 477.1 [M+H] ⁺

[000625] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 13.77 (br s, 1H), 8.97 - 8.81 (m, 2H), 7.71 (s, 1H), 7.66 - 7.40 (m, 2H), 5.05 - 4.91 (m, 1H), 4.60 - 4.48 (m, 1H), 3.21 - 3.03 (m, 2H), 2.43 - 2.28 (m, 1H), 2.22 - 2.06 (m, 2H), 2.02 - 1.85 (m, 1H), 1.84 - 1.54 (m, 3H), 0.81 - 0.69 (m, 1H), 0.48 - 0.34 (m, 2H), 0.20 - 0.04 (m, 2H)

Example 62. Synthesis of viral protease inhibitor compound 529

Step 1: methyl (2S)-2-[[(2S)-2-[(6-chloro-lH-indole-2-carbonyl)amino]-3-cyc lopropyl- propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000626] A mixture of 6-chloro-lH-indole-2-carboxylic acid (800 mg, 4.08 mmol, 1 eq) in DCM (6 mL) and DMF (3 mL) was added DMAP (1.50 g, 12.24 mmol, 3 eq) in one portion at 25 °C. The mixture added methyl(2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.36 g, 4.08 mmol, 1 eq, HC1) and EDCI (2.34 g, 12.24 mmol, 3 eq) in one portion at 25 °C and stirred for 2.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10: 1). Compound methyl (2S)-2-[[(2S)-2-[(6-chloro-lH-indole-2-carbonyl)amino]-3-cyc lopropyl- propanoyl]amino] -3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (900 mg, 1.89 mmol, 46.45% yield, 90% purity) was obtained as a white solid. MS (ESI) m/z 475.1 [M+H] ⁺ .

Step 2: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl ] amino ]- l-(cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-lH-indole-2-carb oxamide [000627] To a mixture of methyl(2S)-2-[[(2S)-2-[(6-chloro-lH-indole-2-carbonyl)amino] - 3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl] propanoate (900 mg, 1.89 mmol, 1 eq) in NH ₃ /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-(cycloprop ylmethyl)-2-oxo-ethyl]-6- chloro- 1 H-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] ⁺ .

Step 3: 6-chloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[000628] A mixture of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6- chloro-lH-indole-2- carboxamide (700 mg, 1.52 mmol, 1 eq) in DCM (7 mL) was added Burgess reagent (725.41 mg, 3.04 mmol, 2.5 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN];B%: 30%- 60%,8min). Compound 6-chloro-N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole -2-carboxamide (60 mg, 133.90 umol, 30.79% yield, 98.622% purity) was obtained as a white solid. MS (ESI) m/z 442.1 [M+H] ⁺ . [000629] ¹ H NMR (400 MHz, DMSO -d ₆ ) δ ppm 11.74 (br s, 1H), 8.95 (br d ,J= 7.72 Hz, 1H), 8.66 (br d ,J= 7.28 Hz, 1H), 7.65 - 7.74 (m, 2H), 7.43 (s, 1H), 7.32 (s, 1H), 7.05 (dd, J= 8.49, 1.87 Hz, 1H), 4.95 - 5.03 (m, 1H), 4.47 (br dd,J= 13.67, 7.94 Hz, 1H), 3.07 - 3.18 (m, 2H), 2.31 - 2.41 (m, 1H), 2.07 - 2.18 (m, 2H), 1.65 - 1.89 (m, 3H), 1.42 - 1.54 (m, 1H), 0.80 (br s, 1H), 0.36 - 0.49 (m, 2H), 0.07 - 0.24 (m, 2H), -0.69 - -0.69 (m, 1H)

Example 63. Synthesis of viral protease inhibitor compound 539

Step 1: (S)-methyl 2-ammo-3-((S)-2-oxopyrrolidm-3-yl)propanoate hydrochloride [000630] A solution 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, 20 mL, 45.81 eq) was stirred at 20 °C for 1 h, and the reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (350 mg, crude, HC1) as a yellow solid.

Step 2: (2S,4R)-tert-butyl 2-(((S)-l -methoxy- 1 -oxo-3-(( S) -2-oxopyrrolidin-3-yl)propan-2- yl)carbamoyl)-4-methylpyrrolidine-l-carboxylate

[000631] To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-methyl-pyrrolidine-2- carboxylic acid (250 mg, 1.09 mmol, 1 eq) and methyl (2 S)-2-amino-3 -[(3 S)-2- oxopyrrolidin-3-yl]propanoate (304.45 mg, 1.64 mmol, 1.5 eq) in DCM (10 mL) was added drop-wise T3P (1.04 g, 1.64 mmol, 972.75 uL, 50% purity, 1.5 eq) and EtsN (662.02 mg, 6.54 mmol, 910.62 uL, 6 eq), and the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition H ₂ O (40 mL) at 0 °C, and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

The residue was purified by column chromatography (SiO ₂ , Petroleum etherEthyl acetate = 10:1 to 0:1) to afford tert-butyl (2S,4R)-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-4-methyl-pyrrolid ine-1-carboxylate (320 mg, 805.10 umol, 73.86% yield) as a colorless oil. MS (ESI) m/z 398.2 [M+H] ⁺ .

Step 3: (S)-methyl 2-((2S, 4R)-4-methylpyrrolidme-2-carboxamido)-3-((S)-2-oxopyrrolidm- 3- yl)propanoate

[000632] A solution of tert-butyl (2S,4R)-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-4-methyl-pyrrolid ine-1-carboxylate (260 mg, 654.15 umol, 1 eq) in HCl/MeOH (4 M, 8 mL, 48.92 eq) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2- [[(2S,4R)-4-methylpyrrolidine-2-carbonyl]amino]-3-[(3S)-2-ox opyrrolidin-3- yl]propanoate (200 mg, crude, HC1) as a colorless oil. MS (ESI) m/z 298.2 [M+H] ⁺ .

Step 4: (S)-methyl 2-((2S,4R)-1-(4-methoxy-JH-indole-2-carbonyl)-4-methylpyrrol idine-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000633] To a solution of methyl (2S)-2-[[(2S,4R)-4-methylpyrrolidine-2- carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 599.14 umol, 1 eq, HC1) and 4-methoxy-lH-indole-2-carboxylic acid (229.09 mg, 1.20 mmol, 2.0 eq) in DMF (2.0 mL) was added DMAP (219.59 mg, 1.80 mmol, 3.0 eq) and EDCI (229.71 mg, 1.20 mmol, 2 eq) and DCM (8.0 mL), the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition H ₂ O (50 mL) at 0 °C, and then extracted with DCM (40 mL * 3). The combined organic layers were washed with brine (60 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 1:1 to 0:1) to afford methyl (2S)-2-[[(2S,4R)-1-(4-methoxy-lH-indole-2-carbonyl)-4- methyl-pyrrolidine-2-carbonyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 494.14 umol, 82.47% yield, 93% purity) as a yellow solid. MS (ESI) m/z 471.3 [M+H] ⁺ . Step 5: (2S, 4R)-N-[ ( l S)-2-amino-2-oxo-l-[[(3S)-2-oxopyrrolidin-3-yl ]methyl] ethyl ]-1-( 4- methoxy-lH-indole-2-carbonyl)-4-methyl-pyrrolidine-2-carboxa mide

[000634] A solution of methyl (2S)-2-[[(2S,4R)-1-(4-methoxy-lH-indole-2-carbonyl)-4- methyl-pyrrolidine-2-carbonyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (220 mg, 434.84 umol, 93% purity, 1 eq) in NH ₃ /MeOH (7 M, 20 mL, 321.96 eq) was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to afford (2S,4R)-N-[(1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]- 1 -(4- methoxy-lH-indole-2-carbonyl)-4-methyl-pyrrolidine-2-carboxa mide (200 mg, crude) as a yellow solid. MS (ESI) m/z 456.2 [M+H] ⁺ .

Step 6: (2S, 4R)-N-[ ( l S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl ]-1-( 4-methoxy-lH- indole-2-carbonyl)-4-methyl-pyrrolidine-2-carboxamide

[000635] A solution of (2S,4R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-1-(4-methoxy-lH-indole-2-carbonyl)-4-methyl -pyrrolidine-2- carboxamide (100 mg, 219.54 umol, 1 eq) in DCM (5 mL) was added methoxy carbonyl - (triethylammonio)sulfonyl-azanide (313.90 mg, 1.32 mmol, 6 eq) was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C 1875 * 30mm * 3um; mobile phase: [water (0.2% FA) - ACN]; B%: 25% - 60%, 8 min) to afford (2S,4R)-N- [( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3-yl Jethyl]- 1 -(4-methoxy- 1 H-indole-2-carbonyl)- 4-methyl-pyrrolidine-2-carboxamide (33 mg, 75.43 umol, 34.36% yield, 100% purity) as a white solid. MS (ESI) m/z 438.2 [M+H] ⁺ .

[000636 ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.73 - 11.47 (m, 1H), 8.85 (br d, J = 8.3 Hz, 1H), 7.84 - 7.54 (m, 1H), 7.24 - 6.84 (m, 3H), 6.74 - 6.48 (m, 1H), 5.10 - 4.47 (m, 2H), 4.20- 3.75 (m, 4H), 3.47 (t, J = 9.0 Hz, 1H), 3.16 (d, J = 7.9 Hz, 1H), 2.61 (s, 1H), 2.43 - 2.36 (m, 1H), 2.27 - 1.43 (m, 7H), 1.07 (d, J = 6.4 Hz, 3H).

[000637] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.25 - 6.75 (m, 3H), 6.59 - 6.40 (m, 1H), 5.15 - 5.00 (m, 1H), 4.84 - 4.61 (m, 1H), 4.30 - 4.06 (m, 1H), 3.98 - 3.84 (m, 3H), 3.55 (t, J = 8.9 Hz, 1H), 3.30 - 3.24 (m, 1H), 3.01 - 2.54 (m, 2H), 2.46 - 2.09 (m, 4H), 2.01 - 1.38 (m, 3H), 1.15 (br d, J = 6.6 Hz, 3H).

Example 64. Synthesis of viral protease inhibitor compound 547

Step J: 9H-fluoren-9-ylmethyl (lS,2S,5R)-2-[[(lS)-l-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carboxylate

[000638] (lS,2S,5R)-3-(9H-fluoren-9-ylmethoxycarbonyl)-3-azabicyclo[3 .2.0]heptane-2- carboxylic acid (150 mg, 412.76 umol, 1 eq), (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanenitrile (75.87 mg, 495.31 umol, 1.2 eq) in DCM (2 mL) was added T3P (394.00 mg, 619.14 umol, 368.22 uL, 50% purity, 1.5 eq) and DIEA (160.04 mg, 1.24 mmol, 215.69 uL, 3 eq), and the resulting mixture was stirred at 25 °C for 2 h. Upon completion, the solution was diluted with H ₂ O (20 mL), extracted with ethyl acetate (20 mL * 3), the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to afford 9H-fluoren-9-ylmethyl (1 S,2S,5R)-2-[[(l S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carboxylate (130 mg, 260.74 umol, 63.17% yield, 100% purity) as white solid. MS (ESI) m/z 499.3 [M+H] ⁺ .

Step 2: (IS, 2S, 5R)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-2-yl ] ethyl ]-3- azabicyclo[ 3.2.0 ]heptane-2-carboxamide

[000639] To a solution of 9H-fluoren-9-ylmethyl ( 1 S,2S,5R)-2-[[(l S)-l -cyano-2-[(3 S)-2- oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-azabicyclo[3.2.0]hepta ne-3-carboxylate (250 mg, 401.15 umol, 80% purity, 1 eq) in DCM (2.5 mL) was added piperidine (68.31 mg,

802.29 umol, 79.23 uL, 2 eq), and the solution was stirred at 25 °C for 2 h. Upon completion, DCM was removed with blow-dry to afford a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give ( 1 S,2S,5R)-N-[( 1 S)- 1 -cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-azabicyclo[3.2.0]heptane -2-carboxamide (80 mg, 289.51 umol, 72.17% yield, 100% purity) as yellow solid. MS (ESI) m/z 277.2 [M+H] ⁺ .

Step 3: (IS, 2S, 5R)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ]-3-( 4-methoxy-lH- indole-2-carbonyl)-3-azabicyclo[3.2.0]heptane-2-carboxamide

[000640] To a solution of (lS,2S,5R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-3-azabicyclo[3.2.0]heptane-2-carboxamide (80 mg, 289.51 umol, 1 eq), 4- methoxy- 1 H-indole-2-carboxylic acid (83.02 mg, 434.26 umol, 1.5 eq) in DCM (1.5 mL) was added the T3P (276.35 mg, 434.26 umol, 258.27 uL, 50% purity, 1.5 eq) and DIEA (112.25 mg, 868.52 umol, 151.28 uL, 3 eq). The resulting solution was stirred at 25 °C for 1 h. Upon completion, the solution was diluted with H ₂ O (20 mL), extracted with ethyl acetate (20 mL * 3), and the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C 18 100*30mm*10um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 20%-50%,8min) to afford (lS,2S,5R)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-(4-methoxy-lH-indole-2-carbonyl) -3- azabicyclo[3.2.0]heptane-2-carboxamide (50 mg, 111.23 umol, 38.42% yield, 100% purity) as white solid. MS (ESI) m/z 449.9 [M+H] ⁺ .

[000641] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.57 (br s, 1H), 9.23 - 8.65 (m, 1H), 7.69 (br s, 1H), 7.23 - 6.82 (m, 3H), 6.52 (br d, J=7.4 Hz, 1H), 5.08 - 4.84 (m, 1H), 4.63 (br d, J=8.2 Hz, 1H), 4.25 (br s, 1H), 4.06 (br s, 1H), 3.89 (br s, 3H), 3.27 - 2.79 (m, 4H), 2.28 - 1.53 (m, 9H).

Example 65. Synthesis of viral protease inhibitor compound 549

Step 1: tert-butyl (2S,4R)-2-[[(JS)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl] ethyl] carbamoyl] -4-(trifluoromethyl)pyrrolidine-l-carboxylate

[000642] To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (283.01 mg, 1.27 mmol, 1.2 eq, HC1) and (2S,4R)-1-tert-butoxycarbonyl-4- (trifluoromethyl)pyrrolidine-2-carboxylic acid (300 mg, 1.06 mmol, 1 eq), DIEA (684.44 mg, 5.30 mmol, 922.43 uL, 5 eq) in THF (3 mL) was added T3P (1.01 g, 1.59 mmol, 944.87 uL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 1 h. Upon completion, the residue was poured into saturated sodium bicarbonate solution (10 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum to give tert-butyl(2S,4R)-2-[[( 1 S)-2- methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]car bamoyl]-4- (trifluoromethyl)pyrrolidine- 1 -carboxylate (0.5 g, crude) as light yellow oil and used directly next step. MS (ESI) m/z 452.1 [M+H] ⁺ .

Step 2: methyl (2S)-3-[(3S)-2-oxopyrrolidin-3-yl]-2-[[(2S, 4R)-4-(trifluoromethyl)pyrrolidine- 2- carbonyl] aminojpropanoate

[000643] To tert-butyl (2S,4R)-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yljmethyl] ethyl]carbamoyl]-4-(trifluoromethyl)pyrrolidine-l -carboxylate (0.5 g, 1.11 mmol, 1 eq) was added HCl/MeOH (4 M, 3 mL, 10.83 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 15 min. Upon completion, the reaction mixture was concentrated to get the crude product methyl (2S)-3-[(3S)-2-oxopyrrolidin-3-yl] -2- [[(2S,4R)-4-(trifluoromethyl)pyrrolidine-2-carbonyl]amino]pr opanoate (450 mg, crude, HC1) as the light yellow oil. MS (ESI) m/z 352.1 [M+H] ⁺ .

Step 3: methyl (2S)-2-[[(2S,4R)-l-(4-methoxy-lH-indole-2-carbonyl)-4- ( trifluoromethyl)pyrrolidine-2- carbonyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000644] To a mixture of methyl (2S)-3-[(3S)-2-oxopyrrolidin-3-yl]-2-[[(2S,4R)-4- (trifluoromethyl) pyrrolidine-2-carbonyl]amino]propanoate (395.52 mg, 1.02 mmol, 1.3 eq, HC1) and 4-methoxy- 1 H-indole-2-carboxylic acid (150 mg, 784.59 umol, 1 eq) and DIPEA (507.01 mg, 3.92 mmol, 683.31 uL, 5 eq) in THF (3 mL) and DCM (3 mL) was added T3P (748.92 mg, 1.18 mmol, 699.93 uL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was poured into saturated sodium bicarbonate solution (5 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (5 mL * 2). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The crude product was purified by prep-TLC (dichloromethane: methanol =

10:1, R _f = 0.43) to give Methyl (2S)-2-[[(2S,4R)-1-(4-methoxy-lH-indole-2-carbonyl) -4- (trifluoromethyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxo pyrrolidin-3-yl]propanoate (250 mg, crude) was obtained as the light yellow solid. MS (ESI) m/z 525.2 [M+H] ⁺ . Step 4: (2S, 4R)-l-( 4-methoxy-lH-indole-2-carbonyl)-N-[ ( l S)-l -(nitrosomethyl) -2- [ ( 3S)-2- oxopyrr olidin-3-yl ] ethyl ]-4-(trifluoromethyl)pyrrolidine-2-carboxamide

[000645] To a mixture of methyl (2S)-2-[[(2S,4R)-1-(4-methoxy-lH-indole-2-carbonyl)- 4- (trifluoromethyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxo pyrrolidin-3- yl]propanoate (250 mg, 476.65 umol, 1 eq) was added NH ₃ /MeOH (7 M, 3 mL, 44.06 eq) in one portion at 25 °C under N ₂ . 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- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 - (nitrosomethyl)-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-(trifl uoromethyl)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] ⁺ .

Step 5: (2S, 4R)-N-[ ( l S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl /- 1 -(4-methoxy- 1H- indole-2- carbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide

[000646] To a mixture of (2S,4R)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 - (nitrosomethyl)-2-[(3 S) -2-oxopyrrolidin-3-yl]ethyl]-4-(trifluoromethyl)pyrrolidine- 2- carboxamide (120 mg, 235.54 umol, 1 eq) in DCM (6 mL) was added Burgess reagent (112.26 mg, 471.07 umol, 2 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C for 4.5 h. Upon completion, the residue was poured into water (0.5 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 (column: Phenomenex Gemini -NX 80*40mm*3um; mobile phase: [water (lOmM NH ₄ HCO ₃ )-ACN];B%: 25%-45%,8min) to give (2S,4R)-N-[(1 S)-1-cyano-2-[(3S)-2-oxopy rrolidin-3-yl]ethyl]-1-(4-methoxy-lH- indole-2-carbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxam ide (22.56 mg, 45.90 umol, 19.49% yield, 100% purity) as a white solid. MS (ESI) m/z 492.2 [M+H] ⁺ .

[000647] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.12 - 7.21 (m, 1 H), 6.84 - 7.10 (m, 2 H), 6.50 (br s, 1 H), 4.94 - 5.26 (m, 1 H), 4.75 (br s, 1 H), 4.07 - 4.47 (m, 2 H), 3.79 - 4.01 (m, 3 H), 3.45 (br s, 1 H), 2.16 - 2.98 (m, 6 H), 1.62 - 2.02 (m, 2 H), 1.39 (br s, 1

H).

Example 66. Synthesis of viral protease inhibitor compound 557

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride

[000648] 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 N ₂ for 3 times, and then the mixture was stirred at 20 °C for 0.5 h under N ₂ atmosphere. 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, HC1) as a yellow oil. MS (ESI) m/z 223.2 [M+H] ⁺ .

Step 2: tert-butyl l-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 - yl)carbamoyl)isoindoline-2-carboxylate

[000649] To a solution of 2-tert-butoxycarbonylisoindoline-1-carboxylic acid (436.93 mg, 1.66 mmol, 1 eq) methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (630 mg, 1.74 mmol, 61.58% purity, 1.05 eq, HC1) in DCM (5 mL) DMF (5 mL) was added T3P (1.58 g, 2.49 mmol, 1.48 mL, 50% purity, 1.5 eq) and TEA (1.01 g, 9.96 mmol, 1.39 mL, 6 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (20 mL), and extracted with ethyl acetate (10 mL * 3).

The combined organic layers were washed with brine 15 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get the product tert-butyl 1 -[[( 1 S)-2-methoxy- 2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]isoindoline-2 -carboxylate (720 mg, crude) as a white solid. MS (ESI) m/z 432.2 [M+H] ⁺ .

Step 3:

(2S)-methyl 2-(isoindoline-l-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)pr opanoate

[000650] A mixture of tert-butyl l-[[(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 N ₂ for 3 times, and then the mixture was stirred at 20 °C for 0.5 h under N ₂ atmosphere. 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, HC1) as a brown oil. MS (ESI) m/z 332.3[M+H] ⁺ .

Step 4:

(2S)-methyl 2-(2-(4-methoxy-lH-indole-2-carbonyl)isoindoline-l-carboxami do)-3-((S)-2- oxopyrrolidin-3-yl)propanoate [000651] A mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (287.43 mg, 1.50 mmol, 1 eq), methyl (2S)-2-(isoindoline-1-carbonylamino)-3-[(3S)-2-oxopyrrolidin -3- yl]propanoate (770 mg, 1.65 mmol, 79% purity, 1.1 eq, HC1), DMAP (367.34 mg, 3.01 mmol, 2 eq), EDCI (576.42 mg, 3.01 mmol, 2 eq) in DCM (8 mL) and DMF (2.7 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 20 °C for 1 h under N ₂ atmosphere. Upon completion, the reaction mixture was quenched by addition H ₂ O (25 mL), and then extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by neutral prep- HPLC (column: Kromasil C18 (250*50mm*10 um);mobile phase: [water(10mM NH4HCO3)- ACN];B%: 25%-45%,10min) to afford methyl (2 S)-2-[[2-(4-methoxy- 1 H-indole-2- carbonyl)isoindoline-1-carbonyl]amino]-3-[(3S)-2-oxopyrrolid in-3-yl]propanoate (Isomer 1 : 150mg, 297.30 umol, 19.78% yield) as white solid. MS (ESI) m/z 505.3[M+H] ⁺ ; and to afford methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)isoindoline- 1 - carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (Isomer 2: 140 mg, 277.48 umol, 18.46% yield) as white solid. MS (ESI) m/z 505.3[M+H]+. Step 5 N-((S)-1 -amino- l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-(4-methoxy- lH- indole-2-carbonyl)isoindoline-l -carboxamide

[000652] A solution of methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)isoindoline- 1 -carbonyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 297.30 umol, 1 eq) in MeOH/NH ₃ (7 M, 849.44 uL, 20 eq) was stirred at 45 °C for 48 h. Upon completion, the reaction mixture was concentrated under reduced pressure to get the product N-[(1S)- 2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl] ethyl]-2-(4-methoxy- 1 H-indole-2- carbonyl)isoindoline- 1 -carboxamide (130 mg, crude) as colorless oil. MS (ESI) m/z 490.3[M+H] ⁺ .

Step 5 N-((S)-1 -amino-1 -oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-(4-methoxy-l H- indole-2-carbonyl)isoindoline-l -carboxamide

[000653] A solution of methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)isoindoline-

1 -carbonyl] amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (140 mg, 277.48 umol, 1 eq) in MeOH/NH ₃ (7 M, 792.81 uL, 20 eq) was stirred at 45 °C for 24 h. Upon completion, the reaction mixture was concentrated under reduced pressure to get the product N-[(1S)-

2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-2-(4-methoxy- lH-indole-2- carbonyl)isoindoline- 1 -carboxamide (110 mg, crude) as colorless oil. MS (ESI) m/z 490.3[M+H] ⁺ .

Step 6N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-meth oxy-lH-indole-2- carbonyl)isoindoline-l -carboxamide

[000654] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)isoindoli ne-1-carboxamide (125 mg, 255.35 umol, 1 eq) in DCM (8 mL) was added Burgess reagent (273.84 mg, 1.15 mmol, 4.5 eq), and the resulting mixture was stirred at 30 °C for 20 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.5 mL), and then concentrated under reduced pressure to give a residue. The residue was purified by neutral prep- HPLC (column: Waters Xb ridge BEH C18 100*25mm*5um;mobile phase: [water(10 mM NH4HCO3)- ACN] ;B% : 20%-50%,10 min) to afford product N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl) isoindoline-1-carboxamide (31.50 mg, 66.81 umol, 26.16% yield, 100% purity) as a white solid. MS (ESI) m/z 472.3[M+H] ⁺ . [000655] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.53 - 11.83 (m, 1 H) 9.11 - 9.78 (m, 1 H) 7.31 - 7.78 (m, 5 H) 6.95 - 7.29 (m, 3 H) 6.42 - 6.63 (m, 1 H) 5.73 (s, 1 H) 5.27 - 5.41 (m, 1 H) 4.91 - 5.05 (m, 1 H) 3.76 - 3.99 (m, 3 H) 2.71 - 3.19 (m, 2 H) 2.00 - 2.30 (m, 3 H) 1.20 - 1.87 (m, 2 H).

Step 6N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-meth oxy-lH-indole-2- carbonyl)isoindoline-l -carboxamide

[000656] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl] -2-(4-methoxy- 1 H-indole-2-carbonyl)isoindoline- 1 -carboxamide (105 mg, 214.49 umol, 1 eq) in DCM (6 mL) was added Burgess reagent (204.47 mg, 857.98 umol, 4 eq). The mixture was stirred at 30 °C for 7 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.5 mL), and then concentrated under reduced pressure to give a residue. The residue was purified by neutral prep- HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HC03 )- ACN] ;B% : 25%-55%,8min) to afford N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl) isoindoline-1-carboxamide (34.83 mg, 73.72 umol, 34.37% yield, 99.791% purity) as a white solid. MS (ESI) m/z 472.3[M+H] ⁺ .

[000657] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.72 (s, 1 H) 9.19 (d, J= 8.11 Hz, 1 H) 7.31 - 7.76 (m, 5 H) 6.92 - 7.29 (m, 3 H) 6.56 (d, J=7.75 Hz, 1 H) 5.74 (s, 1 H) 5.34 (br d, J=10.13 Hz, 1 H) 4.96 (q, J=8.23 Hz, 1 H) 3.86 - 3.89 (m, 1 H) 3.86 - 4.55 (m, 1 H) 3.84 - 4.01 (m, 3 H) 2.96 - 3.22 (m, 2 H) 2.25 - 2.41 (m, 1 H) 2.02 - 2.20 (m, 2 H) 1.47 - 1.87 (m, 2 H).

Example 67. Synthesis of viral protease inhibitor compound 647 [000658] 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.

Step 2: methyl (2S)-2-[[(2S)-2-[(4-chloro-JH-indole-2-carbonyl)amino]-3-cyc lopropyl- propanoyl ] amino ]-3-[( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000659] To a mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (500 mg, 1.68 mmol, 1 eq) in DCM (6 mL) and DMF (2 mL), the mixture was added DMAP (616.30 mg, 5.04 mmol, 3 eq) in one portion at 25 °C. The mixture was added 4-chloro- 1 H-indole-2-carboxylic acid (394.69 mg, 2.02 mmol, 1.2 eq) and EDCI (967.04 mg, 5.04 mmol, 3 eq) and stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to ethyl acetate/methanol = 10/1) to give methyl (2S)-2-[[(2S)-2- [(4-chloro-lH-indole-2-carbonyl)amino]-3-cyclopropyl-propano yl]amino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (760 mg, 1.60 mmol, 95.16% yield) as a white solid. MS (ESI) m/z 475.2 [M+H] ⁺ .

Step 3: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-1-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl]amino]~ l-(cyclopropylmethyl)-2-oxo-ethyl]-4-chloro-lH-indole-2-carb oxamide

[000660] A mixture of methyl (2S)-2-[[(2S)-2-[(4-chloro-lH-indole-2-carbonyl)amino]-3- cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]pr opanoate (700 mg, 1.47 mmol, 1 eq) in NH ₃ /MeOH (7 M, 15 mL, 71.24 eq) was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N- [(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]m ethyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-chloro-lH-indole-2-carbox amide (660 mg, 1.44 mmol, 97.36% yield) as a white solid. MS (ESI) m/z 460.2 [M+H] ⁺ .

Step 4: 4-chloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-2-yl ] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide [000661] To a mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4- chloro-lH-indole-2- carboxamide (630 mg, 1.37 mmol, 1 eq) in DCM (10 mL) was added Burgess reagent (652.87 mg, 2.74 mmol, 2 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition, column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 30%-50%,8min) to give 4-chloro-N-[(1S)-2-[[(1S)-1-cyano-2- [(3 S)-2-oxopyrrolidin-3-yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]- lH-indole- 2-carboxamide (110 mg, 248.92 umol, 18.17% yield) as a white solid. MS (ESI) m/z 442.2 [M+H] ⁺ .

[000662] ¹ H NMR (400MHz, DMSO-d6) δ = 11.96 (br s, 1H), 8.93 (d, J=8.2 Hz, 1H),

8.76 (d, J=7.7 Hz, 1H), 7.78 - 7.67 (m, 1H), 7.46 - 7.36 (m, 2H), 7.21 - 7.09 (m, 2H), 5.04 - 4.89 (m, 1H), 4.55 - 4.43 (m, 1H), 3.12 (quin, J=9.3 Hz, 2H), 2.43 - 2.29 (m, 1H), 2.19 - 2.07 (m, 2H), 1.91 - 1.63 (m, 3H), 1.54 - 1.41 (m, 1H), 0.82 (br dd, J=5.6, 7.4 Hz, 1H), 0.50 - 0.34 (m, 2H), 0.26 - 0.04 (m, 2H).

Example 68. Synthesis of viral protease inhibitor compound 649

Step 1: methyl (2S) -2-[[( 2S) -2-amino-3-cyclopropyl-propanoyl ] amino ]-3-[(3S)-2- oxopyrrolidin-3-yl ]propanoate

[000663] A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (500 mg, 968.64 umol, 77% purity, 1 eq) in HCl/MeOH (10 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-oxop yrrolidin-3- yl]propanoate (300 mg, crude) as a white solid.

Step 2: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[3-(3,5- difluorophenyl)propanoylamino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000664] 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 -difluoropheny l)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 H ₂ O (5 mL) and extracted with ethyl acetate (8 mL * 3). The combined organic layers were washed with brine (15 mL * 1), dried over with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/l 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-oxo pyrrolidin-3- yl Jpropanoate (300 mg, 547.81 umol, 56.56% yield, 85% purity) as a white solid. MS (ESI) m/z 466.2 [M+H] ⁺ .

Step 3: (2S)-N-[ ( l S)-2-amino-2-oxo-l-[[ ( 3S)-2-oxopyrrolidin-3-yl ]methyl ] ethyl] -3- cyclopropyl-2-[ 3-( 3, 5 -difluoropheny l)propanoylamino ]propanamide

[000665] A mixture of methyl (2 S)-2-[ [(2 S)-3 -cy clopropy l-2-[3 -(3 , 5- difluorophenyl)propanoylamino]propanoyl]amino]-3-[(3S)-2-oxo pyrrolidin-3- yl Jpropanoate (300 mg, 644.48 umol, 1 eq) in NH3/methanol (7 M, 5.45 mL, 59.24 eq) was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-3-cyclopropyl-2-[3-(3,5-difluorophenyl)prop anoylamino]propanamide (260 mg, 577.16 umol, 89.55% yield) as a white solid. MS (ESI) m/z 451.2 [M+H] ⁺ .

Step 4: (2S)-N-[ (1S)-1 -cyano-2-[ ( 3S)-2-oxopyrrolidin-2-yl ] ethyl ]-3-cyclopropyl-2-[ 3-(3,5- difluorophenyl)propanoylamino]propanamide

[000666] To a mixture of (2S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-3-cyclopropyl-2-[3-(3,5-difluorophenyl)prop anoylamino]propanamide (70 mg, 155.39 umol, 1 eq) in ACN (1 mL) was added POCl ₃ (47.65 mg, 310.78 umol, 28.88 uL, 2 eq) in one portion at 25 °C. The mixture was stirred at 80 °C for 0.5 h. Upon completion, the reaction mixture was quenched by addition NaHCO ₃ (1 mL) at 25 °C, and then extracted with ethyl acetate (1 mL * 3). The combined organic layers were concentrated under reduced pressure to give crude product. The crude was purified by prep-HPLC (neutral condition, column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HCO ₃ )-ACN];B%: 20%-50%,8min) to give (2S)-N-[(1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl -2-[3- (3,5-difluorophenyl)propanoylamino]propanamide (7 mg, 16.19 umol, 10.42% yield) as a white solid. MS (ESI) m/z 433.2 [M+H] ⁺ .

[000667] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.09 - 8.81 (m, 1H), 8.15 (br d, J=7.5 Hz, 1H), 7.83 - 7.70 (m, 1H), 7.10 - 6.89 (m, 3H), 4.99 - 4.83 (m, 1H), 4.33 - 4.19 (m, 1H), 3.19 - 3.04 (m, 2H), 2.89 - 2.78 (m, 2H), 2.46 (br s, 2H), 2.39 - 2.03 (m, 3H), 1.84 - 1.46 (m, 3H), 1.40 - 1.19 (m, 1H), 0.59 (br s, 1H), 0.34 (br s, 2H), 0.14 -0.05 (m, 2H).

[000668] ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 6.84 (br t, J=5.7 Hz, 2H), 6.74 (tt, J=2.2, 9.3 Hz, 1H), 5.06 - 4.92 (m, 1H), 4.37 - 4.22 (m, 1H), 3.38 - 3.32 (m, 2H), 2.97 - 2.88 (m, 2H), 2.71 - 2.57 (m, 2H), 2.54 - 2.10 (m, 3H), 2.01 - 1.77 (m, 2H), 1.76 - 1.58 (m, 1H), 1.55 - 1.36 (m, 1H), 0.72 - 0.59 (m, 1H), 0.53 - 0.36 (m, 2H), 0.18 - 0.02 (m,

2H).

Example 69. Synthesis of viral protease inhibitor compound 653

[000669] To a mixture of N-[(1S)-1-[[(1S)-1-formyl-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl -butyl]-4-methoxy-lH-indole-2-carboxamide (1 g, 1.81 mmol, 80% purity, 1 eq) in EtOH (20 mL) was added 2-aminoacetic acid (271.74 mg, 3.62 mmol, 20.52 uL, 2 eq), ZnCl2 (1 M, 18.10 uL, 0.01 eq). The mixture was stirred at 25 °C for 30 min, and then TMSCN (359.14 mg, 3.62 mmol, 452.89 uL, 2 eq) was added and the resulting mixture was stirred at 40 °C for 6 h. Upon the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by HC1 prep-HPLC (column: Phenomenex luna CIS 80*40mm*3 um; mobile phase: [water (0.04%HC1)-ACN]; B%: 25%-45%, 7 min) to get the mixture product 400 mg. The mixture was separated by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm,10um); mobile phase: [Neu-ETOH]; B%: 50%-50%, 10 min) to get the compound 2-[[(2S)-1-cyano-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4-methyl-pentanoyl]amino] -3-[(3S)-2-oxopyrrolidin-3- yl]propyl]amino]acetic acid (125 mg, 235.87 umol, 13.03% yield, 99.363% purity) and 2- [[(2S)-1-cyano-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)a mino]-4-methyl - pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propyl]amino]a cetic acid (205 mg,

373.82 umol, 20.65% yield, 96.023% purity) as a white solid. MS (ESI) m/z 527.3 [M+H] ⁺ .

[000670] Isomer 1 : ¹ H NMR (400MHz, DMSO-J6) δ = 11.56 (d, J=2.0 Hz, 1H), 8.52 - 8.21 (m, 2H), 7.58 (s, 1H), 7.35 (d, J=1.7 Hz, 1H), 7.14 - 7.05 (m, 1H), 7.03 - 6.97 (m, 1H), 6.50 (d, J=7.7 Hz, 1H), 4.57 - 4.41 (m, 1H), 4.14 (tdd, J=4.2, 8.2, 12.2 Hz, 1H), 3.97 - 3.82 (m, 4H), 3.52 - 3.36 (m, 2H), 3.18 - 2.98 (m, 2H), 2.41 - 2.27 (m, 1H), 2.12 - 2.04 (m, 2H), 1.82 - 1.36 (m, 5H), 0.91 (dd,J=6.4, 15.8 Hz, 6H)

[000671] Isomer 2: ¹ H NMR (400MHz, DMSO-J6) δ = 11.57 (d, J=2.0 Hz, 1H), 8.39 (d, J=7.8 Hz, 1H), 8.20 (d, J=9.5 Hz, 1H), 7.54 (s, 1H), 7.37 (d,J= 1.6 Hz, 1H), 7.16 - 6.94 (m, 2H), 6.50 (d, J=7.6 Hz, 1H), 4.53 - 4.36 (m, 1H), 4.18 - 4.01 (m, 1H), 3.88 (s, 3H), 3.77 (d, J=8.8 Hz, 1H), 3.43 - 3.33 (m, 2H), 3.15 - 2.96 (m, 2H), 2.38 - 2.25 (m, 1H), 2.08 - 2.01 (m, 1H), 1.91 - 1.47 (m, 6H), 0.91 (dd,J=6.4, 14.8 Hz, 6H)

[000672] To a mixture of N-[(1S)-1-[[(1S)-1-formyl-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl] -3-methyl-butyl]-4-methoxy-lH-indole-2-carboxamide (700 mg, 1.27 mmol, 80% purity, 1 eq) in EtOH (10 mL) was added pyrrolidine (180.01 mg, 2.53 mmol, 211.28 uL, 2 eq), ZnC12 (1 M, 12.66 uL, 0.01 eq), and the resulting mixture was stirred at 25 °C for 30 min. After the addition of TMSCN (251.10 mg, 2.53 mmol, 316.65 uL, 2 eq), the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC to afford N-[( 1 S)- 1 -[[( 1 S)-2-cy ano- 1 -[[(3 S)- 2-oxopyrrolidin-3-yl]methyl]-2-pyrrolidin-1-yl-ethyl]carbamo yl]-3-methyl-butyl]-4- methoxy- 1 H-indole-2-carboxamide (110 mg, 199.95 umol, 15.80% yield, 95% purity) and N-[( 1 S)- 1 -[[( 1 S)-2-cyano- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]-2-pyrrolidin- 1 -yl- ethyl] carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2-carboxamide (110 mg, 199.95 umol, 15.80% yield, 95% purity) as a white solid. MS (ESI) m/z 523.4 [M+H] ⁺

[000673] column: Phenomenex luna CN 5u 100*30mm;mobile phase: [Hexane-IPA];B%: 5%-40%,20min

[000674] Isomer 1 : ¹ H NMR (400MHz, DMSO-d6) δ = 11.58 (s, 1H), 8.43 (d, J=7.7 Hz, 1H), 8.20 (d, J=9.4 Hz, 1H), 7.68 - 7.49 (m, 1H), 7.38 (d, J=1.2 Hz, 1H), 7.18 - 6.93 (m, 2H), 6.50 (d, J=7.6 Hz, 1H), 4.57 - 3.99 (m, 3H), 3.88 (s, 3H), 3.19 - 2.95 (m, 2H), 2.64 - 2.53 (m, 4H), 2.38 - 2.27 (m, 1H), 2.15 - 2.01 (m, 1H), 1.85 - 1.44 (m, 10H), 0.91 (dd, J=6.4, 16.3 Hz, 6H)

[000675] Isomer 2: ¹ H NMR (400MHz, DMSO-d6) δ = 11.59 (br s, 1H), 8.39 (br d, J=7.6 Hz, 1H), 8.01 (br d, J=9.1 Hz, 1H), 7.69 - 7.49 (m, 1H), 7.43 - 7.28 (m, 1H), 7.16 - 6.86 (m, 2H), 6.50 (d, J=7.6 Hz, 1H), 4.59 - 4.24 (m, 3H), 3.88 (s, 3H), 3.19 - 2.94 (m, 2H), 2.71 - 2.57 (m, 2H), 2.49 - 2.32 (m, 3H), 2.18 - 2.08 (m, 1H), 2.06 - 1.93 (m, 1H), 1.83 - 1.37 (m, 9H), 0.90 (dd, J=6.5, 15.2 Hz, 6H)

Example 70. Synthesis of viral protease inhibitor compound 655 Step 1: (2S,4R)-di-tert-butyl 4-hydroxypyrrolidine-l,2-dicarboxylate [000676] To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2- carboxylic acid (5 g, 21.62 mmol, 1 eq) in THF (75 mL) was added 2-tert-butyl-l,3- diisopropyl-isourea (6.50 g, 32.43 mmol, 1.5 eq) at 25 °C, and then the resulting solution was stirred at 60 °C for 2.5 h. 2-tert-butyl-l, 3-diisopropyl-isourea (6.50 g, 32.43 mmol, 1.5 eq) was added to the mixture and then stirred at 60 °C for 14 h. Upon completion, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to give (2S,4R)-di-tert-butyl 4-hydroxypyrrolidine- 1 ,2-dicarboxylate (4.3 g, 14.22 mmol, 65.75% yield, 95% purity) as a colorless oil. MS (ESI) m/z 288.2 [M+H] ⁺

Step 2: (2S,4S)-di-tert-butyl 4-bromopyrrolidine-l,2-dicarboxylate

[000677] 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 PPhs (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 drop wise 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 (SiO ₂ , petroleum ether: ethyl acetate = 100:0 to 10:1) to give (2S,4S)-di-tert-butyl 4-bromopyrrolidine-l ,2- dicarboxylate (1.5 g, 4.07 mmol, 29.23% yield, 95% purity) as light yellow oil.

Step 3: (2S,4S)-di-tert-butyl 4-(tert-butyl)pyrrolidine-l ,2-dicarboxylate [000678] 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 N ₂ . Upon completion, the reaction was quenched by pouring into a solution of saturated aqueous NH ₄ CI (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 NaHCO ₃ (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , concentrated under reduced pressure to give a crude. The residue was purified by column chromatography (SiO ₂ , 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.

Step 4: (2S,4S)-4-(tert-butyl)pyrrolidine-2-carboxylic acid

[000679] A mixture of (2S,4S)-di-tert-butyl 4-(tert-butyl)pyrrolidine- 1 ,2-dicarboxylate (250 mg, 763.46 umol, 1 eq) in HC1 (6 M, 2.5 mL, 19.65 eq) was stirred at 100 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S,4S)-4-tert-butylpyrrolidine-2-carboxylic acid (158 mg, crude, HC1) as a yellow solid.

Step 5: (2S,4S)-l-(tert-butoxycarbonyl)-4-(tert-butyl)pyrrolidine-2- carboxylic acid [000680] To a mixture of (2S,4S)-4-tert-butylpyrrolidine-2-carboxylic acid (158 mg, 760.72 umol, 1 eq, HC1) in THF (1 mL) and H ₂ O (1 mL) was added KzCO ₃ (315.41 mg, 2.28 mmol, 3 eq) and Boc ₂ O (199.23 mg, 912.87 umol, 209.72 uL, 1.2 eq). The reaction was stirred at 25 °C for 14 h under N ₂ . Upon completion, the reaction mixture was concentrated under reduced pressure to afford (2S,4S)-1-(tert-butoxycarbonyl)-4-(tert- butyl)pyrrolidine-2-carboxylic acid (650 mg, crude) as a yellow solid.

Step 6: (2S,4S)-tert-butyl 4-(tert-butyl)-2-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidi n-3- yl)propan-2-yl)carbamoyl)pyrrolidine-l-carboxylate

[000681] To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-(tert-butyl)pyrrolidine-2- carboxylic acid (630 mg, 696.51 umol, 30% purity, 1 eq) in DCM (6 mL) and DMF (3 mL) was added TEA (422.88 mg, 4.18 mmol, 581.68 uL, 6 eq), methyl (2S)-2-amino-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (186.11 mg, 835.82 umol, 1.2 eq, HC1). After adding T3P (1.33 g, 2.09 mmol, 1.24 mL, 50% purity, 3 eq) at 0 °C, the mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was quenched with water (10.0 mL) and extracted with DCM (10.0 mL * 3). The organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 0: 1) to afford tert-butyl (2S,4S)-tert-butyl 4-(tert-butyl)-2- (((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-y l)carbamoyl)pyrrolidine-l- carboxylate (240 mg, 546.02 umol, 78.39% yield) as yellow solid. MS (ESI) m/z 440.3 [M+H] ⁺ .

Step 7: (S)-methyl 2-((2S,4S)-4-(tert-butyl)pyrrolidine-2-carboxamido)-3-((S)-2 - oxopyrrolidin-3-yl)propanoate

[000682] A solution of tert-butyl (2S,4S)-tert-butyl 4-(tert-butyl)-2-(((S)- 1 -methoxy- 1 - oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)pyrrol idine-1-carboxylate (230 mg, 523.27 umol, 1 eq) in HCl/MeOH (4 M, 2.3 mL, 17.58 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (S)-methyl 2-((2S,4S)-4-(tert-butyl)pyrrolidine-2-carboxamido)-3-((S)-2 - oxopyrrolidin-3-yl)propanoate (196 mg, crude, HC1) as a light yellow solid. MS (ESI) m/z 340.2 [M+H] ⁺ .

Step 8: (S)-methyl 2-((2S,4S)-4-(tert-butyl)-l-(4-methoxy-lH-indole-2-carbonyl) pyrrolidine-

2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000683] To a solution of (S)-methyl 2-((2S,4S)-4-(tert-butyl)pyrrolidine-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (196 mg, 521.43 umol, 1 eq, HC1) in DCM (2 mL) and DMF (1 mL) was added 4-methoxy- 1 H-indole-2-carboxylic acid (99.69 mg, 521.43 umol, 1 eq), DMAP (127.41 mg, 1.04 mmol, 2 eq), and then EDCI (199.92 mg, 1.04 mmol, 2 eq) at 0 °C. The mixture was then stirred at 25 °C for 1 h.

Upon completion, the mixture was quenched with water (10.0 mL) and extracted with DCM (10 mL * 3). The organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane: methanol = 10:1 to 4:1) to give (S)-methyl 2-((2S,4S)-4-(tert-butyl)-1-(4-methoxy-lH-indole-2- carbonyl)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3 -yl)propanoate (250 mg, 414.56 umol, 79.50% yield, 85% purity) as a yellow solid. MS (ESI) m/z 513.3 [M+H] ⁺ .

Step 9: (2S,4S)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)pro pan-2-yl)-4-(tert- butyl)- l-(4-methoxy-lH-indole-2-carbonyl)pyrrolidine-2-carboxamide

[000684] A solution of (S)-methyl 2-((2S,4S)-4-(tert-butyl)- 1 -(4-methoxy- 1 H-indole-2- carbonyl)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3 -yl)propanoate (235 mg, 389.68 umol, 85% purity, 1 eq) in NH3/methanol (7 M, 5 mL) was stirred at 40 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S,4S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)pro pan-2-yl)-4-(tert- butyl)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)pyrrolidine-2-carboxamide (193 mg, crude) as a yellow solid. MS (ESI) m/z 498.3 [M+H] ⁺ .

Step 10: (2S,4S)-4-(tert-butyl)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin -3-yl)ethyl)-l-(4- methoxy-lH-indole-2-carbonyl)pyrrolidine-2-carboxamide

[000685] To a solution of (2S,4S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-4-(tert-butyl)-1-(4-methoxy-lH-indole-2-carb onyl)pyrrolidine-2- carboxamide (193 mg, 329.69 umol, 85% purity, 1 eq) in DCM (3 mL) was added Burgess reagent (235.71 mg, 989.08 umol, 3 eq), and then was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25mm*5um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 30%-55%,10min) to give (2S,4S)-4-(tert-butyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin -3-yl)ethyl)-1-(4- methoxy- 1 H-indole-2-carbonyl)pyrrolidine-2-carboxamide (59.58 mg, 124.24 umol, 37.68% yield, 100% purity) as a white solid. MS (ESI) m/z 480.2 [M+H] ⁺ .

[000686] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.69 - 11.55 (m, 1H), 9.17 - 8.75 (m, 1H), 7.81 - 7.44 (m, 1H), 7.16 - 7.07 (m, 1H), 7.06 - 6.98 (m, 2H), 6.55 - 6.46 (m, 1H), 5.03 - 4.53 (m, 2H), 4.04 - 3.74 (m, 4H), 3.69 - 3.36 (m, 1H), 3.22 - 2.55 (m, 2H), 2.35 - 1.95 (m, 5H), 1.83 - 1.51 (m, 3H), 1.00 - 0.82 (m, 9H).

[000687] ¹ H NMR (400MHz, DMSO-d ₆ , 273+80K) δ = 11.31 (s, 1H), 8.68 (s, 1H), 7.38 (s, 1H), 7.18 - 7.02 (m, 2H), 6.90 (s, 1H), 6.60 - 6.47 (m, 1H), 4.96 (q, J=7.6 Hz, 1H), 4.72 (s, 1H), 4.07 - 3.80 (m, 4H), 3.66 - 3.50 (m, 1H), 3.28 - 3.05 (m, 2H), 2.32 - 1.97 (m, 5H), 1.95 - 1.64 (m, 3H), 0.95 (s, 9H).

Example 71. Synthesis of viral protease inhibitor compound 659

Step 1: (S)-tert-butyl (l-hydroxy-4,4-dimethylpentan-2-yl)carbamate

[000688] 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, BH ₃ -Me ₂ S (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. NaHCO ₃ (150 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , 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.

Step 2: (S)-tert-butyl (4,4-dimethyl-l-oxopentan-2-yl)carbamate

[000689] 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 H ₂ O (60 mL) at 0 °C, and then added drop-wise aq. NaHCO ₃ to pH = 8 at 0 °C, and extracted with EtOAc (40 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 0:1 to 1:1) to afford tert-butyl N-[( 1 S)- 1 -formyl-3 ,3- dimethyl-butyl]carbamate (1.6 g, 6.98 mmol, 67.25% yield) as a colorless oil.

[000690] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.40 (s, 1 H) 7.30 (br d, J=8.00 Hz, 1 H) 3.91 - 3.82 (m, 1 H) 1.66 (dd, J=14.38, 2.75 Hz, 1 H) 1.39 (s, 9 H) 1.32 (br d, J=9.26 Hz, 1 H) 0.90 (s, 9 H).

Step 3: (S)-methyl2-(((S)-2-((tert-butoxycarbonyl)amino)-4, 4-dimethylpentyl)amino)-3-((S)~ 2-oxopyrrolidin-3-yl)propanoate

[000691] To a solution of tert- butyl N-[( 1 S)- 1 -formyl-3, 3-dimethyl-butyl]carbamate (0.8 g, 3.49 mmol, 1 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.17 g, 5.23 mmol, 1.5 eq, HC1) in DCE (20 mL) was added Et ₃ N (529.52 mg, 5.23 mmol, 728.36 uL, 1.5 eq) and NaBH(OAc) ₃ (2.22 g, 10.47 mmol, 3 eq), and the reaction was stirred at 20 °C for 2 h.

[000692] The reaction mixture was quenched by addition aq. NaHCO ₃ (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , 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] ⁺ .

Step 4: (S)-methyl 2-(((S)-2-amino-4,4-dimethylpentyl)amino)-3-((S)-2-oxopyrrol idin-3- yl)propanoate

[000693] A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 500.60 umol, 1 eq) in HCl/MeOH (4 M, 4.00 mL, 31.96 eq) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2-[[(2S)-2-amino-4,4- dimethyl-pentyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoa te (168 mg, crude, HC1) as a white solid. Step 5: (S)-methyl 2-(((S)-2-(4-methoxy-lH-indole-2-carboxamido)-4,4- dimethylpentyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000694] To a solution of methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (168 mg, 500.20 umol, 1 eq, HC1) and 4-methoxy- 1 H-indole-2-carboxylic acid (95.63 mg, 500.20 umol, 1 eq) in DMF (1 mL) was added DMAP (183.32 mg, 1.50 mmol, 3.0 eq) and EDCI (191.78 mg, 1.00 mmol, 2 eq) and DCM (3 mL), the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition H ₂ O 40 mL at 0 °C, and then extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1:0 to 0:1) to afford methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4,4- dimethyl- pentyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 301.54 umol, 60.28% yield, 95% purity) as a yellow oil. MS (ESI) m/z 473.2 [M+H] ⁺ .

Step 6: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (, S)-2-oxopyrrolidin-3-yl)propan-2-yl)ammo)-4 , 4- dimethylpentan-2-yl)-4-methoxy-lH-indole-2-carboxamide

[000695] A solution of methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentyl]amino]-3-[(3S)-2-oxopyrr olidin-3-yl]propanoate (130 mg, 275.09 umol, 1 eq) in NH ₃ /MeOH (7 M, 15 mL, 381.70 eq) was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , ethyl acetate: methanol = 50:3) to get the product N-[(1S)-1-[[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]methyl]-3,3-dimethyl-butyl]-4-methoxy- lH-indole-2-carboxamide (60 mg, 131.13 umol, 47.67% yield) as a yellow solid. MS (ESI) m/z 458.3 [M+H] ⁺ .

Step 7: N-( (S)-l-( ( (S)-l-cyano-2-( (S)-2-oxopyrrolidin-3-yl)ethyl)ammo)-4, 4-dimethylpentan- 2-yl)-4-methoxy-JH-indole-2-carboxamide

[000696] To a solution of N-[( 1 S)- 1 -[[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]methyl]-3,3-dimethyl-butyl]-4-methoxy- lH-indole-2-carboxamide (50 mg, 109.27 umol, 1 eq) in EtOAc (2 mL) was added T3P (2.14 g, 3.36 mmol, 2 mL, 50% purity, 30.77 eq) drop-wise, and then the mixture was stirred at 65 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C 1875 * 30 mm * 3 um; mobile phase: [water (0.2% FA) - ACN]; B%: 15% - 45%, 8 min) and was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um);mobile phase: [0.1% NH3H ₂ O ETOH]; B%: 25% - 25%, 20 min) to afford N-[( 1 S)- !-[[[(! S)- 1 -cyano-2-[(3 S)- 2-oxopyrrolidin-3-yl]ethyl]amino]methyl]-3,3-dimethyl-butyl] -4-methoxy-lH-indole-2- carboxamide (4.4 mg, 9.92 umol, 29.07% yield, 99.1% purity) as a white solid. MS (ESI) m/z 440.2 [M+H] ⁺ .

[000697] i H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.22 - 6.99 (m, 3 H) 6.52 (br d, J=7.72 Hz, 1 H) 4.74 - 4.65 (m, 1 H) 4.61 - 4.48 (m, 1 H) 4.03 - 3.91 (m, 4 H) 3.62 - 3.51 (m, 1 H) 3.47 - 3.36 (m, 1 H) 3.27 - 3.19 (m, 1 H) 2.50 - 2.41 (m, 1 H) 2.29 - 2.18 (m, 1 H) 1.81 (br s, 1 H) 1.74 - 1.64 (m, 2 H) 1.60 (br d, J=10.14 Hz, 1 H) 1.34 - 1.28 (m, 1 H) 0.98 (s, 9 H).

Example 72. Synthesis of viral protease inhibitor compound 671

Step J: 2-(2-methoxyethoxy)ethyl carbonochloridate

[000698] A mixture of triphosgene (4.93 g, 16.61 mmol, 4.99e-l eq), NazCO ₃ (3.53 g, 33.29 mmol, 1 eq) and DMF (95.00 mg, 1.30 mmol, 0.1 mL, 3.90e-2 eq) in toluene (50 mL) was cooled to 0 °C and stirred for 0.5 h under N ₂ atmosphere. Then a solution of 2- (2-methoxy ethoxy )ethanol (4 g, 33.29 mmol, 3.92 mL, 1 eq) was added dropwise. The mixture was stirred at 0 °C for 4 h. Upon completion, the mixture was filtered, and the filtrate was concentrated under the reduced pressure affording 2-(2-methoxy ethoxy )ethyl carbonochloridate (6 g) as a yellow oil.

Step 2: (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((S)-2-oxopyrroli din-3- yl)propanoate

[000699] A mixture of methyl(2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cycloprop yl- propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (600 mg, 1.51 mmol, 1 eq) was in HCl/MeOH (4 M, 12.00 mL, 31.80 eq) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressure affording methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxopyrrolidin-3- yl]propanoate (450 mg) as a white solid.

Step 3: (11S, 14S) -methyl 1 l-(cyclopropylmethyl) -9, 12-dioxo-14-(((S)-2-oxopyrrolidin-3- yl)methyl)-2,5,8-trioxa-10,13-diazapentadecan-15-oate

[000700| To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (450 mg, 1.51 mmol, 1 eq) in THF (10 mL) and H ₂ O (1 mL) was added DIEA (391.19 mg, 3.03 mmol, 527.20 uL, 2 eq), and then 2-(2- methoxy ethoxy )ethyl carbonochloridate (414.52 mg, 2.27 mmol, 1.5 eq) was added at 0 °C. The mixture was stirred at 30 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (100 mL), and then extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Kromasil C18 (250 * 50 mm * 10 um); mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 1% - 25%, 10 min) affording methyl(2S)-2- [[(2S)-3-cyclopropyl-2-[2-(2-methoxy ethoxy )ethoxycarbonylamino]propanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (400 mg, 901.94 umol, 59.60% yield) as a yellow oil. MS (ESI) m/z 444.2 [M+H] ⁺ .

Step 4: 2-(2-methoxyethoxy)ethyl((S)-l-(((S)-l -amino-1 -oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)amino)-3-cyclopropyl-l-oxopropan-2-yl)carbama te [000701] A mixture of methyl(2S)-2-[[(2S)-3-cyclopropyl-2-[2-(2- methoxy ethoxy )ethoxycarbonylamino]propanoyl]amino]-3-[(3S)-2-oxopyrrolidi n-3- yl]propanoate (400 mg, 901.94 umol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 77.61 eq) was stirred at 70 °C for 12 h. Upon completion, the mixture was concentrated under the reduced pressure to afford 2-(2-methoxy ethoxy )ethylN-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 - [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cycloprop ylmethyl)-2-oxo- ethyl]carbamate (400 mg, crude) as a yellow oil. MS (ESI) m/z 429.2 [M+H] ⁺

Step 5: 2-(2-methoxyethoxy)ethyl( (S)-l-( ( (S)-l-cyano-2-( ( S)-2-oxopyrrolidin-3 - yl)ethyl)amino)-3-cyclopropyl-l-oxopropan-2-yl)carbamate

[000702] To a solution of 2-(2-methoxy ethoxy )ethyl N-[( 1 S)-2-[ [( 1 S)-2-ami no-2-oxo- 1 - [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cycloprop ylmethyl)-2-oxo- ethyl]carbamate (380 mg, 886.86 umol, 1 eq) in DCM (5 mL) was added Burgess reagent (422.69 mg, 1.77 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (50 mL), and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified with prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 10% - 40%, 8 min) affording 2-(2-methoxy ethoxy )ethyl N-[( 1 S)-2-[[( 1 S)- 1 -cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo- ethyl]carbamate (150 mg, crude) as a white solid. MS (ESI) m/z 411.2 [M+H] ⁺

Step 6: 2-(2-methoxyethoxy)ethyl( (S)-l-( ( (S)-l-cyano-2-( ( S)-2-oxopyrrolidin-3 - yl)ethyl)amino)-3-cyclopropyl-l-oxopropan-2-yl)carbamate

[000703] 2-(2-methoxy ethoxy )ethylN-[( 1 S)-2-[[( 1 S)- 1 -cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (150 mg, crude) was separated by SFC (column: DAICEL CHIRALPAK AD(250 mm * 30 mm, 10 um); mobile phase: [Neu-EtOH]; B%: 44% - 44%, 8 min) affording 2 -(2-methoxy ethoxy )ethyl N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl] amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]carbamate (110 mg, 262.36 umol, 71.79% yield, 97.9% purity) as a colorless gum. MS (ESI) m/z 411.2 [M+H] ⁺ . [000704] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.81 (br d, J= 7.8 Hz, 1H), 7.72 (s, 1H), 7.54 (br d,J= 7.4 Hz, 1H), 4.95 (q, J= 8.2 Hz, 1H), 4.08 - 3.86 (m, 3H), 3.53 (td, J= 4.6, 15.2 Hz, 4H), 3.47 - 3.39 (m, 2H), 3.33 (s, 3H), 3.19 - 3.05 (m, 2H), 2.41 - 2.28 (m, 1H), 2.19 - 2.03 (m, 2H), 1.81 - 1.59 (m, 3H), 1.28 (td,J= 6.8, 13.6 Hz, 1H), 0.74 (br d,J =

5.6 Hz, 1H), 0.46 - 0.33 (m, 2H), 0.18 - 0.01 (m, 2H).

Example 73. Synthesis of viral protease inhibitor compound 691

Step 1: methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate

[000705] A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (13.00 g, 45.40 mmol, 1 eq) and HCl/MeOH (4 M, 35 mL, 3.08 eq) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2-amino-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (10 g, crude, HC1) was obtained as white solid. MS (ESI) m/z 223.1 [M+H] ⁺ .

Step 2: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-pro panoyl]amino]- 3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000706] A solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (9.71 g, 43.62 mmol, 1 eq, HC1), (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoic acid (10 g, 43.62 mmol, 1 eq) and TEA (22.07 g, 218.08 mmol, 30.35 mL, 5 eq) in DCM (100 mL) was cooled to 0 °C, and then T3P (83.27 g, 130.85 mmol, 77.82 mL, 50% purity, 3 eq) was added into the solution. The mixture was stirred for 1 h and warmed to 20 °C gradually. Upon completion, the mixture was added H ₂ O (100 mL) and then extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Then the residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 0: 1) to afford methyl(2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[(3S)- 2-oxopyrrolidin-3- yl]propanoate (12 g, 23.41 mmol, 53.67% yield, 77.53% purity) as a white solid. MS (ESI) m/z 398.2 [M+H] ⁺ .

Step 3: methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2- oxopyrrolidin-3-yl ]propanoate

[000707] A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.5 g, 3.77 mmol, 1 eq) in HCl/methanol (4 M, 100 mL, 105.99 eq) was stirred at 20 °C for 1 h. Upon completion, the 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 (1.1 g, crude, HC1) as a white solid. MS (ESI) m/z 298.2 [M+H] ⁺ .

Step 4: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,7-dichloro-lH-indole-2- carbonyl)amino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000708] A mixture of 4,7-dichloro-lH-indole-2-carboxylic acid (650 mg, 2.83 mmol, 1 eq), methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2- oxopyrrolidin-3-yl]propanoate (943.18 mg, 2.83 mmol, 1 eq, HC1), EDCI (1.08 g, 5.65 mmol, 2 eq) and DMAP (1.04 g, 8.48 mmol, 3 eq) in DCM (10 mL) was stirred at 20 °C for 1 h. Upon completion, the mixture was added H ₂ O (50 mL) and then extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 0:1) to afford methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,7-dichloro-1H-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl ]propanoate (550 mg,

1.01 mmol, 35.92% yield, 93.99% purity) as a white solid. MS (ESI) m/z 509.1 [M+H] ⁺ . Step5: N-f ( l S)-2-[[ ( l S)-2-amino-2-oxo-l-[ [ ( 3S)-2-oxopyrrolidin-2-yl ] methyl ] ethyl ]amino ]- l-(cyclopropylmethyl)-2-oxo-ethyl]-4,7-dichloro-lH-indole-2- carboxamide

[000709] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,7-dichloro-1H-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl ]propanoate (550 mg,

1.08 mmol, 1 eq) in NH ₃ /methanol (7 M, 154.25 uL, 1 eq) was stirred at 60 °C for 12 h. Upon completion, the mixture was concentrated under reduced pressure to give N-[(1S)- 2-[[( 1S)-2-amino-2-oxo- 1 -[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-4,7-dichloro- 1H-indole-2-carboxamide (500 mg, crude) as white solid. MS (ESI) m/z 494.1 [M+H] ⁺ .

Step6: 4, 7-dichloro-N-[ ( lS)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[000710] 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, 7-dichloro-1H-indole-2- carboxamide (450 mg, 910.25 umol, 1 eq) and Burgess reagent (1.30 g, 5.46 mmol, 6 eq) in DCM (10 mL) was stirred at 20 °C for 9 h. Upon completion, the mixture was concentrated under reduced pressure to give the residue. Then the residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 * 40 mm * 3um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 25% - 55%, 8 min) to give the product 4,7-dichloro-N- [(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]am ino]-1-(cyclopropylmethyl)- 2-oxo-ethyl]-1H-indole-2-carboxamide (300 mg, 629.78 umol, 69.19% yield, 100% purity) as a white solid. MS (ESI) m/z 476.1 [M+H] ⁺ .

[000711] 1 H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.66 - 7.56 (m, 1H), 7.52 - 7.45 (m, 1H), 7.22 - 7.14 (m, 1H), 5.16 - 5.05 (m, 1H), 4.68 - 4.61 (m, 1H), 3.36 - 3.32 (m, 2H), 2.70 - 2.57 (m, 1H), 2.40 - 2.27 (m, 2H), 1.99 - 1.69 (m, 4H), 0.91 - 0.79 (m, 1H), 0.62 - 0.52 (m, 2H), 0.27 - 0.15 (m, 2H).

Example 74. Synthesis of viral protease inhibitor compound 695

Step 1: (S)-methyl 2-ammo-3-((S)-2-oxopyrrolidm-3-yl)propanoate hydrochloride [000712] 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, HCI) as a white solid.

Step 2: (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanami do)-3-((S)- 2-oxopyrrolidin-3-yl)propanoate

[000713] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.4 g, 6.29 mmol, 1 eq, HCI) and (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoic acid (1.44 g, 6.29 mmol, 1.00 eq) in DCM (30 mL) at 0 °C was added DIEA (3.25 g, 25.15 mmol, 4.38 mL, 4 eq) and T ₃ P (12.00 g, 18.86 mmol, 11.22 mL, 50% purity, 3 eq) was added drop wise, and then the mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (60 mL) at 0 °C, and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over NazSO _d , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5:1 to 0:1) to give the product methyl (2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[(3S)- 2-oxopyrrolidin-3- yl]propanoate (1.9 g, 4.73 mmol, 75.27% yield, 99% purity) as a yellow solid. MS (ESI) m/z 398.4 [M+H] ⁺ .

Step 3: (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((S)-2-oxopyrroli din-3- yl)propanoate hydrochloride

[000714] A solution of methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbony lamino)-3 - cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]pr opanoate (0.8 g, 2.01 mmol, 1 eq) in HCl/MeOH (4 M, 15 mL, 29.81 eq) 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-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2- oxopyrrolidin-3-yl]propanoate (670 mg, crude, HC1) as a white solid.

Step 4: (S)-methyl 2-((S)-2-(7-chloro-5-methoxy-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoa te [000715] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (670 mg, 2.01 mmol, 1.51 eq, HC1) and 7-chloro-5-methoxy-lH-indole-2-carboxylic acid (300 mg, 1.33 mmol, 1 eq) in DMF (5 mL) was added DMAP (487.32 mg, 3.99 mmol, 3 eq), EDCI (509.78 mg, 2.66 mmol, 2 eq) and DCM (15 mL), and the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (40 mL) at 0 °C, and then extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5:1 to 0:1) to afford methyl (2S)-2-[[(2S)-2-[(7-chloro-5-methoxy- lH-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3 -[(3S)-2-oxopyrrolidin- 3-yl]propanoate (350 mg, 658.47 umol, 49.52% yield, 95% purity) as a yellow solid. MS (ESI) m/z 505.2 [M+H] ⁺ .

Step 5: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)ammo)-3- cyclopropyl-l-oxopropan-2-yl)-7-chloro-5-methoxy-lH-indole-2 -carboxamide [000716] A solution of methyl(2S)-2-[[(2S)-2-[(7-chloro-5-methoxy-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo pyrrolidin-3- yl]propanoate (320 mg, 633.71 umol, 1 eq) in NH ₃ /MeOH (7 M, 40 mL, 441.84 eq) was stirred at 50 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product N-[(l S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl]amino]-1-(cyclopropylmethyl) -2-oxo-ethyl]-7-chloro-5- methoxy- 1 H-indole-2-carboxamide (290 mg, crude) as a yellow solid. MS (ESI) m/z 490.2 [M+H] ⁺ .

Step 6: 7-chloro-N-((S)-l-(((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl) ethyl)amino)-3- cyclopropyl- l-oxopropan-2-yl)-5-methoxy-lH-indole-2-carboxamide

[000717] To a solution of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-7- chloro-5-methoxy-lH- indole-2-carboxamide (270 mg, 551.08 umol, 1 eq) in DCM (10 mL) was added Burgess reagent (393.97 mg, 1.65 mmol, 3 eq). After stirring at 20 °C for 7 h, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HCO ₃ )-ACN];B%: 20%-50%,8min) to give the product 7-chloro-N- [(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]am ino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-5-methoxy-lH-indole-2-carbo xamide (139.27 mg, 295.10 umol, 53.55% yield, 100% purity) as a white solid. MS (ESI) m/z 472.2 [M+H] ⁺ .

[000718] 1 H NMR (400 MHz, MeOD-d ₄ ) δ = 7.17 (s, 1H), 7.07 (d, J= 2.0 Hz, 1H), 6.96 (d, J= 2.1 Hz, 1H), 5.08 (dd, J= 6.0, 10.3 Hz, 1H), 4.55 (t, J= 7.4 Hz, 1H), 3.82 (s, 3H), 3.30 - 3.27 (m, 2H), 2.70 - 2.60 (m, 1H), 2.40 - 2.28 (m, 2H), 1.97 - 1.77 (m, 3H), 1.72 - 1.60 (m, 1H), 0.86 (br s, 1H), 0.55 (d, J= 8.0 Hz, 2H), 0.20 (dd, J= 4.8, 9.4 Hz, 2H)

[000719] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.59 (br s, 1H), 9.00 (d, J = 7.9 Hz, 1H), 8.66 (d, J = 7.6 Hz, 1H), 7.72 (s, 1H), 7.17 (s, 1H), 7.13 (d, J = 2.2 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 5.00 (q, J = 7.9 Hz, 1H), 4.60 - 4.45 (m, 1H), 3.78 (s, 3H), 3.18 - 3.05 (m, 2H), 2.40 - 2.34 (m, 1H), 2.21 - 2.06 (m, 2H), 1.86 - 1.64 (m, 3H), 1.50 (ddd, J = 6.1, 7.6, 13.9 Hz, 1H), 0.90 - 0.75 (m, 1H), 0.50 - 0.37 (m, 2H), 0.25 - 0.15 (m, 1H), 0.13 - 0.04 (m, 1H)

Example 75. Synthesis of viral protease inhibitor compound 711

Step 1: methyl (2S) -2-[[( 2S) -2-amino-3-cyclopropyl-propanoyl ] amino ]-3-[(3S) -2-oxopyrroli din-3-yl ]propanoate

[000720] A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-[(3 S)-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 afford methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxopyrrolidin- 3-yl]propanoate (600 mg, crude, HC1) as white oil. MS (ESI) m/z 298.1 [M+H] ⁺ .

Step 2: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-(4,5,6,7-tetrahydro-lH-indole- 2- carbonylamino)propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[000721 ] To a mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (600 mg, 1.80 mmol, 1 eq, HC1) in DCM (7 mL) and DMF (0.5 mL) was added 4,5,6,7-tetrahydro-lH-indole-2-carboxylic acid (415.68 mg, 2.52 mmol, 1.4 eq), TEA (1.09 g, 10.78 mmol, 1.50 mL, 6 eq) and T3P (1.72 g, 2.70 mmol, 1.60 mL, 50% purity, 1.5 eq). After stirring at 25 °C for 3 h, the reaction mixture was diluted with water (10 mL) and extracted with DCM (3 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) and TLC (SiO ₂ , DCM:MeOH = 10: 1) to get the product methyl (2S)-2-[[(2S)-3-cyclopropyl- 2-(4,5,6,7-tetrahydro-lH-indole-2-carbonylamino)propanoyl]am ino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (350 mg, 787.36 umol, 43.80% yield) as yellow oil. MS (ESI) m/z 445.3 [M+H] ⁺ . Step 3: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl]amino]~ l-(cyclopropylmethyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-lH-ind ole-2-carboxamide

[000722] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-(4,5,6,7-tetrahydro-lH- indole-2-carbonylamino)propanoyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (350 mg, 787.36 umol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 88.90 eq) was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4, 5,6,7-tetrahydro-lH- indole-2-carboxamide (300 mg, crude) as yellow solid. MS (ESI) m/z 430.2 [M+H] ⁺ .

Step 4: N-f ( l S)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-lH-indol e-2-carboxamide

[000723] A mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4, 5,6,7-tetrahydro-lH- indole-2-carboxamide (290 mg, 675.19 umol, 1 eq) in T3P (3 mL, 50% purity) and ethyl acetate (3 mL) was stirred at 40 °C for 16 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters X bridge BEH C18 100 * 25 mm * 5 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 25% - 55%, 10 min) to afford N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro- lH-indole-2- carboxamide (61.92 mg, 150.48 umol, 22.29% yield, 100% purity) as white solid. MS (ESI) m/z 412.3 [M+H] ⁺ .

[000724] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.96 (br s, 1H), 9.00 - 8.77 (m, 1H), 7.89 - 7.66 (m, 2H), 6.60 (br s, 1H), 5.04 - 4.81 (m, 1H), 4.48 - 4.28 (m, 1H), 3.24 - 3.04 (m, 2H), 2.47 - 1.96 (m, 7H), 1.81 - 1.61 (m, 7H), 1.40 (br dd, J=6.6, 13.1 Hz, 1H), 0.74 (br s, 1H), 0.38 (br s, 2H), 0.22 - 0.03 (m, 2H).

[000725] 1 H NMR (400 MHz, DMSO-d ₆ ) δ = 10.67 (br s, 1H), 8.74 - 8.49 (m, 1H), 7.53 - 7.28 (m, 2H), 6.54 (d, J=2.2 Hz, 1H), 5.05 - 4.84 (m, 1H), 4.54 - 4.38 (m, 1H), 3.17 (br d, J=7.2 Hz, 2H), 2.54 (br t, J=6.1 Hz, 2H), 2.43 (br t, J=5.6 Hz, 3H), 2.28 - 2.08 (m, 2H), 1.90 - 1.79 (m, 1H), 1.77 - 1.65 (m, 6H), 1.56 (qd, J=6.7, 13.7 Hz, 1H), 0.83 - 0.70 (m, 1H), 0.42 (br d, J=7.8 Hz, 2H), 0.20 - 0.04 (m, 2H).

Example 76. Synthesis of viral protease inhibitor compound 719

Step 1: tert-butyl 7-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2- yl) carbamoyl) -6-azaspiro[ 3.4 ]octane-6-carboxylate

[000726] To a solution of methyl (2 S)-2-amino-3 -[(3 S)-2-oxo-3 -piperidy 1 ]propanoate (1.08 g, 4.57 mmol, 1 eq, HC1) and 6-tert-butoxycarbonyl-6-azaspiro[3.4]octane-7- carboxylic acid (1.4 g, 5.48 mmol, 1.2 eq) in DCM (15 mL) and DMF (1 mL) was added EDCI (1.75 g, 9.14 mmol, 2 eq) and DMAP (1.67 g, 13.71 mmol, 3 eq), and the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2/1 to 0: 1) to give tert-butyl 7-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-6-azaspiro[3.4]octane-6-ca rboxylate (1.4 g, 2.56 mmol, 56.02% yield, 80% purity) as a yellow oil. MS (ESI) m/z 438.3 [M+H] ⁺ .

Step 2: tert-butyl 7-(((S)-l -amino- l-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)carbamoyl)- 6-azaspiro[ 3.4 ]octam-6-carboxylate

[000727] 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-ca rboxylate (0.7 g, 1.60 mmol, 1 eq) in HCl/MeOH (4 M, 20 mL, 50.00 eq) was stirred at 25 °C for 2 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 (0.6 g, crude, HC1) as a white solid. MS (ESI) m/z 338.1 [M+H] ⁺ .

Step 3: methyl (2S)-2-[[6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspiro[3.4]o ctane-7- carbonyl ] amino ]-3-[( 3S)-2-oxo-3 -piper idyl ]propanoate

[000728] To a mixture of methyl (2S)-2-(6-azaspiro[3.4]octane-7-carbonylamino)-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (0.6 g, 1.60 mmol, 1 eq, HC1) and 4-methoxy-lH- indole-2-carboxylic acid (368.18 mg, 1.93 mmol, 1.2 eq) in DCM (10 mL) and DMF (2 mL) was added EDCI (461.47 mg, 2.41 mmol, 1.5 eq) and DMAP (588.18 mg, 4.81 mmol, 3 eq). After stirring at 25 °C for 1 h, the reaction mixture was diluted with water (50 mL) and extracted with DCM (20 mL * 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2: 1 to 0/1) to give methyl (2S)-2-[[6-(4-methoxy-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (0.65 g, 1.15 mmol, 71.39% yield, 90% purity) as a yellow solid. MS (ESI) m/z 511.3 [M+H] ⁺ .

Step 4: N-f ( l S) -2-amino-2-oxo- 1 -[ [ ( 3S)-2-oxo-3-piperidyl ]methyl ] ethyl ]-6-( 4-methoxy-lH- indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000729] A mixture of methyl (2S)-2-[[6-(4-methoxy-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (0.65 g, 1.15 mmol, 90% purity, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 61.10 eq) was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethy l]-6-(4-methoxy- lH-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide (0.6 g, crude) as a yellow solid. MS (ESI) m/z 496.3 [M+H] ⁺ .

Step 5: N-f ( l S) -2-amino-2-oxo- 1 -[ [ ( 3S)-2-oxo-3-piperidyl ] methyl ] ethyl ]-6-( 4-methoxy-lH- indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000730] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-6-(4-methoxy-lH-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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was separated by prep-TLC (SiO ₂ , ethyl acetate :MeOH = 20: 1) to get N-[( 1 S)-l -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]-6-(4- methoxy-lH-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carbox amide Isomer 1 and N- [(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-6-(4-methoxy- lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carboxamide Isomer 2.

[000731] N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-6-(4-methox y-lH-indole-2- carbonyl)-6-azaspiro[3.4]octane-7-carboxamide Isomer 1 was purified by prep-HPLC (column: Waters Xb ridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 25%-55%,8min) to give N-[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspi ro[3.4]octane-7- carboxamide Isomer 1 (92.10 mg, 192.86 umol, 16.48% yield, 100% purity) as a white solid. MS (ESI) m/z 478.3 [M+H] ⁺ .

[000732] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.17 - 7.07 (m, 1H), 7.03 (d ,J= 8.2 Hz, 1H), 7.01 - 6.96 (m, 1H), 6.55 - 6.44 (m, 1H), 5.05 - 4.89 (m, 1H), 4.43 (t, J= 7.2 Hz, 1H), 4.01 - 3.79 (m, 5H), 3.13 - 2.76 (m, 2H), 2.31 - 2.05 (m, 4H), 2.03 - 1.73 (m, 8H), 1.60 - 0.97 (m, 3H);

[000733] 1 HNMR (400 MHz, DMSO-d ₆ ) δ = 11.49 - 11.19 (m, 1H), 8.81 - 8.41 (m, 1H), 7.31 - 7.20 (m, 1H), 7.11 (br d, J= 7.7 Hz, 1H), 7.09 - 7.02 (m, 1H), 7.02 - 6.81 (m, 1H), 6.53 (br d,J= 7.7 Hz, 1H), 5.06 - 4.89 (m, 1H), 4.53 (br s, 1H), 4.07 - 3.79 (m, 5H), 3.10 - 3.02 (m, 2H), 2.19 (br s, 4H), 2.06 - 1.31 (m, 11H).

[000734] N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-6-(4-methox y-lH-indole-2- carbonyl)-6-azaspiro[3.4]octane-7-carboxamide Isomer 2 was purified by prep-HPLC (column: Waters Xb ridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM

NH ₄ HCO ₃ )- ACN] ;B% : 25%-55%,8min) to give N-[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspi ro[3.4]octane-7- carboxamide Isomer 2 (30.29 mg, 63.43 umol, 5.42% yield, 100% purity) as a white solid. MS (ESI) m/z 478.3 [M+H] ⁺ . [000735] ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 10.26 - 9.64 (m, IH), 8.99 - 8.34 (m, IH), 7.26 - 7.16 (m, IH), 7.15 - 6.74 (m, 2H), 6.62 - 6.32 (m, IH), 6.27 - 5.80 (m, IH), 5.06 - 4.83 (m, IH), 4.81 - 4.54 (m, IH), 4.14 - 3.82 (m, 5H), 3.31 - 3.03 (m, 2H), 2.56 - 2.35 (m, 2H), 2.35 - 2.16 (m, 2H), 2.11 - 1.73 (m, 9H), 1.52 - 1.23 (m, 2H).

Example 77. Synthesis of viral protease inhibitor compound 721

Step 1: (S)-methyl2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethyl pentanamido)-3-((S)-2- oxopiperidin-3-yl)propanoate

[000736] To a solution of (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (2.49 g, 10.14 mmol, 1.2 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl] propanoate (2 g, 8.45 mmol, 1 eq, HCI) in DCM (60 mL) was added DMAP (3.10 g, 25.35 mmol, 3 eq). After EDCI (3.24 g, 16.90 mmol, 2 eq) was added, the mixture was stirred at 25 °C for 1 h. Upon the reaction completement, the mixture was quenched by water (400 mL) and was extracted with DCM (150 mL * 3). The organic layer was dried by sat. NaCl (50 mL), concentrated in vacuum and was purified by column (SiO ₂ , petroleum ether: ethyl acetate = 2:1 to 0: 1), washed with HCI (1 M, 150 mL), extracted with DCM (50 mL * 3), and then the pH was adjusted to ~8 with sat. NaHCO ₃ (30 mL). After extracting with DCM (100 mL), the residue was concentrated in vacuum to obtain (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4- dimethylpentanamido)-3-((S)-2- oxopiperidin-3-yl) propanoate (3 g, 6.32 mmol, 74.74% yield, 90% purity) as a white solid.

[000737] ¹ H NMR (400MHz, CDCl ₃ -d) δ ppm 7.61 (d ,J= 7.0 Hz, IH), 6.85 - 6.51 (m, IH), 6.22 (s, IH), 5.06 - 4.85 (m, IH), 4.63 - 4.47 (m, IH), 4.30 - 4.02 (m, IH), 3.79 - 3.66 (m, 3H), 3.35 - 3.25 (m, 2H), 2.42 - 2.24 (m, 1H), 2.14 - 2.05 (m, 1H), 1.96 - 1.66 (m, 4H), 1.63 - 1.52 (m, 1H), 1.43 (s, 9H), 1.03 - 0.90 (m, 9H).

Step 2: (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((S)-2-oxopiperidi n-3- yl)propanoate

[000738] A solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl) amino)-4,4- dimethylpentanamido) -3-((S)-2-oxopiperidin-3-yl) propanoate (1.5 g, 3.51 mmol, 1 eq) in HCl/MeOH (4 M, 20 mL)n was stirred at 25 °C for 1 h. Upon the reaction completed, the mixture was concentrated in vacuum to obtain (S)-methyl 2-((S)-2-amino-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin -3-yl)propanoate (1.1 g, crude, HC1) as a white solid.

[000739] ¹ H NMR (400MHz, D ₂ 0) δ ppm 4.57 (dd, J = 4.8, 10.3 Hz, 1H), 3.98 (dd, J = 5.2, 7.8 Hz, 1H), 3.78 - 3.65 (m, 3H), 3.29 - 3.14 (m, 2H), 2.75 - 2.33 (m, 1H), 2.24 - 1.47 (m, 8H), 1.04 - 0.86 (m, 9H).

Step 3:

(S)-methyl2-( (, S)-2-(7-chloro-lH-indole-2-carboxamido)-4 , 4-dimethylpentanamido)-3-( (S)-2- oxopiperidin-3-yl)propanoate

[000740] To a solution of (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((S)-2- oxopiperidin -3-yl)propanoate (550 mg * 2, HC1 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 (SiO ₂ , petroleum ether: ethyl acetate = 1:1 to 0:1) and was concentrated in vacuum, then was washed with 1M HC1 (100 mL) and was extracted with DCM (30 mL * 3) and the pH of the organic phase was adjusted to pH~7 with sat. NaHCO ₃ (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] ⁺ [000741] ¹ H NMR (400MHz, MeOD-d4) δ ppm 7.58 (d ,J= 7.8 Hz, 1H), 7.32 - 7.17 (m, 2H), 7.06 (t ,J= 7.8 Hz, 1H), 4.73 (dd, J = 3.8, 8.6 Hz, 1H), 4.55 (dd, J = 4.0, 11.7 Hz, 1H), 3.71 (s, 3H), 3.35 (s, 1H), 3.24 - 3.01 (m, 2H), 2.49 - 2.22 (m, 2H), 2.02 - 1.40 (m, 8H), 1.08 - 0.96 (m, 9H).

Step 4:

N-((S)-1-(((S)-1 -amino- 1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-4, 4-dimethyl- 1- oxopentan-2-yl)-7-chloro-1H-indole-2-carboxamide

[000742] A solution of (S)-methyl 2-((S)-2-(7-chloro-1H-indole-2-carboxamido)-4,4- dimethylpentanamido) -3 -((S)-2-oxopi peri din-3 -yl)propanoate (650 mg, 1.29 mmol, 1 eq) in NH ₃ /MeOH (7M, 10 mL) was stirred at 50 °C for 16 h. Upon the reaction completement, the mixture was concentrated in vacuum to obtained N-((S)-\-(((S)-\- amino-1-oxo-3-((S)-2-oxopiperidin-3-yl) propan-2-yl) amino)-4,4- dimethyl-1- oxopentan-2-yl)-7-chloro-lH-indole-2-carboxamide (450 mg, crude) as a light yellow solid. MS (ESI) m/z 490.3 [M+H] ⁺ .

Step 5: 7-chloro-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)e thyl)amino)-4, 4- dimethyl-l-oxopentan-2-yl)-lH-indole-2-carboxamide

[000743] To a solution of N-((S)- 1 -(((S)- 1 -amino-1 -oxo-3-((S)-2-oxopiperidin-3-yl) propan-2-yl) amino)-4,4- dimethyl- 1 -oxopentan-2-yl)-7-chloro- 1H-indole-2-carboxamide (430 mg, 877.56 umol, 1 eq) in DCM (10 mL) was added Burgess reagent (627.38 mg, 2.63 mmol, 3 eq), and the reaction was stirred at 25 °C for 4 h. Upon the reaction completement, the mixture was quenched by water (10 mL) and was dried by blowing N ₂ and was purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 um); mobile phase: [water (10 mMNH4HCO ₃ )-ACN]; B%: 35%-65%, lOmin) to obtain 7-chloro-N- ((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopi peri din-3 -yl)ethyl)amino)-4, 4-dimethyl- 1 -oxopentan- 2-yl)-1H-indole-2-carboxamide (205 mg, 424.79 umol, 48.41% yield, 97.8% purity) as a white solid. MS (ESI) m/z 472.2 [M+H] ⁺ .

[000744] ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 11.70 (s, 1H), 9.02 (d, J = 8.0 Hz, 1H), 8.71 (d, J= 8.0 Hz, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.52 (s, 1H), 7.34 - 7.23 (m, 2H), 7.07 (t ,J= 7.8 Hz, 1H), 5.05 (q ,J= 8.2 Hz, 1H), 4.63 - 4.54 (m, 1H), 3.07 (s, 2H), 2.30 - 2.18 (m, 2H), 1.88 - 1.32 (m, 7H), 0.95 (s, 9H). Example 78. Synthesis of viral protease inhibitor compound 723

Step 1: tert-butyl 2,2-difluoro-7-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopiperidin-3 -yl)propan-2- yl) carbamoyl) -6-azaspiro[ 3.4 ]octam-6-carboxylate

[000745] A mixture of (7 S)-6-tert-butoxy carbonyl-2, 2-difluoro-6-azaspiro[34]octane-7- carboxylic acid (500 mg, 1.72 mmol, 1 eq ), methyl (2S)-2-amino-3-[(3S)-2-oxo-3- piperidyl]propanoate (406.29 mg, 1.72 mmol, 1 eq, HC1), EDCI (987.17 mg, 5.15 mmol, 3 eq), DMAP (629.10 mg, 5.15 mmol, 3 eq) in DCM (5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 20 °C for 2 h under N ₂ atmosphere. Upon completion, the reaction mixture was poured into H ₂ O (25 mL) at 20 °C, and then extracted with DCM (25 mL * 3). The combined organic layers were washed with brine (25 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 1/1) to afford tert-butyl (7S)-2,2-difluoro-7- [[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-6- azaspiro[3.4]octane-6-carboxylate (800 mg, crude) as a white solid. MS (ESI) m/z 474.1 [M+H] ⁺ . Step 2: (2S)-methyl 2-(2,2-difluoro-6-azaspiro[3.4]octane-7-carboxamido)-3-((S)- 2- oxopiperidin-3-yl)propanoate

[000746] A solution of tert-butyl (7S)-2,2-difluoro-7-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2- oxo-3-piperidyl]methyl]ethyl]carbamoyl]-6-azaspiro[34]octane -6-carboxylate (710 mg, 1.50 mmol, 1 eq ) in HCl/MeOH (4 M, 8 mL, 21.34 eq) was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give methyl (2S)-2-[[(7S)-2,2-difluoro-6-azaspiro[3.4]octane-7- carbony 1 ]amino]-3 -[(3 S)-2-oxo-3 -piperidy 1 ]propanoate (614 mg, crude, HC1) as a yellow oil. MS (ESI) m/z 374.1 [M+H] ⁺ .

Step 3: (2S)-methyl 2-(2,2-difluoro-6-(4-methoxy-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carboxamido)-3-((S)-2-oxopiperidin-3-y l)propanoate

[000747] To a solution of methyl (2S)-2-[[(7S)-2,2-difluoro-6-azaspiro[3.4]octane-7- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (614 mg, 1.50 mmol, 1 eq, HC1), 4-methoxy- 1 H-indole-2-carboxylic acid (286.41 mg, 1.50 mmol, 1 eq), DMAP (549.06 mg, 4.49 mmol, 3 eq) in DCM (7 mL) was added EDCI (861.56 mg, 4.49 mmol, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O (25 mL) at 20 °C, and then extracted with DCM (25 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 80/1 to 1/1) to give methyl (2S)-2-[[(7S)-2,2-difluoro-6-(4-methoxy-lH-indole-2-carbonyl )-6- azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (550 mg,

1.01 mmol, 67.17% yield) as a yellow solid. MS (ESI) m/z 547.2 [M+H] ⁺ .

Step 4: N-((S)-l-ammo-l-oxo-3-((S)-2-oxopiperidm-3-yl)propan-2-yl)-2 ,2-difluoro-6-(4- methoxy-lH-indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000748] A solution of methyl (2S)-2-[[(7S)-2,2-difluoro-6-(4-methoxy-lH-indole-2- carbonyl)-6-azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2- oxo-3- piperidyl]propanoate (535 mg, 978.85 umol, 1 eq) in NH ₃ /MeOH (7 M, 10.70 mL, 76.52 eq) was stirred at 30 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to afford (7 S)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)- 2-oxo-3-piperidyl]methyl]ethyl]-2,2-difluoro-6-(4-methoxy-lH -indole-2-carbonyl)-6- azaspiro[34]octane-7-carboxamide (520 mg, crude) as a yellow solid. MS (ESI) m/z 532.2 [M+H] ⁺ .

Step5: N-((S)-l-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2,2-difluor o-6-(4-methoxy-lH- indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000749] A solution of (7 S)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]-2,2-difluoro-6-(4-methoxy-lH-indole- 2-carbonyl)-6- azaspiro[3.4]octane-7-carboxamide (515 mg, 968.86 umol, 1 eq) in EtOAc (2.5 mL) was added T3P (2.68 g, 4.20 mmol, 2.5 mL, 50% purity, 4.34 eq) was stirred at 20 °C for 16 h. Upon completion, the reaction mixture was poured into H ₂ O (25 mL) at 20 °C, and then extracted with EtOAc (25 mL * 3). The combined organic layers were washed with brine (25 mL * 2), dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 um);mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 45%- 75%,10min) to give (7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2,2-di fluoro- 6-(4-methoxy- 1 H-indole-2-carbonyl)-6-azaspiro[34]octane-7-carboxamide (188 mg, 364.99 umol, 37.67% yield, 99.7% purity) as a white solid. MS (ESI) m/z 514.3 [M+H] ⁺ .

Step 6: N-((S)-l-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2,2-difluor o-6-(4-methoxy-lH- indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000750] Isomer 1 : (7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2,2-di fluoro- 6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-c arboxamide (170 mg) was separated by SFC (column: REGIS(S,S)WHELK-01(250mm*25mm,10um);mobile phase: [0.1%NH ₃ H ₂ 0 ETOH];B%: 60%-60%,10min) to give (7S)-N-[(1S)-1-cyano-2- [(3S)-2-oxo-3-piperidyl]ethyl]-2,2-difluoro-6-(4-methoxy-lH- indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carboxamide (42.5 mg, 82.76 umol, 25.00% yield, 100% purity) as a white solid. MS (ESI) m/z 514.3 [M+H] ⁺ .

[000751] Isomer 1 : ¹ H NMR (400MHz, MeOD-d ₄ ) δ = 7.26 - 6.72 (m, 3H), 6.53 (d, J= 7.6Hz, 1H), 5.03 (d , J= 5.7, 10.5Hz, 1H), 4.64 (d, J= 1.7Hz, 1H), 4.25 (d , J= 10.1Hz, 1H), 4.15 - 4.01 (m, 1H), 3.98 - 3.87 (m, 2H), 4.16 - 3.86 (m, 1H), 3.13 (s, 2H), 2.87 - 2.15 (m, 8H), 1.99 - 1.28 (m, 5H); and to give (7S)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-2,2-difluoro-6-(4-methoxy-lH-indole-2-carbo nyl)-6-azaspiro[3.4]octane- 7-carboxamide (89.8 mg, 173.47 umol, 52.40% yield, 99.2% purity) as a white solid. MS (ESI) m/z 514.3 [M+H] ⁺ .

[000752] Isomer 2: ¹ H NMR (400MHz, MeOD-d ₄ ) δ = 7.17 - 6.82 (m, 3H), 6.56 - 6.44 (m, IH), 5.17 - 5.03 (m, IH), 4.61 (t , J= 7.5Hz, IH), 4.15 (s, IH), 4.01 - 3.78 (m, 4H), 3.26 - 2.86 (m, 2H), 2.75 - 2.14 (m, 8H), 2.06 - 1.30 (m, 5H).

Example 79. Synthesis of viral protease inhibitor compound 725

Step 1: (S)-methyl2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethyl pentanamido)-3-((S)-2- oxopiperidin-3-yl)propanoate

[000753] To a solution of (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (1.24 g, 5.07 mmol, 1.2 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl] propanoate (1 g, 4.22 mmol, 1 eq, HCI) in DCM (30 mL) was added DMAP (1.55 g,

12.67 mmol, 3 eq), and then was added EDCI (1.62 g, 8.45 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was quenched by water (400 mL) and was extracted with DCM (150 mL * 3). After drying with sat. NaCl (50 mL), the reaction was concentrated in vacuum. The crude product was purified by column (SiO ₂ , petroleum ethenethyl acetate = 2: 1 to 0: 1) and was washed with 1M HCI (100 mL), extracted with DCM (50 mL * 3), the pH was adjusted to pH~8 with sat. NaHCO ₃ (50 mL), extracted with DCM (50 mL) and concentrated to afford (S)-methyl2-((S)-2-((tert- butoxycarbonyl)amino)-4,4-dimethylpentanamido)-3-((S)-2-oxop iperidin-3-yl)propanoate (1.4 g, 2.95 mmol, 69.76% yield, 90% purity) as a white solid. Step 2:tert-butyl((S)-1-(((S)-1-amino- J-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)- 4,4-dimethyl- l-oxopentan-2-yl)carbamate

[000754] A solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl) amino)-4, 4- dimethylpentanamido) -3-((S)-2-oxopiperidin-3-yl) propanoate (1.4 g, 3.27 mmol, 1 eq) in NH ₃ /MeOH (18 mL, 7M) was stirred at 50 °C for 16 h. Upon completion, the mixture was concentrated in vacuum to give tert-butyl((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2- oxopiperidin-3-yl)propan-2-yl)amino)-4,4- dimethyl- 1 -oxopentan-2-yl) carbamate (1.1 g, crude) as a white solid.

Step 3: (S)-2-amino-N-((S)-l-ammo-l-oxo-3-((S)-2-oxopiperidm-3-yl)pr opan-2-yl)-4,4- dimethylpentanamide

[000755] A solution of tert- butyl ((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl) propan-2-yl) amino) -4,4-dimethyl- 1 -oxopentan-2-yl) carbamate (1.5 g, 3.64 mmol, 1 eq) in HCl/MeOH (4 M, 20 mL) was stirred at 25 °C for 1 h. Upon the reaction completion, the mixture was concentrated in vacuum to give (S)-2-amino-N-((S)-l -amino- l-oxo-3- ((S)-2-oxopiperidin-3-yl)propan-2-yl)-4,4- dimethylpentanamide (1.2 g, crude) as a white solid.

Step 4: N-[(lS)-l-[[(lS)-2-amino-2-oxo-l-[[(3S)-2-oxo-3- piperidyl ] methyl ] ethyl ] carbamoyl ]-3, 3-dimethyl-butyl ]-6, 7-dichloro-lH-indole-2- carboxamide

[000756] A mixture of (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-4,4-dimethyl-pentanamide (900 mg, 2.58 mmol, 1 eq, HC1) in DCM (8 mL) and DMF (3 mL) was added DMAP (945.50 mg, 7.74 mmol, 3 eq) in one portion at 25 °C. The mixture was added 6,7-dichloro-lH-indole-2-carboxylic acid (593.47 mg, 2.58 mmol, 1 eq) and EDCI (1.48 g, 7.74 mmol, 3 eq), and the reaction was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 0/1) to give N-[(1S)-1-[[(1S)-2-amino-2- oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-3,3-d imethyl-butyl]-6,7- dichloro- 1 H-indole-2-carboxamide (450 mg, 858.06 umol, 33.26% yield) as a yellow solid. MS (ESI) m/z 524.2 [M+H] ⁺ .

Step 5: 6, 7-dichloro-N-[(lS)-l-[[(lS)-l-cyano-2-[(3S)-2-oxo-3-piperidy l]ethyl]carbamoyl]- 3, 3-dimethyl-butyl ]-lH-indole-2-carboxamide

[000757] To a mixture of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-6,7-di chloro-lH-indole-2- carboxamide (400 mg, 762.72 umol, 1 eq) in DCM (5 mL) was added Burgess reagent (363.53 mg, 1.53 mmol, 2 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (3 mL), and then combined organic layer was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (column: Phenomenex Gemini -NX C18 75*30mm*3um;mobile phase: [water(0.05%NH3H20+10mMNH4HC03)- ACN];B%: 35%-65%,8min) to give 6,7-dichloro-N-[(1S)-1-[[(1S)-1-cyano-2-[(3S)-2- oxo-3-piperidyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-lH-indo le-2-carboxamide (165 mg, 325.81 umol, 42.72% yield) as a white solid. MS (ESI) m/z 506.1 [M+H] ⁺ .

[000758] ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.54 (d, J=8.4 Hz, 1H), 7.25 - 7.16 (m, 2H), 5.13 - 5.05 (m, 1H), 4.66 (dd,J=4.3, 8.3 Hz, 1H), 3.25 - 3.13 (m, 2H), 2.50 - 2.35 (m, 2H), 1.99 - 1.88 (m, 2H), 1.87 (d, J=4.4 Hz, 1H), 1.79 (br dd, J=8.4, 14.6 Hz, 2H), 1.71 - 1.56 (m, 1H), 1.55 - 1.43 (m, 1H), 1.03 (s, 9H).

Example 80. Synthesis of viral protease inhibitor compound 727

Step 1: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-pro panoyl]amino]- 3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000759] A mixture of methyl (2 S)-2-amino-3 -[(3 S)-2-oxo-3 -piperidy 1 Jpropanoate (1.3 g, 5.49 mmol, 1 eq, HC1) in DCM (12 mL) was added (2S)-2-(tert-butoxycarbonylamino)-3- cyclopropyl-propanoic acid (1.51 g, 6.59 mmol, 1.2 eq), TEA (3.33 g, 32.95 mmol, 4.59 mL, 6 eq) and T3P (5.24 g, 8.24 mmol, 4.90 mL, 50% purity, 1.5 eq). The reaction was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (3 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , DCM:MeOH = 10: 1) and TLC (SiO ₂ , DCM:MeOH =

10:1) to afford methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.99 g, 4.11 mmol, 74.84% yield, 85% purity) as a yellow oil. MS (ESI) m/z 412.2 [M+H] ⁺ .

Step 2: methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxo-3- piperidyl ]propanoate

[000760] A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.20 g, 2.48 mmol, 85% purity, 1 eq) in HCI/MeOH (4 M, 15 mL, 24.21 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 afford methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxo-3- piperidyl]propanoate (850 mg, crude, HC1) as a yellow oil. MS (ESI) m/z 312.1 [M+H] ⁺ .

Step 3: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(6,7-dichloro-JH-indole-2- carbonyl)amino ]propanoyl ] amino ]-3-[( 3S)-2-oxo-3-piperidyl ]propanoate

[000761] A mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (850 mg, 2.44 mmol, 1 eq, HC1) in DCM (10 mL) and DMF (0.5 mL) was added with 6,7-dichloro-lH-indole-2-carboxylic acid (674.59 mg, 2.93 mmol, 1.2 eq, 1.2), DMAP (746.35 mg, 6.11 mmol, 2.5 eq) and EDCI (936.91 mg, 4.89 mmol, 2 eq), and then the resulting mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (3 mL * 3). The combined organic layers were dried over Na ₂ SC>4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , DCM MeOH = 10: 1) and TLC (SiO ₂ , DCM MeOH = 10: 1) to afford methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(6,7-dichloro-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (1.24 g, 1.50 mmol, 61.27% yield, 63% purity) as a yellow solid. MS (ESI) m/z 523.2 [M+H] ⁺ .

Step 4: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ] methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-6,7-dichloro-lH-indole-2-ca rboxamide

[000762] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(6,7-dichloro-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (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- lH-indole-2-carboxamide (1 g, crude) as a yellow oil. MS (ESI) m/z 508.2 [M+H] ⁺ .

Step 5: 6, 7-dichloro-N-[ ( l S)-2-[[( l S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[000763] A mixture of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-6,7-dichloro-lH- indole-2-carboxamide (1 g, 1.97 mmol, 1 eq) in T3P (5 mL, 50% purity) and ethyl acetate (5 mL) was stirred at 40 °C for 18 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (20 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters X bridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30%

- 60%, 8 min) to get the product 6,7-dichloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH -indole-2-carboxamide (288.22 mg, 587.75 umol, 29.88% yield, 100% purity) as a white solid. MS (ESI) m/z 490.1 [M+H] ⁺ .

[000764] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.94 (br s, 1H), 9.01 (d, J=7.9 Hz, 1H), 8.76 (br d, J=7.5 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.55 (br s, 1H), 7.33 - 7.21 (m, 2H), 5.21 - 4.90 (m, 1H), 4.60 - 4.38 (m, 1H), 3.16 - 3.01 (m, 2H), 2.35 - 2.18 (m, 2H), 1.90 - 1.65 (m, 4H), 1.63 - 1.33 (m, 3H), 0.80 (br d, J=5.5 Hz, 1H), 0.49 - 0.35 (m, 2H), 0.26 - 0.05 (m, 2H).

Example 81. Synthesis of viral protease inhibitor compound 729

Step 1: (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(6-azaspiro[3.4]octane-7- carboxamido)propanoate [000765] A solution of tert-butyl 7-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)carbamoyl)-6-azaspiro[3.4]octane-6-carboxylat e (1 g, 2.29 mmol, 1 eq) in HCl/MeOH (40 mL) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove HCl/MeOH, and then DCM (50 mL) (three times) was added. The reaction was concentrated under reduced pressure to give a crude product (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(6-azaspiro[3.4]octane-7- carboxamido)propanoate (800 mg, crude, HC1) was obtained as a yellow solid. MS (ESI) m/z 338.2 [M+H] ⁺ .

Step 2: (2S)-methyl 2-(6-(7-chloro-JH-indole-2-carbonyl)-6-azaspiro[3.4Joctane-7 - carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000766] To a solution of (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(6- azaspiro[3.4]octane-7-carboxamido)propanoate (580 mg, 1.72 mmol, 1 eq) and 7-chloro- 1 H-indole-2-carboxylic acid (504.35 mg, 2.58 mmol, 1.5 eq) in DCM (10 mL) was added DMAP (420.00 mg, 3.44 mmol, 2 eq) and EDCI (494.29 mg, 2.58 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction was quenched by H ₂ O (100 mL) and then extracted with DCM (50 mL * 3). The combined organic phase was washed with brine (50 mL * 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 0/1) to afford (2S)-methyl 2-(6-(7-chloro-lH-indole-2- carbonyl)-6-azaspiro[3.4]octane-7-carboxamido)-3-((S)-2-oxop iperidin-3-yl)propanoate (680 mg, 1.19 mmol, 69.13% yield, 90% purity) as a yellow solid. MS (ESI) m/z 515.2 [M+H] ⁺ .

Step 3: N-f ( l S)-2-amino-2-oxo-l-[[(3S)-2-oxo-3-piperidyl ]methyl ] ethyl ]-6-(7-chloro-lH- indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000767] To a solution of methyl (2S)-2-[[6-(7-chloro-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (675 mg, 1.31 mmol, 1 eq) in NH ₃ (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]ethy l]-6-(7-chloro- lH-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] ⁺ .

Step 4: 6-(7-chloro-lH-indole-2-carbonyl)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxo-3- piperidyl ] ethyl ]-6-azaspiro[ 3.4 ] octane- 7 -carboxamide [000768] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-6-(7-chloro-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7- carboxamide (695 mg, 1.39 mmol, 1 eq) in DCM (15 mL) was added Burgess reagent (1.66 g, 6.95 mmol, 5 eq) under N ₂ . The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue at 30 °C. The residue was purified by prep-TLC (SiO ₂ , ethyl acetate :MeOH = 20:1) to give desired compound (450 mg, purity 96%) as a yellow solid, which was further separated by SFC (condition : column : DAICEL CHIRALPAK AS(250mm * 30mm, lOum); mobile phase: [Neu-ETOH];B%: 50%-50%,min ) to give 6-(7-chloro-lH- indole-2-carbonyl)-N-[( 1 S)-l -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]-6- azaspiro[3.4]octane-7-carboxamide (145 mg, 300.85 umol, 21.64% yield, 100% purity) as a white solid. MS (ESI) m/z 482.3 [M+H] ⁺ .

[000769] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.67 - 7.49 (m, 1H), 7.31 - 7.23 (m, 1H), 7.19 - 6.99 (m, 2H), 5.14 - 4.95 (m, 1H), 4.60 - 4.52 (m, 1H), 4.07 - 3.77 (m, 2H), 3.27 - 3.16 (m, 2H), 2.56 - 1.50 (m, 15H).

[000770] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.27 - 11.09 (m, 1H), 8.82 - 8.62 (m, 1H), 7.72 - 7.53 (m, 1H), 7.36 - 7.24 (m, 2H), 7.19 - 7.02 (m, 2H), 5.11 - 4.85 (m, 1H), 4.67 - 4.42 (m, 1H), 4.05 - 3.73 (m, 2H), 3.10 - 3.06 (m, 2H), 2.30 - 1.38 (m, 15H).

[000771] 6-(7-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]-6-azaspiro[3.4]octane-7-carboxamide (170 mg, 348.13 umol, 25.04% yield, 98.7% purity) as a white solid. MS (ESI) m/z 482.3 [M+H] ⁺ .

[000772] ¹ H NMR (400 MHz, MeOM ₄ ) δ = 7.67 - 7.55 (m, 1H), 7.31 - 7.25 (m, 1H), 7.18 - 7.11 (m, 1H), 7.10 - 7.04 (m, 1H), 4.93 (br s, 1H), 4.60 - 4.54 (m, 1H), 4.13 - 3.79 (m, 2H), 2.98 (br s, 2H), 2.42 - 1.54 (m, 15H).

[000773] 1 H NMR (400 MHz, DMSO-d ₆ ) δ = 11.27 - 10.98 (m, 1H), 8.88 - 8.54 (m, 1H), 7.82 - 7.49 (m, 1H), 7.34 - 6.98 (m, 4H), 5.10 - 4.95 (m, 1H), 4.69 - 4.39 (m, 1H), 4.03 - 3.72 (m, 2H), 3.10 - 3.05 (m, 2H), 2.32 - 1.39 (m, 15H).

Example 82. Synthesis of viral protease inhibitor compound 731

Step 1: tert-butyl 3-[[(lS)-2-methoxy-2-oxo-l-[[(3S)-2-oxo-3- piperidyl ] methyl ] ethyl ] carbamoyl ]-2-azaspiro[ 4.5 ] decane-2 -car boxy late

[000774] To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (1 g, 4.22 mmol, 1 eq, HC1) and 2-tert-butoxycarbonyl-2-azaspiro[4.5]decane-3-carboxylic acid (1.26 g, 4.44 mmol, 1.05 eq), DIPEA (2.73 g, 21.12 mmol, 3.68 mL, 5 eq) in THF (10 mL) was added T3P (4.03 g, 6.34 mmol, 3.77 mL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 20 °C for 2 h. Upon completion, the residue was poured into saturated sodium bicarbonate solution (30 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (20 mL * 2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 0/1) to afford tert-butyl 3-[[(1S)-2-methoxy-2-oxo-1- [[(3S)-2- oxo-3-piperidyl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decan e-2-carboxylate (1.6 g, crude) as alight yellow oil. MS (ESI) m/z 466.3 [M+H] ⁺ .

Step 2: methyl (2S)-2-(2-azaspiro[4.5Jdecane-3-carbonylamino)-3-[(3S)-2-oxo -3- piperidyl ]propanoate [000775] To a mixture of tert-butyl 3-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl] ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxylate (1.6 g, 3.44 mmol, 1 eq) was added HCl/MeOH (4 M, 16.00 mL, 18.62 eq) at 0 °C under N ₂ . The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated to get methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3S)-2- oxo-3-piperidyl]propanoate (1.5 g, crude, HC1) as a light yellow oil. MS (ESI) m/z 366.2 [M+H] ⁺ .

Step 3: methyl (2S)-2-[[2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]de cane-3- carbonyl ] amino ]-3-[ ( 3S)-2-oxo-3 -piper idyl ]propanoate

[000776] To a mixture of methyl(2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3- [(3S)-2-oxo-3- piperidyl]propanoate (1.5 g, 3.73 mmol, 1 eq, HC1) and 7-chloro-lH- indole-2-carboxylic acid (729.99 mg, 3.73 mmol, 1 eq), DIPEA (1.45 g, 11.20 mmol,

1.95 mL, 3 eq) in DMF (10 mL) was added HATU (1.70 g, 4.48 mmol, 1.2 eq) at 20 °C under N ₂ . The mixture was stirred at 20 °C for 2 h. Upon completion, the residue was poured into ice-water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (5 mL * 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 2/1 to 0/1) to afford methyl (2S)-2-[[2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]de cane-3- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.60 g, crude) as a light yellow oil. MS (ESI) m/z 543.2 [M+H] ⁺ .

Step 4: N-f ( l S) -2-amino-2-oxo- 1 -[ [ ( 3S)-2-oxo-3-piperidyl ] methyl ] ethyl ]-2-(7-chloro-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide

[000777] To a mixture of methyl (2S)-2-[[2-(7-chloro-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane -3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.6 g, 2.95 mmol, 1 eq) was added NH ₃ /MeOH (7 M, 22.86 mL, 54.31 eq) at 20 °C under N ₂ . The mixture was stirred at 65 °C for 12 h. Upon completion, the mixture was cooled to 25 °C and concentrated in reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 0/1) to give N-[(1S)-2- amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-2-(7-ch loro-lH-indole -2- carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (1.2 g, crude) as a light yellow solid. MS (ESI) m/z 528.2 [M+H] ⁺ .

Step 5: 2-(7-chloro-lH-indole-2-carbonyl)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxo-3- piperidyl ] ethyl ]-2-azaspiro[ 4.5 ]decane-3 -carboxamide

[000778] To a mixture of N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]-2- (7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3- carboxamide (1.2 g, 2.27 mmol, 1 eq) in DCM (5 mL) was added Burgess reagent (1.2 g, 5.04 mmol, 2.22 eq) in one portion at 20 °C under N ₂ . The mixture was stirred at 20 °C for 2.5 h. Upon completion, the mixture was added water (3 mL) and stirred for 20 min, then concentrated to get the crude. The residue was purified by prep-TLC (SiO ₂ , EtOAc:MeOH = 25:1) to afford 2-(7-chloro-lH-indole-2-carbonyl) -N-[( 1 S)- 1 -cy ano-2- [(3S)-2-oxo-3-piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carbo xamide (0.75 g, 1.45 mmol, 64.00% yield, 98.9% purity) as a light yellow solid. MS (ESI) m/z 528.2 [M+H] ⁺ .

Step 6: 2-(7-chloro-lH-indole-2-carbonyl)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxo-3- piperidyl ] ethyl ]-2-azaspiro[ 4.5 ]decane-3 -carboxamide

[000779] 2-(7-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide (0.9 g, 1.76 mmol, 1 eq) was separated by chiral separation (column: REGIS(S,S)WHELK-

01 (250mm*25mm, 10um);mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 60%-60%,6.7min) to afford 2-(7-chloro-lH-indole-2-carbonyl)-N-[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide Isomer 1 (298.31 mg, 578.46 umol, 32.78% yield, 98.9% purity) as a white solid. MS (ESI) m/z 510.3 [M+H] ⁺ .

[000780] 1 H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.62 (br d ,J= 7.94 Hz, 1 H), 7.56 - 7.56 (m, 1 H), 7.22 - 7.30 (m, 1 H), 7.01 - 7.13 (m, 2 H), 5.11 (br dd,J= 10.58, 5.73 Hz, 1 H), 4.62 (br dd, J= 9.81, 7.83 Hz, 1 H), 3.83 - 3.96 (m, 1 H), 3.71 (br d,J= 10.36 Hz, 1 H), 3.16 - 3.27 (m, 2 H), 2.40 - 2.62 (m, 2 H), 1.70 - 2.08 (m, 4 H), 1.29 - 1.65 (m, 12 H).

[000781] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.15 (br s, 1 H), 8.71 (br s, 1 H), 7.62 (br s, 1 H), 7.18 - 7.35 (m, 2 H), 6.94 - 7.13 (m, 2 H), 4.96 (br s, 1 H), 4.62 (br s, 1 H), 3.51 - 3.87 (m, 2 H), 3.09 - 3.20 (m, 2 H), 2.09 - 2.36 (m, 3 H), 1.60 - 1.89 (m, 4 H), 1.19 - 1.55 (m, 12 H). [000782] To give 2-(7-chloro-lH-indole-2-carbonyl)-N-[(l S)- 1 -cy ano-2-[(3 S)-2-oxo-3 - piperidyl]ethyl] -2-azaspiro[4.5]decane-3-carboxamide Isomer 2 (252.99 mg, 487.10 umol, 27.60% yield, 98.20% purity) as the white solid. MS (ESI) m/z 510.3 [M+H] ⁺ ;

[000783] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.64 (d, J=7.72 Hz, 1 H), 7.21 -

7.33 (m, 1 H), 7.12 (s, 1 H), 7.04 - 7.10 (m, 1 H), 7.07 (t, J=7.83 Hz, 1 H), 5.02 (dd,

J=10.25, 6.06 Hz, 1 H), 4.62 (dd, J=9.70, 7.72 Hz, 1 H), 3.95 (br d, J=10.14 Hz, 1 H), 3.77 (br d, J=10.58 Hz, 1 H), 3.01 - 3.22 (m, 2 H), 2.22 - 2.40 (m, 3 H), 1.86 - 2.04 (m, 2 H), 1.77 - 1.86 (m, 1 H), 1.72 (br dd, J=12.46, 10.03 Hz, 1 H), 1.39 - 1.68 (m, 12 H).

[000784] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.10 (br s, 1 H), 8.65 (br d, J= 6.24 Hz, 1 H), 7.63 (br d, J= 6.85 Hz, 1 H), 7.17 - 7.34 (m, 2 H), 7.08 (br t, J= 7.70 Hz, 2 H),

4.99 (br d,J= 7.46 Hz, 1 H), 4.61 (br s, 1 H), 3.56 - 3.89 (m, 2 H), 3.10 (br s, 2 H), 2.09 - 2.31 (m, 3 H), 1.64 - 1.95 (m, 4 H), 1.38 - 1.62 (m, 12 H).

Example 83. Synthesis of viral protease inhibitor compound 733

Step 1: tert-butyl 3-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2- yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylate [000785] To a solution of methyl (S)-methyl 2-amino-3-((S)-2-oxopiperidin-3- yl)propanoate (500 mg, 2.11 mmol, 1 eq, HC1) in DCM (4 mL) and DMF (2 mL) was added 2-tert-butoxycarbonyl-2-azaspiro[4.5]decane-3-carboxylic acid (718.30 mg, 2.53 mmol, 1.2 eq), DMAP (774.22 mg, 6.34 mmol, 3 eq), and then EDCI (809.90 mg, 4.22 mmol, 2 eq) at 0 °C. The mixture was then stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM: MeOH = 1 :0 to 10: 1) to give tert-butyl 3-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2- yl)carbamoyl)-2- azaspiro[4.5]decane-2-carboxylate (775 mg, 1.50 mmol, 70.92% yield, 90% purity) as a yellow solid. MS (ESI) m/z 466.3 [M+H] ⁺ .

Step 2: (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2-azaspiro[4.5]decane-3- carboxamido)propanoate

[000786] A mixture of tert-butyl 3-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylat e (775 mg, 1.50 mmol, 90% purity, 1 eq) in HCl/MeOH (4 M, 8 mL, 21.36 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S)- methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2-azaspiro[4.5]decane-3-carbo xamido)propanoate (800 mg, crude, HC1) as a yellow solid.

Step 3: (2S)-methyl 2-(2-(6-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3 - carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000787] To a solution of (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2- azaspiro[4.5]decane-3-carboxamido)propanoate (740 mg, 1.38 mmol, 75% purity, 1 eq, HC1) in DCM (6 mL) and DMF (3 mL) was added 6-chloro-lH-indole-2-carboxylic acid (297.11 mg, 1.52 mmol, 1.1 eq), DMAP (506.09 mg, 4.14 mmol, 3 eq), then EDCI (529.42 mg, 2.76 mmol, 2 eq) at 0 °C, and then the mixture was then stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

The residue was purified by column chromatography (SiO ₂ , DCM: MeOH = 1 :0 to 10: 1) to give (2S)-methyl 2-(2-(6-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3 - carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (980 mg, 1.35 mmol, 98.02% yield, 75% purity) as a yellow solid. MS (ESI) m/z 543.3 [M+H] ⁺ .

Step 4: N-( (S)-l -amino-1 -oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)-2-( 6-chloro-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide

[000788] A mixture of (2S)-methyl 2-(2-(6-chloro- 1 H-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carboxamido)-3-((S)-2-oxopiperidin-3-y l)propanoate (980 mg,

1.35 mmol, 75% purity, 1 eq) in NIL.MeOH (7 M, 15 mL, 77.58 eq) was stirred at 65 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure togiveN-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan -2-yl)-2-(6-chloro-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (960 mg, crude) as a yellow solid. MS (ESI) m/z 528.2 [M+H] ⁺ .

Step 5: 2-(6-chloro-lH-indole-2-carbonyl)-N-((S)-l-cyano-2-((S)-2-ox opiperidin-3-yl) ethyl)- 2-azaspiro[ 4.5 ]decane-3-carboxamide

[000789] To a solution of N-((S)-1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)- 2-(6-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-ca rboxamide (960 mg, 1.36 mmol, 75% purity, 1 eq) in DCM (10 mL) was added Burgess reagent (1.95 g, 8.18 mmol, 6 eq) and then stirred at 25 °C for 4 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 um); mobile phase: [water (lOmM NH4HCO3)- ACN]; B%: 35%-65%, lOmin) to give 2-(6-chloro- 1 H-indole-2-carbonyl)-N-((S)- 1 - cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2-azaspiro[4.5]decan e-3-carboxamide (280 mg, 39.66% yield, 98.5% purity) as a white solid. MS (ESI) m/z 510.2 [M+H] ⁺ .

Step 6: 2-(6-chloro-lH-indole-2-carbonyl)-N-((S)-l-cyano-2-((S)-2-ox opiperidin-3-yl) ethyl)- 2-azaspiro[ 4.5 ]decane-3-carboxamide

[000790] 2-(6-chloro-lH-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-ox opiperidin-3- yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide (280 mg, 98.5% purity) was purified by SFC (column: REGIS(S, S)WHELK-01 (250 mm*25 mm, 10 um); mobile phase: [0.1% NH3H ₂ O IP A]; B%: 60% - 60%, 8min) to give 2-(6-chloro- 1 H-indole-2-carbonyl)-N- ((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2-azaspiro[4. 5]decane-3-carboxamide Isomer 1 (90.34 mg, 175.89 umol, 12.90% yield, 99.3% purity) as a white solid. MS (ESI) m/z 510.2 [M+H] ⁺ .

[000791] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.68 (s, 1H), 9.10 - 8.79 (m, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.58 - 7.47 (m, 1H), 7.46 - 7.36 (m, 1H), 7.14 - 6.62 (m, 2H), 5.10 - 4.73

(m, 1H), 4.51 (t, J=8.4 Hz, 1H), 3.95 - 3.73 (m, 1H), 3.65 (d, J=10.4 Hz, 1H), 3.17 - 2.83 (m, 2H), 2.35 - 2.07 (m, 3H), 1.93 - 1.19 (m, 16H).

[000792] ¹ H NMR (400MHz, DMSO-d ₆ )(T=273+80K) δ = 11.48 (br s, 1H), 8.74 (br s, 1H), 7.65 (br s, 1H), 7.47 (br s, 1H), 7.31 (br s, 1H), 7.06 (br d, J=9.0 Hz, 2H), 4.98 (br s, 1H), 4.57 (br s, 1H), 3.87 (br d, J=10.1 Hz, lH), 3.64 (br s, 1H), 3.10 - 3.04 (m, 2H), 2.39 - 2.11 (m, 3H), 1.90 - 1.36 (m, 16H).

[000793] To give 2-(6-chloro- 1 H-indole-2-carbonyl)-N-((S)- 1 -cyano-2-((S)-2- oxopiperidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide Isomer 2 (143.12 mg, 280.61 umol, 20.58% yield, 100% purity) as a white solid. MS (ESI) m/z 510.2 [M+H] ⁺ .

[000794] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.69 (s, 1H), 9.12 - 8.72 (m, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.57 - 7.40 (m, 2H), 7.14 - 6.60 (m, 2H), 5.08 - 4.78 (m, 1H), 4.51 (t, J=8.4 Hz, 1H), 3.92 - 3.78 (m, 1H), 3.69 (d, J=10.4 Hz, 1H), 3.13 - 2.92 (m, 2H), 2.28 - 2.06 (m, 3H), 1.87 - 1.29 (m, 16H).

[000795] ¹ H NMR (400MHz, DMSO-d ₆ ) (T=273+80K) δ = 11.49 (br s, 1H), 8.69 (br s, 1H), 7.79 - 7.57 (m, 1H), 7.48 (s, 1H), 7.27 (br s, 1H), 7.06 (br d, J=8.4 Hz, 2H), 4.97 (br s, 1H), 4.57 (br s, 1H), 3.88 (d, J=10.4 Hz, 1H), 3.68 (br s, 1H), 3.10 - 3.04 (m, 2H), 2.20 (br s, 3H), 1.91 - 1.31 (m, 16H).

Example 83a. Synthesis of viral protease inhibitor compound 743

Step 7: tert-butyl 2,2-difluoro-7-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopiperidin-3 -yl)propan-2- yl) carbamoyl) -6-azaspiro [3.4 ]octam-6-carboxylate

[000796] A mixture of (7 S)-6-tert-butoxy carbonyl-2, 2-difluoro-6-azaspiro[3 ,4]octane-7- carboxylic acid (500 mg, 1.72 mmol, 1 eq ), methyl (2S)-2-amino-3-[(3S)-2-oxo-3- piperidyl]propanoate (406.29 mg, 1.72 mmol, 1 eq, HC1), EDCI (987.17 mg, 5.15 mmol, 3 eq), DMAP (629.10 mg, 5.15 mmol, 3 eq) in DCM (5 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 20 °C for 2 h under N ₂ atmosphere. Upon completion, the reaction mixture was poured into H ₂ O (50 mL) at 20 °C, and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 1/1) to give tert-butyl (7S)-2,2-difluoro-7- [[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]eth yl]carbamoyl]-6- azaspiro[3.4]octane-6-carboxylate (800 mg, crude) was obtained as a white solid. MS (ESI) m/z 474.1 [M+H] ⁺

Step 2: (2S)-methyl 2-(2,2-difluoro-6-azaspiro[3.4]octane-7-carboxamido)-3-((S)- 2- oxopiperidin-3-yl)propanoate [000797] A solution of tert-butyl (7S)-2,2-difluoro-7-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2- oxo-3-piperidyl]methyl]ethyl]carbamoyl]-6-azaspiro[34]octane -6-carboxylate (800 mg,

1.69 mmol, 1 eq) in HCl/MeOH (4 M, 8 mL, 18.94 eq) was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give methyl (2S)-2-[[(7S)-2,2-difluoro-6-azaspiro[3.4]octane-7- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (690 mg, crude, HC1) as a yellow oil. MS (ESI) m/z 374.1 [M+H] ⁺ .

Step 3: (2S)-methyl 2-(6-(7-chloro-lH-indole-2-carbonyl)-2,2-difluoro-6- azaspiro[3.4Joctane-7-carboxamido)-3-((S)-2-oxopiperidin-3-y l)propanoate [000798] To a solution of methyl (2S)-2-[[(7S)-2,2-difluoro-6-azaspiro[3.4]octane-7- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (690 mg, 1.68 mmol, 1 eq, HC1), 7-chloro-lH-indole-2-carboxylic acid (329.30 mg, 1.68 mmol, 1 eq), DMAP (617.03 mg, 5.05 mmol, 3 eq) in DCM (10 mL), was added EDCI (968.19 mg, 5.05 mmol, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O (35 mL) at 20 °C, and then extracted with (35 mL * 3). The combined organic layers were washed with brine (35 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 80/1 to 1/1) to give methyl (2S)-2- [[(7S)-6-(7-chloro-lH-indole-2-carbonyl)-2,2-difluoro-6-azas piro[3.4]octane-7- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (640 mg, 1.16 mmol, 69.00% yield) as a yellow solid. MS (ESI) m/z 551.2 [M+H] ⁺ .

Step 4: N-( (S)-l -amino-1 -oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)-6-(7-chloro-lH- indole-2-carbonyl)-2, 2-difluoro-6-azaspiro[3.4 ] octane-7 -carboxamide [000799] To a solution of methyl (2S)-2-[[(7S)-6-(7-chloro-lH-indole-2-carbonyl)-2,2- difluoro-6-azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-o xo-3-piperidyl]propanoate (625 mg, 1.13 mmol, 1 eq) in NH ₃ /MeOH (7 M, 12 mL, 74.05 eq). The mixture was stirred at 30 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give (7S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo- 3-piperidyl]methyl]ethyl]-6-(7-chloro-lH-indole-2-carbonyl)- 2,2-difluoro-6- azaspiro[3.4]octane-7-carboxamide (605 mg, crude) as a yellow solid. MS (ESI) m/z 536.2 [M+H] ⁺ . Step 5: 6-(7-chloro-lH-indole-2-carbonyl)-N-( (S)-l-cyano-2-( (S)-2-oxopiperidin-3-yl) ethyl) - 2, 2-difluoro-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000800] To a solution of (7 S)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]-6-(7-chloro-lH-indole-2-carbonyl)-2, 2-difluoro-6- azaspiro[34]octane-7-carboxamide (585 mg, 1.09 mmol, 1 eq) in DCM (10 mL) was added Burgess reagent (1.17 g, 4.91 mmol, 4.5 eq). The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was poured into H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 um);mobile phase: [water(10mM NH4HCC>3)-ACN];B%: 30%- 60%,10min) to give (7S)-6-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-[(3 S)-2- oxo-3-piperidyl]ethyl]-2,2-difluoro-6-azaspiro[3 4]octane-7-carboxamide (135 mg,

260.64 umol, 23.88% yield) as a white solid. MS (ESI) m/z 518.2 [M+H] ⁺ .

Step 6: 6-(7-chloro-JH-indole-2-carbonyl)-N-( ( S)-l-cyano-2-( (S)-2-oxopiperidin-3-yl) ethyl) - 2, 2-difluoro-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000801] Isomer 1 : 6-(7-chloro-lH-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2- oxopiperidin-3-yl)ethyl)-2,2-difluoro-6-azaspiro[3.4]octane- 7-carboxamide (133 mg) was separated by SFC (column: REGIS(S,S)WHELK-01(250mm*25mm,10um);mobile phase: [0.1%NH ₃ H ₂ 0 ETOH];B%: 60%-60%,15min) to give (7S)-6-(7-chloro-lH-indole- 2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]-2,2-difluoro-6- azaspiro[3.4]octane-7-carboxamide (48.2 mg, 93.06 umol, 36.24% yield) as a white solid. MS (ESI) m/z 518.2 [M+H] ⁺ .

[000802] Isomer 1 : ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.34 - 11.12 (m, 1H), 8.83 - 8.63 (m, 1H), 7.71 - 7.55 (m, 1H), 7.30 (d, J= 7.1Hz, 2H), 7.13 - 7.04 (m, 1H), 5.09 - 4.92 (m, 1H), 4.71 - 4.52 (m, 1H), 4.20 - 3.87 (m, 2H), 3.09 - 3.05 (m, 1H), 3.10 - 3.03 (m, 2H), 2.91 - 2.52 (m, 4H), 2.48 - 2.35 (m, 2H), 2.29 - 2.08 (m, 2H), 1.96 - 1.31 (m, 5H).

Isomer 2: To give (7S)-6-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2- [(3 S)-2-oxo-3-piperidyl]ethyl]-2,2-difluoro-6-azaspiro[34]octan e-7-carboxamide (83.2 mg, 160.63 umol, 62.56% yield) as a white solid. MS (ESI) m/z 518.2 [M+H] ⁺ . [000804] Isomer 2: ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.32 - 11.13 (m, 1H), 8.90 - 8.67 (m, 1H), 7.69 - 7.48 (m, 1H), 7.33 - 7.26 (m, 1H), 7.19 - 6.89 (m, 2H), 5.07 - 4.88 (m,

1H), 4.74 - 4.51 (m, 1H), 4.15 - 3.84 (m, 2H), 3.11 - 3.06 (m, 2H), 3.10 - 3.06 (m, 1H), 2.82 - 2.55 (m, 4H), 2.43 (d ,J= 3.2, 5.2Hz, 2H), 2.32 - 2.07 (m, 2H), 2.02 - 1.01 (m, 5H).

Example 84. Synthesis of viral protease inhibitor compound 745

Step 1: methyl(2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3S)-2-oxo-3- piperidyl ]propanoate [000805] 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] ⁺ .

Step 2: methyl (2S)-2-[[(2S)-2-[(6-chloro-lH-indole-2-carbonyl)aminoJ-4,4-d imethyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000806] To a mixture of 6-chloro- 1 H-indole-2-carboxylic acid (400 mg, 2.04 mmol, 1 eq) in DCM (10 mL) and DMF (5 mL) was added DMAP (749.49 mg, 6.13 mmol, 3 eq) in one portion at 25 °C. The mixture was added with methyl (2S)-2-[[(2S)-2-amino-4,4- dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoa te (892.94 mg, 2.45 mmol, 1.20 eq, HC1) and EDCI (784.05 mg, 4.09 mmol, 2 eq) in one portion at 25 °C and the reaction was stirred for 2.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO ₂ , DCM:MeOH = 10:1). Compound methyl (2S)-2-[[(2S)-2-[(6-chloro-lH- indole-2-carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3 S)-2-oxo-3- piperidyl]propanoate (800 mg, 1.58 mmol, 77.47% yield) was obtained as a yellow solid. MS (ESI) m/z 505.2 [M+H] ⁺ .

Step 3: N-[(lS)-l-[[(lS)-2-amino-2-oxo-l-[[(3S)-2-oxo-3- piperidyl ] methyl ] ethyl ] carbamoyl ]-3, 3-dimethyl-butyl ]-6-chloro-lH-indole-2-carboxamide [000807] To a mixture of methyl (2S)-2-[[(2S)-2-[(6-chloro-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo- 3-piperidyl]propanoate (605 mg, 1.20 mmol, 1 eq) in NH ₃ /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-[( 1 S)- 1 -[[(1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]- 3,3-dimethyl-butyl]-6-chloro-lH-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] ⁺ .

Step 4: 6-chloro-N-[ (1S)-1-[[(1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ] ethyl] carbamoyl ]-3, 3- dimethyl-butyl]-lH-indole-2-carboxamide

[000808] A mixture of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-6-chlo ro-lH-indole-2- carboxamide (500 mg, 1.02 mmol, 1 eq) in DCM (6 mL) was added Burgess reagent (607.94 mg, 2.55 mmol, 2.5 eq), and the mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC {column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (10mMNH ₄ HCO3)-ACN]; B%: 40%-60%, 8min } . Compound 6-chloro-N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3 - piperidyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-lH-indole-2-c arboxamide (202 mg, 405.64 umol, 39.75% yield, 94.78% purity) was obtained as a white solid. MS (ESI) m/z 472.3 [M+H] ⁺ .

[000809] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.41 - 7.65 (m, 2 H), 7.01 - 7.22 (m, 2 H), 5.08 (br s, 1 H), 4.65 (br s, 1 H), 3.15 - 3.25 (m, 2 H), 2.43 (br s, 1 H), 1.46 - 2.05 (m, 8 H), 1.02 (br s, 9 H) Example 85. Synthesis of viral protease inhibitor compound 791

Step 7: tert-butyl 7-[[(JS)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl ] methyl ] ethyl ] carbamoyl ]-6-azaspiro[ 3.4 ]octane-6-carboxylate

[000810] To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (2.32 g, 9.79 mmol, 1 eq, HC1) in DCM (30 mL) and DMF (10 mL) was added DMAP (3.59 g, 29.38 mmol, 3 eq) in one portion at 25 °C. The mixture was added 6-tert- butoxycarbonyl-6-azaspiro[3.4]octane-7-carboxylic acid (3 g, 11.75 mmol, 1.2 eq) and EDCI (3.75 g, 19.58 mmol, 2 eq) stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (40 mL) and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (80 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/l to 0/1) to give tert-butyl 7-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-6-azaspiro[3.4]octane-6-ca rboxylate (5 g, crude) as a yellow oil. MS (ESI) m/z 438.2 [M+H] ⁺ .

Step 2: methyl (2S)-2-(6-azaspiro[3.4]octane-7-carbonylamino)-3-[(3S)-2-oxo -3- piperidyl ]propanoate [000811] 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-ca rboxylate (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-piperid yl]propanoate (1.3 g, crude) as a yellow solid.

Step 3: methyl (2S)-2-[[6-(6-chloro-JH-indole-2-carbonyl)-6-azaspiro[3.4Joc tane-7- carbonyl ] amino ]-3-[( 3S)-2-oxo-3-piperidyl ]propanoate

[000812] To a mixture of methyl (2S)-2-(6-azaspiro[3 4]octane-7-carbonylamino)-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (1.3 g, 3.85 mmol, 1 eq) and 6-chloro- 1 H-indole-2- carboxylic acid (904.35 mg, 4.62 mmol, 1.2 eq) in DCM (9 mL) and DMF (3 mL) was added DMAP (1.41 g, 11.56 mmol, 3 eq) and EDCI (1.48 g, 7.71 mmol, 2 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (25 mL * 3). The combined organic layers were washed with brine (20 mL * 1), dried over with Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/l to 0/1) to give methyl (2S)-2-[[6-(6-chloro-lH-indole-2-carbonyl)-6-azaspiro[3.4]oc tane-7- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.2 g, 2.21 mmol, 57.45% yield, 95% purity) as a yellow oil. MS (ESI) m/z 515.3 [M+H] ⁺

Step 4: N-f ( l S) -2-amino-2-oxo- 1 -[ [ ( 3S)-2-oxo-3-piperidyl ] methyl ] ethyl ]-6-( 6-chloro- 1H- indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000813] A mixture of methyl (2S)-2-[[6-(6-chloro-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (1.2 g, 2.33 mmol, 1 eq) in NH ₃ /MeOH (7 M, 15 mL, 45.06 eq) was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N- [(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl] -6-(6-chloro-lH-indole-2- carbonyl)-6-azaspiro[3.4]octane-7-carboxamide (980 mg, 1.96 mmol, 84.12% yield) as a yellow solid. MS (ESI) m/z 500.2 [M+H] ⁺ .

Step 5: 6-( 6-chloro- lH-indole-2-carbonyl)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxo-3- piperidyl ] ethyl ]-6-azaspiro[ 3.4 ] octane- 7 -carboxamide [000814] To a mixture of N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]-6-(6-chloro-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7- carboxamide (980 mg, 1.96 mmol, 1 eq) in DCM (10 mL) was added Burgess reagent (1.87 g, 7.84 mmol, 4 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition; column: Kromasil C18 (250*50mm*10 um);mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 30%-50%,10min) to afford 6-(6-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)- 2-oxo-3-piperidyl]ethyl]-6-azaspiro[3.4]octane-7-carboxamide (600 mg, 1.24 mmol, 63.51% yield) as a white solid. MS (ESI) m/z 482.2 [M+H] ⁺

Step 6: 6-( 6-chloro-lH-indole-2-carbonyl)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxo-3- piperidyl ] ethyl ]-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000815] The white solid was separated by SFC (column: REGIS(S,S)WHELK-

01 (250mm*25mm, 10um);mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 60%-60%,min) to give 6-(6-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]-6-azaspiro[3.4]octane-7-carboxamide (140 mg, 290.47 umol, 23.33% yield) and 6-(6-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]-6-azaspiro[3.4]octane-7-carboxamide (110 mg, 228.23 umol, 18.33% yield) as a white solid. MS (ESI) m/z 482.2 [M+H] ⁺ .

[000816] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.41 (br s, 1H), 8.60 (br s, 1H), 7.65 (br d, J=8.3 Hz, 1H), 7.49 (s, 1H), 7.24 - 6.88 (m, 3H), 5.10 - 4.82 (m, 1H), 4.56 (br s, 1H), 4.02 - 3.86 (m, 2H), 3.09 (br s, 2H), 2.36 - 2.26 (m, 1H), 2.25 - 2.07 (m, 3H), 2.07 - 1.77 (m, 8H), 1.73 - 1.32 (m, 3H).

[000817] ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.70 - 7.53 (m, 1H), 7.46 (s, 1H), 7.15 - 6.63 (m, 2H), 5.02 (dd,J=6.0, 10.6 Hz, 1H), 4.65 - 4.52 (m, 1H), 4.17 - 3.74 (m, 2H), 3.25 - 2.90 (m, 2H), 2.56 - 2.13 (m, 4H), 2.11 - 1.74 (m, 8H), 1.72 - 0.99 (m, 3H).

[000818] ¹ H NMR (400MHz, DMSO -d ₆ ) δ = 11.42 (br s, 1H), 8.66 (br s, 1H), 7.64 (br s, 1H), 7.49 (br s, 1H), 7.32 - 6.79 (m, 3H), 4.97 (br s, 1H), 4.57 (br s, 1H), 3.93 (br s, 2H), 3.11 (br s, 2H), 2.38 - 2.11 (m, 4H), 2.05 - 1.77 (m, 8H), 1.73 - 1.34 (m, 3H). [000819] 1 H NMR (400MHz, METHANOL-d ₄ ) δ = 7.64 (d, J=8.6 Hz, 1H), 7.55 - 7.42 (m, 1H), 7.13 - 6.99 (m, 2H), 5.09 (dd,J=6.3, 10.7 Hz, 1H), 4.55 (t, >=7.5 Hz, 1H), 4.12 - 3.95 (m, 2H), 3.27 - 3.17 (m, 2H), 2.63 - 2.36 (m, 3H), 2.13 - 1.90 (m, 9H), 1.80 (br s, 2H), 1.51 (br d, J=9.3 Hz, 1H).

Example 86. Synthesis of viral protease inhibitor compound 793

Step 1: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pent anoyl]amino]-3- [ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000820] To a solution of (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (4.97 g, 20.28 mmol, 1.2 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3- piperidyl]propanoate (4 g, 16.90 mmol, 1 eq, HC1) in DCM (60 mL) was added DMAP (6.19 g, 50.70 mmol, 3 eq), and then EDCI (6.48 g, 33.80 mmol, 2 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the mixture was quenched by H ₂ O (50 mL), extracted with DCM (40 mL * 3), then was washed with 1M HC1 (40 mL) and was extracted with DCM (80 mL * 3), and then was dried by NaCl (100 mL), then was concemtration in vacuum. The crude product was purified by column (Plate 1, SiO ₂ , petroleum ether: ethyl acetate = 2:1 to 0:1, Iz, Rf = 0.22), then was concentrated in vacuum to afford methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (5.75 g, 11.43 mmol, 67.65% yield, 85% purity) as a white solid. MS (ESI) m/z 428.3 [M+H] ⁺

Step 2: methyl (2S)-2-[[(2S)-2-amino-4, 4-dimethyl-pentanoyl ]amino]-3-[ ( 3S)-2-oxo-3- piperidyl ]propanoate

[000821 ] 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 (10 mL) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give methyl (2S)-2-[[(2S)- 2-amino-4, 4-dimethyl -pentanoyl]amino]-3-[(3 S)-2-oxo-3-piperidyl]propanoate (425 mg, crude, HC1) as a white solid. MS (ESI) m/z 328.2 [M+H] ⁺

Step 3 : methyl (2S)-2-[[(2S)-2-[(4-chloro-JH-indole-2-carbonyl)amino]-4,4-d imethyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000822] To a solution of methyl (2 S)-2-[ [(2 S)-2-amino-4,4-dimethy 1-pentanoy 1 ]ami no]- 3 -[(3 S)-2-oxo-3 -piperidyl Jpropanoate (409.27 mg, 1.12 mmol, 1 eq, HC1) and 4-chloro- 1 H-indole-2-carboxylic acid (220 mg, 1.12 mmol, 1 eq) in DCM (15 mL) was added EDCI (646.84 mg, 3.37 mmol, 3 eq), and then was added DMAP (412.22 mg, 3.37 mmol, 3 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was poured into H ₂ O (50 mL) at 20 °C, and extracted with DCM (20 mL * 3). The combined organic layers were washed with 1M HC1 (20 mL * 2), and then was dried by NaCl (10 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give methyl (2S)-2-[[(2S)-2-[(4-chloro-lH-indole-2-carbonyl)amino]-4,4-d imethyl- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (321 mg, 572.07 umol, 50.86% yield, 90% purity) as a white solid. MS (ESI) m/z 505.2 [M+H] ⁺ .

Step 4: N-[(lS)-l-[[(lS)-2-amino-2-oxo-l-[[(3S)-2-oxo-3- piperidyl ] methyl ] ethyl ] carbamoyl ]-3, 3-dimethyl-butyl ]-4-chloro-lH-indole-2-carboxamide [000823] A solution of methyl (2S)-2-[[(2S)-2-[(4-chloro-lH-indole-2-carbonyl)amino]- 4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]prop anoate (306 mg, 605.93 umol, 1 eq) in NH ₃ /MeOH (7 M, 3 mL, 34.66 eq) was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N- [(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]meth yl]ethyl]carbamoyl]-3,3- dimethyl-butyl]-4-chloro-lH-indole-2-carboxamide (250 mg, crude) as a yellow solid. MS (ESI) m/z 490.2 [M+H] ⁺ .

Step 5: 4-chloro-N-[ (1S)-1-[[(1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ] ethyl] carbamoyl ]-3, 3- dimethyl-butyl]-lH-indole-2-carboxamide

[000824] To a solution of N-[(l S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-chlo ro-lH-indole-2- carboxamide (230 mg, 469.39 umol, 1 eq) in DCM (3 mL) was added Burgessreagent (335.58 mg, 1.41 mmol, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 4- chloro-N-[(l S)- 1 -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3 -piperidy 1 ]ethy 1 ]carbamoy 1 ]-3 , 3 - dimethyl-butyl]- 1 H-indole-2-carboxamide (114 mg, 241.54 umol, 51.46% yield, 100% purity) as a white solid. MS (ESI) m/z 472.2 [M+H] ⁺ .

[000825] 1H NMR (400MHz, MeOD-d ₄ ) δ = 7.39 (d, J = 8.4Hz, 1H), 7.28 (s, 1H), 7.18 (t,J= 7.8Hz, 1H), 7.12 - 7.04 (m, 1H), 7.09 (d, J= 7.4Hz, 1H), 5.16 - 5.02 (m, 1H), 4.65 (d, J= 4.4, 8.4Hz, 1H), 3.24 - 3.16 (m, 2H), 2.49 - 2.38 (m, 2H), 2.00 - 1.73 (m, 5H), 1.66 (d ,J= 8.4Hz, 1H), 1.55 - 1.45 (m, 1H), 1.03 (s, 8H)

Example 87. Synthesis of viral protease inhibitor compound 795

Step J: (S)-methyl2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethyl pentanamido)-3-((S)-2- oxopiperidin-3-yl)propanoate

[000826] To a solution of (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (4.97 g, 20.28 mmol, 1.2 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3- piperidyl]propanoate (4 g, 16.90 mmol, 1 eq, HC1) in DCM (120 mL) was added DMAP (6.19 g, 50.70 mmol, 3 eq), and then was added EDCI (6.48 g, 33.80 mmol, 2 eq). The resulting mixture was stirred at 20 °C for 1 h. Upon completion, The mixture was quenched by H ₂ O (500 mL) and was extracted with DCM (200 mL * 3), then was washed with 1M HC1 (200 mL) and was extracted with DCM (80 mL * 3), and then was dried by NaCl (100 mL), then was concentrated in vacuum. The crude product was purified by column (Plate 1, SiO ₂ , petroleum ether: ethyl acetate = 2:1 to 0:1, Iz, Rf= 0.22), then was concentrated in vacuum to give (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (5.75 g, 11.43 mmol, 67.65% yield, 85% purity) as a white solid. MS (ESI) m/z 428.3 [M+H] ⁺ . Step 2: (S)-methyl2-((S)-2-amino-4, 4-dimethylpentanamido)-3-((S)-2-oxopiperidin-3- yl)propanoate

[000827] A solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (700 mg, 1.64 mmol, 1 eq) in HCl/MeOH (10 mL) was stirred at 25 °C for 1 h. Upon completion, the reaction was concentrated in the vacuum to give (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)- 3-((S)-2-oxopiperidin-3-yl)propanoate (630 mg, crude, HC1) as yellow solid. MS (ESI) m/z 328.2 [M+H] ⁺ .

Step 3: (S)-methyl 2-((S)-2-(4,6-dichloro-lH-indole-2-carboxamido)-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000828] To a solution of (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((S)-2- oxopiperidin-3-yl)propanoate (630 mg, 1.73 mmol, 1 eq, HC1) in DCM (20 mL) was added 4,6-dichloro-lH-indole-2-carboxylic acid (438.12 mg, 1.90 mmol, 1.1 eq), DMAP (634.54 mg, 5.19 mmol, 3 eq), and EDCI (431.47 mg, 2.25 mmol, 1.3 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction was quenched by addition H ₂ O (100 mL) and then extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over NazSC^, filtered and concentrated under reduced pressure and purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 7/3 to 0/1) to give product (S)-methyl 2-((S)-2-(4,6-dichloro- 1 H- indole-2-carboxamido)-4,4-dimethylpentanamido)-3-((S)-2-oxop iperidin-3-yl)propanoate (400 mg, 595.42 umol, 34.39% yield, 80.3% purity) as yellow solid. MS (ESI) m/z 539.2 [M+H] ⁺ .

Step 4: N-( (S)-l-( ( (S)-l -amino-1 -oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-4, 4- dimethyl-1-oxopentan-2-yl)-4,6-dichloro-JH-indole-2-carboxam ide

[000829] A solution of (S)-methyl 2-((S)-2-(4,6-dichloro- 1 H-indole-2-carboxamido)-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (370 mg, 685.88 umol, 1 eq) in NH ₃ (7 M, 20 mL, 204.12 eq) was stirred at 30 °C for 8 h. Upon completion, the reaction was concentrated in the vacuum to afford product N-((S)- 1 -(((S)- 1 -amino- 1 -oxo- 3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-4,4-dimethyl-1 -oxopentan-2-yl)-4,6- dichloro- 1 H-indole-2-carboxamide (340 mg, crude) was yellow solid. MS (ESI) m/z 524.2 [M+H] ⁺ . Step5: 4, 6-dichloro-N-( (S)-l-( ( (S)-l-cyano-2-( (S)-2-oxopiperidin-3-yl)ethyl)ammo)-4, 4- dimethyl-l-oxopentan-2-yl)-lH-indole-2-carboxamide

[000830] To a solution of N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-4,6-dichloro- 1 H-indole-2- carboxamide (320 mg, 610.18 umol, 1 eq) in DCM (15 mL) was added Burgess reagent (1.02 g, 4.27 mmol, 7 eq), and the mixture was stirred at 40 °C for 3 h. Upon completion, the reaction was concentrated in the vacuum and purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(0.05%NH3H ₂ O+ 1 OmM NH ₄ HC03)-ACN];B%:40%-60%,8min) to afford 4,6-dichloro-N-((S)- 1 -(((S)- 1 -cyano-2- ((S)-2-oxopiperidin-3-yl)ethyl)amino)-4,4-dimethyl-1-oxopent an-2-yl)-lH-indole-2- carboxamide (110 mg, 217.21 umol, 35.60% yield, 100% purity) as a white solid. MS (ESI) m/z 506.2 [M+H] ⁺

[000831] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.00 (br s, 1H), 8.94 - 8.92 (m, 1H), 8.81 - 8.80 (m, 1H), 7.52 (br s, 1H), 7.42 (s, 2H), 7.24 (s, 1H), 5.11 - 4.98 (m, 1H), 4.54 - 4.49 (m, 1H), 3.12 - 3.01 (m, 2H), 2.34 - 2.19 (m, 2H), 1.85 - 1.63 (m, 5H), 1.58 - 1.45 (m, 1H), 1.43 - 1.32 (m, 1H), 0.94 (s, 9H)

Example 88. Synthesis of viral protease inhibitor compound 797

Step 1: (2S)-2-[[(2S)-2-amino-4, 4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3- piperidyl Ipropanoate

[000832] A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (800 mg, 1.87 mmol, 1 eq) and HCl/MeOH (4 M, 25 mL, 53.44 eq) 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-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)- 2-oxo-3- piperidyl]propanoate (650 mg, crude, HC1) as a white solid. MS (ESI) m/z 328.2 [M+H] ⁺ .

Step 2: methyl (2S)-2-[[(2S)-2-[(4,7-dichloro-lH-indole-2-carbonyl)amino]-4 ,4-dimethyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000833] A mixture of methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3S)-2-oxo-3-piperidyl]propanoate (650 mg, 1.79 mmol, 1.2 eq, HC1), 4,7-dichloro-1H- indole-2-carboxylic acid (342.45 mg, 1.49 mmol, 1 eq), EDCI (856.10 mg, 4.47 mmol, 3 eq) and DMAP (545.57 mg, 4.47 mmol, 3 eq) in DCM (10 mL) was stirred at 20 °C for 1 h. Upon completion, the mixture was added H ₂ O (50 mL) and then extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10:1) to afford methyl (2S)-2-[[(2S)-2-[(4,7-dichloro-1H-indole-2-carbonyl)amino]-4 ,4- dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoa te (650 mg, 1.17 mmol, 78.79% yield, 97.34% purity) as a white solid. MS (ESI) m/z 539.2 [M+H] ⁺ .

Step 3: N-[(lS)-l-[[(lS)-2-amino-2-oxo-l-[[(3S)-2-oxo-3- piperidyl ] methyl ]ethyl ] carbamoyl ]-3, 3-dimethyl-butyl ]-4, 7-dichloro-lH-indole-2- carboxamide

[000834] A mixture of methyl (2S)-2-[[(2S)-2-[(4,7-dichloro-1H-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo- 3-piperidyl]propanoate (620 mg, 1.15 mmol, 1 eq) and NH ₃ /MeOH (7 M, 20 mL, 121.81 eq) was stirred at 65 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure to give the product N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4,7-di chloro-1H-indole-2- carboxamide (550 mg, crude) as a white solid. MS (ESI) m/z 524.2 [M+H] ⁺ .

Step 4: 4, 7-dichloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl ]aminoJ-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide [000835] A mixture of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4,7-di chloro-1H-indole-2- carboxamide (530 mg, 1.01 mmol, 1 eq) and Burgess reagent (722.50 mg, 3.03 mmol, 3 eq) in DCM (10 mL) was stirred at 20 °C for 3.5 h. Upon completion, the mixture was concentrated under reduced pressure to give the residue. Then the residue was purified by prep-HPLC (column: Kromasil C18 (250 * 50 mm * 10 um); mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 45% - 75%, 10 min) to afford 4,7-dichloro-N-[(1S)-1- [[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]carbamoyl]-3, 3-dimethyl-butyl]-1H- indole-2-carboxamide (170 mg, 334.61 umol, 33.11% yield, 99.68% purity) as a white solid. MS (ESI) m/z 506.2 [M+H] ⁺ .

[000836] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.62 - 7.56 (m, IH), 7.52 - 7.46 (m, IH), 7.21 - 7.14 (m, IH), 5.14 - 5.07 (m, IH), 4.70 - 4.64 (m, IH), 3.25 - 3.17 (m, 2H), 2.51 - 2.38 (m, 2H), 2.02 - 1.85 (m, 3H), 1.85 - 1.61 (m, 3H), 1.58 - 1.44 (m, IH), 1.08 - 1.02 (m, 9H)

Example 89. Synthesis of viral protease inhibitor compound 799 Step 1: 7-chloro-4-methoxy-lH-indole-2-carboxylic acid

[000837] A mixture of methyl 7-chloro-4-methoxy- 1 H-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 HC1 (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 Na ₂ SO ₄ , filtered, concentrated under reduced pressure to give 7-chloro-4-methoxy- 1 H-indole-2-carboxylic acid (400 mg, crude) as a yellow solid.

Step 2: (S)-2-amino-N-((S)-l -amino-1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-4, 4- dimethylpentanamide [000838] A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (800 mg, 1.87 mmol, 1 eq) in HCl/MeOH (4 M, 8 mL, 17.10 eq) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give (S)-2-amino-N-((S)-l -amino- 1- oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-4,4-dimethylpent anamide (810 mg, crude, HC1) as a white solid.

Step 3: (S)-methyl 2-((S)-2-(7-chloro-4-methoxy-lH-indole-2-carboxamido)-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000839] To a solution of 7-chloro-4-methoxy- 1 H-indole-2-carboxylic acid (440 mg, 1.95 mmol, 1 eq) in DCM (8 mL) and DMF (4 mL) was added (S)-2-amino-N-((S)-l -amino- 1- oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-4,4-dimethylpent anamide (851.53 mg, 2.34 mmol, 1.2 eq, HC1), DMAP (714.74 mg, 5.85 mmol, 3 eq), and then was added EDCI (747.67 mg, 3.90 mmol, 2 eq) at 0 °C. The mixture was then stirred at 25 °C for 2 h.

Upon completion, the mixture was quenched with water (20 mL) and extracted with DCM (10 mL* 3). The organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 100: 1 to 10: 1) to give (S)- methyl 2-((S)-2-(7-chloro-4-methoxy- 1 H-indole-2-carboxamido)-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (1.3 g, 1.82 mmol, 93.45% yield, 75% purity) as yellow solid. MS (ESI) m/z 535.1 [M+H] ⁺ .

Step 4: N-((S)-1-(((S)-1 -amino-1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-4, 4- dimethyl-l-oxopentan-2-yl)-7-chloro-4-methoxy-lH-indole-2-ca rboxamide [000840] A solution of (S)-methyl 2-((S)-2-(7-chloro-4-methoxy- 1 H-indole-2- carboxamido)-4,4-dimethylpentanamido)-3-((S)-2-oxopiperidin- 3-yl)propanoate (1.3 g, 1.82 mmol, 75% purity, 1 eq) in NH ₃ /MeOH (7 M, 15 mL, 57.62 eq) was stirred at 65°C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure togiveN-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-y l)propan-2-yl)amino)-4,4- dimethyl-1-oxopentan-2-yl)-7-chloro-4-methoxy-lH-indole-2-ca rboxamide (1.25 g, crude) as a yellow solid. MS (ESI) m/z 520.3 [M+H] ⁺ .

Step 5: 7-chloro-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)e thyl)amino)-4, 4- dimethyl-l-oxopentan-2-yl)-4-methoxy-lH-indole-2-carboxamide

[000841 ] To a mixture of N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-7-chloro-4-methoxy- 1 H-indole-2- carboxamide (1.21 g, 1.75 mmol, 75% purity, 1 eq) in EtOAc (6 mL) was added T3P (6.42 g, 10.09 mmol, 6 mL, 50% purity, 5.78 eq), and then the reaction was stirred at 40 °C for 14 h. Upon completion, the mixture was quenched with water (20 mL) and extracted with EtOAc (10 mL* 3). The organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

The residue was purified by prep-HPLC (column: Kromasil C18 (250* 50mm* 10 um);mobile phase: [water (10 mM NH4HCO3)- ACN]; B%: 30% - 60%, 10 min) to give 7-chloro-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)e thyl)amino)-4,4-dimethyl-1- oxopentan-2-yl)-4-methoxy-lH-indole-2-carboxamide (496.09 mg, 988.22 umol, 56.63% yield, 100% purity) as a white solid. MS (ESI) m/z 502.2 [M+H] ⁺ .

[000842] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.64 (br s, 1H), 9.12 - 8.90 (m, 1H), 8.72 - 8.54 (m, 1H), 7.52 (br s, 1H), 7.28 (s, 1H), 7.20 (d, J= 8.3 Hz, 1H), 6.56 (d, J= 8.3 Hz, 1H), 5.05 (q, J= 8.0 Hz, 1H), 4.62 - 4.50 (m, 1H), 3.89 (s, 3H), 3.07 (br s, 2H), 2.31 - 2.15 (m, 2H), 1.88 - 1.63 (m, 5H), 1.60 - 1.33 (m, 2H), 1.06 - 0.85 (m, 9H).

Example 90. Synthesis of viral protease inhibitor compound 801

Step 1: 4-chloro-JH-indole-2-carbonyl chloride

[000843] A solution of 4-chloro- 1 H-indole-2-carboxylic acid (600 mg, 3.07 mmol, 1 eq) in DCM (9 mL) was added DMF (6.73 mg, 92.02 umol, 7.08 uL, 0.03 eq) and (COCl)z (778.70 mg, 6.13 mmol, 537.04 uL, 2 eq) was stirred at 40 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 4-chloro- 1 H-indole- 2-carbonyl chloride (655 mg, crude) was obtained as a yellow oil.

Step 2: 2-(4-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-ca rboxylic acid

[000844] A mixture of 4-chloro- 1 H-indole-2-carbonyl chloride (655 mg, 3.06 mmol, 1.1 eq) in THF (6 mL) DCM (6 mL) was poured into a mixture of 2-azaspiro[4.5]decane-3- carboxylic acid (611.20 mg, 2.78 mmol, 1 eq, HC1), Na2CO ₃ (884.85 mg, 2.78 mmol, 3 eq) in DCM (6 mL) and H ₂ O (6 mL). The mixture was stirred at 15 °C for 0.5 h under N ₂ atmosphere. Upon completion, the reaction mixture was quenched by addition HC1 (1M) (15 mL) and extracted with DCM (10 mL * 4). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (3 mL) at 20 °C for 15 min. to give 2-(4-chloro- 1 H-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carboxylic acid (710 mg, 1.97 mmol, 70.73% yield) was obtained as white solid. MS (ESI) m/z 361.2 [M+H] ⁺ .

Step 3: (2S)-methyl 2-(2-(4-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3 - carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000845] To a solution of methyl (2 S)-2-amino-3 -[(3 S)-2-oxo-3 -piperidy 1 ]propanoate (512.31 mg, 2.16 mmol, 1.1 eq, HC1) 2-(4-chloro- 1 H-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carboxylic acid (710 mg, 1.97 mmol, 1 eq) in DMF (15 mL) was added DIPEA (762.90 mg, 5.90 mmol, 1.03 mL, 3 eq) and HATU (748.17 mg, 1.97 mmol, 1 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (40 mL), and then extracted with ethyl acetate (20 mL * 4). The combined organic layers were washed with brine (20 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give methyl (2S)-2-[[2-(4- chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbony l]amino]-3-[(3S)-2-oxo-3- piperidyl]propanoate (850 mg, 1.57 mmol, 79.55% yield) as a yellow oil.

Step 4: N-((S)-l-amino-l-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl) -2-(4-chloro-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide

[000846] A solution of methyl (2S)-2-[[2-(4-chloro-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (850 mg,

1.57 mmol, 1 eq) in MeOH/NH3 (7 M, 11.05 mL, 49.42 eq) was stirred at 65 °C for 17 h. Upon completion, The reaction mixture was concentrated under reduced pressure to give N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]-2-(4-chloro- lH-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (820 mg, crude) was obtained as colorless oil. MS (ESI) m/z 528.3 [M+H] ⁺ .

Step 5: 2-(4-chloro-lH-indole-2-carbonyl)-N-((S)-l-cyano-2-((S)-2-ox opiperidin-3-yl)ethyl)- 2-azaspiro[ 4.5 ]decane-3-carboxamide

[000847] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-2-(4-chloro-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3- carboxamide (820 mg, 1.55 mmol, 1 eq) in DCM (15 mL) was added Burgess reagent (999.20 mg, 4.19 mmol, 2.7 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (3 mL) and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Kromasil C18 (250*50mm* 10 um);mobile phase: [water(10mMNH ₄ HCO3)- ACN];B%: 45%-75%,10min) to give desired compound (450 mg) as a white solid, which was further separated by SFC (column: REGIS(S,S)WHELK-

01(250mm*25mm,10um);mobile phase: [0.1%NH3H ₂ O ETOH];B%: 60%-60%,min) to afford 2-(4-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide (168.83 mg, 331.02 umol, 21.32% yield, 100% purity) as white solid. MS (ESI) m/z 510.3 [M+H] ⁺ .

[000848] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.72 (br s, 1 H) 8.52 - 9.07 (m, 1 H) 6.72 - 7.49 (m, 5 H) 4.81 - 5.16 (m, 1 H) 4.43 - 4.78 (m, 1 H) 3.51 - 3.92 (m, 2 H) 2.10 - 2.39 (m, 3 H) 1.25 - 1.98 (m, 16 H).

[000849] To give 2-(4-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide (180.55 mg, 354.00 umol, 22.80% yield, 100% purity) was obtained as white solid. MS (ESI) m/z 510.3 [M+H] ⁺ .

[000850] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.56 - 11.85 (m, 1 H) 8.45 - 8.94 (m, 1 H) 7.43 (br d, J = 8.16 Hz, 1 H) 7.04 - 7.35 (m, 3 H) 6.75 - 7.03 (m, 1 H) 4.42 - 5.12 (m, 2 H) 3.58 - 3.91 (m, 2 H) 2.06 - 2.30 (m, 3 H) 1.21 - 1.94 (m, 16 H).

Example 91. Synthesis of viral protease inhibitor compound 803

Step 1: (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(6-azaspiro[3.4]octane-7- carboxamido)propanoate [000851] A solution of tert-butyl 7-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)carbamoyl)-6-azaspiro[3.4]octane-6-carboxylat e (1.2 g, 2.47 mmol, 90% purity, 1 eq) in HCl/MeOH (4 M, 12 mL, 19.45 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S)- methyl 3-((S)-2-oxopiperidin-3-yl)-2-(6-azaspiro[3.4]octane-7-carbo xamido)propanoate (1.3 g, crude, HC1) as a yellow solid. MS (ESI) m/z 338.2 [M+H] ⁺ . Step 2: (2S)-methyl 2-(6-(4-chloro-JH-indole-2-carbonyl)-6-azaspiro[3.4Joctane-7 - carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000852] To a solution of (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(6- azaspiro[3.4]octane-7-carboxamido)propanoate (1.25 g, 2.34 mmol, 70% purity, 1 eq, HC1) in DCM (8 mL) and DMF (4 mL) was added 4-chloro-lH-indole-2-carboxylic acid (457.78 mg, 2.34 mmol, 1 eq), DMAP (857.77 mg, 7.02 mmol, 3 eq), and then was added EDCI (897.29 mg, 4.68 mmol, 2 eq). The mixture was then stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (10 mL * 3). The organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane : methanol = 100:1 to 10:1) to give (2S)-methyl 2-(6-(4-chloro-lH-indole-2-carbonyl)-6-azaspiro[3.4]octane-7 - carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (1.51 g, 2.20 mmol, 93.96% yield, 75% purity) as a yellow solid. MS (ESI) m/z 515.2 [M+H] ⁺ .

Step 3: N-( (S)-l -amino-1 -oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)-6-( 4-chloro-lH- indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000853] A solution of (2S)-methyl 2-(6-(4-chloro- 1 H-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carboxamido)-3-((S)-2-oxopiperidin-3-y l)propanoate (1.51 g, 2.20 mmol, 75% purity, 1 eq) in NH ₃ /MeOH (7 M, 15 mL, 47.75 eq) was stirred at 65 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to giveN-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2 -yl)-6-(4-chloro-lH- indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide (1.5 g, crude) as a yellow solid. MS (ESI) m/z 500.3 [M+H] ⁺ .

Step 4: 6-(4-chloro-lH-indole-2-carbonyl)-N-((S)-l-cyano-2-((S)-2-ox opiperidin-3-yl) ethyl)- 6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000854] To a solution of N-((S)-1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)- 6-(4-chloro- 1 H-indole-2-carbonyl)-6-azaspiro[34]octane-7-carboxamide (1.5 g, 2.10 mmol, 70% purity, 1 eq) in EtOAc (8 mL) was added T3P (8.56 g, 13.45 mmol, 8 mL, 50% purity, 6.41 eq), and then the reaction was stirred at 40 °C for 14 h. Upon completion, the mixture was quenched with water (25 mL) and extracted with EtOAc (15 mL * 3). The organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Kromasil C18 (250* 50mm* 10 um); mobile phase:[water (10 mM NH4HCO ₃ )-ACN]; B%: 30%-50%, lOmin) to give 6-(4-chloro-lH-indole-2-carbonyl)-N- ((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-6-azaspiro[34]octan e-7-carboxamide (420 mg, 865.32 umol, 41.20% yield, 99.3% purity) as a white solid. MS (ESI) m/z 482.2 [M+H] ⁺ .

Step 5: 6-(4-chloro-lH-indole-2-carbonyl)-N-((S)-l-cyano-2-((S)-2-ox opiperidin-3-yl) ethyl)- 6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000855] 6-(4-chloro-lH-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-ox opiperidin-3- yl)ethyl)-6-azaspiro[3.4]octane-7-carboxamide (420 mg, 99.3% purity) was separation by SFC (column: REGIS(S,S)WHELK-Ol(250 mm* 25 mm, 10 um); mobile phase: [0.1% NH3H ₂ O EtOH]; B%: 60%-60%, min) to give 6-(4-chloro-lH-indole-2-carbonyl)-N-((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-6-azaspiro[3 4]octane-7-carboxamide Isomer 1 (8.72 mg, 18.09 umol, 2.09% yield, 100% purity) as a white solid. MS (ESI) m/z 482.2 [M+H] ⁺ .

[000856] ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.49 - 7.34 (m, 1H), 7.20 (br t, J=7.5 Hz, 1H), 7.15 - 6.67 (m, 2H), 5.15 - 5.00 (m, 1H), 4.65 - 4.54 (m, 1H), 4.15 - 3.78 (m, 2H), 3.25 - 2.99 (m, 2H), 2.58 - 1.25 (m, 15H).

[000857] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.96 (br s, 1H), 9.06 - 8.67 (m, 1H), 7.53 (br d, J=11.2 Hz, 1H), 7.43 (br d, 3=1.1 Hz, 1H), 7.27 - 7.05 (m, 2H), 7.04 - 6.54 (m, 1H), 5.06 - 4.86 (m, 1H), 4.57 - 4.36 (m, 1H), 4.18 - 3.66 (m, 2H), 3.08 (br s, 2H), 2.37 - 2.11 (m, 4H), 2.07 - 1.17 (m, 11H).

[000858] To give 6-(4-chloro- 1 H-indole-2-carbonyl)-N-((S)- 1 -cyano-2-((S)-2- oxopiperidin-3-yl)ethyl)-6-azaspiro[3.4]octane-7-carboxamide Isomer 2 (197.12 mg, 408.99 umol, 47.26% yield, 100% purity) as a white solid. MS (ESI) m/z 482.2 [M+H] ⁺ .

[000859] ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.46 - 7.34 (m, 1H), 7.25 - 7.18 (m, 1H), 7.17 - 6.65 (m, 2H), 5.08 - 4.97 (m, 1H), 4.58 (t, J= 7.5 Hz, 1H), 4.22 - 3.72 (m, 2H), 3.24 - 2.87 (m, 2H), 2.53 - 2.18 (m, 4H), 2.13 - 1.75 (m, 8H), 1.70 - 1.22 (m, 3H). [000860] 1 H NMR (400MHz, DMSO-d ₆ ) δ = 11.95 (s, 1H), 9.30 - 8.55 (m, 1H), 7.58 - 7.32 (m, 2H), 7.31 - 7.07 (m, 2H), 7.05 - 6.55 (m, 1H), 5.16 - 4.85 (m, 1H), 4.47 (t ,J = 7.2 Hz, 1H), 4.13 - 3.68 (m, 2H), 3.17 - 2.82 (m, 2H), 2.34 - 2.10 (m, 4H), 2.10 - 1.67 (m, 9H), 1.63 - 1.01 (m, 2H).

[000861 ] To give 6-(4-chloro- 1 H-indole-2-carbonyl)-N-((S)- 1 -cyano-2-((S)-2- oxopiperidin-3-yl)ethyl)-6-azaspiro[3.4]octane-7-carboxamide Isomer 3 (111.90 mg, 232.17 umol, 26.83% yield, 100% purity) as a white solid. MS (ESI) m/z 482.2 [M+H] ⁺ .

[000862] ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.43 - 7.34 (m, 1H), 7.22 - 7.16 (m, 1H), 7.13 - 6.73 (m, 2H), 5.10 (dd, J= 5.7, 10.3 Hz, 1H), 4.57 (t, J= 7.9 Hz, 1H), 4.16 - 3.97 (m, 2H), 3.27 - 3.19 (m, 2H), 2.63 - 2.33 (m, 3H), 2.30 - 2.19 (m, 1H), 2.11 - 1.92 (m, 8H), 1.85 - 1.68 (m, 2H), 1.55 - 1.47 (m, 1H).

[000863] 1 H NMR (400MHz, DMSO-d ₆ ) δ = 11.95 (br s, 1H), 9.43 - 8.64 (m, 1H), 7.63 - 7.33 (m, 2H), 7.27 - 7.05 (m, 2H), 7.04 - 6.56 (m, 1H), 5.10 - 4.86 (m, 1H), 4.46 (br t, J = 7.4 Hz, 1H), 4.08 - 3.60 (m, 2H), 3.18 - 2.88 (m, 2H), 2.36 - 2.09 (m, 4H), 2.04 - 1.17 (m,

11H).

[000864] To give 6-(4-chloro- 1 H-indole-2-carbonyl)-N-((S)- 1 -cyano-2-((S)-2- oxopiperidin-3-yl)ethyl)-6-azaspiro[3.4]octane-7-carboxamide Isomer 4 (2.11 mg, 4.24 umol, 0.49% yield, 96.8% purity) as a white solid. MS (ESI) m/z 482.2 [M+H] ⁺ .

[000865] ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.44 - 7.36 (m, 1H), 7.24 - 7.17 (m, 1H), 7.16 - 6.69 (mz, 2H), 5.21 - 5.01 (m, 1H), 4.68 - 4.51 (m, 1H), 4.12 - 3.81 (m, 2H), 3.25 - 3.19 (m, 2H), 2.56 - 2.15 (m, 3H), 2.12 - 1.69 (m, 8H), 1.64 - 1.26 (m, 4H).

[000866] 1 H NMR (400MHz, DMSO-d ₆ ) δ = 11.96 (br s, 1H), 9.02 - 8.65 (m, 1H), 7.62 - 7.46 (m, 1H), 7.45 - 7.34 (m, 1H), 7.27 - 7.06 (m, 2H), 7.04 - 6.57 (m, 1H), 5.04 - 4.86 (m, 1H), 4.57 - 4.37 (m, 1H), 4.10 - 3.63 (m, 2H), 3.17 - 2.83 (m, 2H), 2.34 - 2.26 (m, 2H), 2.23 - 2.10 (m, 2H), 2.04 - 1.82 (m, 7H), 1.80 - 1.37 (m, 2H), 1.37 - 1.13 (m, 2H).

Example 92. Synthesis of viral protease inhibitor compound 805

Step 7: ethyl 2-(7-chloro-lH-indole-2-carbonyl)-8,8-difluoro-2-azaspiro[4. 5]decane-3- carboxylate

[000867] To a solution of ethyl 8,8-difluoro-2-azaspiro[4.5]decane-3-carboxylate (1.5 g,

6.07 mmol, 1 eq) and 7-chloro- 1H-indole-2-carboxylic acid (1.42 g, 7.28 mmol, 1.2 eq) in DCM (25 mL) was added DMAP (1.48 g, 12.13 mmol, 2 eq) and EDCI (2.33 g, 12.13 mmol, 2 eq), then the mixture was stirred at 20 °C for 2 h. Upon the reaction completement, the mixture was quenched by water (20 mL) and was extracted with DCM (10 mL * 3), then was concentrated in vacuum and was purified by column (SiO ₂ , petroleum ether: ethyl acetate = 20: 1 to 2.5:1) to obtained ethyl 2-(7-chloro-1H-indole-2- carbonyl)-8, 8-difluoro-2-azaspiro[4.5] decane-3 -carboxylate (1.6 g, 3.58 mmol, 58.98% yield, 95% purity) as a pink oil. MS (ESI) m/z 425.2 [M+H] ⁺ .

Step 2: 2-(7-chloro-lH-indole-2-carbonyl)-8,8-difluoro-2-azaspiro[4. 5]decane-3-carboxylic acid

[000868] 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 H ₂ O (6 mL) was added LiOH.H ₂ O (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=~l with 1M HC1 (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.

Step 3:

(2S)-methyl2-(2-(7-chloro-lH-indole-2-carbonyl)-8,8-diflu oro-2-azaspiro[4.5]decane-3- carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000869] To a solution of 2-(7-chloro-1H-indole-2-carbonyl)-8,8-difluoro-2- azaspiro[4.5]decane-3-carboxylic acid (1.7 g, 4.28 mmol, 1 eq) and methyl (2S)-2-amino- 3-[(3S)-2-oxo-3-piperidyl] propanoate (1.01 g, 4.28 mmol, 1 eq, HC1) in DMF (30 mL) was added PyBOP (2.23 g, 4.28 mmol, 1 eq), and then was added TEA (1.30 g, 12.85 mmol, 1.79 mL, 3 eq) in DMF (5 mL) at -40 °C. The mixture was stirred at -40 °C for 2 h. Upon the reaction completion, the mixture was poured into water (100 mL) and was extracted with DCM (40 mL * 3), then was dried by NazSC> ₄ and was concentrated in vacuum and was purified by column (SiO ₂ , petroleum ether: ethyl acetate = 1 : 1 to DCM:MeOH = 10:1) to obtained (2S)-methyl 2-(2-(7-chloro-1H-indole-2-carbonyl)-8, 8- difluoro-2-azaspiro [4.5] decane-3-carboxamido)-3-((S)-2-oxopiperidin-3-yl) propanoate (2.2 g, 3.04 mmol, 70.95% yield, 80% purity) as a colorless solid. MS (ESI) m/z 579.3 [M+H] ⁺ .

Step 4: N-( (S)-l -amino- l-oxo-3-( (, S)-2-oxopiperidm-3-yl)propan-2-yl)-2-(7-chloro-lH - indole-2-carbonyl)-8, 8-difluoro-2-azaspiro[ 4.5]decane-3-carboxamide

[000870] A solution of (2S)-methyl 2-(2-(7-chloro-1H-indole-2-carbonyl)-8,8-difluoro-2- azaspiro [4.5] decane-3 -carboxami do)-3 -((S)-2-oxopi peri din-3 -yl) propanoate (400 mg, 518.10 umol, 75% purity, 1 eq) in NH ₃ /MeOH (6 mL, 7M) was stirred at 30 °C for 16 h. Upon the reaction completion, the mixture was concentrated in vacuum to obtain N-((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl) propan-2 -yl)-2-(7-chloro- 1H-indole-2- carbonyl) -8, 8-difluoro-2-azaspiro[4.5]decane-3-carboxamide (1.4 g, batch 5, crude) as a white solid. MS (ESI) m/z 564.2 [M+H] ⁺

Step 5: 2-(7-chloro-lH-indole-2-carbonyl)-N-( ( S)-l-cyano-2-( (, S)-2-oxopiperidin-3-yl) ethyl )- 8,8-difluoro-2-azaspiro[ 4.5 ]decane-3-carboxamide

[000871] To a solution of N-((S)- 1 -amino-1 -oxo-3-((S)-2-oxopiperidin-3-yl) propan-2-yl)- 2-(7-chloro -1H-indole-2-carbonyl)-8,8-difluoro-2-azaspiro[4.5] decane-3-carboxamide (1.4 g, 2.48 mmol, 1 eq) in DCM (30 mL) was added Burgess reagent (1.77 g, 7.45 mmol, 3 eq). The mixture was stirred at 30 °C for 2 h. Upon the reaction completion, the reaction mixture was quenched with water (2 mL) and was dried by blowing N ₂ . The concentrate was purified by prep-HPLC (column: Welch Xtimate C18250 * 70 mm#10um; mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 30%-60%, 20min) to obtain 2-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-ox opiperidin-3- yl)ethyl)-8,8-difluoro-2-azaspiro[4.5]decane-3-carboxamide (740 mg, 1.33 mmol, 53.51% yield, 98% purity) as a white solid. MS (ESI) m/z 546.2 [M+H] ⁺

Step 6: 2-(7-chloro-lH-indole-2-carbonyl)-N-( ( S)-l-cyano-2-( (S)-2-oxopiperidin-3-yl) ethyl) - 8,8-difluoro-2-azaspiro[ 4.5 ]decane-3-carboxamide)

[000872] The 2-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-ox opiperidin-3- yl)ethyl)-8,8 -difluoro-2-azaspiro[4.5]decane-3-carboxamide (740 mg, 1.33 mmol, 53.51% yield, 98% purity) was separated by SFC (column: REGIS(S,S)WHELK- Ol(250mm*25mm, lOum); mobile phase: [Neu-ETOH]; B%: 60%-60%, 7min) to obtained 2-(7-chloro-1H-indole-2-carbonyl)-N-((S) - 1 -cyano-2-((S)-2-oxopiperidin-3- yl)ethyl)-8,8-difluoro-2-azaspiro[4.5]decane-3-carboxamide (Isomer 1: 340 mg, 622.70 umol, 45.95% yield, 100% purity) as a white solid. MS (ESI) m/z 546.1 [M+H] ⁺

[000873 ] ¹ H NMR (400MHz, MeOD-d ₄ ) δ ppm 7.67 - 7.47 (m, 1H), 7.28 (d ,J= 7.6 Hz, 1H), 7.18 - 6.82 (m, 2H), 5.15 - 4.97 (m, 1H), 4.82 - 4.58 (m, 1H), 4.05 - 3.73 (m, 2H), 3.27 - 2.92 (m, 2H), 2.63 - 2.44 (m, 2H), 2.39 (dd,J= 7.7, 12.5 Hz, 1H), 2.07 - 1.72 (m, 11H), 1.68 - 1.40 (m, 3H).

[000874] 2-(7-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-ox opiperidin-3- yl)ethyl)-8,8-difluoro-2-azaspiro[4.5]decane-3-carboxamide (Isomer 2: 325 mg, 595.23 umol, 43.92% yield, 100% purity) as a white solid. MS (ESI) m/z 546.2 [M+H] ⁺ .

[000875] ¹ H NMR (400MHz, MeOD-d ₄ ) δ ppm 7.64 (d ,J= 8.0 Hz, 1H), 7.28 (d ,J= 7.4 Hz, 1H), 7.20 - 6.81 (m, 2H), 5.02 (dd, J = 6.2, 10.1 Hz, 1H), 4.66 (dd, J = 7.9, 9.4 Hz, 1H), 4.08 - 3.81 (m, 2H), 3.23 - 3.00 (m, 2H), 2.55 - 2.23 (m, 3H), 2.02 - 1.72 (m, 10H), 1.71 - 1.59 (m, 3H), 1.58 - 1.44 (m, 1H).

Example 93. Synthesis of viral protease inhibitor compound 806a

Step 1: methyl (Z)-2-azido-3-(3-chloro-2-methoxy-phenyl)prop-2-enoate [000876] 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 H ₂ O 5(0 mL) at 0 °C, and then diluted with H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , 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.

Step 2: methyl 5-chloro-4-methoxy-lH-indole-2-carboxylate

[000877] 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 (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 5/1) to get the compound methyl 5-chloro-4-m ethoxy- 1 H- indole-2-carboxylate (1.7 g, 6.38 mmol, 81.37% yield, 90% purity) as a white solid.

Step 3: 5-chloro-4-methoxy-lH-indole-2-carboxylic acid

[000878] To a mixture of methyl 5-chloro-4-methoxy-lH-indole-2-carboxylate (1.2 g, 5.01 mmol, 1 eq) in THF (20 mL) and H ₂ O (10 mL) was added LiOH.H ₂ O (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 HC1, and then diluted with H ₂ O (30 mL). The reaction was extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue 5-chloro-4-methoxy- 1 H-indole-2- carboxylic acid (0.95 g, 4.00 mmol, 79.88% yield, 95% purity) as a white solid.

Step 4: methyl (2S)-2-[[(2S)-2-[(5-chloro-4-methoxy-lH-indole-2-carbonyl)am ino]-4,4- dimethyl- pentanoyl ] amino ]-3-[( 3S)-2-oxo-3-piperidyl ]propanoate

[000879] To a mixture of methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-

3-[(3S)-2-oxo-3- piperidyljpropanoate (468 mg, 1.29 mmol, 1 eq, HC1) and 5-chloro-4- methoxy- 1 H-indole-2- carboxylic acid (290.19 mg, 1.29 mmol, 1 eq) in DMF (10 mL) and DCM (20 mL) was added EDCI (493.11 mg, 2.57 mmol, 2 eq) and DMAP (314.25 mg, 2.57 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (100 mL) and extracted with ethyl acetate (200 mL, which was extracted as 100 mL * 2). The combined organic layers were washed with HC1 (1 M, 100 mL) and brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si 02, petroleum ether/ethyl acetate = 5/1 to 0/1) to get the compound methyl (2S)-2-[[(2S)-2-[(5-chloro-4-methoxy-lH-indole-2-carbonyl)am ino]-4,4- dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoa te (600 mg, 1.02 mmol, 79.35% yield, 91% purity) as a white solid. MS (ESI) m/z 535.2/537.2 [M+H] ⁺

Step 5: N-f ( l S)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl]amino]-l- (cyclopropylmethyl) -2-oxo-ethyl /- 7-methoxy-lH-benzimidazole-2-carboxamide

[000880] A mixture of methyl (2S)-2-[[(2S)-2-[(5-chloro-4-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentan oyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (450 mg, 841.07 umol, 1 eq) and NH ₃ /MeOH (7 M, 15 mL, 124.84 eq) was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3 - piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-5-chlo ro-4-methoxy-lH-indole-2- carboxamide (440 mg, 719.20 umol, 85.51% yield, 85% purity) as a white solid. MS (ESI) m/z 520.3 [M+H] ⁺

Step 6: 5-chloro-N-[ (1S)-1-[[(1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl ] carbamoyl ]-3, 3- dimethyl -butyl ]-4-methoxy-lH-indole-2-carboxamide

[000881] To a mixture of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-5-chlo ro-4-methoxy-lH-indole-2- carboxamide (440 mg, 846.12 umol, 1 eq) in DCM (6 mL) was added Burgess reagent (604.92 mg, 2.54 mmol, 3 eq). The mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was diluted with H ₂ O (20 mL) and then extracted with DCM (20 mL * 2). The combined organic layers were concentrated and blow-drying by N ₂ to give a residue. The residue was purified by neutral prep-HPLC ( column: Kromasil C18 (250 * 50 mm * 10 um); mobile phase: [water(10mM NH4HCO ₃ )-ACN]; B%: 30% - 60%, 10 min) to afford 5-chloro-N-[(1S)-1-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]carbamoyl]-3,3- dimethyl-butyl]-4-methoxy-lH-indole-2-carboxamide (220 mg, 430.07 umol, 50.83% yield, 98.134% purity) as a white solid. MS (ESI) m/z 502.2 [M+H] ⁺ .

[000882] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.85 (br s, 1H), 8.96 (d, J=7.9 Hz, 1H),

8.63 (d, J=8.1 Hz, 1H), 7.67 - 7.38 (m, 2H), 7.24 - 7.05 (m, 2H), 5.16 - 4.92 (m, 1H), 4.63 - 4.42 (m, 1H), 4.11 - 4.02 (m, 3H), 3.14 - 3.00 (m, 2H), 2.36 - 2.17 (m, 2H), 1.88 - 1.62 (m, 5H), 1.59 - 1.29 (m, 2H), 0.94 (s, 9H),

Example 94. Synthesis of viral protease inhibitor compound 808

Step 1: methyl (Z)-2-azido-3-(2-chloro-3-methoxy-phenyl)prop-2-enoate

[000883] 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.

Step 2: methyl 4-chloro-5-methoxy-lH-indole-2-carboxylate

[000884] 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-m ethoxy- 1 H-indole-2-carboxylate (450 mg,

1.13 mmol, 30.16% yield, 60% purity) as a yellow solid.

Step 3: 4-chloro-5-methoxy-lH-indole-2-carboxylic acid

[000885] To a mixture of methyl 4-chloro-5-methoxy- 1 H-indole-2-carboxylate (450.00 mg, 1.88 mmol, 1 eq) in THF (10 mL) and H ₂ O (5 mL) was added LiOH.H ₂ O (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 HC1, and then diluted with H ₂ O (30 mL) and extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue compound 4-chloro-5-methoxy- 1 H-indole-2-carboxylic acid (320 mg, 992.78 umol, 52.87% yield, 70% purity) as a yellow solid.

Step 4: methyl (2S)-2-[[(2S)-2-amino-4, 4-dimethyl-pentanoyl ]amino]-3-[ ( 3S)-2-oxo-3- piperidyl] propanoate

[000886] A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoyljaminoj- 3-[(3S)-2-oxo-3-piperidyl]propanoate (500 mg, 1.17 mmol, 1 eq) in HCl/MeOH (4 M, 50.00 mL, 171.01 eq) was stirred at 25 °C for 1 hr. 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- piperidyljpropanoate (420 mg, 1.15 mmol, 98.69% yield, HC1) as a white solid.

Step 5: methyl (2S)-2-[[(2S)-2-[(4-chloro-5-methoxy-lH-indole-2-carbonyl)am ino]-4,4- dimethyl- pentanoyl ] amino ]-3-[( 3S)-2-oxo-3-piperidyl ]propanoate

[000887] To a mixture of methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]- 3-[(3S)-2-oxo-3- piperidyljpropanoate (420 mg, 1.15 mmol, 1 eq, HC1) and 4-chloro-5- methoxy- 1 H-indole-2- carboxylic acid (260.43 mg, 1.15 mmol, 1 eq) in DMF (10 mL) and DCM (20 mL) was added EDCI (442.53 mg, 2.31 mmol, 2 eq) and DMAP (282.02 mg, 2.31 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was filtered and then diluted with H ₂ O (100 mL) and extracted with ethyl acetate 300 mL (150 mL * 2). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/l to 0/1) to afford methyl (2 S)-2-[[(2S)-2-[(4-chloro-5-methoxy- 1 H- indole-2-carbonyl)amino]-4,4-dimethyl-pentano yl]amino]-3-[(3 S)-2-oxo-3 - piperidyljpropanoate (350 mg, 588.75 umol, 51.01% yield, 90% purity) as a yellow solid. MS (ESI) m/z 535.3 [M+H] ⁺

Step 6: N-[(lS)-l-[[(lS)-2-amino-2-oxo-l-[[(2S)-2-oxo-2- piperidyl ] methyl ] ethyl ] carbamoyl ]-3,3- dimethyl-butyl ]-4-chloro-5-methoxy-lH-indole-2- carboxamide [000888] A mixture of methyl (2S)-2-[[(2S)-2-[(4-chloro-5-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentano yl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (300.00 mg, 560.72 umol, 1 eq) and NH ₃ /MeOH (7 M, 10 mL, 124 eq) was stirred at 60 °C for 16 h in seal tube. 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]-4-chlo ro-5-methoxy-lH-indole-2- carboxamide (290 mg, 501.90 umol, 89.51% yield, 90% purity) as a white solid. MS (ESI) m/z 520.3 [M+H] ⁺

Step7: 4-chloro-N-[ ( l S)-l-[[(lS)-l-cyano-2-[ ( 3S)-2-oxo-3-piperidyl] ethyl ] carbamoyl ]-3, 3- dimethyl- butyl ]-5-methoxy-lH-indole-2-carboxamide

[000889] To a mixture of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl] carbamoyl]-3,3-dimethyl-butyl]-4-chloro-5-methoxy-lH-indole- 2-carboxamide (330 mg, 634.59 umol, 1 eq) in DCM (10 mL) was added Burgess reagent (453.69 mg, 1.90 mmol, 3 eq). The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was diluted with H ₂ O (20 mL) and extracted with DCM (40 mL, which was extracted as 20 mL * 2). The combined organic layers were concentrated by blow-drying by N ₂ to give a residue. The residue was purified by neutral prep-HPLC(column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(10mM NH4HC03)-ACN];B%: 30%-60%,10min) to get the compound 4-chloro- N-[(1S)-1-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]carbamoyl]-3,3-dimethyl- butyl]-5-methoxy-lH-indole-2-carboxamide (140 mg, 276.09 umol, 43.51% yield, 99% purity) as a white solid. MS (ESI) m/z 502.2 [M+H] ⁺ .

[000890] ¹ H NMR (400MHz, DMSO-d6) δ = 11.74 (s, 1H), 8.89 (d, J= 8.1 Hz, 1H), 8.68 (d, J=8.1 Hz, 1H), 7.51 (br s, 1H), 7.41 - 7.25 (m, 2H), 7.13 (d, J=8.9 Hz, 1H), 5.12 - 4.96 (m, 1H), 4.52 (dt,J=3.8, 8.4 Hz, 1H), 3.91 - 3.76 (m, 3H), 3.14 - 2.95 (m, 2H), 2.37 - 2.13 (m, 2H), 1.90 - 1.29 (m, 7H), 1.01 - 0.81 (m, 9H)

Example 95. Synthesis of viral protease inhibitor compound 810

Step 1: 7 -chloro-5-methoxy-lH -indole

[000891] 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 NH ₄ CI (200 mL) and concentrated and extracted with ethyl acetate (80 mL * 3) and concentrated to give a crude. The crude was purified by column (SiO ₂ , petroleum ether: ethyl acetate = 30: 1 to 10: 1) to give product 7-chloro-5-methoxy-lH-indole (2100 mg, 11.56 mmol, 50.44% yield) as a brown oil. MS (ESI) m/z 182.1 [M+H] ⁺ .

Step 2: 7-chloro-5-methoxy-l-(p-tolylsulfonyl)indole

[000892] To a solution of 7-chloro-5-methoxy-lH-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 H ₂ O (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 (SiO ₂ , 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] ⁺

Step 3: 7-chloro-5-methoxy-l-(p-tolylsulfonyl)indole-2-carboxylic acid

[000893] 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 H ₂ O (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 HC1 (con) and extracted with ethyl acetate (90 mL * 2) and dried over Na ₂ SO ₄ and 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] ⁺

Step 4: 7-chloro-5-methoxy-lH-indole-2-carboxylic acid

[000894] 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 H ₂ O (40 mL) and acidified to pH=5-6 with HC1 (1M) and filtered and the cake was collected to give 7-chloro-5-methoxy-lH-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] ⁺

Step 5: methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)- 2-oxo-3- piperidyl]propanoate; hydrochloride

[000895] 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;hydroc hloride (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] ⁺ Step 6: methyl (2S)-2-[[(2S)-2-[(7-chloro-5-methoxy-lH-indole-2-carbonyl)am ino]-4,4- dimethyl-pentanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000896] A solution of methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3S)-2-oxo-3-piperidyl]propanoate;hydrochloride (420 mg, 1.15 mmol, 1 eq) and DMAP (282.02 mg, 2.31 mmol, 2 eq) in DCM (20 mL) and DMF (10 mL) was added 7-chloro-5- methoxy- 1 H-indole-2-carboxylic acid (299.49 mg, 1.33 mmol, 1.15 eq) and EDCI (442.54 mg, 2.31 mmol, 2 eq). The reaction was stirred for 1 h at 25 °C. Upon completion, the solution was diluted with H ₂ O (40 mL), extracted with ethyl acetate (50 mL * 3), and washed with brine (80 mL * 2) and concentrated to give crude product. The crude was purified by column (SiO ₂ , ethyl acetate :MeOH = 1:0 to 10: 1) to give product methyl(2S)-2-[[(2S)-2-[(7-chloro-5-methoxy-lH-indole-2-carbo nyl)amino]-4, 4-dimethyl- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (370 mg, 691.55 umol, 59.91% yield) as a yellow solid. MS (ESI) m/z 535.3 [M+H] ⁺

Step 7: N-[ (IS)- 1-[[(1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3- piperidyl ] methyl ] ethyl ] carbamoyl ]-3, 3-dimethyl-butyl ]- 7-chloro-5-methoxy-lH-indole-2- carboxamide

[000897] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-5-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo- 3-piperidyl]propanoate (370 mg, 691.55 umol, 1 eq) in NH ₃ /MeOH (7 M, 16.44 mL, 166.45 eq) was stirred for 25 h at 60 °C. Upon completion, the solution was concentrated to give N-[(1S)-1-[[(1S)- 2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbam oyl]-3, 3-dimethyl-butyl]- 7-chloro-5-methoxy-lH-indole-2-carboxamide (350 mg, crude) as an off-white solid. The crude was used directly for the next step. MS (ESI) m/z 520.3 [M+H] ⁺

Step 8: 7-chloro-N-[ (IS)- 1-[[(1 S)-l-cyano-2-[ ( 3S)-2-oxo-3-piperidyl] ethyl] carbamoyl ]-3, 3- dimethyl-butyl]-5-methoxy-lH-indole-2-carboxamide

[000898] A solution of N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-7-chlo ro-5-methoxy-lH-indole-2- carboxamide (350 mg, 673.05 umol, 1 eq) and Burgess reagent (641.57 mg, 2.69 mmol, 4 eq) in DCM (20 mL) was stirred for 2 h at 25 °C. Upon completion, the solution was washed with brine (30 mL * 2) and blow dried with N ₂ to give crude product. The crude was purified by prep-HPLC (Column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(0.05%NH ₃ H ₂ 0+10mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,8min) to afford 7-chloro-N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-5-methoxy-lH- indole-2-carboxamide (100 mg, 199.20 umol, 29.60% yield) as a white solid. MS (ESI) m/z 502.1 [M+H] ⁺ .

[000899] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.55 (br s, 1H), 9.11 - 8.94 (m, 1H), 8.64 (br d, J=8.4 Hz, 1H), 7.52 (br s, 1H), 7.17 - 7.08 (m, 2H), 6.98 (d, J=2.0 Hz, 1H), 5.27 - 4.92 (m, 1H), 4.69 - 4.37 (m, 1H), 3.76 (s, 3H), 3.05 (br s, 2H), 2.30 - 2.16 (m, 2H), 2.06 (s, 1H), 1.83 - 1.66 (m, 4H), 1.57 - 1.32 (m, 2H),

Example 96. Synthesis of viral protease inhibitor compound 812

Step 1: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-pro panoyl]amino]- 3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000900] To a solution of methyl (2 S)-2-amino-3 -[(3 S)-2-oxo-3 -piperidy 1 Jpropanoate (1 g, 4.22 mmol, 1 eq, HC1) and (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoic acid (968.64 mg, 4.22 mmol, 1 eq), TEA (1.28 g, 12.67 mmol, 1.76 mL, 3 eq) in DCM (15 mL) was added T3P (8.07 g, 12.67 mmol, 7.54 mL, 50% purity, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (20 mL) at 0 °C, the combined organic layers were washed with DCM (10 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=2/l to 0/1) to give methyl (2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[(3S)- 2-oxo-3- piperidyl]propanoate (1.08 g, 2.05 mmol, 48.46% yield, 78% purity) as a yellow oil. MS (ESI) m/z 413.2 [M+H] ⁺ . Step 2: methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxo-3- piperidyl ]propanoate

[000901 ] A solution of methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbony lamino)-3 - cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate (1.04 g, 2.53 mmol, 1 eq) in HCl/MeOH (15 mL) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give methyl (2S)- 2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-ox o-3-piperidyl]propanoate (879 mg, crude, HC1) as a yellow oil. MS (ESI) m/z 313.2 [M+H] ⁺

Step 3 : methyl (2S)-2-[[(2S)-2-[(4-chloro-lH-indole-2-carbonyl)amino]-3-cyc lopropyl- propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[000902 ] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (879 mg, 2.82 mmol, 1 eq) and 4-chloro- 1 H-indole-2-carboxylic acid (552.18 mg, 2.82 mmol, 1 eq) TEA (856.96 mg, 8.47 mmol, 1.18 mL, 3 eq) in DCM (10 mL) was added T3P (5.39 g, 8.47 mmol, 5.04 mL, 50% purity, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (20 mL) at 0 °C, the combined organic layers were washed with DCM (10 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=2/l to 0/1) to afford methyl (2S)-2- [[(2S)-2-[(4-chloro-lH-indole-2-carbonyl)amino]-3-cyclopropy l-propanoyl]amino]-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (636 mg, 1.04 mmol, 36.86% yield, 80% purity) as a yellow solid. MS (ESI) m/z 489.2 [M+H] ⁺

Step 4: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-1-[[( 3S)-2-oxo-3-piperidyl ]methyl ] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-chloro-lH-indole-2-carbox amide

[000903] A solution of methyl (2S)-2-[[(2S)-2-[(4-chloro-lH-indole-2-carbonyl)amino]- 3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pro panoate (621 mg, 1.27 mmol, 1 eq) in NH ₃ /MeOH (7 M, 5 mL, 27.56 eq) was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N- [(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]meth yl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-chloro-lH-indole-2-carbox amide (460 mg, crude) as a yellow solid. MS (ESI) m/z 474.2 [M+H] ⁺ . Step 5: 4-chloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[000904] To a solution of N-[(l S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-chloro-lH-indole- 2-carboxamide (440 mg, 928.37 umol, 1 eq) in DCM (8 mL) was added Burgess reagent (663.70 mg, 2.79 mmol, 3 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 4- chloro-N-[(l S)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide (105.2 mg, 229.35 umol, 24.70% yield, 99.4% purity) as a white solid. MS (ESI) m/z 456.2 [M+H] ⁺ .

[000905] ¹ H NMR (400MHz, DMSO -d ₆ ) δ = 11.95 (s, 1H), 8.92 (d ,J= 8.4 Hz, 1H), 8.81 - 8.70 (m, 1H), 7.55 - 7.49 (m, 1H), 7.44 - 7.37 (m, 2H), 7.24 - 7.07 (m, 2H), 5.14 - 5.00 (m, 1H), 4.54 - 4.40 (m, 1H), 3.18 - 2.99 (m, 2H), 2.31 - 2.21 (m, 2H), 1.93 - 1.66 (m, 4H), 1.61 - 1.34 (m, 3H), 0.89 - 0.76 (m, 1H), 0.52 - 0.33 (m, 2H), 0.24 - 0.04 (m, 2H)

Example 97. Synthesis of viral protease inhibitor compound 814

Step 1: (2S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-(6-azaspiro[3.4]octane-7- carboxamido)propanoate [000906] A solution of tert-butyl 7-(((S)- 1 -methoxy-1 -oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl) carbamoyl)-6-azaspiro[3.4]octane-6-carboxylate (1.4 g, 3.31 mmol, 1 eq) in HCl/MeOH (4 M, 14 mL) was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was concentrated in vacuum to obtain (2S)-methyl 3-((S)-2-oxopyrrolidin-3- yl)-2-(6-azaspiro[3.4] octane-7-carboxamido) propanoate (1.29 g, crude) as a light yellow solid.

Step 2: (2S)-methyl2-(6-(6, 7-dichloro-JH-indole-2-carbonyl)-6-azaspiro[3.4Joctane-7- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000907] To a solution of (2S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-(6-azaspiro[3.4] octane-7-carboxamido) propanoate (1.14 g, 2.22 mmol, 70% purity, 1 eq, HC1) in DCM (25 mL) was added 6,7-dichloro-lH-indole-2-carboxylic acid (612.19 mg, 2.66 mmol, 1.2 eq) and DMAP (541.85 mg, 4.44 mmol, 2 eq) and EDCI (850.23 mg, 4.44 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon the reaction completion, the residue was poured into water (60 mL) and was extracted with DCM (20 mL * 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum and was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1, Rf = 0.35) to obtained (2S)-methyl 2-(6-(6,7-dichloro-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl) propanoate (800 mg, 1.48 mmol, 66.70% yield, 99% purity) as a light yellow solid. MS (ESI) m/z 535.2 [M+H] ⁺

Step 3: N-((S)-1 -amino- l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6-(6, 7-dichloro-JH- indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000908] A solution of (2S)-methyl 2-(6-(6,7-dichloro-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl) propanoate (270 mg, 504.28 umol, 1 eq) in NH ₃ /MeOH (6 mL, 7 M) was stirred at 30 °C for 20 h. Upon the reaction compl element, the mixture was concentrated in vacuum to obtained N-((S)-1- amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2-yl)-6-(6,7-dichloro-lH-indole -2- carbonyl)-6-azaspiro[3.4]octane-7-carboxamide (800 mg, crude) as a light yellow solid. MS (ESI) m/z 520.2 [M+H] ⁺

Step 4: N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6-(6, 7-dichloro-lH-indole-2- carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide [000909] To a solution of N-((S)- 1 -amino-1 -oxo-3-((S)-2-oxopyrrolidin-3-yl) propan-2- yl)-6-(6,7-dichloro-lH-indole-2-carbonyl)-6-azaspiro[3.4]oct ane-7-carboxamide (800 mg, 1.54 mmol, 1 eq) in DCM (15 mL) was added Burgess reagent (1.10 g, 4.61 mmol, 3 eq), and the mixture was stirred at 30 °C for 4 h. Upon the reaction completion, the mixture was quenched by H ₂ O (2 mL) and dried by blowing N ₂ and was purified by prep- HPLC (column: Waters Xbridge C18 150 * 50 mm * 10 um; mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 35%-65%, 10 min) to obtained N-((S)-1-cyano-2-((S)-2- oxopyrrolidin-3-yl)ethyl)-6-(6,7-dichloro-lH-indole-2-carbon yl)-6-azaspiro[3.4]octane-7- carboxamide (380 mg, 756.38 umol, 49.20% yield) as a white solid. MS (ESI) m/z 502.2 [M+H] ⁺ .

Step 5: N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-6-(6, 7-dichloro-lH-indole-2- carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[000910] The N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl) ethyl) -6-(6,7-dichloro-lH- indole-2-carbonyl) -6-azaspiro[3.4]octane-7-carboxamide was separated by SFC (column: DAICEL CHIRALPAK AS(250mm * 30mm, lOum); mobile phase: [0.1% NH ₃ H ₂ 0 MEOH]; B%: 45%-45%, 15min) to obtained N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl) ethyl) -6-(6,7-dichloro-lH-indole-2-carbonyl) -6-azaspiro[3.4]octane-7-carboxamide (Isomer 1: 110 mg, 218.95 umol, 28.95% yield, 100% purity) as a white solid. MS (ESI) m/z 502.1 [M+H] ⁺

[000911] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ ppm 7.62 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.17 (s, 1H), 5.01 (dd, J = 5.8, 10.3 Hz, 1H), 4.58 (t, J = 7.6 Hz, 1H), 4.08 - 3.80 (m, 2H), 3.15 - 2.58 (m, 1H), 2.55 - 2.15 (m, 5H), 2.11 - 1.74 (m, 9H).

[000912] To obtain N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl) -6-(6,7-dichloro- lH-indole-2- carbonyl)-6-azaspiro[3.4]octane-7-carboxamide (Isomer 2: 85 mg, 169.19 umol, 22.37% yield, 100% purity) after repurification by prep-HPLC (column: Waters Xbridge BEH C18 100 * 25mm * 5 um; mobile phase: [water(10 mM NH4HCO3)- ACN] ; B%: 30%-65%, 10 min) as a white solid. MS (ESI) m/z 502.1 [M+H] ⁺

[000913] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ ppm 7.61 (d, J = 8.6 Hz, 1H), 7.24 - 7.15 (m, 1H), 7.13 (s, 1H), 5.09 - 4.90 (m, 1H), 4.78 - 4.51 (m, 1H), 4.06 - 3.72 (m, 2H), 2.83 - 2.63 (m, 1H), 2.61 - 2.28 (m, 3H), 2.22 - 1.76 (m, 10 H), 1.72 - 1.40 (m, 1H). Example 98. Synthesis of viral protease inhibitor compound 171

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000914] A mixture of methyl (2 S)-2-(tert-butoxy carbonyl amino)-3 -[(3 S)-2- oxopyrrolidin-3-yl]propanoate (0.55 g, 1.92 mmol, 1 eq) and HCl/EtOAc (4 M, 10 mL, 20.82 eq) was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin- 3-yl)propanoate (0.35 g, crude) as a yellow oil.

Step 2: (2S,4S)-tert-butyl 2-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 - yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate

[000915] A mixture of (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (0.15 g, 805.55 umol, 1 eq), (2S,4S)-1-tert-butoxycarbonyl-4-phenyl-pyrrolidine-2-carboxy lic acid (234.69 mg, 805.55 umol, 1 eq), DMAP (196.83 mg, 1.61 mmol, 2 eq), EDCI (308.85 mg, 1.61 mmol, 2 eq) in DMF (1 mL) and DCM (2 mL) was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 2:1 to 0: 1) to give (2S,4S)-tert-butyl 2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-4-phenyl-pyrrolidine-1-carboxylat e (0.25 g, 500.51 umol, 62.13% yield, 92% purity) as a colorless oil. MS (ESI) m/z 460.1 [M+H] ⁺ .

Step 3: (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((2S,4S)-4-phenylpyrrolidine- 2- carboxamido)propanoate [000916] A mixture of tert-butyl (2S,4S)-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-4-phenyl-pyrrolid ine-1-carboxylate (0.25 g, 544.03 umol, 1 eq) and HCl/EtOAc (4 M, 10 mL, 73.53 eq) was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2S)-3-[(3S)-2-oxopyrrolidin-3-yl]-2-[[(2S,4S)-4-phenylpyrro lidine-2- carbonyl]amino]propanoate (0.2 g, crude) as a yellow oil. MS (ESI) m/z 360.1 [M+H] ⁺ .

Step 4: (S)-methyl 2-((2S,4S)-l-((E)-3-(4-chloro-2-fluorophenyl)acryloyl)-4- phenylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl )propanoate [000917] A mixture of methyl (2S)-3-[(3S)-2-oxopyrrolidin-3-yl]-2-[[(2S,4S)-4- phenylpyrrolidine-2-carbonyl]amino]propanoate (0.17 g, 472.99 umol, 1 eq), (E)-3-(4- chloro-2-fluoro-phenyl)prop-2-enoic acid (94.88 mg, 472.99 umol, 1 eq), T3P (451.48 mg, 709.48 umol, 421.95 uL, 50% purity, 1.5 eq), TEA (143.58 mg, 1.42 mmol, 197.50 uL, 3 eq) in DMF (4 mL) was degassed and stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 2:1 to 0: 1) to give 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 (0.11 g, 162.36 umol, 34.33% yield, 80% purity) as a white solid. MS (ESI) m/z 542.1 [M+H] ⁺ .

Step 5: (2S, 4S)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-l-((E)-3-(4- chloro-2-fluorophenyl)acryloyl)-4-phenylpyrrolidine-2-carbox amide

[000918] 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-ox opyrrolidin-3- yl]propanoate (0.1 g, 184.50 umol, 1 eq) in NH ₃ /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-e noyl]-4-phenyl-pyrrolidine- 2-carboxamide (0.09 g, crude) as a yellow oil. MS (ESI) m/z 527.0 [M+H] ⁺ .

Step 6: (2S, 4S)-1-( (E)-3-( 4-chloro-2-fluorophenyl)acryloyl)-N-( (S)-l-cyano-2-( (, S)-2 - oxopyrrolidin-3-yl)ethyl)-4-phenylpyrrolidine-2-carboxamide [000919] To a solution of (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-e noyl]-4-phenyl-pyrrolidine- 2-carboxamide (0.09 g, 170.78 umol, 1 eq) in DCM (1 mL) was added Burgess reagent (203.50 mg, 853.91 umol, 5 eq), and then the solution 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-HPLC (column: Waters Xbridge BEH C18 100*25mm*5um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,10min) to give (2S,4S)-1-[(E)-3-(4-chloro-2-fluoro-phenyl)prop-2-enoyl]-N-[ (l S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-phenyl-pyrrolidine-2-car boxamide (29.73 mg, 56.89 umol, 33.31% yield, 97.4% purity) as a white solid. MS (ESI) m/z 509.1 [M+H] ⁺ .

[000920] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.17 - 8.86 (m, 1H), 8.07 - 7.75 (m, 1H), 7.75 - 7.65 (m, 1H), 7.62 - 7.49 (m, 2H), 7.48 - 7.30 (m, 5H), 7.26 (tt, J= 3.0, 5.6 Hz, 1H), 7.22 - 6.73 (m, 1H), 5.09 - 4.83 (m, 1H), 4.69 - 4.47 (m, 1H), 4.40 - 4.01 (m, 1H), 3.77 - 3.50 (m, 3H), 3.19 - 3.04 (m, 2H), 2.44 - 2.31 (m, 2H), 2.22 - 2.09 (m, 2H), 1.88 - 1.59 (m, 2H).

Example 99. Synthesis of viral protease inhibitor compound 253

Step 1: methyl 2-amino-3-(2-oxo-l,2-dihydropyridin-3-yl)propanoate

[000921 ] A mixture of 2-amino-3-(2-oxo-lH-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-l,2-dihydropyridin-3-yl)propanoate (650 mg, crude, HC1) as a yellow oil and used directly for next step. MS (ESI) m/z 197.0 [M+H] ⁺

Step 2: methyl-2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentana mido)-3-(2-oxo-J,2- dihydropyridin-3-yl)propanoate [000922] A mixture of methyl 2-amino-3-(2-oxo-lH-pyridin-3-yl)propanoate (650 mg, 2.79 mmol, 1 eq, HC1), (2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoic acid (646.16 mg, 2.79 mmol, 1 eq), EDCI (1.07 g, 5.59 mmol, 2 eq), DMAP (682.62 mg, 5.59 mmol, 2 eq), DMF (2 mL) and DCM (4 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1) to get the product methyl-2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentana mido)-3-(2-oxo-l,2- dihydropyridin-3-yl)propanoate (900 mg, 1.89 mmol, 67.68% yield, 86.02% purity), as white solid. MS (ESI) m/z 410.1 [M+H] ⁺

Step 3: methyl 2-((S)-2-amino-4-methylpentanamido)-3-(2-oxo-l,2-dihydropyri din-3- yl)propanoate

[000923] A mixture of methyl-2-((S)-2-((tert-butoxycarbonyl)amino)-4- methylpentanamido)-3-(2-oxo-l,2-dihydropyridin-3-yl)propanoa te (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-l,2-dihydropyridin-3-yl)propanoa te (170 mg, crude, HC1) as a white solid and used directly for next step.

Step 4: methyl 2-((S)-2-(4-methoxy-lH-indole-2-carboxamido)-4-methylpentana mido)-3-(2- oxo-l,2-dihydropyridin-3-yl)propanoate

[000924] A mixture of methyl 2-((S)-2-amino-4-methylpentanamido)-3-(2-oxo-l,2- dihydropyridin-3-yl)propanoate (170 mg, 491.58 umol, 1 eq, HC1), 4-methoxy-lH- indole-2-carboxylic acid (93.98 mg, 491.58 umol, 1 eq), EDCI (188.47 mg, 983.17 umol, 2 eq), DMAP (120.11 mg, 983.17 umol, 2 eq), DMF (2 mL) and DCM (4 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1) to afford methyl 2-((S)-2-(4-methoxy-lH-indole-2-carboxamido)-4- methylpentanamido)-3-(2-oxo- 1 ,2-dihydropyridin-3-yl)propanoate (130 mg, 269.41 umol, 54.81% yield) as white solid. MS (ESI) m/z 483.1 [M+H] ⁺

Step 5: N-( (2S)-l-( ( l -amino- 1 -oxo-3 -( 2-oxo-J, 2-dihydropyridin-3-yl)propan-2-yl)ammo)-4- methyl-l-oxopentan-2-yl)-4-methoxy-lH-indole-2-carboxamide

[000925] A mixture of methyl 2-((S)-2-(4-methoxy-lH-indole-2-carboxamido)-4- methylpentanamido)-3-(2-oxo-l,2-dihydropyridin-3-yl)propanoa te (190 mg, 393.76 umol, 1 eq), NH ₃ /MeOH (7 M, 10 mL) was stirred at 80 °C for 15 h. The reaction mixture was concentrated under reduced pressure to give a residue N-((2S)-1-((l-amino-1-oxo-3- (2-oxo- 1 ,2-dihydropyridin-3-yl)propan-2-yl)amino)-4-methyl- 1 -oxopentan-2-yl)-4- methoxy-lH-indole-2-carboxamide (190 mg, crude) as a yellow solid. MS (ESI) m/z 468.2 [M+H] ⁺

Step 6: N-( (2S)-l-( ( l -cyano-2-(2-oxo-J, 2-dihydropyridin-3-yl)ethyl)amino)-4-methyl-l- oxopentan-2-yl)-4-methoxy-lH-indole-2-carboxamide

[000926] A mixture of N-((2S)- 1 -(( 1 -amino- 1 -oxo-3-(2-oxo- 1 ,2-dihydropyridin-3- yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-4-methoxy-l H-indole-2-carboxamide (180 mg, 385.01 umol, 1 eq), Burgess reagent (917.53 mg, 3.85 mmol, 10 eq) and DCM (30 mL) was stirred at 25 °C for 8 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30mm*3um;mobile phase:

[water(0.05%NH ₃ H ₂ 0+10mM NH4HCO ₃ )-ACN];B%: 25%-45%,8min) to get the product N-((2S)- 1 -(( 1 -cyano-2-(2-oxo- 1 ,2-dihydropyridin-3-yl)ethyl)amino)-4-methyl- 1 - oxopentan-2-yl)-4-methoxy-lH-indole-2-carboxamide (24 mg, 52.18 umol, 13.55% yield, 97.73% purity), as yellow solid. MS (ESI) m/z 450.2 [M+H] ⁺ .

[000927] 1 H NMR (400MHz, DMSO-d ₆ ) δ = 11.90-11.40 (m, 2H), 9.08 - 8.85 (m, 1H), 8.55 - 8.35 (m, 1H), 7.51 - 7.26 (m, 3H), 7.16 - 7.05 (m, 1H), 7.04 - 6.94 (m, 1H), 6.51 (d, J=7.5 Hz, 1H), 6.15 (t, J=6.6 Hz, 1H), 5.19 - 5.01 (m, 1H), 4.55 - 4.33 (m, 1H), 3.89 (s, 3H), 3.02 - 2.78 (m, 2H), 1.75 - 1.33 (m, 3H), 0.98 - 0.72 (m, 6H).

Example 100. Synthesis of viral protease inhibitor compound 267 & 267A

Step 7: tert-Butyl 3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-lH-pyrrole-2-carbo xylate [000928] To a solution of tert-butyl-but-3-ynoxy-dimethyl-silane (5.00 g, 27.10 mmol, 1.5 eq) and AgzCO3 (498 mg, 1.81 mmol, 0.1 eq) in dioxane (8 mL) was added tert- butyl 2- isocyanoacetate (2.55 g, 18.06 mmol, 2.63 mL, 1 eq). Then the mixture was stirred at 80 °C for 1 hr. TLC (petroleum ether/ethyl acetate = 10/1, UV) showed that the starting material was consumed completely and new spots formed. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-10% ethyl acetate/petroleum ether gradient @ 30 mL/min). tert-butyl 3-[2 -[tert- butyl(dimethyl)silyl]oxyethyl]-1H-pyrrole-2-carboxylate (2.5 g, 42.5% yield) was obtained as a white solid.

Step 2: tert-Butyl 3-(2-hydroxyethyl)-lH-pyrrole-2-carboxylate

[000929] To a solution of tert-butyl 3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-1H-pyrrole-

2-carboxylate (2.5 g, 7.68 mmol, 1 eq) in THF (20 mL) was added TBAF (1 M, 15.3 mL, 2 eq) at 0 °C, and then the mixture was stirred at 25 °C for 16 hr. TLC (petroleum ether/ethyl acetate = 5/1, UV) showed that the starting material was consumed completely and new spot formed. The reaction mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM/MeOH @ 30 mL/min). tert-butyl 3 -(2-hydroxy ethyl)- 1H-pyrrole-2-carboxylate (1.3 g, 80.1% yield) was obtained as colorless oil.

Step 3: tert-Butyl 3-(2-oxoethyl)-lH-pyrrole-2-carboxylate [000930] 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 H ₂ O (10 mL), brine (10 mL) and dried over Na ₂ SO ₄ , 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.

[000931] 1 H NMR (400 MHz, CDCl ₃ ) δ 9.80 - 9.60 (m, 1H), 9.48 (br s, 1H), 6.91 (t ,J= 2.76 Hz, 1H), 6.16 (1,./= 2.51 Hz, 1H), 3.82 (d ,J= 1.76 Hz, 2H,), 1.56 (s, 9H).

Step 4: tert-Butyl 3-[ 2-[ [ ( JS)-1-(cyclopropylmethyl)-2-methoxy-2-oxo-ethyl ] amino ] ethyl ]- lH-pyrrole-2-carboxylate [000932] 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, HC1) in MeOH (20 mL) was stirred at 25 °C for 0.5 hr. Then NaBFLCN (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 H ₂ O (10 mL), extracted with ethyl acetate (15 mL><3). The combined organic phase was washed with H ₂ O (10 ml) and brine (10 mL><2), dried over Na ₂ SO ₄ , 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-py rrole-2-carboxylate (0.6 g, 24.8% yield) was obtained as colorless oil. [000933] 1 H NMR (400 MHz, CDCl ₃ ) δ 8.98 (br s, 1H), 6.91 - 6.65 (m, 1H), 6.15 (t, J= 2.56 Hz, 1H), 3.71 (s, 3H), 3.40 (t ,J= 6.69 Hz, 1H), 2.99 - 2.92 (m, 2H), 2.82 - 2.90 (m, 1H), 2.78 - 2.69 (m, 1H), 1.68 - 1.63 (m, 1H), 1.57 (s, 9H), 1.50 - 1.42 (m, 1H), 0.76 - 0.66 (m, 1H), 0.48 - 0.36 (m, 2H), 0.11 - 0.01 (m, 2H).

Step 5: 3- [ 2-[ f(JS)-1-( Cyclopropylmethyl)-2-methoxy-2-oxo-ethyl ]amino ] ethyl ]-lH-pyrrole- 2-carboxylic acid

[000934 ] 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.

Step 6: Methyl (2S)-3-cyclopropyl-2-(7-oxo-4,5-dihydro-lH-pyrrolo[2,3-c]pyr idin-6- yl)propanoate [000935] 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 H ₂ O (20 mL), extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with H ₂ O (10 mL), brine (10 mL) and dried over Na ₂ SO ₄ , 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. [000936] LCMS: Rt = 0.773 min; for C 14H18N2O3 MS Calcd. 262.13; MS Found 263.0 [M+H ⁺ ],

[000937] ¹ H NMR (400 MHz, CD ₃ OD) δ 6.97 - 6.85 (m, 1H), 6.04 (d ,J= 2.26 Hz, 1H,), 5.09 (dd, J= 10.26, 5.27 Hz, 1H), 3.71 (s, 3H), 3.67 - 3.58 (m, 2 H), 2.93 - 2.74 (m, 2H), 2.02 - 1.87 (m, 1H), 1.81 - 1.70 (m, 1H), 0.83 - 0.68 (m, 1H), 0.56 - 0.39 (m, 2H), 0.22 - 0.07 (m, 2H).

Step 7: (2S)-3-cyclopropyl-2-(7-oxo-4, 5-dihydro- lH-pyrrolo[2, 3-c]pyridin-6-yl)propanoic acid

[000938] 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 H ₂ O (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 H ₂ O (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 H ₂ O (5 mL), brine (5 mL) and dried over Na ₂ SO ₄ , 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]pyr idin-6- yl)propanoic acid was obtained as a white solid.

[000939] LCMS: Rt = 0.706 min; for C13H16N2O3 MS Calcd. 248.12; MS Found 248.9 [M+H ⁺ ],

[000940] 267A: (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyirolidin-3-yl]ethyl]-3-c yclopropyl-

2-(7-oxo-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6-yl)propan amide

[000941] 267: (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyirolidin-3-yl]ethyl]-3-c yclopropyl-2-

(7-oxo-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6-yl)propanam ide

[000942] To a solution of (2S)-3-cyclopropyl-2-(7-oxo-4,5-dihydro-1H-pyrrolo[2,3- c]pyridin-6-yl)propanoic acid (40 mg, 0.16 mmol, 1 eq) and (2S)-2-amino-3-[(3S)-2- oxopyrrolidin-3-yl]propanenitrile (30.5 mg, 0.16 mmol, 1 eq, HC1) in DMF (1 mL) were added TEA (32.6 mg, 0.32 mmol, 44 uL, 2 eq) and T3P (153.7 mg, 0.241 mmol, 0.14 mL, 50% purity, 1.5 eq) at 25 °C, and the mixture was stirred at 25 °C for 1 hr. LCMS showed that the starting material was consumed completely and 86% of the desired product was detected. The reaction mixture was concentrated in vacuum. The residue was checked by HPLC and purified by prep- HPLC (column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [water (0.05%NH ₃ H ₂ 0+10 mM NH ₄ HCO ₃ )-ACN]; B%: 20%-50%, 7.8 min). (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-c yclopropyl-2-(7-oxo- 4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6-yl)propanamide (22 mg, 35.6% yield) was obtained as a white solid.

[000943] The crude product was purified by chiral SFC (column: DAICEL CHIRALPAK AS(250mm*30mm,10um); mobile phase: [0.1%NH ₃ H ₂ 0 ETOH]; B%: 30%-30%,min). (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-c yclopropyl-2-(7-oxo-4,5- dihydro-1H-pyrrolo[2,3-c]pyridin-6-yl)propanamide (2.0 mg, 8.7% yield) was obtained as a white solid and (2S)-N-[(1S)- 1 -cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3- cyclopropyl-2-(7-oxo-4,5-dihydro-1H-pyrrolo[2,3-c]pyridin-6- yl)propanamide (15.1 mg, 68.2% yield) was obtained as a white solid.

267A:

[000944] LCMS: Rt = 0.746 min; for C ₂₀ H ₂₅ N ₅ O ₃ MS Calcd. 383.20; MS Found 384.1 [M+H ⁺ ],

[000945] ¹ H NMR (400 MHz, CD ₃ OD) δ 6.91 (d,J = 2.50 Hz, 1H). 6.04 (d, J= 2.38 Hz, 1H), 5.15 (dd, J = 8.44, 6.94 Hz, 1H),5.04 (br d,J= 6.75 Hz, 1H), 3.66 - 3.55 (m, 2H), 3.33 (br s, 2H), 2.88 - 2.76 (m, 2H), 2.55 - 2.42 (m, 1H), 2.39 - 2.23 (m, 2H), 1.96 - 1.83 (m, 2H), 1.82 - 1.74 (m, 2H), 0.70 (br s, 1H), 0.46 (t ,J= 7.88 Hz, 2H), 0.15 (d ,J= 4.38 Hz, 2H).

267:

[000946] LCMS: Rt = 0.751 min; for C ₂₀ H ₂₅ N ₅ O ₃ MS Calcd. 383.20; MS Found 384.1 [M+H ⁺ ],

[000947] ¹ H NMR (400 MHz, CD ₃ OD) δ 6.90 (d ,J= 2.38 Hz, 1H), 6.03 (d, J= 2.25 Hz, 1H), 5.02 (dd, J = 10.13, 6.63 Hz, 2H), 3.66 (tq, J = 13.12, 6.34 Hz, 2H), 3.30 - 3.18 (m, 2H), 2.80 (br t,J= 6.19 Hz, 2H), 2.59 - 2.44 (m, 1H), 2.37 - 2.21 (m, 2H), 1.97 - 1.69 (m, 4H), 0.78 - 0.67 (m, 1H), 0.60 - 0.42 (m, 2H), 0.17 (d, J= 4.50 Hz, 2H). Example 101. Synthesis of viral protease inhibitor compound 481 & 269A

Step 1: 4-chloro-JH-imidazo[4,5-cJpyridine

[000948] A mixture of 2-chloropyridine-3 ,4-diamine (3 g, 20.90 mmol, 1 eq) and HC1 (2.06 g, 20.90 mmol, 2.0 mL, 37% purity, 1 eq) in diethoxymethoxy ethane (30.9 g,

208.95 mmol, 34.7 mL, 10 eq) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 12 hr under N ₂ atmosphere. The precipitate formed was filtered, washed with PE. No purification. Compound 4-chloro-lH-imidazo[4,5- c]pyridine (3 g, 93.4% yield) was obtained as a white solid.

Step 2: l,5-dihydroimidazo[4,5-c]pyridin-4-one

[000949] To a solution of 4-chloro-lH-imidazo[4,5-c]pyridine (3 g, 19.54 mmol, 1 eq) and HC1 (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 l,5-dihydroimidazo[4,5-c]pyridin-4-one (2.5 g, crude) was obtained as yellow solid.

Step 3: 3-(2-trimethylsilylethoxymethyl)-5H-imidazo[4,5-c]pyridin-4- one [000950] To a solution of l,5-dihydroimidazo[4,5-c]pyridin-4-one (2.5 g, 18.50 mmol, 1 eq) and SEM-C1 (3.0 g, 18.50 mmol, 3.2 mL, 1 eq) in THF (1 mL) was added NaH (2.2 g, 55.50 mmol, 60% purity, 3 eq). The mixture was stirred at 25 °C for 2 hr. TLC (petroleum ether/ethyl acetate = 0:1, UV 254) indicated starting material was remained and new spots formed. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate (30 mL *3). The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 100% petroleum ether/ethyl acetate @ 35 mL/min). Compound 3-(2-trimethylsilylethoxymethyl)-5H-imidazo[4,5-c]pyridin- 4-one (1.8 g, 32.2% yield, 88% purity) was obtained as yellow solid.

Step 4: Methyl 3-cyclopropyl-2-[4-oxo-3-(2-trimethylsilylethoxymethyl)imida zo[4,5- c ]pyridin-5-yl ]propanoate

[000951] 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 K ₂ CO ₃ (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 H ₂ O (30 mL) and extracted with ethyl acetate (30 mL *3). The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ , 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 Jpropanoate (865 mg, 36.7% yield, 94% purity) was obtained as a white solid.

Step5: 3-cyclopropyl-2-[4-oxo-3-(2-trimethylsilylethoxymethyl)imida zo[4,5-c]pyridin-5- yljpropanoic acid

[000952 ] To a solution of methyl 3-cyclopropyl-2-[4-oxo-3-(2- trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-5-yl]propan oate (865 mg, 2.21 mmol,

1 eq) in H ₂ O (1 mL) and THF (1 mL) was added LiOH.H ₂ O (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 H ₂ O (2 mL) and added HC1 (2 mL, 2 N). The reaction mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate (30 mL *3). The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ , 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)imida zo[4,5-c]pyridin-5- yl]propanoic acid (746 mg, 86.7% yield, 97% purity) was obtained as a white solid.

[000953] 481 (N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclo propyl-2-[4- oxo-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-5- yl]propenamide): A mixture of (2S)-3-cyclopropyl-2-[4-oxo-3-(2-trimethylsilylethoxymethyl) imidazo[4,5- c]pyridin-5-yl]propanoic acid (600 mg, 1.59 mmol, 1 eq), (2S)-2-amino-3-[(3S)-2- oxopyrrolidin-3-yl]propanenitrile (301.4 mg, 1.59 mmol, 1 eq, HC1), HATU (604.3 mg, 1.59 mmol, 1 eq), DIPEA (410.8 mg, 3.18 mmol, 0.55 mL, 2 eq) in DCM (1 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 1 hr under N2 atmosphere. TLC (petroleum ether/ethyl acetate = 3:1, UV 254) indicated starting material was remained and new spots formed. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate (30 mL *3). The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ S0 ₄ , 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 ~ 45% petroleum ether/ethyl acetate @ 35 mL/min). Compound N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-2-[4-oxo-3-(2- trimethylsilylethoxymethyl)imidazo[4,5-c]pyridin-5-yl]propan amide (645 mg, 66.4% yield, 84% purity) was obtained as a white solid.

[000954] 269A: To a solution of N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3- cyclopropyl-2-[4-oxo-3-(2-trimethylsilylethoxymethyl)imidazo [4,5-c]pyridin-5- yl]propanamide (600 mg, 1.17 mmol, 1 eq) in THF (1 mL) was added TBAF (1 M, 2.3 mL, 2 eq). The mixture was stirred at 60 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX 80*40mm*3um;mobile phase: [water(0.05% NH3H ₂ O + 10 mM NH4HCO3)- ACN] ;B% : 5%-35%,9.5 min). Compound C19H22N6O3 (34 mg, 7.6% yield, 100% purity) was obtained as white solid.

[000955] (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyirolidin-3-yl]ethyl]-3-c yclopropyl-2-(4- oxo-3H-imidazo[4,5-c]pyridin-5-yl)propanamide (34 mg, 88.9 umol, 1 eq) was purity by SFC. The residue was purified by prep-HPLC (column: (s,s) WHELK-Ol (250mm*30mm,5um);mobile phase: [0.1%NH ₃ H ₂ O EtOH];B%: 40%-40%,min). Compound (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-c yclopropyl-2-(4- oxo-3H-imidazo[4,5-c]pyridin-5-yl)propanamide (18.56 mg, 54.5% yield, 100% purity) was obtained as white solid.

[000956] LCMS : Rt = 0.627 min; for C19H22N6O3MS Calcd.: 382.42; MS Found: 383.1

[M+H ⁺ ],

[000957] ¹ H NMR (400MHz, CD ₃ OD) δ 9.28 (br s, 1H), 7.94 - 7.79 (m, 1H), 6.86 (br d, J = 7.3 Hz, 1H), 5.74 - 5.50 (m, 2H), 4.62 - 4.18 (m, 2H), 3.50 - 3.32 (m, 1H), 3.14 (br s, 1H), 2.66 - 2.37 (m, 1H), 2.28 (br s, 1H), 2.16 - 1.95 (m, 3H), 1.92 - 1.72 (m, 2H), 0.62 (br s, 1H), 0.41 (br d, J= 3.8 Hz, 2H), 0.18 (br s, 1H), 0.03 (br d, J= 4.5 Hz, 1H).

Example 102. Synthesis of viral protease inhibitor compound 269

[000958] (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyirolidin-3-yl]ethyl]-3-c yclopropyl-2-(4- oxo-3H-imidazo[4,5-c]pyridin-5-yl)propanamide (28 mg, 73.2 umol, 1 eq) was purity by SFC. The residue was purified by prep-HPLC (column: (s,s) WHELK-01 (250mm*30mm,5um);mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 40%-40%,min). Compound (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-c yclopropyl-2-(4- oxo-3H-imidazo[4,5-c]pyridin-5-yl)propanamide (15.52 mg, 55.4% yield, 100% purity) was obtained as a white solid.

[000959] LCMS : Rt = 0.647 min; for C19H22N6O3MS Calcd.: 382.42; MS Found: 383.1

[M+H ⁺ ],

[000960] ¹ H NMR (400 MHz, CD3OD) δ 9.29 (br s, 1H), 7.88 (br d ,J= 6.3 Hz, 1H), 6.87 (br d,J= 6.5 Hz, 1H), 5.89 - 5.41 (m, 1H), 4.74 - 4.29 (m, 1H), 3.48 (br s, 1H), 3.30 - 3.09 (m, 1H), 2.67 - 2.42 (m, 1H), 2.39 - 2.21 (m, 1H), 2.21 - 1.99 (m, 3H), 1.94 - 1.55 (m, 1H), 0.63 (br s, 1H), 0.42 (br s, 2H), 0.27 - 0.08 (m, 2H).

Example 103. Synthesis of viral protease inhibitor compound 271 & 271A [000961] 271 A Isomer 1: (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3- cyclopropyl-2-[(5R)-1-methyl-6-oxo-l,7-diazaspiro[4.4]nonan- 7-yl]propanamide

[000962] 271 A Isomer 2: (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3- cyclopropyl-2-[(5S)-1-methyl-6-oxo-l,7-diazaspiro[4.4]nonan- 7-yl]propanamide

[000963] 271 Isomer 3: (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3- cyclopropyl-2-[(5R)-1-methyl-6-oxo-l,7-diazaspiro[4.4]nonan- 7-yl]propanamide

[000964] 271 Isomer 4: (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3- cyclopropyl-2-[(5S)-1-methyl-6-oxo-l,7-diazaspiro[4.4]nonan- 7-yl]propanamide

[000965] 270 was purified by prep- SFC (column: DAICEL CHIRALPAK

AS(250mm*30mm,10um);mobile phase: [0.1%NH3H2O ETOH];B%: 20%-20%,min) to give 271 A (30 mg) and 271 (20 mg). 271 A Isomer 1 & 2 was purified by prep-SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O Π>Α];Β%: 25%-25%,min) to give 271 A Isomer 1 (2.65 mg, 2% yield) and 271 A Isomer 2 (2.76 mg, 2% yield) as two white solid. 271 Isomer 1 & 271 Isomer 2 was purified by prep-SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, lOum); mobile phase: [0.1%NH ₃ H ₂ O MEOH]; B%: 40%-40%, min) to give 271 Isomer 1 (15.96 mg, 15% yield) and 271 Isomer 2 (13.71 mg, 13% yield) as two white solid.

[000966] 271 A Isomer 1 : LCMS: Rt = 1.208 min; for C _2I H _3I N ₅ O ₃ MS Calcd. : 401.24;

MS Found: 402.2 [M+H ⁺ ]; ¹ H NMR (400MHz, CD ₃ OD) δ 4.96 (dd, J = 6.8, 9.3 Hz,

1H), 4.66 - 4.61 (m, 1H), 3.50 (dd,J= 5.6, 8.1 Hz, 2H), 3.37 - 3.31 (m, 2H), 3.11 - 3.02 (m, 1H), 2.91 - 2.81 (m, 1H), 2.53 - 2.42 (m, 1H), 2.40 - 2.31 (m, 4H), 2.30 - 2.09 (m, 3H), 2.02 - 1.81 (m, 7H), 1.61 (td ,J= 7.2, 14.1 Hz, 1H), 0.69 - 0.60 (m, 1H), 0.55 - 0.40 (m, 2H), 0.20 - 0.13 (m, 2H).

[000967] 271 A Isomer 2: LCMS: Rt = 1.180 min; for C _2I H _3I N ₅ O ₃ MS Calcd.: 401.24;

MS Found: 402.2 [M+H ⁺ ]; ¹ H NMR (400MHz, CD ₃ OD) δ 5.01 (dd, J = 6.3, 9.9 Hz,

1H), 4.57 (t ,J= 7.8 Hz, 1H), 3.55 - 3.47 (m, 2H), 3.37 - 3.31 (m, 2H), 3.11 - 2.99 (m, 1H), 2.90 - 2.80 (m, 1H), 2.60 - 2.46 (m, 1H), 2.37 - 2.14 (m, 6H), 2.09 - 1.72 (m, 8H), 1.63 - 1.50 (m, 1H), 0.74 - 0.63 (m, 1H), 0.58 - 0.44 (m, 2H), 0.24 - 0.15 (m, 2H). [000968] 271 Isomer 1: LCMS: Rt = 1.217 min; for C21H31N5O3 MS Calcd.: 401.24;

MS Found: 402.2 [M+H ⁺ ]; ¹ H NMR (400MHz, CD3OD) δ 5.04 - 4.92 (m, 1H), 4.67 -

4.60 (m, 1H), 3.73 - 3.39 (m, 2H), 3.37 - 3.32 (m, 2H), 3.15 - 3.00 (m, 1H), 2.88 (d ,J = 6.5 Hz, 1H), 2.62 - 2.42 (m, 1H), 2.40 - 2.15 (m, 6H), 2.11 - 1.76 (m, 8H), 1.68 - 1.51 (m, 1H), 0.75 - 0.57 (m, 1H), 0.57 - 0.39 (m, 2H), 0.23 - 0.11 (m, 2H).

[000969] 271 Isomer 2: LCMS: Rt = 1.222 min; for C21H31N5O3 MS Calcd.: 401.24; MS Found: 402.2 [M+H ⁺ ]; ¹ H NMR (400MHz, CD3OD) δ 5.01 (dd, J = 6.1, 9.9 Hz, 1H), 4.56 (t ,J= 7.8 Hz, 1H), 3.70 - 3.61 (m, 1H), 3.49 - 3.40 (m, 1H), 3.37 - 3.32 (m, 1H), 3.30 - 3.23 (m, 1H), 3.06 - 2.98 (m, 1H), 2.87 - 2.77 (m, 1H), 2.53 (dq, J = 5.5, 9.3 Hz, 1H), 2.37 - 2.16 (m, 6H), 2.10 - 1.75 (m, 8H), 1.65 - 1.54 (m, 1H), 0.72 - 0.61 (m, 1H), 0.57 - 0.46 (m, 2H), 0.21 - 0.11 (m, 2H).

Example 104. Synthesis of viral protease inhibitor compound 273A, 273B & 273C

Step 1: 3-cyclopropyl-2-( 1 -oxo-2, 6-diazaspiro [4.5 ]decan-2-yl)propanoic acid

[000970] 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-(l-oxo-2,6-diazaspiro[4.5]decan-2-yl)propano ic acid (500 mg, crude) was obtained as a colorless oil.

Step 2: (2S)-3-cyclopropyl-2-(6-methyl-l-oxo-2,6-diazaspiro[4.5Jdeca n-2-yl)propanoic acid

[000971] 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 H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 0.5 hour. One spot was detected on TLC (Dichloromethane: Methanol=5/l, KMn0 ₄ ). 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 (SiO ₂ , 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.

Step 3: (2S)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ]-3-cyclopropyl-2-( 6-methyl- 1 -oxo-2, 6-diazaspiro[ 4.5 ]decan-2-yl)propanamide

[000972] To a solution of (2S)-3-cyclopropyl-2-(6-methyl- 1 -oxo-2, 6- diazaspiro[4.5]decan-2-yl)propanoic acid (0.3 g, 1.0 mmol, 1 eq) in DCM (6 mL) was added HATU (610.3 mg, 1.61 mmol, 1.5 eq), DIPEA (276.5 mg, 2.14 mmol, 0.37 mL,

2.0 eq), and 3a (243.51 mg, 1.28 mmol, 1.2 eq, HC1). The mixture was stirred at 25 °C for 1 hr. LC-MS showed 3 was consumed completely and 15% of desired compound was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini- NX 80*40mm*3um; mobile phase: [water (0.05%NH ₃ H ₂ 0+10mM NH ₄ HCO ₃ )-ACN]; B%: 17%-47%, 9.5 min) to give (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-3-cyclopropyl-2-(6-methyl- 1 -oxo-2, 6-diazaspiro[4.5]decan-2-yl)propanamide (60 mg, 13% yield) as a white solid.

[000973] 273 A: (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-c yclopropyl-

2-[(5R)-6-methyl-1-oxo-2,6-diazaspiro[4.5]decan-2-yl]prop anamide

[000974] 273B: (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-c yclopropyl-

2-[(5S)-6-methyl- 1 -oxo-2, 6-diazaspiro[4.5]decan-2-yl]propanamide

[000975] 273C: (2S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-c yclopropyl-

2-[(5R)-6-methyl-1-oxo-2,6-diazaspiro[4.5]decan-2-yl]prop anamide

[000976] 4 was purified by prep-SFC (column: DAICEL CHIRALPAK

AS(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 20%-20%,min) to give 273A & 273B (20 mg) and 273C (2.79 mg, 6.5 umol, 4% yield, 97% purity). 273A & 273B (20 mg) was purified by prep-SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH3H ₂ O ETOH];B%: 40%-40%,min) to give 273A (2.50 mg, 4.1% yield) and 273B (2.59 mg, 4% yield).

[000977] 273 A: LCMS: Rt = 1.362 min; for C22H33N5O3 MS Calcd. : 415.26; MS

Found: 416.2 [M+H ⁺ ], ¹ H NMR (400MHz, CD3OD) δ 4.79 (s, 1H), 4.52 - 4.47 (m, 1H), 3.34 - 3.24 (m, 2H), 3.20 - 3.15 (m, 2H), 2.60 - 2.44 (m, 1H), 2.35 - 2.24 (m, 1H), 2.22 - 2.00 (m, 4H), 1.94 (s, 3H), 1.83 - 1.64 (m, 4H), 1.60 - 1.31 (m, 7H), 0.55 - 0.38 (m, 1H), 0.37 - 0.20 (m, 2H), 0.06 - 0.12 (m, 2H).

[000978] 273B: LCMS: Rt = 1.353 min; for C22H33N5O3 MS Calcd.: 415.26; MS

Found: 416.2 [M+H ⁺ ], ¹ H NMR (400MHz, CD3OD) δ 4.83 (dd, J= 6.8, 9.3 Hz, 1H), 4.52 - 4.49 (m, 1H), 3.47 - 3.38 (m, 1H), 3.34 - 3.25 (m, 1H), 3.23 - 3.17 (m, 2H), 2.60 - 2.50 (m, 1H), 2.41 - 2.27 (m, 1H), 2.25 - 2.03 (m, 4H), 1.97 (s, 3H), 1.82 - 1.31 (m, 11H), 0.50 - 0.40 (m, 1H), 0.37 - 0.23 (m, 2H), 0.05 -0.06 (m, 2H).

[000979] 273C: LCMS: Rt = 1.363 min; for C22H33N5O3 MS Calcd.: 415.26; MS

Found: 416.2 [M+H ⁺ ], ¹ H NMR (400MHz, CD3OD) δ 4.82 (dd, J= 6.0, 10.0 Hz, 1H), 4.42 - 4.38 (m, 1H), 3.41 - 3.23 (m, 2H), 3.18 - 3.14 (m, 1H), 3.12 - 3.06 (m, 1H), 2.57 - 2.46 (m, 1H), 2.45 - 2.29 (m, 1H), 2.17 - 1.95 (m, 4H), 1.93 (s, 3H), 1.80 - 1.58 (m, 4H), 1.57 - 1.26 (m, 7H), 0.57 - 0.41 (m, 1H), 0.40 - 0.23 (m, 2H), 0.06 - 0.07 (m, 2H).

Example 105. Synthesis of viral protease inhibitor compound 278

7 -Amino-5, 6, 7, 8-tetrahydroquinoline- 7-carbonitrile

[000980] A solution of 6, 8-dihydro- 5H-quinolin-7-one (350 mg, 1.91 mmol, 1 eq, HC1) in

DCM (7 mL) were added NH ₃ (7 M, 2.72 mL, 10 eq) and Ti(i-PrO) ₄ (650.0 mg, 2.29 mmol, 0.67 mL, 1.2 eq) was stirred at 25 °C for 2 hr. TMSCN (283.6 mg, 2.86 mmol, 0.35 mL, 1.5 eq) was added and the solution was stirred at 25 °C for 16 hr. LC- MS showed starting material was consumed completely and one main peak with desired MS was detected. Ethyl acetate (50 mL) and H ₂ O (2.0 mL) were added, the reaction mixture was filtered, the filtrate was concentrated to reduce pressure. Compound 7- amino-6,8-dihydro-5H-quinoline-7-carbonitrile (260 mg, crude) was obtained as a yellow solid.

[000981] 278: N-(l-((7-Cyano-5,6,7,8-tetrahydroquinolin-7-yl)amino)-3-cycl opropyl- 1 - oxopropan-2-yl)-4-methoxy-1H-indole-2-carboxamide

[000982] A solution of 7-amino-6, 8-dihydro- 5H-quinoline-7-carbonitrile (80 mg, 0.46 mmol, 1 eq), (2S)-3-cyclopropyl-2-[(4-methoxy-1H-indole-2-carbonyl)amino] propanoic acid (153.5 mg, 0.50 mmol, 1.1 eq) and pyridine (365.3 mg, 4.62 mmol, 0.37 mL, 10 eq) in THF (2 mL) was stirred at 25 °C for 15 min. After POCl ₃ (177.0 mg, 1.15 mmol, 0.10 mL, 2.5 eq) was added drop wise at 0 °C, the reaction mixture was stirred at 25 °C for 16 hours. LC-MS showed starting material was remained and one peak with desired MS was detected. The reaction mixture was basified with Sat.NaHCO ₃ to pH=8 and extracted with ethyl acetate (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduce pressure. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water (0.05% NH ₃ H ₂ O+lO mM NH ₄ HCO ₃ )-ACN]; B%: 23% - 53%, 9.5 min) to give the title compound as a light yellow solid. Compound N-[2-[(7-cyano-6, 8-dihydro- 5H-quinolin- 7-yl)amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy- 1H-indole-2-carboxamide (2.32 mg, 1.08% yield, 98.6% purity) was obtained as a light yellow solid.

[000983] LCMS: Rt = 0.754 min; for C26H ₂ 7N5O3 MS Calcd.: 457.21; MS Found: 458.1

[M+H ⁺ ],

[000984] ¹ H NMR (400 MHz, CD ₃ OD) δ 8.37 - 8.24 (m, 1H), 7.65 - 7.56 (m, 1H), 7.29 - 7.12 (m, 3H), 7.03 (d ,J= 8.3 Hz, 1H), 6.52 (d ,J= 7.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 3.93 (s, 3H), 3.76 - 3.57 (m, 1H), 3.45 - 3.33 (m, 1H), 3.17 - 2.94 (m, 2H), 2.60 - 2.36 (m, 2H), 1.88 - 1.78 (m, 1H), 1.75 - 1.60 (m, 1H), 0.89 - 0.72 (m, 1H), 0.56 - 0.41 (m, 2H), 0.24 - 0.12 (m, 2H). [000985] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.56 (s, 1H), 8.79 (d ,J= 15.8 Hz, 1H),

8.53 - 8.43 (m, 1H), 8.36 (dd, J= 4.6, 11.4 Hz, 1H), 7.56 (d, J= 7.5 Hz, 1H), 7.35 (d, J= 14.3 Hz, 1H), 7.25 - 7.15 (m, 1H), 7.14 - 7.06 (m, 1H), 7.05 - 6.98 (m, 1H), 6.51 (d, J= 7.5 Hz, 1H), 4.61 - 4.45 (m, 1H), 3.89 (s, 3H), 3.59 (d, J= 16.8 Hz, 1H), 3.23 (d, J= 16.8 Hz, 1H), 2.98 - 2.83 (m, 2H), 2.42 (dd, J= 6.1, 12.9 Hz, 1H), 2.36 - 2.18 (m, 1H), 1.87 - 1.68 (m, 1H), 1.57 - 1.34 (m, 1H), 0.88 - 0.64 (m, 1H), 0.46 - 0.25 (m, 2H), 0.23 - 0.01 (m, 2H)

Example 106. Synthesis of viral protease inhibitor compound 323

Step for 323 Isomer 1& 2: N-[(lS)-l-[[(lS)-2-(tert-butylamino)-2-cyano-l-[[(3S)-2- oxopyrrolidin -3-yl ]methyl ] ethyl ] carbamoyl ] -3-methyl-butyl ]-4-methoxy-lH-indole-2- carboxamide

[000986] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- y 1 ]ethy 1 ]carbamoy 1 ]-3 -methyl- butyl]-4-methoxy-lH-indole-2-carboxamide (100 mg, 180.79 umol, 80% purity, 1 eq) in DCM (5 mL) was added PdCh (6.41 mg, 36.16 umol, 0.2 eq), Na ₂ SO ₄ (89.88 mg, 632.76 umol, 64.20 uL, 3.5 eq) and 2-methylpropan-2-amine (26.44 mg, 361.58 umol, 37.99 uL, 2 eq). The mixture was stirred at 25 °C for 30 min, then added TMSCN (35.87 mg, 361.58 umol, 45.23 uL, 2 eq), the mixture was stirred at 25 °C for 2 h. Upon the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by Hexane-IPA prep-HPLC to get the compound N-[(l S)-1-[[(l S)-2-(tert-butylamino)-2- cyano- 1 -[[(3 S)-2-oxo pyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4- methoxy- 1 H-indole-2-carboxamide (16.10 mg, 25.59 umol, 14.16% yield, 83.4% purity) and N-[( 1 S)- 1 -[[( 1 S)-2-(tert-butylamino)- 2-cyano- 1-[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indo le-2-carboxamide (7.92 mg, 12.27 umol, 6.79% yield, 81.3% purity) as white solid. MS (ESI) m/z 524.8 [M+H] ⁺ [000987] column: Phenomenex luna CN 5u 100*30 mm; mobile phase: [Hexane-

IPA];B%: 5%-60%,10 min

[000988] 1H NMR (400 MHz, DMSO-a¾) δ = 11.57 (s, 1H), 8.45 - 8.35 (m, 1H), 7.98 (d, J=9.3 Hz, 1H), 7.56 (s, 1H), 7.42 - 7.30 (m, 1H), 7.15 - 7.05 (m, 1H), 7.03 - 6.96 (m, 1H), 6.50 (d, J=7.6 Hz, 1H), 4.51 - 4.41 (m, 1H), 3.99 - 3.91 (m, 1H), 3.88 (s, 3H), 3.63 (dd, J=7.7, 10.2 Hz, 1H), 3.16 - 2.99 (m, 2H), 2.37 - 2.21 (m, 1H), 2.16 - 2.03 (m, 1H), 1.90 - 1.45 (m, 6H), 1.05 - 1.00 (m, 9H), 0.97 - 0.84 (m, 6H)

[000989] 1H NMR (400 MHz, DMS(M6) δ = 11.81 - 11.42 (m, 1H), 8.62 - 7.84 (m, 2H), 7.69 - 7.47 (m, 1H), 7.42 - 7.28 (m, 1H), 7.20 - 6.94 (m, 2H), 6.50 (d, J=7.6 Hz, 1H), 4.61 - 4.40 (m, 1H), 4.13 - 3.58 (m, 5H), 3.23 - 2.91 (m, 2H), 2.38 - 1.98 (m, 3H), 1.91 - 1.37 (m, 5H), 1.12 - 1.00 (m, 9H), 0.97 - 0.79 (m, 6H)

Example 107. Synthesis of viral protease inhibitor compound 325

N-[ (1S)-1-[[(1 S)-2-cyano-l-[[( 3S)-2-oxopyrrolidin-3-yl ] methyl ]-2-(2, 2, 2- trifluoroethylamino)ethyl ] carbamoyl ] -3-methyl-butyl ]-4-methoxy-lH-indole-2-carboxamide

[000990 ] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2-ca rboxamide (180 mg, 325.42 umol, 80% purity, 1 eq) in EtOH (2 mL) was added 2,2,2-trifluoroethanamine (64.47 mg, 650.84 umol, 51.17 uL, 2 eq) and ZnCh (8.87 mg, 65.08 umol, 3.05 uL, 0.2 eq). The mixture was stirred at 25 °C for 30 min, and then TMSCN (64.57 mg, 650.84 umol, 81.42 uL, 2 eq) was added. The mixture was stirred at 25 °C for 2 h. The residue was purified by HC1 prep-HPLC to get the compound N-[( 1 S)- 1 -[[( 1 S)-2-cyano- 1 -[[(3 S)- 2-oxopyrrolidin-3-yl]methyl]-2-(2,2,2- trifluoroethylamino)ethyl]carbamoyl]-3-methyl- butyl]-4-methoxy- 1 H-indole-2-carboxamide (120 mg, 215.78 umol, 66.31% yield, 99% purity) as a white solid. MS (ESI) m/z 551.2 [M+H] ⁺ [000991] Column: Phenomenex luna C 1880*40mm*3 um;mobile phase: [ water(0.04%HC1)- ACN] ;B% : 38%-62%,7min

[000992] ¹ H NMR (400MHz, DMSO-a¾) δ = 11.56 (dd, J=2.0, 5.5 Hz, 1H), 8.39 (br t, J=8.6 Hz, 1H), 8.32 - 8.16 (m, 1H), 7.59 (br d, J=17.6 Hz, 1H), 7.37 (dd, J=1.5, 5.7 Hz, 1H), 7.15 - 6.92 (m, 2H), 6.50 (d, J=7.7 Hz, 1H), 4.57 - 4.36 (m, 1H), 4.25 - 4.02 (m, 1H), 4.00 - 3.81 (m, 4H), 3.78 - 3.40 (m, 2H), 3.19 - 2.94 (m, 2H), 2.42 - 1.94 (m, 3H), 1.88 - 1.36 (m, 5H), 0.91 (dd,J=6.3, 15.1 Hz, 6H).

Example 108. Synthesis of viral protease inhibitor compound 327

[000993] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2-ca rboxamide (180 mg,

325.42 umol, 80% purity, 1 eq) in EtOH (4 mL) was added ZnCh (8.87 mg, 65.08 umol, 3.05 uL, 0.2 eq) and aniline (60.61 mg, 650.84 umol, 59.42 uL, 2 eq), and the mixture was stirred at 25 °C for 30 min. After the addition of TMSCN (64.57 mg, 650.84 umol,

81.42 uL, 2 eq), the mixture was stirred at 25 °C for 2 h. Upon the reaction was completed. The reaction mixture was filtered to get the product. The reaction mixture was purified by prep-HPLC to get the product N-[( 1 S)- 1 -[[( 1 S)-2-anilino-2-cyano- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4 -methoxy-lH-indole-2- carboxamide (70 mg, 122.10 umol, 37.52% yield, 95% purity) as a white solid. MS (ESI) m/z 545.3 [M+H] ⁺

[000994] 1H NMR (400MHz, DMSO-rf6) δ = 11.59 (br d, J=2.0 Hz, 1H), 8.44 (br d, J=7.7 Hz, 1H), 8.26 (d, J=9.5 Hz, 1H), 7.63 - 7.51 (m, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.26 - 6.94 (m, 4H), 6.80 - 6.65 (m, 3H), 6.51 (d, J=7.5 Hz, 1H), 6.34 (d, J=9.9 Hz, 1H), 4.59 - 4.20 (m, 3H), 3.89 (s, 3H), 3.18 - 2.95 (m, 2H), 2.44 - 2.30 (m, 1H), 2.24 - 2.00 (m, 1H), 1.97 - 1.43 (m, 6H), 0.99 - 0.82 (m, 6H)

Example 109. Synthesis of viral protease inhibitor compound 329

[000995] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy- lH-indole-2-carboxamide ( 100 mg, 180.79 umol, 80% purity, 1 eq) in EtOH (4 mL) was added (1S)-1-phenylethanamine (43.82 mg, 361.58 umol, 46.02 uL, 2 eq), ZnCh (4.93 mg, 36.16 umol, 1.69 uL, 0.2 eq). The mixture was stirred at 25 °C for 30 min, and then TMSCN (35.87 mg, 361.58 umol, 45.24 uL, 2 eq) was added. After stirring the mixture at 25 °C for 2 h, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by HC1 prep-HPLC to provide compound N-[( 1 S)- 1 -[[( 1 S)-2-cyano- l-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-2-[[(1S)-1-phenylethyl ]amino]ethyl]carbamoyl]-3- methyl-butyl]-4-methoxy-lH-indole-2-carboxamide (90 mg, 154.01 umol, 85.19% yield, 98% purity) as a white solid. MS (ESI) m/z 573.2 [M+H] ⁺

[000996] column: Phenomenex luna C1880*40mm*3 um;mobile phase:

[ water(0.04%HC1)- ACN] ;B% : 40%-70%,7 min

[000997] 1H NMR (400MHz, DMSO-d6) δ = 11.39 (br s, 1H), 8.46 - 7.80 (m, 2H), 7.52 - 6.89 (m, 9H), 6.51 (br d, J=7.5 Hz, 1H), 4.64 - 4.35 (m, 1H), 4.26 - 4.03 (m, 1H), 3.96 - 3.83 (m, 4H), 3.36 - 3.03 (m, 3H), 2.37 - 1.51 (m, 8H), 1.39 - 1.21 (m, 3H), 0.90 (br dd, J=5.7, 14.6 Hz, 6H)

Example 110. Synthesis of viral protease inhibitor compound 331

[000998] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy- lH-indole-2-carboxamide ( 100 mg, 180.79 umol, 80% purity, 1 eq) in EtOH (4 mL) was added pyrrolidine (25.72 mg, 361.58 umol, 30.18 uL, 2 eq), ZnCh (1 M, 1.81 uL, 0.01 eq). The mixture was stirred at 25 °C for 30 min, and then was added TMSCN (35.87 mg, 361.58 umol, 45.24 uL, 2 eq). The mixture was stirred at 25 °C for 2 h, and then the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by Hexane-IPA prep-HPLC to get the compound N-[( 1 S)- 1 -[[( 1 S)-2-cy ano- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]-2- pyrrolidin- 1 -y 1-ethy 1 ]carbamoy 1 ]-3 -methy 1-buty 1 ]-4- methoxy- 1 H-indole-2-carboxamide (19.34 mg, 33.19 umol, 18.36% yield, 89.7% purity) and N-[( 1 S)- 1 -[[( 1 S)-2-cyano- 1 -[[(3 S)-2-oxopyrrolidin -3-yl]methyl]-2-pyrrolidin-1-yl- ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2-carbo xamide (10.41 mg, 13.70 umol, 7.58% yield, 68.8% purity) as white solid. MS (ESI) m/z 523.4 [M+H] ⁺

[000999] column: Phenomenex luna CN 5u 100*30mm;mobile phase: [Hexane-IPA];B%: 5%-60%,10min

[0001000] 1H NMR (400MHz, DMSO-J6) δ = 11.58 (s, 1H), 8.43 (d, J=7.7 Hz, 1H), 8.19 (d, J=9.4 Hz, 1H), 7.61 - 7.50 (m, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.14 - 6.95 (m, 2H), 6.50 (d,J=7.6 Hz, 1H), 4.54 - 4.35 (m, 1H), 4.17 - 4.00 (m, 1H), 3.99 - 3.92 (m, 1H), 3.88 (s, 3H), 3.14 - 2.94 (m, 2H), 2.64 - 2.53 (m, 4H), 2.39 - 2.27 (m, 1H), 2.17 - 2.02 (m, 1H), 1.88 - 1.66 (m, 7H), 1.63 - 1.44 (m, 3H), 0.91 (dd,J=6.3, 16.2 Hz, 6H)

[0001001 ] 1H NMR (400MHz, DMSO-rf6) δ = 11.56 (br d, J=1.8 Hz, 1H), 8.43 - 8.30 (m, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=1.8 Hz, 1H), 7.16 - 6.94 (m, 2H), 6.50 (d, J=7.6 Hz, 1H), 4.55 - 4.35 (m, 1H), 4.13 - 4.03 (m, 1H), 4.02 - 3.94 (m, 1H), 3.88 (s, 3H), 3.13 - 3.01 (m, 2H), 2.70 - 2.57 (m, 2H), 2.43 - 2.29 (m, 1H), 2.17 - 1.94 (m, 2H), 1.88 - 1.34 (m, 9H), 0.90 (dd,J=6.5, 15.2 Hz, 6H)

Example 111. Synthesis of viral protease inhibitor compound 345

Step 1: tert-butyl ((S)-l-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carba mate [0001002] 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 N ₂ . The mixture was then stirred at 25 °C for 1 h. The mixture was quenched with NH ₄ CI aq. (20.0 mL), and extracted with EtOAc (20.0 mL*5). The organic layers were washed with brine (20.0 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate:petroleum ether=l :2 at 25 °C for 1 h to give tert-butyl ((S)-1- 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] ⁺ .

Step 2: (S)-3-((S)-2-ammo-3-hydroxypropyl)pyrrolidin-2-one

[0001003] A solution of tert- butyl ((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamate (2.39 g, 9.25 mmol, 1 eq) in HCl/MeOH (4 M, 23.9 mL, 10.33 eq) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give (S)- 3-((S)-2-amino-3-hydroxypropyl)pyrrolidin-2-one (1.8 g, crude, HC1) as a yellow oil.

Step 3:(2S, 4S)-tert-butyl 2-(((S)-l-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamoyl)-4-phenylpyrrolidine-l-carboxylate [0001004] To a solution of (S)-3-((S)-2-amino-3-hydroxypropyl)pyrrolidin-2-one (1.8 g, 9.25 mmol, 1 eq, HC1) in DMF (12 mL) and DCM (6 mL) was added TEA (5.61 g, 55.48 mmol, 7.72 mL, 6 eq), (2S,4S)-1-tert-butoxycarbonyl-4-phenyl-pyrrolidine-2-carboxy lic acid (2.69 g, 9.25 mmol, 1 eq), then T3P (17.65 g, 27.74 mmol, 16.5 mL, 50% purity, 3 eq) at 0 °C. After the mixture was stirred at 0 °C for 1 h, the mixture was quenched with water (40 mL) and extracted with EtOAc (20 mL* 5). The organic layers were washed with brine (20.0 mL), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by column chromatography (SiO ₂ , DCM: MeOH = 10:1 to 1: 1) to give (2S,4S)-tert-butyl 2-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)ca rbamoyl)- 4-phenylpyrrolidine- 1 -carboxylate (3.04 g, 6.69 mmol, 72.38% yield, 95% purity) as yellow solid. MS (ESI) m/z 432.2 [M+H] ⁺ .

Step 4: (2S,4S)-N-((S)-l-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-4- phenylpyrrolidine-2-carboxamide

[0001005] A mixture of (2S,4S)-tert-butyl 2-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamoyl)-4-phenylpyrrolidine-1-carboxylate (3.04 g, 7.04 mmol, 1 eq) in HCl/EtOAc (4 M, 30 mL, 17.03 eq) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure to give (2S,4S)-N-((S)-l -hydroxy-3 -((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-4-phenylpyrrolidine-2-carbox amide (2.59 g, crude, HC1) as white solid. MS (ESI) m/z 332.2 [M+H] ⁺ .

Step 5: (2S,4S)-N-((S)-l-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-l-(4-methoxy-lH- indole-2-carbonyl)-4-phenylpyrrolidine-2-carboxamide

[0001006] To a solution of (2S,4S)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-4-phenylpyrrolidine-2-carboxamide (2.58 g, 7.01 mmol, 1 eq, HC1) in DMF (16 mL) and DCM (8 mL) was added 4-methoxy- 1 H-indole-2-carboxylic acid (1.34 g, 7.01 mmol, 1 eq), DMAP (1.71 g, 14.03 mmol, 2 eq), and EDCI (2.69 g, 14.03 mmol, 2 eq). The mixture was stirred at 0 °C for 1 h. The mixture was quenched with water (50.0 mL) and extracted with EtOAc (20.0 mL* 4). The organic layers were washed with brine (20.0 mL), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by column chromatography (SiO ₂ , DCM: MeOH = 10:1 to 3:1) to give (2S,4S)-N-((S)-1- hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(4-methox y-lH-indole-2-carbonyl)- 4-phenylpyrrolidine-2-carboxamide (2.1 g, 3.79 mmol, 54.00% yield, 91% purity) as light yellow solid. MS (ESI) m/z 505.1 [M+H] ⁺ .

Step 6: (2S,4S)-l-(4-methoxy-lH-indole-2-carbonyl)-N-((S)-l-oxo-3-(( S)-2-oxopyrrolidin-3- yl)propan-2-yl)-4-phenylpyrrolidine-2-carboxamide

[0001007] To a mixture of (2S,4S)-N-((S)- 1 -hydroxy -3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)-1-(4-methoxy-lH-indole-2-carbonyl)-4-phenylpyrrolidine-2 -carboxamide (200 mg, 376.55 umol, 95% purity, 1 eq) in DMSO (2 mL) was added TFA (64.40 mg, 564.83 umol, 41.82 uL, 1.5 eq) and IBΧ (332.97 mg, 1.13 mmol, 95% purity, 3 eq), the mixture was stirred at 25 °C for 14 h. The mixture was quenched with NaHCO ₃ aq. (15.0 mL) and extracted with EtOAc (10.0 mL* 3). The organic layers were washed with brine (10.0 mL), dried over NazSO4, filtered, concentrated under reduced pressure, and purified by prep-HPLC to give (2S,4S)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)-N-((S)- 1 -oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-4-phenylpyrrolidine-2-carbox amide (58 mg, 111.95 umol, 29.73% yield, 97.0% purity) as white solid. MS (ESI) m/z 503.2 [M+H] ⁺ .

[0001008] prep-HPLC condition: column: Waters Xbridge BEH CIS

100*30mm*10um;mobile phase: [water(10mM NH4HC03)-ACN];B%: 20%- 50%,10min.

[0001009] ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 11.66 - 11.41 (m, 1H), 9.51 - 7.92 (m, 1H), 7.82 - 7.47 (m, 1H), 7.43 - 7.20 (m, 5H), 7.17 - 6.98 (m, 2H), 6.98 - 6.78 (m, 1H), 6.55 - 6.39 (m, 1H), 5.83 - 5.67 (m, 1H), 4.84 - 4.59 (m, 1H), 4.48 - 4.35 (m, 1H), 4.32 - 4.12 (m, 1H), 3.94 - 3.66 (m, 4H), 3.64 - 3.39 (m, 1H), 3.20 - 3.03 (m, 1H), 2.98 - 2.54 (m, 1H), 2.47 - 2.12 (m, 3H), 2.03 - 1.78 (m, 1H), 1.72 - 1.22 (m, 2H)

Step 7: (2S,4S)-N-((2S)-l-cyano-l-hydroxy-3-((S)-2-oxopyrrolidin-3-y l)propan-2-yl)-l-(4- methoxy-lH-indole-2-carbonyl)-4-phenylpyrrolidine-2-carboxam ide

[0001010] To a mixture of (2S,4S)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)-N-((S)- 1 -oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-4-phenylpyrrolidine-2 -carboxamide (90 mg, 179.08 umol, 1 eq) in DCM (1 mL) was added a solution ofNaHSO3 (74.54 mg, 716.33 umol, 50.37 uL, 4 eq) in H20 (0.5 mL), and then KCN (46.64 mg, 716.33 umol, 30.69 uL, 4 eq) at 0° C. The mixture was stirred at 25 °C for 14 h. The mixture was quenched with water (15.0 mL) and extracted with EtOAc (10.0 mL* 3). The organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure, and purified by prep-HPLC to give (2S,4S)-N-((2S)- 1 -cy ano- 1 -hydroxy-3 -((£)- 2-oxopyrrolidin-3-yl)propan-2-yl)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)-4- phenylpyrrolidine-2-carboxamide (29 mg, 54.76 umol, 30.58% yield, 100% purity) as white solid. MS (ESI) m/z 530.2 [M+H] ⁺ .

[0001011 ] prep-HPLC condition: column: Phenomenex luna C 1880*40mm*3 um;mobile phase: [water(0.04%HCl)-ACN];B%: 32%-48%,7min.

[0001012] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ ppm 11.66 - 11.42 (m, 1H), 8.63 - 8.22 (m, 1H), 7.62 (d ,J= 5.6 Hz, 0.5H), 7.44 (s, 0.5H), 7.41 - 7.29 (m, 4H), 7.29 - 7.21 (m, 1H), 7.15 - 7.07 (m, 1H), 7.06 - 6.99 (m, 1H), 6.98 - 6.92 (m, 0.5H), 6.86 - 6.78 (m, 0.5H), 6.70 (s, 1H), 6.53 - 6.41 (m, 1H), 5.32 - 5.18 (m, 0.5H), 4.86 - 4.66 (m, 0.5H), 4.66 - 4.54 (m, 0.5H), 4.45 - 4.34 (m, 1H), 4.24 - 4.15 (m, 0.5H), 4.12 - 3.96 (m, 1H), 3.95 - 3.87 (m, 0.5H), 3.87 - 3.76 (m, 3H), 3.76 - 3.66 (m, 0.5H), 3.64 - 3.56 (m, 0.5H), 3.52 - 3.42 (m, 1H), 3.20 - 3.09 (m, 1H), 2.85 - 2.74 (0.5, 1H), 2.62 - 2.54 (m, 0.5H), 2.46 - 2.35 (m, 1.5H), 2.30 - 1.98 (m, 2H), 1.92 - 1.80 (m, 0.5H), 1.68 - 1.19 (m, 2.5H).

Step8: (2S,4S)-N-((2S)-l-cyano-l-hydroxy-3-((S)-2-oxopyrrolidin-3-y l)propan-2-yl)-l-(4- methoxy-lH-indole-2-carbonyl)-4-phenylpyrrolidine-2-carboxam ide [0001013] (2S,4S)-N-((2S)- 1 -cyano- 1 -hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-l - (4-methoxy-lH-indole-2-carbonyl)-4-phenylpyrrolidine-2-carbo xamide (27 mg, 50.98 umol, 1 eq) was purified by SFC separation to give (2S, 4S)-N-((2S)-l -cyano- 1-hydroxy- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-1-(4-methoxy-lH-ind ole-2-carbonyl)-4- phenylpyrrolidine-2-carboxamide (13.03 mg, 22.71 umol, 44.54% yield, 92.3% purity) as a white solid. MS (ESI) m/z 530.2 [M+H] ⁺ , (2S,4S)-N-((2S)- 1 -cyano- 1 -hydroxy-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)-4- phenylpyrrolidine-2-carboxamide (12.12 mg, 19.86 umol, 38.96% yield, 86.8% purity) as white solid. MS (ESI) m/z 530.2 [M+H] ⁺ .

[0001014] Isomer 1 : ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 11.64 - 11.47 (m, 1H), 8.62 - 8.30 (m, 1H), 7.64 (s, 0.5H), 7.45 (s, 0.5H), 7.42 - 7.30 (m, 4H), 7.30 - 7.21 (m, 1H), 7.16 - 7.06 (m, 1H), 7.05 - 6.99 (m, 1H), 6.97 - 6.92 (m, 0.5H), 6.86 - 6.80 (m, 0.5H), 6.75 - 6.65 (m, 1H), 6.53 - 6.41 (m, 1H), 5.32 - 5.23 (m, 0.5H), 4.85 - 4.78 (m, 0.5H), 4.66 - 4.54 (m, 1H), 4.45 - 4.35 (m, 0.5H), 4.24 - 4.14 (m, 0.5H), 4.13 - 3.98 (m, 1H), 3.95 - 3.87 (m, 0.5H), 3.87 - 3.75 (m, 3H), 3.75 - 3.66 (m, 0.5H), 3.64 - 3.56 (m, 0.5H), 3.53 - 3.41 (m, 0.5H), 3.22 - 3.11 (m, 1H), 2.80 (t ,J= 8.8 Hz, 0.5H), 2.62 - 2.53 (m, 0.5H), 2.46 - 2.36 (m, 2H), 2.29 - 2.15 (m, 1.5 H), 2.14 - 1.97 (m, 1H), 1.69 - 1.54 (m, 0.5H), 1.51 - 1.12 (m, 2.5H)

[0001015] Isomer 2: ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 11.64 - 11.506 (m, 1H), 8.48 (d ,J= 9.6 Hz, 0.5H), 8.29 (d, J=9.6 Hz, 0.5H), 7.62 (s, 0.5H), 7.44 (s, 0.5H), 7.40 - 7.31 (m, 4H), 7.29 - 7.23 (m, 1H), 7.11 (q,J= 8.4 Hz, 1H), 7.05 - 6.99 (m, 1H), 6.98 - 6.94 (s, 0.5H), 6.84 - 6.78 (m, 0.5H), 6.77 - 6.69 (m, 1H), 6.52 - 6.42 (m, 1H), 5.23 (d, J= 7.2 Hz, 0.5H), 4.70 (d ,J= 6.8 Hz, 0.5H), 4.48 - 4.32 (m, 1H), 4.26 - 4.15 (m, 0.5H), 4.13 - 3.95 (m, 1H), 3.94 - 3.88 (m, 0.5H), 3.86 - 3.76 (m, 3H), 3.76 - 3.69 (m, 0.5H), 3.66 - 3.53 (m, 0.5H), 3.51 - 3.40 (m, 0.5H), 3.20 - 3.09 (m, 1H), 2.84 - 2.74 (m, 1H), 2.45 - 2.35 (m,

2H), 2.31 - 2.11 (m, 2H), 1.92 - 1.80 (m, 1H), 1.60 - 1.21 (m, 3H)

Example 112. Synthesis of viral protease inhibitor compound 355

Step 1: N-((2S)-l-(((2S)-l-cyano-l-hydroxy-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)amino)- 4-methyl-l-oxopentan-2-yl)-4-methoxy-lH-indole-2-carboxamide [0001016] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indole-2-ca rboxamide (150 mg, 338.98 umol, 1 eq) in DCM (2 mL) was added saturated NaHSCh (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 H ₂ O (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 Na ₂ SO ₄ , and concentrated to get the crude. The liquid water was added NaOH to pH=9, then quenched by aq NaCIO, then added NaOH to pH > 14. The crude was used to next step directly and without further purification. N-[(l S)-1-[[(l S)-2-cyano-2-hydroxy-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4-methoxy-lH-indo le-2-carboxamide (140 mg, crude) was obtained as yellow solid. MS (ESI) m/z 470.1 [M+H] ⁺ .

Step 2: (2S)-l-cyano-2-((S)-2-( 4-methoxy-lH-indole-2-carboxamido)-4-methylpentanamido)- 3-((S)-2-oxopyrrolidin-3-yl)propyl propylcarbamate

[0001017] A solution of 1 -i socy anatopropane (27.19 mg, 319.47 umol, 30.21 uL, 5 eq) in dry toluene (0.1 mL) was added dropwise to a solution of the N-[(1S)-1-[[(1 S)-2-cyano-2- hydroxy-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl ]-3-methyl-butyl]-4- methoxy- 1 H-indole-2-carboxamide (30 mg, 63.89 umol, 1 eq) in dry toluene (0.5 mL) at 0 °C, then the TEA (64.65 ug, 6.39e-l umol, 8.89e-2 uL, 0.01 eq) was added and the solution was stirred at 25 °C for 17 h under N ₂ . Upon completion, the solution was concentrated to give the crude. The residue was purified by prep-HPLC (FA condition), column: Phenomenex Luna C18200*40mm* lOum; mobile phase: [water (0.2%FA)- ACN]; B%: 30%-80%, 8min. [(2S)-1-cyano-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl) amino]-4-methyl-pentanoyl] amino]-3-[(3S)-2-oxopyrrolidin-3-yl] propyl] N- propylcarbamate (8 mg, 14.15 umol, 22.15% yield, 98.124% purity) was obtained as white solid.

[0001018] NMR (400MHz, METHANOL-d ₄ ) δ = 7.27 (s, 1H), 7.19 - 7.10 (m, 1H),

7.02 (d, J=8.3 Hz, 1H), 6.51 (d, J=7.7 Hz, 1H), 5.48 - 5.40 (m, 1H), 4.64 - 4.53 (m, 1H), 4.46 - 4.34 (m, 1H), 3.93 (s, 3H), 3.29 - 3.19 (m, 2H), 3.15 - 3.03 (m, 2H), 2.72 - 2.57 (m, 1H), 2.34 - 2.11 (m, 2H), 1.89 - 1.44 (m, 7H), 1.07 - 0.88 (m, 9H). MS (ESI) m/z 555.3 [M+H] ⁺ .

Step 3: N-( (2S)-l-( (( 1 S)-l-(4-imino-2-oxo-3-propyloxazolidin-5-yl)-2-( (S)-2-oxopyrrolidin-3- yl)ethyl)amino)-4-methyl-l-oxopentan-2-yl)-4-methoxy-lH-indo le-2-carboxamide

[0001019] A mixture of [(2S)-1-cyano-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl) amino]-4-methyl-pentanoyl] amino]-3-[(3S)-2-oxopyrrolidin-3-yl] propyl] N- propylcarbamate (50 mg, 90.15 umol, 1 eq) in NH ₄ HCO3 (0.01 M, 45.07 mL, 5 eq) and ACN (5 mL) was stirred at 25 °C for 17 h. Upon completion, the solution was extracted with EA(40 mL*3), the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The residue was purified by prep-HPLC, column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water ( 1 OmM NH4HCO3)- ACN]; B%: 25%-55%, 8min. N-[(l S)-1-[[(l S)-1-(4-imino-2-oxo-3-propyl-oxazolidin-5- yl)-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-methyl-b utyl]-4-methoxy-lH- indole-2-carboxamide (20 mg, 34.21 umol, 16.06% yield, 94.871% purity) was obtained as white solid. ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.31 - 7.21 (m, 1H), 7.19 - 7.10 (m, 1H), 7.06 - 6.98 (m, 1H), 6.56 - 6.46 (m, 1H), 5.16 - 5.03 (m, 1H), 4.79 - 4.37 (m, 2H), 3.96 - 3.88 (m, 3H), 3.58 - 3.40 (m, 2H), 3.28 - 3.13 (m, 2H), 2.65 - 2.51 (m, 1H), 2.41 - 2.05 (m, 2H), 1.90 - 1.40 (m, 7H), 1.07 - 0.87 (m, 9H).

Example 113. Synthesis of viral protease inhibitor compound 357

Step 1: (2S)-l-cyano-2-((S)-2-(4-methoxy-lH-indole-2-carboxamido)-4- methylpentanamido)- 3-((S)-2-oxopyrrolidin-3-yl)propyl isopropylcarbamate

[0001020] A solution of 2-i socy anatopropane (10.88 mg, 127.79 umol, 12.53 uL, 3 eq) in dry toluene (0.1 mL) was added dropwise to a solution of the N-[(1S)-1-[[(1 S)-2-cyano-2- hydroxy-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl ]-3-methyl-butyl]-4- methoxy- 1 H-indole-2-carboxamide (20 mg, 42.60 umol, 1 eq) in dry toluene (0.5 mL) at 0 °C. After the addition of TEA (4.31 mg, 42.60 umol, 5.93 uL, 1 eq), the solution was stirred at 25 °C for 16 h under dry argon atmosphere. Upon completion, the solution was concentrated to remove the toluene. The residue was purified by prep-HPLC (FA condition), column: Phenomenex Luna C 1875*30 mm*3 um; mobile phase: [water (0.2% FA)- ACN]; B%: 30%-70%, 8 min. [(2S)-1-cyano-2-[[(2S)-2-[(4-methoxy-lH- indole-2-carbonyl) amino]-4-methyl-pentanoyl] amino]-3-[(3 S)-2-oxopyrrolidin-3-yl] propyl] N-isopropylcarbamate (8 mg, 14.30 umol, 33.57% yield, 99.129% purity) was obtained as white solid. [0001021 ] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.27 (s, 1H), 7.19 - 7.10 (m, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.51 (d, J=7.7 Hz, 1H), 5.48 - 5.39 (m, 1H), 4.64 - 4.53 (m, 1H), 4.44 - 4.33 (m, 1H), 3.93 (s, 3H), 3.80 - 3.64 (m, 1H), 3.28 - 3.17 (m, 2H), 2.72 - 2.58 (m, 1H), 2.34 - 2.10 (m, 2H), 1.88 - 1.58 (m, 5H), 1.23 - 1.09 (m, 6H), 1.01 (td,J=5.7, 11.5 Hz, 6H). MS (ESI) m/z 555.3 [M+H] ⁺ .

Step 2: N-( (2S)-l-( ((JS)-1-( 4-imino-3-isopropyl-2-oxooxazolidin-5-yl)-2-((S)-2- oxopyrrolidin-3-yl)ethyl)amino)-4-methyl-l-oxopentan-2-yl)-4 -methoxy-lH-indole-2- carboxamide

[0001022] [(2S)-1-cyano-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl) amino]-4-methyl- pentanoyl] amino]-3-[(3S)-2-oxopyrrolidin-3-yl] propyl] N-isopropylcarbamate (110 mg, 198.33 umol, 1 eq) in NH4HCO3 (0.01 M, 30 mL, 1.51 eq) /ACN (5 mL) was stirred at 25 °C for 17 h. Upon completion, the solution was extracted with ethyl acetate (30 mL*3); the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The residue was purified by prep-HPLC (neutral condition), column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (lOmM NH4HC03 )- ACN] ; B%: 20%-50%, 8min. N-[( 1 S)-l -[[( 1 S)- 1 -(4-imino-3-isopropyl-2- oxo-oxazolidin-5-yl)-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carb amoyl]-3-methyl-butyl]-4- methoxy- 1 H-indole-2-carboxamide (27 mg, 48.55 umol, 24.48% yield, 99.738% purity) was obtained as white solid. ¹ H NMR (400MHz, METHANOL-i/4) δ = 7.33 - 7.21 (m, 1H), 7.19 - 7.10 (m, 1H), 7.07 - 6.97 (m, 1H), 6.57 - 6.46 (m, 1H), 5.06 - 4.96 (m, 1H), 4.73 (br d, J=11.2 Hz, 1H), 4.64 - 4.53 (m, 1H), 4.44 - 4.28 (m, 1H), 3.96 - 3.89 (m, 3H), 3.27 - 3.15 (m, 2H), 2.66 - 2.49 (m, 1H), 2.43 - 2.15 (m, 2H), 1.85 - 1.24 (m, 4H), 1.07 - 0.91 (m, 6H)

Example 114. Synthesis of viral protease inhibitor compound 359

Step 1: (2S)-1-cyano-2-((S)-2-(4-methoxy-JH-indole-2-carboxamido)-4- methylpentanamido)- 3-((S)-2-oxopyrrolidin-3-yl) propyl phenylcarbamate [0001023] 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-lH-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-l 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 H ₂ O (10 mL), extracted with ethyl acetate (20 mL * 3), the combined organic phase was dried over Na ₂ SO ₄ , 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-lH-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] ⁺ .

Step 2: N-[(lS)-l-[[(lS)-l-(4-imino-2-oxo-3-phenyl-oxazolidin-5-yl)- 2-[(3S)-2- oxopyrrolidin-3-yl ] ethyl ] carbamoyl / -3-methyl-butyl ]-4-methoxy-lH-indole-2-carboxamide [0001024] [(2S)-1-cyano-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl) amino]-4-methyl- pentanoyl] amino]-3-[(3S)-2-oxopyrrolidin-3-yl] propyl] N-phenylcarbamate (50 mg, 84.94 umol, 1 eq) in the solution of NH4HCO3 (0.01 M, 42.47 mL, 5 eq) and ACN (3 mL) was stirred at 25 °C for 17 h. Upon completion, the solution was extracted with ethyl acetate(40 mL * 3), and the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude, the residue was purified by prep-HPLC (neutral condition), column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 25%-50%,8min. N-[(1S)-1-[[(1S)-1-(4-imino-2- oxo-3-phenyl-oxazolidin-5-yl)-2-[(3S)-2-oxopyrrolidin-3-yl]e thyl]carbamoyl]-3-methyl- butyl]-4-methoxy-lH-indole-2-carboxamide (6 mg, 9.70 umol, 11.42% yield, 95.16% purity) was obtained as white solid. ¹ H NMR (400MHz, METHANOL-i/4) δ = 7.60 - 7.38 (m, 4H), 7.38 - 7.20 (m, 2H), 7.18 - 7.10 (m, 1H), 7.07 - 6.98 (m, 1H), 6.55 - 6.46 (m,

1H), 5.29 - 5.15 (m, 1H), 4.85 - 4.74 (m, 1H), 4.61 - 4.47 (m, 1H), 3.98 - 3.87 (m, 3H), 3.29 - 3.18 (m, 2H), 2.72 - 2.56 (m, 1H), 2.48 - 2.20 (m, 2H), 1.91 - 1.42 (m, 5H), 1.08 - 0.85 (m, 6H) MS (ESI) m/z 589.3 [M+H] ⁺ .

Example 115. Synthesis of viral protease inhibitor compound 361

Step 1: methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)-2-ox opyrrolidin-3- yljpropanoate

[0001025] 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 (2 S)-2-[ [(2 S)-2-amino-4-methy 1- 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] ⁺

Step 2: methyl (2S)-2-[[(2S)-4-methyl-2-[[4-(trifluoromethoxy)-lH-indole-2- carbonyl ] amino ]pentanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate [0001026] To a mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 901.91 umol, 90% purity, 1 eq) and 4- (trifluoromethoxy)- 1 H-indole-2-carboxylic acid (221.11 mg, 901.91 umol, 1 eq) in DCM (12 mL) and DMF (4 mL) was added EDCI (691.58 mg, 3.61 mmol, 4 eq) and DMAP (440.74 mg, 3.61 mmol, 4 eq). The mixture was stirred at 25 °C and stirred for 3 hours.

[0001027] LCMS showed the reaction was finished. The residue was concentrated in vacuum. The residue was purified by prep-HPLC (column: Kromasil C18 (250*

50mm* 10 um); mobile phase: [water (lOmM NH ₄ HCO ₃ )- ACN] ; B%: 30%-70%, 10 min) to give methyl (2S)-2-[[(2S)-4-methyl-2-[[4-(trifluoromethoxy)-lH-indole-2- carbonyl]amino]pentanoyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (250 mg, 427.35 umol, 47.38% yield, 90% purity) as white solid. MS (ESI) m/z 526.2 [M+H] ⁺ Step 3: N-f (1S)-1-[[(1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ] -3-methyl-butyl ]-4-( trifluoromethoxy)-lH-indole-2-carboxamide [0001028] A mixture of methyl (2S)-2-[[(2S)-4-methyl-2-[[4-(trifluoromethoxy)-lH- indole-2-carbonyl]amino]pentanoyl]amino]-3-[(3S)-2-oxopyrrol idin-3-yl]propanoate (250 mg, 474.83 umol, 1 eq) in ammonia (29.14 g, 1.71 mol, 28.57 mL, 3603.85 eq) was stirred at 80 °C and stirred for 16 hours. LCMS showed the reaction was finished. The reaction was concentrated to give the crude N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4 -(trifluoromethoxy)-lH- indole-2-carboxamide (200 mg, crude) (white solid). Crude product was used directly without further purification. MS (ESI) m/z 511.2 [M+H] ⁺

Step 4: N-f (1S)-1-[[(1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ] carbamoyl ]-3-methyl- butyl]-4-(trifluoromethoxy)-lH-indole-2-carboxamide

[0001029] 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-(trifluorometho xy)-lH-indole-2- carboxamide (35 mg, 68.43 umol, 1 eq) in DCM (2 mL) was added Burgess reagent (65.23 mg, 273.71 umol, 4 eq). The mixture was stirred at 25 °C and stirred for 3 hours. LCMS and HPLC showed the reaction was finished. The reaction was concentrated and purified by prep-HPLC (column: Phenomenex Gemini -NX C18 75* 30 mm* 3 um; mobile phase: [water(10mm NH4HCO3)- ACN] ; B%: 35 %-55 %, 8min) to give N-[(1S)- 1 -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-methyl-butyl]-4- (trifluoromethoxy)- 1 H-indole-2-carboxamide (10.02 mg, 20.30 umol, 29.67% yield, 100% purity) (white solid). MS (ESI) m/z 493.2 [M+H] ⁺

[0001030] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 12.04 (s, 1 H), 8.94- 9.08 (m, 1 H), 8.72- 8.74 (d, J=7.60 Hz, 1 H), 7.71- 7.76 (m, 1 H), 7.44 - 7.46 (d, J=7.60 Hz, 2 H), 7.21 -7.23 (m, 1 H), 7.02 - 7.05 (d, J=7.60 Hz, 1 H), 4.97 - 5.01 (m, 1 H), 4.47 - 4.50 (m, 1 H), 3.10- 3.14 (m, 2 H), 2.14- 2.15 (m, 1 H), 2.01 - 2.10 (m, 2 H), 1.67 - 1.70 (m, 1 H) 1.67 - 1.70 (m, 1 H), 1.69 - 1.72 (m, 4 H), 0.92 - 0.95 (m, 3 H), 1.69 - 1.72 (m, 3

H),

Example 116. Synthesis of viral protease inhibitor compound 363

Step J: 2-(trichloromethyl)-7-(trifluoromethoxy)-lH-benzo[d]imidazol e

[0001031 ] To a solution of 3-(trifluoromethoxy)benzene-l, 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 H ₂ O (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)- 1 H-benzimidazole (720 mg, crude) was obtained as a yellow solid. MS (ESI) m/z 320.8 [M+H] ⁺

Step 2: methyl 7-(trifluoromethoxy)-lH-benzo[d]imidazole-2-carboxylate

[0001032] To a solution of 2-(trichloromethyl)-7-(trifluoromethoxy)- 1 H-benzimidazole (720 mg, 2.25 mmol, 1 eq) in MeOH (10 mL) was added Na ₂ CO ₃ (238.85 mg, 2.25 mmol, 1 eq), and the mixture was stirred at 70 °C for 14 h. IN HC1 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 Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to get the product methyl 7-(trifluoromethoxy)- 1 H-benzimidazole-2-carboxylate (520 mg, crude) was obtained as a yellow solid. MS (ESI) m/z 260.8 [M+H] ⁺

Step 3: 7-(trifluoromethoxy)-lH-benzo[d]imidazole-2-carboxylic acid

To a solution of methyl 7-(trifluoromethoxy)- 1 H-benzimidazole-2-carboxylate (300 mg, 1.15 mmol, 1 eq) in THF (6 mL) and H ₂ O (2 mL) was added LiOH (165.69 mg, 6.92 mmol, 6 eq), and 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 (column: Waters Xbridge BEH C18 100 * 25mm * Sum; mobile phase: [water (lOmM NH4HCO ₃ )-ACN]; B%: 2%-40%, 9min) to get the product 7-(trifluoromethoxy)- lH-benzimidazole-2-carboxylic acid (150 mg, 591.12 umol, 51.26% yield, 97% purity) as a white solid. MS (ESI) m/z 245.1 [M-H] ⁺

[0001034] ¹ H NMR (DMSO-d ₆ , 400 MHz): δ ppm 7.46 (d, J= 8.2 Hz, 1H), 7.22 (t, J= 7.9 Hz, 1H), 7.10 - 7.14 (m, 1H)

Step 4: (S)-methyl 2-((S)-2-amino-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3 - yl)propanoate hydrochloride

[0001035] 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, HC1) as a white solid.

Step 5: (S)-methyl 2-((S)-4-methyl-2-(4-(trifluoromethoxy)-lH-benzo[d]imidazole -2- carboxamido)pentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propano ate

[0001036] To a solution of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 595.55 umol, 1.22 eq, HC1) and 7- (trifluoromethoxy)-lH-benzimidazole-2-carboxylic acid (120 mg, 487.52 umol, 1 eq) in DMF (1 mL) and DCM (6 mL) was added drop-wise EtsN (295.99 mg, 2.93 mmol, 407.14 uL, 6.0 eq) and T3P (930.72 mg, 1.46 mmol, 869.83 uL, 50% purity, 3.0 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition H ₂ O (40 mL) at 0 °C, and then extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate = 10/1 to 0/1) to get the product methyl (2S)-2- [[(2S)-4-methyl-2-[[7-(trifluoromethoxy)-lH-benzimidazole-2- carbonyl]amino]pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl ]propanoate (180 mg, 307.11 umol, 62.99% yield, 90% purity) was obtained as a colorless oil. MS (ESI) m/z 528.2 [M+H] ⁺ . [0001037] ¹ H NMR (400 MHz, METHANOL-d ₄ ): δ ppm 7.58 (br d ,J= 7.9 Hz, 1H), 7.40 (br t,J= 8.0 Hz, 1H), 7.21 - 7.33 (m, 1H), 4.64 (br t, J= 6.9 Hz, 1H), 4.55 - 4.59 (m, 1H), 3.72 (s, 3H), 3.22 - 3.30 (m, 2H), 2.60 (br d ,J= 9.0 Hz, 1H), 2.27 - 2.37 (m, 1H), 2.15 - 2.24 (m, 1H), 1.72 - 1.92 (m, 5H), 1.02 (br dd,J= 12.8, 6.1 Hz, 6H)

Step 6: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4- methyl-l-oxopentan-2-yl)-4-(trifluoromethoxy)-lH-benzo[d]imi dazole-2-carboxamide [0001038] A solution of methyl (2S)-2-[[(2S)-4-methyl-2-[[7-(trifluoromethoxy)-lH- benzimidazole-2-carbonyl]amino]pentanoyl]amino]-3-[(3S)-2-ox opyrrolidin-3- yl]propanoate (170 mg, 322.28 umol, 1 eq) in ammonia (7 M, 17 mL, 369.24 eq) was stirred at 80 °C for 12 h. [0001039 ] The reaction mixture was concentrated under reduced pressure to get the product N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1-[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]- 3-methyl-butyl]-7-(trifluoromethoxy)-lH-benzimidazole-2-carb oxamide (150 mg, crude) was obtained as a white solid. MS (ESI) m/z 513.2 [M+H] ⁺ .

Step 7: N-( (S)-l-( ( ( S)-l-cyano-2-( (S)-2-oxopyrrolidin-3-yl)ethyl)ammo)-4-methyl-l- oxopentan-2-yl)-4-(trifluoromethoxy)-lH-benzo[d]imidazole-2- carboxamide [0001040] To a solution of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-7-(trifluorometho xy)-lH-benzimidazole-2- carboxamide (100 mg, 195.13 umol, 1 eq) in DCM (6 mL) was added methoxy carbonyl - (triethylammonio)sulfonyl-azanide (232.51 mg, 975.65 umol, 5.0 eq). 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 (column: Phenomenex Luna C 18 75 * 30 mm *3 um; mobile phase: [water (0.2% FA)-ACN]; B%: 30%-70%, 8 min) to get the product N-[(l S)-1-[[(l S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3- methyl-butyl]-7-(trifluoromethoxy)-lH-benzimidazole-2-carbox amide (35.5 mg, 70.86 umol, 36.32% yield, 98.7% purity) was obtained as a white solid. MS (ESI) m/z 495.1 [M+H] ⁺ . [0001041 ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 13.73 (s, 1H), 8.86 - 9.04 (m, 2H), 7.71 (s, 1H), 7.56 (d ,J= 7.6 Hz, 1H), 7.37 - 7.44 (m, 1H), 7.26 - 7.37 (m, 1H), 4.98 (dd,J= 6.9, 1.2 Hz, 1H), 4.54 (br s, 1H), 3.07-3.19 (m, 2H), 2.33 - 2.43 (m, 1H), 2.14 (br dd ,J = 8.8, 4.9 Hz, 2H), 1.55 - 1.90 (m, 5H), 0.92 (dd,J= 8.8, 6.2 Hz, 6H)

Example 117. Synthesis of viral protease inhibitor compound 365

Step 1: methyl (2S)-2-[[(2S)-2-[[3-(4-chlorophenyl)-3-hydroxy-hutanoyl]amin o]-4-methyl - penta noyl ] amino ]-3-[( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001042] To a mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3- [(3 S)-2-oxopyrrolidin- 3 -y 1 Jpropanoate; hydro chloride (315.00 mg, 937.99 umol, 1 eq) and 3 -(4-chloropheny l)-3 -hydroxy- butanoic acid (201.33 mg, 937.99 umol, 1 eq) in DCM (3 mL) and DMF (6 mL) was added EDCI (359.62 mg, 1.88 mmol, 2 eq) and DMAP (229.19 mg, 1.88 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Upon the reaction was completed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC to get the compound methyl (2S)-2-[[(2S)-2-[[3-(4-chlorophenyl)-3-hydroxy-butanoyl]amin o]- 4-methyl -penta noyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (90 mg, 172.38 umol, 18.38% yield, 95% purity) and methyl (2S)-2-[[(2S)-2-[[3-(4-chlorophenyl)-3- hydroxy-butanoyl]amino]-4-methyl-pentaneyl]amino]-3-[(3S)-2- oxopyrrolidin-3- yl Jpropanoate (120 mg, 229.84 umol, 24.50% yield, 95% purity) as white solid. MS (ESI) m/z 496.3 [M+H] ⁺

[0001043] column: Kromasil C18 (250*50mm*10 um);mobile phase: [water(10mM NH4HC03 )- ACN] ;B% : 25%-55%,10min. Step 2: 3-(4-chlorophenyl)-3-hydroxy-butanoic acid

[0001044] To a mixture of ethyl 3-(4-chlorophenyl)-3-hydroxy-butanoate (500 mg, 2.06 mmol, 1 eq) in H ₂ O (3 mL) and THF (6 mL) was added LiOH.H ₂ O (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 H ₂ O (20 mL) and extracted with ethyl acetate 60 mL (30 mL * 2). The combined organic layers were washed with brine 930 mL), dried over Na ₂ SO ₄ , 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.

Step 3: (2S)-N-[ ( l S)-2-amino-2-oxo-l-[[ ( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl ]-2-[[3-( 4- chloro phenyl)-3- hydroxy-butanoyl] amino] -4-methyl-pentanamide [0001045] To a mixture of methyl (2S)-2-[[(2S)-2-[[3-(4-chlorophenyl)-3-hydroxy- butanoyl]amino]-4-methyl -pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (80 mg, 153.23 umol, 95% purity, 1 eq) was added NH ₃ /MeOH(7M) (7 M, 9.50 mL, 434.00 eq). The mixture was stirred at 80 °C for 16 h, and then the reaction mixture was concentrated under reduced pressure to give a residue compound (2S)-N-[(1S)-2-amino- 2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl] -2-[[3-(4-chlorophenyl)-3-hydroxy- butanoyl]amino]-4-methyl-pentanamide (70 mg, 130.98 umol, 85.48% yield, 90% purity) as a yellow oil. MS (ESI) m/z 481.2 [M+H] ⁺ .

Step 3:(2S)-2-[[3-(4-chlorophenyl)-3-hydroxy-butanoyl ]amino]-N-[ ( l S)-l-cyano-2-[ ( 3S)-2- oxopyrro lidin-3-yl ] ethyl ]-4-methyl-pentanamide

[0001046] 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 H ₂ O (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] ⁺ [0001047] Isomer 1 : 1H NMR (400MHz, METHANOL-d4) δ = 7.51 - 7.42 (m, 2H), 7.36 - 7.26 (m, 2H), 4.96 (dd, J=6.0, 10.1 Hz, 1H), 4.27 - 4.17 (m, 1H), 3.30 - 3.23 (m, 2H), 2.83 - 2.63 (m, 2H), 2.51 (dq, J=5.3, 9.3 Hz, 1H), 2.34 - 2.17 (m, 2H), 1.94 - 1.72 (m, 2H), 1.57 (s, 3H), 1.54 - 1.26 (m, 3H), 0.93 - 0.77 (m, 6H)

[0001048] Isomer 2: 1H NMR (400MHz, METHANOL-d4) δ = 7.44 (d, J=8.6 Hz, 2H), 7.34 - 7.24 (m, 2H), 5.06 - 4.93 (m, 1H), 4.26 - 4.13 (m, 1H), 3.38 - 3.32 (m, 1H), 3.29 - 3.24 (m, 1H), 2.85 - 2.62 (m, 2H), 2.53 (dq, J=5.5, 9.3 Hz, 1H), 2.42 - 2.17 (m, 2H), 1.98 - 1.74 (m, 2H), 1.52 (s, 3H), 1.49 - 1.36 (m, 2H), 1.31 - 1.18 (m, 1H), 0.90 - 0.79 (m, 3H), 0.72 (d, J=6.5 Hz, 3H)

Example 118. Synthesis of viral protease inhibitor compound 265

Step 1: Methyl (2S)-3-cyclopropyl-2-(7-oxo-lH-pyrrolo[2,3-c]pyridin-6-yl)pr opanoate [0001049] 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 Na ₂ SO ₄ , 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.

[0001050] LCMS: Rt = 0.746 min; for C14H16N ₂ O3 MS Calcd. : 260.12; MS Found: 260.9 [M+H ⁺ ],

[0001051 ] ¹ H NMR (400 MHz, CDCl ₃ ) δ 11.17 (br s, 1H), 7.29 (t, J= 2.76 Hz, 1H), 6.98 (d, J= 7.03 Ηζ,ΙΗ), 6.64 (d, J= 7.03 Hz, 1H), 6.39 (t, J= 2.38 Hz, 1H), 5.61 (dd, J= 9.79, 5.52 Hz, 1H), 3.74 (s, 3H), 2.17 - 2.07 (m, 1H), 2.06 -1.99 (m, 1H), 0.71 - 0.55 (m, 1H), 0.49 - 0.32 (m, 2H), 0.18 - 0.10 (m, 1H), 0.05 - 0.00 (m, 1H).

Step 2: (2S)-3-cyclopropyl-2-(7-oxo-JH-pyrrolo[2, 3-c]pyridin-6-yl)propanoic acid

[0001052] 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 K ₂ CO3 (15.9 mg, 0.115 mmol, 3 eq) in H ₂ O (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 H ₂ O (5 mL), adjusted pH to about 4 with 1M aq. HC1 and extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL) and dried over Na ₂ SO ₄ , 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)pr opanoic acid (8 mg, 32.1 umol, 83.7% yield, 99% purity) was obtained as a white solid.

[0001053] LCMS: Rt = 0.701 min; for C13H14N2O3 MS Calcd. : 246.10; MS Found: 246.9 [M+H ⁺ ],

265: N-[ ( l S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl ]-3-cyclopropyl-2-(7-oxo-lH- pyrrolo[ 2, 3-c ]pyridin-6-yl)propanamide

[0001054] To a solution of (2S)-3-cyclopropyl-2-(7-oxo- 1H-pyrrolo[2,3-c]pyridin-6- yl)propanoic acid (8 mg, 32.4 umol, 1 eq) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanenitrile (4.9 mg, 26.2 umol, HC1) in DMF (1 mL) was added TEA (3.2 mg, 32.4 umol, 4 uL, 1 eq) and T3P (31.0 mg, 48.7 umol, 28 uL, 50% purity, 1.5 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated in vacuum. The crude product was checked by HPLC and purified by prep- HPLC (column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [ water(0.05%NH3H ₂ O+ 10 mM NH4HCO3)- ACN]; B%: 14%-44%, 9.5min). N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3- cyclopropyl-2-(7-oxo-1H-pyrrolo[2,3-c]pyridin-6-yl)propanami de (2.9 mg, 23.5% yield) was obtained as a white solid.

[0001055] LCMS: Rt = 0.702 min; for C20H23N5O3 MS Calcd. : 381.18; MS Found: 382.0 [M+H ⁺ ], [0001056] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.21 - 7.15 (m, 1H), 7.11 - 7.02 (m, 1H), 6.60 - 6.49 (m,lH), 6.28 - 6.19 (m, 1H), 5.55 - 5.35 (m, 1H), 4.95 - 4.78 (m, 1H), 3.12 - 2.94 (m, 2H), 2.39 - 2.27 (m, 1H), 2.16 -1.99 (m, 2H), 1.90 - 1.82 (m, 2H), 1.76 - 1.61 (m, 2H), 0.56 - 0.43 (m, 1H), 0.31 - 0.17 (m, 2H), 0.04 - 0.02 (m, 1H), 0.02 - 0.00 (m, 1H).

Example 118a. Synthesis of viral protease inhibitor compound 369

Step 1: (2S)-methyl 2-((2S)-4-methyl-2-(4,4,4-trifluoro-3-hydroxy-3-phenylbutana mido)penta namido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

To a solution of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (140 mg, 467.66 umol, 1 eq) 4, 4, 4-trifluoro-3 -hydroxy-3 - phenyl-butanoic acid (164.27 mg, 701.48 umol, 1.5 eq) in DCM (1.5 mL) THF (1.5 mL) was added T3P (446.40 mg, 701.48 umol, 417.19 uL, 50% purity, 1.5 eq) and DIEA (181.32 mg, 1.40 mmol, 244.37 uL, 3 eq). The mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was complected, and desired MS was observed. The reaction mixture was concentrated under reduced pressure to remove solvent. The residure was purified by neutral prep- HPLC to get the product methyl (2S)-2-[[(2S)-4-methyl-2-[(4,4,4-trifluoro-3-hydroxy- 3-phenyl-butanoyl)amino]pentanoyl]amino]-3-[(3S)-2-oxopyrrol idin-3-yl]propanoate (120 mg, 232.77 umol, 49.77% yield) was obtained as white solid. MS (ESI) m/z 516.2 [M+H] ⁺ .

Step 2: (2S)-N-( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)-4-methyl-2- ( 4, 4, 4-trifluoro-3-hydroxy-3-phenylbutanamido)pentanamide

[0001057] 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-oxopyrrolid in-3-yl]propanoate (120 mg, 232.77 umol, 1 eq) in MeOH/NH ₃ (7 M, 5 mL, 150.36 eq) The mixture was stirred at 80 °C for 15 h. LCMS showed the reaction was complected, 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-ph enyl- butanoyl)amino]pentanamide (120 mg, crude) was obtained as colorless oil. MS (ESI) m/z 501.2 [M+H] ⁺ .

Step 3:

(2S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-4- methyl-2-(4,4,4-trifluoro-3- hydroxy-3-phenylbutanamido)pentanamide

[0001058] 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-ph enyl- 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 complected, and desired MS was observed. The reaction mixture was quenched by addition H ₂ O 5 mL, and then extracted with DCM (2.5 mL *

3). The combined organic layers were washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residure 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-hyd roxy-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] ⁺ .

Prep- HPLC condition:

[0001059] column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 25%-55%,8min

[0001060] column: Phenomenex Luna C 1875*30mm*3um;mobile phase: [water(0.2%FA)-ACN];B%: 40%-65%,8min

[0001061 ] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.83 (d, J=7.72 Hz, 1 H) 8.37 (d, J=8.16 Hz, 1 H) 7.72 (s, 1 H) 7.53 (br d, J=7.06 Hz, 2 H) 7.29 - 7.42 (m, 3 H) 7.16 (s, 1 H) 4.77 - 4.99 (m, 1 H) 4.15 - 4.28 (m, 1 H) 3.03 - 3.20 (m, 4 H) 2.16 - 2.27 (m, 1 H) 1.95 - 2.09 (m, 2 H) 1.57 - 1.78 (m, 2 H) 1.29 - 1.44 (m, 3 H) 0.69 - 0.88 (m, 6 H).

[0001062] (2S)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]-4-methyl-2-[(4,4,4- trifluoro-3-hydroxy-3-phenyl-butanoyl)amino]pentanamide (13.28 mg, 27.20 umol,

11.34% yield, 98.809% purity) was obtained as white solid MS (ESI) m/z 483.3[M+H]+.

[0001063] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 8.86 (d, J=7.94 Hz, 1 H) 8.58 (d, J=8.16 Hz, 1 H) 7.73 (s, 1 H) 7.51 - 7.62 (m, 2 H) 7.31 - 7.42 (m, 3 H) 6.92 (s, 1 H) 4.86 - 4.96 (m, 1 H) 4.11 (ddd, J=9.65, 8.32, 5.18 Hz, 1 H) 3.29 (br d, J=14.55 Hz, 1 H) 3.06 - 3.20 (m, 2 H) 2.89 (d, J=14.55 Hz, 1 H) 2.21 - 2.36 (m, 1 H) 2.02 - 2.17 (m, 2 H) 1.62 - 1.82 (m, 2 H) 1.20 - 1.38 (m, 2 H) 1.02 - 1.14 (m, 1 H) 0.73 (d, J=6.62 Hz, 3 H) 0.49 (d, J=6.39 Hz, 3 H).

Example 119. Synthesis of viral protease inhibitor compound 375

Step 1: methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate

[0001064] A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (1.2 g, 4.19 mmol, 1 eq) in HCl/MeOH (10 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to crude methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (770 mg, 4.14 mmol, 98.67% yield) as a yellow oil.

Step 2: methyl(2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cycloprop yl-propanoyl]amino]- 3-[ ( 3S)-2- oxopyrrolidin-3-yl ]propanoate

[0001065] To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (750 mg, 4.03 mmol, 1 eq) and (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoic acid (923.45 mg, 4.03 mmol, 1 eq) in DCM (3 mL) was added TEA (2.04 g, 20.14 mmol, 2.80 mL, 5 eq) in one portion at 0 °C. The mixture was added with T3P (3.84 g, 12.08 mmol, 3.59 mL, 3 eq) at 0 °C and stirred at 25 °C for 2 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine 10 mL (10 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude methyl (2S)-2-[[(2S)-2- (tert-butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3- yl]propanoate (1.5 g, 3.77 mmol, 93.70% yield) as a yellow oil. MS (ESI) m/z 398.3 [M+H] ⁺

Step 3: methyl (2S)-2-[[( 2S) -2 -amino- 3 -cyclopropyl-propanoyl ] amino ]-3-[(3S)-2- oxopyrrolidin-3-yl] propanoate

[0001066] 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 (10 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give crude methyl (2 S)-2-[ [(2 S)-2-amino-3 - cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]pr opanoate (900 mg, 3.03 mmol, 92.54% yield) as a yellow oil.

Step 4: methyl(2S)-2-[[(2S)-3-cyclopropyl-2-[(4-cyclopropyl-lH-indol e-2- carbonyl)amino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate [0001067] 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-cyclopropyl- 1 H-indole-2-carboxylic acid (364.61 mg, 1.81 mmol, 1.2 eq) in DCM (8 mL) was added DMF (2 mL) and EDCI (868.40 mg, 4.53 mmol, 3 eq) in one portion at 25 °C. The mixture was added with DMAP (553.43 mg, 4.53 mmol, 3 eq) and the reaction was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/l to 0/1) to afford methyl (2S)-2-[[(2S)-3-cyclopropyl-2- [(4-cyclopropyl-lH-indole-2-carbonyl)amino]propanoyl]amino]- 3-[(3S)-2-oxopyrrolidin- 3-yl]propanoate (500 mg, 1.04 mmol, 68.90% yield) as a white solid. MS (ESI) m/z 481.2 [M+H] ⁺ Step 5: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-2-yl ]methyl ]ethyl]amino]~ l-(cyclopropylmethyl)-2-oxo-ethyl]-4-cyclopropyl-lH-indole-2 -carboxamide

[0001068] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-cyclopropyl-lH-indole- 2-carbonyl)amino]propanoyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (500 mg,

1.04 mmol, 1 eq) in NH ₃ /MeOH (7M) (7 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give N-[(l S)-2-[[(l S)-2-amino-2- oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]-l -(cyclopropylmethyl)-2-oxo- ethyl]-4-cyclopropyl-lH-indole-2-carboxamide (390 mg, 837.73 umol, 80.52% yield) as a white solid. MS (ESI) m/z 466.3 [M+H] ⁺

Step 6: N-[ ( l S)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl]amino]-l- (cyclopropylmethyl)-2 -oxo-ethyl]-4-cyclopropyl-lH-indole-2-carboxamide [0001069] 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-lH-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-[( 1 S)-2-[[( 1 S)- 1 -cyano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmeth yl)-2-oxo-ethyl]-4- cyclopropyl-lH-indole-2-carboxamide (68 mg, 151.95 umol, 18.14% yield) as a white solid. MS (ESI) m/z 448.3 [M+H] ⁺

[0001070] Column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 30%-55%,8min

[0001071 ] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.55 (s, 1H), 9.12 - 8.84 (m, 1H), 8.59 (d, J=7.6 Hz, 1H), 7.84 - 7.65 (m, 1H), 7.48 (d, J=1.3 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.06 (t, J=7.7 Hz, 1H), 6.64 (d, J=7.2 Hz, 1H), 5.09 - 4.87 (m, 1H), 4.69 - 4.36 (m, 1H), 3.20 - 3.06 (m, 2H), 2.46 - 2.07 (m, 4H), 1.95 - 1.39 (m, 4H), 1.01 (br dd, J=2.2, 8.3 Hz, 2H), 0.92 - 0.74 (m, 3H), 0.55 - 0.34 (m, 2H), 0.28 - 0.00 (m, 2H)

Example 120. Synthesis of viral protease inhibitor compound 377

Step 1: methyl (2S)-2-[[(2S)-2-[(4-ethoxy -JH-indole-2-carbonyl)aminoJ-4-methyl- pentanoyl ] amino ] -3- [( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001072] To a mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3- [(3S)-2-oxopyrrolidin -3-yl]propanoate;hydrochloride (250.00 mg, 671.53 umol, 1 eq, HC1) and 4-ethoxy- 1 H-indole-2- carboxylicacid (165.36 mg, 805.83 umol, 1.2 eq) in DCM (10 mL) and DMF (5 mL) was added EDCI (257.46 mg, 1.34 mmol, 2 eq) and DMAP (164.08 mg, 1.34 mmol, 2 eq). After stirring the mixture at 25 °C for 2 h, the reaction mixture was diluted with H ₂ O (20 mL) and extracted with ethyl acetate (60 mL, which was extracted as 30 mL * 2). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether: ethyl acetate = 0: 1) to afford methyl(2S)-2-[[(2S)-2-[(4-ethoxy -lH-indole-2-carbonyl)amino]-4-methyl- pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 369.94 umol, 55.09% yield, 90% purity) as a yellow oil.

Step 2: N-[ (lS)-l-[[( lS)-2-amino-2-oxo- l-[[(2S)-2- oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ]-3- methyl-butyl ] -4-ethoxy- lH-indole-2-carboxamide

[0001073] A mixture of methyl (2S)-2-[[(2S)-2-[(4-ethoxy-lH-indole-2-carbonyl)amino]- 4-methyl-pentanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (120 mg, 246.63 umol, 1 eq) was added NH3/MeOH(7M) (4.20 mg, 246.63 umol, 20 mL, 1 eq) was stirred at 80 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue and used next directly. Compound N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 - [[(3S)-2- oxopyrrolidin -3-yl]methyl] ethyl]carbamoyl]-3-methyl-butyl]-4-ethoxy-lH- indole-2-carboxamide (112 mg, 213.76 umol, 86.67% yield, 90% purity) was obtained as a yellow oil. Step 3: N-[ (1S)-1-[[(1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl / ethyl ] carbamoyl /-3-methyl- butyl ]-4- ethoxy- lH-indole-2-carboxamide

[0001074] 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-lH-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 HC1 prep-HPLC to get the compound N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl] carbamoyl]-3-methyl-butyl]-4-ethoxy-lH-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] ⁺

[0001075] Column: Waters Xbridge BEH C18 100*30 mm* 10 um; mobile phase: [water(10 mM NH4HC03)-ACN]; B%: 30%-60%, 10 min

[0001076] H NMR (400 MHz, DMSO-d6) δ = 11.56 (br s, 1H), 8.90 (d, J= 8.1 Hz, 1H), 8.52 (br d, J=7.6 Hz, 1H), 7.72 (s, 1H), 7.39 (s, 1H), 7.11 - 7.03 (m, 1H), 7.01 - 6.96 (m, 1H), 6.48 (d, J=7.6 Hz, 1H), 5.04 - 4.92 (m, 1H), 4.57 - 4.37 (m, 1H), 4.14 (q, J=7.0 Hz, 2H), 3.21 - 3.03 (m, 2H), 2.43 - 2.28 (m, 1H), 2.21 - 2.04 (m, 2H), 1.82 - 1.46 (m, 5H), 1.41 (t, J=7.0 Hz, 3H), 0.91 (dd, J=6.4, 19.5 Hz, 6H)

Example 121. Synthesis of viral protease inhibitor compound 379

Step 1: methyl (2S) -2-[[( 2S) -2-amino-3-cyclopropyl-propanoyl /amino ]-3-[(3S)-2- oxopyrrolidin-3-yl /propanoate [0001077] 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 (10 mL) was stirred at 25 °C for 30 min. 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]pr opanoate (900 mg, 3.03 mmol, 92.54% yield) as a yellow oil.

Step 2: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-propoxy-lH-indole-2- carbonyl)amino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001078] 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-lH- 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 H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography (Si02, petroleum ether/ethyl acetate=5/l to 0/1) to afford methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-propoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3 S)-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] ⁺

Step 3: N-f ( l S)-2-[[( 1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ] ethyl ] amino ]- J-(cyclopropylmethyl)-2-oxo-ethyl]-4-propoxy-JH-indole-2-car boxamide

[0001079] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-propoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (480 mg, 962.75 umol, 1 eq) in NH ₃ /MeOH (7M) (3 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude N-[(1S)-2- [[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]et hyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-propoxy-lH-indole-2-carbo xamide (380 mg, 785.84 umol, 81.62% yield) as a white solid. MS (ESI) m/z 484.3 [M+H] ⁺ Step 4: N-f ( l S)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-propoxy-lH-indole-2-carbo xamide [0001080] To a mixture of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4- propoxy-lH-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-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-4- propoxy- 1 H-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] ⁺

[0001081 ] Column: Waters Xbridge Prep OBD C 18 150*40 mm* 10 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,8 min

[0001082] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.55 (br d, J=1.7 Hz, 1H), 9.07 - 8.85 (m, 1H), 8.57 (d, J=7.6 Hz, 1H), 7.83 - 7.61 (m, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.14 - 6.90 (m, 2H), 6.48 (d, J=7.6 Hz, 1H), 5.09 - 4.86 (m, 1H), 4.60 - 4.28 (m, 1H), 4.04 (t, J=6.4 Hz, 2H), 3.22 - 3.01 (m, 2H), 2.45 - 2.03 (m, 3H), 1.94 - 1.59 (m, 5H), 1.58 - 1.34 (m, 1H), 1.06 (t, J=7.4 Hz, 3H), 0.95 - 0.69 (m, 1H), 0.55 - 0.30 (m, 2H), 0.28 - -0.02 (m, 2H)

Example 122. Synthesis of viral protease inhibitor compound 383

Step 1: methyl (2S)-2-[[(2S)-2-[ ( 4, 4-difluorocyclohexyl)methoxycarbonylamino]-4-methyl- pentanoy l ] amino ]-3-[( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001083] To a mixture of bis(trichloromethyl) carbonate (940 mg, 3.17 mmol, 1.36 eq) in THF (2 mL) was added DIEA (602.47 mg, 4.66 mmol, 811.95 uL, 2 eq) at 25 °C, and then (4,4-difluorocyclohexyl)methanol (350 mg, 2.33 mmol, 1 eq) in THF (2 mL) was added at 0 °C. After stirring the mixture at 0 °C for 15 min, the reaction was heated to 25 °C and stirred for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue (4,4-difluorocyclohexyl)methyl carbonochloridate (400 mg, 1.51 mmol, 64.57% yield, 80% purity) as a yellow oil.

[0001084] To a mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3- [(3S)-2-oxopyrrolidin -3-yl]propanoate;hydrochloride (300 mg, 893.32 umol, 1 eq) in THF (3 mL) was added DIEA (346.37 mg, 2.68 mmol, 466.80 uL, 3 eq) and (4,4- difluorocyclohexyl)methyl carbonochloridate (356.14 mg, 1.34 mmol, 80% purity, 1.5 eq) in THF (2 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min and 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 column chromatography (SiO ₂ , petroleum ether/ethyl acetate=8/l to 0/1) to afford methyl (2S)-2- [[(2S)-2-[(4,4- difluorocyclohexyl)methoxycarbonylamino]-4-methyl-pentanoyl] amino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (320 mg, 605.65 umol, 67.80% yield, 90% purity) as a yellow oil. MS (ESI) m/z 476 [M+H] ⁺

Step 2: 4,4-difluorocyclohexyl)methyl N-[(lS)-l-[[(lS)-2- amino-2-oxo-1-[[(3S)-2- oxopyrrolidin -3-yl ] methyl ] ethyl ] carbamoyl ]-3-methyl-butyl ] carbamate [0001085] To a mixture of methyl (2S)-2-[[(2S)-2-[(4,4- difluorocyclohexyl)methoxycarbonylamino]-4-methyl- pentanoyl]amino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (300 mg, 630.88 umol, 1 eq) was added NH3/MeOH(7M) (10.74 mg, 630.89 umol, 1 eq). After stirring the mixture at 80 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give a residue and used next step directly. Compound (4,4-difluorocyclohexyl)methyl N-[(1S)-1-[[(1S)-2- amino-2-oxo-1- [[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-but yl]carbamate (280 mg, 364.81 umol, 57.83% yield, 60% purity) was obtained as a yellow oil. MS (ESI) m/z 461.3 [M+H] ⁺

Step 3: (4,4-difluorocyclohexyl)methyl N-[(lS)-l-[[(lS)-l-cyano-2-[(3S)-2-oxopyrrolidin-3- yl ] ethyl ] carbamoyl ]-3-methyl-butyl ] carbamate

[0001086] To a mixture of (4,4-difluorocyclohexyl)methylN-[(l S)-1-[[(l S)-2-amino-2- oxo- 1 -[ [(3 S)-2-oxopy rrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]carbama te (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 H ₂ O (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-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-[(3 S)-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]+

Column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water(10 mM NH4HC03)-ACN]; B%: 25%-45%,8 min

H NMR (400 MHz, DMSO-d6) δ = 8.81 (d, J=8.0 Hz, 1H), 7.81 - 7.66 (m, 1H), 7.40 (br d, J=7.8 Hz, 1H), 5.01 - 4.81 (m, 1H), 4.03 - 3.88 (m, 1H), 3.83 (br d, J=6.1 Hz, 2H), 3.21 - 3.03 (m, 2H), 2.40 - 2.22 (m, 1H), 2.18 - 1.94 (m, 4H), 1.90 - 1.54 (m, 8H), 1.53 - 1.30 (m, 2H), 1.29 - 1.10 (m, 2H), 0.87 (dd, J=6.5, 12.8 Hz, 6H)

Example 123. Synthesis of viral protease inhibitor compound 385

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001087] A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (350 mg, 1.22 mmol, 1 eq) in HCl/EtOAc (4 M, 5 mL, 16.36 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated to give methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (272 mg, crude, HC1) as a yellow oil.

Step 2:

(2S)-tert-butyl 4-(bicyclo[l.1.1 ]pentan- l-yl)-2-(((S)-l -methoxy- 1 -oxo-3 -(( S)-2-oxopyrrolidin-

3-yl)propan-2-yl)carbamoyl)pyrrolidine-l-carboxylate

[0001088] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (272 mg, 1.22 mmol, 1 eq, HC1) in DCM (6 mL) was added DMAP (298.47 mg, 2.44 mmol, 2 eq) and EDCI (468.34 mg, 2.44 mmol, 2 eq), and then (2S)-4-(l- bicyclo[l .1. l]pentanyl)-1-tert-butoxycarbonyl-pyrrolidine-2-carboxylic acid (343.68 mg,

1.22 mmol, 1 eq) was added. The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O (20 mL) at 25 °C, and then extracted with DCM (25 mL * 3). The combined organic layers were washed with brine (25 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 0/1) to give tert- butyl (2S)-4-(l-bicyclo[l .1.1 ]pentanyl)-2-[[( 1S)-2-methoxy-2- oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]pyr rolidine-1-carboxylate (450 mg, 1.00 mmol, 81.95% yield) as a yellow solid. MS (ESI) m/z 450.1 [M+H] ⁺

Step 3:

(2S)-methyl 2-( (2S)-4-(bicyclo[ 1.1.1 ]pentan- l-yl)pyrrolidine-2-carboxamido)-3-((S)-2- oxopyrrolidin-3-yl)propanoate

[0001089] A solution of tert- butyl (2S)-4-( 1 -bicyclo[ 1.1.1 ]pentanyl)-2-[[( 1 S)-2-methoxy-2- oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]pyr rolidine-1-carboxylate (350 mg, 778.58 umol, 1 eq) in HCl/MeOH (5 mL) was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was concentrated to give methyl (2S)-2-[[(2S)-4-(l- bicyclo[l.1. l]pentanyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxopyrrol idin-3- yl]propanoate (300 mg, crude, HC1) as a yellow solid.

Step 4:

(2S)-methyl 2-((2S)-4-(bicyclo[ 1.1.1 ]pentan- l-yl)-l -(4-methoxy-l H-indole-2- carbonyl)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3 -yl)propanoate [0001090] To a solution of 4-methoxy-1H-indole-2-carboxylic acid (222.95 mg, 1.17 mmol, 1.5 eq), methyl (2S)-2-[[(2S)-4-( 1 -bicyclo[ 1.1.1 ]pentanyl)pyrrolidine-2- carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 777.43 umol, 1 eq, HC1) in DCM (6 mL) was added DMAP (284.94 mg, 2.33 mmol, 3 eq) and GDI (378.18 mg, 2.33 mmol, 3 eq). The mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was poured into H ₂ O (20 mL) at 25 °C, and then extracted with DCM (30 mL *3). The combined organic layers were washed with brine (25 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Column: Kromasil C18 (250 * 50 mm * 10 um);mobile phase: [water(10 mM HCOONH4)-ACN]; B%: 35%-55%, 10 min) to give methyl (2S)-2- [[(2S)-4-( 1 -bicyclo[ 1.1.1 ]pentanyl)- 1 -(4-methoxy- 1H-indole-2-carbonyl)pyrrolidine-2- carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 373.91 umol, 48.09% yield, 97.70% purity) and methyl (2S)-2-[[(2S)-4-( 1 -bicyclo[ 1.1.1 ]pentanyl)- 1 -(4- methoxy-1H-indole-2-carbonyl)pyrrolidine-2-carbonyl]amino]-3 -[(3S)-2-oxopyiTolidin- 3-yl]propanoate (70 mg, 127.20 umol, 16.36% yield, 94.96% purity) as a yellow solid.

MS (ESI) m/z 523.2 [M+H] ⁺

Step 5: (2S)-N-( (S)-l -amino- 1 -oxo-3-( (, S)-2-oxopyrrolidin-3-yl)propan-2-yl)-4 - (bicyclof 1.1.1 ]pentan-l-yl)-l -(4-methoxy- lH-indole-2-carbonyl)pyrrolidine-2-carboxamide

[0001091 ] Isomer 1 : A solution of methyl (2S)-2-[[(2S)-4-(l-bicyclo[l .1. l]pentanyl)-1-(4- methoxy-lH-indole-2-carbonyl)pyrrolidine-2-carbonyl]amino]-3 -[(3S)-2-oxopyrrolidin- 3-yl]propanoate (200 mg, 382.71 umol, 1 eq) in NH ₃ /MeOH (7 M, 8 mL, 146.33 eq) was stirred at 80 °C for 24 h. Upon completion, the reaction mixture was concentrated to give (2S)-N-[( 1 S)-2-amino-2-oxo-l -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-4-( 1 - bicyclo[l .1. l]pentanyl)-l -(4-methoxy- lH-indole-2-carbonyl)pyrrolidine-2-carboxamide (150 mg, crude) as a yellow solid. MS (ESI) m/z 508.2 [M+H] ⁺

[0001092] Isomer 2: A solution of methyl (2S)-2-[[(2S)-4-(l-bicyclo[l .1. l]pentanyl)-1-(4- methoxy-lH-indole-2-carbonyl)pyrrolidine-2-carbonyl]amino]-3 -[(3S)-2-oxopyrrolidin- 3-yl]propanoate (70 mg, 133.95 umol, 1 eq) in NH ₃ /MeOH (7 M, 4 mL, 209.04 eq) was stirred at 80 °C for 24 hr. Upon completion, the reaction mixture was concentrated to give (2S)-N-[( 1 S)-2-amino-2-oxo-l -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-4-( 1 - bicyclo[l.1.1 ]pentanyl)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)pyrrolidine-2-carboxamide (50 mg, crude) as a yellow solid. MS (ESI) m/z 508.2 [M+H] ⁺

Step 6: (2S)-4-(bicyclo[ 1.1.1 ]pentan-l-yl)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)eth yl)- l-( 4-methoxy- lH-indole-2-carbonyl)pyrrolidine-2-carboxamide

[0001093 ] Isomer 1 : To a solution of (2S)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl]-4-(l-bicyclo[l .1. l]pentanyl)-l -(4-methoxy- lH-indole- 2-carbonyl)pyrrolidine-2-carboxamide (145 mg, 285.67 umol, 1 eq) in DCM (4 mL) was added Burgess reagent (680.76 mg, 2.86 mmol, 10 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O (20 mL) at 25 °C, and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75 * 30 mm * 3 um; mobile phase: [water(10 mM NH4HC03)- ACN];B%: 30%-50%,8 min) to give (2S)-4-(l-bicyclo[l.l.l]pentanyl)-N-[(1S)-1-cyano- 2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]- 1 -(4-methoxy- lH-indol e-2-carbonyl)pyrrolidine-2- carboxamide (46 mg, 93.11 umol, 32.59% yield, 99.09% purity) as a white solid. MS (ESI) m/z 490.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.24 - 6.79 (m, 3H), 6.56 - 6.41 (m, 1H), 5.05 (s, 1H), 4.63 (d, J=4.4 Hz, 1H), 4.34 - 3.36 (m, 6H), 3.03 - 1.50 (m, 15H), 1.37 (d, J=8.4 Hz, 1H).

[0001094] Isomer 2 : To a solution of (2S)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl]-4-(l-bicyclo[l .1. l]pentanyl)-l -(4-methoxy- lH-indole- 2-carbonyl)pyrrolidine-2-carboxamide (50 mg, 98.51 umol, 1 eq) in DCM (2 mL) was added Burgess reagent (70.42 mg, 295.52 umol, 3 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O (20 mL) at 25 °C, and then extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 um; mobile phase: [water(10 mM NH4HC03)-ACN];B%: 30%-50%,8 min) to give (2S)-4-(l-bicyclo[l.l.l]pentanyl)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-1-(4-methoxy-lH-indole-2-carbonyl) pyrrolidine-2-carboxamide (10 mg, 20.14 umol, 20.45% yield, 98.61% purity) as a white solid. MS (ESI) m/z 490.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.16 (d, J=7.9 Hz, 1H), 7.10 - 7.00 (m, 2H), 6.53 (d, J=7.7 Hz, 1H), 5.01 (s, 1H), 4.66 (d, J=5.4, 8.3 Hz, 1H), 4.18 - 4.05 (m, 1H), 3.95 (s, 3H), 3.89 (s, 1H), 3.79 (d, J=6.4, 9.9 Hz, 1H), 2.70 - 2.60 (m, 1H), 2.51 (d, J=17.0 Hz, 2H), 2.43 (d, J=4.3, 8.5, 12.5 Hz, 1H), 2.30 (d, J=6.6, 13.7 Hz, 1H), 2.20 - 2.11 (m, 1H), 2.04 - 1.83 (m, 3H), 1.81 - 1.69 (m, 7H).

Example 124. Synthesis of viral protease inhibitor compound 387

Step 1: (S)-methyl 2-ammo-3-((S)-2-oxopyrrolidm-3-yl)propanoate

[0001095] A mixture of methyl (2 S)-2-(tert-butoxy carbonyl amino)-3 -[(3 S)-2- oxopyrrolidin-3-yl]propanoate (0.3 g, 1.05 mmol, 1 eq) in HCl/EtOAc (4 M, 5 mL, 19.09 eq) was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (0.2 g, crude) as a yellow gum.

Step 2: tert-butyl 3-( ( (S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamoyl)-8-oxa-2-azaspiro[ 4.5 ]decane-2-carboxylate

[0001096] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (0.18 g, 808.38 umol, 1 eq, HC1) in DMF (1 mL) and DCM (2 mL) was added DMAP (197.52 mg, 1.62 mmol, 2 eq), 2-tert-butoxycarbonyl-8-oxa-2-azaspiro[4.5]decane-3- carboxylic acid (230.66 mg, 808.38 umol, 1 eq) and EDCI (309.93 mg, 1.62 mmol, 2 eq), and then the resulting solution was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1:1 to 0:1) to give tert-butyl 3-[[(l S)-2-methoxy-2-oxo-1- [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-8-oxa-2- azaspiro[4.5]decane-2- carboxylate (0.3 g, 562.26 umol, 69.55% yield, 85% purity) as a colorless oil. MS (ESI) m/z 454.2 [M+H] ⁺ .

Step 3: (2S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-(8-oxa-2-azaspiro[4.5]decane- 3- carboxamido)propanoate

[0001097] A mixture of tert-butyl 3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-8-oxa-2-azaspiro[4.5]decane-2-car boxylate (0.25 g, 551.23 umol, 1 eq) in HCl/EtOAc (5 mL) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-(8-oxa- 2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (0.2 g, crude, HC1) as a yellow oil.

Step 4: (2S)-methyl 2-(2-(4-methoxy-lH-indole-2-carbonyl)-8-oxa-2-azaspiro[4.5]d ecane-3- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001098 ] To a solution of methyl (2 S)-2-(8-oxa-2-azaspiro[4.5 ]decane-3 -carbony lamino)- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (0.2 g, 512.99 umol, 1 eq, HC1) in DMF (1 mL) and DCM (2 mL) was added DMAP (125.34 mg, 1.03 mmol, 2 eq), and then 4-methoxy- 1 H-indole-2-carboxylic acid (107.88 mg, 564.29 umol, 1.1 eq) and EDCI (196.68 mg,

1.03 mmol, 2 eq) was added. The solution was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (5 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 0:1 to DCM:MeOH = 10:1) to give methyl (2S)-2- [[2-(4-methoxy-lH-indole-2-carbonyl)-8-oxa-2-azaspiro[4.5]de cane-3-carbonyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (0.13 g, 232.06 umol, 45.24% yield, 94% purity) as a yellow solid. MS (ESI) m/z 527.2 [M+H] ⁺ .

Step 5: N-( (S)-l -amino-1 -oxo-3-( (, S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-( 4-methoxy-lH- indole-2-carbonyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxamide

[0001099] A mixture of methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)-8-oxa-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidi n-3-yl]propanoate (0.13 g, 246.88 umol, 1 eq) in NH ₃ .MeOH (7 M, 3 mL, 85.06 eq) was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-2-(4-methoxy-lH- indole-2-carbonyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxamide (0.12 g, crude) as a yellow oil. MS (ESI) m/z 512.2 [M+H] ⁺ .

Step 6: N-( (S)-l-cyano-2-( (S)-2-oxopyrrolidin-3-yl)ethyl)-2-( 4-methoxy-lH-indole-2- carbonyl)-8-oxa-2-azaspiro[4.5]decane-3-carboxamide

[0001100] To a solution of N-[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)-8-oxa-2- azaspiro[4.5]decane-3- carboxamide (0.12 g, 234.57 umol, 1 eq) in DCM (2 mL) was added Burgess reagent (167.70 mg, 703.72 umol, 3 eq), and then the solution was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic layers were dried over NazSC^, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge BEH C18 100*25mm*5 um; mobile phase: [water(10 mM NH4HCO3)- ACN] ;B% : 15%-45%, 10 min) to give N-[(l S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl) -8-oxa-2- azaspiro[4.5]decane-3-carboxamide (44.25 mg, 88.76 umol, 37.84% yield, 99% purity) as a white solid. MS (ESI) m/z 494.2 [M+H] ⁺ .

[0001101 ] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.23 - 7.08 (m, 2H), 7.08 - 6.98 (m, 1H), 6.53 (br d ,J= 7.6 Hz, 1H), 5.02 (br dd ,J= 5.7, 10.1 Hz, 1H), 4.72 - 4.62 (m, 2H),

4.19 - 4.03 (m, 1H), 3.98 - 3.81 (m, 4H), 3.77 - 3.62 (m, 4H), 3.29 - 3.17 (m, 1H), 2.52 -

2.20 (m, 3H), 2.02 - 1.42 (m, 8H).

Example 125. Synthesis of viral protease inhibitor compound 389

Step 1: (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide

[0001102] A solution of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamate (2 g, 7.37 mmol, 1 eq) in HCl/EtOAc (4 M, 50 mL, 27.13 eq) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressure affording the product (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanamide (1.2 g, crude) as a white solid.

Step 2: methyl 2-azaspiro[4.5]decane-3-carboxylate

[0001103 ] 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 -carboxyl ate (2 g, crude) as a yellow oil.

Step 3: methyl 2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-c arboxylate

[0001104] To a solution of methyl 2-azaspiro[4.5]decane-3-carboxylate (2 g, 10.14 mmol,

1 eq) and 4-methoxy-1H-indole-2-carboxylic acid (2.33 g, 12.17 mmol, 1.2 eq) in DCM (30 mL) and DMF (5 mL) was added T3P (12.90 g, 20.28 mmol, 12.06 mL, 50% purity, 2 eq) and DIEA (3.93 g, 30.41 mmol, 5.30 mL, 3 eq). The mixture was stirred at 25 °C for

2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (100 mL), and extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 0: 1) affording the product methyl 2-(4-methoxy- 1H-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxylate (3 g, 8.10 mmol, 79.88% yield) as a white solid. MS (ESI) m/z 371.1 [M+H] ⁺

Step 4: 2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-c arboxylic acid

[0001105] 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 H ₂ O (15 mL) was added LiOH.H ₂ O (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 H ₂ O (50 mL), and then added aq. HC1 (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure affording the product 2-(4- methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbox ylic acid (2.6 g, crude) as a white solid. MS (ESI) m/z 357.1 [M+H] ⁺

Step 5: N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-2-(4-methoxy-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide

[0001106] To a solution of 2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.5]decane-3- carboxylic acid (1 g, 2.81 mmol, 1 eq) and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanamide (720.49 mg, 4.21 mmol, 1.5 eq) in DCM (30 mL) was added T3P (3.57 g, 5.61 mmol, 3.34 mL, 50% purity, 2 eq) and DIEA (1.09 g, 8.42 mmol, 1.47 mL, 3 eq) at 0 °C. The mixture was stirred at 30 °C for 1 h. Upon completion, the mixture was quenched by addition H ₂ O (100 mL), and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 1:0 to 10: 1) affording the product N- [(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]eth yl]-2-(4-methoxy-1H- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (700 mg, 1.37 mmol, 48.96% yield) as a white solid. MS (ESI) m/z 510.3 [M+H] ⁺ Step 6: N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-metho xy-lH-mdole-2- carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001107] To a solution of N-[( 1S)-2-amino-2-oxo- 1 -[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-2-(4-methoxy-1H-indole-2-carbonyl)-2-azaspi ro[4.5]decane-3- carboxamide (700 mg, 1.37 mmol, 1 eq) in DCM (10 mL) was added Burgess reagent (982.03 mg, 4.12 mmol, 3 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Kromasil C18 (250 * 50 mm * 10 um); mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30% - 60%, 10 min) affording the product N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-met hoxy-1H-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (500 mg, 1.02 mmol, 74.05% yield) as a white solid. MS (ESI) m/z 492.3 [M+H] ⁺

Step 7: N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-metho xy-lH-indole-2- carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001108] N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-met hoxy-1H-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (500 mg, 1.02 mmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: [0.1% NH ₃ H ₂ O IP A]; B%: 55% - 55%, 9 min) affording the product N-[( IS)- l-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-methoxy-1H-indole-2-c arbonyl)-2- azaspiro[4.5]decane-3-carboxamide Isomer 1 (264 mg, 537.04 umol, 52.80% yield, 100% purity) as a white solid. MS (ESI) m/z 492.3 [M+H] ⁺

[0001109] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.28 - 6.76 (m, 3H), 6.60 - 6.38 (m, 1H), 5.05 (br dd ,J= 5.2, 10.2 Hz, 1H), 4.63 - 4.60 (m, 1H), 4.03 - 3.85 (m, 5H), 3.74 - 3.28 (m, 1H), 2.73 (br dd,J= 5.0, 8.6 Hz, 1H), 2.51 - 2.28 (m, 2H), 2.27 - 2.08 (m, 1H), 1.96 - 1.72 (m, 2H), 1.69 - 1.38 (m, 11H), 1.37 - 1.09 (m, 1H).

[0001110] N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-met hoxy-1H-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide Isomer 2 (140 mg, 284.51 umol, 27.97% yield, 99.9% purity) as a white solid. MS (ESI) m/z 492.3 [M+H] ⁺ [0001111 ] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.30 - 6.81 (m, 3H), 6.53 (br d ,J = 2.0 Hz, 1H), 5.12 - 4.95 (m, 2H), 4.70 - 4.55 (m, 2H), 4.08 - 3.86 (m, 4H), 3.84 - 3.72 (m, 1H), 2.62 - 2.40 (m, 1H), 2.36 - 2.18 (m, 2H), 1.94 - 1.69 (m, 3H), 1.68 - 1.34 (m, 11H).

Example 126. Synthesis of viral protease inhibitor compound 391

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate [0001112] 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] ⁺

Step 2: (2S,3S)-tert-butyl3-ethyl-2-(((S)-l-methoxy-l-oxo-3-((S)-2-o xopyrrolidin-3- yl)propan-2-yl)carbamoyl)azetidine-l-carboxylate

[0001113] To a solution of (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (330 mg, 1.77 mmol, 1 eq), (2S,3 S)- 1 -(tert-butoxycarbonyl)-3 -ethylazetidine-2- carboxylic acid (406.32 mg, 1.77 mmol, 1 eq) in DMF (2 mL) and DCM (10 mL) was added EDCI (679.47 mg, 3.54 mmol, 2 eq) and DMAP (433.02 mg, 3.54 mmol, 2 eq). After stirring the mixture at 25 °C for 1 h, the mixture was quenched by addition H ₂ O (50 mL) and then extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue and was purified by prep-TLC (SiO ₂ , petroleum ether: ethyl acetate = 0: 1) to give the crude product (2S,3S)-tert-butyl 3-ethyl-2-(((S)- 1 -methoxy- 1 - oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)azetid ine- 1 -carboxylate (270 mg, 679.31 umol, 38.33% yield) was obtained as yellow oil. MS (ESI) m/z 398.2 [M+H] ⁺ Step 3: (S)-methyl 2-((2S,3S)-3-ethylazetidine-2-carboxamido)-3-((S)-2-oxopyrro lidm-3- yl)propanoate

[0001114] 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-carboxy late (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 NaHCO ₃ (10 mL) and was extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , 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)pr opanoate (200 mg, crude) as white solid. MS (ESI) m/z 298.2 [M+H] ⁺

Step 4:(S)-methyl2-((2S,3S)-3-ethyl-l-(4-methoxy-lH-indole-2-carb onyl)azetidine-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001115] To a solution of (S)-methyl 2-((2S,3S)-3-ethylazetidine-2-carboxamido)-3-((S)- 2-oxopyrrolidin-3-yl)propanoate (200 mg, 672.61 umol, 1 eq), 4-methoxy- 1 H-indole-2- carboxylic acid (128.59 mg, 672.61 umol, 1 eq) in DCM (1 mL) was added EDCI (257.88 mg, 1.35 mmol, 2 eq), and DMAP (164.34 mg, 1.35 mmol, 2 eq), and the mixture was stirred at 25 °C for 1 h. Upon completion, the residue was poured into H ₂ O (10 mL) and was extracted with EtOAc (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum and was purified by prep-TLC (SiO ₂ , [etroleum ether: ethyl acetate = 0:1) to give product (S)- methyl 2-((2S,3S)-3-ethyl-1-(4-methoxy-lH-indole-2-carbonyl)azetidi ne-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (90 mg, 191.28 umol, 28.44% yield) as white solid. MS (ESI) m/z 471.2 [M+H] ⁺

Step5:(2S, 3S)-N-( (S) -1 -amino- 1 -oxo-3 -( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)-3-ethyl-1-( 4- methoxy-lH-indole-2-carbonyl)azetidine-2-carboxamide

[0001116] A solution of (S)-methyl 2-((2S,3 S)-3-ethyl- 1 -(4-methoxy- lH-indole-2- carbonyl)azetidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-y l)propanoate (80 mg, 170.03 umol, 1 eq) in NH ₃ /MeOH (7 M, 16.00 mL, 658.72 eq) was stirred at 80 °C for 16 h. Upon completion, the mixture was concentrated in the vacuum to give product (2S,3S)- N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-3-ethyl-1-(4-methoxy- lH-indole-2-carbonyl)azetidine-2-carboxamide (66 mg, crude) as a white solid. MS (ESI) m/z 456.2 [M+H] ⁺

Step6:(2S,3S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl) ethyl)-3-ethyl-l-(4-methoxy-lH- indole-2-carbonyl)azetidine-2-carboxamide

[0001117] To a solution of (2S,3 S)-N-((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-3-ethyl-1-(4-methoxy-lH-indole-2-carbonyl)az etidine-2-carboxamide (66 mg, 144.89 umol, 1 eq) in DCM (3 mL) was added Burgess reagent (414.35 mg, 1.74 mmol, 12 eq), and then the mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was concentrated in the vacuum and was purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30 mm*3 um; mobile phase: [water(0.05% NH3H ₂ O+IO mM NH4HCO3)- ACN] ;B% : 15%-45%,8 min) to give (2S,3S)-N-((S)-1- cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-3-ethyl- 1 -(4-methoxy- lH-indole-2- carbonyl)azetidine-2-carboxamide (5 mg, 11.43 umol, 7.89% yield). MS (ESI) m/z 438.2 [M+H] ⁺

[0001118] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.24 - 7.11 (m, 1H), 7.09 - 6.61 (m, 2H), 6.52 - 6.51 (m, 1H), 5.08 - 4.87 (m, 0.5H), 4.75-4.73 (m, 1.5H), 4.56 - 4.43 (m, 1H), 4.42 - 4.00 (m, 1H), 3.93 (s, 3H), 3.22 - 2.90 (m, 1H), 2.65 - 2.63 (m, 2H), 2.42 - 2.07 (m, 2H), 2.04 - 1.49 (m, 5H), 1.01 - 0.99 (m, 3H)

Example 127. Synthesis of viral protease inhibitor compound 395

Step 1: methyl (2S)-2-amino-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate; hydrochloride

[0001119] To methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3- yl Jpropanoate (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.

Step 2:

(S)-tert-butyl 2-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 -yl)carbamoyl)-

4,4-dimethylpyrrolidine-l-carboxylate

[0001120] A mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (230 mg, 1.03 mmol, 1 eq, HCI), (2S)-1-tert-butoxy carbonyl-4, 4-dimethyl-pyrrolidine-2- carboxylic acid (251.31 mg, 1.03 mmol, 1 eq), DMAP (252.38 mg, 2.07 mmol, 2 eq), EDCI (396.02 mg, 2.07 mmol, 2 eq), DMF (2 mL) and DCM (4 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1) to afford (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, 47.05% yield), as a yellow oil. MS (ESI) m/z 412.2 [M+H] ⁺ .

Step 3: (S)-methyl-2-((S)-4, 4-dimethylpyrrolidme-2-carboxamido)-3-((S)-2-oxopyrrolidm-3- yl)propanoate

[0001121 ] 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-carboxyl ate (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, HC1) as a yellow oil and used directly for next step.

Step 4: (S)-methyl 2-((S)-l-(4-methoxy-lH-indole-2-carbonyl)-4,4-dimethylpyrrol idme-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001122] A mixture of (S)-methyl-2-((S)-4,4-dimethylpyrrolidine-2-carboxamido)-3-( (S)- 2-oxopyrrolidin-3-yl)propanoate (170 mg, 488.74 umol, 1 eq, HC1), 4-methoxy-lH- indole-2-carboxylic acid (93.44 mg, 488.74 umol, 1 eq), DMAP (119.42 mg, 977.47 umol, 2 eq), EDCI (187.38 mg, 977.47 umol, 2 eq), DMF (2 mL) and DCM (4 mL) was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 0/1) to get the compound (S)-methyl-2-((S)-l -(4-methoxy- lH-indole-2-carbonyl)-4, 4- dimethylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate ( 180 mg, 371.48 umol, 76.01% yield) as yellow solid. MS (ESI) m/z 485.2 [M+H] ⁺ .

Step 5: (S)-N-( (S)-l -amino-1 -oxo-3-( (, S)-2-oxopyrrolidin-3-yl)propan-2-yl)-l-( 4-methoxy- 1H- indole-2-carbonyl)-4,4-dimethylpyrrolidme-2-carboxamide

[0001123] A mixture of (S)-methyl-2-((S)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)-4,4- dimethylpyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate ( 180 mg, 371.48 umol, 1 eq), and NH ₃ /MeOH (7 M, 7 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a product (S)-N-((S)-1- amino- 1 -oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 1 -(4-methoxy- 1 H-indole-2- carbonyl)-4,4-dimethylpyrrolidine-2-carboxamide (170 mg, crude) as a yellow solid. MS (ESI) m/z 470.2 [M+H] ⁺ .

Step 6: (S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-1-(4-m ethoxy- JH-indole-2- carbonyl)-4,4-dimethylpyrrolidine-2-carboxamide

[0001124] A mixture of (S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2- yl)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)-4,4-dimethylpyrrolidine-2-carboxamide (160 mg, 340.76 umol, 1 eq), Burgess reagent (649.66 mg, 2.73 mmol, 8 eq) and DCM (25 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 um; mobile phase: [water(0.05% NH3H ₂ O+IO mM NH4HCO3)- ACN] ;B% : 15%-40%,8 min) to get the product (S)-N-((S)-1-cyano-2-((S)-2- oxopyrrolidin-3-yl)ethyl)-1-(4-methoxy-lH-indole-2-carbonyl) -4,4-dimethylpyrrolidine- 2-carboxamide Isomer 1 (27 mg, 58.95 umol, 17.30% yield, 98.58% purity), as white solid. MS (ESI) m/z 452.3 [M+H] ⁺ .

[0001125] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.76 - 11.39 (m, 1H), 9.18 - 8.79 (m, 1H), 7.85 - 7.46 (m, 1H), 7.21 - 6.67 (m, 3H), 6.58 - 6.35 (m, 1H), 5.13 - 4.81 (m, 1H), 4.74 - 4.31 (m, 1H), 3.97 - 3.55 (m, 5H), 3.31 - 3.05 (m, 2H), 2.47 - 1.96 (m, 4H), 1.85 - 1.27 (m, 3H), 1.25 - 0.80 (m, 6H).

[0001126] (S)-N-((S)- 1 -cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)- 1 -(4-methoxy- 1 H-indole-

2-carbonyl)-4,4-dimethylpyrrolidine-2-carboxamide Isomer 2 (3 mg, 6.41 umol, 1.88% yield, 96.44% purity), as white solid. MS (ESI) m/z 452.3 [M+H] ⁺ .

[0001127] ¹ H NMR (400MHZ, DMSO- d ₆ ) δ = 11.78 - 11.34 (m, 1H), 9.33 - 8.76 (m, 1H), 7.91 - 7.53 (m, 1H), 7.23 - 6.67 (m, 3H), 6.61 - 6.31 (m, 1H), 5.09 - 4.80 (m, 1H), 4.61 - 4.43 (m, 1H), 4.01 - 3.67 (m, 5H), 3.20 - 2.99 (m, 2H), 2.43 - 1.91 (m, 4H), 1.86 - 1.55 (m, 3H), 1.33 - 0.83 (m, 6H).

Example 128. Synthesis of viral protease inhibitor compound 397

[0001128] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (1 g, 3.49 mmol, 1 eq) in NH ₃ /MeOH (7 M, 15 mL) was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The tert- butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamate (900 mg, crude) was obtained as white solid. MS (ESI) m/z 272.2 [M+H] ⁺ .

Step 2: (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-ylJpropammide

[0001129] A solution of tert-butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- y 1 ]methy 1 ]ethy 1 ]carbamate (900 mg, 3.32 mmol, 1 eq) in HCl/EA (4 M, 15 mL) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to get the product (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanamide (650 mg, crude, HC1) as white solid. MS (ESI) m/z 172.1 [M+H] ⁺ .

Step 3: tert-butyl (6S)-6-[[(lS)-2-amino-2-oxo-l-[[(3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ]-5-azaspiro[ 2.4 ]heptane-5-carboxylate

[0001130] A solution of (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (400 mg, 1.93 mmol, 1 eq, HCI), (6S)-5-tert-butoxycarbonyl-5-azaspiro[2.4]heptane-6-carboxyl ic acid (464.77 mg, 1.93 mmol, 1 eq) and TEA (974.58 mg, 9.63 mmol, 1.34 mL, 5 eq) was dissolved in DCM (8 mL) and DMF (3 mL), and then the solution cooled to 0 °C. After adding T3P (3.68 g, 5.78 mmol, 3.44 mL, 50% purity, 3 eq) to the solution, the mixture was stirred for 1 h and warmed to 25 °C gradually. Upon completion, the mixture was added H ₂ O (50 mL) and then extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get the product tert-butyl (6S)-6-[[( 1 S)-2-amino- 2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]- 5-azaspiro[2.4]heptane-5- carboxylate (200 mg, crude) was obtained as yellow solid. MS (ESI) m/z 395.2 [M+H] ⁺ .

Step 4: ( 6S)-N-[ ( l S)-2-amino-2-oxo-l-[[ ( 3S)-2-oxopyrrolidin-3-yl ]methyl ] ethyl] -5-azaspiro[ 2.4 ]heptane-6-carboxamide

[0001131 ] A solution of tert-butyl (6S)-6-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-5-azaspiro[2.4]heptane-5-carboxyl ate (200 mg, 464.12 umol, 1 eq, HC1) in HCl/EtOAc (4 M, 15 mL) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford (6S)-N-[(1S)-2- amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-5-az aspiro[2.4]heptane-6- carboxamide (140 mg, crude, HC1) as a white solid. MS (ESI) m/z 295.2 [M+H] ⁺ .

Step 5: ( 6S)-N-[ ( l S)-2-amino-2-oxo- 1-[[ ( 3S)-2-oxopyrrolidin-2-yl ]methyl ]ethyl ]-5-( 4-methox y-lH-indole-2-carbonyl)-5-azaspiro[2.4 ]heptane-6-carboxamide

[0001132] To a solution of (6S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-5-azaspiro[2.4]heptane-6-carboxamide (140 mg, 423.20 umol, 1 eq, HC1), 4-methoxy- 1 H-indole-2-carboxylic acid (80.91 mg, 423.20 umol, 1 eq), EDCI (202.82 mg, 1.06 mmol, 2.5 eq) was added DMAP (155.11 mg, 1.27 mmol, 3 eq) in DCM (3 mL), and then the reaction was stirred at 25 °C for 1 h. Upon completion, the mixture was added H ₂ O (30 mL) and then extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to afford (6S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]-5-(4-methoxy-lH-indole-2-ca rbonyl)-5- azaspiro[2.4]heptane-6-carboxamide (80 mg, 117.37 umol, 27.73% yield, 68.59% purity) as yellow solid. MS (ESI) m/z 468.2 [M+H] ⁺ .

Step 6: ( 6S)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ]-5-( 4-methoxy- lH-indole-2- carbonyl)-5-azaspiro[2.4 ]heptane-6-carboxamide

[0001133] A solution of (6S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-5-(4-methoxy-1H-indole-2-carbonyl)-5-azaspi ro[2.4]heptane-6- carboxamide (80 mg, 171.12 umol, 1 eq) and methoxy carbonyl- (triethylammonio)sulfonyl-azanide (163.11 mg, 684.47 umol, 4 eq) in DCM (5 mL) was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was concentrated and concentrated under reduced pressure to afford (6S)-N-[( 1 S)- 1 -cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-5-(4-methoxy-lH-indole-2-carbonyl) -5-azaspiro[2.4]heptane-6- carboxamide (15.5 mg, 34.44 umol, 20.13% yield, 99.88% purity) as a white solid. MS (ESI) m/z 450.2 [M+H] ⁺ .

[0001134] NMR (400 MHz, METHANOL-d ₄ ) δ = 7.23 - 7.12 (m, 1H), 6.87 - 7.10(m, 2H), 6.59 - 6.39 (m, 1H), 5.35 - 5.07 (m, 2H), 4.85 - 4.69 (m, 1H), 4.10 - 3.61 (m, 5H), 3.03 - 2.17 (m, 4H), 2.13 - 1.62 (m, 3H), 1.62 - 1.22 (m, 1H), 0.87 - 0.57 (m, 4H).

Example 129. Synthesis of viral protease inhibitor compound 399

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride

[0001135] A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (130 mg, 454.03 umol, 1 eq) in HCl/dioxane (4 M, 2.27 mL, 20 eq) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (173.4 mg, 451.67 umol, 99.48% yield, 58% purity, HC1) as a yellow liquid.

Step 2: (S)-tert-butyl 7-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 - yl) carbamoyl) -6-azaspiro[ 3.4 ]octam-6-carboxylate

[0001136] To a solution of (7S)-6-tert-butoxycarbonyl-6-azaspiro[3.4]octane-7-carboxyli c acid (105.34 mg, 412.59 umol, 1 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (158.4 mg, 412.59 umol, 58% purity, 1 eq, HC1) in DCM (1.2 mL) and DMF (0.4 mL) was added DMAP (100.81 mg, 825.19 umol, 2 eq) and EDCI (158.19 mg, 825.19 umol, 2 eq). After stirring the mixture at 25 °C for 1 h, the residue was diluted with H ₂ O (6 mL) and extracted with ethyl acetate (3 mL). The combined organic layers were washed with ethyl acetate (3 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether/ethyl acetate =0/1) afford tert-butyl (7S)-7-[[(1S)-2-methoxy-2-oxo-1- [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6-azaspi ro[3.4]octane-6- carboxylate (66.3 mg, 156.55 umol, 37.94% yield) as a yellow liquid. MS (ESI) m/z 424.0 [M+H] ⁺

Step 3: (S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-((S)-6-azaspiro[3.4Joctane-7- carboxamido)propanoate

[0001137] A solution of tert-butyl (7S)-7-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-6-azaspiro[3.4]oc tane-6-carboxylate (66.3 mg, 156.55 umol, 1 eq) in HCl/MeOH (4 M, 782.76 uL, 20 eq) was stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2-[[(7S)-6-azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S )-2-oxopyrrolidin-3- yl]propanoate (71.1 mg, 156.09 umol, 99.71% yield, 79% purity, HC1) as a yellow liquid.

Step 4: (S)-methyl 2-((S)-6-(4-methoxy-JH-indole-2-carbonyl)-6-azaspiro[3.4Joct ane-7- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001138] To a solution of methyl (2S)-2-[[(7S)-6-azaspiro[3.4]octane-7-carbonyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (62.8 mg, 137.87 umol, 79% purity, 1 eq, HC1) and 4-methoxy- 1 H-indole-2-carboxylic acid (26.36 mg, 137.87 umol, 1 eq) in DCM (1.2 mL) and DMF (0.4 mL) was added DMAP (33.69 mg, 275.74 umol, 2 eq) and EDCI (52.86 mg, 275.74 umol, 2 eq) at 25 °C for 1 h. The residue was diluted with brine (6 mL) and extracted with EtOAc (3 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether/ethyl acetate =0/1) to get the product methyl (2S)-2-[[(7S)-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspiro[ 3.4]octane-7- carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (33.2 mg, 66.86 umol, 48.50% yield) was obtained as a white solid. MS (ESI) m/z 497.1 [M+H] ⁺

Step 5: (S)-N-( (S)-l -amino-1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)-6-( 4-methoxy- 1H- indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide [0001139] A mixture of methyl (2S)-2-[[(7S)-6-(4-methoxy-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-oxopyrrolidi n-3-yl]propanoate (23.0 mg, 46.32 umol, 1 eq) and ammonia (7 M, 4 mL, 604.50 eq) was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford (7S)-N-[(1S)-2- amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-6-(4-methoxy- lH-indole-2- carbonyl)-6-azaspiro[3.4]octane-7-carboxamide (15 mg, crude) as a yellow solid. MS (ESI) m/z 482.2 [M+H] ⁺

Step 6: (S)-N-( ( S)-l-cyano-2-( (S)-2-oxopyrrolidin-3-yl)ethyl)-6-( 4-methoxy- lH-indole-2- carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[0001140] A solution of (7S)-N-[(1 S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6-(4-methoxy-lH-indole-2-carbonyl)-6-azaspi ro[3.4]octane-7- carboxamide (15 mg, 28.66 umol, 92% purity, 1 eq) and Burgess reagent (13.66 mg,

57.32 umol, 2 eq) was stirred at 25 °C for 24 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 30 mm * 10 um; mobile phase: [water(10 mM NH4HCO3)- ACN] ; B%: 20% - 45%, 8 min) to afford (7S)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-6-(4-methoxy-lH-indole-2-carbonyl) -6-azaspiro[3.4]octane-7- carboxamide (3.01 mg, 6.49 umol, 22.66% yield, 100% purity) as a white solid. MS (ESI) m/z 464.3 [M+H] ⁺

[0001141 ] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 6.95 - 7.24 (m, 3 H) 6.47 - 6.58

(m, 1 H) 5.01 (br dd, J=10.67, 5.19 Hz, 1 H) 4.58 (t, J=7.09 Hz, 1 H) 3.82 - 4.19 (m, 5 H) 3.19 (br t,J=8.52 Hz, 1 H) 2.93 - 3.07 (m, 1 H) 2.28 - 2.56 (m, 3 H) 2.16 - 2.27 (m, 2 H)

1.94 - 2.14 (m, 6 H) 1.47 - 1.86 (m, 2 H).

Example 130. Synthesis of viral protease inhibitor compound 401

[0001142] methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (400 mg, 1.40 mmol, 1 eq) in HCl/EtOAc (4 M, 10 mL, 28.63 eq) was stirred at 25 °C for 0.5 h. Upon completion, the mixture was concentrated under the reduced pressure affording the product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (300 mg, crude, HC1) as a yellow solid.

Step 2: (S)-tert-butyl3-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin -3-yl)propan-2- yl) carbamoyl) -2-azaspiro[ 4.4 ]nonane-2-carboxylate

[0001143] methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (300 mg, 1.35 mmol, 1 eq, HC1) and (3S)-2-tertbutoxycarbonyl-2-azaspiro[4.4]nonane-3-carboxylic acid (362.87 mg, 1.35 mmol, 1 eq) in DMF (2 mL) and DCM (5 mL) was added DMAP (329.19 mg, 2.69 mmol, 2 eq) and EDCI (516.56 mg, 2.69 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (10 mL), and then extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate = 5:1 to 0:1) affording the product tert-butyl(3S)-3- [[( 1 S)-2-methoxy-2-oxo- 1 - [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-2- azaspiro[4.4]nonane-2-carboxylate (340 mg, 777.09 umol, 57.68% yield) as a yellow oil.

Step 3: (S)-methyl3-( (S)-2-oxopyrrolidin-3-yl)-2-( (S)-2-azaspiro[ 4.4 ]nonane-3- carboxamido)propanoate

[0001144] tert-butyl(3S)-3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrol idin-3- yl]methyl]ethyl]carbamoyl]-2-azaspiro[4.4]nonane-2-carboxyla te (340 mg, 777.09 umol, 1 eq) in HCl/EtOAc (4 M, 10 mL, 51.47 eq) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressured affording the product methyl(2S)-2-[[(3S)-2-azaspiro[4.4]nonane-3-carbonyl]amino] -3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (250 mg, crude, HC1) as a yellow oil.

Step 4: (S)-methyl2-((S)-2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspi ro[4.4]nonane-3- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001145] methyl(2S)-2-[[(3S)-2-azaspiro[4.4]nonane-3-carbonyl]amino]- 3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (250 mg, 668.67 umol, 1 eq, HC1) and 4-methoxy-1H- indole-2-carboxylic acid (127.84 mg, 668.67 umol, 1 eq) in DMF (2 mL) and DCM (6 mL) was added DMAP (163.38 mg, 1.34 mmol, 2 eq) and EDCI (256.37 mg, 1.34 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (10 mL), and then extracted with DCM (10 mL*3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , PE:EA = 0: 1) affording the product methyl(2S)-2-[[(3S)-2-(4-methoxy- 1H-indole-2-carbonyl)-2 -azaspiro[4.4]nonane-3-carbonyl]amino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (180 mg, 352.54 umol, 52.72% yield) as a yellow oil. MS (ESI) m/z 511.2 [M+H] ⁺

Step 5: (S)-N-( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-( 4-methoxy-lH- indole-2-carbonyl) -2-azaspiro[ 4.4 ]nonane-3-carboxamide

[0001146] methyl(2S)-2-[[(3S)-2-(4-methoxy- 1H-indole-2-carbonyl)-2- azaspiro[4.4]nonane-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidi n-3-yl]propanoate ( 180 mg, 352.54 umol, 1 eq) in ammonia (7 M, 20 mL, 397.12 eq) was stirred as 80 °C for 16 h. Upon completion, the mixture was concentrated under the reduced pressure affording the product (3S)-N-[(1S)-2-amino-2-oxo-1-[[(3,S)-2-oxopynOlidin-3-yl] methyl]ethyl]-2- (4-methoxy- 1H-indole-2- carbonyl)-2-azaspiro[4.4]nonane-3-carboxamide (170 mg, crude) as a yellow oil.

Step 6: (S)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-m ethoxy-lH-indole-2- carbonyl)-2-azaspiro[ 4.4 ]nonane-3-carboxamide

[0001147] (3S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopynOlidin-3-yl]meth yl]ethyl]-2-(4- methoxy-1H-indole-2-carbonyl)-2-azaspiro[4.4]nonane-3-carbox amide (170 mg, 343.04 umol, 1 eq) in DCM (3 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl- azanide (408.74 mg, 1.72 mmol, 5 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH Cl 8 100*25mm*5 um; mobile phase: [water(10 mM NH4HCO3) - ACN]; B%: 30% - 60%, 10 min) affording the product (3S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2- (4-methoxy- 1H-indole-2 -carbonyl)-2-azaspiro[4.4]nonane-3-carboxamide (25 mg, 51.09 umol, 14.89% yield, 97.6% purity) as a white solid. MS (ESI) m/z 41&.2 [M+H] ⁺

[0001148] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.22 - 7.12 (m, 1H), 7.11 - 6.98 (m, 2H),

6.58 - 6.45 (m, 1H), 5.11 - 4.95 (m, 1H), 4.65 - 4.52 (m, 1H), 3.94 (s, 3H), 3.93 - 3.80 (m, 2H), 3.28 - 3.18 (m, 1H), 2.54 - 2.02 (m, 4H), 2.01 - 1.48 (m, 12H).

Step 7: (S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-m ethoxy-JH-indole-2- carbonyl)-2-azaspiro[ 4.4 ]nonane-3-carboxamide

[0001149] Isomer 1 : (S)-N-((S)- 1 -cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-methoxy- lH-indole-2-carbonyl)-2-azaspiro[4.4]nonane-3-carboxamide (30 mg, 62.82 umol) was separated by prep-SFC (column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 5 um); mobile phase: [Neu-ETOH]; B%: 40% - 40%, 15 min) affording the product (3S)-N- [(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-metho xy-lH- indole-2-carbonyl)- 2-azaspiro[4.4]nonane-3-carboxamide (12.11 mg, 24.62 umol, 39.20% yield, 97.1% purity) as a white solid. MS (ESI) m/z 478.2 [M+H] ⁺ [0001150] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.20 - 7.11 (m, 1H), 7.08 - 6.85 (m, 2H), 6.59 - 6.42 (m, 1H), 5.05 (br dd, J = 5.6, 10.4 Hz, 1H), 4.58 (br dd, J = 7.4, 9.6 Hz, 1H), 3.97 - 3.92 (m, 3H), 3.88 - 3.52 (m, 2H), 3.28 (br s, 1H), 2.87 - 2.65 (m, 1H), 2.47 - 2.29 (m, 2H), 2.25 - 2.16 (m, 1H), 2.03 - 1.53 (m, 11H), 1.34 - 1.20 (m, 1H).

[0001151 ] Isomer 2: (S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-m ethoxy- 1H-indole-2-carbonyl)-2-azaspiro[4.4]nonane-3-carboxamide (30 mg, 62.82 umol) was separated by prep-SFC (column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 5 um); mobile phase: [Neu-ETOH]; B%: 40% - 40%, 15 min) affording the product (3 S)-N- [( 1S)- 1 -cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-(4-methoxy- 1 H- indole-2-carbonyl)- 2-azaspiro[4.4]nonane-3-carboxamide (16.81 mg, 34.46 umol, 54.86% yield, 97.9% purity) as a white solid. MS (ESI) m/z 478.2 [M+H] ⁺

[0001152] ¹ H NMR (400 MHz, MeOM ₄ ) δ = 7.23 - 7.13 (m, 1H), 7.10 - 6.84 (m, 2H), 6.52 (d,J = 7.7 Hz, 1H), 5.03 (br dd, J= 5.7, 10.4 Hz, 1H), 4.67 - 4.54 (m, 1H), 4.00 - 3.57 (m, 5H), 3.27 - 3.16 (m, 1H), 2.55 - 2.39 (m, 1H), 2.37 - 2.04 (m, 3H), 2.02 - 1.44 (m, 11H), 1.43 - 1.16 (m, 1H).

Example 131. Synthesis of viral protease inhibitor compound 405

Step J: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pent anoyl]ammo]-3- [ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001153] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (225 mg, 1.21 mmol, 1 eq) in DMF (2 mL) and DCM (4 mL) was added TEA (733.62 mg, 7.25 mmol, 1.01 mL, 6 eq) and T3P (1.15 g, 3.62 mmol, 1.08 mL, 3 eq) and (2S)-2- (tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (296.42 mg, 1.21 mmol, 1 eq). The solution was stirred for 1 h at 25 °C. The reaction was diluted with H ₂ O (40 mL) and extracted with ethyl acetate (50 mL* 3) and the organic layer was cautiously concentrated to give crude Compound methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4- dimethyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propa noate (440 mg, crude) as a yellow solid used directly for the next step. MS (ESI) m/z 414.1 [M+H] ⁺

Step 2: methyl (2S)-2-[[(2S)-2-amino-4, 4-dimethyl-pentanoyl ]amino]-3-[ ( 3S)-2- oxopyrrolidin-3-yl ]propanoate

[0001154] 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 Jpropanoate (310 mg, crude) as a yellow solid used directly for the next step. MS (ESI) m/z 314.3 [M+H] ⁺

Step 3: methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4, 4-dimethyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001155] To a solution of methyl (2 S)-2-[ [(2 S)-2-amino-4,4-dimethy 1-pentanoy 1 ]ami noj- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (310 mg, 989.18 umol, 1 eq) in DMF (4 mL) and DCM (4 mL) was added EDCI (379.25 mg, 1.98 mmol, 2 eq) was added DMAP (241.70 mg, 1.98 mmol, 2 eq) and 4-m ethoxy- 1 H-indole-2-carboxylic acid (189.11 mg, 989.18 umol, 1 eq). The solution was stirred for 3 h at 25 °C, and then the reaction was diluted with H ₂ O (40 mL) and extracted with ethyl acetate (80 mL* 3) and the organic layer was cautiously concentrated to give crude. The crude was purified by pre-TLC (SiO ₂ , EA:MeOH=10: 1) to give product. Compound methyl (2S)-2-[[(2S)-2-[(4-methoxy- lH-indole-2-carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3- yl Jpropanoate (200 mg, 411.05 umol, 41.55% yield) was obtained. MS (ESI) m/z 487.2 [M-H] ⁺

Step 4: N-f (1S)-1-[[(1 S)-2-amino-2-oxo-1-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ]-3, 3-dimethyl-butyl ]-4-methoxy-lH-indole-2-carboxamide

[0001156] A solution of methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxop yrrolidin-3- yl Jpropanoate (135 mg, 277.46 umol, 1 eq) in NH ₃ /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-[(l S)-1-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-methoxy-lH- 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] ⁺

[0001157] Prep-HPLC condition: column: Phenomenex Gemini-NX C1875*30 mm*3 um; mobile phase: [water(0.05% NH3H ₂ O+IO mM NH ₄ HC0 ₃ )-ACN];B%: 35%-55%,8 min

Step 5: N-f (1S)-1-[[(1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ] carbamoyl ]-3, 3- dimethyl-butyl]-4-methoxy-lH-indole-2-carboxamide

[0001158] To a solution of N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-methoxy-lH- indole-2-carboxamide (130 mg, 275.69 umol, 1 eq) in DCM (7 mL) was added Burgess reagent (197.09 mg, 827.06 umol, 3 eq). The solution was stirred for 1 h at 25 °C. The reaction was cautiously concentrated to give crude, and the crude was purified by pre-HPLC(TFA) to give N- [(1S)-1-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]ca rbamoyl]-3, 3-dimethyl- butyl ]-4-methoxy- 1 H-indole-2-carboxamide (36 mg, 75.41 umol, 27.35% yield, 95% purity) as a white solid. MS (ESI) m/z 454.1 [M+H] ⁺ .

[0001159] Prep-HPLC condition: column: Phenomenex luna C1880*40 mm*3 um; mobile phase: [water(0.04% HC1)-ACN];B%: 30%-55%,7 min

[0001160] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.02 (s, 9 H) 1.74 - 1.94 (m, 4 H) 2.21 - 2.37 (m, 2 H) 2.52 - 2.63 (m, 1 H) 3.16 - 3.26 (m, 2 H) 3.92 (s, 3 H) 4.63 (dd, J=8.49, 4.30 Hz, 1 H) 4.98 - 5.06 (m, 1 H) 6.50 (d, J=7.72 Hz, 1 H) 7.02 (d, J=8.38 Hz, 1 H) 7.10 - 7.16 (m, 1 H) 7.23 (d,J=0.88 Hz, 1 H).

Example 132. Synthesis of viral protease inhibitor compound 409

Step 1: (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide

[0001161 ] A mixture of tert- butyl N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl] carbamate (300 mg, 1.11 mmol, 1 eq) in HCl/EtOAc (4 M, 10 mL, 36.17 eq) was stirred at 25 °C for 0.5 h. Upon completion, the mixture was concentrated under the reduced pressure affording the product (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanamide (200 mg, crude, HC1) as a white solid.

Step 2: (2S,4R)-tert-butyl2-(((S)-l-ammo-l-oxo-3-((S)-2-oxopyrrolidi n-3-yl)propan-2- yl)carbamoyl)-4-ethoxypyrrolidine-l-carboxylate

[0001162] (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (200 mg, 963.12 umol, 1 eq, HC1) and (2S,4R)- l-tert-butoxy carbonyl -4-ethoxy-pyrrolidine-2-carboxylic acid (249.74 mg, 963.12 umol, 1 eq) in DMF (4 mL) and DCM (8 mL) was added TEA (487.29 mg, 4.82 mmol, 670.27 uL, 5 eq) and T3P (1.84 g, 2.89 mmol, 1.72 mL, 50% purity, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was quenched by addition H ₂ O (30 mL) and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) affording the product tert- butyl (2S,4R)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]- 4-ethoxypyrrolidine- 1 -carboxylate (140 mg, 339.41 umol, 35.24% yield) as a yellow solid. MS (ESI) m/z 413.1 [M+H] ⁺

Step 3: (2S, 4R)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-4- ethoxypyrrolidine-2-carboxamide [0001163] A mixture of tert-butyl(2S,4R)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2- oxopy rrolidin-3 -y 1 ]methy 1 ]ethy 1 ] carbamoyl]-4-ethoxypyrrolidine-1-carboxylate (100 mg, 242.44 umol, 1 eq) in HCl/EtOAc (4 M, 10 mL, 164.99 eq) was stirred at 25 °C for 0.5 h. Upon completion, the mixture was concentrated under the reduced pressure affording the product (2S,4R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]-4- ethoxy-pyrrolidine-2-carboxamide (80 mg, crude, HC1) as a white solid.

Step 4: (2S, 4R)-N-( (S)-l -amino- 1 -oxo- 3 -( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)-4-ethoxy-l- (4-methoxy-lH-indole-2-carbonyl)pyrrolidine-2-carboxamide [0001164] A mixture of (25 ^, ,4R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-4-ethoxy -pyrrolidine-2-carboxamide (80 mg, 229.34 umol, 1 eq, HC1) and 4-methoxy- lH-indole-2-carboxylic acid (65.77 mg, 344.01 umol, 1.5 eq) in DCM (3 mL) and DMF (1 mL) was added DMAP (56.04 mg, 458.68 umol, 2 eq) and EDCI (87.93 mg, 458.68 umol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was quenched by addition H ₂ O (30 mL) and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (S1O2, DCM:MeOH = 10: 1) affording the product (2S,4R)-N-[(1S)- 2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-4- ethoxy-1-(4-methoxy- lHindole-2-carbonyl)pyrrolidine-2-carboxamide (100 mg, crude) as a yellow oil. MS (ESI) m/z 486.2 [M+H] ⁺

Step 5: (2S, 4R)-N-( (S)-l-cyano-2-( (, S)-2-oxopyrrolidin-3-yl)ethyl)-4-ethoxy-l-( 4-methoxy- lH-indole-2-carbonyl)pyrrolidine-2-carboxamide

[0001165] To a mixture of (25 ^, ,4R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-4-ethoxy- 1 -(4-methoxy- 1H-indole-2-carbonyl)pyrrolidine-2- carboxamide (80 mg, 164.77 umol, 1 eq) in DCM (3 mL) was added Burgess reagent (196.33 mg, 823.84 umol, 5 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 25mm * 5 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 20% - 45%, 10 min) affording the product (25 ^, ,4R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-4- ethoxy- 1 -(4-methoxy- 1H-indole-2-carbonyl)pyrrolidine-2-carboxamide (28 mg, 58.81 umol, 35.69% yield, 98.2% purity) as a white solid. MS (ESI) m/z 468.2 [M+H] ⁺

[0001166] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.19 - 7.13 (m, 1H), 7.09 - 6.86 (m, 2H), 6.57 - 6.42 (m, 1H), 5.17 - 5.01 (m, 1H), 4.69 - 4.58 (m, 1H), 4.36 - 4.18 (m, 1H), 4.16 - 3.97 (m, 2H), 3.96 - 3.85 (m, 3H), 3.68 - 3.44 (m, 2H), 3.00 - 2.54 (m, 2H), 2.50 - 2.31 (m, 2H), 2.25 - 2.02 (m, 2H), 2.01 - 1.72 (m, 2H), 1.69 - 1.26 (m, 1H), 1.25 - 1.13 (m,

3H).

Example 133. Synthesis of viral protease inhibitor compound 433

Step 1: methyl 2 -amino-2 -(3-pyridyl)acetate

[0001167] 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 N ₂ . 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, HC1) was obtained as a yellow oil and used directly next step. MS (ESI) m/z 167.1 [M+H] ⁺

Step 2: methyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoyl ] amino ]-2- ( 3-pyridyl)acetate [0001168] To a mixture of (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl- pentanoic acid (600.76 mg, 1.97 mmol, 1 eq) and methyl 2-amino-2-(3-pyridyl)acetate (400 mg, 1.97 mmol, 1 eq, HC1), DIPEA (1.28 g, 9.87 mmol, 1.72 mL, 5 eq) in THF (1.2 mL) and DCM (1.2 mL) was added T3P (1.88 g, 2.96 mmol, 1.76 mL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. 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 pre-HPLC. Methyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4-methyl-pentanoyl]amino]-2-(3-pyridyl)aceta te (0.3 g, crude) was obtained as a white solid. MS (ESI) m/z 453.2 [M+H] ⁺

[0001169] Prep-HPLC condition: column: Kromasil C18 (250*50 mm* 10 um);mobile phase: [water(10 mM NH ₄ HCO ₃ )-ACN];B%: 30%-50%,10 min.

Step 3: N-[(lS)-l-[[2-amino-2-oxo-l-(3-pyridyl)ethyl]carbamoyl]-3-me thyl-butyl]-4- methoxy-lH- indole-2-carboxamide

[0001170] To a mixture of methyl 2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoyl] amino]-2-(3-pyridyl)acetate (0.2 g, 441.99 umol, 1 eq) was added NH ₃ /MeOH (7 M, 6 mL, 95.03 eq) in one portion at 25 °C under N ₂ . 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 (SiO ₂ , DCM: MeOH = 10:1, R _f = 0.22). N-[(l S)-1-[[2-amino-2-oxo-1-(3-pyridyl)ethyl]carbamoyl]-3-methyl- butyl]-4- methoxy-lH-indole-2-carboxamide (70 mg, crude) was obtained as a light yellow solid. MS (ESI) m/z 438.2 [M+H] ⁺

Step 4: N-f ( l S)-l-[[cyano( 3-pyridyl)methyl ] carbamoyl ]-3-methyl-butyl ]-4-methoxy-JH- indole-2- carboxamide

[0001171 ] To a mixture of N-[(1S)-1-[[2-amino-2-oxo-1-(3-pyridyl)ethyl]carbamoyl]-3- methyl-butyl]-4- methoxy-lH-indole-2-carboxamide (60 mg, 137.15 umol, 1 eq) in DCM (0.2 mL) was added Burgess reagent (65.37 mg, 274.29 umol, 2 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated to get the crude product. The crude product was purified by pre-HPLC twice. N-[(l S)-1-[[cyano(3-pyridyl)methyl]carbamoyl]-3-methyl-butyl] -4-methoxy-lH- indole-2-carboxamide (12.78 mg, 29.52 umol, 21.52% yield, 96.878% purity) was obtained as a white solid. MS (ESI) m/z 423.2 [M+H] ⁺

[0001172] Prep-HPLC condition: column: Waters Xbridge BEH C18 100*25mm*5 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )- ACN] ;B% : 25%-55%,10 min.

[0001173] Column: Phenomenex Gemini-NX C18 75*30 mm*3 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )-ACN];B%: 30%-55%,8 min.

[0001174] ¹ H NMR (400 MHz, DMSO-d6) δ ppm 11.61 (dd, J = 7.03, 1.77 Hz, 1 H), 9.49 (dd,J= 17.24, 7.83 Hz, 1 H), 8.59 - 8.71 (m, 2 H), 8.53 (d ,J= 7.82 Hz, 1 H), 7.85 - 7.93 (m, 1 H), 7.47 - 7.55 (m, 1 H), 7.38 (t, J= 2.51 Hz, 1 H), 7.06 - 7.14 (m, 1 H), 7.01 - 7.01 (m, 1 H), 7.01 (dd, J= 8.25, 3.24 Hz, 1 H), 6.51 (dd, J= 7.70, 1.34 Hz, 1 H), 6.32 (dd, J = 12.41, 7.76 Hz, 1 H), 4.44 - 4.61 (m, 1 H), 3.89 (d, J= 1.10 Hz, 3 H), 1.62 - 1.81 (m, 2 H), 1.46 - 1.60 (m, 1 H), 0.81 - 1.03 (m, 7 H).

Step 6: (S)-tert-butyl 2-(4-methoxy-lH-indole-2-carboxamido)-4-methylpentanoate [0001175] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (15 g, 78.46 mmol, 1 eq) and tert-butyl (2S)-2-amino-4-methyl-pentanoate (21.07 g, 94.15 mmol, 1.2 eq, HC1) in DMF (150 mL) was added EDCI (19.55 g, 102.00 mmol, 1.3 eq), HOBt (13.78 g, 102.00 mmol, 1.3 eq), TEA (23.82 g, 235.38 mmol, 32.76 mL, 3 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 2 h. The reaction mixture was added water (450 mL) and extracted with ethyl acetate (250 mL * 3) to get the organic phase. The organic phase was washed with 5% citric acid (300 mL) and 5% aqueous solution of sodium bicarbonate (300 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to get the product. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate=30: 1 to 10:1) to afford tert-butyl (2S)-2-[(4- methoxy- 1 H-indole-2-carbonyl)amino]-4-methyl- pentanoate (24 g, 66.58 mmol, 84.87% yield) as light yellow solid. MS (ESI) m/z 361.2 [M+H] ⁺

Step 7: (S)-2-(4-methoxy-lH-indole-2-carboxamido)-4-methylpentanoic acid [0001176] To a mixture of tert-butyl (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4- methyl-pentanoate (10 g, 27.74 mmol, 1 eq) in DCM (30 mL) was added TFA (61.60 g, 540.26 mmol, 40 mL, 19.47 eq) and H ₂ O (4.00 g, 221.98 mmol, 4.00 mL, 8.00 eq) in one portion at 0 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 2 h. The reaction mixture was concentrated to get the crude product. The crude product was purified by pulping with petroleum ether: ethyl acetate = 10: 1 (20 mL) and filtered to get the product. (2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4-methyl-pent anoic acid (6 g, 19.22 mmol, 69.27% yield, 97.48% purity) was obtained as a light yellow solid. MS (ESI) m/z 305.1 [M+H] ⁺

Example 134. Synthesis of viral protease inhibitor compound 439

Step 1: methyl (2S)-2-amino-3-(2-pyridyl)propanoate

[0001177] To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3-(2-pyridyl)propanoic acid (1 g, 3.76 mmol, 1 eq) was added HCl/MeOH (4 M, 10 mL, 10.65 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C for lh. The reaction mixture was concentrated to get the product. Methyl (2S)-2-amino-3-(2-pyridyl)propanoate (900 mg, 3.48 mmol, 92.79% yield, 98% purity, 2HC1) was obtained as a white solid and used directly next step. MS (ESI) m/z 181.1 [M+H] ⁺

Step 2: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-pro panoyl]amino]- 3-(2- pyridyl)propanoate

[0001178] To a mixture of methyl (2S)-2-amino-3-(2-pyridyl)propanoate (0.9 g, 3.56 mmol, 1 eq, 2HC1) and (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (978.23 mg, 4.27 mmol, 1.2 eq) and DIPEA (2.30 g, 17.78 mmol, 3.10 mL, 5 eq) in DCM (6 mL) and THF (6 mL) was added T3P (3.39 g, 5.33 mmol, 3.17 mL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 2 h. The reaction mixture was added saturated sodium bicarbonate solution (10 mL) and extracted with DCM (10 mL x 2) to get the organic phase. The organic phase was concentrated to get the crude product. Methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-pro panoyl]amino] -3- (2-pyridyl)propanoate (1.1 g, 2.81 mmol, 79.03% yield) was obtained as a light yellow solid and used directly next step. MS (ESI) m/z 392.2 [M+H] ⁺

Step 3: methyl (2S)-2-[[( 2S) -2 -amino- 3 -cyclopropyl-propanoyl ] amino ]-3-(2- pyridyl)propanoate

[0001179] 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 N ₂ . 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-py ridyl)propanoate (1 g, crude, HC1) was obtained as a brown solid and used directly next step. MS (ESI) m/z 292.2 [M+H] ⁺

Step 4: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino ]propanoyl ] amino ]-3-(2-pyridyl)propanoate

[0001180] To a mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3- (2-pyridyl)propanoate (0.8 g, 2.20 mmol, 1 eq, 2HC1) and 4-methoxy-lH-indole-2- carboxylic acid (461.86 mg, 2.42 mmol, 1.1 eq) and DIPEA (1.42 g, 10.98 mmol, 1.91 mL, 5 eq) in DCM (0.5 mL) and THF (0.5 mL) was added T3P (2.10 g, 3.29 mmol, 1.96 mL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 12 h. The reaction mixture was added saturated sodium bicarbonate solution (10 mL) and extracted with DCM (10 mL x 2) to get the organic phase. The organic phase was concentrated to get the crude product. The residue was purified by flash silica gel chromatography. Methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2-carbon yl)amino] propanoyl]amino]-3-(2-pyridyl)propanoate (0.8 g, 1.50 mmol, 68.38% yield, 87.2% purity) was obtained as a light yellow solid. MS (ESI) m/z 465.2 [M+H] ⁺

Step5: N-[(JS)-1-(cyclopropylmethyl)-2-[[(JS)-1-(nitrosomethyl)-2-( 2-pyridyl)ethyl]amino]- 2-oxo -ethyl ]-4-methoxy-lH-indole-2-carboxamide [0001181 ] To a mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole- 2-carbonyl)amino] propanoyl]amino]-3-(2-pyridyl)propanoate (0.2 g, 430.56 umol, 1 eq) was added NH ₃ /MeOH (7 M, 4 mL, 65.03 eq) in one portion at 25 °C under N ₂ . 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-(cyclopro pylmethyl)-2-[[(1S)-1- (nitrosomethyl)-2-(2-pyridyl)ethyl]amino]-2-oxo-ethyl]-4-met hoxy-lH-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] ⁺

Step 6: N-[ ( l S)-2-[[( 1 S)-l-cyano-2-(2-pyridyl)ethyl ] amino] -l-(cyclopropylmethyl)-2-oxo- ethyl ]-4- methoxy-lH-indole-2-carboxamide

[0001182] To a mixture of N-[(l S)-1-(cyclopropylmethyl)-2-[[(l S)-1-(nitrosomethyl)-2-(2- pyridyl)ethyl]ami no]-2-oxo-ethyl]-4-methoxy-lH-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 N ₂ . 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-[(l S)-2-[[(l S)-1-cyano-2-(2-pyridyl)ethyl]amino] -1-(cyclopropylmethyl)- 2-oxo-ethyl]-4-methoxy-lH-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] ⁺

[0001183] Prep-HPLC condition: column: Phenomenex Gemini-NX C1875*30 mm*3 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )-ACN]; B%: 30%-50%,8 min

[0001184] ¹ H NMR (400 MHz, MeOD-d4) δ ppm 8.27 - 8.39 (m, 1 H), 7.64 - 7.73 (m, 1

H), 7.31 - 7.39 (m, 1 H), 7.23 - 7.30 (m, 1 H), 7.12 - 7.23 (m, 2 H), 7.00 - 7.07 (m, 1 H), 6.52 (d, J= 7.50 Hz, 1 H), 5.28 (t, J= 7.17 Hz, 1 H), 4.51 - 4.63 (m, 1 H), 3.87 - 3.98 (m, 3 H), 3.30 - 3.31 (m, 2 H), 1.57 - 1.83 (m, 2 H), 0.62 - 0.85 (m, 1 H), 0.34 - 0.54 (m, 2 H), 0.05 - 0.22 (m, 2 H).

[0001185] ¹ H NMR (400 MHZ, CHLOROFORM-d) δ ppm 9.35 (br s, 1 H), 8.50 - 8.68 (m, 1 H), 8.04 - 8.26 (m, 1 H), 7.51 (td, J=7.69, 1.75 Hz, 1 H), 6.93 - 7.11 (m, 4 H), 6.77 - 6.90 (m, 2 H), 6.34 - 6.42 (m, 1 H), 5.11 - 5.23 (m, 1 H), 4.61 - 4.71 (m, 1 H), 3.76 - 3.87 (m, 3 H), 3.07 - 3.25 (m, 2 H), 1.55 - 1.69 (m, 2 H), 0.48 - 0.67 (m, 1 H), 0.28 - 0.40 (m, 2 H), -0.09 - 0.08 (m, 2 H). Example 135. Synthesis of viral protease inhibitor compound 448

Step 1: Methyl (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-l-pyridyl)propa noate [0001186] 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 mixtue 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 N ₂ . LCMS showed one peak with desired MS was detected. The mixture was quenched with H ₂ O (50 mL), and extracted with ethyl acetate (150 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , 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.

[0001187] LCMS: Rt = 0.780 min; for C13H16N ₂ O5 MS Calcd.: 280.11; MS Found: 281.0 [M+H ⁺ ],

[0001188] ¹ H NMR (400 MHZ, DMSO-d ₆ ) δ 7.93 (d ,J= 7.03 Hz, 1H), 6.43 (d ,J= 7.03 Hz, 1H), 5.30 (t ,J= 7.65 Hz, 1H), 3.65 (s, 3H), 2.23 (s, 3H), 1.99 (t ,J= 7.40 Hz, 2H), 0.56 - 0.45 (m, 1H), 0.38 - 0.25 (m, 2H), 0.15 - 0.13 (m, 2H).

Step 2: (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-l-pyridyl)propa noic acid [0001189] 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.H ₂ O (151.5 mg, 3.61 mmol, 4 eq) in THF (2.1 mL), MeOH (0.7 mL), H ₂ O (0.7 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 1 hr under N ₂ atmosphere. LCMS showed one peak with desired MS was detected. The mixture was added H ₂ O (5 mL), then the mixture was added 2 M HC1 (2 mL) to adjust the pH to about 6~7. The mixture was added H ₂ O (10 mL), and extracted with ethyl acetate (30 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , 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.

[0001190] LCMS: Rt = 0.732 min; for C ₁₂ H ₁₄ N ₂ O ₅ MS Calcd. : 266.09; MS Found: 267.0 [M+H ⁺ ],

Step 3: (2S)-N-[ ( l S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ] ethyl ]-3-cyclopropyl-2-(4- methyl-3-nitro-2-oxo-l-pyridyl)propanamide

[0001191 ] To a solution of (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1- pyridyl)propanoic acid (207 mg, 0.77 mmol, 1 eq) in DMF (2 mL) was added T3P (989.5 mg, 1.55 mmol, 0.92 mL, 50% purity, 2 eq), TEA (314.6 mg, 3.11 mmol, 0.43 mL, 4 eq)and (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (147.4 mg, 0.77 mmol,

1 eq, HC1). The mixture was stirred at 25 °C for 4 h. LCMS showed the peak with desired MS was detected. The mixture was quenched with H ₂ O (20 mL), and extracted with ethyl acetate (30 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , 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 Compound (2S)-N-[(1S)-1-cyano- 2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-2-(4-methyl-3-n itro-2-oxo- 1 - pyridyl)propanamide (60 mg, 17.8% yield) as a yellow solid.

[0001192] LCMS: Rt = 1.336 min; for C ₁ 9HZ3N5O5 MS Calcd. : 401.17; MS Found: 402.1 [M+H ⁺ ],

(2S)-2-( 3-amino-4-methyl-2-oxo-l-pyridyl)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3- yl ] ethyl / -3-cyclopropyl-propanamide

[0001193] 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 (60 mg, 0.14 mmol, 1 eq) in THF (2 mL) was added Pd/C (70 mg, 65.7 umol, 10% purity, 0.44 eq). The mixture was stirred at 25 °C for 15 min under H ₂ . LCMS showed one peak with desired MS was detected. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80 *30 mm *3 um; mobile phase: [water(0.05% NH3H ₂ O+IO mM NH ₄ HC0 ₃ )-ACN];B%: 13%-43%,9.5 min) to give (2S)-2-(3-amino-4-methyl-2-oxo-1-pyridyl)-N-[(1S)-1-cyano-2- [(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (7.45 mg, 19.7 umol, 13.2% yield, 98.4% purity) as a brown solid.

[0001194] LCMS : Rt = 0.698 min; for C19H25N5O3 MS Calcd. : 371.20; MS Found: 372.1 [M+H ⁺ ],

[0001195] ¹ H NMR (400 MHz, CD3OD) δ 6.94 - 6.82 (m, 1H), 6.11 - 6.01 (m, 1H), 5.40 -

5.23 (m, 1H), 4.86 (br dd, J=6.0, 9.8 Hz, 1H), 3.14 - 3.08 (m, 2H), 2.47 - 2.27 (m, 1H),

2.23 - 2.03 (m, 2H), 1.99 - 1.91 (m, 3H), 1.83 - 1.57 (m, 4H), 0.48 (br d, J=7.3 Hz, 1H), 0.34 - 0.19 (m, 2H), 0.02 - 0.16 (m, 2H).

Example 136. Synthesis of viral protease inhibitor compound 449

[0001196] To a solution of (2S)-N-[( IS)- 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 H ₂ . LCMS showed one peak with desired MS was detected. The reaction mixture was filtered and the filtrate was quenched with H ₂ O (20 mL), and extracted with ethyl acetate (30 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , 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% NH3H ₂ O IPA];B%: 45%-45%, min) to give 2-[( 1 S)-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.

[0001197] Isomer 1 : LCMS : Rt = 0.659 min; for C19H25N5O3 MS Calcd. : 371.20; MS Found: 394.1 [M+Na ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 7.02 (d, J=7.0 Hz, 1H), 6.22 (d, J=7.1 Hz, 1H), 5.50 (t, J=7.8 Hz, 1H), 5.04 - 4.98 (m, 1H), 3.37 - 3.32 (m, 2H), 2.52 - 2.46 (m, 1H), 2.38 - 2.24 (m, 2H), 2.11 (s, 3H), 1.94 - 1.81 (m, 4H), 0.61 - 0.56 (m, 1H), 0.42 - 0.38 (m, 2H), 0.13 - 0.02 (m, 2H).

[0001198] Isomer 2: LCMS : Rt = 0.704 min; for C19H25N5O3 MS Calcd.: 371.20; MS Found: 372.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 7.03 (d, J=7.1 Hz, 1H), 6.20 (d, J=7.0 Hz, 1H), 5.41 (dd, J=7.1, 8.4 Hz, 1H), 5.00 (br dd, J=6.1, 10.0 Hz, 1H), 3.29 - 3.24 (m, 2H), 2.49 (dq, J=5.4, 9.3 Hz, 1H), 2.31 - 2.21 (m, 2H), 2.09 (s, 3H), 1.98 - 1.76 (m, 4H), 0.69 - 0.57 (m, 1H), 0.50 - 0.41 (m, 2H), 0.17 - 0.04 (m, 2H).

Example 137. Synthesis of viral protease inhibitor compound 450

Step 1: Methyl (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-l-pyridyl)propa noate

[0001199] 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 N ₂ . LCMS showed one peak with desired MS was detected. The mixture was quenched with H ₂ O (20 mL), and extracted with ethyl acetate (50 mL * 3). The combined organic layers was washed with brine (40 mL) dried over Na ₂ SO ₄ , 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.

[0001200] LCMS: Rt = 0.785 min; for C ₁ 3H ₁ 6N ₂ O5 MS Calcd. : 280.11 ; MS Found: 281.1 [M+H ⁺ ],

Step 2: (2S)-3-cyclopropyl-2-(4-methyl-3-mtro-2-oxo-l-pyridyl)propan oic acid

[0001201 ] 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.H ₂ O (519.2 mg, 12.37 mmol, 4 eq) in THF (6 mL), MeOH (2 mL), H ₂ O (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 1 h under N ₂ atmosphere. LCMS showed one peak with desired MS was detected. The mixture was added H ₂ O (5 mL), then the mixture was added 2 M HC1 (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 NazSC^, 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.

[0001202] LCMS: Rt = 0.735 min; for C ₁₂ H ₁₄ N ₂ O5MS Calcd.: 266.09; MS Found: 267.0 [M+H ⁺ ],

Step 3: N-f ( l S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl ]-3-cyclopropyl-2-( 4-methyl-3- nitro-2-oxo-l-pyridyl)propanamide

[0001203 ] To a solution of (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-1- pyridyl)propanoic acid (791 mg, 2.97 mmol, 1 eq) in DCM (10 mL) was added HATU (1.36 g, 3.57 mmol, 1.2 eq), DIPEA (1.15 g, 8.91 mmol, 1.55 mL, 3 eq) and (2S)-2- amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (676.0 mg, 3.57 mmol, 1.2 eq,

HC1). The mixture was stirred at 25 °C for 2 h. LCMS showed one peak with desired MS was detected. The mixture was quenched with H ₂ O (20 mL), and extracted with DCM (40 mL * 3). The combined organic layers was washed with brine (20 mL) dried over Na ₂ SO ₄ , filtered and concentrated under reduce pressure. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM/MeOH ethergradient @ 35 mL/min) to give N-[( 1 S)- 1 -cy ano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-2-(4-methyl-3-nitro- 2-oxo-1- pyridyl)propanamide (838 mg, 64.5% yield) as yellow oil. LCMS: Rt = 0.741 min; for C19H23N5O5 MS Calcd.: 401.17; MS Found: 402.1 [M+H ⁺ ],

Step 4: 2-(3-Amino-4-methyl-2-oxo-l-pyridyl)-N-[(lS)-l-cyano-2-[(3S) -2-oxopyrrolidin-3- yl ] ethyl / -3-cyclopropyl-propanamide

[0001204] 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 H ₂ . 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-ox opyrrolidin-3-yl]ethyl]-3- cyclopropyl-propanamide (616 mg, 68.7% yield) as a white solid.

[0001205] LCMS : Rt = 0.703 min; for C19H25N5O3 MS Calcd. : 371.20; MS Found: 372.1 [M+H ⁺ ],

N-[( 1 S)- 1 -Cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-2-[4-methyl-2-o xo-3- (2,2,2-trifluoroethylamino)- 1 -pyridyl]propanamide

[0001206] To a solution 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 DMA (5 mL) was added NazCO ₃ (730.5 mg, 6.89 mmol, 25.60 eq) and 2,2,2- trifluoroethyl trifluoromethanesulfonate (1.6 g, 6.89 mmol, 25.6 eq). The mixture was stirred at 40 °C for 16 h. The mixture was filtered, and then the filtrate was quenched with H ₂ O (20 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , 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% NH3H ₂ O+IO mM NH4HCO3)- ACN];B%: 23%-53%,7.8 min). Compound N-[( 1 S)- 1 -cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-3-cyclopropyl-2-[4-methyl-2-oxo-3-(2,2,2-trifluoro ethylamino)-1- pyridyl]propanamide (71.7 mg, 57.9% yield) was obtained as a white solid. LCMS: Rt = 0.794 min; for C21H26F3N5O3 MS Calcd.: 453.20; MS Found: 454.1 [M+H ⁺ ],

[0001207] ¹ H NMR (400 MHz, CD3OD) δ 7.24 (dd, J=3.9, 7.2 Hz, 1H), 6.22 (dd, J=5.5, 7.0 Hz, 1H), 5.52 - 5.32 (m, 1H), 5.01 (dd, J=6.1, 9.9 Hz, 1H), 4.03 - 3.73 (m, 2H), 3.36 - 3.32 (m, 1H), 3.29 - 3.21 (m, 1H), 2.56 - 2.45 (m, 1H), 2.41 - 2.22 (m, 2H), 2.21 (d, J=5.3 Hz, 3H), 2.04 - 1.91 (m, 2H), 1.91 - 1.71 (m, 2H), 0.67 - 0.55 (m, 1H), 0.48 - 0.35 (m, 2H), 0.18 -0.02 (m, 2H).

Example 138. Synthesis of viral protease inhibitor compound 451

[0001208] N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclop ropyl-2-[4- methyl-2-oxo-3-(2,2,2-trifluoroethylamino)-1-pyridyl]propana mide (69 mg, 0.15 mmol, 1 eq) was separated by SF C(condition : column : DAICEL CHIRALPAK AD(250 mm * 30 mm, 10 um);mobile phase: [0.1% NH3H20 ETOH];B%: 45%-45%, min ) to afford (2R)- N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclop ropyl-2-[4-methyl-2-oxo-3- (2,2,2-trifluoroethylamino)- 1 -pyridyl]propanamide (17.12 mg, 24.8% yield) as a white solid.

[0001209] Isomer 1 : LCMS: Rt = 0.799 min; for C21H26F3N5O3 MS Calcd.: 453.20; MS Found: 454.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 7.24 (d, J=7.0 Hz, 1H), 6.23 (d, J=7.3 Hz, 1H), 5.45 (t, J=7.8 Hz, 1H), 5.01 (dd, J=6.7, 9.4 Hz, 1H), 4.03 - 3.70 (m, 2H), 3.36 - 3.32 (m, 2H), 2.56 - 2.46 (m, 1H), 2.41 - 2.24 (m, 2H), 2.21 (s, 3H), 1.98 - 1.93 (m, 2H), 1.93 - 1.76 (m, 2H), 0.64 - 0.50 (m, 1H), 0.44 - 0.33 (m, 2H), 0.17 - 0.04 (m, 2H).

[0001210] Isomer 2: LCMS: Rt = 0.800 min; for C21H26F3N5O3 MS Calcd.: 453.20; MS Found: 454.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 7.25 (d, J=7.3 Hz, 1H), 6.22 (d, J=7.0 Hz, 1H), 5.38 (dd, J=7.0, 8.5 Hz, 1H), 5.01 (dd, J=6.0, 10.0 Hz, 1H), 3.89 (q, J=9.5 Hz, 2H), 3.30 - 3.21 (m, 2H), 2.50 (dq, J=5.3, 9.3 Hz, 1H), 2.32 - 2.22 (m, 2H), 2.20 (s, 3H), 2.06 - 1.90 (m, 2H), 1.89 - 1.68 (m, 2H), 0.69 - 0.57 (m, 1H), 0.50 - 0.36 (m, 2H), 0.22 - 0.04 (m, 2H).

Example 139. Synthesis of viral protease inhibitor compound 455

[0001211] To a solution of (3R,6S)-6-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-5-oxo-2,3,6,7,8,8a-hexahydrothiazolo[3,2-a]pyridin e-3-carboxamide (40.0 mg, 0.11 mmol, 1 eq) in DMF (0.5 mL) was added NazCO ₃ (24.1 mg, 0.22 mmol, 2 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (26.4 mg, 0.11 mmol, 1 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was added H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water(0.05% NH ₃ H ₂ O+lO mM NH4HC03)-ACN];B%: 8%-38%, 9.5 min). (3R,6S,8aS)-N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-5-oxo-6-(2,2,2-trifluoroethylamino )-2,3,6,7,8,8a- hexahydrothiazolo[3,2-a]pyridine-3-carboxamide (8.02 mg, 18.5 umol, 16.2% yield,

100% purity) was obtained as a white solid.

[0001212] LCMS: Rt = 0.686 min; for C17H ₂₂ F ₃ N5O3SMS Calcd.: 433.45; MS Found: 434.0 [M+H ⁺ ],

[0001213] ¹ H NMR (400 MHz, CD ₃ OD) δ 5.02 (dd, J = 10.79, 5.27 Hz, 1 H), 4.90 - 4.98 (m, 2 H), 4.77 - 4.83 (m, 1 H), 3.33 - 3.49 (m, 4 H), 3.20 - 3.29 (m, 1 H), 3.11 - 3.20 (m, 1 H), 2.67 (qd, J = 9.29, 5.27 Hz, 1 H), 2.17 - 2.45 (m, 4 H), 1.72 - 1.99 (m, 4 H).

Example 140. Synthesis of viral protease inhibitor compound 457 ( 3R, 6S, 8aS)-6-amino-N-((S)-l-cyano-2-( (S)-2-oxopyrrolidin-3-yl)ethyl)-5-oxohexahydro-2H- thiazolof 3, 2 -a ]pyridine-3-carboxamide

[0001214] To a solution of 9H-fluoren-9-ylmethyl N-[(3R,6S)-3-[[( 1 S)- 1 -cyano-2-[(3 S)-2- oxopyrrolidin-3-yl]ethyl]carbamoyl]-5-oxo-2,3,6,7,8,8a-hexah ydrothiazolo[3,2-a]pyridin- 6-yl]carbamate (50 mg, 87.1 umol, 1 eq) in DCM (0.2 mL) was added piperidine (14.8 mg, 0.17 mmol, 17 uL, 2 eq). The mixture was stirred at 25 °C for 0.5 hr.

Compound (3R,6S)-6-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl]-5-oxo- 2,3,6,7,8,8a-hexahydrothiazolo[3,2-a]pyridine-3-carboxamide (30 mg, crude) was obtained as a yellow oil.

Benzyl((3R,6S,8aS)-3-(((S)-l-cyano-2-((S)-2-oxopyrrolidin -3-yl)ethyl)carbamoyl)-5- oxohexahydro-2H-thiazolo[ 3, 2 -a ]pyridin-6-yl) carbamate

[0001215] To a solution of (3R,6S)-6-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-5-oxo-2,3,6,7,8,8a-hexahydrothiazolo[3,2-a]pyridin e-3-carboxamide (30 mg, 85.3 umol, 1 eq) in DCM (1 mL) was added benzyl carbonochloridate (29.1 mg, 0.17 mmol, 24 uL, 2 eq) and TEA (25.9 mg, 0.25 mmol, 35 uL, 3 eq). The mixture was stirred at 25 °C for 2 h. LCMS detected desired compound. The reaction mixture was added H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous NazSCb, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10 um; mobile phase: [water (0.05% NH ₃ H ₂ O+lO mM NH4HC03)-ACN]; B%: 15%-45%, 9.5 min). Then the residue was purified by prep-HPLC (column: Waters Xbridge 150*25mm* 5 um; mobile phase:

[water (0.04% NH ₃ H ₂ O+10 mM NH4HC03)-Me0H]; B%: 40%-80%, 9.5 min). Compound benzyl N-[(3R,6S)-3-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-5-oxo-2,3,6,7,8,8a-hexahydrothiazolo[3,2 -a]pyridin-6-yl]carbamate (1.41 mg, 2.8 umol, 3.3% yield, 99% purity) was obtained as a white solid. LCMS: Rt = 0.751 min; for C23H27N5O5S MS Calcd.: 485.56; MS Found: 486.1 [M+H ⁺ ],

[0001216] ¹ H NMR (400 MHz, CDCl3) δ8.32 (br s, 1 H), 7.37 (br s, 5 H), 6.07 (br s, 1 H), 5.67 (br s, 1 H), 5.38 (br s, 1 H), 5.17 (br d ,J= 10.26 Hz, 2 H), 4.90 (br s, 1 H), 4.80 (br s, 1 H), 3.97 (br s, 1 H), 3.52 (br s, 1 H), 3.25 (br s, 1 H), 3.33 (br s, 3 H), 2.44 (br s, 1 H), 2.33 (br d,J= 15.38 Hz, 1 H), 1.97 - 2.13 (m, 2 H), 1.85 (br s, 3 H). Example 141. Synthesis of viral protease inhibitor compound 459

N-((3R,6S,8aS)-3-(((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-y l)ethyl)carbamoyl)-5- oxohexahydro-2H-thiazolo[ 3, 2 -a ]pyridin-6-yl)-5-methylisoxazole-3-carboxamide

[0001217] A mixture of 5-methylisoxazole-3-carboxylic acid (36.1 mg, 0.28 mmol, 2 eq), HATU (108.2 mg, 0.28 mmol, 2 eq) and DIEA (73.5 mg, 0.56 mmol, 99 uL, 4 eq) in DMF (1 mL) was stirred at 25 °C for 0.5 h, and then (3R,6S)-6-amino-N-[(1S)-1- cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-5-oxo-2,3,6,7,8,8a -hexahydrothiazolo[3,2- a]pyridine-3-carboxamide (50.0 mg, 0.14 mmol, 1 eq) was added into the reaction. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was added H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water(0.05% NH ₃ H ₂ O+10 mM NH ₄ HC0 ₃ )-ACN];B%: 7%-37%,9.5 min). Compound N- [(3R,6S,8aS)-3-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]e thyl]carbamoyl]-5-oxo- 2,3,6,7,8,8a-hexahydrothiazolo[3,2-a]pyridin-6-yl]-5-methyl- isoxazole-3-carboxamide (15.28 mg, 33.0 umol, 23.2% yield, 99.7% purity) was obtained as a white solid.

LCMS: Rt = 0.698 min; for C20H24N6O5S MS Calcd.: 460.51; MS Found: 461.1 [M+H ⁺ ],

[0001218] ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 6.52 (d ,J= 0.75 Hz, 1 H), 4.98 - 5.07 (m, 3 H), 4.44 (dd,J= 11.17, 6.90 Hz, 1 H), 3.41 (dd, J= 11.67, 7.65 Hz, 1 H), 3.23 - 3.29 (m, 3 H), 2.58 - 2.69 (m, 1 H), 2.48 (s, 3 H), 2.27 - 2.44 (m, 4 H), 2.08 - 2.21 (m, 1 H), 1.79 - 2.01 (m, 3 H).

Example 142. Synthesis of viral protease inhibitor compound 465

Methyl (2S)-3-cyclopropyl-2-(3-nitro-2-oxo-l-pyridyl)propanoate [0001219] To a solution of 3-nitro- 1H-pyridin-2-one (1 g, 7.14 mmol, 1 eq) in DMF (10 mL) was added NaH (428.2 mg, 10.71 mmol, 60% purity, 1.5 eq) at 0 °C for 15 min. Then, methyl (2R)-2-bromo-3-cyclopropyl-propanoate (1.6 g, 7.85 mmol, 1.1 eq) was added into the mixture, and the mixture was stirred at 25 °C for 2 hr. TLC (petroleum ether: ethyl acetate = 1:1) showed new spot was detected. The reaction mixture was quenched by addition H20 (10 mL) at 0 °C, and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-50% petroleum ether/ethyl acetate ethergradient @ 30 mL/min) to give methyl (2S)-3- cyclopropyl-2-(3-nitro-2-oxo-1-pyridyl)propanoate (552 mg, 28.7% yield, 98.9% purity) as a yellow solid.

(2S)-3-cyclopropyl-2-(3-nitro-2-oxo-l-pyridyl)propcmoic acid

[0001220] 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.H ₂ O (108.7 mg, 2.59 mmol, 3 eq) in H ₂ O (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 HC1 to pH = 4. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic phase was washed with brine (5 mL * 3), dried with anhydrous Na ₂ SO ₄ , 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. (2S)-N-[(J S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-2-yl ]ethyl]-3-cyclopropyl-2-( 3-nitro-2-oxo-l- pyridyl)propanamide

[0001221 ] To a solution of (2S)-3-cyclopropyl-2-(3-nitro-2-oxo-1-pyridyl)propanoic acid (260 mg, 1.03 mmol, 1 eq) in DCM (3 mL) was added HATU (470.3 mg, 1.24 mmol, 1.2 eq), DIPEA (266.4 mg, 2.06 mmol, 0.35 mL, 2 eq) and (2S)-2-amino-3-[(3S)-2- oxopyrrolidin-3-yl]propanenitrile (234.5 mg, 1.24 mmol, 1.2 eq, HC1). The mixture was stirred at 25 °C for 16 h. TLC (DCM /MeOH = 10: 1) showed new spot was detected. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM/MeOH ethergradient @ 20 mL/min) to give (2S)-N-[( 1 S)- 1 -cyano-2-[(3S)- 2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-2-(3-nitro-2-oxo-1 -pyridyl)propanamide (225 mg, 54.0% yield, 96% purity) as a yellow solid.

(2S)-2-( 3-amino-2-oxo-l-pyridyl)-N-[ (lS)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ]-3- cyclopropyl-propanamide

[0001222] To a solution of (2S)-N-[(1 S)-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-l eq) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (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-y l]ethyl]-3-cyclopropyl- propanamide (119 mg, 64.3% yield, 99.7% purity) as a brown solid.

[0001223] LCMS: Rt = 0.669 min; for C18H23N5O3 MS Calcd.: 357.18; MS Found: 358.1 [M+H ⁺ ], [0001224] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.06 - 7.01 (m, 1H), 6.70 - 6.64 (m, 1H), 6.24 (s, 1H), 5.56 - 5.41 (m, 1H), 5.06 - 4.97 (m, 1H), 3.30 - 3.24 (m, 2H), 2.57 - 2.43 (m, 1H), 2.38 - 2.18 (m, 2H), 2.04 - 1.85 (m, 3H), 1.85 - 1.69 (m, 1H), 0.70 - 0.54 (m, 1H), 0.50 - 0.36 (m, 2H), 0.21 - 0.12 (m, 1H), 0.10 - 0.02 (m, 1H).

Example 143. Synthesis of viral protease inhibitor compound 465

[0001225] The residue was purification by SFC. LC-MS showed the desired compound was detected. The residue was purified by SFC (column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H ₂ O EtOH]; B%: 30%-30%, min).

[0001226] Isomer 1: 2-[( 1 S)-3-amino-2-oxo- 1 -pyridyl]-N-[( 1 S)- 1 -cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (2.84 mg, 6.3% yield, 98.9% purity) as a brown solid. LCMS: Rt = 0.660 min; for C ₁ 8H ₂ 3N5O3 MS Calcd.: 357.41; MS Found: 358.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD ₃ OD) δ 7.03 (dd,J= 1.4, 7.0 Hz, 1H), 6.68 (dd,J= 1.4, 7.2 Hz, 1H), 6.26 (t , J= 7.1 Hz, 1H), 5.53 (t ,J= 7.7 Hz, 1H), 5.02 (dd, J= 6.8, 9.3 Hz, 1H), 3.38 - 3.32 (m, 2H), 2.56 - 2.46 (m, 1H), 2.36 (m, 1H), 2.32 - 2.23 (m, 1H), 1.97 - 1.87 (m, 3H), 1.87 - 1.79 (m, 1H), 0.67 - 0.54 (m, 1H), 0.45 - 0.34 (m, 2H), 0.19 - 0.10 (m, 1H), 0.07 - 0.02 (m, 1H).

[0001227] Isomer 2: Compound 2-[( 1 R)-3 -amino-2-oxo- 1 -pyridyl]-N-[( 1 S}- 1 -cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (21.3 mg, 46.5% yield) was obtained as a brown solid. LCMS: Rt = 0.671 min; for C ₁ 8H ₂ 3N5O3 MS Calcd.: 357.41; MS Found: 358.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD ₃ OD) δ 7.04 (dd, J= 1.5, 7.0 Hz, 1H), 6.67 (dd,J= 1.5, 7.3 Hz, 1H), 6.24 (t , J= 7.1 Hz, 1H), 5.44 (t ,J= 7.7 Hz, 1H), 5.01 (dd, J= 6.1, 10.1 Hz, 1H), 3.30 - 3.24 (m, 2H), 2.49 (dq,J= 5.4, 9.3 Hz, 1H), 2.32 - 2.20 (m, 2H), 2.01 - 1.83 (m, 3H), 1.83 - 1.70 (m, 1H), 0.70 - 0.59 (m, 1H), 0.51 - 0.38 (m, 2H), 0.20 - 0.12 (m, 1H), 0.10 - 0.00 (m, 1H). Example 144. Synthesis of viral protease inhibitor compound 466

N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyc lopropyl-2-[2-oxo-3-(2,2,2- trifluoroethylamino)- 1 -pyridyl]propanamide

[0001228] To a solution of 2-(3-amino-2-oxo- 1 -pyridyl)-N-[( 1 S)- 1 -cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (110 mg, 0.30 mmol, 1 eq) in DMA (1 mL) was added NazCO ₃ (326.2 mg, 3.08 mmol, 10 eq) and 2,2,2- trifluoroethyl trifluoromethanesulfonate (2.1 g, 9.23 mmol, 30 eq). The mixture was stirred at 40 °C for 16 h. TLC (DCM: MeOH = 10:1) showed new spot was detected. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10:1) to give N-[( 1 S)- 1 -cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-3-cyclopropyl-2-[2-oxo-3-(2,2,2-trifluoroethylam ino)-1-pyridyl]propanamide (23 mg, 16.8% yield, 98.8% purity) as a white solid.

[0001229] LCMS: Rt = 0.797 min; for C ₂ 0H ₂₄ F3N5O3 MS Calcd.: 439.18; MS Found: 440.1 [M+H ⁺ ],

[0001230] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.06 (dt, J = 1.5, 6.8 Hz, 1H), 6.65 - 6.55 (m, 1H), 6.37 - 6.27 (m, 1H), 5.56 - 5.40 (m, 1H), 5.05 - 4.98 (m, 1H), 3.88 (dq, J = 6.0, 9.2 Hz, 2H), 3.34 (br d, J= 3.0 Hz, 1H), 3.30 - 3.24 (m, 1H), 2.57 - 2.42 (m, 1H), 2.39 - 2.20 (m, 2H), 2.08 - 1.88 (m, 3H), 1.86 - 1.74 (m, 1H), 0.71 - 0.52 (m, 1H), 0.50 - 0.36 (m, 2H), 0.22 - 0.11 (m, 1H), 0.10 - 0.03 (m, 1H).

Example 145. Synthesis of viral protease inhibitor compound 467 [0001231 ] The residue was further separated by SFC. The residue was further separated by SFC (column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 um); mobile phase: [0.1% NH3H ₂ O ETOH]; B%: 20%-20%, min).

[0001232] Isomer 1: (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3- cyclopropyl-2-[2-oxo-3-(2,2,2-trifluoroethylamino)-1-pyridyl ]propanamide (2.56 mg, 12.3% yield) as a white solid. LCMS: Rt = 0.837 min; for C ₂ 3H3 ₁ N5O5 MS Calcd. : 457.23; MS Found: 458.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD ₃ OD) δ 7.06 (dt, J= 1.5, 6.8 Hz, 1H), 6.65 - 6.55 (m, 1H), 6.37 - 6.27 (m, 1H), 5.56 - 5.40 (m, 1H), 5.05 - 4.98 (m,

1H), 3.88 (dq, J = 6.0, 9.2 Hz, 2H), 3.34 (br d, J= 3.0 Hz, 1H), 3.30 - 3.24 (m, 1H), 2.57 - 2.42 (m, 1H), 2.39 - 2.20 (m, 2H), 2.08 - 1.88 (m, 3H), 1.86 - 1.74 (m, 1H), 0.71 - 0.52 (m, 1H), 0.50 - 0.36 (m, 2H), 0.22 - 0.11 (m, 1H), 0.10 - 0.03 (m, 1H).

Isomer 2: Compound (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3- cyclopropyl-2-[2-oxo-3-(2,2,2-trifluoroethylamino)-1-pyridyl ]propanamide (2.56 mg, 12.3% yield, 96.3% purity) as a white solid. LCMS: Rt = 0.794 min; for C20H24F3N5O3 MS Calcd. : 439.18; MS Found: 440.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 7.04 (dd, J = 1.5, 7.0 Hz, 1H), 6.61 (d ,J= 7.0 Hz, 1H), 6.32 (t , J= 7.2 Hz, 1H), 5.52 (t , J= 7.8 Hz, 1H), 5.01 (dd,J= 6.5, 9.3 Hz, 1H), 3.89 (q, J= 9.3 Hz, 2H), 3.37 - 3.32 (m, 2H), 2.55 - 2.46 (m, 1H), 2.36 (m, 1H), 2.32 - 2.24 (m, 1H), 1.99 - 1.93 (m, 2H), 1.93 - 1.87 (m, 1H), 1.87 - 1.78 (m, 1H), 0.64 - 0.54 (m, 1H), 0.46 - 0.34 (m, 2H), 0.18 - 0.09 (m, 1H), 0.07 -0.02 (m, 1H).

Example 146. Synthesis of viral protease inhibitor compound 468

Step J: tert-Butyl 7-[(JS)-1-(cyclopropylmeihyl)-2-meihoxy-2-oxo-e ihyl] -6-oxo- 1, 7- diazaspiro[ 4.4 ]nonane-l -carboxylate

[0001233] To a solution of tert-butyl 6-oxo-l,7-diazaspiro[4.4]nonane-1-carboxylate (0.5 g, 2.08 mmol, 1 eq) in toluene (7 mL) was added NaH (124.8 mg, 3.12 mmol, 60% purity, 1.5 eq) at 0°C. After stirring at 25°C for lh, methyl (R)-2-bromo-3- cyclopropylpropanoate (517.0 mg, 2.50 mmol, 1.2 eq) was added at 0°C and the mixture was stirred at 80°C for 8 h. The reaction mixture was quenched by addition H ₂ O (15 mL) and extracted with EtOAc (15 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to give tert-butyl 7-(3-cyclopropyl-1-methoxy-1-oxopropan-2-yl)-6-oxo-l,7- diazaspiro[4.4]nonane- 1 -carboxylate (600 mg, crude) as a colorless oil.

Step 2: 2-(l-tert-butoxycarbonyl-6-oxo-l, 7-diazaspiro[4.4]nonan-7-yl)-3-cyclopropyl- propanoic acid

[0001234] To a solution of 2 (450.0 mg, 1.23 mmol, 1 eq) in H ₂ O (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 lh. LC-MS showed 2 was consumed completely and 66% of desired compound was detected. The reaction mixture was quenched by addition H ₂ O (15 mL). The pH of the mixture was adjusted whit HC1 (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 Na ₂ SO ₄ filtered and concentrated under reduced pressure to give a residue, and 2- (l-tert-butoxycarbonyl-6-oxo-l,7-diazaspiro[4.4]nonan-7-yl)- 3-cyclopropyl-propanoic acid (0.4 g, crude) was obtained as a colorless oil.

468: tert-butyl 7-[2-[[(lS)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino ]-l-(cyclo propylmethyl)-2-oxo-ethyl ] -6-oxo- 1, 7-diazaspiro[ 4.4 ]nonane-l -carboxylate

[0001235] To a solution of 2-( 1 -tert-butoxycarbonyl-6-oxo- 1 ,7-diazaspiro[4.4]nonan-7-yl)- 3 -cyclopropyl-propanoic acid (50.0 mg, 0.14 mmol, 1 eq) and in THF (1 mL) was added Et ₃ N (14.3 mg, 0.14 mmol, 19.7 uL, 1.0 eq) and isobutyl carbonochloridate (21.3 mg,

0.15 mmol, 20.4 uL, 1.1 eq) at 0°C. The mixture was stirred at 25 °C for 1 h. A solution of (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (32.2 mg, 0.17 mmol, 1.2 eq, HC1) and EtsN (15.7 mg, 0.15 mmol, 21.7 uL, 1.1 eq) in DMF (1 mL) was added and the mixture was stirred at 25 °C for lh. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150*25mm*10 um; mobile phase: [water (0.05% NH ₃ H ₂ O+IO mM NH4HC03)- ACN]; B%: 23%-53%, 9.5 min) to give 468 (9.02 mg, 13% yield) as a white solid. [0001236] LCMS: Rt = 0.821 min; for C25H37N5O5 MS Calcd. : 487.28; MS Found: 388.1 [M-Boc+H ⁺ ],

[0001237] ¹ H NMR (400MHz, CD3OD) δ 8.34 - 8.15 (m, 1H), 5.72 (d ,J= 10.0 Hz, 1H),

5.29 - 4.98 (m, 1H), 4.95 - 4.81 (m, 1H), 3.59 - 3.47 (m, 2H), 3.46 - 3.19 (m, 4H), 2.64 -

2.29 (m, 4H), 2.28 - 2.16 (m, 1H), 2.10 - 2.00 (m, 2H), 1.97 - 1.84 (m, 4H), 1.73 - 1.60 (m, 2H), 1.53 - 1.38 (m, 9H), 0.71 - 0.52 (m, 1H), 0.51 - 0.38 (m, 2H), 0.17 - 0.07 (m,

2H).

Example 147. Synthesis of viral protease inhibitor compound 469

[0001238] Isomer 1 & Isomer 2: tert-butyl 7-[( 1 R)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2- oxopyrrolidin-3-yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-6-oxo- 1 ,7- diazaspiro[4.4]nonane- 1 -carboxylate; Isomer 3: tert- butyl (5R)-7-[( 1S)-2-[[( 1S)- 1 -cyano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmeth yl)-2-oxo-ethyl]-6-oxo- 1 ,7-diazaspiro[4.4]nonane- 1 -carboxylate; Isomer 3: tert-butyl (5S)-7-[( 1 S)-2-[[( 1S)- 1 - cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cycloprop ylmethyl)-2-oxo-ethyl]-6- oxo-1, 7-diazaspiro[4.4]nonane-1-carboxylate

[0001239] To a solution of 2-(l-(tert-butoxycarbonyl)-6-oxo-l,7-diazaspiro[4.4]nonan-7- yl)-3-cyclopropylpropanoic acid (200 mg, 0.56 mmol, 1 eq) and in DMF (2 mL) was added HATU (431.5 mg, 1.13 mmol, 2.0 eq), (S)-2-amino-3-((S)-2-oxopyrrolidin-3- yl)propanenitrile (129.1 mg, 0.68 mmol, 1.2 eq, HC1) and DIPEA (146.6 mg, 1.13 mmol, 197.7 uL, 2.0 eq). The mixture was stirred at 25°C for 0.5h. TLC (Dichloromethane: Methanol=10/1, PMA) indicated reactant 1 was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Dichloromethane: Methanol= 100/1 to 10/1) to give compound 469 (150 mg) as a white solid, compound 469 (150 mg) was purified by prep-HPLC column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water (0.05% NH3H ₂ O+IO mM NH4HCO3)- ACN] ; B%: 25%- 55%, 9.5 min) to give compound 469 (60 mg) as a white solid. Compound 469 (60 mg) was purified by prep-SFC (column: DAICEL CHIRALPAK IC(250 mm*30 mm, 10 um);mobile phase: [0.1% NH3H ₂ O ETOH];B%: 55%-55%, min) to Isomer 1 & Isomer 2 (15 mg, 30.7 umol, 5.42% yield), Isomer 3 (8.46 mg, 16.3 umol, 2% yield, 94% purity) Isomer 4 (9.97 mg, 18.2 umol, 3% yield, 89% purity) as three white solids.

[0001240] Isomer 1 & 2: LCMS: Rt = 1.610 for C25H37N5O5 MS Calcd. : 487.28; MS Found: 488.2 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 5.20 - 4.98 (m, 1H), 4.81 - 4.71 (m, 1H), 3.61 - 3.41 (m, 3H), 3.38 - 3.32 (m, 3H), 2.61 - 2.41 (m, 2H), 2.40 - 2.19 (m, 2H), 2.18 - 1.66 (m, 9H), 1.52 - 1.33 (m, 9H), 0.78 - 0.57 (m, 1H), 0.56 - 0.38 (m, 2H), 0.25 - 0.04 (m, 2H).

[0001241 ] Isomer 3 : LCMS: Rt = 1.631 for C25H37N5O5 MS Calcd. : 487.28; MS Found: 488.2 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 5.20 - 4.97 (m, 1H), 4.53 - 4.32 (m, 1H), 3.64 - 3.41 (m, 3H), 3.31 (s, 3H), 2.63 - 2.35 (m, 2H), 2.35 - 2.12 (m, 2H), 2.12 - 1.74 (m, 8H), 1.73 - 1.52 (m, 1H), 1.73 - 1.52 (m, 1H), 1.50 - 1.35 (m, 9H), 0.75 (s, 1H), 0.62 - 0.36 (m, 2H), 0.24 - 0.07 (m, 2H).

[0001242 ] Isomer 4: LCMS: Rt = 1.630 for C25H37N5O5 MS Calcd. : 487.28; MS Found: 488.2 [M+H ⁺ ], ¹ H NMR (400MHz, CD3OD) δ 5.23 - 5.01 (m, 1H), 4.81 - 4.74 (m, 1H), 3.64 - 3.37 (m, 3H), 3.35 (s, 3H), 2.67 - 2.42 (m, 2H), 2.42 - 2.10 (m, 3H), 2.10 - 1.68 (m, 8H), 1.54 - 1.39 (m, 9H), 0.68 - 0.57 (m, 1H), 0.55 - 0.39 (m, 2H), 0.24 - 0.05 (m, 2H).

Example 148. Synthesis of viral protease inhibitor compound 471

[0001243 ] A solution of tert-butyl 7-( 1 -(((S)- 1 -cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-6-oxo-l,7-di azaspiro[4.4]nonane-1- carboxylate (90 mg, 0.18 mmol, 1 eq) in H20 (4 mL) was stirred at 100 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water (0.05% NH3H ₂ O+IO mM NH ₄ HC0 ₃ )-ACN]; B%: 11%-41%, 9.5 min) to giveN-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cy clopropyl-2-(6-oxo-l,7- diazaspiro[4.4]nonan-7-yl)propanamide (2.41 mg, 6.10 umol, 3% yield, 98% purity) as a white solid.

[0001244] LCMS: Rt = 0.603 min; for C20H29N5O3 MS Calcd. : 387.23; MS Found: 388.1 [M+H ⁺ ],

[0001245] ¹ H NMR (400 MHz, CD3OD) δ 5.01 (dd, J = 6.3, 9.8 Hz, 1H), 4.55 (s, 1H), 3.57 - 3.47 (m, 2H), 3.37 - 3.32 (m, 2H), 3.18 - 3.08 (m, 1H), 2.99 - 2.87 (m, 1H), 2.61 - 2.48 (m, 1H), 2.34 - 2.24 (m, 2H), 2.13 - 2.00 (m, 2H), 1.93 - 1.80 (m, 7H), 1.65 - 1.56 (m,

1H), 0.75 - 0.63 (m, 1H), 0.56 - 0.45 (m, 2H), 0.17 (d, J= 3.5 Hz, 2H).

Example 149. Synthesis of viral protease inhibitor compound 473

Step J: (2R)-2-bromo-3-cyclopropyl-propanoic acid

[0001246] 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 H2SO4 (35 mL) was added NaNO2 (2.43 g, 35.23 mmol, 1.3 eq) in H ₂ O (7 mL) drop wise 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 Na2S0 ₄ , filtered and concentrated to dryness under reduced pressure to give (2R)-2-bromo-3-cyclopropyl- propanoic acid (7.4 g, crude) as colorless oil. [0001247] ¹ H NMR (400MHz, CDCl ₃ ) δ 4.33 (t, J=7.4 Hz, 1H), 1.99 (dt, J= 2.1, 7.1 Hz, 2H), 0.91 - 0.79 (m, 1H), 0.58 - 0.51 (m, 2H), 0.22 - 0.15 (m, 2H).

Step 2: Methyl (2R)-2-bromo-3-cyclopropyl-propanoate [0001248] 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 HC1 (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 Na ₂ SO ₄ , 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.

[0001249] ¹ H NMR (400MHz, CDCl ₃ ) δ 4.31 (t, J=7.4 Hz, 1H), 3.80 (s, 3H), 2.00 - 1.94 (m, 2H), 0.86 - 0.75 (m, 1H), 0.57 - 0.44 (m, 2H), 0.22 - 0.09 (m, 2H).

Step 3: 2-( 6-tert-butoxycarbonyl-l-oxo-2, 6-diazaspiro[ 4.5 ]decan-2-yl) -3-cyclopropyl- propanoic acid

[0001250] To a solution of tert- butyl l-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 Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure to give tert-butyl 2-[l-(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 HC1 (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 Na ₂ SO ₄ , 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-c yclopropyl-propanoic acid (120 mg, crude) as light yellow oil.

[0001251 ] Isomer 1: tert- butyl 2-[2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]- 1 -oxo-2,6-diazaspiro[4.5]decane-6- carboxylate; Isomer 2: tert- butyl 2-[2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]- 1 -oxo-2,6-diazaspiro[4.5]decane-6- carboxylate

[0001252] To a solution of 2-(6-(tert-butoxy carbonyl)- 1 -oxo-2,6-diazaspiro[4.5]decan-2- yl)-3-cyclopropylpropanoic acid (0.1 g, 0.27 mmol, 1 eq) in DMF (1 mL) was added HATU (207.5 mg, 0.54 mmol, 2.0 eq), (S)-2-ami no-3 -((S)-2-oxopyrrolidi n-3 - yl)propanenitrile hydrochloride (62.1 mg, 0.32 mmol, 1.2 eq, HC1) and DIPEA (52.9 mg, 0.40 mmol, 71.3 uL, 1.5 eq). The mixture was stirred at 25°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water (0.05% NH3H ₂ O+IO mM NH ₄ HC0 ₃ )-ACN]; B%: 27%-57%, 9.5 min) to give Isomer 1 (18.9 mg, 13% yield) and Isomer 2 (2.54 mg, 1.8% yield) as two white solids.

[0001253] Isomer 1: LCMS: Rt = 0.831 min; for C26H39N5O5 MS Calcd.: 501.30; MS Found: 502.2 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 5.20 - 5.01 (m, 1H), 4.81 - 4.68 (m, 1H), 3.90 (td,J= 4.6, 8.6 Hz, 1H), 3.59 - 3.40 (m, 1H), 3.34 (d ,J= 3.3 Hz, 3H), 3.07 - 2.85 (m, 1H), 2.64 - 2.45 (m, 1H), 2.45 - 2.22 (m, 3H), 2.21 - 2.07 (m, 1H), 2.05 - 1.92 (m, 1H), 1.90 - 1.62 (m, 7H), 1.57 (d, J= 10.5 Hz, 2H), 1.51 - 1.39 (m, 9H), 0.81 - 0.57 (m, 1H), 0.55 - 0.33 (m, 2H), 0.22 - 0.04 (m, 2H).

[0001254] Isomer 2: LCMS: Rt = 0.845 min; for C26H39N5O5 MS Calcd.: 501.30; MS Found: 502.2 [M+H ⁺ ], ¹ HNMR (400 MHz, CD3OD) δ 5.28 - 5.14 (m, 1H), 5.28 - 5.14 (m, 1H), 4.77 (t, J= 7.7 Hz, 1H), 3.93 (br d,J= 13.1 Hz, 1H), 3.51 - 3.38 (m, 1H), 3.35 - 3.31 (m, 1H), 3.35 - 3.31 (m, 2H), 3.06 - 2.92 (m, 1H), 2.61 - 2.48 (m, 1H), 2.45 - 2.22 (m, 3H), 2.19 - 2.08 (m, 1H), 1.97 (td, J= 8.2, 13.7 Hz, 1H), 1.89 - 1.65 (m, 7H), 1.64 - 1.52 (m, 2H), 1.49 (s, 9H), 0.64 - 0.54 (m, 1H), 0.53 - 0.30 (m, 2H), 0.22 - 0.00 (m, 2H).

Example 150. Synthesis of viral protease inhibitor compound 475

[0001255] Isomer 1 & Isomer 2: (2R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]- 3-cyclopropyl-2-(l-oxo-2,6-diazaspiro[4.5]decan-2-yl)propena mide; Isomer 3: (2S)-N- [( 1S)- 1 -cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-2-[ (5R)- 1 -oxo-2,6- diazaspiro[4.5]decan-2-yl]propenamide; Isomer 4: (2S)-N-[( 1 S}- 1 -cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-2-[(5S)-l -oxo-2, 6-diazaspiro[4.5]decan-2- yl]propanamide

[0001256] A solution of tert- butyl 2-( 1 -(((S)- 1 -cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-1-oxo-2,6-di azaspiro[4.5]decane-6- carboxylate (0.15 g, 0.29 mmol, 1 eq) in H ₂ O (5 mL) was stirred at 100°C for 16 h . The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water (0.05% NH3H ₂ O+IO mM NH ₄ HC0 ₃ )-ACN]; B%: 1%-31%, 9.5 min) to give 475 Isomer 1 & Isomer 2 (6.00 mg, 5% yield) and 475 Isomer 3 & Isomer 4 (24.65 mg) as two white solids. 475 Isomer 3 & Isomer 4 was purified by prep-SFC (column: DAICEL CHIRALPAK AD(250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H ₂ O ETOH]; B%: 40%-40%, min) to give 475 Isomer 3 (5.53 mg, 4% yield) and 475 Isomer 4 (4.84 mg, 3% yield) as two white solids.

[0001257] 475 Isomer 1 & Isomer 2: LCMS: Rt = 1.232 min; for C21H31N5O3 MS Calcd.:

401.24; MS Found: 402.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 5.04 - 4.92 (m, 1H), 4.67 - 4.60 (m, 1H), 3.73 - 3.39 (m, 2H), 3.37 - 3.32 (m, 2H), 3.15 - 3.00 (m, 1H), 2.88 (d, J= 6.5 Hz, 1H), 2.62 - 2.42 (m, 1H), 2.40 - 2.15 (m, 6H), 2.11 - 1.76 (m, 8H), 1.68 - 1.51 (m, 1H), 0.75 - 0.57 (m, 1H), 0.57 - 0.39 (m, 2H), 0.23 - 0.11 (m, 2H). [0001258] Isomer 3: LCMS: Rt = 1.332 min; for C21H31N5O3 MS Calcd.: 401.24; MS Found: 402.2 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 4.90 - 4.82 (m, 1H), 4.47 (dd, J = 6.5, 9.0 Hz, 1H), 3.46 - 3.34 (m, 1H), 3.31 - 3.23 (m, 1H), 3.20 - 3.15 (m, 3H), 3.02 - 2.89 (m, 1H), 2.64 - 2.48 (m, 1H), 2.43 - 2.32 (m, 1H), 2.27 - 2.01 (m, 3H), 1.92 - 1.65 (m,

5H), 1.55 - 1.39 (m, 5H), 0.53 - 0.41 (m, 1H), 0.39 - 0.23 (m, 2H), 0.07 - -0.08 (m, 2H).

[0001259] Isomer 4: LCMS: Rt = 1.329 min; for C ₂ 1H31N5O3 MS Calcd.: 401.24; MS Found: 402.2 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 4.96 (d, J = 3.0 Hz, 1H), 4.66 (dd, J= 6.0, 9.5 Hz, 1H), 3.65 - 3.56 (m, 1H), 3.49 - 3.40 (m, 1H), 3.37 - 3.32 (m, 3H), 3.20 - 3.09 (m, 1H), 2.82 - 2.69 (m, 1H), 2.50 (td, J= 8.1, 16.3 Hz, 1H), 2.41 - 2.31 (m, 2H), 2.25 (ddd, J= 6.3, 9.5, 13.9 Hz, 1H), 2.10 (td, J= 9.0, 12.6 Hz, 1H), 2.01 - 1.79 (m, 4H), 1.71 - 1.57 (m, 5H), 0.65 - 0.55 (m, 1H), 0.54 - 0.37 (m, 2H), 0.21 - 0.08 (m, 2H).

Example 151. Synthesis of viral protease inhibitor compound 477

Step 1: (9H-fluoren-9-yl)methyl((3S, 6S,8aS)-3-(chlorocarbonyl)-5-oxohexahydro-2H- thiazolo[ 3, 2 -a ]pyridin-6-yl) carbamate

[0001260] 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)z (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 N ₂ . 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-hexahydrothiazo lo[3,2-a]pyridin-6- yl]carbamate (200 mg, crude) was obtained as a yellow solid.

(9H-fluoren-9-yl)methyl((3R, 6S, 8aS)-3-(((S)-l-cyano-2-( ( S)-2-oxopyrrolidin-3 - yl)ethyl)carbamoyl)-5-oxohexahydro-2H-thiazolo[3,2-a]pyridin -6-yl)carbamate [0001261 ] To a solution of 9H-fluoren-9-ylmethyl N-[(3 S,6S)-3-chlorocarbonyl-5-oxo- 2,3,6,7,8,8a-hexahydrothiazolo[3,2-a]pyridin-6-yl]carbamate (200 mg, 0.43 mmol, 1 eq) in DMF (5 mL) was added TEA (132.8 mg, 1.31 mmol, 0.18 mL, 3 eq) and (2S)-2- amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (99.6 mg, 0.52 mmol, 1.2 eq, HC1). The mixture was stirred at 25 °C for 1 hr. TLC (petroleum ether/ethyl acetate = 0:1, UV 254). The reaction mixture was added with H ₂ O (10 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , 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 0-100% ethyl acetate/petroleum ethergradient @ 30 mL/min) to give a yellow solid. The residue purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [water(0.05% HC1)- ACN];B%: 30%-60%,8.5 min). Compound 9H-fluoren-9-ylmethyl N-[(3R,6S)-3-[[(1S)- l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-5-oxo- 2,3,6,7,8,8a- hexahydrothiazolo[3,2-a]pyridin-6-yl]carbamate (10.63 mg, 18.4 umol, 4.2% yield, 99.7% purity) was obtained as a white solid. LCMS: Rt = 0.834 min; for C30H31N5O5S MS Calcd. : 573.66; MS Found: 574.2 [M+H ⁺ ],

[0001262 ] ¹ H NMR (400 MHz, CD3OD) δ 7.82 (d, J= 7.53 Hz, 2 H), 7.65 - 7.72 (m, 2 H), 7.37 - 7.45 (m, 2 H), 7.29 - 7.36 (m, 2 H), 5.02 - 5.11 (m, 3 H), 4.43 (d, J= 6.78 Hz, 2 H), 4.23 - 4.30 (m, 1 H), 4.01 (br dd, J= 11.29, 6.78 Hz, 1 H), 3.42 (dd, J= 11.54, 7.78 Hz, 1 H), 3.19 - 3.30 (m, 3 H), 2.52 - 2.65 (m, 1 H), 2.17 - 2.43 (m, 4 H), 2.03 - 2.13 (m, 1 H), 1.84 - 1.97 (m, 2 H), 1.73 - 1.83 (m, 1 H).

Example 152. Synthesis of viral protease inhibitor compound 479

[0001263] To a solution of 9H-fluoren-9-ylmethyl N-[(3R,6S)-3-[[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]carbamoyl]-5-oxo-2,3,6,7,8,8a-hexah ydrothiazolo[3,2-a]pyridin- 6-yl]carbamate (100 mg, 0.17 mmol, 1 eq) in MeOH (0.1 mL) was added NH3 (7 M, 2.00 mL, 80.31 eq). The mixture was stirred at 25 °C for 1.5 h. The reaction mixture was added H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The aqueous phase were concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water(0.05% NH3H ₂ O+IO mMNH ₄ HC0 ₃ )-ACN];B%: 0%-23%,7.8 min). Compound (3R,6S)-6-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl]-5-oxo- 2,3,6,7,8,8a-hexahydrothiazolo[3,2-a]pyridine-3-carboxamide (16.59 mg, 47.2 umol, 27.0% yield, 100% purity) was obtained as a white solid.

[0001264] LCMS: Rt = 1.495 min; for C ₁ 5H ₂₁ N5O3SMS Calcd. : 351.42; MS Found: 352.1 [M+H ⁺ ],

[0001265] ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 4.99 (br dd, J= 10.63, 5.63 Hz, 3 H), 3.33 - 3.45 (m, 4 H), 3.14 - 3.25 (m, 1 H), 2.58 - 2.71 (m, 1 H), 2.19 - 2.44 (m, 4 H), 1.75 - 2.00 (m, 4 H).

Example 153. Synthesis of viral protease inhibitor compound 483

[0001266] To a solution of (3S)-5-oxo-6-[(2-oxo-2-phenoxy-ethyl)amino]-2,3-dihydro-1H- indolizine-3-carboxylic acid (100 mg, 0.30 mmol, 1 eq) in DCM (3 mL) was added HATU (138.9 mg, 0.36 mmol, 1.2 eq) and DIPEA (118.0 mg, 0.91 mmol, 0.15 mL, 3 eq) for 1 h. Then, (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (55.9 mg, 0.29 mmol, 9.69e-l eq, HC1) was added into the mixture, and the resulting mixture was stirred at 25 °C for 15 h. TLC (DCM/MeOH = 10: 1). The reaction mixture was diluted with H ₂ O (5 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic phase was washed with brine (5 mL * 3), dried with anhydrous Na ₂ SO ₄ filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM/MeOH ethergradient @ 20 mL/min) to give phenyl 2-[[(3S)-3-[[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]carbamoyl]-5-oxo-2,3-dihydro-1H-ind olizin-6-yl]amino]acetate (35 mg, 75.3 umol, 24.7% yield, 99.8% purity) as a white solid.

[0001267] LCMS: Rt = 0.770 min; for C24H25N5O5 MS Calcd. : 463.19; MS Found: 464.1 [M+H ⁺ ],

[0001268] ¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 (br s, 1H), 7.46 - 7.24 (m, 5H), 6.32 (br d, J= 7.6 Hz, 1H), 5.19 (s, 2H), 5.10 - 4.99 (m, 3H), 3.34 (br d,J= 3.3 Hz, 1H), 3.24 - 3.06 (m, 2H), 2.74 - 2.63 (m, 1H), 2.62 - 2.45 (m, 2H), 2.40 - 2.23 (m, 3H), 1.97 - 1.80 (m,

2H).

Example 154. Synthesis of viral protease inhibitor compound 489

Step 1: (1R,2S,6R 7R)-8-trimethylsilyloxy-4-azatricyclo[5.2.2.0 ^2,6 ]undec-8-ene-3, 5-dione [0001269 ] A solution of cyclohexa-l,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, 12) 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 (lR,2S,6R,7R)-8-trimethylsilyloxy-4- azatricyclo[5.2.2.0 ^2,6 ]undec-8-ene-3 , 5-dione (5.2 g, 65.9% yield) was obtained as a white solid

Step 2: (1R,2S,6R 7R) -4-azatricyclof 5.2.2.0 ² · ⁶ ]undecane-3, 5, 8-trione [0001270] A solution of (lR,2S,6R,7R)-8-trimethylsilyloxy-4-azatricyclo[5.2.2.0 ^2,6 ]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 (lR,2S,6R,7R)-4-azatricyclo[5.2.2.0 ^2,6 ]undecane- 3,5,8-trione (2.16 g, crude) was obtained as a white solid.

Step 3: (1R,2S,6R 7R)-4-[(4-methoxyphenyl)methyl]-4-azatricyclo[5.2.2.0 ² ' ⁶ ]undecane-3, 5,8- trione

[0001271 ] To a solution of (1R, 2S, 6R, 7R)-4-azatricyclo[5.2.2.0 ^2,6 ]undecane-3, 5,8-trione (2.1 g, 11.18 mmol, 1 eq) in DMF (20 mL) was added PMBC1 (2.1 g, 13.42 mmol, 1.83 mL, 1.2 eq) and K2CO3 (2.3 g, 16.77 mmol, 1.5 eq). The mixture was stirred at 25 °C for 16 h. LCMS showed the desired compound was detected. TLC (petroleum ether: ethyl acetate = 1:1). The reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na ₂ SO ₄ filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-40% petroleum ether/ethyl acetate ethergradient @ 25 mL/min). Compound (1R, 2S,6R, 7R)-4-[(4-methoxyphenyl)methyl]-4- azatricyclo[5.2.2.0 ^2,6 ]undecane-3, 5,8-trione (3.03 g, 86.4% yield) was obtained as a white solid.

Step 4: (1R,2S,6R 7R)-8-Amino-4-[(4-methoxyphenyl)methyl]-3,5-dioxo-4- azatricyclo[ 5.2.2.0 ² · ⁶ ]undecane-8-carbonitrile

[0001272] To a solution of (1R, 2S,6R, 7R)-4-[(4-methoxyphenyl)methyl]-4- azatricyclo[5.2.2.0 ^2,6 ]undecane-3 , 5,8-trione (1.7 g, 5.43 mmol, 1 eq) in DCM (25 mL) were added N¾ (7 M, 7.75 mL, 10 eq) and Ti(i-PrO)4 (1.85 g, 6.51 mmol, 1.92 mL, 1.2 eq). The reaction mixture was stirred at 25 °C for 2 hr. TMSCN (807.3 mg, 8.14 mmol, 1.02 mL, 1.5 eq) was added and the solution was stirred at 25 °C for 16 h. Ethyl acetate (100 mL) and H ₂ O (10 mL) were added, the reaction mixture was filtered, the filtrate was concentrated to reduce pressure. Compound ( 1R,2S,6R,7R)-8-amino-4-[(4- methoxyphenyl)methyl]-3 , 5-dioxo-4-azatricyclo[5.2.20 ^2,6 ]undecane-8-carbonitrile (1.75 g, crude) was obtained as a white solid. Step 5: (2S)-2-(benzyloxycarbonylamino)-3-cyclopropyl-propanoic acid [0001273] To a solution of (2S)-2-amino-3-cyclopropyl-propanoic acid (3.0 g, 23.23 mmol, 1 eq) in THF (45 mL) was added NazCO ₃ (2 M, 13.94 mL, 1.2 eq) at 0 °C. CbzCl (5.15 g, 30.20 mmol, 4.29 mL, 1.3 eq) was added, and the reaction mixture was stirred at 25 °C for 16 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 Na ₂ SO ₄ , 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 3:1) to afford (2S)- 2-(benzyloxycarbonylamino)-3-cyclopropyl-propanoic acid as a colorless oil.

Compound (2S)-2-(benzyloxycarbonylamino)-3-cyclopropyl-propanoic acid (3.2 g, 10.21 mmol, 43.9% yield, 84% purity) was obtained as colorless oil. ¹ H NMR (400MHz, CDsOD) δ 7.43 - 7.20 (m, 5H), 5.09 (s, 2H), 4.23 (dd, J= 5.5, 8.0 Hz, 1H), 1.73 - 1.58 (m, 2H), 0.86 - 0.72 (m, 1H), 0.53 - 0.39 (m, 2H), 0.20 - 0.02 (m, 2H).

Step 6: Benzyl N-[ ( l S)-2-[[( IR 2S, 6R, 7R)-8-cyano-4-[ ( 4-methoxyphenyl)methyl ]-3, 5- dioxo-4-azatricyclo[5.2.2.0 ^2,6 ]undecan-8-yl ] amino ]-l-(cyclopropylmethyl)-2-oxo- ethyl ] carbamate

[0001274] A solution of (lR,2S,6R,7R)-8-amino-4-[(4-methoxyphenyl)methyl]-3,5-dioxo- 4-azatricyclo[5.2.20 ^2,6 ]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 POCl ₃ (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 Na ₂ SO ₄ , 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-[[(lR,2S,6R,7R)-8-cyano-4-[(4- methoxyphenyl)methyl]-3 , 5-dioxo-4-azatricyclo[5.2.2.0 ^2,6 ]undecan-8-yl Jamino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]carbamate (2.4 g, 72.9% yield, 89% purity) as a colorless oil. Step 7: Benzyl N-[(1S)-2-[[(1R,2S,6R, 7R)-8-cyano-3, 5-dioxo-4-azatricyclo[ 5.2.2.0 ^2,6 ]

[0001275] To a solution of benzyl N-[(1S)-2-[[(1R,2S,6R,7R)-8-cyano-4-[(4- methoxyphenyl)methyl]-3 , 5-dioxo-4-azatricyclo[5.2.2.0 ^2,6 ]undecan-8-yl ]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]carbamate (500 mg,0. 85 mmol, 1 eq) in ACN (15 mL) and H ₂ O (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 Na ₂ SO ₄ , 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-[( 1 S)-2-[[( lR,2S,6R,7R)-8-cyano-3 , 5-dioxo-4- azatricyclo[5.2.2.0 ^2,6 ]undecan-8-yl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl ]carbamate (260 mg, 62.8% yield, 96% purity) as a white solid.

Step 8: (2S)-2-amino-N-[ (1R2S, 6R, 7R)-8-cyano-2, 5-dioxo-4-azatricyclo[5.2.2.0 ^2,6 ]undecan- 8-yl ]- 3-cyclopropyl-propanamide

[0001276] To a solution of benzyl N-[( 15)-2-[[( 1 R,2S,6R, 7R)-8-cy ano-3 ,5-dioxo-4- azatricyclo[5.2.2.0 ^2,6 ]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 N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (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[5.2.2.0 ^2,6 ]undecan-8-yl]-3-cyclopropyl- propanamide (140 mg, crude) was obtained as colorless oil.

[0001277] Isomer 1 : N-[(1S)-2-[[(lR,2S,6R,7R,8S)-8-Cyano-3,5-dioxo-4- azatricyclo[5.2.2.02,6]undecan-8-yl]amino]-l -(cyclopropylmethyl)-2-oxo-ethyl]-4- methoxy-1H-indole-2-carboxamide; Isomer 2: N-[( 1 S)-2-[ [( 1 S,2R,6S, 7S, 8S)-8-Cy ano-3 ,5- dioxo-4-azatricyclo[5.2.2.02,6]undecan-8-yl]amino]-1-(cyclop ropylmethyl)-2-oxo-ethyl]- 4-methoxy-1H-indole-2-carboxamide

[0001278] To a solution of (2S)-2-amino-N-[( 1 R,2S,6R, 7R)-8-cy ano-3 , 5 -dioxo-4- azatricyclo[5.2.2.0 ^2,6 ]undecan-8-yl]-3-cyclopropyl-propanamide (140 mg, 0.42 mmol, 1 eq), 4-methoxy-1H-indole-2-carboxylic acid (81.01 mg, 0.42 mmol, 1 eq) and DIPEA (109.5 mg, 0.84 mmol, 147.62 uL, 2 eq) in DCM (4 mL) was added HATU (193.3 mg, 0.50 mmol, 1.2 eq). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with DCM (20 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by Pre- TLC (DCM: MeOH =10:1) to give the crude product. The residue was purified by prep- HPLC (column: Phenomenex Gemini- NX 80*40 mm*3 urn; mobile phase: [water (0.05% NH3H ₂ O+IO mM NH ₄ HCO ₃ )-ACN]; B%: 23%-53%, 9.5 min) to give Isomer 1 (13.30 mg, 6.0% yield, 97.4% purity) and Isomer 2 (31.40 mg, 14.6% yield, 99.5% purity) as two white solids.

[0001279] Isomer 1 : LCMS: Rt = 0.808 min; for C27H29N5O5 MS Calcd.: 503.22; MS Found: 504.2 [M+H ⁺ ],

[0001280] ¹ H NMR (400 MHz, CD3OD) δ 7.28 (s, 1H), 7.18 - 7.12 (m, 1H), 7.03 (d ,J = 8.3 Hz, 1H), 6.52 (d ,J= 7.5 Hz, 1H), 4.56 (dd, J = 4.4, 9.9 Hz, 1H), 3.93 (s, 3H), 3.17 (d, J= 2.5 Hz, 1H), 3.02 - 2.97 (m, 1H), 2.96 - 2.90 (m, 1H), 2.41 (d ,J= 15.3 Hz, 1H), 2.33 (d,J= 2.3 Hz, 1H), 2.22 - 2.10 (m, 1H), 1.94 (d, J= 15.3 Hz, 1H), 1.88 - 1.63 (m, 5H), 0.90 - 0.75 (m, 1H), 0.56 - 0.40 (m, 2H), 0.31 - 0.13 (m, 2H).

[0001281] Isomer 2: LCMS: Rt = 0.806 min; for C27H29N5O5 MS Calcd.: 503.22; MS Found: 504.2 [M+H ⁺ ],

[0001282] ¹ H NMR (400MHz, CD3OD) δ 7.25 (s, 1H), 7.18 - 7.11 (m, 1H), 7.03 (d, J= 8.3 Hz, 1H), 6.51 (d, J= 7.8 Hz, 1H), 4.64 - 4.60 (m, 1H), 3.93 (s, 3H), 3.17 (d, J= 2.0 Hz, 1H), 3.00 - 2.93 (m, 1H), 2.92 - 2.86 (m, 1H), 2.43 (d, J= 15.6 Hz, 1H), 2.31 (s, 1H),

2.23 - 2.11 (m, 1H), 1.94 (d ,J= 15.6 Hz, 1H), 1.84 - 1.61 (m, 5H), 0.85 - 0.70 (m, 1H), 0.55 - 0.40 (m, 2H), 0.23 - 0.09 (m, 2H).

Example 155. Synthesis of viral protease inhibitor compound 491

Step 7: methyl (2S)-2-[[3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001283 ] To the mixture of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (240 mg, 1.01 mmol, 1 eq, HC1), (2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoic acid (412.2 mg, 1.22 mmol, 1.2 eq, HC1) and TEA (410.4 mg, 4.06 mmol, 0.56 mL, 4 eq) in DMF (3 mL) was added T3P (1.2 g, 2.03 mmol, 1.21 mL, 50% purity, 2 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. TLC (DCM:MeOH =10: l/UV254nm). The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 100-25% Ethyl acetate/MeOH@ 30 mL/min). Compound methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (256 mg, 0.48 mmol, 48.2% yield, 92.5% purity) was obtained as yellow solid.

Step 2: N-[2-[[( 1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide [0001284] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (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-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-methoxy-lH- indole-2-carboxamide (220 mg, crude) was obtained as yellow solid, which was used into the next step without further purification. Step 3: N-[2-[[( 1 S)-l-cyano-2-[ ( 3S)-2-oxo-3-piperidyl ]ethyl ]amino]-1-(cyclopropylmethyl)~ 2-oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide

[0001285] A mixture of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-methoxy-lH- indole-2-carboxamide (250 mg, 0.53 mmol, 1 eq) and methoxycarbonyl- (triethylammonio)sulfonyl-azanide (444.0 mg, 1.86 mmol, 3.5 eq) in DCM (3 mL) was stirred at 25 °C for 16 h. LC-MS showed the desired compound was detected. The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (lOmL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*30 mm*3 um; mobile phase: [water (0.05% NH ₃ H ₂ O+10 mM NH ₄ HCO ₃ )-ACN]; B%: 23%-53%, 9.5 min). Compound N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide (83 mg, 0.18 mmol, 34.2% yield, 99.0% purity) was obtained as a white solid.

[0001286] Isomer 1: N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-1H-indole-2-carbo xamide; Isomer 2: N- [(1S)-2-[[(lR)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino ]-1-(cyclopropylmethyl)-2- oxo-ethyl]-4-methoxy-1H-indole-2-carboxamide; Isomer 3: N-[( 1 R)-2-[ [( 1 S)- 1 -cyano-2- [(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2 -oxo-ethyl]-4-methoxy- 1H-indole-2-carboxamide; Isomer 3: N-[( lR)-2-[[( 1R)- 1 -cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy- 1H-indole-2- carboxamide

[0001287] N-[2-[[ 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)- 2-oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide (50 mg, 0.11 mmol, 1 eq) was purified by SFC (column: DAICEL CHIRALPAK AD(250 mm*30 mm, 10 um);mobile phase: [0.1% NH ₃ H _Z O ETOH];B%: 55%-55%, min) to get three fragments: Isomer 1 , mixture of Isomer 2 &3 and Isomer 4.

[0001288] Isomer 1 : N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide (28.1 mg, 62.2 umol, 56.2% yield, 100% purity) was obtained as white solid. [0001289] LCMS: Rt = 0.755min; for C24H29N5O4 MS Calcd. : 451.22, MS Found: 452.2 [M+H ⁺ ],

[0001290] ¹ H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.91 (br d ,J= 8.0 Hz, 1H), 8.50 (br d, J= 7.5 Hz, 1H), 7.53 (br s, 1H), 7.37 (d, J= 1.4 Hz, 1H), 7.15 - 7.06 (m, 1H), 7.04 - 6.97 (m, 1H), 6.51 (d, J= 7.6 Hz, 1H), 5.07 (q, J= 8.2 Hz, 1H), 4.49 - 4.40 (m, 1H), 3.89 (s, 3H), 3.15 - 3.01 (m, 2H), 2.34 - 2.20 (m, 2H), 1.91 - 1.76 (m, 3H), 1.70 (br dd, J= 4.4, 8.7 Hz, 1H), 1.64 - 1.53 (m, 1H), 1.35 (br s, 1H), 0.86 - 0.76 (m, 1H), 0.48 - 0.35 (m, 2H), 0.25 - 0.04 (m, 2H).

[0001291 ] Isomer 4: N-[( 1 R)-2-[[( 1 R)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide (6.1 mg, 13.5 umol, 12.2% yield, 100% purity) was obtained as white solid.

[0001292] LCMS: Rt = 0.752min; for C24H29N5O4 MS Calcd.: 451.22, MS Found: 452.2 [M+H ⁺ ],

[0001293] ¹ H NMR (400 MHz, CD3OD) δ 7.27 (s, 1H), 7.18 - 7.12 (m, 1H), 7.03 (d ,J = 8.4 Hz, 1H), 6.51 (d, J= 7.6 Hz, 1H), 5.12 (dd, J= 6.4, 7.7 Hz, 1H), 4.85 (br s, 1H), 3.93 (s, 3H), 3.24 - 3.16 (m, 2H), 2.50 - 2.32 (m, 2H), 2.06 - 1.92 (m, 2H), 1.92 - 1.82 (m, 2H), 1.70 (dt, J= 7.0, 14.2 Hz, 2H), 1.63 - 1.54 (m, 1H), 1.31 - 1.31 (m, 1H), 1.41 - 1.27 (m, 1H), 0.91 - 0.80 (m, 1H), 0.53 (br d ,J= 8.0 Hz, 2H), 0.25 - 0.14 (m, 2H).

[0001294] The mixture of Isomer 2 & Isomer 3 (20.0 mg, 44.3 umol, 1 eq) was purified by SFC (column: DAICEL CHIRALCEL OD-H(250 mm*30 mm, 5um);mobile phase:

[0.1% NH3H ₂ O ETOH];B%: 45%-45%, min) to get two fragments.

[0001295] Isomer 3 : N-[( 1 R)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide (5.1 mg, 11.3 umol, 25.6% yield, 100% purity) was obtained as white solid.

[0001296 ] LCMS: Rt = 0.754min; for C24H29N5O4 MS Calcd: 451.22, MS Found: 452.1 [M+H ⁺ ], [0001297] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.28 (s, 1H), 7.18 - 7.12 (m, 1H), 7.03 (d ,J = 8.3 Hz, 1H), 6.52 (d, J= 7.5 Hz, 1H), 5.06 (dd, J= 6.5, 9.8 Hz, 1H), 4.81 (br s, 1H), 3.93 (s, 3H), 3.18 (br s, 2H), 2.43 - 2.35 (m, 1H), 2.45 - 2.27 (m, 1H), 2.31 (br s, 1H), 2.06 - 1.95 (m, 1H), 1.94 - 1.78 (m, 3H), 1.76 - 1.59 (m, 2H), 1.58 - 1.45 (m, 1H), 1.40 (s, 1H), 1.29 (s, 1H), 0.92 - 0.79 (m, 1H), 0.58 - 0.44 (m, 2H), 0.26 - 0.12 (m, 2H).

[0001298] Isomer 2: N-[(l S)-2-[[(lR)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1 - (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide (6.3 mg, 14.0 umol, 31.6% yield, 100% purity) was obtained white solid.

[0001299 ] LCMS: Rt = 0.754min; for C24H29N5O4 MS Calcd: 451.22, MS Found: 452.1 [M+H ⁺ ],

[0001300] ¹ H NMR (400 MHz, CD3OD) δ 7.12 (s, 1H), 7.01 - 6.96 (m, 1H), 6.87 (d ,J = 8.3 Hz, 1H), 6.35 (d, J= 7.8 Hz, 1H), 4.89 (t , J= 7.2 Hz, 1H), 4.43 (dd, J= 6.3, 8.3 Hz, 2H), 3.77 (s, 3H), 3.08 - 3.00 (m, 2H), 2.32 - 2.22 (m, 1H), 2.20 - 2.10 (m, 1H), 2.27 - 2.07 (m, 1H), 1.84 - 1.73 (m, 2H), 1.72 - 1.62 (m, 2H), 1.60 - 1.50 (m, 2H), 1.43 - 1.34 (m, 1H), 0.75 - 0.62 (m, 1H), 0.40 - 0.27 (m, 2H), 0.08 - -0.04 (m, 2H).

Example 156. Synthesis of viral protease inhibitor compound 493

Step 1: Methyl (2R)-2-(benzyloxycarbonylamino)-3-bromo-propanoate

[0001301 ] To a solution of methyl (2S)-2-(benzyloxycarbonylamino)-3-hydroxy- propanoate (10 g, 39.49 mmol, 1 eq) and CBr4 (15.7 g, 47.38 mmol, 1.2 eq) in THF (120 mL) was added PPh3 (12.4 g, 47.38 mmol, 1.2 eq) in THF (20 mL) at 0 °C. Then the mixture was stirred at 25 °C for 16 hr. TLC (petroleum ether/ethyl acetate = 5/1, I ₂ ). The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-20% Ethylacetate/Petroleum ethergradient @ 30 mL/min) to give methyl (2R)-2-(benzyloxycarbonylamino)-3-bromo-propanoate (8.2 g, 65.6% yield) as a white solid.

Step 2: methyl (2S)-3-(3-acetyl-2-oxo-imidazolidm-l-yl)-2-(benzyloxycarbony lammo) propanoate

[0001302] To a solution of l-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 H ₂ O (20 mL) and extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na ₂ SO ₄ , 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.

Step 3: benzyl N-[2-ammo-2-oxo-l-[(2-oxoimidazolidin-l-yl)methyl]ethyl]carb amate

[0001303] A solution of methyl 3-(3-acetyl-2-oxo-imidazolidin-1-yl)-2-

(benzyloxycarbonylamino)propanoate (2.0 g, 5.50 mmol, 1 eq) in ammonia (7 M, 14.94 mL, 19 eq) was stirred at 65 °C for 16 hr. TLC (DCM:MeOH = 10: 1). The reaction mixture was filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0-30% DCM/MeOH ethergradient @30 mL/min). Compound benzyl N-[2-amino-2-oxo- 1 -[(2-oxoimidazolidin- 1 -yl)methyl]ethyl]carbamate (462 mg, 27.4% yield) was obtained as a white solid.

Step 4: 2-amino-3-(2-oxoimidazolidin-l-yl)propanamide [0001304] 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 N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 25°C for 1 h. TLC (dichloromethane: methanol=10/l, 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.

Step 5: tert-butyl (2S)-2-amino-3-cyclopropyl-propanoate

[0001305] To a solution of 2-amino-3-(2-oxoimidazolidin-1-yl)propanamide (0.3 g, 2.3 mmol, 1 eq) in tert-butyl acetate (4.33 g, 37.2 mmol, 5 mL, 16.0 eq) was added HCIO4 (533.3 mg, 3.7 mmol, 0.32 mL, 70% purity, 1.6 eq) slowly at 0°C. The mixture was stirred at 25 °C for 15 h. TLC (petroleum ether: ethyl acetate=2/l, ninhydrin). The reaction mixture was diluted with H ₂ O (10 mL) followed by an addition of 1 N HC1 (8 mL). The pH of the mixture was adjusted to about 9 with 10% aq NazCO ₃ , and then extracted with DCM (3 * 15 mL). The combined organic layers were dried over NazSC> ₄ to give tert-butyl (2 S)-2-amino-3 -cyclopropyl -propanoate (0.4 g, crude) as a colorless oil.

Step 6: tert-butyl (2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2-carbonyl)amino] propanoate

[0001306] To a solution of 4-methoxy- 1 H-indole-2-carboxylic acid (206.3 mg, 1.08 mmol, 1 eq) and HOBt (153.1 mg, 1.1 mmol, 1.0 eq) in DCM (6 mL) was added EDCI (223.5 mg, 1.17 mmol, 1.0 eq) and tert-butyl (2S)-2-amino-3-cyclopropyl-propanoate (200 mg, 1.08 mmol, 1 eq). The mixture was stirred at 25 °C for 16 h. TLC (petroleum ether: ethyl acetate=2/l, UV). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/rthyl acetate= 100/1 to 2/1) to give tert-butyl (2 S)-3 -cy clopropy l-2-[(4-methoxy- 1 H- indole-2-carbonyl)amino]propanoate (150 mg, 38% yield) as a yellow solid.

Step 7: (2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2-carbonyl)amino] propanoic acid

[0001307] To a solution of tert- butyl (2S)-3-cyclopropyl-2-[(4-methoxy-lH-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/l, UV). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate= 100/1 to 2/1) to give (2S)-3- cyclopropyl-2-[(4-methoxy-lH-indole-2-carbonyl)amino]propano ic acid (50 mg, 59.2% yield) as a white solid.

Step 8: N-[ ( 1 S) -2 -[ [2-amino-2-oxo- 1-[( 2-oxoimidazolidin- 1 -yl) methyl ] ethyl ] amino ]-1-

(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-ca rboxamide

[0001308] To a solution of (2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoic acid (50 mg, 0.16 mmol, 1 eq) in DMF (2 mL) was added HATU (94.3 mg, 0.24 mmol, 1.5 eq), 2-amino-3-(2-oxoimidazolidin-1-yl)propanamide (42.7 mg, 0.24 mmol, 1.5 eq) and DIPEA (53.4 mg, 0.41 mmol, 72.0 uL, 2.5 eq). The mixture was stirred at 25 °C for 1 h. TLC (dichloromethane: methanol=10/l, UV). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate= 100/1 to 10/1) to give 10 (60 mg, 79% yield) as a white solid.

Step 9: N-[ ( l S)-2-[[ 1 -cyano-2-(2-oxoimidazolidin-l-yl) ethyl ]amino]-1-(cyclopropylmethyl)- 2-oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide

[0001309] To a solution of 10 (60 mg, 0.13 mmol, 1 eq) in DCM (3.0 mL) was added Burgess reagent (93.9 mg, 0.39 mmol, 3.0 eq). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was 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% NH ₃ H ₂ O+IO mM NH ₄ HCO ₃ )-ACN]; B%: 21%-51%, 9.5 min) to give N-[( 1 S)-2-[[ 1 -cyano-2-(2-oxoimidazolidin- 1 -yl)ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide (9.72 mg, 16% yield) as a white solid.

[0001310] LCMS: Rt = 0.772 min; for C ₂₂ H ₂ 6N6O ₄ MS Calcd. : 438.20; MS Found: 439.1 [M+H ⁺ ],

[0001311] ¹ H NMR (400 MHz, CD3OD) δ 7.28 (s, 1H), 7.19 - 7.12 (m, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.52 (d ,J= 7.6 Hz, 1H), 5.22 - 5.01 (m, 1H), 4.59 (s, 1H), 3.93 (s, 3H), 3.62 - 3.52 (m, 4H), 3.44 - 3.34 (m, 2H), 1.92 - 1.78 (m, 1H), 1.70 (tt ,J= 6.8, 13.2 Hz, 1H), 0.83 (d ,J= 6.0 Hz, 1H), 0.61 - 0.40 (m, 2H), 0.27 - 0.08 (m, 2H). Example 157. Synthesis of viral protease inhibitor compound 495

[0001312] Isomer 1 : benzyl N-[( 1S)-2-[[( 1R,2S,6R, 7R,8S)-8-cyano-3, 5-dioxo-4- azatricyclo[5.2.2.0 ^2,6 ]undecan-8-yl]amino]-1-(cyclopropylmethyl)-2-oxo- ethyl]carbamate; Isomer 2: Benzyl N-[( 1S)-2-[[( 1S,2R, 6S,7S, 8R)-8-cyano-3, 5-dioxo-4- azatricyclo[5.2.2.0 ^2,6 ]undecan-8-yl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl ]carbamate

[0001313] A mixture of benzyl N-[( 1 S)-2-[[(lR,2S,6R,7R)-8-cyano-4-[(4- methoxyphenyl)methyl]-3 , 5-dioxo-4-azatricyclo[5.2.20 ^2,6 ]undecan-8-yl ]amino]-l - (cyclopropylmethyl)-2-oxo-ethyl]carbamate (200 mg, 0.34 mmol, 1 eq), ammonia; cerium(4+); nitric acid; tetranitrate (1.13 g, 2.05 mmol, 1.02 mL, 6 eq) in H ₂ O (1 mL) and MeCN (3 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 25 °C for 16 h under N2 atmosphere. The mixture was quenched with H ₂ O (20 mL), and extracted with ethyl acetate (40 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , filtered and concentrated under reduce pressure. The residue was purified by prep- HPLC (column: 3_Phenomenex Luna C18 75 * 30 mm * 3 um; mobile phase: [water(0.05% HC1)-ACN]; B%: 25%-55%, 8.5 min) to give benzyl N-[(1S)-2-[[(lR,2S,6R,7R,8S)-8-cyano-3,5-dioxo-4- azatricyclo[5.2.2.0 ^2,6 ]undecan-8-yl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl ]carbamate (17.25 mg, 35.6 umol, 10.4% yield, 96.1% purity) was obtained as a white solid and benzyl N-[( 1 S)-2-[[( 1 S,2R,6S,7S,8R)-8-cyano-3 , 5-dioxo-4- azatricyclo[5.2.2.0 ^2,6 ]undecan-8-yl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl ]carbamate (17.56 mg, 36.37 umol, 10.63% yield, 96.2% purity) was obtained as a white solid.

[0001314] Isomer 1 : LCMS: Rt = 0.798 min; for C25H28N4O5 MS Calcd.: 464.21; MS Found: 465.1 [M+H ⁺ ], ¹ HNMR (400 MHz, CD ₃ OD) δ 7.47 - 7.21 (m, 5H), 5.17 - 5.08 (m, 2H), 4.10 (dd, J=4.3, 9.8 Hz, 1H), 3.12 (br d, J=2.5 Hz, 1H), 3.01 - 2.88 (m, 2H), 2.42 - 2.28 (m, 2H), 2.20 - 2.09 (m, 1H), 1.89 (br d, J=15.3 Hz, 1H), 1.80 - 1.73 (m, 2H), 1.72 - 1.61 (m, 2H), 1.56 (br d, J=7.5 Hz, 1H), 0.82 - 0.67 (m, 1H), 0.42 - 0.42 (m, 1H), 0.48 - 0.38 (m, 1H), 0.23 - 0.09 (m, 2H).

[0001315] Isomer 2: LCMS: Rt = 0.818 min; for C25H ₂ 8N4O5 MS Calcd.: 464.21; MS Found: 465.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD ₃ OD) δ 7.45 - 7.25 (m, 5H), 5.18 - 5.09 (m, 2H), 4.17 (br dd, J=6.0, 7.6 Hz, 1H), 3.35 (s, 1H), 3.11 - 2.93 (m, 2H), 2.42 (br d, J=15.6 Hz, 1H), 2.31 (br s, 1H), 2.23 - 2.12 (m, 1H), 1.91 (br d, J=15.3 Hz, 1H), 1.76 (br d, J=6.8 Hz, 2H), 1.68 (br d,J=11.4 Hz, 1H), 1.65 - 1.58 (m, 1H), 1.56 - 1.45 (m, 1H), 0.78 - 0.67 (m, 1H), 0.44 (d, J=5.1 Hz, 2H), 0.12 (br s, 2H).

Example 158. Synthesis of viral protease inhibitor compound 496

Step 1: Methyl 4,4-difluoro-2-[(4-methoxy-lH-indole-2-carbonyl)amino]pentan oate

[0001316] To a solution of 4-methoxy-1H-indole-2-carboxylic acid (281.6 mg, 1.47 mmol, 1 eq) in DCM (1 mL) was added HATU (672.2 mg, 1.77 mmol, 1.2 eq), DIPEA (571.2 mg, 4.42 mmol, 0.76 mL, 3 eq) and methyl 2-amino-4,4-difluoro-pentanoate (300 mg,

1.47 mmol, 1 eq, HC1). The mixture was stirred at 25 °C for 2 h. TLC (petroleum ether: ethyl acetate = 0: 1). The reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-30% petroleum ether/ethyl acetate ethergradient @ 20 mL/min) to give methyl 4,4-difluoro-2-[(4-methoxy-1H-indole-2-carbonyl)amino]pentan oate (357 mg, 1.04 mmol, 70.7% yield, 99.4% purity) as a yellow solid.

Step 2: 4,4-Difluoro-2-[(4-methoxy-lH-indole-2-carbonyl)amino]pentan oic acid

[0001317] 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.H ₂ O (132.0 mg, 3.15 mmol, 3 eq) in H ₂ O (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 HC1. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic phase was washed with brine (5 mL * 3), dried with anhydrous Na ₂ SO ₄ , 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.

Step 3: N-f l-[[(l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ] carbamoyl ]-3, 3-difluoro- butyl]-4-methoxy-lH-indole-2-carboxamide

[0001318] To a solution of 4,4-difluoro-2-[(4-methoxy- 1H-indole-2- carbonyl)amino]pentanoic acid (20 mg, 61.2 umol, 1 eq) in DCM (0.5 mL) was added (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (13.9 mg, 73.5 umol, 1.2 eq, HC1), TEA (18.6 mg, 0.18 mmol, 25.5 uL, 3 eq) and T3P (50.7 mg, 79.6 umol, 50% purity, 1.3 eq) in DMF (0.2 mL). The mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX 80*40 mm*3um; mobile phase: [water(0.05% NH3H ₂ O+IO mM NH4HCO3)- ACN] ;B% : 17%-47%,9.5 min) to give N-[l-[[(1S)-1- cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl]-3,3-difl uoro-butyl]-4-methoxy-1H- indole-2-carboxamide (2.54 mg, 8.7% yield, 97.7% purity) as a white solid.

[0001319] LCMS: Rt = 0.772 min; for C22H25F2N5O4 MS Calcd. : 461.19; MS Found: 462.1 [M+H ⁺ ],

[0001320] ¹ H NMR (400 MHz, CD3OD) δ 7.24 (d ,J= 3.8 Hz, 1H), 7.15 (dt, J = 2.3, 8.0 Hz, 1H), 7.03 (dd,J= 2.5, 8.3 Hz, 1H), 6.52 (dd, J= 1.5, 7.5 Hz, 1H), 5.07 - 5.00 (m, 1H), 4.84 (br s, 1H), 3.93 (d ,J= 1.8 Hz, 3H), 3.30 - 3.18 (m, 2H), 2.67 - 2.57 (m, 1H), 2.56 - 2.40 (m, 2H), 2.37 - 2.25 (m, 2H), 1.95 - 1.85 (m, 1H), 1.85 - 1.76 (m, 1H), 1.69 (dt, J= 2.6, 18.8 Hz, 3H).

Example 159. Synthesis of viral protease inhibitor compound 501

[0001321 ] To a solution of phenyl 2-[[(3S)-3-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-5-oxo-2,3-dihydro-lH-indolizin-6-yl]amin o]acetate (100 mg, 0.21 mmol, 1 eq) in THF (1 mL) and MeOH (0.3 mL) was added LiOH.H ₂ O (27.1 mg, 0.64 mmol, 3 eq) in H ₂ O (0.5 mL). The mixture was stirred at 25 °C for 4 h. LC-MS and

HPLC showed the desired compound was detected. The pH of the reaction was adjusted to about 1 with 4 M HC1. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with ethyl acetate (5 mL * 3). The combined organic phase was washed with brine (5 mL * 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [water (0.05% HC1)-ACN]; B%: 0%-30%, 8.5 min). The residue was checked by LCMS and HPLC. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C 18 75*30 mm*3 um; mobile phase: [water (0.05% HC1)-ACN]; B%: 0%-30%, 8.5 min). Compound 2-[[(3S)-3-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-5-oxo-2,3-dihydro-lH-indolizin-6-yl]amin o]acetic acid (1.2 mg, 1.27% yield, 98.9% purity, CHOOH) was obtained as a white solid.

[0001322] LCMS: Rt = 0.643 min; for C18H ₂ 1N5O5 MS Calcd. : 387.15; MS Found: 388.1 [M+H ⁺ ],

[0001323] ¹ H NMR (400 MHz, CD3OD) δ 8.49 (br s, 1H), 8.03 (s, 1H), 6.32 (d ,J= 7.5 Hz, 1H), 5.09 - 5.03 (m, 2H), 3.74 (s, 2H), 3.34 (br s, 1H), 3.26 - 3.18 (m, 2H), 3.17 - 3.07 (m, 1H), 2.74 - 2.64 (m, 1H), 2.62 - 2.51 (m, 1H), 2.40 - 2.26 (m, 3H), 2.24 - 2.15 (m,

1H), 1.97 - 1.88 (m, 1H), 1.87 - 1.77 (m, 1H).

Example 160. Synthesis of viral protease inhibitor compound 505

[0001324] To a solution of 2-(3-amino-2-oxo- 1 -pyridyl)-N-[( 1 S)- 1 -cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (100 mg, 0.27 mmol, 1 eq) in THF (1 mL) was added Boc20 (610.6 mg, 2.80 mmol, 0.64 mL, 10 eq). The mixture was stirred at 25 °C for 16 h. TLC (DCM: MeOH = 10:1). The reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na ₂ SO ₄ filtered and concentrated in vacuum. The residue was purified by prep- TLC (S1O2, DCM: MeOH = 20: 1) to give tert- butyl N-[l-[2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-2-oxo-3-pyridyl]carbamate (12.62 mg, 9.0 % yield, 91.4 % purity) as a white solid.

[0001325] LCMS: Rt = 0.832 min; for C ₂ 3H3 ₁ N5O5 MS Calcd. : 457.23; MS Found: 458.2 [M+H ⁺ ],

[0001326] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (d ,J= 6.3 Hz, 1H), 7.39 - 7.31 (m, 1H), 6.45 - 6.34 (m, 1H), 5.56 - 5.39 (m, 1H), 5.03 (d ,J= 6.8 Hz, 1H), 3.34 (s, 1H), 3.29 - 3.22 (m, 1H), 2.57 - 2.43 (m, 1H), 2.41 - 2.30 (m, 1H), 2.29 - 2.20 (m, 1H), 2.01 - 1.94 (m, 2H), 1.92 - 1.72 (m, 2H), 1.52 (d ,J= 2.5 Hz, 9H), 0.62 (dd,J= 7.4, 12.3 Hz, 1H), 0.50 - 0.36 (m, 2H), 0.21 - 0.12 (m, 1H), 0.09 - 0.02 (m, 1H).

Example 161. Synthesis of viral protease inhibitor compound 504

[0001327] The residue was further separated by SFC. The residue was further separated by SFC (column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3H ₂ O ETOH]; B%: 30%-30%, min). [0001328] Isomer 1 : Compound tert-butyl N-[l-[(1R)-2-[[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo- ethyl]-2-oxo-3- pyridyl]carbamate (2.47 mg, 23.1% yield) was obtained as a white solid. LCMS: Rt = 0.837 min; for C ₂₃ H ₃₁ N ₅ O ₅ MS Calcd.: 457.23; MS Found: 458.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (d , J= 7.1 Hz, 1H), 7.34 (dd,J= 1.7, 7.1 Hz, 1H), 6.39 (t ,J= 7.2 Hz, 1H), 5.56 - 5.31 (m, 1H), 5.01 (dd, J= 6.8, 9.3 Hz, 1H), 3.34 (d, J= 2.8 Hz, 2H), 2.56 - 2.44 (m, 1H), 2.41 - 2.32 (m, 1H), 2.32 - 2.24 (m, 1H), 2.00 - 1.91 (m, 3H), 1.89 - 1.82 (m, 1H), 1.52 (s, 9H), 0.59 (s, 1H), 0.46 - 0.37 (m, 2H), 0.15 (d, J= 8.4 Hz, 1H), 0.03 (d, J= 11.3 Hz, 1H).

[0001329] Isomer 2: Compound tert- butyl N-[ 1 -[( 1 S)-2-[[( 1 S)- 1 -cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo- ethyl]-2-oxo-3- pyridyl]carbamate (2.71 mg, 25.5% yield) was obtained as a white solid. LCMS: Rt = 0.837 min; for C ₂₃ H ₃₁ N ₅ O ₅ MS Calcd.: 457.23; MS Found: 458.1 [M+H ⁺ ], ¹ H NMR (400 MHz, CD ₃ OD) δ 7.97 (d, J= 7.3 Hz, 1H), 7.35 (dd, J= 1.8, 7.0 Hz, 1H), 6.38 (t, J= 7.3 Hz, 1H), 5.42 (dd, J= 7.0, 8.5 Hz, 1H), 5.44 - 5.40 (m, 1H), 5.03 - 4.99 (m, 1H), 3.30 - 3.25 (m, 2H), 2.48 (dq,J= 5.3, 9.2 Hz, 1H), 2.29 - 2.22 (m, 1H), 2.32 - 2.22 (m, 1H), 2.02 - 1.94 (m, 2H), 1.91 - 1.85 (m, 1H), 1.84 - 1.73 (m, 1H), 1.51 (s, 9H), 0.63 (br d, J= 6.8 Hz, 1H), 0.49 - 0.42 (m, 2H), 0.18 - 0.13 (m, 1H), 0.06 (dd,J= 4.3, 8.8 Hz, 1H).

Example 162. Synthesis of viral protease inhibitor compound 509

Step 1: methyl (2S)-2-[[(2S)-2-[[4-(difluoromethoxy)-lH-indole-2-carbonyl]a mino]-4-methyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001330] To a mixture of methyl (2S)-2-[[(2S)-2-amino-4-methyl-pentanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (160 mg, 476.44 umol, 1 eq, HC1) and 4- (difluoromethoxy)-lH-indole-2-carboxylic acid (108.23 mg, 476.44 umol, 1 eq) in DCM (4 mL) was added DMAP (174.62 mg, 1.43 mmol, 3 eq) and EDCI (274.00 mg, 1.43 mmol, 3 eq), The mixture was added DMF (1 mL) and stirred at 25 °C for 14 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (neutral condition, column: Waters Xbridge BEH C18 100*30 mm* 10 um; mobile phase: [water(10 mM NH4HCO3)- ACN] ;B% : 30%-60%,10 min). Compound methyl (2 S)-2-[ [(2 S)-2-[ [4-(difluoromethoxy )- 1 H-indole-2- carbonyl]amino]-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrro lidin-3-yl]propanoate (150 mg, 294.98 umol, 61.91% yield) was obtained as a white solid. MS (ESI) m/z 494.3 [M+H] ⁺

Step 2: N-f (1S)-1-[[(1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ] -3-methyl-butyl ]-4-(difluoromethoxy) -lH-indole-2-carboxamide [0001331 ] A mixture of methyl (2 S)-2-[ [(2 S)-2-[ [4-(difluoromethoxy )- 1 H-indole-2- carbonyl]amino]-4-methyl-pentanoyl]amino]-3-[(3S)-2-oxopyrro lidin-3-yl]propanoate (150 mg, 294.98 umol, 1 eq) in ammonia (7.65 g, 449.19 mmol, 7.50 mL, 1522.81 eq) was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3-methyl-butyl]-4 -(difluoromethoxy)-lH- indole-2-carboxamide (100 mg, 202.63 umol, 68.69% yield) was obtained as a white solid and used for the next step. MS (ESI) m/z 494.3 [M+H] ⁺

Step 3: N-f (IS)- 1-[[(1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ) ethyl ] carbamoyl ]-3-methyl- butyl]-4-(difluoromethoxy)-lH-indole-2-carboxamide

[0001332] 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-(difluoromethox y)-lH-indole-2- carboxamide (100 mg, 202.63 umol, 1 eq) in DCM (3 mL) was added Burgess reagent (193.16 mg, 810.53 umol, 4 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, column: Waters Xbridge BEH C18 100*30 mm* 10 um; mobile phase: [water(10 mM NH4HCC>3)-ACN];B%: 30%-60%, 10 min). Compound N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl-butyl]-4-(difluoromethoxy)-lH-i ndole-2-carboxamide (30 mg, 63.09 umol, 31.14% yield) was obtained as a white solid. MS (ESI) m/z 476.3 [M+H] ⁺

[0001333] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.88 (d, J=1.8 Hz, 1H), 8.93 (d, J=8.1 Hz, 1H), 8.65 (d, J=7.7 Hz, 1H), 7.78 - 7.67 (m, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.35 - 7.27 (m, 1H), 7.21 - 7.12 (m, 1H), 6.82 (d, J=7.6 Hz, 1H), 5.04 - 4.85 (m, 1H), 4.56 - 4.40 (m,

1H), 3.20 - 3.03 (m, 2H), 2.42 - 2.04 (m, 3H), 1.85 - 1.47 (m, 5H), 1.00 - 0.84 (m, 6H)

Example 163. Synthesis of viral protease inhibitor compound 515

Step 1: 4-hydroxy- 1H-indole-2-carboxylic acid

[0001334] To a mixture of 4-methoxy- 1 H-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 H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 4-hydroxy- 1 H-indole-2-carboxylic acid (200 mg, crude) as a red solid. MS (ESI) m/z 176.1 [M-H]+

Step 2: methyl 4-hydroxy- lH-indole-2-carboxylate

[0001335] 4-hydroxy- 1 H-indole-2-carboxylic acid (200 mg, 1.13 mmol, 1 eq) was added HCl/MeOH (4 M, 10 mL, 35.43 eq). The mixture was stirred at 70 °C for 5 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=9/l to 8/1) to give methyl 4-hydroxy- 1 H-indole-2-carboxylate (170 mg, 800.28 umol, 70.89% yield, 90% purity) as a yellow solid. MS (ESI) m/z 190.1 [M-H] ⁺

Step 3: methyl 4-(2-morpholinoethoxy)-lH-indole-2-carboxylate

[0001336] To a mixture of methyl 4-hydroxy- lH-indole-2-carboxylate (300 mg, 1.57 mmol, 1 eq) and 2-morpholinoethanol (205.83 mg, 1.57 mmol, 192.37 uL, 1 eq) in THF (4 mL) was added PPh3 (452.73 mg, 1.73 mmol, 1.1 eq), DIAD (317.30 mg, 1.57 mmol, 305.10 uL, 1 eq) was added at 0 °C under N ₂ . The mixture was stirred at 25 °C for 60 min. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 2). The combined organic layers were washed with brine 20 mL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC(petroleum ethenethyl acetate=0: 1) to give methyl 4-(2-morpholinoethoxy)-lH- indole-2-carboxylate (200 mg, 591.44 umol, 37.69% yield, 90% purity) as a yellow solid. MS (ESI) m/z 304.9 [M+H] ⁺

Step 4: 4-(2-morpholinoethoxy)-lH-indole-2-carboxylic acid

[0001337] To a mixture of methyl 4-(2-morpholinoethoxy)-lH-indole-2-carboxylate (200 mg, 657.16 umol, 1 eq) in THF (2 mL) and H ₂ O (1 mL) was added LiOH.H ₂ O (41.37 mg, 985.74 umol, 1.5 eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was purified by HC1 prep-HPLC to give 4-(2-morpholinoethoxy)-lH-indole-2-carboxylic acid (80 mg, 261.79 umol, 39.84% yield, 95% purity) as a white solid. MS (ESI) m/z 289.2 [M-H] ⁺

[0001338] column: Phenomenex luna C1880*40 mm*3 um; mobile phase: [water(0.04% HC1)-ACN];B%: l%-32%,6.5 min

Step 5: N-f ( l S)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-(2-morpholinoethoxy)-JH-i ndole-2-carboxamide

[0001339] To a mixture of 4-(2-morpholinoethoxy)-lH-indole-2-carboxylic acid (70 mg, 241.12 umol, 1 eq) and (2S)-2-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]-3-cyclopropyl-propanamide (159.33 mg, 241.12 umol, 40% purity, 1 eq) in DCM (2 mL) was added DIEA (93.49 mg, 723.36 umol, 125.99 uL, 3 eq) and T3P (230.16 mg, 361.68 umol, 215.10 uL, 50% purity, 1.5 eq) in one portion at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was added EDTA solution (2 mL) and stirred at 25 °C for 10 min, and then extracted with DCM (6 mL, which was extracted as 2 mL * 3). The combined organic layers were washed with brine (5 mL, which was washed as 5 mL * 3), and 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-(2-morpholinoethoxy)-lH-indole-2-carboxamide (13 mg, 24.23 umol, 10.05% yield) as a white solid. MS (ESI) m/z 537.3 [M+H] ⁺ column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )- ACN] ;B% : 20%-50%,8 min

[0001340] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.57 (s, 1H), 8.92 (d, J=7.9 Hz, 1H), 8.60 (br d,J=7.5 Hz, 1H), 7.79 - 7.68 (m, 1H), 7.35 (d, J=1.5 Hz, 1H), 7.14 - 6.93 (m, 2H),

6.51 (d, J=7.5 Hz, 1H), 4.98 (q, J=7.9 Hz, 1H), 4.54 - 4.38 (m, 1H), 4.21 (br d, J=3.5 Hz, 2H), 3.59 (t, J=4.5 Hz, 4H), 3.20 - 3.05 (m, 2H), 2.78 (t, J=5.6 Hz, 2H), 2.60 - 2.52 (m, 4H), 2.43 - 2.28 (m, 1H), 2.23 - 2.04 (m, 2H), 1.92 - 1.60 (m, 3H), 1.56 - 1.38 (m, 1H), 0.80 (br d, J=5.3 Hz, 1H), 0.51 - 0.30 (m, 2H), 0.25 - 0.05 (m, 2H)

[0001341 ] ¹ H NMR (400MHZ, METHANOL-d ₄ ) δ = 7.34 - 7.28 (m, 1H), 7.18 - 7.11 (m, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.53 (d, J=7.5 Hz, 1H), 5.08 (dd, J=5.8, 10.3 Hz, 1H), 4.54 (t, J=7.4 Hz, 1H), 4.30 (t, J=5.3 Hz, 2H), 3.77 - 3.72 (m, 4H), 3.30 - 3.27 (m, 2H), 2.92 (t, J=5.3 Hz, 2H), 2.75 - 2.59 (m, 5H), 2.40 - 2.26 (m, 2H), 1.99 - 1.79 (m, 3H), 1.78 - 1.60 (m, 1H), 0.93 - 0.76 (m, 1H), 0.58 - 0.52 (m, 2H), 0.20 (br dd, J=5.0, 11.6 Hz, 2H)

Example 164. Synthesis of viral protease inhibitor compound 519

Step 1: methyl(2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl ]amino]-3-[ ( 3S)-2- oxopyrrolidin-3-yl] propanoate

[0001342] 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]pr opanoate (170 mg, 571.72 umol, 98.80% yield) as a white solid.

Step 2: methyl(2S)-2-[[(2S)-2-[(5-chloro-JH-indole-2-carbonyl)amino] -3-cyclopropyl- propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ] propanoate

[0001343] To a mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (170 mg, 571.72 umol, 1 eq) in DCM (2 mL) and DMF (0.5 mL) was added DMAP (209.54 mg, 1.72 mmol, 3 eq) in one portion at 25 °C. The mixture was added with 5-chloro- 1 H-indole-2-carboxylic acid (134.20 mg, 686.06 umol, 1.2 eq) and EDCI (328.80 mg, 1.72 mmol, 3 eq) and stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was purified by prep-TLC (SiO ₂ , EA: MeOH = 10: 1) to give methyl(2S)-2- [[(2S)-2-[(5-chloro-lH-indole-2-carbonyl)amino]-3-cyclopropy l-propanoyl] amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (140 mg, 294.78 umol, 51.56% yield) as a white solid. MS (ESI) m/z 475.2 [M+H] ⁺

Step 3: N-[ ( l S)-2-[[ ( l S)-2-amino-2-oxo-l-[ [ ( 3S)-2-oxopyrrolidin-3-yl ]methyl ] ethyl ]amino ]- 1- (cyclopropylmethyl)-2-oxo-ethyl]-5-chloro-lH-indole-2-carbox amide [0001344] To a mixture of methyl (2S)-2-[[(2S)-2-[(5-chloro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo pyrrolidin-3- yl]propanoate (130 mg, 273.72 umol, 1 eq) in NH ₃ /MeOH(7M) (5 mL), the mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-5-chloro-lH-indole-2- carboxamide (100 mg, 217.43 umol, 79.43% yield) as a white solid. MS (ESI) m/z 460.2 [M+H] ⁺

Step 4: 5-chloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-2-yl ] ethyl ]amino]-l-

(cyclopropyl methyl) -2-oxo-ethyl ]-lH-irtdole-2-carboxamide

[0001345] To a mixture of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-5- chloro-lH-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]-lH-indole-2-carboxamide (33 mg, 74.68 umol, 34.35% yield) as a white solid. MS (ESI) m/z 442.1 [M+H] ⁺

[0001346] Column: Waters Xbridge Prep OBD C 18 150*40 mm* 10 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,8 min

[0001347] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.71 (s, 1H), 8.85 (d, J=8.2 Hz, 1H), 8.59 (d, J=7.5 Hz, 1H), 7.71 - 7.56 (m, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.19 (s, 1H), 7.10 (dd, J=1.5, 8.8 Hz, 1H), 4.97 - 4.80 (m, 1H), 4.48 - 4.30 (m, 1H), 3.12 - 2.94 (m, 2H), 2.36 - 2.21 (m, 1H), 2.13 - 1.96 (m, 2H), 1.83 - 1.54 (m, 3H), 1.47 - 1.34 (m, 1H), 0.82 - 0.65 (m, 1H), 0.39 - 0.26 (m, 2H), 0.19 - 0.04 (m, 2H)

Example 165. Synthesis of viral protease inhibitor compound 531

Step 1: methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]-3-cyc lopropyl- propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001348] A mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (500 mg, 1.68 mmol, 1 eq) in DCM (10 mL) and DMF (2.5 mL), the mixture was added DMAP (616.30 mg, 5.04 mmol, 3 eq) in one portion at 25 °C. The mixture was added with 7-chloro-lH-indole-2-carboxylic acid (394.69 mg, 2.02 mmol, 1.2 eq) and EDCI (967.04 mg, 5.04 mmol, 3 eq) and the reaction was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 0/1) to give methyl (2S)-2-[[(2S)-2-[(7- chloro-lH-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]a mino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (550 mg, 1.16 mmol, 68.87% yield) as a white solid. MS (ESI) m/z 475.1 [M+H] ⁺

Step 2: N-f ( l S)-2-[[ ( l S)-2-amino-2-oxo-l-[ [ ( 3S)-2-oxopyrrolidin-3-yl ]methyl ] ethyl ]amino ]- l-(cyclopropylmethyl)-2-oxo-ethyl]-7-chloro-lH-indole-2-carb oxamide

[0001349] A mixture of methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]-3- cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]pr opanoate (500 mg, 1.05 mmol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 66.49 eq) was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-[[(1S)-2- amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]- 1 -(cyclopropylmethyl)- 2-oxo-ethyl]-7-chloro- 1 H-indole-2-carboxamide (440 mg, 956.68 umol, 90.87% yield) as a white solid. MS (ESI) m/z 460.3 [M+H] ⁺ Step 3: 7-chloro-N-[ ( lS)-2-[[( 1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[0001350] To a mixture of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-7- chloro-lH-indole-2- carboxamide (430 mg, 934.94 umol, 1 eq) in DCM (6 mL) was added Burgess reagent (445.61 mg, 1.87 mmol, 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 the crude product. The crude was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 um; mobile phase: [water(0.05% NH3H ₂ O+ 10 mM NH4HCO3 ₎ - ACN] ;B% : 30%-60%,8 min) to give 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]- 1 H-indole-2-carboxamide ( 180 mg, 407.32 umol, 43.57% yield) as a white solid. MS (ESI) m/z 442.2 [M+H] ⁺

[0001351 ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.71 (br s, 1H), 9.01 (d, J=7.9 Hz, 1H), 8.72 (d, J=7.5 Hz, 1H), 7.71 (s, 1H), 7.63 (dd, J=0.7, 7.9 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.07 (t, J=7.8 Hz, 1H), 5.00 (q, J=7.9 Hz, 1H), 4.58 - 4.49 (m, 1H), 3.13 (quin, J=9.2 Hz, 2H), 2.42 - 2.31 (m, 1H), 2.22 - 2.05 (m, 2H), 1.89 - 1.64 (m, 3H), 1.57 - 1.46 (m, 1H), 0.89 - 0.75 (m, 1H), 0.50 - 0.37 (m, 2H), 0.25 - 0.07 (m, 2H)

Example 166. Synthesis of viral protease inhibitor compound 539

Step J: (S)-methyl 2-ammo-3-((S)-2-oxopyrrolidm-3-yl)propanoate hydrochloride [0001352] A solution 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, 20 mL, 45.81 eq) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to get the product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanoate (350 mg, crude, HC1) as a yellow solid.

Step 2: (2S,4R)-tert-butyl 2-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 - yl)carbamoyl)-4-methylpyrrolidine-l-carboxylate

[0001353] To a solution of (2S,4R)- 1 -tert-butoxycarbonyl-4-methyl-pyrrolidine-2- carboxylic acid (250 mg, 1.09 mmol, 1 eq) and methyl (2S)-2-amino-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (304.45 mg, 1.64 mmol, 1.5 eq) in DCM (10 mL) was added drop-wise T3P (1.04 g, 1.64 mmol, 972.75 uL, 50% purity, 1.5 eq) and EtsN (662.02 mg, 6.54 mmol, 910.62 uL, 6 eq), and the reaction was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition H ₂ O (40 mL) at 0 °C, and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine 40 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 0: 1) to get the product tert-butyl (2S,4R)-2-[[(l S)-2-methoxy-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-4-methyl-pyrrolid ine-1-carboxylate (320 mg, 805.10 umol, 73.86% yield) as a colorless oil. MS (ESI) m/z 398.2 [M+H] ⁺ .

Step 3: (S)-methyl 2-((2S, 4R)-4-methylpyrrolidme-2-carboxamido)-3-((S)-2-oxopyrrolidm- 3- yl)propanoate

[0001354] A solution of tert-butyl (2S,4R)-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-4-methyl-pyrrolid ine-1-carboxylate (260 mg, 654.15 umol, 1 eq) in HCl/MeOH (4 M, 8 mL, 48.92 eq) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to get the product methyl (2S)-2-[[(2S,4R)-4-methylpyrrolidine-2-carbonyl]amino]-3-[(3 S)-2-oxopyiTolidin-3- yl]propanoate (200 mg, crude, HC1) as a colorless oil. MS (ESI) m/z 298.2 [M+H] ⁺ .

Step 4: (S)-methyl 2-((2S,4R)-l-(4-methoxy-lH-indole-2-carbonyl)-4-methylpyrrol idine-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001355] To a solution of methyl (2S)-2-[[(2S,4R)-4-methylpyrrolidine-2- carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 599.14 umol, 1 eq, HC1) and 4-methoxy-lH-indole-2-carboxylic acid (229.09 mg, 1.20 mmol, 2.0 eq) in DMF (2.0 mL) was added DMAP (219.59 mg, 1.80 mmol, 3.0 eq) and EDCI (229.71 mg, 1.20 mmol, 2 eq) and DCM (8.0 mL), the mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition H ₂ O (50 mL) at 0 °C, and then extracted with DCM (40 mL * 3). The combined organic layers were washed with brine 60 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate =

1 : 1 to 0: 1) to get the product methyl (2S)-2-[[(2S,4R)-1-(4-methoxy-lH-indole-2- carbonyl)-4-methyl-pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-o xopyrrolidin-3- yl]propanoate (250 mg, 494.14 umol, 82.47% yield, 93% purity) as a yellow solid. MS (ESI) m/z 471.3 [M+H] ⁺ .

Step 5: (2S, 4R)-N-[ ( l S)-2-amino-2-oxo-l-[[(3S)-2-oxopyrrolidin-3-yl ]methyl] ethyl ]-1-( 4- methoxy-lH-indole-2-carbonyl)-4-methyl-pyrrolidine-2-carboxa mide

[0001356] A solution of methyl (2S)-2-[[(2S,4R)-1-(4-methoxy-lH-indole-2-carbonyl)-4- methyl-pyrrolidine-2-carbonyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (220 mg, 434.84 umol, 93% purity, 1 eq) in NH ₃ /MeOH (7 M, 20 mL, 321.96 eq)was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get the product (2S,4R)-N-[(1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]- 1 - (4-methoxy-lH-indole-2-carbonyl)-4-methyl-pyrrolidine-2-carb oxamide (200 mg, crude) as a yellow solid. MS (ESI) m/z 456.2 [M+H] ⁺ .

Step 6: (2S, 4R)-N-[ ( l S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl ]-l-( 4-methoxy-lH- indole-2-carbonyl)-4-methyl-pyrrolidine-2-carboxamide

[0001357 ] To a solution of (2S,4R)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-1-(4-methoxy-lH-indole-2-carbonyl)-4-methyl -pyrrolidine-2- carboxamide (100 mg, 219.54 umol, 1 eq) in DCM (5 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (313.90 mg, 1.32 mmol, 6 eq), and the mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C 18 75 * 30 mm * 3 um; mobile phase: [water (0.2% FA) - ACN]; B%: 25% - 60%, 8 min) to get the product (2S,4R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]- 1-(4- methoxy-lH-indole-2-carbonyl)-4-methyl-pyrrolidine-2-carboxa mide (33 mg, 75.43 umol, 34.36% yield, 100% purity) as a white solid. MS (ESI) m/z 438.2 [M+H] ⁺ .

[0001358] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.73 - 11.47 (m, 1H), 8.85 (br d, J = 8.3 Hz, 1H), 7.84 - 7.54 (m, 1H), 7.24 - 6.84 (m, 3H), 6.74 - 6.48 (m, 1H), 5.10 - 4.47 (m, 2H), 4.20- 3.75 (m, 4H), 3.47 (t, J = 9.0 Hz, 1H), 3.16 (d, J = 7.9 Hz, 1H), 2.61 (s, 1H), 2.43 - 2.36 (m, 1H), 2.27 - 1.43 (m, 7H), 1.07 (d, J = 6.4 Hz, 3H).

[0001359] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.25 - 6.75 (m, 3H), 6.59 - 6.40 (m, 1H), 5.15 - 5.00 (m, 1H), 4.84 - 4.61 (m, 1H), 4.30 - 4.06 (m, 1H), 3.98 - 3.84 (m, 3H), 3.55 (t, J = 8.9 Hz, 1H), 3.30 - 3.24 (m, 1H), 3.01 - 2.54 (m, 2H), 2.46 - 2.09 (m, 4H), 2.01 - 1.38 (m, 3H), 1.15 (br d, J = 6.6 Hz, 3H).

Example 167. Synthesis of viral protease inhibitor compound 547

Step J: 9H-fluoren-9-ylmethyl (lS,2S,5R)-2-[[(lS)-l-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carboxylate

[0001360] (lS,2S,5R)-3-(9H-fluoren-9-ylmethoxycarbonyl)-3-azabicyclo[3 .2.0]heptane-2- carboxylic acid (250 mg, 687.94 umol, 1 eq), (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3- yl]propanenitrile (486.36 mg, 825.52 umol, 26% purity, 1.2 eq) in DCM (3 mL) was added T ₃ P (656.67 mg, 1.03 mmol, 613.71 uL, 50% purity, 1.5 eq) and DIEA (266.73 mg, 2.06 mmol, 359.48 uL, 3 eq), the solution was stirred at 25 °C for 2 h. After completion, the solution was diluted with H ₂ O (20 mL), extracted with ethyl acetate (30 mL * 3), the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10: 1). 9H-fluoren-9-ylmethyl (1 S,2S,5R)-2-[[(l S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carboxylate (185 mg, 371.06 umol, 53.94% yield, 100% purity) was obtained as yellow solid. MS (ESI) m/z 499.2 [M+H] ⁺ .

Step 2: (IS, 2S, 5R)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ]-3- azabicyclo[ 3.2.0 ]heptane-2-carboxamide

[0001361] To a solution of 9H-fluoren-9-ylmethyl ( 1 S,2S,5R)-2-[[(l S)-l -cyano-2-[(3 S)-2- oxopyrrolidin-3-yl]ethyl]carbamoyl]-3-azabicyclo[3 ,2.0]heptane-3-carboxylate (440 mg, 706.02 umol, 80% purity, 1 eq) in DCM (4.5 mL) was added the piperidine (60.11 mg, 706.02 umol, 69.72 uL, 1 eq) and the solution was stirred at 25 °C for 1 h. The solution was blow dry to remove the DCM and give the residue. The residue was purified by prep- TLC (SiO ₂ , DCM: MeOH = 10:1). (1 S,2S,5R)-N-[(1 S)-1-cyano-2-[(3S)-2-oxopyrrolidin- 3 -y 1 ]ethy 1 ]-3 -azabi cy clo[3.2.0]heptane-2-carboxamide (165 mg, 597.10 umol, 84.57% yield, 100% purity) was obtained as yellow solid.

Step 3: (IS, 2S, 5R)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ]-3-( 4-methoxy-lH- indole-2-carbonyl)-3-azabicyclo[3.2.0]heptane-2-carboxamide

[0001362] To a solution of N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3- azabicy clo[3.20]heptane-2-carboxamide ( 165.00 mg, 597.10 umol, 1 eq), 4-methoxy-lH- indole-2-carboxylic acid (171.23 mg, 895.66 umol, 1.5 eq) in DCM (2 mL) was added the T ₃ P (284.98 mg, 895.66 umol, 266.34 uL, 1.5 eq), DIEA (154.34 mg, 1.19 mmol, 208.01 uL, 2 eq), the solution was stirred at 25 °C for 1 h. Upon completion, the solution was diluted with H ₂ O (20 mL), extracted with ethyl acetate (30 mL * 3), the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The residue was purified by prep-HPLC (neutral condition).

[0001363] Column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN];B%: 25%-45%,8 min.

[0001364] (lS,2S,5R)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-3-(4-methoxy- lH-indole-2-carbonyl)-3-azabicyclo[3.2.0]heptane-2-carboxami de (98 mg, 218.02 umol, 36.51% yield, 100% purity) was obtained as white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 11.57 (br s, 1H), 8.79 (br d, J=7.4 Hz, 1H), 7.69 (br s, 1H), 7.17 - 6.95 (m, 3H), 6.52 (br d, J=7.3 Hz, 1H), 4.97 (br d, J=6.8 Hz, 1H), 4.63 (br d, J=8.2 Hz, 1H), 4.33 - 3.97 (m, 2H), 3.89 (br s, 3H), 3.28 - 2.79 (m, 4H), 2.30 - 1.55 (m, 9H). MS (ESI) m/z 450.3 [M+H]+.

[0001365] (lR,2R,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethy l]-3-(4-methoxy- lH-indole-2-carbonyl)-3-azabicyclo[3.2.0]heptane-2-carboxami de (23 mg, 51.17 umol, 8.57% yield, 100% purity) was obtained as white solid. ¹ H NMR (400 MHz, DMSO-d6) δ = 11.56 (br s, 1H), 9.13 - 8.71 (m, 1H), 7.83 - 7.44 (m, 1H), 7.23 - 6.89 (m, 3H), 6.77 - 6.36 (m, 1H), 5.18 - 4.57 (m, 2H), 4.32 - 3.94 (m, 2H), 3.92 - 3.74 (m, 3H), 3.71 - 3.40 (m, 1H), 3.23 - 2.76 (m, 3H), 2.32 - 1.47 (m, 9H). MS (ESI) m/z 450.3 [M+H] ⁺ .

Example 168. Synthesis of viral protease inhibitor compound 549

Step 1: tert-butyl (2S, 4R)-2-[[( lS)-2-methoxy-2-oxo-l-[[(3S)-2-oxopyrrolidin-3-yl /methyl ] ethyl ] carbamoyl ]-4-(trifluoromethyl)pyrrolidine-l-carboxylate

[0001366] To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (283.01 mg, 1.27 mmol, 1.2 eq, HC1) and (2 S,4R)- 1 -tert-butoxy carbonyl -4- (trifluoromethyl)pyrrolidine-2-carboxylic acid (300 mg, 1.06 mmol, 1 eq), DIEA (684.44 mg, 5.30 mmol, 922.43 uL, 5 eq) in THF (3 mL) was added T3P (1.01 g, 1.59 mmol, 944.87 uL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 1 h. Upon completion, the residue was poured into saturated sodium bicarbonate solution (10 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (10 mL * 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum to give Tert-butyl(2S,4R)-2-[[(1S)-2- methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]car bamoyl]-4- (trifluoromethyl)pyrrolidine- 1 -carboxylate (0.5 g, crude) as light yellow oil and used directly next step. MS (ESI) m/z 452.1 [M+H] ⁺ . Step 2: methyl (2S)-3-[ ( 3S)-2-oxopyrrolidin-2-yl ]-2-[ [ (2S, 4R)-4-(trifluoromethyl)pyrrolidine- 2- carbonyl] aminojpropanoate

[0001367] To a mixture of tert-butyl (2S,4R)-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl] ethyl]carbamoyl]-4-(trifluoromethyl)pyrrolidine- 1 - carboxylate (0.5 g, 1.11 mmol, 1 eq) was added HCl/MeOH (4 M, 3 mL, 10.83 eq) at 25 °C under N ₂ . The mixture was stirred at 25 °C for 15 min. Upon completion, the reaction mixture was concentrated to get the crude product Methyl (2S)-3-[(3S)-2- oxopyrrolidin-3-yl] -2-[[(2S,4R)-4-(trifluoromethyl)pyrrolidine-2- carbonyl]amino]propanoate (450 mg, crude, HC1) as the light yellow oil. MS (ESI) m/z 352.1 [M+H] ⁺ .

Step 3: methyl (2S)-2-[[(2S,4R)-l-(4-methoxy-lH-indole-2-carbonyl)-4- ( trifluoromethyl)pyrrolidine-2- carbonyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001368] To a mixture of methyl (2S)-3-[(3S)-2-oxopyrrolidin-3-yl]-2-[[(2S,4R)-4- (trifluoromethyl) pyrrolidine-2-carbonyl]amino]propanoate (395.52 mg, 1.02 mmol, 1.3 eq, HC1) and 4-methoxy- 1 H-indole-2-carboxylic acid (150 mg, 784.59 umol, 1 eq) and DIPEA (507.01 mg, 3.92 mmol, 683.31 uL, 5 eq) in THF (3 mL) and DCM (3 mL) was added T3P (748.92 mg, 1.18 mmol, 699.93 uL, 50% purity, 1.5 eq) at 0 °C under N ₂ . The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was poured into saturated sodium bicarbonate solution (5 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (5 mL * 2). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The crude product was purified by prep-TLC (dichloromethane: methanol =

10:1, R _f = 0.43) to give methyl (2S)-2-[[(2S,4R)-1-(4-methoxy-lH-indole-2-carbonyl) -4- (trifluoromethyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxo pyrrolidin-3-yl]propanoate (250 mg, crude) as a light yellow solid. MS (ESI) m/z 525.2 [M+H] ⁺ .

Step 4: (2S, 4R)-l-( 4-methoxy-lH-indole-2-carbonyl)-N-[ ( l S)-l -(nitrosomethyl) -2- [ ( 3S)-2- oxopyrr olidin-3-yl ] ethyl ]-4-(trifluoromethyl)pyrrolidine-2-carboxamide

[0001369] To a mixture of methyl (2S)-2-[[(2S,4R)-1-(4-methoxy-lH-indole-2-carbonyl)- 4- (trifluoromethyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxo pyrrolidin-3- yl]propanoate (250 mg, 476.65 umol, 1 eq) was added NH ₃ /MeOH (7 M, 3 mL, 44.06 eq) in one portion at 25 °C under N ₂ . 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- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 - (nitrosomethyl)-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-(trifl uoromethyl)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] ⁺ .

Step 5: (2S, 4R)-N-[ ( l S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl /- 1 -(4-methoxy- 1H- indole-2- carbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxamide

[0001370] To a mixture of (2S,4R)- 1 -(4-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 - (nitrosomethyl)-2-[(3 S) -2-oxopyrrolidin-3-yl]ethyl]-4-(trifluoromethyl)pyrrolidine- 2- carboxamide (120 mg, 235.54 umol, 1 eq) in DCM (6 mL) was added Burgess reagent (112.26 mg, 471.07 umol, 2 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C for 4.5 h. Upon completion, the residue was poured into water (0.5 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 (column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase: [water (10 mM NH4HCO3)- ACN] ;B% : 25%-45%,8 min) to give (2S,4R)-N-[(1 S)-1-cyano-2-[(3S)-2-oxopy rrolidin-3-yl]ethyl]-1-(4-methoxy-lH- indole-2-carbonyl)-4-(trifluoromethyl)pyrrolidine-2-carboxam ide (22.56 mg, 45.90 umol, 19.49% yield, 100% purity) as a white solid. MS (ESI) m/z 492.2 [M+H] ⁺ .

[0001371 ] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.12 - 7.21 (m, 1 H), 6.84 - 7.10 (m, 2 H), 6.50 (br s, 1 H), 4.94 - 5.26 (m, 1 H), 4.75 (br s, 1 H), 4.07 - 4.47 (m, 2 H), 3.79 - 4.01 (m, 3 H), 3.45 (br s, 1 H), 2.16 - 2.98 (m, 6 H), 1.62 - 2.02 (m, 2 H), 1.39 (br s, 1

H)

Example 169. Synthesis of viral protease inhibitor compound 551

Step J: 9H-fluoren-9-ylmethyl (2S,4R)-2-[[(lS)-2-amino-2-oxo-l-[[(3S)-2-oxopyrrolidin-3- yl ] methyl ] ethyl ] carbamoyl ]-4-methylsulf any l-pyrrolidine-1 -car boxy late

[0001372] To a mixture (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (200.57 mg, 782.35 umol, 81% purity, 1 eq, HC1) and (2S,4R)-1-(9H-fluoren-9- ylmethoxy carbonyl)- 4-methylsulfanyl-pyrrolidine-2-carboxylic acid (300 mg, 782.35 umol, 1 eq) in DCM (4 mL) and DMF (2 mL) was added EDCI (299.96 mg, 1.56 mmol, 2 eq) and DMAP (191.16 mg, 1.56 mmol, 2 eq) in one portion at 25 °C under N ₂ . The mixture was stirred at 25 °C and stirred for 1 hours. Upon completion. The aqueous phase was extracted with ethyl acetate (30 mL * 3) and H ₂ O (40 mL).The combined organic phase was washed with brine (30 mL * 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. To afford 9H-fluoren-9-ylmethyl (2S,4R)-2-[[(1S)-2-amino-2- oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-4- methylsulfanyl- pyrrolidine- 1 -carboxylate (180 mg, 322.00 umol, 41.16% yield, 96% purity) as white solid. MS (ESI) m/z 537.3 [M+H] ⁺

Step 2: (2S, 4R)-N-[ ( l S)-2-amino-2-oxo-l-[[(3S)-2-oxopyrrolidin-3-yl ]methyl ] ethyl ]-4- methylsulfanyl-pyrrolidine-2-carboxamide

[0001373] To a mixture of 9H-fluoren-9-ylmethyl (2S,4R)-2-[[(1S)-2-amino-2-oxo-1- [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-4-methyl sulfanyl-pyrrolidine-1- carboxylate (180 mg, 335.42 umol, 1 eq) in DCM (2 mL) was added piperidine (344.88 mg, 4.05 mmol, 0.4 mL, 12.08 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 1 h. Upon completion. The crude was purified by pre-TLC (SiO ₂ , DCM/MEOH = 5/1). To afford (2S,4R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-4- methylsulfanyl- pyrrolidine-2-carboxamide (80 mg, 127.23 umol, 37.93% yield, 50% purity) as a white solid.

[0001374] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ = 8.15 (br d, J=9.6 Hz, 1H), 7.63 (s, 1H), 7.53 (s, 1H), 7.12 (br s, 1H), 4.28 (br s, 1H), 3.73 (br t, 3=1.2 Hz, 1H), 3.22 - 3.03 (m, 4H), 2.99 (br s, 2H), 2.78 (br d, J=7.2 Hz, 1H), 2.28 - 1.86 (m, 8H), 1.74 - 1.43 (m, 6H).

Step 3: (2S, 4R)-N-[ ( l S)-2-amino-2-oxo-l-[[(3S)-2-oxopyrrolidin-3-yl ]methyl ] ethyl] -l-( 4- methoxy-lH-indole-2-carbonyl)-4-methylsulfanyl-pyrrolidine-2 -carboxamide

[0001375] To a mixture of (2S,4R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-4- methylsulfanyl-pyrrolidine-2-carboxamide (80 mg, 254.45 umol, 1 eq) and 4-methoxy-lH-indole-2-carboxylic acid (48.65 mg, 254.45 umol, 1 eq) in DCM (2 mL) and DMF (1 mL) was added EDCI (97.56 mg, 508.90 umol, 2 eq) and DMAP (62.17 mg, 508.90 umol, 2 eq) in one portion at 20 °C and stirred for lh. Upon completion, the mixture was dried by N ₂ . The crude was purified by pre-HPLC, column: Phenomenex Gemini-NX C1875*30 mm*3um; mobile phase: [water(10 mM NH4HCO3)- ACN] ;B% : 25%-45%,8 min. To afford (2S,4R)-N-[( 1 S)-2-amino-2-oxo- 1 - [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-1-(4-methoxy-lH-in dole-2-carbonyl)-4- methylsulfanyl-pyrrolidine-2-carboxamide (80 mg, 164.08 umol, 64.48% yield, 100% purity) as white solid. MS (ESI) m/z 488.3 [M+H] ⁺

Step 4: (2S, 4R)-N-[ ( l S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl ]-l-(4-methoxy-lH- indole-2-carbonyl)-4-methylsulfanyl-pyrrolidine-2-carboxamid e

[0001376] To a mixture of (2S,4R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-1- (4-methoxy-lH-indole-2-carbonyl)-4-methylsulfanyl-pyrrolidin e-2- carboxamide (80 mg, 164.08 umol, 1 eq) in DCM (4 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (312.81 mg, 1.31 mmol, 8 eq) in one portion at 20 °C and stirred for 3 h. Upon completion. The crude was dried by N ₂ . The crude was purified by pre-HPLC, column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water(10 mM NH ₄ HCO ₃ )-ACN];B%: 15%-45%,10 min. To afford (2S,4R)-N-[(1S)-1- cyano-2-[(3 S)-2-oxopyrrolidin-3-yl]ethyl]- 1 -(4-methoxy- 1 H-indole-2-carbonyl)-4- methylsulfanyl-pyrrolidine-2-carboxamide (31.9 mg, 67.94 umol, 41.40% yield, 100% purity) as white solid. MS (ESI) m/z 470.2 [M+H] ⁺ [0001377] ¹ H NMR (400MHZ, DMSO-d6) δ = 11.38 (br s, 1H), 8.85 (br s, 1H), 7.46 (br s, 1H), 7.17 - 7.09 (m, 1H), 7.09 - 7.02 (m, 1H), 6.91 (br s, 1H), 6.52 (d, J=7.5 Hz, 1H), 4.95 (br d, J=7.1 Hz, 1H), 4.86 - 4.60 (m, 1H), 4.27 (br s, 1H), 3.90 (s, 4H), 3.54 (br s, 1H), 3.18 - 3.12 (m, 2H), 2.50-2.39 (br s, 8H), 1.89 - 1.61 (m, 2H).

Example 170. Synthesis of viral protease inhibitor compound 555

Step 1: methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate

[0001378] A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (300 mg, 1.05 mmol, 1 eq) and HC1/EA (3 mL) was stirred at 25 °C for 0.5 h. Upon completion, the residue was concentrated under reduced pressure to get the product methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, crude, HC1) as white solid MS (ESI) m/z 187.1 [M+H] ⁺ .

Step 2: tert-butyl (1S)-1-[[(1 S)-2-methoxy-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl] ethyl ] carbamoyl] -3, 4-dihy dr o-lH-isoquinoline-2-car boxy late

[0001379] A solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 898.19 umol, 1 eq, HCI), ( 1 S)-2-tert-butoxy carbonyl-3 ,4-dihydro- 1 H- isoquinoline-1-carboxylic acid (249.08 mg, 898.19 umol, 1 eq) and TEA (454.44 mg, 4.49 mmol, 625.09 uL, 5 eq) in DCM (2 mL) and DMF (1 mL) was cooled to 0 °C. After adding T3P (1.71 g, 2.69 mmol, 1.60 mL, 50% purity, 3 eq) at 0 °C, the mixture was stirred for 1 h and warmed to 25 °C gradually. Upon completion, the mixture was added H ₂ O (30 mL) and then extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get the product tert-butyl (1S)-1-[[(1 S)-2-methoxy-2-oxo- 1 - [[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3,4-dihy dro-1H-isoquinoline-2- carboxylate (300 mg, crude) as a yellow solid. MS (ESI) m/z 446.2 [M+H] ⁺ .

Step 3: methyl (2S)-3-[(3S)-2-oxopyrrolidin-3-yl]-2-[[(lS)-l,2, 3, 4-tetrahydroisoquinoline-l-c arbonyl ] amino ]propanoate

[0001380] A solution of tert-butyl (1S)-1-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-3,4-dihydro-1H-is oquinoline-2-carboxylate (300 mg, 673.39 umol, 1 eq) in HC1/EA (4 M) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to get the product methyl(2S)-3-[(3S)-2-oxopyrrolidin-3-yl]-2-[[(1S)-l, 2,3,4- tetrahydroisoquinoline-1-carbonyl]amino]propanoate (210 mg, crude) as white solid. MS (ESI) m/z 346.2 [M+H] ⁺ .

Step 4: methyl (2S)-2-[[(lS)-2-(4-methoxy-lH-indole-2-carbonyl)-3,4-dihydro -lH- isoquinoline-1 -carbonyl ] amino] -3- [ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001381 ] A solution of methyl (2S)-3-[(3S)-2-oxopyrrolidin-3-yl]-2-[[(1S)-l ,2,3,4- tetrahydroisoquinoline-1-carbonyl]amino]propanoate (190 mg, 497.57 umol, 1 eq, HC1), 4-methoxy- 1 H-indole-2-carboxylic acid (95.13 mg, 497.57 umol, 1 eq), EDCI (286.16 mg, 1.49 mmol, 3 eq) and DMAP (182.36 mg, 1.49 mmol, 3 eq) in DCM (4 mL) was stirred at 25 °C for 1 h. Upon completion, the mixture was added H ₂ O (30 mL) and then extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini- NX C1875 * 30 mm * 3 um; mobile phase: [water (0.05% NH ₃ H ₂ O + 10 mM NH4HCO3) - ACN]; B%: 30% - 60%, 8 min) to get the product methyl (2S)-2-[[(1S)-2-(4- methoxy-1H-indole-2-carbonyl)-3,4-dihydro-1H-isoquinoline-1- carbonyl]amino]-3-[(3S)- 2-oxopyrrolidin-3-yl]propanoate (40.1 mg, 73.46 umol, 14.76% yield, 95% purity) as a white solid. MS (ESI) m/z 519.2 [M+H] ⁺ .

Step 5: ( l S)-N-[ ( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl ]-2-( 4-methox y-lH-indole-2-carbonyl)-3,4-dihydro-lH-isoquinoline-l-carbox amide

[0001382] A solution of methyl (2S)-2-[[( 1 S)-2-(4-methoxy- 1H-indole-2-carbonyl)-3 ,4- dihydro-1H-isoquinoline-1-carbonyl]amino]-3-[(3S)-2-oxopyrro lidin-3-yl]propanoate (40 mg, 77.14 umol, 1 eq) and NH ₃ /MeOH (7 M, 10 mL, 907.48 eq) was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford (1S)-Af-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]me thyl]ethyl]-2-(4- methoxy- 1H-indole-2-carbonyl)-3 ,4-dihydro- \H-\ soquinoline- 1 -carboxamide (35 mg, crude) as a yellow solid. MS (ESI) m/z 504.2 [M+H] ⁺ .

Step 6: ( l S)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl ]-2-( 4-methoxy-lH-indole-2- carbonyl)-3, 4-dihydro- lH-isoquinoline-1 -carboxamide

[0001383] A solution of ( 1 S)-N-[( 1 S)-2-amino-2-oxo- 1 -[ [(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-2-(4-methoxy-1H-indole-2-carbonyl)-3,4-dihy dro-lH-isoquinoline-1- carboxamide (35 mg, 69.51 umol, 1 eq) and methoxycarbonyl-(triethylammonio)sulfonyl- azanide (82.82 mg, 347.53 umol, 5 eq) in DCM (5 mL) was stirred at 25 °C for 5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75 * 30 mm * 3 um; mobile phase: [water (0.05% NH3H ₂ O + 10 mM NH4HCO3) - ACN]; B%: 20% - 50%, 8 min) to get the product ( 1 S)-N-[( 1 S)- 1 -cyano-2-[(3S)-2-oxopyrrolidin- 3-yl]ethyl]-2-(4-methoxy-1H-indole-2-carbonyl)-3,4-dihydro-1 H-isoquinoline-1- carboxamide (6 mg, 12.08 umol, 17.38% yield, 97.74% purity) as white solid. MS (ESI) m/z 486.2 [M+H] ⁺ .

[0001384] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.57 - 7.47 (m, 1H), 7.40 - 7.25 (m,

1H), 7.12 - 7.11 (m, 1H), 7.10 - 6.99 (m, 2H), 6.59 - 6.50 (m, 1H), 6.82 - 6.61 (m, 1H), 5.67 (s, 1H), 5.03 - 4.96 (m, 1H), 4.46 (s, 1H), 4.05 - 3.95 (m, 1H), 3.94 - 3.86 (m, 3H), 3.37 - 3.32 (m , 1H), 3.28 - 3.16 (m, 2H), 3.05 - 2.90 (m, 2H), 2.62 (s, 1H), 2.44 - 2.20 (m, 2H), 1.98 - 1.67 (m, 2H)

Example 171. Synthesis of viral protease inhibitor compound 557

Step 1: (S)-methyl 2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride

[0001385] 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 N ₂ for 3 times, and then the mixture was stirred at 20 °C for 0.5 h under N ₂ atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2-amino-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (630 mg, crude, HC1) as yellow oil. MS (ESI) m/z 223.2 [M+H] ⁺

Step 2: tert-butyl l-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2 - yl)carbamoyl)isoindoline-2-carboxylate

[0001386] To a solution of 2-tert-butoxycarbonylisoindoline-1-carboxylic acid (436.93 mg, 1.66 mmol, 1 eq) methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (630 mg, 1.74 mmol, 61.58% purity, 1.05 eq, HC1) in DCM (5 mL) and DMF (5 mL) was added T ₃ P (1.58 g, 2.49 mmol, 1.48 mL, 50% purity, 1.5 eq) and TEA (1.01 g, 9.96 mmol, 1.39 mL, 6 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (20 mL), and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get the product tert-butyl l-[[(1S)-2- methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]ethyl]car bamoyl]isoindoline-2- carboxylate (720 mg, crude) as a white solid. MS (ESI) m/z 432.2 [M+H] ⁺ .

Step 3: (2S)-methyl 2-(isoindolme-l-carboxamido)-3-((S)-2-oxopyrrolidm-3-yl)prop anoate

[0001387] A mixture of tert-butyl l-[[(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 N ₂ for 3 times, and then the mixture was stirred at 20 °C for 0.5 h under N ₂ atmosphere. 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, HC1) as a brown oil. MS (ESI) m/z 332.3[M+H] ⁺ .

Step 4: (2S)-methyl 2-(2-(4-methoxy-JH-indole-2-carbonyl)isoindoline-l-carboxami do)-3- ((S)-2-oxopyrrolidin-3-yl)propanoate

[0001388] A mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (287.43 mg, 1.50 mmol, 1 eq), methyl (2S)-2-(isoindoline-1-carbonylamino)-3-[(3S)-2-oxopyrrolidin -3- yl]propanoate (770 mg, 1.65 mmol, 79% purity, 1.1 eq, HC1), DMAP (367.34 mg, 3.01 mmol, 2 eq), EDCI (576.42 mg, 3.01 mmol, 2 eq) in DCM (8 mL) and DMF (2.7 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 20 °C for 1 h under N ₂ atmosphere. Upon completion, the reaction mixture was quenched by addition H ₂ O (25 mL), and then extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (15 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by neutral prep- HPLC (column: Kromasil C18 (250*50 mm*10 um); mobile phase: [water(10 mM NH4HCO3)- ACN];B%: 25%-45%, 10 min) to get the product methyl (2S)-2-[[2-(4-methoxy- 1 H- indole-2-carbonyl)isoindoline-1-carbonyl]amino]-3-[(3S)-2-ox opyrrolidin-3- yl]propanoate (Isomer 1: 150 mg, 297.30 umol, 19.78% yield) as a white solid. MS (ESI) m/z 505.3[M+H] ⁺ . [0001389] To get methyl (2S)-2-[[2-(4-methoxy- lH-indole-2-carbonyl)isoindoline- 1 - carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (Isomer 2: 140 mg, 277.48 umol, 18.46% yield) as white solid. MS (ESI) m/z 505.3[M+H]+.

Step 5.1: N-((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopyrrolidin-3-yl)pr opan-2-yl)-2-(4-methoxy- 1H- indole-2-carbonyl)isoindoline-l -carboxamide

[0001390] A solution of methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)isoindoline-

1-carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 297.30 umol, 1 eq) in MeOH/NH ₃ (7 M, 849.44 uL, 20 eq) was stirred at 45 °C for 48 h. Upon completion, the reaction mixture was concentrated under reduced pressure to get the product N-[(1S)-

2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl] ethyl]-2-(4-methoxy- lH-indole-2- carbonyl)isoindoline-l -carboxamide (130 mg, crude) as a colorless oil. MS (ESI) m/z 490.3[M+H] ⁺ .

Step 5.2: N-((S)- 1 -amino- l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-(4-methoxy- lH- indole-2-carbonyl)isoindoline-l -carboxamide

[0001391 ] A solution of methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)isoindoline-

1-carbonyl] amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (140 mg, 277.48 umol, 1 eq) in MeOH/NH ₃ (7 M, 792.81 uL, 20 eq) was stirred at 45 °C for 24 h. Upon completion, the reaction mixture was concentrated under reduced pressure to get the product N-[(1S)-

2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-2-(4-methoxy- lH-indole-2- carbonyl)isoindoline-l -carboxamide (110 mg, crude) as a colorless oil. MS (ESI) m/z 490.3[M+H] ⁺ .

Step 6.1: N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-metho xy-lH-indole-2- carbonyl)isoindoline-l -carboxamide

[0001392] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)isoindoli ne-1-carboxamide (125 mg, 255.35 umol, 1 eq) in DCM (8 mL) was added Burgess reagent (273.84 mg, 1.15 mmol, 4.5 eq). The mixture was stirred at 30 °C for 20 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.5 mL), and then concentrated under reduced pressure to give a residue. The residue was purified by neutral prep- HPLC (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water(10 mM NH4HCO3)- ACN];B%: 20%-50%,10 min) to get the product N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl) isoindoline-1-carboxamide (31.50 mg, 66.81 umol, 26.16% yield, 100% purity) as a white solid. MS (ESI) m/z 472.3[M+H] ⁺ .

[0001393] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.53 - 11.83 (m, 1 H) 9.11 - 9.78 (m, 1 H) 7.31 - 7.78 (m, 5 H) 6.95 - 7.29 (m, 3 H) 6.42 - 6.63 (m, 1 H) 5.73 (s, 1 H) 5.27 - 5.41 (m, 1 H) 4.91 - 5.05 (m, 1 H) 3.76 - 3.99 (m, 3 H) 2.71 - 3.19 (m, 2 H) 2.00 - 2.30 (m, 3 H) 1.20 - 1.87 (m, 2 H).

Step 6.2: N-((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2-(4-metho xy-lH-indole-2- carbonyl)isoindoline-l -carboxamide

[0001394] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl] -2-(4-methoxy- 1 H-indole-2-carbonyl)isoindoline- 1 -carboxamide (105 mg, 214.49 umol, 1 eq) in DCM (6 mL) was added Burgess reagent (204.47 mg, 857.98 umol, 4 eq). The mixture was stirred at 30 °C for 7 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.5 mL), and then concentrated under reduced pressure to give a residue. The residue was purified by neutral prep- HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water(10 mM NH4HC03 )- ACN] ;B% : 25%-55%,8 min) to get the product N-[(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl) isoindoline-1-carboxamide (34.83 mg, 73.72 umol, 34.37% yield, 99.791% purity) as a white solid. MS (ESI) m/z 472.3[M+H] ⁺ .

[0001395] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.72 (s, 1 H) 9.19 (d, J= 8.11 Hz, 1 H) 7.31 - 7.76 (m, 5 H) 6.92 - 7.29 (m, 3 H) 6.56 (d, J=7.75 Hz, 1 H) 5.74 (s, 1 H) 5.34 (br d, J=10.13 Hz, 1 H) 4.96 (q, J=8.23 Hz, 1 H) 3.86 - 3.89 (m, 1 H) 3.86 - 4.55 (m, 1 H) 3.84 - 4.01 (m, 3 H) 2.96 - 3.22 (m, 2 H) 2.25 - 2.41 (m, 1 H) 2.02 - 2.20 (m, 2 H) 1.47 - 1.87 (m, 2 H). Example 172. Synthesis of viral protease inhibitor compound 577

Step 1: (S)-methyl 2-ammo-3-((S)-2-oxopyrrolidm-3-yl)propanoate

[0001396] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (350 mg, 1.22 mmol, 1 eq) in MeOH (1 mL) was added drop-wise HCl/MeOH (4 M, 10 mL, 32.72 eq), and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to get methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (240 mg, crude, HC1) as a colourless oil. MS (ESI) m/z 187.1 [M+H] ⁺

Step 2: (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-cyclobutylpropanamid o)-3-((S)-2- oxopyrrolidin-3-yl)propanoate

[0001397] A solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 898.19 umol, 1 eq, HC1) and (2S)-2-(tert-butoxycarbonylamino)-3-cyclobutyl- propanoic acid (218.53 mg, 898.19 umol, 1 eq) in DCM (5 mL), and Et3N (545.33 mg, 5.39 mmol, 750.11 uL, 6.0 eq) and T3P (1.71 g, 2.69 mmol, 1.60 mL, 50% purity, 3.0 eq) were added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition H ₂ O (40 mL) at 0 °C, and then extracted with DCM (20 mL * 3). The combined organic layers were washed with brine 30 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO ₂ , petroleum ether/ethyl acetate = 0/1) to get the product methyl (2S)-2-[[(2S)- 2-(tert-butoxycarbonylamino)-3-cyclobutyl-propanoyl]amino]-3 -[(3S)-2-oxopyrrolidin-3- yl]propanoate (200 mg, 486.04 umol, 54.11% yield) was obtained as a white solid. MS (ESI) m/z 412.1 [M+H] ⁺ Step 3: (S)-methyl 2-((S)-2-amino-3-cyclobutylpropanamido)-3-((S)-2-oxopyrrolid m-3- yl)propanoate

[0001398] To a solution of methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbonyl amino)-3 - cyclobutyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]pro panoate (180 mg, 437.43 umol, 1 eq) in MeOH (1 mL) was added drop-wise HCl/MeOH (4 M, 12.00 mL, 109.73 eq), and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford methyl (2 S)-2-[ [(2 S)-2-amino-3 - cyclobutyl-propanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]pro panoate (150 mg, HC1) as a white solid. MS (ESI) m/z 312.2 [M+H] ⁺

Step 4: (S)-methyl 2-((S)-3-cyclobutyl-2-( 4-methoxy-lH-indole-2- carboxamido)propanamido)-3-((S)-2-oxopyrrolidin-3-yl)propano ate

[0001399] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclobutyl-propanoyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 431.24 umol, 1 eq, HC1) and 4- methoxy- 1 H-indole-2-carboxylic acid (82.45 mg, 431.24 umol, 1 eq) in DMF (1.5 mL) was added DMAP (105.37 mg, 862.47 umol, 2.0 eq), EDCI (165.34 mg, 862.47 umol, 2.0 eq) and DCM (6 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition H ₂ O (40 mL) at 0 °C, and extracted with DCM (20 mL * 3). The combined organic layers were washed with brine 30 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (SiO ₂ , petroleum ether/ethyl acetate =0/1) to afford methyl (2S)-2-[[(2S)-3- cyclobutyl-2-[(4-methoxy-lH-indole-2-carbonyl)amino]propanoy l]amino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (120 mg, 247.66 umol, 57.43% yield) as a yellow oil. MS (ESI) m/z 485.2 [M+H] ⁺

Step 5: N-( (S)-l-( ( (S)-l -amino-1 -oxo-3-( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)ammo)-3- cyclobutyl-l-oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxami de

[0001400] A solution of methyl (2S)-2-[[(2S)-3-cyclobutyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate ( 100 mg, 206.38 umol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 339.18 eq) was stirred at 80 °C for 6 h. The reaction mixture was concentrated under reduced pressure to afford N-[(1S)-2-[[(1S)- 2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]amino]- 1 -(cyclobutylmethyl)- 2-oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide (90 mg, crude) as a yellow solid. MS (ESI) m/z 470.1 [M+H] ⁺

Step 7: N-( (S)-l-( ( (S)-l-cyano-2-( (S)-2-oxopyrrolidin-3-yl)ethyl)amino)-3-cyclobutyl-1- oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxamide

[0001401] To a solution of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclobutylmethyl)-2-oxo-ethyl]-4-m ethoxy-lH-indole-2- carboxamide (90 mg, 191.68 umol, 1 eq) in DCM (2 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (228.40 mg, 958.40 umol, 5.0 eq), and 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 (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30%-60%, 8 min) to afford N-[( 1 S)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2- oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclobutylmethyl)-2-oxo-e thyl]-4-methoxy-lH- indole-2-carboxamide (18.04 mg, 39.95 umol, 20.84% yield, 100% purity) as a white solid. MS (ESI) m/z 452.3 [M+H] ⁺ .

[0001402 ] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 7.26 (d, J = 0.7 Hz, 1H), 7.11 - 7.18 (m, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 5.05 (dd, J = 10.1, 5.9 Hz, 1H), 4.41 (dd, J = 8.6, 6.2 Hz, 1H), 3.93 (s, 3H), 3.25 - 3.30 (m, 2H), 2.61 (dd, J =

8.7, 5.3 Hz, 1H), 2.42 - 2.53 (m, 1H), 2.25 - 2.39 (m, 2H), 2.06 - 2.18 (m, 2H), 1.73 - 2.01 (m, 8H).

Example 173. Synthesis of viral protease inhibitor compound 589

Step 1: tert-butyl(J-(bicyclo[3.1.0]hexan-3-yl)-2-(((S)-l-cyano-2-(( S)-2-oxopyrrolidin-3- yl)ethyl)amino)-2-oxoethyl)carbamate

[0001403] A mixture of (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (89.1 mg, 0.47 mmol, 1.2 eq, HC1), HATU (223.3 mg, 0.58 mmol, 1.5 eq) and DIEA (151.8 mg, 1.18 mmol, 0.20 mL, 3 eq) in DCM (2 mL) was stirred at 25 °C for 0.5 h, and then 2-(3-bicyclo[3.1 0]hexanyl)-2-(tert-butoxycarbonylamino)acetic acid (100 mg, 0.39 mmol, 1 eq) was added into the reaction. The resulting mixture was stirred 25 °C for 2 h. LCMS detected desired compound. The reaction mixture was added H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , 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 0-100% ethyl acetate/petroleum ethergradient @ 20 mL/min). Compound tert-butyl N-[l-(3- bicyclo[3.1.0]hexanyl)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrroli din-3-yl]ethyl]amino]-2- oxo-ethyl]carbamate (150 mg, 0.23 mmol, 58.8% yield, 60% purity) was obtained as colorless oil.

Step 2: 2-amino-2-(bicyclo[3.1.0]hexan-3-yl)-N-((S)-l-cyano-2-((S)-2 -oxopyrrolidin-3- yl)ethyl)acetamide

[0001404] To a solution of tert-butyl N-[l-(3-bicyclo[3.1.0]hexanyl)-2-[[(1S)-1-cyano-2- [(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-2-oxo-ethyl]carbamat e (140 mg, 0.21 mmol, 60% purity, 1 eq) in EtOAc (0.1 mL) was added HCl/EtOAc (4 M, 0.84 mL, 15.62 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. It was used into next step without purification. Compound 2-amino-2-(3-bicyclo[3.1.0]hexanyl)-N-[(1S)-1-cyano-2-[(3S)- 2- oxopyrrolidin-3-yl]ethyl]acetamide (110 mg, crude, HC1) was obtained as a white solid.

Step 3: N-(l-(bicyclo[3.1.0]hexan-3-yl)-2-(((S)-l-cyano-2-((S)-2-oxo pyrrolidin-3- yl)ethyl)amino)-2-oxoethyl)-4-methoxy-lH-indole-2-carboxamid e

[0001405] A mixture of 4-methoxy-lH-indole-2-carboxylic acid (52.1 mg, 0.27 mmol, 1.2 eq), HATU (129.6 mg, 0.34 mmol, 1.5 eq) and DIEA (88.1 mg, 0.68 mol, 0.11 mL, 3 eq) in DCM (2 mL) was stirred at 25 °C for 0.5 h, and then 2-amino-2-(3- bicyclo[3.1.0]hexanyl)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolid in-3-yl]ethyl]acetamide (110 mg, 0.22 mmol, 60% purity, 1 eq) was added into the reaction. The resulting mixture was stirred 25 °C for 2 h. TLC (petroleum ether/ethyl acetate = 0:1, UV 254) indicated starting material was consumed completely and new spots formed. LCMS detected desired compound. The reaction mixture was added H ₂ O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , 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 0-100% ethyl acetate/petroleum ethergradient @ 30 mL/min) to give 50 mg 46% of desire compound. Then it was purified by prep-HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase: [water(0.05% NH ₃ H ₂ O+IO mM NH ₄ HCO ₃ )-ACN];B%: 25%-55%,9.5 min). Compound N-[l-(3-bicyclo[3.1.0]hexanyl)-2-[[(1S)-1-cyano-2-[(3S)-2-ox opyrrolidin-3- yl]ethyl]amino]-2-oxo-ethyl]-4-methoxy-lH-indole-2-carboxami de (7 mg, 15.1 umol, 6.6% yield, 100% purity) was obtained as a white solid.

[0001406] LCMS: Rt = 0.813 min; for C25H29N5O4 MS Calcd. : 463.53; MS Found: 464.1 [M+H ⁺ ],

[0001407] NMR (400 MHz, CD3OD) δ 7.22 - 7.31 (m, 1 H), 7.11 - 7.18 (m, 1 H), 7.00 - 7.06 (m, 1 H), 6.51 (d ,J= 7.63 Hz, 1 H), 4.93 - 5.01 (m, 2 H), 4.16 - 4.34 (m, 1 H), 3.93 (s, 3 H), 3.24 - 3.29 (m, 1 H), 2.45 - 2.67 (m, 1 H), 2.25 - 2.38 (m, 2 H), 2.00 - 2.17 (m, 2 H), 1.76 - 1.95 (m, 3 H), 1.60 - 1.71 (m, 1 H), 1.27 - 1.45 (m, 3 H), 0.74 (br d, J= 5.00 Hz, 1 H), 0.13 - 0.38 (m, 2 H).

Example 174. Synthesis of viral protease inhibitor compound 590

Step 2: Methyl (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo-l-pyridyl)propa noate

[0001408] 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 N ₂ . The mixture was quenched with H ₂ O (20 mL), and extracted with ethyl acetate (50 mL * 3). The combined organic layers was washed with brine (40 mL) dried over Na ₂ SO ₄ , 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.

[0001409] LCMS: Rt = 0.785 min; for CnHieN ₂ Os MS Calcd. : 280.11; MS Found: 281.1 [M+H ⁺ ],

Step 3: (2S)-3-cyclopropyl-2-(4-methyl-3-intro-2-oxo-l-pyridyl)propa noic acid

[0001410] 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.H ₂ O (519.2 mg, 12.37 mmol, 4 eq) in THF (6 mL), MeOH (2 mL), H ₂ O (2 mL) was degassed and purged with N ₂ for 3 times, and then the mixture was stirred at 25 °C for 1 h under N ₂ atmosphere. LCMS showed one peak with desired MS was detected. The mixture was added H ₂ O (5 mL), and then the mixture was added 2 M HC1 (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 Na ₂ SO ₄ , 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.

[0001411 ] LCMS: Rt = 0.735 min; for C ₁₂ H ₁₄ N ₂ O5 MS Calcd. : 266.09; MS Found: 267.0 [M+H ⁺ ],

Step 4: N-f ( l S)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl ]ethyl ]-3-cyclopropyl-2-( 4-methyl-3- nitro-2-oxo-l-pyridyl)propanamide

[0001412] To a solution of (2S)-3-cyclopropyl-2-(4-methyl-3-nitro-2-oxo- 1 - pyridyl)propanoic acid (791 mg, 2.97 mmol, 1 eq) in DCM (10 mL) was added HATU (1.36 g, 3.57 mmol, 1.2 eq), DIPEA (1.15 g, 8.91 mmol, 1.55 mL, 3 eq) and (2S)-2- amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile (676.0 mg, 3.57 mmol, 1.2 eq,

HC1). The mixture was stirred at 25 °C for 2 h. The mixture was quenched with H ₂ O (20 mL) and extracted with DCM (40 mL * 3). The combined organic layers was washed with brine (20 mL) dried over Na ₂ SO ₄ , filtered and concentrated under reduce pressure. The residue was purified by flash silica gel chromatography (ISCO®; 24 g SepaFlash® Silica Flash Column, Eluent of 0-10% DCM/MeOH ethergradient @ 35 mL/min) to give N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-3-cyclop ropyl-2-(4-methyl-3-nitro- 2-oxo- 1 -pyridyl)propanamide (838 mg, 64.5% yield) as a yellow oil.

[0001413] LCMS: Rt = 0.741 min; for C19HZ3N5O5 MS Calcd.: 401.17; MS Found: 402.1 [M+H ⁺ ],

Step 5: 2-(3-Amino-4-methyl-2-oxo-l-pyridyl)-N-[(lS)-l-cyano-2-[(3S) -2-oxopyrrolidin-3- yl ] ethyl / -3-cyclopropyl-propanamide

[0001414] 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 H ₂ . The mixture was filtered and concentrated under reduce pressure to give 2-(3-amino-4-methyl-2-oxo- 1 -pyridyl)-N-[( IS)- 1 -cyano-2-[(3S)- 2-oxopyrrolidin-3-yl]ethyl]-3-cyclopropyl-propanamide (616 mg, 1.43 mmol, 68.7% yield, 86.5% purity) as a white solid.

[0001415] LCMS : Rt = 0.703 min; for C19HZ5N5O3 MS Calcd. : 371.20; MS Found: 372.1 [M+H ⁺ ],

Step 6: tert-Butyl N-[l-[2-[[(lS)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]am ino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-methyl-2-oxo-3-pyridyl]ca rbamate

[0001416] 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 Boc ₂ O (1 mL) and THF (1 mL), and then the mixture was stirred at 66 °C for 16 h under N ₂ atmosphere. The mixture was concentrated under reduce pressure. The mixture was quenched with H ₂ O (20 mL), and extracted with ethyl acetate (30 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , 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% NH ₃ H ₂ O+lO mM NH4HCO3)- ACN] ;B% : 26%-56%,7.8 min) to give tert-butyl N-[l-[2-[[(1S)-l -cyano- 2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmeth yl)-2-oxo-ethyl]-4-methyl- 2-oxo-3-pyridyl]carbamate (44.33 mg, 33.5% yield) as a white solid.

[0001417] LCMS: Rt = 0.798 min; for C34H51N5O10 MS Calcd.: 471.55; MS Found: 472.2 [M+H ⁺ ],

[0001418] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.53 (dd, J=1.5, 7.3 Hz, 1H), 6.36 - 6.27 (m, 1H), 5.56 - 5.35 (m, 1H), 5.18 - 4.97 (m, 1H), 3.35 - 3.32 (m, 1H), 3.29 - 3.25 (m, 1H), 2.52 (tq, J=4.8, 9.3 Hz, 1H), 2.45 - 2.22 (m, 2H), 2.18 (d, J=5.0 Hz, 3H), 2.06 - 1.92 (m, 2H), 1.91 - 1.71 (m, 2H), 1.48 (d,J=2.5 Hz, 9H), 0.69 - 0.56 (m, 1H), 0.50 - 0.37 (m, 2H), 0.19 - 0.01 (m, 2H).

Example 175. Synthesis of viral protease inhibitor compound 591

[0001419] tert-Butyl N-[l-[2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]am ino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methyl-2-oxo-3-pyridyl]ca rbamate (42 mg, 89.0 umol, 1 eq) was further separated by SFC (condition: column: DAICEL CHIRALPAK AD(250 mm * 30 mm, 10 um);mobile phase: [0.1% NH3H ₂ O ETOH];B%: 45%-45%, min) to afford tert- butyl N-[ 1 -[( 1R)-2-[[( 1 S)- 1 -cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methyl- 2-oxo-3-pyridyl]carbamate (8.32 mg, 19.8% yield) as a white solid.

[0001420] Isomer 1 : LCMS: Rt = 0.803 min; for C34H51N5O10 MS Calcd. : 471.55; MS Found: 472.2 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 7.53 (d, J=7.3 Hz, 1H), 6.32 (d, J=7.3 Hz, 1H), 5.50 (t, J=7.8 Hz, 1H), 5.01 (dd, J=7.0, 9.0 Hz, 1H), 3.35 - 3.32 (m, 1H), 2.56 - 2.45 (m, 1H), 2.42 - 2.23 (m, 2H), 2.19 (s, 3H), 2.00 - 1.92 (m, 2H), 1.92 - 1.78 (m, 2H), 1.49 (s, 9H), 0.65 - 0.55 (m, 1H), 0.46 - 0.36 (m, 2H), 0.20 - 0.01 (m, 2H).

[0001421] Isomer 2: LCMS: Rt = 0.794 min; for C34H51N5O10 MS Calcd. : 471.55; MS Found: 472.2 [M+H ⁺ ], ¹ H NMR (400 MHz, CD3OD) δ 7.53 (d, J=7.0 Hz, 1H), 6.31 (d, J=7.3 Hz, 1H), 5.41 (t,J=7.8 Hz, 1H), 5.10 - 4.97 (m, 1H), 3.30 - 3.25 (m, 2H), 2.52 (dq, J=5.5, 9.2 Hz, 1H), 2.33 - 2.19 (m, 2H), 2.18 (s, 3H), 2.05 - 1.90 (m, 2H), 1.89 - 1.71 (m, 2H), 1.48 (s, 9H), 0.70 - 0.58 (m, 1H), 0.52 - 0.35 (m, 2H), 0.20 - 0.04 (m, 2H).

Example 176. Synthesis of viral protease inhibitor compound 611

[0001422] 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, HC1) 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 H ₂ O (10 mL), and extracted with ethyl acetate (20 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , 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-car boxylate (100 mg, 60.4% yield) as a white solid.

[0001423] LCMS: Rt = 0.826 min; for C25H35N3O6 MS Calcd. : 473.25; MS Found: 474.1 [M+H ⁺ ],

Step 2: Methyl (2S)-3-[ (3S)-2-oxo-3-piperidyl ]-2-[ [ (2S, 4S)-4-phenylpyrrolidine-2- carbonyl ] amino ]propanoate [0001424] 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-car boxylate (90 mg, 0.17 mmol, 1 eq, HC1) in 2 M HCl/EtOAc (6 mL), and then the mixture was stirred at 25 °C for 3 h under N ₂ atmosphere. 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-c arbonyl]amino]propanoate (70 mg, 83.3% yield, HC1) was obtained as a yellow solid.

Step 3: Methyl (2S)-2-[[(2S,4S)-l-(4-methoxy-lH-indole-2-carbonyl)-4-phenyl - pyrrolidine-2-carbonyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001425] 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 -piperidy 1 ]-2- [[(2S,4S)-4-phenylpyrrolidine-2-carbonyl]amino]propanoate (58 mg, 0.14 mmol, 1 eq,

HC1) 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 H ₂ O (20 mL) and then extracted with ethyl acetate (30 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , 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.

[0001426] LCMS: Rt = 1.730 min; for C30H34N4O6 MS Calcd. : 546.25; MS Found: 547.1 [M+H ⁺ ],

Step 4: (2S, 4S)-N-[ ( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ] ethyl ]-1-( 4- methoxy-lH-indole-2-carbonyl)-4-phenyl-pyrrolidine-2-carboxa mide

[0001427] To a solution of methyl (2S)-2-[[(2S,4S)-1-(4-methoxy-lH-indole-2-carbonyl)- 4-phenyl-pyrrolidine-2-carbonyl]amino]-3-[(3 S)-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-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]-l -(4-methoxy- 1 H- indole-2-carbonyl)-4-phenyl-pyrrolidine-2-carboxamide (29 mg, 99.40% yield) as a yellow solid.

Step 5: (2S, 4S)-N-[ ( lS)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl ]-1-(4-methoxy- JH-indole-2- carbonyl)-4-phenyl-pyrrolidine-2-carboxamide

[0001428] To a solution of (2S,4S)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2-oxo-3- piperidy 1 ]methy 1 ]ethy 1 ]- 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 H ₂ O (5 mL), and extracted with ethyl acetate (10 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , 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.

[0001429] LCMS: Rt = 1.730 min; for C30H34N4O6 MS Calcd. : 546.25; MS Found: 547.1 [M+H ⁺ ],

[0001430] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.38 - 7.31 (m, 1H), 7.30 - 7.23 (m, 4H), 7.19 - 7.13 (m, 1H), 7.10 - 7.04 (m, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.41 (br d, J=7.5 Hz, 1H), 5.17 - 5.02 (m, 1H), 4.43 - 4.20 (m, 1H), 3.96 - 3.76 (m, 4H), 3.74 - 3.41 (m, 1H), 3.18 - 3.11 (m, 1H), 3.01 - 2.55 (m, 2H), 2.51 - 2.20 (m, 3H), 2.15 - 1.62 (m, 4H), 1.55 - 1.27 (m,

2H).

Example 177. Synthesis of viral protease inhibitor compound 619 Step 1: N-[ ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-5-methoxy-lH-indole-2-carbo xamide

[0001431 ] 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- 1 H-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 H ₂ O (10 mL) and extracted with ethyl acetate (25 mL * 3). The combined organic layers were washed with Brine (10 mL* 3 ) , dried over Na2S04, 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-lH-indole-2-carboxamide (180.0 mg, 94.6% yield) was obtained as a white solid.

Step 2: N-f ( l S)-2-[[ ( l S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-5-methoxy-lH-indole-2-carbo xamide [0001432] 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-et hyl]-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 H ₂ O (5 mL) and extracted with DCM (10 mL *3). The combined organic layers were washed with Brine (5 mL*3), dried over Na ₂ SO ₄ , 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% NH ₃ H ₂ O+lO mMNH ₄ HCO ₃ )-ACN]; B%: 24%-54%, 7.8 min). Compound N-[(1S)-2- [[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyc lopropylmethyl)-2-oxo- ethyl]-5-methoxy-1H-indole-2-carboxamide (37.3 mg, 82.6 umol, 5.4 yield) was obtained as a white solid. [0001433] LCMS: Rt = 0.785 min; for C24H29N5O4 MS Calcd. : 451.52; MS Found: 452.1 [M+H ⁺ ],

[0001434] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.32 (d, J=8.8 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.89 (dd, J=2.4, 8.9 Hz, 1H), 5.16 - 5.10 (m, 1H), 4.55 (t, J=7.4 Hz, lH), 3.81 (s, 3H), 3.26 - 3.20 (m, 2H), 2.54 - 2.41 (m, 2H), 2.04 - 1.85 (m, 3H), 1.84 - 1.77 (m, 1H), 1.74 - 1.62 (m, 2H), 1.56 - 1.47 (m, 1H), 0.95 - 0.79 (m, 1H), 0.60 - 0.47 (m, 2H), 0.19 (br dd, J=4.8, 10.0 Hz, 2H).

Example 178. Synthesis of viral protease inhibitor compound 621

Step 1 : (2S)-2-amino-N-[ ( l S)-2-amino-2-oxo-l-[ [ ( 3S)-2-oxo-3-piperidyl ] me thy l ] ethyl ]-3- cyclopropyl-propanamide

[0001435] To a solution of benzyl N-[( 1 S)-2-[ [( 1 S)-2-amino-2-oxo- 1 -[ [(3S)-2-oxo-3 - piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]carbamate (400 mg, 0.92 mmol, 1 eq) in MeOH (5 mL) was added Pd (200 mg, 10% purity) and H ₂ (0.92 mmol) The mixture was stirred at 25 °C under 15psi 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-[( 1 S)-2-amino-2- oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-p ropanamide (274 mg, 99.5% yield) as a white solid.

Step 2: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl ]-5-methoxy-lH-pyrrolo[ 3, 2-b ]pyridine-2-carboxamide

[0001436] To a solution of (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (137 mg, 0.46 mmol, 1 eq) and 5- methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (88.8 mg, 0.46 mmol, 1 eq) in DMF (2 mL) was added DIPEA (119.4 mg, 0.92 mmol, 0.16 mL, 2 eq) and HATU (210.9 mg, 0.55 mmol, 1.2 eq). The mixture was stirred at 25 °C for 1 h . LCMS showed one peak with desired MS was detected. The mixture was 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 Compound N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-5-methoxy-1H- pyrrolo[3,2-b]pyridine-2-carboxamide (144 mg, 63.1% yield) as a white solid.

[0001437] LCMS: Rt = 0.675 min; for C23H ₃ 0N ₆ 05 MS Calcd. : 470.23; MS Found: 471.1 [M+H ⁺ ],

Step 3: N-f ( l S)-2-[[ ( l S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl ]-5-methoxy-lH-pyrrolo[ 3, 2-b ]pyridine-2-carboxamide

[0001438] 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-et hyl]-5-methoxy-1H- pyrrolo[3,2-b]pyridine-2-carboxamide (44 mg, 93.5 umol, 1 eq) in DCM (1 mL) was added Burgess reagent (66.86 mg, 0.28 mmol, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hr. LCMS showed one peak with desired MS was detected. The mixture was quenched with H ₂ O (10 mL), and extracted with DCM (20 mL * 3). The combined organic layers was washed with brine (10 mL) dried over Na ₂ SO ₄ , 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% NH ₃ H ₂ O+lO mM NH4HCO3)- ACN] ;B% : 23%-53%, 7.8 min) to give compound N-[(1S)-2-[[(1S)-1- cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylm ethyl)-2-oxo-ethyl]-5- methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxamide (12.08 mg, 9.3% yield) as a white solid.

[0001439] LCMS: Rt = 0.727 min; for C23H ₂ 8N6O4 MS Calcd. : 452.22; MS Found: 453.1 [M+H ⁺ ],

[0001440] ¹ H NMR (400 MHz, CD ₃ OD) δ7.79 - 7.74 (m, 1H), 7.17 (s, 1H), 6.72 (d, J=9.0 Hz, 1H), 5.17 - 5.04 (m, 1H), 4.56 (t, J=7.4 Hz, 1H), 3.97 - 3.96 (m, 1H), 3.95 (s, 2H), 3.26 - 3.19 (m, 2H), 2.56 - 2.40 (m, 2H), 2.02 - 1.87 (m, 3H), 1.85 - 1.78 (m, 1H), 1.76 - 1.63 (m, 2H), 1.59 - 1.46 (m, 1H), 0.90 - 0.77 (m, 1H), 0.59 - 0.46 (m, 2H), 0.27 - 0.07 (m, 2H). Example 179. Synthesis of viral protease inhibitor compound 623

Step 1: Methoxy-lH-pyrrolo[3,2-c]pyridine-2-carboxylic acid

[0001441] To a solution of methyl 4-methoxy- lH-pyrrolo[3,2-c]pyridine-2-carboxylate (150 mg, 0.72 mmol, 1 eq) in THF (1 mL) was added LiOH.H ₂ O (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 H ₂ O (30 mL) and extracted with DCM (30 mL *3). The aqueous layer acidified with concentrated HC1 and extracted with DCM. The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ , 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- lH-pyrrolo[3, 2- c]pyridine-2-carboxylic acid (120 mg, 84.9% yield, 99% purity) was obtained as white solid.

Step 2: N-f ( l S)-2-[[( 1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ] methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-pyrrolo[3,2-c] pyridine-2-carboxamide

[0001442] A solution of (2S)-2-amino-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (150 mg, 0.50 mmol, 1 eq) in DMF (1 mL) was added HATU (192.4 mg, 0.50 mmol, 1 eq), 4-methoxy- 1 H-pyrrolo[3 ,2- c]pyridine-2-carboxylic acid (106.9 mg, 0.55 mmol, 1.1 eq) and DIEA (130.8 mg, 1.01 mmol, 0.17 mL, 2 eq) was stirred at 25 °C for 16 hr. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate (30 mL *3). The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. 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-pyrrolo[3,2-c]pyridine-2-carboxamide (110 mg, crude) was obtained as white solid.

Step 3: N-f ( l S)-2-[[ ( l S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-pyrrolo[3,2-c] pyridine-2-carboxamide

[0001443] 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]-4-methoxy- 1 H- pyrrolo[3,2-c]pyridine-2-carboxamide (110 mg, 0.23 mmol, 1 eq) in DCM (1 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (167.1 mg, 0.70 mmol, 3 eq). The mixture was stirred at 25 °C for 24 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL *3). The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ , 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% NH3H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN];B%: 15%-45%,9.5 min). Compound N-[( 1 S)-2-[[( 1 S)- 1 -cyano-2- [(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2 -oxo-ethyl]-4-methoxy- 1H-pyrrolo[3,2-c]pyridine-2-carboxamide (40.69 mg, 38.4% yield, 100% purity) was obtained as white solid.

[0001444] LCMS : Rt = 1.387 min; for C ₂ 3H ₂ 8N6O ₄ MS Calcd. : 452.51; MS Found: 453.1 [M+H ⁺ ],

[0001445] ¹ H NMR (400 MHz, CD3OD) δ 7.77 (d ,J= 6.0 Hz, 1H), 7.34 (s, 1H), 7.05 (d, J = 6.3 Hz, 1H), 4.47 (dd, J= 4.0, 11.8 Hz, 1H), 4.57 (dd, J= 6.0, 8.3 Hz, 1H), 4.05 (s,

3H), 3.28 - 3.17 (m, 2H), 2.47 - 2.35 (m, 1H), 2.28 (ddd, J= 4.4, 12.0, 14.0 Hz, 1H), 2.08 - 1.95 (m, 1H), 1.90 - 1.77 (m, 3H), 1.77 - 1.63 (m, 2H), 1.62 - 1.48 (m, 1H), 0.96 - 0.78 (m, 1H), 0.59 - 0.42 (m, 2H), 0.26 - 0.11 (m, 2H).

Example 180. Synthesis of viral protease inhibitor compound 625

Step 1: (2S)-2-(benzyloxycarbonylamino)-3-cyclopropyl-propanoic acid

[0001446] A solution of (2S)-2-amino-3-cyclopropyl-propanoic acid (5 g, 38.71 mmol, 1 eq) was added NaOH (1 M, 135.4 mL, 3.5 eq) and benzyl carbonochloridate (8.5 g, 50.33 mmol, 7.1 mL, 1.3 eq) was stirred at 25 °C for 2 hr. TLC (petroleum ether/ethyl acetate = 1:1, PMA). The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL *3). The aqueous layer acidified with concentrated HC1 and extracted with DCM. The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Compound (2S)-2-(benzyloxycarbonylamino)-3-cyclopropyl-propanoic acid (7.7 g, 68.1% yield, 90% purity) was obtained as white solid.

Step 2: (S)-methyl2-((S)-2-(((benzyloxy)carbonyl)amino)-3-cyclopropy lpropanamido)-3-((S)- 2-oxopiperidin-3-yl)propanoate

[0001447] To a solution of (2S)-2-(benzyloxycarbonylamino)-3-cyclopropyl-propanoic acid (3.5 g, 13.29 mmol, 1 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3- piperidyl]propanoate (3.15 g, 13.29 mmol, 1 eq, HCl)in DMF (60 mL) was added TEA (4.04 g, 39.88 mmol, 5.55 mL, 3 eq) and T3P (8.46 g, 13.29 mmol, 7.91 mL, 50% purity,

1 eq). The mixture was stirred at 25 °C for 2 hr. TLC (petroleum ether/ethyl acetate =

0:1, 12). LCMS detected desired compound. The reaction mixture was added H ₂ O (10 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , 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 0-100% ethyl acetate/petroleum ether gradient @ 40 mL/min). Compound methy 1(2 S)-2-[ [(2 S)-2- (benzyloxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[( 3S)-2-oxo-3- piperidyl]propanoate (4.5 g, 9.49 mmol, 71.4% yield, 94% purity) was obtained as a colorless oil.

Step 3: benzyl((S)-1-(((S)-1-amino- J-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl-l-oxopropan-2-yl)carbamate

[0001448] To a stirred solution of methyl (2 S)-2-[ [(2 S)-2-(benzy loxy carbony lamino)-3 - cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate (4.5 g, 10.10 mmol, 1 eq) in MeOH (10 mL) was added with a solution ofNH ₃ (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, Iz). 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-(cyclopropylm ethyl)-2-oxo- ethyl]carbamate (3.6 g, 7.69 mmol, 76.17% yield, 92% purity) was obtained as a white solid.

Step 4: (S)-2-amino-N-((S)-l-amino-l-oxo-3-((S)-2-oxopiperidin-3-yl) propan-2-yl)-3- cyclopropylpropanamide

[0001449] To a solution of benzyl N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]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 H ₂ (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]met hyl]ethyl]-3- cyclopropyl-propanamide (550 mg, 1.86 mmol, 99.87% yield) was obtained as colorless oil.

Step 5: N-( (S)-l-( ( (S)-l -amino- l-oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-lH-pyrrolo[ 3, 2-c ] pyridine-2 -carboxamide

[0001450] A mixture of lH-pyrrolo[3,2-c]pyridine-2-carboxylic acid (90.2 mg, 0.55 mmol, 1.1 eq), HATU (288.6 mg, 0.75 mmol, 1.5 eq) and DIPEA (196.2 mg, 1.52 mmol, 0.26 mL, 3 eq) in DMF (2 mL) was stirred at 25 °C for 0.5 h, and then (2S)-2-amino-N- [(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl] -3-cyclopropyl- propanamide (150 mg, 0.50 mmol, 1 eq) was added into the reaction. The resulting mixture was stirred 25 °C for 2 hr. TLC (DCM/MeOH = 5:1, UV 254) indicated starting material was consumed completely and new spots formed. LCMS detected desired compound. The reaction mixture was added H ₂ O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , 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 0-20% MeOH/ DCM @ 30 mL/min). Compound N- [(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]meth yl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-pyrrolo[3,2-c]pyridine-2 -carboxamide (200 mg, 0.43 mmol, 86.1% yield, 96% purity) was obtained as a white solid.

Step 6: N-( (S)-l-( ( (S)-l-cyano-2-( (S)-2-oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl-l- oxopropan-2-yl)-lH-pyrrolo[3,2-c]pyridine-2-carboxamide

[0001451 ] 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-et hyl]-lH-pyrrolo[3,2- c]pyridine-2-carboxamide (120 mg, 0.27 mmol, 1 eq) in DCM (10 mL) was added Burgess reagent (194.7 mg, 0.81 mmol, 3 eq). The mixture was stirred at 25 °C for 16 h under N ₂ . LCMS detected desired compound. The reaction mixture was added H ₂ O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , 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% NH ₃ H ₂ O+lO mM NH ₄ HCO ₃ )-ACN];B%: 7%-37%,9.5 min) to give -20 mg crude product. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water (0.05% ammonia hydroxide v/v)-MeOH];B%: 0%-60%,7.8 min). Compound N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-pyrrolo[3,2-c]pyridine-2 -carboxamide (2.37 mg,

5.4 umol, 1.9% yield, 96.8% purity) was obtained as a white solid.

[0001452] LCMS: Rt = 1.321 min; for C22H ₂ 6N6O3 MS Calcd. : 422.48; MS Found: 423.1 [M+H ⁺ ], [0001453] ¹ H NMR (400 MHz, CD ₃ OD) δ 9.03 (s, 1 H), 8.43 (br d ,J= 6.27 Hz, 1 H), 8.25 (d ,J= 6.27 Hz, 1 H), 7.14 - 7.26 (m, 1 H), 5.16 (t, J= 8.16 Hz, 1 H), 4.64 (br d ,J= 2.01 Hz, 1 H), 3.25 - 3.29 (m, 2 H), 2.41 - 2.60 (m, 2 H), 1.93 - 2.09 (m, 2 H), 1.71 - 1.91 (m, 4 H), 1.49 - 1.63 (m, 1 H), 0.88 (br s, 1 H), 0.46 - 0.53 (m, 2 H), 0.12 - 0.26 (m, 2 H).

Example 181. Synthesis of viral protease inhibitor compound 669

Step 1: 4-chloro-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid

[0001454] To a solution of ethyl 4-chloro-lH-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.H ₂ O (280.2 mg, 6.68 mmol, 5 eq) and H ₂ O (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 HC1, filtered, and then the cake concentrated under reduced pressure to give a residue. 4-chloro-lH- pyrrolo[2,3-c]pyridine-2-carboxylic acid (190 mg, 0.96 mmol, 72.3% yield) was obtained as a white solid.

Step 3: N-( (S)-l-( ( (S)-l -amino- l-oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl) -4 -chloro- lH-pyrrolo[ 2, 3-c]pyridine-2-carboxamide

[0001455] To a solution of 4-chloro-lH-pyrrolo[2,3-c]pyridine-2-carboxylic acid (70 mg, 0.35 mmol, 1 eq) and (2 S)-2-amino-N-[( 1 S)-2-ami no-2-oxo- 1 -[ [(3 S)-2-oxo-3 - piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (105.5 mg, 0.35 mmol, 1 eq) in DMF (2 mL) was added T3P (226.5 mg, 0.35 mmol, 0.21 mL, 50% purity, 1 eq) and TEA (108.0 mg, 1.07 mmol, 0.14 mL, 3 eq). The mixture was stirred at 25 °C for 2 h. TLC (DCM/MeOH = 5:1, UV 254). The reaction mixture was added with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ 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 0-15% MeOH/DCM @ 30 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]-4-chloro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (80 mg, 0.16 mmol, 46.8% yield, 99% purity) was obtained as a white solid.

Step 3: 4-chloro-N-((S)-l-(((S)-l-cyano-2-((S)-2-oxopiperidin-3-yl)e thyl)amino)-3- cyclopropyl-1-oxopropan-2-yl)-JH-pyrrolo[ 2, 3-c ]pyridine-2-carboxamide

[0001456] To a solution of N-[(l S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-chloro-lH- pyrrolo[2,3-c]pyridine-2-carboxamide (60 mg, 0.12 mmol, 1 eq) in DCM (2 mL) was added Burgess (60.2 mg, 0.25 mmol, 2 eq). The mixture was stirred at 25 °C for 16 h under N ₂ . The reaction mixture was added with H ₂ O (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-MeOH ]; B%: 53%-83%,7.8 min). Compound 4-chloro-N-[( 1 S)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-lH-pyrrolo[2,3-c]pyridine-2 -carboxamide (9.41 mg, 19.8 umol, 15.7% yield, 96.6% purity) was obtained as a white solid.

[0001457] LCMS: Rt = 1.895 min; for CzzH ₂ sCINeCh MS Calcd.: 456.93; MS Found: 457.1 [M+H ⁺ ],

[0001458] ¹ H NMR (400 MHz, CD ₃ OD) δ 8.72 (s, 1 H), 8.13 (s, 1 H), 7.35 - 7.39 (m, 1 H),

5.14 (dd,J= 10.04, 6.02 Hz, 1 H), 4.56 (t ,J= 7.53 Hz, 1 H), 3.22 - 3.28 (m, 2 H), 2.40 - 2.57 (m, 2 H), 1.88 - 2.05 (m, 3 H), 1.82 (td, J= 9.16, 4.27 Hz, 1 H), 1.68 (dd,J= 14.43,

7.15 Hz, 1 H), 1.47 - 1.58 (m, 1 H), 1.31 (t, J= 7.28 Hz, 1 H), 0.80 - 0.91 (m, 1 H), 0.48 - 0.57 (m, 2 H), 0.15 - 0.26 (m, 2 H).

Example 182. Synthesis of viral protease inhibitor compound 633 Step 1: N-[ ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-5-chloro-lH-indole-2-carbox amide

[0001459] 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 H ₂ O (10 mL) and extracted with ethyl acetate (25 mL * 3). The combined organic layers were washed with Brine (10 mL), dried over Na ₂ SO ₄ , 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-et hyl]-5-chloro-1H-indole- 2-carboxamide (150.0 mg, 90.9% yield) was obtained as a yellow solid.

Step 2: 5-chloro-N-[ ( l S)-2-[[( l S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl ]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[0001460] 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-et hyl]-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 H ₂ O (15 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , 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%NH ₃ H _Z O+10 mMNH ₄ HCO ₃ )-ACN]; B%: 31%-61%, 7.8 min). Compound 5- chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]et hyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide (40.2 mg, 30.2% yield) was obtained as a white solid. [0001461 ] LCMS: Rt = 0.832 min; for C23H26CIN5O3 MS Calcd. : 455.94; MS Found: 456.1 [M+H ⁺ ],

[0001462] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (d, J=1.8 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.19 (dd, J=2.0, 8.8 Hz, 1H), 7.14 (s, 1H), 5.13 (br dd, J=6.1, 10.2 Hz, 1H), 4.57 - 4.52 (m, 1H), 3.24 - 3.20 (m, 1H), 2.56 - 2.40 (m, 2H), 2.05 - 1.84 (m, 4H), 1.80 - 1.59 (m, 3H), 1.57 - 1.42 (m, 1H), 0.85 (br s, 1H), 0.54 (br d, J=8.3 Hz, 2H), 0.19 (br dd, J=5.1, 9.9 Hz, 2H).

Example 183. Synthesis of viral protease inhibitor compound 635

Step 1 : (2S)-2-amino-N-[ ( l S)-2-amino-2-oxo-l-[ [ ( 3S)-2-oxo-3-piperidyl ] methyl ] ethyl ]-3- cyclopropyl-propanamide

[0001463] To a solution of benzyl N-[( 1 S)-2-[ [( 1 S)-2-amino-2-oxo- 1 -[ [(3S)-2-oxo-3 - piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]carbamate (400 mg, 0.92 mmol, 1 eq) in MeOH (5 mL) was added Pd (200 mg, 10% purity) and H ₂ (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]met hyl]ethyl]-3-cyclopropyl- propanamide (274 mg, 0.92 mmol, 99.5% yield) as a white solid.

Step 2: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-lH-indole-2-carbox amide [0001464] To a solution of (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (137 mg, 0.46 mmol, 1 eq) and 6- chloro-1H-indole-2-carboxylic acid (90.4 mg, 0.46 mmol, 1 eq) in DMF (2 mL) was added DIPEA (119.4 mg, 0.92 mmol, 0.16 mL, 2 eq) and HATU (210.9 mg, 0.55 mmol, 1.2 eq). The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduce pressure, and 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 giveN-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-6-chloro-1H-indole- 2-carboxamide (200 mg, 89.0% yield) as a white solid.

[0001465] LCMS: Rt = 0.780 min; for C23H28CIN5O4 MS Calcd. : 473.18; MS Found: 474.1 [M+H ⁺ ],

Step 3: 6-Chloro-N-[ ( 1 S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl ]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-1H-indole-2-carboxamide

[0001466] 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-et hyl]-6-chloro-1H-indole- 2-carboxamide (47.5 mg, 0.1 mmol, 1 eq) in DCM (1 mL) was added Burgess reagent (71.6 mg, 0.3 mmol, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduce pressure, and the residue was purified by prep- HPLC (column: Phenomenex Gemini-NX 80 * 40 mm * 3 um; mobile phase: [water(0.05% NH3H20+10 mM NH4HCO3)- ACN] ;B% : 31%-61%,7.8 min) to give 6-chloro-N-[(1S)-2- [[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyc lopropylmethyl)-2-oxo- ethyl]-1H-indole-2-carboxamide(64.33 mg, 34.7% yield) as a white solid.

[0001467] LCMS: Rt = 0.832 min; for C23H26CIN5O3; MS Calcd. :455.17; MS Found: 456.1 [M+H ⁺ ],

[0001468] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.73 (br s, 1H), 8.95 (br d, J=8.0 Hz, 1H), 8.66 (br d, J=7.5 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.53 (br s, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 7.05 (dd, J=1.8, 8.5 Hz, 1H), 5.11 - 4.96 (m, 1H), 4.52 - 4.42 (m, 1H), 3.09 (br s, 2H), 2.34 - 2.21 (m, 2H), 1.89 - 1.75 (m, 3H), 1.74 - 1.65 (m, 1H), 1.56 (br s, 1H), 1.51 - 1.29 (m, 2H), 0.79 (br s, 1H), 0.42 (br d, J=7.0 Hz, 2H), 0.23 - 0.01 (m, 2H).

Example 184. Synthesis of viral protease inhibitor compound 637

Step 1: 4, 7-Dichloro-2-(trichloromethyl)-lH-benzimidazole

[0001469] To a solution of 3, 6-di chlorobenzene- 1,2-diamine (0.3 g, 1.69 mmol, 1 eq) in AcOH (12.57 g, 209.2 mmol, 11.97 mL, 123.8 eq) was added methyl 2,2,2- trichloroacetimidate (313.0 mg, 1.77 mmol, 0.21 mL, 1.05 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h. LC-MS showed 48% of 1 was remained and 43% of desired compound was detected. The reaction mixture was diluted with H ₂ O (40 mL) and filtered to give 2 (300 mg, crude) as a white solid.

Step 2: 4, 7-Dichloro-lH-benzimidazole-2-carboxylic acid

[0001470] To a solution ofNaOH (0.8 g, 20.0 mmol, 20.2 eq) in H ₂ O (10 mL) was added 4,7-dichloro-2-(trichloromethyl)-lH-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 HC1 (2 M) to 2-3 and then the mixture was filtered to give 4,7-dichloro-lH- benzo[d]imidazole-2-carboxylic acid (0.2 g, crude) as a white solid.

Step 3: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4,6-dichloro-lH-benzimidazo le-2-carboxamide

[0001471 ] To a solution of (S)-2-amino-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)-3-cyclopropylpropanamide (130 mg, 0.43 mmol, 1 eq) and 4,7-dichloro- lH-benzo[d]imidazole-2-carboxylic acid (101.3 mg, 0.43 mmol, 1.0 eq) in DMF (3 mL) was added HATU (250.1 mg, 0.65 mmol, 1.5 eq) and DIPEA (113.3 mg, 0.87 mmol, 0.15 mL, 2.0 eq). The mixture was stirred at 25 °C for 1 h. TLC (Dichloromethane: Methanol=10/1, UV). The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/l to 10/1) to give N-((S)-1-(((S)-1 -amino- l-oxo-3-((S)-2- oxopiperidin-3-yl)propan-2-yl)amino)-3-cyclopropyl-1-oxoprop an-2-yl)-4,7-dichloro-lH- benzo[d]imidazole-2-carboxamide (0.2 g, 0.39 mmol, 89% yield) as a white solid.

Step 4: 4, 7-dichloro-N-[(lS)-2-[[(lS)-l-cyano-2-[(3S)-2-oxo-3-piperidy l]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-benzimidazole-2-carboxam ide

[0001472] To a solution of N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4,7-di chloro-lH- benzo[d]imidazole-2-carboxamide (100.00 mg, 0.19 mmol, 1 eq) in DCM (3.0 mL) was added Burgess reagent (140.3 mg, 0.58 mmol, 3.0 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was 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% NH3H ₂ O+IO mM NH4HC03)-ACN]; B%: 20%-50%, 7.8 min) to give compound 637 (22.11 mg, 22% yield) as a white solid.

[0001473] LCMS: Rt = 0.824 min; for C ₂₂ H ₂₄ CI ₂ N6O3 MS Calcd. : 490.13; MS Found: 491.1 [M+H ⁺ ],

[0001474] ¹ H NMR (400 MHz, CD3OD) δ 7.30 (s, 2H), 5.22 - 5.09 (m, 1H), 4.60 (t,J= 7.1 Hz, 1H), 3.27 - 3.19 (m, 2H), 2.56 - 2.37 (m, 2H), 2.06 - 1.88 (m, 3H), 1.87 - 1.79 (m, 1H), 1.73 (td, J= 7.2, 14.0 Hz, 2H), 1.60 - 1.44 (m, 1H), 0.96 - 0.75 (m, 1H), 0.54 (d, J= 6.9 Hz, 2H), 0.21 (dd, J= 4.8, 10.4 Hz, 2H).

Example 185. Synthesis of viral protease inhibitor compound 639

Step 1: N-[ ( l S)-2-[[( 1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-7-chloro-lH-indole-2-car boxamide

[0001475] To a solution of (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (70 mg, 0.23 mmol, 1 eq) in DMF (1 mL) was added HATU (89.8 mg, 0.23 mmol, 1 eq), 7-chloro-lH-indole-2-carboxylic acid (50.8 mg, 0.25 mmol, 1.1 eq) and DIEA (61.0 mg, 0.47 mmol, 82.2 uL, 2 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate (30 mL *3). The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ 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% NH3H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN];B%: 16%-46%,9.5 min). Compound N-[( 1 S)-2-[[( 1 S)-2-amino-2- oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclop ropylmethyl)-2-oxo-ethyl]- 7-chloro-1H-indole-2-carboxamide (67 mg, 0.12 mmol, 53.8% yield, 90% purity) was obtained as a white solid.

Step 2: 7-chloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[0001476] 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-et hyl]-7-chloro-1H-indole- 2-carboxamide (60 mg, 0.12 mmol, 1 eq) in DCM (1 mL) was added methoxycarbonyl- (triethylammonio)sulfonyl-azanide (90.5 mg, 0.37 mmol, 3 eq). The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL *3). The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ 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% NH3H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN];B%: 26%-56%,7.8 min). 7-chloro-N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH -indole-2-carboxamide (12.34 mg, 21.3% yield, 100% purity) was obtained as white solid.

[0001477] LCMS : Rt = 2.130 min; for C23H26CIN5O3 MS Calcd.: 455.94; MS Found: 456.1 [M+H ⁺ ],

[0001478] ¹ H NMR (400 MHz, CD3OD) δ 7.58 (d ,J= 8.0 Hz, 1H), 7.32 - 7.21 (m, 2H), 7.07 (t, J= 7.8 Hz, 1H), 5.14 (dd, J= 6.0, 10.0 Hz, 1H), 4.57 (t, J= 7.4 Hz, 1H), 3.28 - 3.16 (m, 2H), 2.56 - 2.28 (m, 2H), 2.05 - 1.88 (m, 3H), 1.87 - 1.78 (m, 1H), 1.77 - 1.61 (m, 2H), 1.59 - 1.44 (m, 1H), 0.92 - 0.80 (m, 1H), 0.60 - 0.49 (m, 2H), 0.26 - 0.14 (m,

2H). Example 185a. Synthesis of viral protease inhibitor compound 639 & 639A

Step 1: Methyl ( 2S) -2-[[( 2S) -2-(tert-butoxycarbonylamino) -3-cyclopropyl-propanoyl ] amino ]- 3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001479] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (1.07 g, 4.65 mmol, 1.1 eq), methyl (2 S)-2-amino-3 -[(3 S)-2-oxo-3 - piperidyl]propanoate (1 g, 4.22 mmol, 1 eq, HC1) in DCM (10 mL) was added the DMAP (1.55 g, 12.67 mmol, 3 eq), EDCI (1.62 g, 8.45 mmol, 2 eq), and the resulting solution was stirred at 25 °C for 1 h. Upon completion, the solution was diluted with H ₂ O (30 mL), extracted with ethyl acetate (30 mL * 3), the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The residue was purified by column chromatography (SiO ₂ , DCM/MeOH = 30/1 to 10/1) to give methyl (2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[(3S)- 2-oxo-3-piperidyl] propanoate (1.2 g, 2.92 mmol, 68.97% yield, 100% purity) as a yellow oil. MS (ESI) m/z 412.3 [M+H] ⁺ .

Step 2: (2R)-N-(4-(tert-butyl)phenyl)-N-(2-oxo-l-(pyridin-3-yl)-2-(( pyridin-4- ylmethyl)amino)ethyl)pyrrolidine-2-carboxamide [0001480 ] Methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-[(3 S)-2-oxo-3-piperidyl]propanoate (600 mg, 1.46 mmol, 1 eq) in ammonia (7 M, 7.2 mL, 8.30 eq) was stirred at 50 °C for 14 h. Upon completion, the solution was concentrated to give 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 (580 mg, crude) as a yellow oil. MS (ESI) m/z 397.3 [M+H] ⁺ .

Step 3: (2S)-2-amino-N-[ ( 1 S) -2-amino-2-oxo-l-[ [ ( 3S)-2-oxo-3-piperidyl ]methyl] ethyl ]-3- cyclopropyl-propanamide

[0001481] 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-et hyl]carbamate (580 mg, 1.46 mmol, 1 eq) in HCl/MeOH (4 M, 10.00 mL, 7.93 eq) was stirred at 25 °C for 1 h. Upon completion, the solution was concentrated to give (2S)-2-amino-N-[(1S)-2-amino- 2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (380 mg, crude) was obtained as a yellow oil. MS (ESI) m/z 297.2 [M+H] ⁺ .

Step 4: (2S)-2-amino-N-[ ( 1 S) -2-amino-2-oxo-l-[ [ ( 3S)-2-oxo-3-piperidyl ]methyl] ethyl ]-3- cyclopropyl-propanamide

[0001482] To a solution of (2S)-2-amino-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (380 mg, 1.28 mmol, 1 eq) in DCM (3 mL) was added 7-chloro-lH-indole-2-carboxylic acid (275.88 mg, 1.41 mmol, 1.1 eq), T3P (1.22 g, 1.93 mmol, 1.14 mL, 50% purity, 1.5 eq) and DIEA (331.44 mg, 2.56 mmol, 446.68 uL, 2 eq) The mixture was stirred at 25 °C for 2 h. Upon completion, the solution was diluted with H ₂ O (20 mL), extracted with DCM (30 mL * 3), the combined organic phase was dried over Na ₂ SO ₄ , filtrated and concentrated to give the crude. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10:1) to giveN-[(1S)-2-[[(1S)-2-amino- 2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo- ethyl]-7-chloro-lH-indole-2-carboxamide (350 mg, 738.47 umol, 57.59% yield, 100% purity) as yellow oil. MS (ESI) m/z 474.3 [M+H] ⁺ .

Step 5: 7-chloro-N-[ ( l S)-2-[[( l S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[0001483] 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-et hyl]-7-chloro-lH-indole- 2-carboxamide (350 mg, 738.47 umol, 1 eq) in DCM (4 mL) was added Burgess reagent (527.94 mg, 2.22 mmol, 3 eq), and the solution was stirred at 25 °C for 6 h. Upon completion, DCM was removed using blow dry to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [water(0.05% NH3H ₂ O+IO mM NH4HC0 ₃ )-ACN];B%: 25%-55%,8 min) to give desired compound as a white solid, which was further separated by SFC (column: DAICEL CHIRALPAK AS(250 mm*30 mm, 10 um);mobile phase: [0.1% NH3H ₂ O ETOH];B%: 33%-33%,8 min) to give 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-

3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethy l]-lH-indole-2-carboxamide (250 mg, 530.89 umol, 74.25% yield, 96.82% purity) as a white solid. MS (ESI) m/z 456.2 [M+H] ⁺ .

[0001484] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.58 (d, J=7.9 Hz, 1H), 7.35 - 7.20

(m, 2H), 7.06 (t, J=7.8 Hz, 1H), 5.22 - 5.05 (m, 1H), 4.57 (t, J=7.5 Hz, 1H), 3.27 - 3.14 (m, 2H), 2.61 - 2.34 (m, 2H), 2.09 - 1.61 (m, 6H), 1.59 - 1.43 (m, 1H), 0.98 - 0.76 (m, 1H), 0.55 (dd, J=1.3, 8.2 Hz, 2H), 0.31 - 0.09 (m, 2H).

[0001485] 7-Chloro-N-[(lR)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide (45 mg, 98.70 umol, 13.37% yield, 100% purity) was obtained as white solid. MS (ESI) m/z 456.2 [M+H] ⁺ .

[0001486] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.59 (dd, J=0.9, 7.9 Hz, 1H), 7.32 -

7.21 (m, 2H), 7.07 (t, J=7.8 Hz, 1H), 5.12 - 5.02 (m, 1H), 4.59 (dd, J=6.4, 7.9 Hz, 1H),

3.21 (dd, J=4.6, 7.7 Hz, 2H), 2.44 - 2.23 (m, 2H), 2.09 - 1.62 (m, 6H), 1.60 - 1.47 (m, 1H), 0.94 - 0.78 (m, 1H), 0.62 - 0.43 (m, 2H), 0.27 - 0.11 (m, 2H).

Example 186. Synthesis of viral protease inhibitor compound 643

Step 1: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pent anoyl]amino]-3- [ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001487] T3P (2.69 g, 4.22 mmol, 2.51 mL, 50% purity, 2 eq) was added to a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (500 mg, 2.11 mmol, 1 eq, HC1), (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (570.0 mg, 2.32 mmol, 1.1 eq) and TEA (855.0 mg, 8.45 mmol, 1.18 mL, 4 eq) in DMF (5 mL). Then the mixture was stirred at 70 °C for 16 h. TLC (petroleum ether: ethyl acetate = 0: 1/PMA).

The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®;20 g SepaFlash® Silica Flash Column, Eluent of 0-100% ethyl acetate/petroleum ether gradient @30 mL/min). Methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pent anoyl]amino]-3-[(3S)-2- oxo-3-piperidyl]propanoate (436 mg, 0.99 mmol, 47.2% yield, 97.9% purity) was obtained as white solid and confirmed by LC-MS, SFC and HNMR.

Step 2: methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)- 2-oxo-3- piper idyl ]propanoate

[0001488] A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (300 mg, 0.70 mmol, 1 eq) in HCl/dioxane (4 M, 175.42 uL, 1 eq) was stirred at 25 °C for 2 h. The reaction mixture was filtered to afford ethyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3S)-2-oxo-3-piperidyl]propanoate (250 mg, crude, HC1) as a white solid.

Step 3: methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4,4- dimethyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate [0001489] A mixture of methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (310 mg, 0.85 mmol, 1 eq, HC1), 4-methoxy-lH- indole-2-carboxylic acid (179.1 mg, 0.93 mmol, 1.1 eq), HATU (647.8 mg, 1.70 mmol, 2 eq) and DIPEA (440.4 mg, 3.41 mmol, 0.60 mL, 4 eq) in DCM (4 mL) was stirred at 25 °C for 2 h. TLC (PE:EA=0: l/UV254nm). The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12g SepaFlash® Silica Flash Column, Eluent of 0-100% ethyl acetate/petroleum ether gradient @ 30mL/min). Methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH- indole-2-carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3 S)-2-oxo-3- piperidyl]propanoate (451 mg, 0.68 mmol, 80.1% yield, 75.8% purity) was obtained as a yellow oil.

Step 4: N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-meth oxy-lH-indole-2-carboxamide [0001490] To a mixture of methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo- 3-piperidyl]propanoate (400 mg, 0.79 mmol, 1 eq) was added NH ₃ (7 M, 11.42 mL, 100 eq), and then the resulting mixture was stirred at 80 °C for 16 h. TLC (DCM:MeOH=10:l/UV254nm). The reaction mixture was concentrated in vacuum, and the residue was purified by flash silica gel chromatography (ISCO®;12g SepaFlash® Silica Flash Column, Eluent of 0-50% Ethyl acetate/MeOH@30 mL/min). N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-meth oxy-lH-indole-2- carboxamide (295 mg, 0.60 mmol, 75.1% yield, 98.9% purity) was obtained as white a solid.

Step 5: N-f (IS)- 1-[[(1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl ] carbamoyl ]-3, 3-dimethyl- butyl]-4-methoxy-lH-indole-2-carboxamide

[0001491 ] Methoxycarbonyl-(triethylammonio)sulfonyl-azanide (284.6 mg, 1.19 mmol, 2 eq) was added to a mixture of N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-meth oxy-lH-indole-2- carboxamide (290 mg, 0.59 mmol, 1 eq) in DCM (3 mL) at 25 °C. Then the mixture was stirred at 25 °C for 16 h. Then, methoxycarbonyl-(triethylammonio)sulfonyl-azanide (142.3 mg, 0.59 mmol, 1 eq) was added to the mixture and the mixture was stirred at 25 °C for another 16 h. The reaction mixture was diluted with H ₂ O (10 mL) and the mixture was extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 2), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-MeOH];B%: 55%-85%, 9.5 min). N-[(1S)-1-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-methoxy-lH- indole-2-carboxamide (28.1 mg, 59.3 umol, 9.9% yield, 98.7% purity) was obtained as a white solid.

[0001492] LCMS: Rt = 0.832 min; for C25H33N5O4 MS Calcd.: 467.25, MS Found: 468.2 [M+H ⁺ ],

[0001493] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.26 - 7.22 (m, 1H), 7.18 - 7.12 (m, 1H), 7.05 - 7.00 (m, 1H), 6.51 (d,J= 7.5 Hz, 1H), 5.08 (dd, J= 6.3, 9.8 Hz, 1H), 4.67 - 4.63 (m, 1H), 3.93 (s, 3H), 3.21 - 3.15 (m, 2H), 2.47 - 2.38 (m, 2H), 1.98 - 1.72 (m, 6H), 1.70 - 1.58 (m, 1H), 1.54 - 1.43 (m, 1H), 1.02 (s, 8H), 1.04 - 1.01 (m, 2H).

Example 187. Synthesis of viral protease inhibitor compound 653

[0001494] To a mixture of N-[( 1 S)- 1 -[[( 1 S)- 1 -formyl-2-[(3 S)-2-oxopyrrolidin-3- yl]ethyl]carbamoyl]-3-methyl -butyl]-4-methoxy-lH-indole-2-carboxamide (1 g, 1.81 mmol, 80% purity, 1 eq) in EtOH (20 mL) was added 2-aminoacetic acid (271.74 mg, 3.62 mmol, 20.52 uL, 2 eq), ZnCl2 (1 M, 18.10 uL, 0.01 eq). The mixture was stirred at 25 °C for 30 min, and then added TMSCN (359.14 mg, 3.62 mmol, 452.89 uL, 2 eq). The mixture was stirred at 40 °C for 6 h. Upon the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by HC1 prep-HPLC (column: Phenomenex luna C18 80*40 mm*3 um; mobile phase: [water (0.04%HC1)- ACN] ; B%: 25%-45%, 7 min) to get a mixture. The mixture was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [Neu-ETOH]; B%: 50%-50%, 10 min) to get the compound 2-[[(2S)-1-cyano-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl )amino]-4-methyl- pentanoyl]amino] -3-[(3S)-2-oxopyrrolidin-3-yl]propyl]amino]acetic acid (125 mg, 235.87 umol, 13.03% yield, 99.363% purity) and 2-[[(2S)-1-cyano-2-[[(2S)-2-[(4- methoxy- 1 H-indole-2-carbonyl)amino]-4-methyl -pentanoyl]amino]-3-[(3S)-2- oxopyrrolidin-3-yl]propyl]amino]acetic acid (205 mg, 373.82 umol, 20.65% yield, 96.023% purity) as white solid. MS (ESI) m/z 527.3 [M+H] ⁺ .

[0001495] Isomer 1 : ¹ H NMR (400MHz, DMSO-J6) δ = 11.56 (d, J=2.0 Hz, 1H), 8.52 - 8.21 (m, 2H), 7.58 (s, 1H), 7.35 (d, J=1.7 Hz, 1H), 7.14 - 7.05 (m, 1H), 7.03 - 6.97 (m, 1H), 6.50 (d, J=7.7 Hz, 1H), 4.57 - 4.41 (m, 1H), 4.14 (tdd, J=4.2, 8.2, 12.2 Hz, 1H), 3.97 - 3.82 (m, 4H), 3.52 - 3.36 (m, 2H), 3.18 - 2.98 (m, 2H), 2.41 - 2.27 (m, 1H), 2.12 - 2.04 (m, 2H), 1.82 - 1.36 (m, 5H), 0.91 (dd,J=6.4, 15.8 Hz, 6H)

[0001496] Isomer 2: ¹ H NMR (400MHz, DMSO-J6) δ = 11.57 (d, J=2.0 Hz, 1H), 8.39 (d, J=7.8 Hz, 1H), 8.20 (d, J=9.5 Hz, 1H), 7.54 (s, 1H), 7.37 (d,J= 1.6 Hz, 1H), 7.16 - 6.94 (m, 2H), 6.50 (d, J=7.6 Hz, 1H), 4.53 - 4.36 (m, 1H), 4.18 - 4.01 (m, 1H), 3.88 (s, 3H), 3.77 (d, J=8.8 Hz, 1H), 3.43 - 3.33 (m, 2H), 3.15 - 2.96 (m, 2H), 2.38 - 2.25 (m, 1H), 2.08 - 2.01 (m, 1H), 1.91 - 1.47 (m, 6H), 0.91 (dd,J=6.4, 14.8 Hz, 6H).

Example 188. Synthesis of viral protease inhibitor compound 655

Step 1: (2S,4R)-di-tert-butyl 4-hydroxypyrrolidine-l,2-dicarboxylate

[0001497 ] A solution of (2S,4R)- 1 -tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2- carboxylic acid (5 g, 21.62 mmol, 1 eq) in THF (75 mL) was added 2-tert-butyl-l,3- diisopropyl-isourea (6.50 g, 32.43 mmol, 1.5 eq) at 25 °C, and then the solution was stirred at 60 °C for 2.5 h. Additional 2-tert-butyl-l, 3-diisopropyl-isourea (6.50 g, 32.43 mmol, 1.5 eq) was added to the mixture and then was stirred at 60 °C for 14 h. Upon completion, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give (2S,4R)-di-tert-butyl 4-hydroxypyrrolidine- 1,2-dicarboxylate (4.3 g, 14.22 mmol, 65.75% yield, 95% purity) as colorless oil. MS (ESI) m/z 288.2 [M+H] ⁺

Step 2: (2S,4S)-di-tert-butyl 4-bromopyrrolidim-l,2-dicarboxylate

[0001498 ] 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 PPhs (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 (SiO ₂ , 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.

Step 3: (2S,4S)-di-tert-butyl 4-(tert-butyl)pyrrolidine-l,2-dicarboxylate [0001499] 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 N ₂ . Upon completion, the reaction was quenched by pouring into a solution of saturated aqueous NH4CI (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 NaHCO ₃ (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , concentrated under reduced pressure to give a crude. The residue was purified by column chromatography (SiO ₂ , 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.

Step 4: (2S,4S)-4-(tert-butyl)pyrrolidim-2-carboxylic acid

[0001500] A mixture of (2S,4S)-di-tert-butyl 4-(tert-butyl)pyrrolidine- 1 ,2-dicarboxylate (250 mg, 763.46 umol, 1 eq) in HC1 (6 M, 2.5 mL, 19.65 eq) was stirred at 100 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S,4S)-4-tert-butylpyrrolidine-2-carboxylic acid (158 mg, crude, HC1) as a yellow solid.

Step 5: (2S,4S)-l-(tert-butoxycarbonyl)-4-(tert-butyl)pyrrolidine-2- carboxylic acid

[0001501 ] A mixture of (2S,4S)-4-tert-butylpyrrolidine-2-carboxylic acid (158 mg, 760.72 umol, 1 eq, HC1) in THF (1 mL) and H ₂ O (1 mL) was added KzCO ₃ (315.41 mg, 2.28 mmol, 3 eq) and Boc ₂ O (199.23 mg, 912.87 umol, 209.72 uL, 1.2 eq). The reaction was stirred at 25 °C for 14 h under N ₂ . Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S,4S)-1-(tert-butoxycarbonyl)-4-(tert- butyl)pyrrolidine-2-carboxylic acid (650 mg, crude) as a yellow solid.

Step 6: (2S,4S)-tert-butyl 4-(tert-butyl)-2-(((S)-l -methoxy- l-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamoyl)pyrrolidine-l-carboxylate

[0001502 ] To a solution of (2S,4S)- 1 -(tert-butoxycarbonyl)-4-(tert-butyl)pyrrolidine-2- carboxylic acid (630 mg, 696.51 umol, 30% purity, 1 eq) in DCM (6 mL) and DMF (3 mL) was added TEA (422.88 mg, 4.18 mmol, 581.68 uL, 6 eq), methyl (2S)-2-amino-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (186.11 mg, 835.82 umol, 1.2 eq, HC1). After adding T3P (1.33 g, 2.09 mmol, 1.24 mL, 50% purity, 3 eq) at 0 °C, the mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was quenched with water (10.0 mL) and extracted with DCM (10 mL * 3). The organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 0: 1) to give tert-butyl (2S,4S)-tert-butyl 4-(tert-butyl)-2-(((S)~ 1 -methoxy- l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)pyrr olidine-l- carboxylate (240 mg, 546.02 umol, 78.39% yield) as a yellow solid. MS (ESI) m/z 440.3 [M+H] ⁺ .

Step 7: (S)-methyl 2-((2S,4S)-4-(tert-butyl)pyrrolidine-2-carboxamido)-3-((S)-2 - oxopyrrolidin-3-yl)propanoate

[0001503] A solution of tert-butyl (2S,4S)-tert-butyl 4-(tert-butyl)-2-(((S)- 1 -methoxy- 1 - oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)pyrrol idine-1-carboxylate (230 mg, 523.27 umol, 1 eq) in HCl/MeOH (4 M, 2.3 mL, 17.58 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (S)-methyl 2-((2S,4S)-4-(tert-butyl)pyrrolidine-2-carboxamido)-3-((S)-2 - oxopyrrolidin-3-yl)propanoate (196 mg, crude, HC1) as a light yellow solid. MS (ESI) m/z 340.2 [M+H] ⁺ .

Step 8: (S)-methyl 2-((2S,4S)-4-(tert-butyl)-l-(4-methoxy-lH-indole-2-carbonyl) pyrrolidine-

2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001504] To a solution of (S)-methyl 2-((2S,4S)-4-(tert-butyl)pyrrolidine-2- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (196 mg, 521.43 umol, 1 eq, HC1) in DCM (2 mL) and DMF (1 mL) was added 4-methoxy- 1 H-indole-2-carboxylic acid (99.69 mg, 521.43 umol, 1 eq), DMAP (127.41 mg, 1.04 mmol, 2 eq), and then EDCI (199.92 mg, 1.04 mmol, 2 eq) at 0 °C. The mixture was then stirred at 25 °C for 1 h.

Upon completion, the mixture was quenched with water (10.0 mL) and extracted with DCM (10 mL * 3). The organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane: methanol = 10:1 to 4:1) to give (S)-methyl 2-((2S,4S)-4-(tert-butyl)-1-(4-methoxy-lH-indole-2- carbonyl)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3 -yl)propanoate (250 mg, 414.56 umol, 79.50% yield, 85% purity) as a yellow solid. MS (ESI) m/z 513.3 [M+H] ⁺ .

Step 9: (2S, 4S)-N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan- 2-yl)-4-(tert- butyl)-l-(4-methoxy-lH-indole-2-carbonyl)pyrrolidine-2-carbo xamide

[0001505] A solution of (S)-methyl 2-((2S,4S)-4-(tert-butyl)- 1 -(4-methoxy- 1 H-indole-2- carbonyl)pyrrolidine-2-carboxamido)-3-((S)-2-oxopyrrolidin-3 -yl)propanoate (235 mg, 389.68 umol, 85% purity, 1 eq) in NH ₃ /MeOH (7 M, 5 mL) was stirred at 40 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S,4S)-N-((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-4-(tert-butyl) - 1 - (4-methoxy- lH-indole-2-carbonyl)pyrrolidine-2-carboxamide (193 mg, crude) as a yellow solid. MS (ESI) m/z 498.3 [M+H] ⁺ .

Step 10: (2S,4S)-4-(tert-butyl)-N-((S)-l-cyano-2-((S)-2-oxopyrrolidin -3-yl)ethyl)-l-(4- methoxy-lH-indole-2-carbonyl)pyrrolidine-2-carboxamide

[0001506] To a solution of (2S,4S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)-4-(tert-butyl)-1-(4-methoxy-lH-indole-2-carb onyl)pyrrolidine-2- carboxamide (193 mg, 329.69 umol, 85% purity, 1 eq) in DCM (3 mL) was added Burgess reagent (235.71 mg, 989.08 umol, 3 eq), and then the reaction was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25mm*5 um; mobile phase: [water(10 mM NH4HCO3)- ACN];B%: 30%-55%,10 min) to give (2S,4S)-4-(tert-butyl)-N-((S)-1-cyano-2-((S)-2- oxopyrrolidin-3-yl)ethyl)-1-(4-methoxy-lH-indole-2-carbonyl) pyrrolidine-2-carboxamide (59.58 mg, 124.24 umol, 37.68% yield, 100% purity) as a white solid. MS (ESI) m/z 480.2 [M+H] ⁺ . [0001507] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.69 - 11.55 (m, 1H), 9.17 - 8.75 (m, 1H), 7.81 - 7.44 (m, 1H), 7.16 - 7.07 (m, 1H), 7.06 - 6.98 (m, 2H), 6.55 - 6.46 (m, 1H), 5.03 - 4.53 (m, 2H), 4.04 - 3.74 (m, 4H), 3.69 - 3.36 (m, 1H), 3.22 - 2.55 (m, 2H), 2.35 - 1.95 (m, 5H), 1.83 - 1.51 (m, 3H), 1.00 - 0.82 (m, 9H).

[0001508 ] ¹ H NMR (400MHz, DMSO-d ₆ , 273+80K) δ = 11.31 (s, 1H), 8.68 (s, 1H), 7.38 (s, 1H), 7.18 - 7.02 (m, 2H), 6.90 (s, 1H), 6.60 - 6.47 (m, 1H), 4.96 (q, J=7.6 Hz, 1H), 4.72 (s, 1H), 4.07 - 3.80 (m, 4H), 3.66 - 3.50 (m, 1H), 3.28 - 3.05 (m, 2H), 2.32 - 1.97 (m, 5H), 1.95 - 1.64 (m, 3H), 0.95 (s, 9H).

Example 189. Synthesis of viral protease inhibitor compound 659

[0001509] 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 BH ₃ -MezS (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. NaHCO ₃ (150 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ethenethyl acetate = 1 :0 to 1 : 1) to afford tert-butyl N-[( 1 S)- 1 -(hydroxy methyl)-3 , 3 -dimethyl -butyl ]carbamate (2.5 g, 10.81 mmol, 53.02% yield) as a colorless oil.

Step 2: (S)-tert-butyl (4,4-dimethyl-l-oxopentan-2-yl)carbamate

[0001510] 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 H ₂ O 60 mL at 0 °C, and then aq. NaHCO ₃ was 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ethenethyl acetate = 0: 1 to 1 : 1) to afford tert- butyl N-[(l S)-l -formyl-3, 3-dimethyl-butyl]carbamate (1.6 g, 6.98 mmol, 67.25% yield) as a colorless oil.

[0001511 ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 9.40 (s, 1 H) 7.30 (br d, J=8.00 Hz, 1 H) 3.91 - 3.82 (m, 1 H) 1.66 (dd, J=14.38, 2.75 Hz, 1 H) 1.39 (s, 9 H) 1.32 (br d, J=9.26 Hz, 1 H) 0.90 (s, 9 H).

Step 3: (S)-methyl2-(((S)-2-((tert-butoxycarbonyl)amino)-4, 4-dimethylpentyl)amino)-3-((S)~ 2-oxopyrrolidin-3-yl)propanoate

[0001512] To a solution of tert- butyl N-[(1S)-1-formyl-3,3-dimethyl-butyl]carbamate (0.8 g, 3.49 mmol, 1 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.17 g, 5.23 mmol, 1.5 eq, HC1) in DCE (20 mL) was added Et ₃ N (529.52 mg, 5.23 mmol, 728.36 uL, 1.5 eq) and NaBH(OAc) ₃ (2.22 g, 10.47 mmol, 3 eq). The reaction was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition aq. NaHCO ₃ (100 mL) at 0 °C and stirred for 0.5 h, and then extracted with DCM (60 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ethenethyl acetate = 0: 1 to 1 :3) to afford methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pent yl]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] ⁺ Step 4: (S)-methyl 2-(((S)-2-amino-4,4-dimethylpentyl)amino)-3-((S)-2-oxopyrrol idin-3- yl)propanoate

[0001513] A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (200 mg, 500.60 umol, 1 eq) in HCl/MeOH (4 M, 4.00 mL, 31.96 eq) was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2-[[(2S)-2-amino-4,4- dimethyl-pentyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoa te (168 mg, crude, HC1) as a white solid.

Step 5: (S)-methyl 2-(((S)-2-(4-methoxy-lH-indole-2-carboxamido)-4,4- dimethylpentyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001514] To a solution of methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (168 mg, 500.20 umol, 1 eq, HC1) and 4-methoxy- 1 H-indole-2-carboxylic acid (95.63 mg, 500.20 umol, 1 eq) in DMF (1 mL) was added DMAP (183.32 mg, 1.50 mmol, 3.0 eq), EDCI (191.78 mg, 1.00 mmol, 2 eq) and DCM (3 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by addition H ₂ O 40 mL at 0 °C, and then extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 1:0 to 0:1) to afford methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4,4- dimethyl- pentyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (150 mg, 301.54 umol, 60.28% yield, 95% purity) as a yellow oil. MS (ESI) m/z 473.2 [M+H] ⁺

Step 6: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (, S)-2-oxopyrrolidin-3-yl)propan-2-yl)ammo)-4 , 4- dimethylpentan-2-yl)-4-methoxy-lH-indole-2-carboxamide

[0001515] A solution of methyl (2S)-2-[[(2S)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentyl]amino]-3-[(3S)-2-oxopyrr olidin-3-yl]propanoate (130 mg, 275.09 umol, 1 eq) in NH ₃ /MeOH (7 M, 15 mL, 381.70 eq) was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , ethyl acetate :MeOH = 50:3) to afford product N-[(1S)-1-[[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]methyl]-3,3-dimethyl-butyl]-4-methoxy- lH-indole-2-carboxamide (60 mg, 131.13 umol, 47.67% yield) as a yellow solid. MS (ESI) m/z 458.3 [M+H] ⁺

Step 7: N-( (S)-l-( ( (S)-l-cyano-2-( ( S)-2-oxopyrrolidin-3-yl)ethyl)amino)-4 , 4-dimethylpentan- 2-yl)-4-methoxy-JH-indole-2-carboxamide

[0001516] To a solution of N-[(1S)-1-[[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]methyl]-3,3-dimethyl-butyl]-4-methoxy- lH-indole-2-carboxamide (50 mg, 109.27 umol, 1 eq) in EtOAc (2 mL) was added T3P (2.14 g, 3.36 mmol, 2 mL, 50% purity, 30.77 eq) drop-wise, and then the resulting mixture was stirred at 65 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue.

The residue was purified by prep-HPLC (column: Phenomenex Luna C18 75 * 30 mm *

3 um; mobile phase: [water (0.2% FA) - ACN]; B%: 15% - 45%, 8 min) and was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: [0.1% NH3H ₂ O ETOH]; B%: 25% - 25%, 20 min) to afford N-[(1S)-1- [[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]amino]met hyl]-3,3-dimethyl-butyl]-4- methoxy-lH-indole-2-carboxamide (4.4 mg, 9.92 umol, 29.07% yield, 99.1% purity) as a white solid. MS (ESI) m/z 440.2 [M+H] ⁺ .

[0001517] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.22 - 6.99 (m, 3 H) 6.52 (br d, J=7.72 Hz, 1 H) 4.74 - 4.65 (m, 1 H) 4.61 - 4.48 (m, 1 H) 4.03 - 3.91 (m, 4 H) 3.62 - 3.51 (m, 1 H) 3.47 - 3.36 (m, 1 H) 3.27 - 3.19 (m, 1 H) 2.50 - 2.41 (m, 1 H) 2.29 - 2.18 (m, 1 H) 1.81 (br s, 1 H) 1.74 - 1.64 (m, 2 H) 1.60 (br d, J=10.14 Hz, 1 H) 1.34 - 1.28 (m, 1 H) 0.98 (s, 9 H).

Example 190. Synthesis of viral protease inhibitor compound 667

Step 1: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4-fluoro-4-methyl - pentanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001518] To a solution of compound (S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-4- methylpentanoic acid (300.0 mg, 1.20 mmol, 1.0 eq) and compound methyl (S)-2-amino- 3-((S)-2-oxopiperidin-3-yl)propanoate (313.3 mg, 1.32 mmol, 1.1 eq, HC1) in DMF (3 mL) was added T3P (1.53 g, 2.41 mmol, 1.43 mL, 50% purity, 2.0 eq) and TEA (487.1 mg, 4.81 mmol, 0.67 mL, 4.0 eq). The mixture was stirred at 80 °C for 16 h. TLC (petroleum ether/ethyl acetate = 0/1, PMA). The mixture was 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 0~1% MeOH/DCM @ 25 mL/min) to give methyl (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-4-fluoro-4- methylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (620 mg, 1.15 mmol, 95.5% yield, 80% purity) as a yellow solid.

[0001519] LCMS: Rt = 0.773 min; for C20H34FN3O6 MS Calcd. : 431.24; MS Found: 432.2 [M+H ⁺ ],

Step 2: Methyl (2S)-2-[[(2S)-2-amino-4-fluoro-4-methyl-pentanoyl]amino]-3-[ (3S)-2-oxo-3- piperidyl ]propanoate

[0001520] A mixture of compound methyl (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-4- fluoro-4-methylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propa noate (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)propa noate (550 mg, crude, HC1, yellow oil) was used into the next step.

Step 3: Methyl (2S)-2-[[(2S)-4-fluoro-2-[(4-methoxy-lH-indole-2-carbonyl)am ino]-4- methyl-pentanoyl ] amino] -3- [ ( 3S)-2-oxo-3-piperidyl ]propanoate [0001521 ] To a solution of compound 4-methoxy- 1 H-indole-2-carboxylic acid (200 mg, 1.05 mmol, 1 eq) in DCM (5 mL) were added HATU (477.3 mg, 1.26 mmol, 1.2 eq) and DIEA (540.8 mg, 4.18 mmol, 0.73 mL, 4 eq). The mixture was stirred at 25 °C for 0.5 h. Compound methyl (S)-2-((S)-2-amino-4-fluoro-4-methylpentanamido)-3-((S)-2- oxopiperidin-3-yl)propanoate (461.8 mg, 1.26 mmol, 1.2 eq, HC1) was added into the mixture. The mixture was stirred at 25 °C for 16 h. TLC (DCM/MeOH = 10/1, UV). The reaction mixture was diluted with H ₂ O (15 mL) and extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , 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 0-100% ethyl acetate/petroleum ether gradient @ 30 mL/min) to give methyl (S)-2-((S)-4-fluoro-2-(4-methoxy- 1 H-indole-2-carboxamido)-4- methylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (480 mg, 83.9% yield) as a yellow solid.

[0001522] LCMS: Rt = 0.794 min; for C25H33FN4O6 MS Calcd. : 504.24; MS Found: 505.2 [M+H ⁺ ],

[0001523] ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.56 - 9.81 (m, 1H), 8.24 (br s, 1H), 7.23 - 7.06 (m, 3H), 7.01 (d, J= 8.28 Hz, 1H), 6.49 (d, J= 7.78 Hz, 1H), 6.17 (br s, 1H), 4.95 - 4.82 (m, 1H), 4.60 - 4.51 (m, 1H), 3.94 (s, 3H), 3.80 - 3.60 (m, 5H), 3.16 (br d, J=7.28 Hz, 2H), 3.00 - 2.77 (m, 1H), 1.98 (br d, J=6.02 Hz, 2H), 1.92 - 1.83 (m, 2H), 1.77 (br s, 2H), 1.51 - 1.44 (m, 6H).

Step 4: N-[(lS)-l-[[(lS)-2-amino-2-oxo-l-[[(3S)-2-oxo-3- piperidyl ] methyl ] ethyl ] carbamoyl ]-3-fluoro-3-methyl-butyl ]-4-methoxy- lH-indole-2- carboxamide

[0001524] A solution of compound methyl (S)-2-((S)-4-fluoro-2-(4-methoxy- 1 H-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-lH-indole-2-carboxamide (370 mg, 0.74 mmol, 37.2% yield, 97.6% purity) as a yellow solid.

[0001525] LCMS: Rt = 0.743 min; for C24H32FN5O5 MS Calcd. : 489.24; MS Found: 490.2 [M+H ⁺ ],

Step 5 : N-[(l S)-l -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]carbamoyl]-3-fluoro-3- methyl-butyl]-4-methoxy-lH-indole-2-carboxamide

[0001526] To a solution of compound N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2- oxopiperidin-3-yl)propan-2-yl)amino)-4-fluoro-4-methyl-1-oxo pentan-2-yl)-4-methoxy- lH-indole-2-carboxamide (350 mg, 0.71 mmol, 1 eq) in DCM (6 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (170.4 mg, 0.71 mmol, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. Methoxycarbonyl- (triethylammonio)sulfonyl-azanide (170.4 mg, 0.71 mmol, 1 eq) was added into the mixture at 0 °C. The mixture was stirred at 25 °C for 0.5 h. methoxycarbonyl- (triethylammonio)sulfonyl-azanide (170.4 mg, 0.71 mmol, 1 eq) was added into the mixture at 0 °C. The mixture was stirred at 25 °C for 16 h. The mixture was diluted with H ₂ O (20 mL) and extracted with ethyl acetate (40 mL * 3). The combined organic layers were washed with brine (30 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was checked by LCMS. The residue was purified by prep- HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase: [water (0.05% NH3H ₂ O+IO mM NH ₄ HC0 ₃ )-ACN]; B%: 28%-58%, 7.8 min) to giveN-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl) amino)-4-fluoro-4-methyl- l-oxopentan-2-yl)-4-methoxy-lH-indole-2-carboxamide (95 mg, 28.1% yield) as a white solid. [0001527] LCMS: Rt = 0.780 min; for C24H30FN5O4 MS Calcd. : 471.23; MS Found: 472.2 [M+H ⁺ ],

[0001528] ¹ H NMR (400 MHz, CD ₃ OD) δ 7.24 - 7.20 (m, 1H), 7.18 - 7.11 (m, 1H), 7.07 - 7.01 (m, 1H), 6.51 (d ,J= 7.78 Hz, 1H), 5.13 - 5.01 (m, 1H), 4.81 - 4.71 (m, 1H), 3.93 (s, 3H), 3.18 (dd, J = 7.40, 5.14 Hz, 2H), 2.49 - 2.34 (m, 2H), 2.32 - 2.11 (m, 2H), 2.00 - 1.87 (m, 2H), 1.83 - 1.73 (m, 1H), 1.72 - 1.60 (m, 1H), 1.54 - 1.37 (m, 7H).

Example 191. Synthesis of viral protease inhibitor compound 681

Step 1: (2S)-methyl 2-(2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane- 3- carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[0001529] To a solution of methyl (2 S)-2-amino-3 -[(3 S)-2-oxo-3 -piperidy 1 ]propanoate (500 mg, 2.11 mmol, 1.1 eq, HC1) 2-(4-methoxy- 1 H-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carboxylic acid (684.45 mg, 1.92 mmol, 1 eq) in DMF (15 mL) was added DIPEA (744.57 mg, 5.76 mmol, 1.00 mL, 3 eq) and HATU (730.19 mg, 1.92 mmol, 1 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the two batch reaction mixture was quenched by addition H ₂ O (80 mL), and extracted with ethyl acetate (40 mL * 3). The combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get the product methyl (2S)- 2-[[2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane -3-carbonyl]amino]-3- [(3S)-2-oxo-3-piperidyl]propanoate (1.35 g, crude) was obtained as white solid. MS (ESI) m/z 539.3 [M+H] ⁺ . Step 2: N-( (S)-l -amino- l-oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)-2-( 4-methoxy-JH- indole-2-carbonyl)-2-azaspiro[4.5Jdecane-3-carboxamide

[0001530 ] A solution of methyl (2 S)-2-[ [2-(4-methoxy- 1 H-i ndole-2-carbony 1 )-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (650 mg, 1.21 mmol, 1 eq) in NH ₃ /MeOH (7 M, 3.45 mL, 20 eq) was stirred at 65 °C for 17 h. Upon completion, the two batch reaction mixture was concentrated under reduced pressure to get the product N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)-2 -azaspiro[4.5]decane-3- carboxamide (1.22 g, crude) as a colorless oil. MS (ESI) m/z 524.3 [M+H] ⁺ .

Step 3:

N-((S)-l-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2-(4-met hoxy-lH-indole-2-carbonyl)-2- azaspiro[ 4.5 ]decane-3-carboxamide

[0001531] To a solution ofN-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)-2 -azaspiro[4.5]decane-3- carboxamide (1.22 g, 2.33 mmol, 1 eq) in DCM (20 mL) was added Burgess reagent (1.39 g, 5.82 mmol, 2.5 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (3 mL) and then concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Agela DuraShell C18250*70 mm* 10 um; mobile phase: [water(10 mM NH4HCO3)- ACN];B%: 43%-63%,20 min) to give desired compound (490 mg) as a white solid, which was further separated by SFC (column: DAICEL CHIRALPAK AD(250 mm*30 mm, 10 um);mobile phase: [0.1% NH3H ₂ O IPA];B%: 58%-58%,10 min) to afford N-[(1S)-1- cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-(4-methoxy-lH-indol e-2-carbonyl)-2- azaspiro[4.5]decane-3-carboxamide Isomer 1 (201.77 mg, 394.36 umol, 16.93% yield, 98.820% purity) as a white solid. MS (ESI) m/z 506.3[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.26 (br s, 1 H) 8.50 - 8.85 (m, 1 H) 7.23 (br s, 1 H) 7.00 - 7.16 (m, 2 H) 6.89 (br s, 1 H) 6.52 (br d ,J= 7.46 Hz, 1 H) 4.86 - 5.06 (m, 1 H) 4.48 - 4.79 (m, 1 H) 3.80 - 3.98 (m, 4 H) 3.59 (br d,J= 4.65 Hz, 1 H) 3.09 (br s, 2 H) 2.15 - 2.31 (m, 3 H)

1.73 - 2.01 (m, 2 H) 1.67 (br dd, J= 12.17, 8.62 Hz, 2 H) 1.33 - 1.61 (m, 12 H).

[0001532] N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-(4-methox y-lH-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxamide Isomer 2 (200.95 mg, 394.35 umol, 16.93% yield, 99.222% purity) was obtained as a white solid. MS (ESI) m/z 506.3[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.27 (br s, 1 H) 8.61 (br d ,J = 1.22 Hz, 1 H) 7.02 - 7.26 (m, 3 H) 6.91 (br s, 1 H) 6.53 (d, J=7.46 Hz, 1 H) 4.91 - 5.06 (m, 1 H) 4.62 (br s, 1 H) 3.82 - 3.98 (m, 4 H) 3.52 - 3.75 (m, 1 H) 3.09 (br s, 2 H) 2.09 - 2.28 (m, 3 H) 1.63 - 1.92 (m, 4 H) 1.33 - 1.62 (m, 12 H).

Example 192. Synthesis of viral protease inhibitor compound 711

Step I: methyl (2S)-2-[[( 2S) -2 -amino- 3 -cyclopropyl-propanoyl ] amino ]-3-[(3S)-2- oxopyrrolidin-3-yl ]propanoate

[0001533] 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 HCI/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, HC1) as a white oil. MS (ESI) m/z 298.1 [M+H] ⁺ .

Step 2: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-(4,5,6,7-tetrahydro-lH-indole- 2- carbonylamino)propanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001534] To a mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (600 mg, 1.80 mmol, 1 eq, HC1) in DCM (7 mL) and DMF (0.5 mL) was added 4,5,6,7-tetrahydro-lH-indole-2-carboxylic acid (415.68 mg, 2.52 mmol, 1.4 eq), TEA (1.09 g, 10.78 mmol, 1.50 mL, 6 eq) and T3P (1.72 g, 2.70 mmol, 1.60 mL, 50% purity, 1.5 eq). The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (3 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep- TLC (Si02, DCM MeOH = 10:1) and TLC (Si02, DCM MeOH = 10:1) to afford methyl (2S)-2-[[(2S)-3-cyclopropyl-2-(4,5,6,7-tetrahydro-lH-indole- 2- carbonylamino)propanoyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (350 mg, 787.36 umol, 43.80% yield) as a yellow oil. MS (ESI) m/z 445.3 [M+H] ⁺ .

Step 3: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3-yl ]methyl ]ethyl]aminof- l-(cyclopropylmethyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-lH-ind ole-2-carboxamide

[0001535] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-(4,5,6,7-tetrahydro-lH- indole-2-carbonylamino)propanoyl]amino]-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (350 mg, 787.36 umol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 88.90 eq) was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4, 5,6,7-tetrahydro-lH- indole-2-carboxamide (300 mg, crude) as a yellow solid. MS (ESI) m/z 430.2 [M+H] ⁺ .

Step 4: N-f ( l S)-2-[[( l S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro-lH-indol e-2-carboxamide [0001536 ] A mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4, 5,6,7-tetrahydro-lH- indole-2-carboxamide (290 mg, 675.19 umol, 1 eq) in T3P (3 mL, 50% purity) and ethyl acetate (3 mL) was stirred at 40 °C for 16 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters X bridge BEH C18 100 * 25 mm * 5 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 25% - 55%, 10 min) to afford N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3- yl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-4,5,6,7-tetrahydro- lH-indole-2- carboxamide (61.92 mg, 150.48 umol, 22.29% yield, 100% purity) as a white solid. MS (ESI) m/z 412.3 [M+H] ⁺ . [0001537] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.96 (br s, 1H), 9.00 - 8.77 (m, 1H), 7.89 - 7.66 (m, 2H), 6.60 (br s, 1H), 5.04 - 4.81 (m, 1H), 4.48 - 4.28 (m, 1H), 3.24 - 3.04 (m, 2H), 2.47 - 1.96 (m, 7H), 1.81 - 1.61 (m, 7H), 1.40 (br dd, J=6.6, 13.1 Hz, 1H), 0.74 (br s, 1H), 0.38 (br s, 2H), 0.22 - -0.03 (m, 2H).

[0001538] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.67 (br s, 1H), 8.74 - 8.49 (m, 1H), 7.53 - 7.28 (m, 2H), 6.54 (d, J=2.2 Hz, 1H), 5.05 - 4.84 (m, 1H), 4.54 - 4.38 (m, 1H), 3.17 (br d, J=7.2 Hz, 2H), 2.54 (br t, J=6.1 Hz, 2H), 2.43 (br t, J=5.6 Hz, 3H), 2.28 - 2.08 (m, 2H), 1.90 - 1.79 (m, 1H), 1.77 - 1.65 (m, 6H), 1.56 (qd, J=6.7, 13.7 Hz, 1H), 0.83 - 0.70 (m, 1H), 0.42 (br d, J=7.8 Hz, 2H), 0.20 - 0.04 (m, 2H).

Example 193. Synthesis of viral protease inhibitor compound 715

Step 1: N-[ ( l S)-2-[[( 1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ] methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-chloro-lH-pyrrolo[3,2-c]p yridine-2-carboxamide

[0001539] To a solution of 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (110.5 mg, 0.56 mmol, 1 eq) in DMF (2 mL) was added HATU (256.6 mg, 0.67 mmol, 1.2 eq), DIEA (218.0 mg, 1.69 mmol, 0.29 mL, 3 eq) and (2S)-2-amino-N-[( 1 S)-2-amino-2-oxo- 1 - [[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propana mide (200 mg, 0.67 mmol, 1.2 eq). The mixture was stirred at 25 °C for 16 hr. LC-MS showed the desired compound was detected. TLC (DCM/MeOH = 10:1). The reaction mixture was diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic phase was washed with brine (10 mL * 3), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0-20% DCM/MeOH ethergradient @ 20 mL/min) to afford N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-chloro-1H- pyrrolo[3,2-c]pyridine-2-carboxamide (214 mg, 76.2% yield) as a yellow solid. Step 2: 4-chloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-lH-pyrrolo[3,2-c]pyridine-2 -carboxamide

[0001540] To a solution of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-chloro-1H- pyrrolo[3,2-c]pyridine-2-carboxamide (214 mg, 0.45 mmol, 1 eq) in DCM (3 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (322.1 mg, 1.35 mmol, 3 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h. TLC (DCM: MeOH = 10: 1). The reaction mixture was filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0-10% petroleum ether/ethyl acetate ethergradient @ 25 mL/min) to give 4-chloro-N- [( 1 S)-2-[[( 1 S)- 1 -cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2- oxo-ethyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide (80 mg, 36.5% yield) as a white solid.

[0001541 ] LCMS: Rt = 1.356 min; for C22H25CIN6O3 MS Calcd.: 456.17; MS Found: 457.1 [M+H ⁺ ],

[0001542] ¹ H NMR (400 MHz, CD ₃ OD) δ 8.75 - 8.65 (m, 1H), 7.53 - 7.43 (m, 1H), 7.41 - 7.31 (m, 1H), 5.14 (br d, J= 9.5 Hz, 1H), 4.54 (br t, J= 7.2 Hz, 1H), 3.24 (br s, 2H), 2.56 - 2.41 (m, 2H), 2.02 - 1.87 (m, 2H), 1.86 - 1.61 (m, 4H), 1.59 - 1.45 (m, 1H), 0.85 (br s, 1H), 0.54 (br d ,J= 8.0 Hz, 2H), 0.23 - 0.15 (m, 2H).

Example 194. Synthesis of viral protease inhibitor compound 639

7-chloro-N-((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl -l - oxopropan-2-yl)- 1 H-indole-2-carboxamide

Step 1:

(S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanami do)-3-((S)-2- oxopiperidin-3-yl)propanoate

[0001543 ] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (1.45 g, 6.34 mmol, 1.5 eq), methyl (2 S)-2-amino-3 -[(3 S)-2-oxo-3 - piperidyl]propanoate (1 g, 4.22 mmol, 1 eq, HCI), DMAP (1.55 g, 12.67 mmol, 3 eq) in DCM (10 mL) was added EDCI (2.43 g, 12.67 mmol, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O 50 mL at 20 °C, and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL *2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 80/1 to 1/2) to give methyl (2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoyl]amino]-3-[(3S)- 2-oxo-3- piperidyl]propanoate (1.5 g, 3.10 mmol, 73.34% yield, 85% purity) as a yellow oil. MS (ESI) m/z 412.2 [M+H] ⁺ .

[0001544] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (29.06 g, 126.75 mmol, 1.5 eq), methyl (2S)-2-amino-3-[(3S)-2-oxo-3- piperidyl]propanoate (20 g, 84.50 mmol, 1 eq, HCI) and DMAP (25.81 g, 211.24 mmol, 2.5 eq) in DCM (200 mL), then EDCI (32.40 g, 168.99 mmol, 2.0 eq) was added. The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was quenched by addition H20300 mL at 0 °C, and extracted with DCM 300 mL (100 mL * 3). The combined organic layers were washed with 0.5N HC1 100 mL and brine (100 mL * 2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si 02, Petroleum ether/Ethyl acetate = 10/1 to 1/2). To give methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbony lamino)-3 -cy clopropy 1- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (23 g, 54.83 mmol, 64.89% yield, 98.1% purity) was obtained as a white solid.

Step 2:

(S)-methyl 2-((S)-2-amino-3-cycIopropyIpropanamido)-3-((S)-2-oxopiperid in-3- yl)propanoate

[0001545] To a solution of methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbonyl amino)-3 - cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate (1.5 g, 3.65 mmol,

1 eq) in HCl/MeOH (4 M, 15.00 mL, 16.46 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3- [(3 S)-2-oxo-3 -piperidy 1 ]propanoate (1.27 g, crude, HC1) as a yellow oil. MS (ESI) m/z 312.2 [M+H] ⁺ .

Step 3:

(S)-methyl 2-((S)-2-(7-chloro-lH-indole-2-carboxamido)-3-cyclopropylpro panamido)-3-((S)-

2-oxopiperidin-3-yl)propanoate

[0001546] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.27 g, 3.65 mmol, 1 eq, HC1), 7-chloro-lH-indole-2-carboxylic acid (714.17 mg, 3.65 mmol, 1 eq), DMAP (1.34 g, 10.95 mmol, 3 eq) in DCM (13 mL) was added EDCI (1.75 g, 9.13 mmol, 2.5 eq) at 0 °C, the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O (20 mL) at 20 °C, and then extracted with DCM (25 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 80/1 to 1/0) to give methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]-3-cyc lopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.3 g, 2.53 mmol, 69.18% yield, 95% purity) as a yellow solid. MS (ESI) m/z 489.2 [M+H] ⁺ .

Step 4:

N-((S)-1 -(((S)-l -amino-1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3-cyclopr opyl-

I-oxopropan-2-yl)-7-chloro-JH-indole-2-carboxamide

[0001547] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]- 3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pro panoate (1.3 g, 2.66 mmol, 1 eq) in NH ₃ /MeOH (7 M, 26 mL, 68.45 eq) was stirred at 65 °C for 16 h. 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]meth yl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-7-chloro-lH-indole-2-carbox amide (1.26 g, crude) as a yellow solid. MS (ESI) m/z 474.2 [M+H] ⁺ .

Step 5:

7-chloro-N-((S)-l-(((S)-l-cyano-2-((S)-2-oxopiperidin-3-y l)ethyl)amino)-3-cyclopropyl-l- oxopropan-2-yl)-lH-indole-2-carboxamide

[0001548] To a solution of N-[(l S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-7-chloro-lH-indole- 2-carboxamide (1.26 g, 2.66 mmol, 1 eq) in DCM (13 mL) was added Burgess reagent (1.58 g, 6.65 mmol, 2.5 eq). The mixture was stirred at 25 °C for 7 h. Upon completion, the reaction mixture was concentrated by N2 remove solvent. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 0/1) to give 7- chloro-N-[(l S)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide (950 mg, crude) as a white solid. MS (ESI) m/z 456.2 [M+H] ⁺ .

Example 195. Synthesis of viral protease inhibitor compound 717

Step 1 : (2S)-2-amino-N-[ ( 1 S)-2-amino-2-oxo-l-[ [ ( 3S)-2-oxo-3-piperidyl ] me thy l ] ethyl ]-3- cyclopropyl-propanamide [0001549] 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-et hyl]carbamate (600 mg,

1.39 mmol, 1 eq) in THF (1 mL) was added Pd/C under N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (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-[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2- oxo-3-piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (400 mg, crude) was obtained as a colorless oil.

Step 2: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[(3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- ( cyclopropyl methyl) -2-oxo-ethyl ]-5-chloro- lH-pyrrolo[ 2, 3-c]pyridine-2-carboxamide

[0001550] A solution of (2S)-2-amino-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-3-cyclopropyl-propanamide (250 mg, 0.84 mmol, 1 eq) in DMF (1 mL) was added HATU (320.7 mg, 0.84 mmol, 1 eq), 5-chloro-lH-pyrrolo[2,3- c]pyridine-2-carboxylic acid (182.4 mg, 0.92 mmol, 1.1 eq) and DIEA (218.0 mg, 1.69 mmol, 0.29 mL, 2 eq) was stirred at 25 °C for 16 hr. TLC (DCM/MeOH = 10:1, Iz). The reaction mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate (30 mL *3). The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ , 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 ~ 7% DCM/MeOH @ 35 mL/min). N-[( 1 S)-2-[[( 1 S)-2- amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1 -(cyclopropylmethyl)-2- oxo-ethyl]-5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (260 mg, 64.3% yield, 99.2% purity) was obtained as a white solid.

Step 3: 5-chloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl]amino]-l- (cyclopropylmethyl) -2-oxo-ethyl ]-lH-pyrrolo[ 2, 3-c ]pyridine-2-cctrboxamide

[0001551 ] 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-et hyl]-5-chloro-1H- pyrrolo[2,3-c]pyridine-2-carboxamide (100 mg, 0.21 mmol, 1 eq) in DCM (1 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (150.5 mg, 0.63 mmol, 3 eq). The mixture was stirred at 25 °C for 24 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with DCM (30 mL *3). The combined organic layers were washed with brine (30 mL *2), dried with anhydrous Na ₂ SO ₄ , 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% NH3H ₂ O + 10 mM NH ₄ HCO ₃ )-ACN];B%: 15%-45%, 9.5 min). 5-Chloro-A4(1S)-2-[[(1S)-1-cyano-2- [(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2 -oxo-ethyl]-1H- pyrrolo[2,3-c]pyridine-2-carboxamide (94 mg, 96.7% yield, 99% purity) was obtained as a yellow solid.

[0001552] LCMS : Rt = 0.754 min; for CzzH ₂ sCINeCh MS Calcd.: 456.93; MS Found: 457.1 [M+H ⁺ ],

[0001553] ¹ H NMR (400MHz, CD3OD) δ 8.58 (s, 1H), 7.72 - 7.65 (m, 1H), 7.20 (s, 1H), 5.13 (dd, J = 6.1, 10.2 Hz, 1H), 4.58 - 4.52 (m, 1H), 3.28 - 3.16 (m, 2H), 2.59 - 2.39 (m, 2H), 2.07 - 1.87 (m, 3H), 1.87 - 1.79 (m, 1H), 1.78 - 1.62 (m, 2H), 1.60 - 1.44 (m, 1H), 0.91 - 0.78 (m, 1H), 0.58 - 0.47 (m, 2H), 0.26 - 0.13 (m, 2H).

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

Step 1: [(2S)-l-hydroxy-2-[[(2S,4S)-l-(4-methoxy-lH-indole-2-carbony l)-4-phenyl- pyrrolidine-2-carbonyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ] propyl ]sulfonyloxypotassium [0001554] To a mixture of (2S,4S)-N-[(1S)-1-formyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl] -1- (4-methoxy-lH-indole-2-carbonyl)-4-phenyl-pyrrolidine-2-carb oxamide (40 mg, 79.59 umol, 1 eq) in THF (0.5 mL) was added K2S2O5 (8.67 mg, 39.00 umol, 0.49 eq) in H ₂ O (0.1 mL) at 45 °C under N ₂ . The mixture was stirred at 45 °C for 3 h, and then stirred at 25 °C for 14 h under N ₂ . Upon completion, the reaction mixture was concentrated under reduced pressure, and then triturated with THF (1 mL) at 25 °C for 1 h to give [(2S)- 1- hydroxy-2-[[(2S,4S)-1-(4-methoxy-lH-indole-2-carbonyl)-4-phe nyl-pyrrolidine-2- carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propyl]sulfonyl oxypotassium (14.09 mg, 20.36 umol, 25.58% yield, 90% purity) as an off-white solid. MS (ESI) m/z 585.3 [M- 36.8] ⁺ .

[0001555] ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 11.68 - 11.40 (m, 1H), 8.08 - 7.64 (m, 0.5H), 7.52 - 7.43 (m, 0.5H), 7.41 - 7.29 (m, 4H), 7.28 - 7.19 (m, 1H), 7.15 - 6.97 (m,

2H), 6.96 - 6.76 (m, 1H), 6.55 - 6.37 (m, 1H), 5.48 - 5.27 (m, 1H), 5.25 - 4.92 (m, 0.5H), 4.80 - 4.60 (m, 0.5H), 4.46 - 4.07 (m, 2H), 4.02 - 3.93 (m, 0.5H), 3.93 - 3.63 (m, 5H),

3.62 - 3.36 (m, 1H), 3.18 - 3.02 (m, 1H), 2.94 - 2.69 (m, 0.5H), 2.35 - 2.17 (m, 3H), 2.10 - 1.87 (m, 1H), 1.82 - 1.27 (m, 3H).

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

Step 1: (2S,4R)-dimethyl 2-((tert-butoxycarbonyl)amino)-4-(cyanomethyl)pentanedioate

[0001556] To a solution of dimethyl 2-(tert-butoxycarbonylamino)pentanedioate (10 g, 36.32 mmol, 1 eq) in THF (150 mL) was added LiHMDS (1 M, 83.55 mL, 2.3 eq) at - 78 °C under N ₂ . The mixture was stirred at -78 °C for 1.5 h. Then, 2-bromoacetonitrile (6.54 g, 54.49 mmol, 3.63 mL, 1.5 eq) was added dropwise to the reaction at -78 °C. The mixture was stirred at -78 °C for 2.5 h. TLC (PE: EA=3: 1, Iz). The reaction was completed, pre-cool ed methanol (15 mL) and glacial acetic acid (12 mL) were sequentially added to quench the reaction. The reaction was warmed to 25 °C, and the solvent was distilled off under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-20% ethyl acetate/petroleum ether gradient @ 80 mL/min). Dimethyl (4R)-2-(tert- butoxycarbonylamino)-4-(cyanomethyl)pentanedioate (15 g, 47.72 mmol, 43.79% yield) was obtained as a yellow oil.

Step 2: (S)-methyl2-((tert-butoxycarbonyl)amino)-3-( (S)-2-oxopyrrolidin-3-yl)propanoate

[0001557] Dimethyl (4R)-2-(tert-butoxycarbonylamino)-4-(cyanomethyl)pentanedioa te ( 15 g, 47.72 mmol, 1 eq) was dissolved in MeOH (250 mL), and CoCI2.6H ₂ O (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, 12). 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.

Step 3: tert-butyl ((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)c arbamate

[0001558] 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 ofNH ₃ (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.

Step 4: Tert-butyl ((S)-l-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)carbamate

[0001559] To a solution of tert-butyl N-[(l S)-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 H ₂ O (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.

Step 5: (S)-2-ammo-3-((S)-2-oxopyrrolidm-3-yl)propanenitrile hydrochloride

[0001560] To a solution of tert-butyl N-[(l S)-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, HC1) was obtained as a white solid.

Example 198. Synthesis of viral protease inhibitor compound 842

Step 1: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(5,7-dichloro-lH-indole-2- carbonyl)amino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001561 ] To a mixture of 5,7-dichloro-lH-indole-2-carboxylic acid (1 g, 4.35 mmol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxo-3- piperidyl]propanoate (1.35 g, 3.89 mmol, 8.95e-l eq, HC1) in DCM (24 mL) was added DMAP (1.59 g, 13.04 mmol, 3 eq) and EDCI (1.67 g, 8.69 mmol, 2 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 H ₂ O (20 mL) and extracted with ethyl acetate (20 mL * 4). The combined organic layers were washed with brine (40 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/l to 0/1) to give methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(5,7-dichloro-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (1.2 g, 2.29 mmol, 52.74% yield) as a white solid. MS (ESI) m/z 521.0 [M-H] ⁺

Step 2: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-5,7-dichloro-lH-indole-2-ca rboxamide

[0001562] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(5,7-dichloro-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (1.2 g, 2.29 mmol, 1 eq) in NH ₃ /MeOH (7M, 30 mL) was stirred at 55 °C for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give N- [(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]meth yl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-5,7-dichloro-lH-indole-2-ca rboxamide (1 g, 1.97 mmol, 85.79% yield) as a white solid. MS (ESI) m/z 508.2 [M+H] ⁺

Step 3: 5, 7-dichloro-N-[ ( l S)-2-[[( l S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ] ethyl ]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[0001563 ] To a mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-5,7-dichloro-lH- indole-2-carboxamide (260 mg, 475.61 umol, 93% purity, 1 eq) in DCM (5 mL) was added Burgess reagent (226.68 mg, 951.23 umol, 2 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition; column: Phenomenex Gemini -NX C18 75*30mm*3um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 40%-60%,8min) to give 5,7-dichloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperi dyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide (100 mg, 203.92 umol, 42.88% yield) as a white solid. MS (ESI) m/z 490.1 [M+H] ⁺ [0001564 ] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ = 11.98 (br s, 1H), 9.00 (d, J=7.9 Hz, 1H), 8.77 (d, J=7.7 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.54 (br s, 1H), 7.41 (d, J=1.8 Hz, 1H), 7.26 (s, 1H), 5.07 (q, J=8.0 Hz, 1H), 4.55 - 4.47 (m, 1H), 3.16 - 3.02 (m, 2H), 2.30 - 2.20 (m, 2H), 1.90 - 1.65 (m, 4H), 1.63 - 1.33 (m, 3H), 0.87 - 0.75 (m, 1H), 0.50 - 0.36 (m, 2H), 0.24 - 0.07 (m, 2H).

Example 199. Synthesis of viral protease inhibitor compound 852

Step 1: 7-bromo-5-fluoro-lH-indole-2-carboxylic acid

[0001565] 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 H ₂ O (4 mL) was added LiOH H ₂ O (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 HC1 (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] ⁺

Step 2: (S)-methyl2-( (S)-2-(7-bromo-5-fluoro-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[0001566 ] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3-[(3S)-2-oxo-3- piperidyl] propanoate (800 mg, 2.30 mmol, 1 eq, HC1) and 7-bromo-5- fluoro-1H-indole-2-carboxylic acid (700 mg, 2.76 mmol, 1.2 eq) in DCM (10 mL) was added DMAP (561.96 mg, 4.60 mmol, 2 eq), and then the mixture was added with EDCI (881.79 mg, 4.60 mmol, 2 eq). After stirring at 20 °C for 2 h, the mixture was poured into water (30 mL) and was extracted with DCM (10 mL * 3) and dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum and was purified by column (SiO ₂ , PE/EA=1 :0 to 0: 1) to obtain (S)-methyl 2-((S)-2-(7-bromo -5-fluoro-1H-indole-2- carboxamido)-3-cyclopropylpropanamido)-3-((S)-2-oxopiperidin -3-yl)propanoate (1 g, 1.75 mmol, 76.09% yield, 96.5% purity) as a light yellow solid. MS (ESI) m/z 551.1 [M+H] ⁺

Step 3: N-( (S)-l-( ( (S)-l -amino-1 -oxo-3-( (, S)-2-oxopiperidin-3-yl)propan-2-yl)ammo)-3 - cyclopropyl- l-oxopropan-2-yl)-7-bromo-5-fluoro-lH-indole-2-carboxamide

[0001567] 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 NH ₃ /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 concentrtaed 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-1 H-indole-2-carboxamide (800 mg, crude) as a light yellow solid. MS (ESI) m/z 536.2 [M+H] ⁺

Step 4: 7-bromo-N-((S)-l-(((S)-l-cyano-2-((S)-2-oxopiperidin-3-yl)et hyl)ammo)-3- cyclopropyl-l-oxopropan-2-yl)-5-fluoro-lH-indole-2-carboxami de

[0001568] To a solution of 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, 1.81 mmol, 1 eq) in DCM (10 mL) was added Burgess reagent (1.30 g, 5.44 mmol, 3 eq), and the mixture was stirred at 30 °C for 4 h. Upon completion of reaction, the reaction mixture was quenched by water (1 mL) and was dried with using N ₂ and was purified by prep-HPLC (column: Welch Xtimate C18250*70mm#10um; mobile phase: [water (lOmM NH4HCO ₃ )-ACN]; B%: 30%-60%, 20min) to obtain 7- bromo-N-((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 -cyclopropyl- 1 - oxopropan-2-yl)-5-fluoro-1H-indole-2-carboxamide (740 mg, 1.33 mmol, 53.51% yield, 98% purity) as a white solid. MS (ESI) m/z 518.1 [M+H] ⁺ [0001569] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ ppm 9.01 (d, J= 7.7 Hz, 1H), 8.81 (d ,J= 7.5 Hz, 1H), 7.59 - 7.48 (m, 2H), 7.45 (dd, J = 2.4, 9.0 Hz, 1H), 7.26 (s, 1H), 5.07 (q, J = 7.8 Hz, 1H), 4.57 - 4.46 (m, 1H), 3.14 - 3.01 (m, 2H), 2.31 - 2.19 (m, 2H), 1.90 - 1.64 (m, 4H), 1.63 - 1.34 (m, 3H), 0.85 - 0.75 (m, 1H), 0.49 - 0.37 (m, 2H), 0.24 - 0.06 (m, 2H).

Example 200. Synthesis of viral protease inhibitor compound 876

Step 1: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pent anoyl]amino]-3- [ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001570] A mixture of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.3 g, 5.49 mmol, 1 eq, HCI) in DCM (20 mL) was added (2S)-2-(tert-butoxycarbonylamino)- 4,4-dimethyl-pentanoic acid (1.62 g, 6.59 mmol, 1.2 eq), DMAP (1.68 g, 13.73 mmol, 2.5 eq) and EDCI (2.11 g, 10.98 mmol, 2 eq). After stirring at 20 °C for 1 h, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , PE:EA = 6/1 — 4/1) to get product methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.9 g, 4.00 mmol, 72.82% yield, 90% purity) as yellow oil. MS (ESI) m/z 428.3 [M+H] ⁺ .

Step 2: methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate

[0001571 ] A mixture of methyl (2 S)-2-(tert-butoxy carbonyl amino)-3 -[(3 S)-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, HC1) as white oil. MS (ESI) m/z 328.3 [M+H] ⁺ .

Step 3: methyl (2S)-2-[[(2S)-2-[[4-[2-(2-methoxyethoxy)ethoxy]-JH-indole-2- carbonyl ] amino ]-4, 4-dimethyl-pentanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001572] A mixture of methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (1.35 g, 3.71 mmol, 1 eq, HC1) in DCM (20 mL) then added 4-[2-(2-methoxy ethoxy )ethoxy]- 1 H-indole-2-carboxylic acid (1.24 g, 4.45 mmol, 1.2 eq), DMAP (1.13 g, 9.28 mmol, 2.5 eq) and EDCI (1.42 g, 7.42 mmol, 2 eq) was stirred at 20 °C for 1.5 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , PE:EA = 8/1 — 4/1) to get methyl (2S)-2-[[(2S)-2- [[4-[2-(2-methoxy ethoxy )ethoxy]-lH-indole-2-carbonyl]amino]-4,4-dimethyl- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (2.1 g, 2.85 mmol, 76.92% yield, 80% purity) as a yellow solid. MS (ESI) m/z 589.4 [M+H] ⁺ .

Step 4: 2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2- oxopyrrolidin-3-yl ] ethyl ]-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001573] A mixture of methyl (2S)-2-[[(2S)-2-[[4-[2-(2-methoxy ethoxy )ethoxy]-lH- indole-2-carbonyl]amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3 S)-2-oxo-3- piperidyl]propanoate (0.52 g, 4 batches in parallel, 706.65 umol, 80% purity, 1 eq) in NH ₃ /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-methoxy ethoxy )ethoxy]- lH-indole-2-carboxamide (1.3 g, crude) as a white solid. MS (ESI) m/z 574.4 [M+H] ⁺ .

Step 5: N-f l-[[l -cyano-2-[ ( 3S)-2-oxo-3-piperidyl ]ethyl ] carbamoyl ]-3, 3-dimethyl-butyl ]-4-

[2-(2-methoxyethoxy)ethoxy]-lH-indole-2-carboxamide

[0001574] A mixture of N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-[2-( 2-methoxyethoxy)ethoxy]- lH-indole-2-carboxamide (1.1 g, 1.92 mmol, 1 eq) in DCM (15 mL) was added with BURGESS REAGENT (1.37 g, 5.76 mmol, 3 eq). The resulting mixture was stirred at 30 °C for 3 h. Upon completion, the mixture were quenched with water (1 mL) and dried with using N ₂ . The residue was purified by prep-HPLC (column: Waters X bridge C18 150 * 50 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30% - 60%, 10 min), which was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: [Neu-ETOH]; B%: 53% - 53%, 10 min): to afford N-[ 1 -[[ 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4- [2-(2-methoxyethoxy)ethoxy]-lH-indole-2-carboxamide Isomer 1 (250.32 mg, 450.49 umol, 23.46% yield) as a white solid. MS (ESI) m/z 556.3 [M+H] ⁺ .

[0001575] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.29 (s, 1H), 7.17 - 7.10 (m, 1H), 7.07 - 7.01 (m, 1H), 6.52 (d, J=7.5 Hz, 1H), 5.08 (dd, J=6.2, 9.9 Hz, 1H), 4.64 (dd, J=4.2, 8.6 Hz, 1H), 4.29 - 4.23 (m, 2H), 3.93 (dd, J=4.0, 5.3 Hz, 2H), 3.79 - 3.74 (m, 2H), 3.62 - 3.54 (m, 2H), 3.37 (s, 3H), 3.23 - 3.14 (m, 2H), 2.49 - 2.37 (m, 2H), 2.00 - 1.41 (m, 7H), 1.03 (s, 9H).

[0001576] N-[l-[[l-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]carbamoyl]-3, 3-dimethyl- butyl]-4-[2-(2-methoxyethoxy)ethoxy]-lH-indole-2-carboxamide Isomer 2 (27.92 mg, 50.25 umol, 2.62% yield) was obtained as a white solid. MS (ESI) m/z 556.3 [M+H] ⁺ .

[0001577] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.29 (d, J=0.9 Hz, 1H), 7.17 - 7.11 (m, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.52 (d, J=7.5 Hz, 1H), 5.08 (dd, J=5.8, 8.0 Hz, 1H), 4.68 (dd, J=4.0, 8.8 Hz, 1H), 4.30 - 4.23 (m, 2H), 3.93 (dd, J=3.9, 5.2 Hz, 2H), 3.80 - 3.73 (m, 2H), 3.62 - 3.56 (m, 2H), 3.37 (s, 3H), 3.22 - 3.13 (m, 2H), 2.45 - 2.28 (m, 2H), 2.01 - 1.76 (m, 5H), 1.71 - 1.49 (m, 2H), 1.02 (s, 9H). [0001578] N-[l-[[l-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]carbamoyl]-3, 3-dimethyl- butyl]-4-[2-(2-methoxyethoxy)ethoxy]-lH-indole-2-carboxamide Isomer 3 (31.42 mg, 56.54 umol, 2.95% yield) was obtained as a a white solid. MS (ESI) m/z 556.3 [M+H] ⁺

[0001579] ¹ H NMR (400 MHz, MeO _D-d4 ) δ = 7.30 (d, J=0.9 Hz, 1H), 7.13 (d, J=7.7 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.53 (d, J=7.3 Hz, 1H), 5.01 (s, 1H), 4.65 (s, 1H), 4.30 - 4.23 (m, 2H), 3.93 (dd, J=4.0, 5.3 Hz, 2H), 3.81 - 3.73 (m, 2H), 3.63 - 3.55 (m, 2H), 3.37 (s, 3H), 3.21 (br d, J=4.6 Hz, 2H), 2.49 - 2.37 (m, 1H), 2.34 - 2.23 (m, 1H), 1.97 - 1.88 (m, 2H), 1.87 - 1.63 (m, 4H), 1.58 - 1.45 (m, 1H), 1.02 (s, 9H).

Example 201. Synthesis of viral protease inhibitor compound 880

Step 1: methyl (Z)-2-azido-3-(2-chloro-3-methoxy-phenyl)prop-2-enoate

[0001580] A mixture 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. The mixture was stirred at 25 °C for 16 h and white solid was observed. Upon completion, the reaction mixture was filtered to give the 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. MS (ESI) m/z 267.0 [M+H] ⁺

Step 2: methyl 4-chloro-5-methoxy-lH-indole-2-carboxylate

[0001581 ] 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 H ₂ 0 (100 mL) and then extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by column chromatography (Si0 ₂ , petroleum ether/ethyl acetate = 10/1 to 5/1) to afford methyl 4- chloro-5-methoxy- 1 H-indole-2-carboxylate (140 mg, 584.17 umol, 15.64% yield) was a brown solid. MS (ESI) m/z 240.0 [M+H] ⁺

Step 3: 4-chloro-5-methoxy-lH-indole-2-carboxylic acid

[0001582] To a solution of methyl 4-chloro-5-methoxy- 1 H-indole-2-carboxylate (0.55 g, 2.29 mmol, 1 eq) in THF (5 mL), H ₂ 0 (2.5 mL) was added LiOH H ₂ 0 (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 HC1. The mixture was extracted with ethyl acetate (100 mL * 3). The combined organic layer was dried over Na ₂ SO ₄ , filtered, concentrated to give 4-chloro-5-methoxy- 1 H-indole-2-carboxylic acid (340 mg, crude) as a brown solid. MS (ESI) m/z 226.0 [M+H] ⁺

Step 4: (2S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-(2-azaspiro[4.5]decane-3- carboxamido)propanoate

[0001583] A solution of tert- butyl 3-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylat e (1.3 g, 2.88 mmol, 1 eq) in HCl/MeOH (15 mL) was stirred for 1 h at 25 °C. Upon completion, the mixture was quenched by the addition NaHCO ₃ (200 mL) and then extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a crude product (2S)-methyl 3- ((S)-2-oxopyrrolidin-3-yl)-2-(2-azaspiro[4.5]decane-3-carbox amido)propanoate (1.1 g, crude) was yellow solid. MS (ESI) m/z 352.2 [M+H] ⁺

Step 5: (2S)-methyl 2-(2-(4-chloro-5-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4. 5]decane-

3-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001584] To a solution of (2S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-(2- azaspiro[4.5]decane-3-carboxamido)propanoate (934.56 mg, 2.66 mmol, 1 eq) in DCM (20 mL) was added 4-chloro-5-methoxy-lH-indole-2-carboxylic acid (600 mg, 2.66 mmol, 1 eq), EDCI (1.02 g, 5.32 mmol, 2 eq), and DMAP (974.62 mg, 7.98 mmol, 3 eq). After stirring the mixture at 25 °C for 1 h, the reaction was quenched by addition H ₂ O (200 mL) and then extracted with ethyl acetate (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over NazSC^, filtered and concentrated under reduced pressure and was purified by prep-TLC (SiO ₂ , DCM MeOH = 10: 1) to afford (2S)-methyl 2-(2-(4-chloro-5-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (1.2 g, 1.93 mmol, 72.57% yield, 89.9% purity) as a yellow solid. MS (ESI) m/z 559.2 [M+H] ⁺

Step 6: N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidm-3-yl)propan-2-yl) -2-(4-chloro-5- methoxy-lH-indole-2-carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001585] A solution of (2S)-methyl 2-(2-(4-chloro-5-m ethoxy- 1 H-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carboxamido)-3-((S)-2-oxopyrrolidin-3- yl)propanoate (1.2 g, 2.15 mmol, 1 eq) in NH ₃ (in MeOH, 7 M, 30 mL, 97.83 eq) was stirred at 40 °C for 8 h. Upon completion, the reaction was concentrated in the vacuum to give crude product N-((S)-1- amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-(4-ch loro-5-methoxy-lH-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (1.15 g, crude) as a yellow solid. MS (ESI) m/z 544.2 [M+H] ⁺

Step 7: (2S)-methyl 2-(2-(4-chloro-5-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4. 5]decane- 3-carboxamido)-3-((S)-2-oxopyrroIidin-3-yI)propanoate

[0001586] To a solution of N-((S)- 1 -amino-1 -oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)-2-(4-chloro-5-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4 .5]decane-3-carboxamide (1.15 g, 2.11 mmol, 1 eq) in DCM (20 mL) was added BURGESS REAGENT (1.51 g, 6.34 mmol, 3 eq), and the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 35%-65%,10min) to give 2- (4-chloro-5-methoxy-lH-indole-2-carbonyl)-N-((S)-1-cyano-2-( (S)-2-oxopyrrolidin-3- yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide (400 mg, 760.42 umol, 35.97% yield) as a white solid. MS (ESI) m/z 526.2 [M+H] ⁺

Step 8: (2S)-methyl 2-(2-(4-chloro-5-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4. 5]decane- 3-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001587] 2-(4-chloro-5-methoxy- 1 H-indole-2-carbonyl)-N-((S)- 1 -cyano-2-((S)-2- oxopyrrolidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamid e was separated by SFC (column: DAICEL CHIRALPAK AS(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ 0 MEOH];B%: 43%-43%,8min) to afford 2-(4-chloro-5-methoxy-lH- indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-y l)ethyl)-2- azaspiro[4.5]decane-3-carboxamide (170 mg, 323.18 umol, 42.50% yield, 100% purity) as a white solid. MS (ESI) m/z 526.2 [M+H] ⁺

[0001588] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.80 - 11.70 (m, 1H), 9.07 - 8.78 (m, 1H), 7.72 - 7.50 (m, 1H), 7.41 - 7.33 (m, 1H), 7.21 - 7.12 (m, 1H), 6.92 - 6.57 (m, 1H), 5.00 - 4.89 (m, 1H), 4.82 - 4.46 (m, 1H), 3.88 - 3.81 (m, 4H), 3.73 - 3.38 (m, 1H), 3.17 - 2.90 (m, 2H), 2.40 - 2.20 (m, 2H) 2.17 - 2.05 (m, 2H), 1.82 - 1.64 (m, 2H), 1.61 - 1.51 (m,

2H), 1.49 - 1.27 (m, 9H)

[0001589] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.52 (br s, 1H), 8.65 (br s, 1H), 7.40 - 7.39 (m, 2H), 7.16 - 7.13(m, 1H), 6.86 (br s, 1H), 4.94 (br s, 1H), 4.59 (br s, 1H), 3.90 - 3.68 (m, 5H), 3.15 - 3.06(m, 2H), 2.26 - 2.05 (m, 4H), 1.80 (br s, 1H), 1.68 (br s, 1H), 1.56 - 1.52(m, 3H), 1.45 - 1.40(m, 8H)

[0001590] 2-(4-chloro-5-methoxy-lH-indole-2-carbonyl)-N-((S)-1-cyano-2 -((S)-2- oxopyrrolidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamid e (170 mg, 323.18 umol, 42.50% yield, 100% purity) was obtained as white solid. MS (ESI) m/z 526.2 [M+H] ⁺

[0001591] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.79 - 11.65 (m, 1H), 9.10 - 8.87 (m, 1H),

7.75 - 7.55 (m, 1H), 7.43 - 7.27 (m, 1H), 7.21 - 7.08 (m, 1H), 6.93 - 6.58 (m, 1H), 4.99 - 4.94(m, 1H), 4.69 - 4.44 (m, 1H), 3.92 - 3.79 (m, 4H), 3.77 - 3.67 (m, 1H), 3.31 - 3.06 (m, 2H), 2.48 - 2.34 (m, 1H), 2.46 - 2.34 (m, 1H), 2.20 - 2.05 (m, 2H), 1.97 - 1.64 (m, 2H), 1.63 - 1.52 (m, 2H), 1.50 - 1.29 (m, 9H)

[0001992] 1H NMR (400MHz, DMSO -d6) δ = 11.52 (br s, 1H), 8.75 (br s, 1H), 7.57 - 7.34 (m, 2H), 7.15 - 7.13 (m, 1H), 6.84 (br s, 1H), 4.91 (br s, 1H), 4.61 (br s, 1H), 3.86 - 3.68 (m, 5H), 3.17 - 3.09 (m, 2H), 2.43 - 2.02 (m, 4H), 1.81 (br s, 1H), 1.67 (br s, 1H), 1.53 (br s, 3H), 1.45 - 1.41 (m, 8H)

Example 202. Synthesis of viral protease inhibitor compound 882

Step 1: methyl (2S)-2-(2-azaspiro[ 4.5 ]decane-3-carbonylamino)-3-[ ( 3S)-2-oxopyrrolidin-3- yl]propanoate

[0001593 ] A mixture of tert-butyl 3-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxyla te (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-oxo pyrrolidin-3- yl]propanoate (1.29 g, crude, HCI) as a white oil MS (ESI) m/z 352.2 [M+H] ⁺ . Step 2: methyl (2S)-2-[[2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-2- azaspiro[ 4.5 ]decane-3-carbonyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001594] To a mixture of methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (1.24 g, 3.20 mmol, 1 eq, HC1) in DCM (15 mL) was added 7-chloro-4-methoxy-lH-indole-2-carboxylic acid (865.52 mg, 3.84 mmol, 1.2 eq), DMAP (976.35 mg, 7.99 mmol, 2.5 eq) and EDCI (1.23 g, 6.39 mmol, 2 eq). The resulting mixture was stirred at 20 °C for 1 h, and then the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , PE:EA = 8/1-5/1) to afford methyl (2S)-2-[[2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-2-azasp iro[4.5]decane-3- carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.6 g, 2.46 mmol, 77.00% yield, 86% purity) as a yellow oil. MS (ESI) m/z 559.3 [M+H] ⁺ .

Step 3: N-[(lS)-2-amino-2-oxo-l-[[(3S)-2-oxopyrrolidm-3-yl]methyl]et hyl]-2-(7-chloro-4- methoxy-lH-indole-2-carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001595] A mixture of methyl (2S)-2-[[2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidi n-3-yl]propanoate (400 mg, 4 batches in parallel, 615.33 umol, 86% purity, 1 eq) in NH ₃ /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-lH- 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] ⁺ .

Step 4: 2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2- oxopyrrolidin-3-yl ] ethyl ]-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001596 ] To a mixture of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-2-(7-chloro-4-methoxy-lH-indole-2-carbonyl) -2-azaspiro[4.5]decane-3- carboxamide (1.2 g, 2.21 mmol, 1 eq) in DCM (15 mL) was added BURGESS REAGENT (1.58 g, 6.62 mmol, 3 eq). After stirring at 30 °C for 1 h, the mixture was quenched with water (1 mL) and dried with using N ₂ . The residue was purified by prep- HPLC (column: Waters X bridge C18 150 * 50 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 35% - 65%, 10 min), which was further separated by SFC (column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 um); mobile phase: [Neu - IP A]; B%: 60% - 60%, 9 min) to afford 2-(7-chloro-4-methoxy- 1 H-indole-2-carbonyl)-N- [(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-azaspiro [4.5]decane-3-carboxamide Isomer 1 (378.42 mg, 719.39 umol, 32.62% yield, 100% purity) as a white solid. MS (ESI) m/z 526.2 [M+H] ⁺ .

[0001597] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.20 - 7.13 (m, 1H), 7.11 (s, 1H), 6.59 - 6.42 (m, 1H), 5.11 - 5.02 (m, 1H), 4.80 - 4.58 (m, 1H), 3.99 - 3.89 (m, 3H), 3.89 - 3.82 (m, 1H), 3.77 - 3.38 (m, 1H), 3.28 (br s, 1H), 2.99 - 2.66 (m, 1H), 2.52 - 2.25 (m, 3H), 2.17 - 1.69 (m, 3H), 1.65 - 1.26 (m, 11H).

[0001598] 2-(7-Chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2- oxopyrrolidin-3-yl]ethyl]-2-azaspiro[4.5]decane-3-carboxamid e Isomer 2 (367.22 mg, 698.10 umol, 31.65% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 526.2 [M+H] ⁺ .

[0001599| ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.18 (d, J=8.2 Hz, lH), 7.14 (s, 1H), 6.54 (d,J=8.3 Hz, 1H), 5.03 (dd, J=6.0, 10.1 Hz, 1H), 4.63 (dd, J=7.8, 9.7 Hz, 1H), 3.99 - 3.88 (m, 4H), 3.76 (d, J=10.3 Hz, 1H), 3.30 - 3.23 (m, 1H), 2.53 - 2.40 (m, 1H), 2.39 - 1.96 (m, 3H), 1.95 - 1.70 (m, 3H), 1.68 - 1.38 (m, 11H).

Example 203. Synthesis of viral protease inhibitor compound 886

Step 1: (2S)-methyl 3-((S)-2-oxopyrrolidin-3-yl)-2-(6-azaspiro[3.4]octane-7- carboxamido)propanoate hydrochloride

[0001600 ] A solution of tert-butyl 7-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-6-azaspiro[34]octane-6-carboxylat e (1.5 g, 3.54 mmol, 1 eq) in HCl/MeOH (4 M, 37.50 mL, 42.35 eq) 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-(6-azaspiro[3.4]octane-7-carbonylamino)-3-[(3S)-2-oxo pyrrolidin-3-yl]propanoate (1.2 g, crude, HCI) as a white solid.

Step 2: (2S)-methyl 2-(6-(4-chloro-5-methoxy-lH-indole-2-carbonyl)-6-azaspiro[3. 4]octane- 7-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0001601 ] To a solution of methyl (2S)-2-(6-azaspiro[3 4]octane-7-carbonylamino)-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (1.1 g, 3.06 mmol, 1 eq, HCI) and 4-chloro-5- methoxy-lH-indole-2-carboxylic acid (700 mg, 3.10 mmol, 1.01 eq) in DMF (7 mL) and DCM (30 mL) at 0 °C was added DMAP ( 1.12 g, 9.17 mmol, 3 eq) and EDCI (1.17 g,

6.11 mmol, 2 eq), and then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5:1 to 0:1) to give methyl (2S)-2-[[6-(4-chloro-5-methoxy-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-oxopyrrolidi n-3-yl]propanoate (1.2 g, 2.19 mmol, 71.71% yield, 97% purity) as a yellow solid. MS (ESI) m/z 531.2 [M+H] ⁺ .

Step 3: N-((S)-l-amino-l-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl )-6-(4-chloro-5- methoxy-lH-indole-2-carbonyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide

[0001602] A solution of methyl (2S)-2-[[6-(4-chloro-5-methoxy-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7-carbonyl]amino]-3-[(3S)-2-oxopyrrolidi n-3-yl]propanoate (1.2 g, 2.26 mmol, 1 eq) in NH ₃ /MeOH (7 M, 50 mL, 154.87 eq) was stirred at 25 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-6-(4-chloro-5- methoxy- 1 H-indole-2-carbonyl)-6-azaspiro[34]octane-7-carboxamide (1.1 g, crude) as a yellow solid. MS (ESI) m/z 516.2 [M+H] ⁺ .

Step 4: 6-( 4-chloro-5-methoxy-lH-indole-2-carbonyl)-N-( ( S)-l-cyano-2-( (S)-2- oxopyrrolidin-3-yl)ethyl)-6-azaspiro[ 3.4 ] octane- 7 -carboxamide [0001603] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-6-(4-chloro-5-methoxy-lH-indole-2-carbonyl) -6-azaspiro[3.4]octane-7- carboxamide (1.1 g, 2.13 mmol, 1 eq) in DCM (40 mL) was added BURGESS REAGENT (1.27 g, 5.33 mmol, 2.5 eq), and then the mixture was stirred at 40 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Titank CIS Bulk 250 * 70 mm 10 u; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 6% - 36%, 20 min) to give desired compound (500 mg, 47% yield, 99% purity) as a white solid, which was further separated by SFC (column: DAICEL CHIRALPAK AS (250 mm * 30 mm,

10 um); mobile phase: [Neu-MeOH]; B%: 55% - 55%, 7 min) to afford 6-(4-chloro-5- methoxy-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-[(3S)-2-oxop yrrolidin-3-yl]ethyl]-6- azaspiro[3.4]octane-7-carboxamide Isomer 1 (232.45 mg, 466.79 umol, 21.90% yield, 100% purity) as a white solid. MS (ESI) m/z 498.2 [M+H] ⁺ . [0001604] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.85 - 11.68 (m, 1H), 9.09 - 8.67 (m, 1H), 7.74 - 7.42 (m, 1H), 7.42 - 7.32 (m, 1H), 7.21 - 7.10 (m, 1H), 7.01 - 6.46 (m, 1H), 5.02 - 4.40 (m, 2H), 4.11 - 3.65 (m, 5H), 3.20 - 2.90 (m, 2H), 2.36 - 1.63 (m, 13H)

[0001605] 6-(4-Chloro-5-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2- oxopyrrolidin-3-yl]ethyl]-6-azaspiro[3.4]octane-7-carboxamid e Isomer 2 (232.89 mg, 467.68 umol, 21.94% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 498.2 [M+H] ⁺ .

[0001606] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.79 - 11.70 (m, 1H), 9.19 - 8.76 (m, 1H), 7.76 - 7.60 (m, 1H), 7.42 - 7.29 (m, 1H), 7.20 - 7.08 (m, 1H), 6.96 - 6.48 (m, 1H), 5.04 - 4.37 (m, 2H), 4.05 - 3.78 (m, 5H), 3.18 - 2.92 (m, 2H), 2.43 - 1.79 (m, 13H)

Example 204. Synthesis of viral protease inhibitor compound 888

Step 1: methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate

[0001607] A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (20 g, 69.85 mmol, 1 eq) in HCI/MeOH (200 mL) was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin- 3-yl]propanoate (13 g, crude, HCI) as a white solid. MS (ESI) m/z 187.1 [M+H] ⁺ Step 2: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pent anoyl]amino]-3- [ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001608] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (13 g, 58.38 mmol, 1 eq, HC1) and (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoic acid (14.32 g, 58.38 mmol, 1 eq) in DCM (200 mL) was added DMAP (21.40 g, 175.15 mmol, 3 eq), and then EDCI (33.58 g, 175.15 mmol, 3 eq) was added. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 100 mL, and then extracted with DCM 100 mL (50 mL * 2). The combined organic layers were washed with HC1 (1M) 100 mL (50 mL * 2), then were washed with brine 100 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 0/1) to give methyl (2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2 -oxopyrrolidin-3- yl Jpropanoate (23 g, 50.62 mmol, 86.70% yield, 91% purity) as a white solid. MS (ESI) m/z 414.3 [M+H] ⁺

Step 3: methyl (2S)-2-[[(2S)-2-amino-4, 4-dimethyl-pentanoyl ]amino]-3-[ ( 3S)-2- oxopyrrolidin-3-yl ]propanoate

[0001609] A solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (23 g, 55.62 mmol, 1 eq) in HCl/MeOH (200 mL) was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give methyl (2S)- 2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo pyrrolidin-3- yl Jpropanoate (19 g, crude, HC1) as a yellow solid. MS (ESI) m/z 314.2 [M+H] ⁺

Step 4: methyl (2S)-2-[[(2S)-2-[(7-chloro-JH-indole-2-carbonyl)amino]-4,4-d imethyl- pentanoyl ] amino ]-3-[ ( 3S)-2-oxopyrrolidin-3-yl ]propanoate

[0001610] 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, HC1) and 7-chloro-lH- 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 H ₂ O (30 mL), and then extracted with DCM 40 mL (20 mL * 2). The combined organic layers were washed with HC1 (1M) 30 mL (15 mL * 2), the combined organic layers were washed with brine (40 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 0/1) to afford methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]-4,4-d imethyl- 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] ⁺ .

Step 5: N-f (1S)-1-[[(1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxopyrrolidin-3- yl ]methyl ] ethyl ] carbamoyl ]-3, 3-dimethyl-butyl ]- 7-chloro-lH-indole-2-carboxamide [0001611 ] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]- 4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]p ropanoate (900 mg, 1.83 mmol, 1 eq) in NH ₃ /MeOH (7 M, 30 mL, 114.56 eq) was stirred at 20 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give N-[(1S)-1-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-7-chloro-lH-i ndole-2-carboxamide (770 mg, crude) as a white solid. MS (ESI) m/z 476.2[M+H] ⁺ .

Step 6: 7-chloro-N-[ (1S)-1-[[(1 S)-l-cyano-2-[ ( 3S)-2-oxopyrrolidin-3-yl ] ethyl ] carbamoyl ]- 3, 3-dimethyl-butyl ]-lH-indole-2-carboxamide

[0001612] To a solution of N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-7-chloro-lH-i ndole-2-carboxamide (760 mg, 1.60 mmol, 1 eq) in DCM (15 mL) was added Burgess reagent (761.03 mg, 3.19 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h, and then the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 35%-55%,10min) to give 7-chloro-N-[(1S)-1- [[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamoyl] -3,3-dimethyl-butyl]-lH- indole-2-carboxamide (421 mg, 919.31 umol, 57.57% yield, 100% purity) as a white solid. MS (ESI) m/z 458.2[M+H] ⁺ .

[0001613] 1H NMR (400MHz, DMSO-d ₆ ) δ = 11.70 (s, 1H), 9.01 (d ,J= 7.8Hz, 1H), 8.72 (d ,J= 8.1Hz, 1H), 7.74 - 7.58 (m, 2H), 7.37 - 7.22 (m, 2H), 7.07 (t ,J= 7.8Hz, 1H), 4.98 (q,J= 7.8Hz, 1H), 4.65 - 4.52 (m, 1H), 3.19 - 3.03 (m, 2H), 2.42 - 2.27 (m, 1H), 2.20 - 2.06 (m, 2H), 1.82 (d ,J= 7.4Hz, 1H), 1.75 - 1.64 (m, 3H), 0.95 (s, 9H).

Example 205. Synthesis of viral protease inhibitor compound 898

Step 1: (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((S)-2-oxopiperid in-3- yl)propanoate hydrochloride

[0001614] A solution of methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbony lamino)-3 - cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate (23 g, 55.89 mmol,

1 eq) in HCI/MeOH (4 M, 230 mL, 16.46 eq) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the produce methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxo-3- piperidyl]propanoate (20 g, crude, HCI) as a white solid. MS (ESI) m/z 312.1 [M+H] ⁺ .

Step 2: (S)-methyl 2-((S)-2-(7-chloro-4-methoxy-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[0001615] 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, HCI) and 7-chloro-4-methoxy- 1 H-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 H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5:1 to 0:1) to give the product methyl (2S)-2-[[(2S)-2-[(7- chloro-4-methoxy-lH-indole-2-carbonyl)amino]-3-cyclopropyl-p ropanoyl]amino]-3- [(3 S)-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] ⁺ .

Step 3: N-( (S)-l-( ( (S)-l -amino-1 -oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl-l-oxopropan-2-yl)-7-chloro-4-methoxy-lH-indole-2 -ccarboxamide [0001616] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-4-methoxy-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3-piperidyl]propanoate (0.9 g, 1.73 mmol, 1 eq) in NH ₃ /MeOH (7 M, 36.00 mL, 145.32 eq) was stirred at 25 °C for 12 h. Upon completion, the reaction mixture was 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-et hyl]-7-chloro-4-methoxy- 1 H-indole-2-carboxamide (0.8 g, crude) as a yellow solid. MS (ESI) m/z 504.2 [M+H] ⁺ .

Step 4: 7-chloro-N-((S)-l-(((S)-l-cyano-2-((S)-2-oxopiperidin-3-yl)e thyl)ammo)-3- cyclopropyl-l-oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxam ide

[0001617] A solution of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-7-chloro-4-methoxy- 1 H-indole-2-carboxamide (0.8 g, 1.59 mmol, 1 eq) in DCM (30 mL) was added with Burgess reagent (945.70 mg, 3.97 mmol, 2.5 eq), and then the mixture was stirred at 40 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini C18250 * 50mm * lOum; mobile phase: [water (lOmM NH4HCO3) - ACN]; B%: 28% - 48%, 20min) to give the product 7-chloro-N-[(1S)-2-[[(1S)-1-cyano- 2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl) -2-oxo-ethyl]-4-methoxy- 1 H-indole-2-carboxamide (0.21 g, 432.13 umol, 27.22% yield, 100% purity) as a white solid. MS (ESI) m/z 486.2 [M+H] ⁺ .

[0001618] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.70 (br d, J= 1.6 Hz, 1H), 8.97 (d ,J = 7.9 Hz, 1H), 8.65 (d ,J= 7.5 Hz, 1H), 7.53 (br s, 1H), 7.28 (s, 1H), 7.21 (d ,J= 8.3 Hz, 1H), 6.56 (d ,J= 8.3 Hz, 1H), 5.07 (q, J = 7.8 Hz, 1H), 4.56 - 4.43 (m, 1H), 3.89 (s, 3H), 3.15 - 3.02 (m, 2H), 2.30 - 2.22 (m, 2H), 1.87 - 1.68 (m, 4H), 1.59 - 1.39 (br s, 3H), 0.86 - 0.77 (m, 1H), 0.48 - 0.38 (m, 2H), 0.23 - 0.08 (m, 2H)

Example 206. Synthesis of viral protease inhibitor compound 902 Step 1: (Z)-ethyl 3-bromo-2-(hydroxyimino)propanoate

[0001619] To a solution of ethyl 3 -bromo-2-oxo-propanoate (60 g, 307.67 mmol, 38.46 mL, 1 eq) in CHCl ₃ (250 mL) was added NH ₂ OH.HCl (23.52 g, 338.44 mmol, 1.1 eq) in H ₂ O (250 mL) under N ₂ . The mixture was stirred at 25 °C for 16 h. The reaction was quenched by H ₂ O (500 mL) and then extracted with DCM (300 mL * 4). The combined organic phase was washed with brine (400 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a (Z)-ethyl 3-bromo-2-(hydroxyimino)propanoate (51 g, crude) as a yellow solid. MS (ESI) m/z 210.3 [M+H] ⁺ .

Step 2: l-(cyclohexylidenemethyl)pyrrolidine

[0001620] A mixture of cyclohexanecarb aldehyde (15 g, 133.73 mmol, 16.09 mL, 1 eq), pyrrolidine (11.41 g, 160.47 mmol, 13.40 mL, 1.2 eq) in toluene (300 mL) was heated at 130 °C for 14 h and water was removed by Dean-Stark trap. The reaction mixture was concentrated under reduced pressure to give a residue at 50 °C to give 1- (cyclohexylidenemethyl)pyrrolidine (20 g, crude) as a yellow oil. MS (ESI) m/z 166.2 [M+H] ⁺ .

Step 3: ethyl l-hydroxy-2-oxa-3-azaspiro[5.5]undec-3-ene-4-carboxylate

[0001621 ] To a solution of l-(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 N ₂ . After 1 h, TEA (12.24 g, 121.01 mmol, 16.84 mL, 1 eq) was added drop-wise at -10 °C under N ₂ . The reaction mixture was stirred at 25 °C for 12 h under N ₂ . The reaction was added with HC1 (36%, 2.2 eq, 26 mL in 3.5 vol H ₂ O) drop-wise at 25 °C, and stirred at 25 °C for 1 h. The reaction mixture was quenched by the addition of H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 1/1) to give a ethyl 1 -hy droxy-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] ⁺ .

Step 4: ethyl 2-azaspiro[4.5]decane-3-carboxylate [0001622] To a solution of ethyl 1 -hydroxy-2-oxa-3-azaspiro[5.5]undec-3-ene-4- carboxylate (15 g, 62.17 mmol, 1 eq) in EtOH (150 mL) was added Raney Nickel (10.65 g, 124.34 mmol, 2 eq) under Arz. The suspension was degassed under vacuum and purged with H ₂ (125.58 mg, 62.17 mmol, 1 eq) several times. The mixture was stirred under H ₂ (125.58 mg, 62.17 mmol, 1 eq) (50 psi) at 50 °C for 18 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 4/1 to ethyl acetate/methanol = 10/1) to give a ethyl 2-azaspiro[4.5]decane-3-carboxylate (6 g, 22.72 mmol, 36.54% yield, 80% purity) as a yellow and ethyl 2-azaspiro[4.5]decane-3- carboxylate (3 g, 5.11 mmol, 8.22% yield, 36% purity) was obtained as a yellow oil. MS (ESI) m/z 212.2 [M+H] ⁺ .

Step 5: 2-tert-butyl 3-ethyl 2-azaspir o [4.5 ]de cane -2, 3-dicar boxy late [0001623] To a solution of ethyl 2-azaspiro[4.5]decane-3-carboxylate (6 g, 28.40 mmol, 1 eq) in DCM (60 mL) was added TEA (5.75 g, 56.79 mmol, 7.90 mL, 2 eq) and Boc ₂ O (7.44 g, 34.07 mmol, 7.83 mL, 1.2 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by the addition of H ₂ O (300 mL), and extracted with ethyl acetate (150 mL * 3). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 9/1) to give a 2-tert-butyl 3-ethyl 2-azaspiro[4.5]decane-2,3- dicarboxylate (6 g, 19.27 mmol, 67.85% yield, N/A purity) was obtained as a yellow oil. MS (ESI) m/z 312.2 [M+H] ⁺ .

Step 6: 2-(tert-butoxycarbonyl)-2-azaspiro[4.5Jdecane-3-carboxylic acid

[0001624 ] 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 H ₂ O (14 mL) and MeOH (56 mL) was added LiOH.H ₂ O (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 H ₂ O (80 mL) and extracted with ethyl acetate.

Step 7: tert-butyl 3-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2- yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylate [0001625] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (6.25 g, 26.40 mmol, 1.1 eq, HC1) and 2-tert-butoxycarbonyl-2-azaspiro[4.5]decane-3- carboxylic acid (6.8 g, 24.00 mmol, 1 eq) in DCM (90 mL) was added DMAP (5.86 g, 48.00 mmol, 2 eq) and EDCI (6.90 g, 36.00 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 h. The reaction was quenched by 0.5 M HC1 (200 mL) and then extracted with DCM (100 mL * 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 0/1) to give a tert-butyl 3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-ca rboxylate (9 g, 18.36 mmol, 76.53% yield, 95% purity) as a white solid. MS (ESI) m/z 466.2 [M+H] ⁺

Step 8: (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2-azaspiro[4.5]decane-3- carboxamido)propanoate

[0001626] A mixture of tert-butyl 3-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylat e (1.5 g, 2.90 mmol, 90% purity, 1 eq) in HCl/MeOH (4 M, 20 mL, 27.59 eq) was cooled to 0 °C, and then stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2-azaspiro[4.5]decane-3- carboxamido)propanoate (1.5 g, crude, HC1) as a white solid. MS (ESI) m/z 366.1 [M+H] ⁺ .

Step 9: (2S)-methyl 2-(2-(7-chloro-4-methoxy-lH-indole-2-car bony l)-2-azaspiro [4.5] decane-

3-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[0001627] To a mixture of (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2- azaspiro[4.5]decane-3-carboxamido)propanoate (1.5 g, 3.55 mmol, 1 eq, HC1) in DCM (30 mL) and DMF (10 mL) was added 7-chloro-4-methoxy-lH-indole-2-carboxylic acid (959.94 mg, 4.25 mmol, 1.2 eq), followed by DMAP (1.30 g, 10.64 mmol, 3 eq) and EDCI (1.36 g, 7.09 mmol, 2 eq) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. and then the reaction mixture was quenched with water (10 mL) at 0 °C. After extraction with with DCM (10 mL * 3). the combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 100: 1 to 10: 1) to give methyl (2S)-2-[[2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (1.91 g, 3.00 mmol, 84.60% yield, 90% purity) as a yellow oil. MS (ESI) m/z 573.3 [M+H] ⁺ .

Step 10: N-((S)-l-amino-l-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl) -2-(7-chloro-4- methoxy-lH-indole-2-carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001628] A mixture of methyl (2S)-2-[[2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (1.91 g, 3.00 mmol, 90% purity, 1 eq) in NH ₃ /MeOH (7 M, 17.79 mL, 41.52 eq) was stirred at 80 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-((S)-1 -amino- l-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-2-(7- chloro-4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane -3-carboxamide (1.3 g, crude) as a yellow solid. MS (ESI) m/z 558.3 [M+H] ⁺ .

Step 11: 2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-N-(l-cyano-2-((S )-2-oxopiperidin-3- yl)ethyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001629] To a mixture of N-((S)- 1 -amino- 1 -oxo-3 -((S)-2-oxopiperidin-3-yl)propan-2-yl)- 2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]d ecane-3-carboxamide (1.3 g, 1.98 mmol, 1 eq) in DCM (25 mL) was added Burgess reagent (1.42 g, 5.94 mmol, 3 eq). After stirring at 25 °C for 3 h, the mixture was quenched with water (1 mL) and concentrated under reduced pressure to give a residue (<30 °C). The residue was purified by prep-HPLC (column: Phenomenex Titank C18 Bulk (250 * 100 mm * 10 um); mobile phase :[water( 10 mM NH4HCO3)- ACN] ; B%:40%-75%, 20 min) to give 2-(7-chloro-4- methoxy-lH-indole-2-carbonyl)-N-(l-cyano-2-((S)-2-oxopiperid in-3-yl)ethyl)-2- azaspiro[4.5]decane-3-carboxamide (350 mg, 648.09 umol, 32.73% yield) as a white solid. MS (ESI) m/z 540.1 [M+H] ⁺ .

Step 12: 2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-N-( 1 -cyano-2-( ( S)-2-oxopiperidin-3 - yl)ethyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001630] 2-(7-Chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-( 1 -cy ano-2-((S)-2- oxopiperidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide (350.00 mg, 550.87 umol, 95% purity, 1 eq) was purified by SFC (column: Waters Xbridge BEH C18 (100 * 30 mm * 10 um;mobile phase :[water( 10 mM NH ₄ HCO ₃ )- ACN] ; B%: 35% - 60%, 8 min) to give 2-(7-chloro-4-methoxy-lH-indole-2-carbonyl)-N-(l-cyano-2-((S )-2-oxopiperidin-3- yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide Isomer 1 (62.40 mg, 112.77 umol, 20.47% yield, 97.6% purity) as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺ .

[0001631 ] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.23 - 6.79 (m, 2H), 6.58 - 6.39 (m, 1H), 5.11 (dd, J = 5.7, 10.6 Hz, 1H), 4.77 - 4.52 (m, 1H), 4.03 - 3.76 (m, 4H), 3.74 - 3.37 (m, 1H), 3.47 - 2.89 (m, 2H), 2.65 - 2.10 (m, 3H), 2.09 - 1.27 (m, 16H).

[0001632 ] 2-(7-Chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-( 1 -cyano-2-((S)-2- oxopiperidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide Isomer 2 (131.81 mg, 244.07 umol, 44.31% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺ .

[0001633] ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.22 - 6.84 (m, 2H), 6.59 - 6.44 (m, 1H), 5.07 - 4.95 (m, 1H), 4.69 - 4.50 (m, 1H), 4.02 - 3.81 (m, 4H), 3.80 - 3.43 (m, 1H), 3.23 - 3.02 (m, 2H), 2.54 - 2.13 (m, 3H), 2.11 - 1.36 (m, 16H).

[0001634] 2-(7-Chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-( 1 -cy ano-2-((S)-2- oxopiperidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide Isomer 3 (34.64 mg, 64.14 umol, 11.64% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺ .

[0001635] 1H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.31 - 6.74 (m, 2H), 6.63 - 6.43 (m, 1H), 5.29 - 4.96 (m, 1H), 4.87 - 4.58 (m, 1H), 3.91 (br d, J = 9.0 Hz, 4H), 3.80 - 3.38 (m, 1H), 3.29 - 3.02 (m, 2H), 2.64 - 2.13 (m, 3H), 2.10 - 1.35 (m, 16H).

[0001636] 2-(7-Chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-( 1 -cy ano-2-((S)-2- oxopiperidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide Isomer 4 (5.66 mg, 10.45 umol, 1.90% yield, 99.7% purity) was obtained as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺ .

[0001637] 1H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.31 - 6.77 (m, 2H), 6.62 - 6.46 (m, 1H), 5.17 - 4.91 (m, 1H), 4.75 - 4.56 (m, 1H), 4.04 - 3.80 (m, 4H), 3.73 (d, J = 10.4 Hz, 1H), 3.28 - 3.01 (m, 2H), 2.55 - 2.44 (m, 1H), 2.44 - 2.25 (m, 2H), 2.08 - 1.40 (m, 16H). [0001638] (50 mL * 2). The aqueous phase were added HC1 aq adjust to pH = 2 and extracted with EA (90 mL * 3), The combined organic layers were washed with brine (90 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a 2-tert- butoxy carbony 1-2-azaspi ro[4.5 ]decane-3 -carboxyl ic 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

Step 1: methyl (Z)-2-azido-3-(4-chloro-2-methoxy-phenyl)prop-2-enoate

To a solution of CH ₃ ONa (2.53 g, 46.90 mmol, 2 eq) in MeOH (40 mL) was added a mixture of 4-chloro-2-methoxy-benzaldehyde (4 g, 23.45 mmol, 1 eq) and methyl 2-azidoacetate (5.40 g, 46.90 mmol, 2 eq) in MeOH (15 mL) at -10 °C. After stirring for 16 h at 20 °C, the solution was diluted with H ₂ O (60 mL) and concentrated and extracted with ethyl acetate (50 mL*3) and concentrated to give crude. The crude was purified by column (SiO ₂ , petroleum ether: ethyl acetate=20: 1 to 3:1) to give product methyl (Z)-2- azido-3-(4-chloro-2-methoxy-phenyl)prop-2-enoate (3.3 g, 12.33 mmol, 52.58% yield) as a white solid. MS (ESI) m/z 268.1 [M+H] ⁺ Step 2: methyl 6-chloro-4-methoxy-lH-indole-2-carboxylate

[0001640] 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 (SiO ₂ , petroleum ether: ethyl acetate=10: 1 to 1 : 10) to give product methyl 6- chloro-4-methoxy- 1 H-indole-2-carboxylate (1500 mg, 6.26 mmol, 55.84% yield) as a white solid. MS (ESI) m/z 240.1 [M+H] ⁺

Step 3: 6-chloro-4-methoxy-lH-indole-2-carboxylic acid

[0001641] A solution of methyl 6-chloro-4-methoxy- 1 H-indole-2-carboxylate (1500 mg, 6.26 mmol, 1 eq) in THF (15 mL) and H ₂ O (15 mL) was added with LiOH.H ₂ O (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 HC1 (con) and extracted with ethyl acetate (80 mL*3) and dried over Na ₂ SO ₄ and concentrated to give crude. The crude was used directly for the next step. 6-chloro-4-methoxy- 1 H- indole-2-carboxylic acid (1070 mg, 4.74 mmol, 75.77% yield) as a brown solid. MS (ESI) m/z 226.2 [M+H] ⁺

Step 4: methyl (2S)-2-[[(2S)-2-[(6-chloro-4-methoxy-lH-indole-2-carbonyl)am ino]-3- cyclopropyl-propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate [0001642] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (500 mg, 1.44 mmol, 1 eq, HC1) in DCM (10 mL) and DMF (10 mL) was added DMAP (351.22 mg, 2.87 mmol, 2 eq), 6- chloro-4-methoxy- 1 H-indole-2-carboxylic acid (372.98 mg, 1.65 mmol, 1.15 eq) and EDCI (551.13 mg, 2.87 mmol, 2 eq). After stirring for 2 h at 20 °C, the mixture was diluted with H ₂ O (30 mL) and extracted with ethyl acetate (50mL *3) and concentrated to give crude. The crude was purified by column (SiO ₂ , petroleum ether: ethyl acetate=10: 1 to EA: MeOH=10: 1) to give methyl (2S)-2-[[(2S)-2-[(6-chloro-4-methoxy-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3-piperidyl]propanoate (500 mg, 963.41 umol, 67.02% yield) as a white solid. MS (ESI) m/z 519.3 [M+H] ⁺

Step 5: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-1-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-4-methoxy-lH-indol e-2-carboxamide [0001643] A solution of methyl (2S)-2-[[(2S)-2-[(6-chloro-4-methoxy-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3-piperidyl]propanoate (500 mg, 963.41 umol, 1 eq ) in NH ₃ /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-(cyclopropylm ethyl)-2-oxo-ethyl]-6- chloro-4-methoxy-lH-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] ⁺

Step 6: 6-chloro-N-[(lS)-2-[[(lS)-l-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide [0001644] 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-et hyl]-6-chloro-4-methoxy- lH-indole-2-carboxamide (470 mg, 932.58 umol, 1 eq) in DCM (25 mL) was added Burgess reagent (666.72 mg, 2.80 mmol, 3 eq). After stirring for 3 h at 20 °C, the solution was washed with brine (50 mL) and dried with using N ₂ to give a crude. The crude was purified by pre-HPLC(neutral) to afford 6-chloro-N-[(1S)-2-[[(1S)-1-cyano-2- [(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy- lH-indole-2-carboxamide (210 mg, 432.13 umol, 46.34% yield) as a white solid. MS (ESI) m/z 486.3 [M+H] ⁺

[0001645] Pre-HPLC condition: column: Waters Xbridge C18 150*50mm* 10um;mobile phase: [water(10mMNH4HCO3)-ACN];B%: 30%-60%,10min

[0001646] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ = 11.72 (s, 1H), 8.91 (br d, J=8.2 Hz, 1H), 8.58 (br d, J=7.3 Hz, 1H), 7.53 (br s, 1H), 7.38 (s, 1H), 7.03 (s, 1H), 6.56 (s, 1H), 5.17 - 4.93 (m, 1H), 4.53 - 4.31 (m, 1H), 3.91 (s, 3H), 3.09 (br s, 2H), 2.37 - 2.15 (m, 2H), 1.89 - 1.27 (m, 7H), 0.80 (br s, 1H), 0.40 (br s, 1H), 0.23 - 0.10 (m, 2H).

Example 208. Synthesis of viral protease inhibitor compound 1511

Step 1: (S)-dimethyl 2-amino-2-methylpentanedioate

[0001647] A mixture of (2S)-2-amino-2-methyl-pentanedioic acid (1 g, 6.21 mmol, 1 eq) in HCI/MeOH (4 M, 10 mL, 6.45 eq) was stirred at 80 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (S)-dimethyl 2-amino- 2-methylpentanedioate (1.4 g, crude) as a yellow oil. MS (ESI) m/z 190.2 [M+H] ⁺ .

Step 2: (S)-dimethyl 2-( ( (benzyloxy)carbonyl)amino)-2-methylpentanedioate [0001648] To a mixture of (S)-dimethyl 2-amino-2-methylpentanedioate (1.1 g, 4.87 mmol, 1 eq, HC1) in DCM (11 mL) was added K2CO3 (2.02 g, 14.62 mmol, 3 eq) and CbzCl (914.69 mg, 5.36 mmol, 762.24 uL, 1.1 eq) at 0 °C. After stirring at 20 °C for 14 h, the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10:1 to 2:1) to give (S)-dimethyl 2-(((benzyloxy)carbonyl)amino)-2-methylpentanedioate (920 mg, 2.85 mmol, 58.37% yield) as a yellow oil. MS (ESI) m/z 324.1 [M+H] ⁺ . Step 3: (2S)-dimethyl 2-(((benzyloxy)carbonyl)amino)-4-(cyanomethyl)-2- methylpentanedioate

[0001649] 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 N ₂ atmosphere 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 N ₂ . Upon completion, the reaction mixture was quenched with pre-cool ed (dry-ice in EtOH) MeOH (2.8 mL) and a precooled (dry-ice in EtOH) acetic acid in THF solution (0.46mL HO Ac/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 Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 10: 1 to 2: 1) to give (2S)-dimethyl 2- (((benzyloxy)carbonyl)amino)-4-(cyanomethyl)-2-methylpentane dioate (740 mg, 1.84 mmol, 75.99% yield, 90% purity) as a yellow oil. MS (ESI) m/z 363.1 [M+H] ⁺ .

Step 4: (2S)-methyl 2-(((benzyloxy)carbonyl)amino)-2-methyl-3-(2-oxopyrrolidin-3 - yl)propanoate

[0001650] 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 CoClz.6H ₂ O (262.37 mg, 1.10 mmol, 0.6 eq) at 0 °C, and then NaBHt (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 NH4CI 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 Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to get the crude product. The residue was purified by column chromatography (SiO ₂ , 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] ⁺ .

Step 5: (2S)-methyl 2-amino-2-methyl-3-(2-oxopyrrolidin-3-yl)propanoate

[0001651 ] 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 H ₂ O (1.5 mL) and t-BuOH (6 mL) under N ₂ was added Pd/C (160 mg, 10% purity). The resulting mixture was degassed and purged with H ₂ for 3 times, and then the mixture was stirred under H ₂ (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] ⁺ .

Step 6: (2S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanami do)-2- methyl-3-(2-oxopyrrolidin-3-yl)propanoate

[0001652] To a solution of (2S)-methyl 2-amino-2-methyl-3-(2-oxopyrrolidin-3- yl)propanoate (140 mg, 699.18 umol, 1 eq) in DCM (2 mL) and DMF (1 mL) was added (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (192.36 mg, 839.02 umol, 1.2 eq), TEA (212.25 mg, 2.10 mmol, 291.95 uL, 3 eq). After the addion of T3P (667.40 mg, 1.05 mmol, 623.74 uL, 50% purity, 1.5 eq) at 0 °C, the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give (2S)- methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanami do)-2-methyl-3- (2-oxopyrrolidin-3-yl)propanoate (280 mg, 612.41 umol, 87.59% yield, 90% purity) as yellow oil. MS (ESI) m/z 412.3 [M+H] ⁺ .

Step 7: (2S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-2-methyl-3-(2-oxopy rrolidin- 3-yl)propanoate

[0001653] A solution of (2S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3- cyclopropylpropanamido)-2-methyl-3-(2-oxopyrrolidin-3-yl)pro panoate (260 mg, 568.66 umol, 90% purity, 1 eq) in HCl/MeOH (4 M, 2.6 mL, 18.29 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-2-methyl-3-(2- oxopyrrolidin-3-yl)propanoate (200 mg, crude, HC1) as yellow solid. MS (ESI) m/z 312.2 [M+H] ⁺ .

Step 8: (2S)-methyl 2-( (S)-3-cyclopropyl-2-(4-methoxy- lH-indole-2- carboxamido)propanamido)-2-methyl-3-(2-oxopyrrolidin-3-yl)pr opanoate

[0001654] To a solution of (2S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-2- methyl-3-(2-oxopyrrolidin-3-yl)propanoate (200 mg, 546.23 umol, 95% purity, 1 eq, HC1) in DCM (4 mL) and DMF (2 mL) was added 4-methoxy- 1 H-indole-2-carboxylic acid (125.32 mg, 655.48 umol, 1.2 eq), DMAP (200.20 mg, 1.64 mmol, 3 eq), and EDCI (209.43 mg, 1.09 mmol, 2 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h, and then the reaction mixture was diluted with water (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give (2S)-methyl 2-((S)-3- cyclopropyl-2-(4-methoxy-lH-indole-2-carboxamido)propanamido )-2-methyl-3-(2- oxopyrrolidin-3-yl)propanoate (300 mg, 451.97 umol, 82.74% yield, 73% purity) as a yellow oil. MS (ESI) m/z 485.3 [M+H] ⁺ .

Step 9: N-( (2S)-l-( ( (, 2S)-l-amino-2-methyl-l-oxo-3-(2-oxopyrrolidin-3-yl)propan-2 - yl)amino)-3-cyclopropyl-l-oxopropan-2-yl)-4-methoxy-lH-indol e-2-carboxamide [0001655] A solution of (2S)-methyl 2-((S)-3-cyclopropyl-2-(4-methoxy-lH-indole-2- carboxamido)propanamido)-2-methyl-3-(2-oxopyrrolidin-3-yl)pr opanoate (280.00 mg, 421.84 umol, 73% purity, 1 eq) in NH ₃ /MeOH (7 M, 6 mL, 99.56 eq) was stirred at 80 °C for 86 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to giveN-((2S)-1-(((2S)-1-amino-2-methyl-1-oxo-3-(2-oxopyrrolid in-3-yl)propan-2- yl)amino)-3-cy clopropyl- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide (35 mg, 70.82 umol, 16.79% yield, 95% purity) as a yellow solid. MS (ESI) m/z 470.3 [M+H] ⁺ .

Step 10: N-((2S)-l-(((2S)-2-cyano-l-(2-oxopyrrolidin-3-yl)propan-2-yl )amino)-3- cyclopropyl- l-oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxamide [0001656] To a solution of N-((2S)- 1 -(((2S)- 1 -amino-2-methyl-l -oxo-3-(2-oxopyrrolidin- 3-yl)propan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-me thoxy-lH-indole-2- carboxamide (30 mg, 60.70 umol, 95% purity, 1 eq) in DCM (1 mL) was added Burgess reagent (43.40 mg, 182.10 umol, 3 eq), and then was stirred at 25 °C for 6 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.1 mL) at 20 °C and then concentrated under reduced pressure (< 20 °C) to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100* 25mm* Sum; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 20%-50%, 10 min) to give N-((2S)-1- (((2S)-2-cyano- 1 -(2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan- 2-yl)-4-methoxy-lH-indole-2-carboxamide (25 mg, 52.60 umol, 86.66% yield, 95% purity) as a white solid. MS (ESI) m/z 452.2 [M+H] ⁺ .

Step 11: N-( (2S)-l-( ( ( 2S)-2-cycmo-l-(2-oxopyrrolidm-3-yl)propan-2-yl)amino)-3 - cyclopropyl- l-oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxamide

[0001657] N-((2S)- 1 -(((2S)-2-cyano- 1 -(2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3- cyclopropyl-1-oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxam ide (25 mg, 52.60 umol, 95% purity, 1 eq) was purified by SFC (column: DAICEL CHIRALPAK AD(250 mm* 30 mm, 10 um); mobile phase: [0.1% NH3H ₂ O IP A]; B%: 50%-50%, 7 min) to give N-((2S)- 1 -(((2S)-2-cyano- 1 -(2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-cyclopropyl- 1 - oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxamide Isomer 1 (2.35 mg, 5.10 umol, 9.69% yield, 97.9% purity) as a white solid. MS (ESI) m/z 452.1 [M+H] ⁺ .

[0001658] ¹ H NMR (400MHz, MeOD-d ₄ ) δ = 7.26 (d, J=0.7 Hz, 1H), 7.19 - 7.11 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 4.59 (t, J = 7.3 Hz, 1H), 3.93 (s, 3H), 3.38 - 3.32 (m, 2H), 2.77 - 2.66 (m, 1H), 2.54 - 2.45 (m, 1H), 2.40 (dd, J = 5.1, 14.3 Hz, 1H), 2.07 (dd, J = 7.3, 14.3 Hz, 1H), 2.02 - 1.91 (m, 1H), 1.86 (td, J = 7.1, 14.0 Hz, 1H), 1.74 (s, 3H), 1.68 (td, J = 7.1, 14.1 Hz, 1H), 0.93 - 0.79 (m, 1H), 0.59 - 0.44 (m, 2H), 0.26 - 0.14 (m, 2H).

[0001659] N-((2S)- 1 -(((2S)-2-cyano- 1 -(2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3- cyclopropyl-1-oxopropan-2-yl)-4-methoxy-lH-indole-2-carboxam ide Isomer 2 (2.08 mg, 4.53 umol, 8.62% yield, 98.4% purity) was obtained as a white solid. MS (ESI) m/z 452.1 [M+H] ⁺ . [0001660) ¹ H NMR (400MHZ, MeOD-d ₄ ) δ = 7.26 (s, 1H), 7.20 - 7.13 (m, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 4.62 (dd, J = 6.4, 7.9 Hz, 1H), 3.93 (s, 3H), 3.28 - 3.16 (m, 2H), 2.73 - 2.61 (m, 1H), 2.39 (td, J = 6.6, 12.8 Hz, 1H), 2.27 (dd, J = 7.4, 14.9 Hz, 1H), 2.01 - 1.92 (m, 1H), 1.92 - 1.78 (m, 2H), 1.76 - 1.66 (m, 4H), 0.89 - 0.78 (m,

1H), 0.55 - 0.44 (m, 2H), 0.24 - 0.14 (m, 2H)

Example 209. Synthesis of viral protease inhibitor compound 749

Step J: benzyl N-(3 -hydroxy-1 , 1 -dimethyl-propyl) carbamate

[0001661 ] To a solution of 3-amino-3-methyl-butan-1-ol (3.5 g, 33.93 mmol, 1 eq) in IPA (60 mL) was added 60 mL of saturated NaHCO ₃ (64.80 g, 771.37 mmol, 30 mL, 22.74 eq), which is a pH=l 1 buffer, adjusted with 4 M NaOH (4 M, 30 mL, 3.54 eq). The reaction mixture was cooled to 0 °C, and then benzyl 2,5 -dioxopyrrolidine- 1 -carboxylate (7.91 g, 33.93 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 H ₂ O (50 mL) and extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

The residue was purified by column chromatography (S1O2, 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] ⁺

Step 2: benzyl N-( 1,1 -dimethyl- 3 -oxo-propyl) carbamate

[0001662] 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 H ₂ O (100 mL) and extracted with ethyl acetate (100 mL * 2). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , 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] ⁺

Step 3: (Z)-5-(benzyloxycarbonylamino)-2-[(2S)-2-(tert-butoxycarbony lamino)-3-methoxy-3- oxo-propyl ]-5-methyl-hex-2-enoic acid

[0001663 ] To a solution of dimethyl (2S)-2-(tert-butoxycarbonylamino)pentanedioate (1.4 g, 5.09 mmol, 1 eq) in THF (15 mL) was added a solution of LiHMDS (1 M, 10.68 mL, 2.1 eq) drop-wise at -60 °C under N ₂ . After stirring at -60 °C for 0.5 h, benzyl N-(l,l- dimethyl-3-oxo-propyl)carbamate (1.20 g, 5.09 mmol, 1 eq) in THF (10 mL) was added at below -60 °C and the reaction mixture was stirred at -60 °C for 3 h. Upon completion, the reaction mixture was quenched by addition AcOH 5 mL in THF (20 mL) at 0 °C and concentrated under reduced pressure to give a residue. The residue was purified by neutral prep-HPLC (column: Welch Xtimate C18250*70mm# 10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 20%-50%,20min) to get (Z)-5- (benzyloxycarbonylamino)-2-[(2S)-2-(tert-butoxycarbonylamino )-3-methoxy-3- oxo- propyl]-5-methyl-hex-2-enoic acid (230 mg, 456.60 umol, 8.98% yield, 95% purity) as a white solid. MS (ESI) m/z 379.1 [M+H-100] ⁺ Step 4: dimethyl (2Z,4S)-2-[3-(benzyloxycarbonylamino)-3-methyl-butylidene]-4 -(tert- butoxycarbony l mino)pentanedioate

[0001664 ] 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 K ₂ CO ₃ (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 H ₂ O (10 mL) at 0 °C, and then diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , 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] ⁺

Step 5: dimethyl (4S)-2-(3-amino-3-methyl-butyl)-4-(tert-butoxy carbonylamino)pentanedioate

[0001665] To a mixture of dimethyl (2Z,4S)-2-[3-(benzyloxycarbonylamino)-3-methyl- butylidene]-4-(tert- butoxycarbonylamino)pentanedioate (230 mg, 466.95 umol, 1 eq) in i-PrOH (10 mL) was added Pd/C (300 mg, 466.95 umol, 10% purity, 1 eq). The mixture was stirred at 50 °C for 5 h under ¾ (50 Psi). Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue compound dimethyl (4S)-2-(3-amino-3-methyl-butyl)-4-(tert-butoxycarbonylamino) pentanedioate (120 mg, 299.63 umol, 64.17% yield, 90% purity) as a colorless oil and used directly next step. MS (ESI) m/z 361.2 [M+H] ⁺

Step 6: methyl (2S)-2-(tert-butoxycarbonylamino)-3-(6,6-dimethyl-2-oxo-3- piperidyl)propanoate

[0001666] 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 CHCl ₃ (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 H ₂ O 5 mL and extracted with ethyl acetate (5 mL * 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , 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] ⁺

Step 7: methyl (2S)-2-amino-3-(6,6-dimethyl-2-oxo-3-piperidyl)propanoate

[0001667] Methyl (2S)-2-(tert-butoxycarbonylamino)-3-(6,6-dimethyl-2-oxo-3- piperidyl)propanoate (100 mg, 304.50 umol, 1 eq) was added with HCl/MeOH (4 M, 76.13 uL, 1 eq). The resulting mixture 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-amino-3-(6,6-dimethyl-2-oxo-3-piperidyl)propanoate (80 mg, 287.07 umol, 94.27% yield, 95% purity, HC1) as a colorless oil.

Step 8: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-pro panoyl]amino]- 3-( 6, 6- dimethyl-2-oxo-3-piperidyl)propanoate

[0001668] To a mixture of methyl (2S)-2-amino-3-(6,6-dimethyl-2-oxo-3- piperidyl)propanoate (80 mg, 302.17 umol, 1 eq, HC1) and (2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoic acid (69.28 mg, 302.17 umol, 1 eq) in DCM (2 mL) and DMF (1 mL) was added DMAP (73.83 mg, 604.35 umol, 2 eq) and EDCI (115.85 mg, 604.35 umol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (20 mL) and extracted with ethyl acetate (20 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1) to afford methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-(6,6-dimethyl-2-oxo-3-piperidyl)propanoat e (110 mg, 225.23 umol, 74.54% yield, 90% purity) as a colorless oil. MS (ESI) m/z 440.3 [M+H] ⁺

Step 9: methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(6,6- dimethyl-2- oxo-3- piperidyl)propanoate

[0001669] Methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-(6,6- dimethyl-2-oxo-3-piperidyl)propanoate (110 mg, 250.26 umol, 1 eq) was added with HCl/MeOH (4 M, 7.33 mL, 117.21 eq). The mixture 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-3- cyclopropyl- propanoyl]amino]-3-(6,6-dimethyl-2-oxo-3-piperidyl)propanoat e (90 mg, 239.43 umol, 95.67% yield, HC1) as a colorless oil.

Step 10: methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]-3-cyc lopropyl- propanoyl ] amino ]-3-( 6, 6-dimethyl-2-oxo-3-piperidyl)propanoate

[0001670] To a mixture of 7-chloro- 1 H-indole-2-carboxylic acid (46.83 mg, 239.43 umol,

1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(6,6- dimethyl-2-oxo-3-piperidyl)propanoate (90 mg, 239.43 umol, 1 eq, HC1) in DCM (4 mL) and DMF (2 mL) was added EDCI (91.80 mg, 478.86 umol, 2 eq) and DMAP (58.50 mg, 478.86 umol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O 20 mL and extracted with EA 40 mL (20 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether: ethyl acetate = 0:1) to get the compound methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl) amino]-3-cyclopropyl- propanoyl]amino]-3-(6,6-dimethyl-2-oxo-3-piperidyl)propanoat e (100 mg, 183.75 umol, 76.74% yield, 95% purity) as a white solid. MS (ESI) m/z 517.3 [M+H] ⁺

Step 11: N-[ ( 1 S)-2-[[( 1 S)-2-amino-l-[ ( 6, 6-dimethyl-2-oxo-3-piperidyl)methyl ]-2-oxo- ethyl]amino]-l-(cyclopropylmethyl)-2-oxo-ethyl]-7-chloro-lH- indole-2-carboxamide [0001671 ] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]- 3-cyclopropyl-propanoyl]amino]-3-(6,6-dimethyl-2-oxo-3-piper idyl)propanoate (100 mg, 193.42 umol, 1 eq) in NH ₃ /MeOH (7 M, 10.00 mL, 361.91 eq) was stirred at 55 °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-[( 1 S)-2-[[( 1 S)-2-amino- 1 - [(6,6-dimethyl-2-oxo-3-piperidyl)methyl]-2-oxo-ethyl]amino]- 1-(cyclopropylmethyl)-2- oxo-ethyl]-7-chloro-lH-indole-2-carboxamide (100 mg, 185.26 umol, 95.78% yield, 93% purity) was obtained as a white solid. MS (ESI) m/z 502.2 [M+H] ⁺

Step 12: 7-chloro-N-[ ( 1 S)-2-[[( 1 S)-l-cyano-2-( 6, 6-dimethyl-2-oxo-3-piperidyl)ethyl ] amino ]- l-(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[0001672] To a mixture of N-[(1S)-2-[[(1S)-2-amino-1-[(6,6-dimethyl-2-oxo-3- piperidyl)methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmethyl)-2 -oxo-ethyl]-7-chloro-lH- indole-2-carboxamide (80 mg, 159.36 umol, 1 eq) in DCM (5 mL) was added Burgess reagent (75.95 mg, 318.72 umol, 2 eq). The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was diluted with H ₂ O (5 mL) and extracted with DCM (5 mL * 2). The combined organic layers were concentrated with using blow-dry to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(10mM NH4HCO ₃ )-ACN];B%: 30%-60%,8min) to give the mixture product (65 mg) as a white solid. The white solid (65 mg) was separated by SFC (column: REGIS (s,s) WHELK-01 (250mm*30mm,5um);mobile phase: [0.1%NH3H2O IPA];B%: 55%-55%,8 min) to get the compound 7-chloro-N-[(1S)- 2-[[( 1 S)- 1 -cyano-2-(6,6-dimethyl-2-oxo-3-piperidyl)ethyl]amino]- 1 -(cyclopropylmethyl)- 2-oxo-ethyl]-lH-indole-2-carboxamide (35 mg, 72.32 umol, 45.38% yield, 100% purity) and 7-chloro-N-[(l S)-2-[[(l S)-1-cyano-2-(6,6-dimethyl-2-oxo-3-piperidyl)ethyl]amino]- l-(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide (25 mg, 51.65 umol, 32.41% yield, 100% purity) as a white solid. MS (ESI) m/z 484.2 [M+H] ⁺

Isomer 1:

[0001673] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.86 - 11.59 (m, 1H), 9.00 (d, J=8.0 Hz, 1H), 8.72 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.07 (t, J=7.8 Hz, 1H), 5.09 (q, J=8.0 Hz, 1H), 4.61 - 4.46 (m, 1H), 2.30 - 2.08 (m, 2H), 1.88 - 1.67 (m, 3H), 1.64 - 1.38 (m, 4H), 1.17 - 1.03 (m, 6H), 0.89 - 0.70 (m, 1H), 0.51 - 0.36 (m, 2H), 0.28 - 0.01 (m, 2H).

Isomer 2:

[0001674] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ = 11.73 (s, 1H), 9.04 (d, J=7.4 Hz, 1H), 8.74 (d, J=7.7 Hz, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.26 (s, 1H), 7.07 (t, J=7.7 Hz, 1H), 5.02 (q, J=7.4 Hz, 1H), 4.61 - 4.52 (m, 1H), 2.32 (td, J=6.8, 13.7 Hz, 1H), 2.20 - 2.06 (m, 1H), 1.88 - 1.49 (m, 7H), 1.12 (d, J=8.0 Hz, 6H), 0.88 - 0.70 (m, 1H), 0.52 - 0.34 (m, 2H), 0.26 - 0.05 (m, 2H).

Example 210. Synthesis of viral protease inhibitor compound 928

[0001675] Step 1: methyl (2S)-2-[[2-(7-chloro-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-(6,6-dimethyl-2-oxo- 3-piperidyl)propanoate

[0001676] To a mixture of 2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3- carboxylic acid (354.36 mg, 982.06 umol, 1 eq) and methyl (2S)-2-amino-3-(6,6- dimethyl-2-oxo-3-piperidyl)propanoate (260 mg, 982.06 umol, 1 eq, HCI) in DMF (10 mL) was added HATU (448.09 mg, 1.18 mmol, 1.2 eq), DIEA (380.78 mg, 2.95 mmol, 513.17 uL, 3 eq) in DMF (5 mL) was added at 0 °C.The mixture was stirred at 0 °C for 30 min. Upon completion, the reaction mixture was diluted with H ₂ O 50 mL and extracted with EA 100 mL (50 mL * 2). The combined organic layers were washed with brine 50 mL (50 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=10/l to 0/1) to get the compound methyl (2S)-2-[[2-(7-chloro-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl] amino]-3-(6,6-dimethyl-2-oxo-3- piperidyl)propanoate (550 mg, 866.74 umol, 88.26% yield, 90% purity) as a white solid. MS (ESI) m/z 571.3 [M+H] ⁺

[0001677] Step 2: N-[(1S)-2-amino-1-[(6,6-dimethyl-2-oxo-3-piperidyl)methyl]-2 -oxo- ethyl]-2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]deca ne-3-carboxamide

[0001678] To a mixture of methyl (2S)-2-[[2-(7-chloro-lH-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 NH ₃ /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-[( 1 S)-2-amino- 1 - [(6,6-dimethyl-2-oxo-3-piperidyl)methyl]-2-oxo-ethyl]-2-(7-c hloro-lH-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] ⁺

[0001679] Step 3: 2-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-(6,6-dim ethyl-2- oxo-3 -pi peri dy l)ethy 1 ] -2-azaspiro[4.5 ]decane-3 -carboxamide

[0001680] To a mixture of N-[(1S)-2-amino-1-[(6,6-dimethyl-2-oxo-3-piperidyl)methyl]-2 - oxo-ethyl]-2- (7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carb oxamide (500 mg, 899.13 umol, 1 eq) in DCM (10 mL) was added BURGESS REAGENT (428.53 mg, 1.80 mmol, 2 eq) at 25 °C. The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was diluted with H ₂ O 10 mL and extracted with DCM 20 mL (10 mL * 2). The combined organic layers were washed with brine 10 mL (10 mL * 1) and blow-drying by N2 to give a residue. The residue was purified by neutral prep- HPLC (column: Waters Xbridge C 18 150*50mm* lOum; mobile phase: [water(10mM NH4HC03 )- ACN] ;B% : 40%-60%,10min). MS (ESI) m/z 538.2 [M+H] ⁺

[0001681] Isomer 1&2:

[0001682] 2-(7-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-(6,6-dimethyl-2-oxo-3- piperidyl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (100 mg, 185.10 umol, 20.59% yield, 99.6% purity) was obtained as a white solid.

[0001683] ¹ H NMR (400MHz, DMSO-d6) δ = 11.10 (br s, 1H), 8.70 (br d, J=16.5 Hz, 1H), 7.62 (br s, 1H), 7.38 - 6.82 (m, 4H), 4.98 (br s, 1H), 4.60 (br s, 1H), 3.83 (br d, J=10.1 Hz, 1H), 3.62 (br s, 1H), 2.31 - 1.96 (m, 3H), 1.94 - 1.26 (m, 16H), 1.22 - 1.01 (m, 6H)

[0001684] Isomer 3: [0001685] 2-(7-chloro-lH-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-(6,6-dimethyl-2-oxo-3- piperidyl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (50 mg, 92.92 umol, 10.33% yield, 100% purity) was obtained as a white solid.

[0001686] ¹ H NMR (400MHz, DMSO-d6) δ = 11.12 (br s, 1H), 9.01 - 8.62 (m, 1H), 7.83 - 7.52 (m, 1H), 7.49 - 6.65 (m, 4H), 4.94 (br d, J=5.7 Hz, 1H), 4.61 (br s, 1H), 4.00 - 3.33 (m, 2H), 2.35 - 1.99 (m, 3H), 1.91 - 1.28 (m, 16H), 1.20 - 1.07 (m, 6H)

[0001687] Isomer 4:

[0001688] 2-(7-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-(6,6-dimethyl-2-oxo-3- piperidyl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (50 mg, 90.69 umol, 10.09% yield, 97.6% purity) was obtained as a white solid.

[0001689] ¹ H NMR (400MHZ, DMSO-d6) δ = 11.54 - 10.62 (m, 1H), 8.96 - 8.58 (m, 1H), 7.63 (br d, J=7.3 Hz, 1H), 7.39 - 6.91 (m, 4H), 4.94 (q, J=6.8 Hz, 1H), 4.60 (br s, 1H), 3.92 - 3.46 (m, 2H), 2.31 - 2.01 (m, 3H), 1.76 - 1.29 (m, 16H), 1.14 (d,J= 18.3 Hz, 6H)

Example 211. Synthesis of viral protease inhibitor compound 930 Step 1: methyl 2-azaspiro[4.5]decane-3-carboxylate

[0001690] A mixture of 2-azaspiro[4.5]decane-3-carboxylic acid (400 mg, 1.82 mmol, 1 eq, HC1) in HCl/MeOH (4 M, 6 mL, 13.18 eq) was stirred at 70 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl 2-azaspiro[4.5]decane-3-carboxylate (400 mg, 1.71 mmol, 94.00% yield, HC1) as a white solid. MS (ESI) m/z 198.2 [M+H] ⁺ .

Step 2: methyl 2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-ca rboxylate [0001691 ] To a mixture of methyl 2-azaspiro[4.5 ]decane-3 -carboxy late (400 mg, 1.71 mmol, 1 eq, HC1) and 7-chloro-lH-indole-2-carboxylic acid (334.74 mg, 1.71 mmol, 1 eq) in DCM (6 mL) was added DIEA (663.54 mg, 5.13 mmol, 894.26 uL, 3 eq) and T3P (816.78 mg, 2.57 mmol, 763.34 uL, 1.5 eq) in one portion at 0 °C. The mixture was stirred at 25 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-TLC (SiO ₂ , petroleum ether: ethyl acetate = 0:1) to give methyl 2-(7-chloro-lH-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxylate (350 mg, 933.68 umol, 54.56% yield) as a white solid. MS (ESI) m/z 375.1 [M+H] ⁺

Step 3: 2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-ca rboxylic acid [0001692] A mixture of methyl 2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane- 3 -carboxyl ate (350 mg, 933.68 umol, 1 eq) in THF (2 mL) and H ₂ O (2 mL) was added LiOH.H ₂ O (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 HC1 and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (15 mL * 1), dried over Na ₂ SO ₄ , and filtered and concentrated under reduced pressure to give 2-(7-chloro-lH-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] ⁺

Step 4: methyl (2S)-2-[[2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]de cane-3- carbonyl ] amino ]-3-[ ( 3R)-5, 5-dimethyl-2-oxo-pyrrolidin-3-yl ]propanoate

[0001693] To a mixture of 2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3- carboxylic acid (250 mg, 692.84 umol, 1 eq) and methyl (2S)-2-amino-3-[(3R)-5,5- dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (225.82 mg, 900.69 umol, 1.3 eq, HC1) in DCM (4 mL) was added T3P (661.35 mg, 1.04 mmol, 618.08 uL, 50% purity, 1.5 eq) and TEA (210.32 mg, 2.08 mmol, 289.30 uL, 3 eq) in one portion at 0 °C. The mixture was stirred at 25 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-TLC (Si02, PE: ethyl acetate = 0: 1) to give methyl (2 S)-2-[[2-(7-chloro- 1 H-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3R)-5, 5-dimethyl-2-oxo- pyrrolidin-3-yl]propanoate (270 mg, 484.67 umol, 69.95% yield) as a white solid. MS (ESI) m/z 557.1 [M+H] ⁺

Step 5: N-f ( l S)-2-amino-1-[(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methyl ]-2-oxo-ethyl ]-2-(7- chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxa mide

[0001694] A mixture of methyl (2S)-2-[[2-(7-chloro-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-(5,5-dimethyl-2-oxo- pyrrolidin-3- yl)propanoate (250 mg, 448.77 umol, 1 eq) in NH ₃ /MeOH(7 M, 5 mL, 77.99 eq) was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-amino-1-[(5,5-dimethyl-2-oxo-pyrrolidin-3- yl)methyl]-2-oxo-ethyl]-2- (7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3- carboxamide (240 mg, 442.75 umol, 98.66% yield) as a white solid. MS (ESI) m/z 542.2 [M+H] ⁺

Step 6: 2-(7-chloro-JH-indole-2-carbonyl)-N-[(JS)-1-cyano-2-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)ethyl ]-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001695] A mixture of N-[(1S)-2-amino-1-[(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methy l]- 2-oxo-ethyl]-2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4. 5]decane-3-carboxamide (250 mg, 392.02 umol, 85% purity, 1 eq) in DCM (5 mL) was added Burgess reagent (186.84 mg, 784.03 umol, 2 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition; column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10 mM NH4HCO3)- ACN] ;B% : 35%-65%,8min) to give 2-(7-chloro-lH-indole-2- carbonyl)-N-[(1S)-1-cyano-2-(5,5-dimethyl-2-oxo-pyrrolidin-3 -yl)ethyl]-2- azaspiro[4.5]decane-3-carboxamide (100 mg, 190.82 umol, 48.68% yield) as a white solid. MS (ESI) m/z 524.2 [M+H] ⁺ Step 7: 2-(7-chloro-JH-indole-2-carbonyl)-N-[(JS)-1-cyano-2-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)ethyl ]-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001696] The white solid was separated by SFC (column: REGIS(S,S)WHELK-

01 (250mm*25mm, 1 Oum);mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 55%-55%,10min) to give 2-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (2 mg, 3.82 umol, 2.00% yield), 2-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (2 mg, 3.82 umol, 2.00% yield), 2-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (30 mg, 57.25 umol, 30.00% yield), 2-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (5 mg, 9.54 umol, 5.00% yield), 2-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (20 mg, 38.16 umol, 20.00% yield) and 2-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (15 mg) as a white solid.MS (ESI) m/z 524.2 [M+H] ⁺

Isomer 1 :

[0001697] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.69 - 11.44 (m, 1H), 8.95 (br d, J=7.9 Hz, 1H), 7.87 - 7.75 (m, 1H), 7.68 - 7.43 (m, 1H), 7.33 - 7.20 (m, 1H), 7.14 (s, 1H), 7.11 - 6.97 (m, 1H), 4.99 - 4.75 (m, 1H), 4.50 (t, J=8.6 Hz, 1H), 3.83 (br d, J=10.4 Hz, 1H),

3.66 (d, J=10.6 Hz, 1H), 2.75 - 2.63 (m, 1H), 2.36 - 2.12 (m, 2H), 1.99 (dd, J=8.5, 12.2 Hz, 1H), 1.83 - 1.69 (m, 1H), 1.60 (br dd, J=9.9, 11.9 Hz, 1H), 1.55 - 1.28 (m, 11H), 1.17 - 1.06 (m, 3H), 1.05 - 0.91 (m, 3H)

[0001698] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.07 (br s, 1H), 8.73 (br d, J=7.5 Hz, 1H), 7.75 - 7.47 (m, 2H), 7.28 (d, J=7.5 Hz, 1H), 7.07 (br t, J=7.7 Hz, 2H), 4.91 (br d, J=7.3 Hz, 1H), 4.59 (br s, 1H), 3.84 (d, J=10.1 Hz, 1H), 3.63 (br s, 1H), 2.30 - 1.92 (m, 3H), 1.78 (br s, 1H), 1.72 - 1.63 (m, 1H), 1.60 - 1.33 (m, 12H), 1.18 (s, 3H), 1.09 (s, 3H)

Isomer 2:

[0001699] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.56 (br s, 1H), 9.00 - 8.79 (m, 1H), 7.82 (s, 1H), 7.68 - 7.48 (m, 1H), 7.32 - 7.22 (m, 1H), 7.15 (s, 1H), 7.12 - 6.99 (m, 1H), 4.98 - 4.71 (m, 1H), 4.50 (t, J=8.7 Hz, 1H), 3.90 - 3.77 (m, 1H), 3.73 - 3.60 (m, 1H), 2.47 - 2.39 (m, 1H), 2.24 (br dd, J=7.9, 12.3 Hz, 1H), 2.17 - 2.08 (m, 1H), 1.98 (br dd, J=8.4, 11.9 Hz, 1H), 1.83 - 1.68 (m, 1H), 1.61 - 1.51 (m, 2H), 1.50 - 1.36 (m, 7H), 1.35 - 1.21 (m, 3H), 1.15 (s, 3H), 1.08 - 0.97 (m, 3H)

[0001700] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.09 (br s, 1H), 8.66 (br s, 1H), 7.65 - 7.53 (m, 2H), 7.26 (d, J=7.7 Hz, 1H), 7.12 - 6.97 (m, 2H), 4.89 (br d, J=5.7 Hz, 1H), 4.57 (br s, 1H), 3.88 - 3.56 (m, 2H), 2.28 - 1.96 (m, 3H), 1.85 - 1.60 (m, 2H), 1.58 - 1.22 (m, 12H), 1.16 (s, 3H), 1.07 (s, 2H), 1.09 - 0.99 (m, 1H)

Isomer 3:

[0001701 ] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.66 - 11.45 (m, 1H), 8.94 (d, J=8.2 Hz, 1H), 7.92 - 7.75 (m, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.17 - 7.12 (m, 1H), 7.11 - 6.98 (m, 1H), 5.00 - 4.73 (m, 1H), 4.50 (br t, J=8.6 Hz, 1H), 3.83 (br d, J=10.4 Hz, 1H), 3.72 - 3.62 (m, 1H), 2.75 - 2.63 (m, 1H), 2.31 - 2.12 (m, 2H), 2.08 - 1.94 (m, 1H), 1.80 - 1.57 (m, 2H), 1.54 - 1.36 (m, 8H), 1.35 - 1.18 (m, 3H), 1.17 - 1.07 (m, 3H), 1.07 - 0.92 (m, 3H)

[0001702] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.07 (br s, 1H), 8.86 - 8.69 (m, 1H), 7.70 - 7.55 (m, 2H), 7.28 (d, J=7.5 Hz, 1H), 7.07 (br t, J=7.6 Hz, 2H), 4.98 - 4.85 (m, 1H), 4.60 (br s, 1H), 3.84 (d,J=10.6 Hz, 1H), 3.64 (s, 1H), 2.29 - 1.96 (m, 3H), 1.77 (br s, 1H), 1.73 - 1.63 (m, 1H), 1.61 - 1.32 (m, 12H), 1.20 - 1.14 (m, 3H), 1.13 - 1.06 (m, 3H)

Isomer 4:

[0001703] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.69 - 11.53 (m, 1H), 9.11 - 8.97 (m, 1H), 7.98 - 7.85 (m, 1H), 7.68 - 7.45 (m, 1H), 7.33 - 7.20 (m, 1H), 7.15 (s, 1H), 7.12 - 6.96 (m, 1H), 4.97 - 4.72 (m, 1H), 4.70 - 4.48 (m, 1H), 3.83 (br d, J=10.4 Hz, 1H), 3.72 - 3.59 (m, 1H), 2.70 - 2.54 (m, 1H), 2.35 - 2.12 (m, 3H), 2.01 - 1.53 (m, 3H), 1.53 - 1.39 (m, 6H), 1.39 - 1.27 (m, 4H), 1.20 - 1.01 (m, 6H)

[0001704] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.13 (br s, 1H), 8.85 (br s, 1H), 7.74 - 7.57 (m, 2H), 7.28 (br d, J=7.7 Hz, 1H), 7.18 - 6.96 (m, 2H), 4.90 (br s, 1H), 4.62 (br s, 1H), 3.85 (br d, J=10.4 Hz, 1H), 3.64 (s, 1H), 2.31 - 2.22 (m, 1H), 2.14 (br s, 2H), 1.89 - 1.75 (m, 1H), 1.73 - 1.64 (m, 1H), 1.60 - 1.28 (m, 12H), 1.20 (s, 3H), 1.14 (s, 3H) Isomer 5:

[0001705] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ = 11.55 (br s, 1H), 9.02 - 8.77 (m, 1H), 7.82 (s, 1H), 7.69 - 7.47 (m, 1H), 7.32 - 7.22 (m, 1H), 7.15 (s, 1H), 7.11 - 6.98 (m, 1H), 4.98 - 4.71 (m, 1H), 4.50 (t, J=8.5 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.74 - 3.59 (m, 1H), 2.47 - 2.40 (m, 1H), 2.35 - 2.20 (m, 1H), 2.19 - 2.08 (m, 1H), 1.98 (dd,J=8.5, 12.5 Hz, 1H), 1.89 - 1.70 (m, 1H), 1.69 - 1.52 (m, 2H), 1.51 - 1.39 (m, 6H), 1.38 - 1.28 (m, 4H), 1.15 (s, 3H), 1.07 - 0.97 (m, 3H)

[0001706] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.12 (br s, 1H), 8.65 (br s, 1H), 7.67 - 7.52 (m, 2H), 7.28 (d, J=7.7 Hz, 1H), 7.14 - 6.92 (m, 2H), 4.91 (br d, J=7.1 Hz, 1H), 4.59 (br s, 1H), 3.83 (br d, J=11.0 Hz, 1H), 3.63 (s, 1H), 2.31 - 2.20 (m, 1H), 2.19 - 1.96 (m, 2H), 1.81 (br s, 1H), 1.68 (br d, J=10.6 Hz, 1H), 1.61 - 1.34 (m, 12H), 1.18 (s, 3H), 1.09 (s,

3H)

Isomer 6:

[0001707] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.69 - 11.50 (m, 1H), 9.10 - 8.98 (m, 1H), 7.97 - 7.88 (m, 1H), 7.68 - 7.45 (m, 1H), 7.33 - 7.19 (m, 1H), 7.15 (s, 1H), 7.11 - 6.97 (m, 1H), 4.96 - 4.71 (m, 1H), 4.69 - 4.47 (m, 1H), 3.83 (br d, J=10.1 Hz, 1H), 3.66 (d, J=10.4 Hz, 1H), 2.69 - 2.54 (m, 1H), 2.39 - 2.12 (m, 3H), 1.97 - 1.56 (m, 2H), 1.55 - 1.47 (m, 3H), 1.42 (br s, 4H), 1.38 - 1.28 (m, 4H), 1.21 - 1.01 (m, 6H)

[0001708] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.12 (br s, 1H), 8.84 (br d, J=7.3 Hz, 1H), 7.74 - 7.56 (m, 2H), 7.28 (br d, J=7.5 Hz, 1H), 7.07 (br t, J=7.6 Hz, 2H), 4.89 (br s, 1H),

4.61 (br s, 1H), 3.84 (br d,J=10.4 Hz, 1H), 3.62 (br s, 1H), 2.29 - 2.06 (m, 3H), 1.85 -

1.61 (m, 2H), 1.59 - 1.33 (m, 12H), 1.20 (s, 3H), 1.14 (s, 3H)

Step 8: 2-(7-chloro-JH-indole-2-carbonyl)-N-[(JS)-1-cyano-2-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)ethyl ]-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001709] The white solid was separated by SFC (column: REGIS(S,S)WHELK-

01 (250mm*25mm, 10um);mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 55%-55%,10min) to give

[0001710] 2-(7-chloro-lH-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-(5,5-dimethyl-2-oxo- pyrrolidin-3-yl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (18 mg, 34.35 umol, 60.00% yield) and 2-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide (4 mg, 7.63 umol, 13.33% yield) as a white solid. MS (ESI) m/z 524.2 [M+H] ⁺

[0001711] Isomer 1:

[0001712] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.68 - 11.45 (m, 1H), 8.95 (br d, J=7.9 Hz, 1H), 7.86 - 7.76 (m, 1H), 7.68 - 7.44 (m, 1H), 7.33 - 7.20 (m, 1H), 7.14 (s, 1H), 7.11 - 6.97 (m, 1H), 4.98 - 4.77 (m, 1H), 4.50 (br t, J=8.5 Hz, 1H), 3.83 (br d, J=10.1 Hz, 1H), 3.66 (br d, J=10.1 Hz, 1H), 2.76 - 2.63 (m, 1H), 2.36 - 2.10 (m, 2H), 2.05 - 1.94 (m, 1H), 1.82 - 1.56 (m, 2H), 1.54 - 1.18 (m, 11H), 1.17 - 1.06 (m, 3H), 1.05 - 0.92 (m, 3H).

[0001713] Isomer 2:

[0001714] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.58 (br s, 1H), 9.10 - 8.90 (m, 1H), 7.89

(s, 1H), 7.70 - 7.44 (m, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.16 (s, 1H), 7.12 - 6.99 (m, 1H), 4.94 - 4.82 (m, 1H), 4.51 (t, J=8.6 Hz, 1H), 3.81 (br d,J=10.4 Hz, 1H), 3.70 (br d,J= 10.4 Hz, 1H), 2.30 - 2.10 (m, 2H), 2.03 (dd, J=8.5, 12.0 Hz, 1H), 1.81 - 1.65 (m, 1H), 1.62 - 1.18 (m, 13H), 1.16 - 1.01 (m, 6H).

Example 212. Synthesis of viral protease inhibitor compound 820

Step 1: 7-fluoro-4-methoxy-lH-indole-2-carboxylic acid

[0001715] To a solution of ethyl 7-fluoro-4-methoxy-lH-indole-2-carboxylate (800 mg, 3.37 mmol, 1 eq ) in THF (10 mL) and H ₂ O (5 mL) was added LiOH H ₂ O (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 HC1 aq (1M). The mixture was extracted with EtOAc (100 mL * 3). The combined organic layer was dried over Na ₂ SO ₄ , filtered, concentrated to give product 7-fluoro-4-methoxy-lH-indole-2-carboxylic acid (680 mg, crude) as white solid. MS (ESI) m/z 210.0 [M+H] ⁺

Step 2: (S)-methyl 2-((S)-3-cyclopropyl-2-(7-fluoro-4-methoxy-lH-indole-2- carboxamido)propanamido)-3-((S)-2-oxopiperidin-3-yl)propanoa te [0001716] To a solution of 7-fluoro-4-methoxy- 1 H-indole-2-carboxylic acid (0.68 g, 3.25 mmol, 1 eq) in DCM (20 mL) was added (S)-methyl 2-((S)-2-amino-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e (1.24 g, 3.58 mmol, 1.1 eq, HC1), EDCI (1.25 g, 6.50 mmol, 2 eq), DMAP (1.19 g, 9.75 mmol, 3 eq) and the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction was quenched by the addition of H ₂ O (200 mL) and then extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by column chromatography (SiO ₂ , EtOAc :MEOH = 10:1) to give product (S)-methyl 2-((S)-3-cyclopropyl-2-(7-fluoro-4- methoxy-lH-indole-2-carboxamido)propanamido)-3-((S)-2-oxopip eridin-3-yl)propanoate (1.15 g, 2.11 mmol, 65.01% yield, 92.35% purity) as white solid. MS (ESI) m/z 503.2 [M+H] ⁺

Step 3: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl-l-oxopropan-2-yl)-7-fluoro-4-methoxy-lH-indole-2 -carboxamide [0001717] To a solution of (S)-methyl 2-((S)-3-cyclopropyl-2-(7-fluoro-4-methoxy-lH- indole-2-carboxamido)propanamido)-3-((S)-2-oxopiperidin-3-yl )propanoate (1.08 g, 2.15 mmol, 1 eq) in NH ₃ (7 M in MeOH, 60 mL, 195.43 eq) was stirred at 50 °C for 48 h. Upon completion, the reaction was concentrated in the vacuum to give crude product 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-fluoro-4-methoxy- 1 H-indole-2-carboxamide (1.06 g, crude) as white solid. MS (ESI) m/z 488.2 [M+H] ⁺

Step 4: N-( (S)-l-( ( (S)-l-cyano-2-( (S)-2-oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl-l- oxopropan-2-yl)-7-fluoro-4-methoxy-lH-indole-2-carboxamide [0001718] To a solution of 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-fluo ro-4-methoxy-lH-indole- 2-carboxamide (1.03 g, 2.11 mmol, 1 eq) in DCM (60 mL) was added Burgess reagent (1.51 g, 6.34 mmol, 3 eq), and the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction was concentrated in the vacuum and was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase:

[water(0.05%NH ₃ H ₂ 0+ 10mM NH ₄ HCO ₃ )-ACN];B%: 20%-50%,8min) to give N-((S)-1- (((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl - 1 -oxopropan-2-yl)- 7-fluoro-4-methoxy-lH-indole-2-carboxamide (400 mg, 845.40 umol, 40.01% yield, 99.23% purity) as white solid. MS (ESI) m/z 470.1 [M+H] ⁺

[0001719] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 8.95 - 8.94 (m, 1H), 8.57 - 8.55 (m, 1H),

7.54 (br s, 1H), 7.36 - 7.33 (m, 1H), 6.95 - 6.90 (m, 1H), 6.43 - 6.40 (m, 1H), 5.09 - 5.04 (m, 1H), 4.52 - 4.41 (m, 1H), 3.87 (s, 3H), 3.15 - 3.03 (m, 2H), 2.33 - 2.19 (m, 2H), 1.89 - 1.75 (m, 3H), 1.72 - 1.69 (m, 1H), 1.64 - 1.52 (m, 1H), 1.51 - 1.34 (m, 2H), 0.86 - 0.76 (m, 1H), 0.47 - 0.37 (m, 2H), 0.24 - 0.15 (m, 1H), 0.14 - 0.06 (m, 1H).

Example 213. Synthesis of viral protease inhibitor compound 838

Step 1: methyl (Z)-2-azido-3-(4-chloro-2-fluoro-phenyl)prop-2-enoate [0001720] 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 ot H ₂ O (20 mL) at 25 °C, diluted with H ₂ O 100 mL and extracted with ethyl acetate (100 mL * 2). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , 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.

Step 2: methyl 6-chloro-4-fluoro-lH-indole-2-carboxylate

[0001721 ] 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-lH-indole-2-carboxylate (2 g, 8.35 mmol, 53.35% yield, 95% purity) as a white solid.

Step 3: 6-chloro-4-fluoro-lH-indole-2-carboxylic acid

[0001722] To a mixture of methyl 6-chloro-4-fluoro-lH-indole-2-carboxylate (1.4 g, 6.15 mmol, 1 eq) in THF (10 mL) and H ₂ O (5 mL) was added LiOH H ₂ O (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 HC1 (1 M), and then diluted with H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was used next step directly. Compound 6-chloro-4-fluoro-lH-indole-2- carboxylic acid (1.3 g, 5.78 mmol, 94.01% yield, 95% purity) was obtained as a white solid.

Step 4: methyl (2S)-2-[[(2S)-2-[(6-chloro-4-fluoro-lH-indole-2-carbonyl)ami no]-3- cyclopropyl-propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001723] To a mixture of 6-chloro-4-fluoro-lH-indole-2-carboxylic acid (600 mg, 2.81 mmol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) - 2-oxo-3-piperidyl]propanoate (977.10 mg, 2.81 mmol, 1 eq, HC1) in DCM (2 mL) and DMF (1 mL) was added EDCI (1.08 g, 5.62 mmol, 2 eq) and DMAP (686.36 mg, 5.62 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O (100 mL) and extracted with ethyl acetate (100 mL * 2). The combined organic layers were washed with brine (100 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 8/1 to 0/1) to get the compound methyl (2S)-2-[[(2S)-2-[(6-chloro-4-fluoro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl] amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.1 g, 1.95 mmol, 69.52% yield, 90% purity) as a white solid. MS (ESI) m/z 507.2 [M+H] ⁺

Step 5: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-4-fluoro-lH-ind ole-2-carboxamide

[0001724] A solution of methyl (2S)-2-[[(2S)-2-[(6-chloro-4-fluoro-lH-indole-2- carbonyl)amino]-3- cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate (1 g, 1.97 mmol, 1 eq) in NH ₃ /MeOH (7 M, 20 mL, 70.97 eq) was stirred at 65 °C for 16 h. Upon completion, the reaction mixture concentrated under reduced pressure to give a residue and used next step directly. Compound N-[(l S)-2-[[(l S)-2-amino-2-oxo-1- [[(3 S)-2-oxo-3 -pi peri dyl Jmethyl ]ethy 1 ] amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-6- chloro-4-fluoro- 1 H-indole-2-carboxamide (950 mg, 1.74 mmol, 88.11% yield, 90% purity) was obtained as a white solid. MS (ESI) m/z 492.2 [M+H] ⁺

Step 6: 6-chloro-N-[(lS)-2-[[(lS)-l-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-4-fluoro-lH-indole-2-car boxamide

[0001725] To a mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-4-fluoro- 1 H-indole-2-carboxamide (500 mg, 1.02 mmol, 1 eq) in DCM (20 mL) was added Burgess reagent (484.42 mg, 2.03 mmol, 2 eq). The mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was diluted with H ₂ O (5 mL) and extracted with DCM (20 mL * 2). The combined organic layers were concentrated with using blow-dry to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 40%- 70%,10min) to get 6-chloro-N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4- fluoro-lH-indole-2- carboxamide (120 mg, 253.20 umol, 24.91% yield, 100% purity) as a white solid. MS (ESI) m/z 474.1 [M+H] ⁺

[0001726] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.08 (br s, 1H), 8.94 (d, J=8.0 Hz, 1H), 8.73 (d, J=7.5 Hz, 1H), 7.61 - 7.23 (m, 3H), 6.99 (d, J=10.1 Hz, 1H), 5.06 (q, J=8.1 Hz, 1H), 4.57 - 4.37 (m, 1H), 3.18 - 2.98 (m, 2H), 2.37 - 2.17 (m, 2H), 1.89 - 1.26 (m, 7H), 0.89 - 0.65 (m, 1H), 0.51 - 0.32 (m, 2H), 0.27 - 0.01 (m, 2H).

Example 214. Synthesis of viral protease inhibitor compound 848

Step 1: methyl 6-bromo-3-fluoro-lH-indole-2-carboxylate

[0001727] To a mixture of methyl 6-bromo- 1 H-indole-2-carboxylate (2 g, 7.87 mmol, 1 eq) in ACN (84 mL) was added NaHCO ₃ (36.42 g, 433.52 mmol, 16.86 mL, 55.07 eq) in one portion at 25 °C. Select F (3.07 g, 8.66 mmol, 1 eq) was added and stirred at 80 °C for 2 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give a crude product. The crude was purified by prep-HPLC (neutral condition, column: Agela DuraShell C18250*50mm* 10um;mobile phase: [water(10 mM NH4HC03 )- ACN] ;B% : 50%-55%, 20 min) to give methyl 6-bromo-3-fluoro- 1 H-indole- 2-carboxylate (500 mg, 1.84 mmol, 23.35% yield) as a yellow solid.

Step 2: 6-bromo-3-fluoro-lH-indole-2-carboxylic acid [0001728] To a mixture of methyl 6-bromo-3-fluoro-lH-indole-2-carboxylate (500 mg,

1.84 mmol, 1 eq ) in THF (5 mL) and H ₂ O (5 mL) was added LiOH.H ₂ O (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 HC1 and extracted with ethyl acetate (6 mL * 3). The combined organic layers were washed with brine (9 mL *

1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 6-bromo- 3-fluoro-lH-indole-2-carboxylic acid (440 mg, 1.71 mmol, 92.78% yield) as a yellow solid. (ESI) m/z 256.0 [M-H] ⁺

Step 3: methyl (2S)-2-[[(2S)-2-[(6-bromo-3-fluoro-lH-indole-2-carbonyl)amin o]-3- cyclopropyl-propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001729] To a mixture of 6-bromo-3-fluoro-lH-indole-2-carboxylic acid (440 mg, 1.71 mmol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) - 2-oxo-3-piperidyl]propanoate (654.28 mg, 1.88 mmol, 1.1 eq, HC1) in DCM (8 mL) and DMF (2 mL) was added DMAP (626.73 mg, 5.13 mmol, 3 eq) and EDCI (655.61 mg,

3.42 mmol, 2 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 H20 (20 mL) and extracted with ethyl acetate (15 mL * 4). The combined organic layers were washed with brine 30 mL (30 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/l to 0/1) to give methyl (2S)-2-[[(2S)-2-[(6-bromo-3-fluoro-lH- indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[( 3S)-2-oxo-3- pi peri dy 1 ] propanoat e (510 mg, 924.91 umol, 54.09% yield) as a white solid. (ESI) m/z 551.1 [M+H] ⁺

Step 4: N-f ( l S)-2-[[( 1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-6-bromo-3-fluoro-lH-indole- 2-carboxamide

[0001730] A mixture of methyl (2S)-2-[[(2S)-2-[(6-bromo-3-fluoro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3-piperidyl]propanoate (510 mg, 924.91 umol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 75.68 eq) was stirred at 55 °C for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-6-bromo-3-fluoro- 1 H-indole-2-carboxamide (500 mg, crude) as a yellow solid. MS (ESI) m/z 536.2 [M+H] ⁺

Step 5: 6-bromo-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-3-fluoro-lH-indole-2-car boxamide

[0001731 ] To a mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-6-bromo-3-fluoro- 1 H-indole-2-carboxamide (500 mg, 745.72 umol, 80% purity, 1 eq) in DCM (8 mL) was added Burgess reagent (533.14 mg, 2.24 mmol, 3 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition; column: Phenomenex Gemini-NX C18 75*30mm*3um;mobile phase: [water(10mM NH4HC03 )- ACN] ;B% : 40%-65%,8min) to give 6-bromo-N-[( 1 S)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-3-fluoro-lH-indole-2-carbox amide (170 mg, 327.95 umol, 43.98% yield) as a white solid. MS (ESI) m/z 518.1 [M+H] ⁺

[0001732 ] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ = 11.70 (s, 1H), 8.98 (d, J=7.9 Hz, 1H), 7.84 (dd,J=3.1, 7.3 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.55 (br s, 1H), 7.26 (dd, J=1.5, 8.6 Hz, 1H), 5.09 (q, J=8.1 Hz, 1H), 4.57 - 4.49 (m, 1H), 3.13 - 3.05 (m, 2H), 2.30 - 2.20 (m, 2H), 1.82 (dt, J=6.6, 14.0 Hz, 3H), 1.77 - 1.67 (m, 1H), 1.64 - 1.51 (m, 2H), 1.47 - 1.35 (m, 1H), 0.81 - 0.70 (m, 1H), 0.48 - 0.37 (m, 2H), 0.21 - 0.07 (m, 2H)

Example 215. Synthesis of viral protease inhibitor compound 862

Step 1: 6-cyano-lH-indole-2-carboxylic acid

[0001733] To a solution of methyl 6-cyano- 1 H-indole-2-carboxylate (1 g, 5.00 mmol, 1 eq) in H ₂ O (4 mL) and THF (8 mL) was added LiOH.H ₂ O (358.88 mg, 14.99 mmol, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give 6-cyano- 1 H-indole-2- carboxylic acid (805 mg, crude) as a white solid. MS (ESI) m/z 187.0 [M+H] ⁺

Step 2: methyl (2S)-2-[[(2S)-2-[(6-cyano-lH-indole-2-carbonyl)amino]-3-cycl opropyl- propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001734] To a solution of 6-cyano- 1 H-indole-2-carboxylic acid (776.06 mg, 4.17 mmol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxo-3- piperidyl]propanoate (1.45 g, 4.17 mmol, 1 eq, HC1) in DCM (50 mL) was added DMAP (1.53 g, 12.51 mmol, 3 eq) and EDCI (2.40 g, 12.51 mmol, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (30 mL), and then extracted with DCM (10 mL * 2). The combined organic layers were washed with HC1 (1M) 20 mL (10 mL * 2), then were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 0/1, dichloromethane : methanol = 10:1, (UV 254 nm)) to give methyl (2S)-2- [[(2S)-2-[(6-cyano-lH-indole-2-carbonyl)amino]-3-cyclopropyl -propanoyl]amino]-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (1.3 g, 2.56 mmol, 61.46% yield, 94.5% purity) as a white solid. MS (ESI) m/z 480.2 [M+H] ⁺ Step 3: N-f ( l S)-2-[[( 1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-6-cyano-lH-indole-2-carboxa mide

[0001735 ] A solution of methyl (2S)-2-[[(2S)-2-[(6-cyano-lH-indole-2-carbonyl)amino]-3- cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate (1.2 g, 2.50 mmol,

1 eq) in NH ₃ /MeOH (7 M, 20 mL, 55.94 eq) was stirred at 50 °C for 16 h. 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]-6-cyano-lH-indole-2-carboxa mide (1.1 g, crude) as a white solid. MS (ESI) m/z 465.2 [M+H] ⁺

Step 4: 6-cyano-N-[ (lS)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ]ethyl ]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[0001736] To a solution of N-[(l S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-6-cyano-lH-indole-2- carboxamide (1 g, 2.15 mmol, 1 eq) in DCM (20 mL) was added Burgess reagent (1.03 g, 4.31 mmol, 2 eq). The mixture was stirred at 20 °C for 6 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 25%-55%,10min) to give 6- cyano-N-[( 1 S)-2-[[(l S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]-l - (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide (414.8 mg, 929.00 umol, 43.15% yield, 100% purity) as a white solid. MS (ESI) m/z 447.2 [M+H] ⁺ .

[0001737] 1H NMR (400MHz, DMSO-d ₆ ) δ = 12.08 (s, 1H), 8.96 (d, J = 8.4Hz, 1H), 8.82 (d ,J= 7.8Hz, 1H), 7.89 - 7.81 (m, 2H), 7.53 (s, 1H), 7.45 - 7.33 (m, 2H), 5.07 (q ,J = 8.2Hz, 1H), 4.54 - 4.46 (m, 1H), 3.17 - 3.01 (m, 2H), 2.35 - 2.20 (m, 2H), 1.91 - 1.65 (m, 4H), 1.63 - 1.32 (m, 3H), 0.88 - 0.73 (m, 1H), 0.50 - 0.35 (m, 2H), 0.25 - 0.07 (m, 2H)

Example 216. Synthesis of viral protease inhibitor compound 866

Step 1: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,5-dichloro-lH-pyrrole-2- carbonyl)amino ]propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001738] To a mixture of 4,5-dichloro-lH-pyrrole-2-carboxylic acid (300 mg, 1.67 mmol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxo- 3-piperidyl]propanoate (637.74 mg, 1.83 mmol, 1.1 eq, HCI) in DCM (8 mL) and DMF (2 mL) was added DIEA (430.84 mg, 3.33 mmol, 580.64 uL, 2 eq), HOBt (450.44 mg, 3.33 mmol, 2 eq) and EDCI (639.05 mg, 3.33 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 diluted with H ₂ O (20 mL) and extracted with ethyl acetate (15 mL * 4). The combined organic layers were washed with brine (30 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/l to 0/1) to give methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,5-dichloro-lH-pyrrole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (550 mg, 1.16 mmol, 69.71% yield) as a white solid. MS (ESI) m/z 473.1 [M+H] ⁺

Step 2: N-f ( l S)-2-[[( 1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4,5-dichloro-lH-pyrrole-2-c arboxamide

[0001739] A mixture of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,5-dichloro-lH-pyrrole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (500 mg, 1.06 mmol, 1 eq) in NH ₃ /MeOH (7 M, 20 mL, 132.54 eq) was stirred at 40 °C for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]me thyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4,5-dichloro-lH-pyrrole-2-c arboxamide (480 mg, 1.05 mmol, 99.14% yield) as a yellow solid. MS (ESI) m/z 458.1 [M+H] ⁺

Step 3: 4, 5-dichloro-N-[ ( l S)-2-[[( 1 S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl ] ethyl ]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-lH-pyrrole-2-carboxamide

[0001740] To a mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4,5-dichloro-lH- pyrrole-2-carboxamide (480 mg, 555.05 umol, 53% purity, 1 eq) in DCM (8 mL) was added Burgess reagent (396.82 mg, 1.67 mmol, 3 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition; column: column: Phenomenex Gemini -NX C18 75*30mm*3um;mobile phase: [water(10mM NH4HC03 )- ACN] ;B% : 25%-50%,8min) to give 4,5-dichloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperi dyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-pyrrole-2-carboxamide (108 mg, 245.27 umol, 44.19% yield) as a white solid. MS (ESI) m/z 440.1 [M+H] ⁺

[0001741] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ = 12.74 (br s, 1H), 8.88 (d, J=8.2 Hz, 1H), 8.22 (br d, J=7.1 Hz, 1H), 7.53 (br s, 1H), 7.05 (s, 1H), 5.10 - 5.00 (m, 1H), 4.44 - 4.33 (m, 1H), 3.15 - 3.02 (m, 2H), 2.30 - 2.17 (m, 2H), 1.91 - 1.65 (m, 4H), 1.55 (br dd, J=3.5, 9.9 Hz, 1H), 1.47 - 1.32 (m, 2H), 0.82 - 0.70 (m, 1H), 0.45 - 0.34 (m, 2H), 0.21 - 0.02 (m,

2H)

Example 217. Synthesis of viral protease inhibitor compound 872 Step 1: (S)-methyl2-((S)-3-cyclopropyl-2-(lH-pyrazole-5-carboxamido) propanamido)-3-((S)- 2-oxopiperidin-3-yl)propanoate

[0001742] To a solution of 1H-pyrazol e- 5 -carboxyl i c acid (500 mg, 4.46 mmol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxo-3- piperidyl]propanoate (1.24 g, 3.57 mmol, 0.8 eq, HC1) in DCM (40 mL) was added DMAP (1.09 g, 8.92 mmol, 2 eq) and EDCI (1.71 g, 8.92 mmol, 2 eq), and then the mixture was stirred at 20 °C for 2 h. Upon the reaction completement, the mixture was poured into water (40 mL) and was extracted with DCM (15 mL * 3) and dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum and was purified by prep-HPLC (column: Waters Xb ridge C18 150 * 50mm * lOum; mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: l%-40%, 10 min) to obtained (S)-methyl 2-((S)-3-cyclopropyl-2- (1H-pyrazole-5-carboxamido)propanamido)-3-((S)-2-oxopiperidi n-3-yl)propanoate (550 mg, 1.26 mmol, 28.25% yield, 92.9% purity) as a white solid. MS (ESI) m/z 406.2 [M+H] ⁺

Step 2: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl-l-oxopropan-2-yl)-lH-pyrazole-5-carboxamide [0001743 ] A solution of (S)-methyl 2-((S)-3-cyclopropyl-2- (1H-pyrazole-5-carboxamido) propanamido)-3-((S)-2-oxopiperidin-3-yl) propanoate (500 mg, 1.23 mmol, 1 eq) in NH ₃ /MeOH (20 mL, 7M) was stirred at 50 °C for 24 h. Upon the reaction completement, 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- l-oxopropan-2-yl)- 1H-pyrazole-5- carboxamide (500 mg, crude) as a light yellow solid. MS (ESI) m/z 391.2 [M+H] ⁺

Step 3: N-( (S)-l-( ( (S)-l-cyano-2-( (S)-2-oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl-l- oxopropan-2-yl)-lH-pyrazole-5-carboxamide & methyl(5-(((S)-l-(((S)-l-cyano-2-((S)-2- oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl-l-oxopropan-2-y l)carbamoyl)-lH-pyrazol-l- yl)sulfonylcarbamate

[0001744] To a solution of N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl) propan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-1H-pyrazo le-5-carboxamide (500 mg, 1.28 mmol, 1 eq) in DCM (8 mL) was added Burgess reagent (915.53 mg, 3.84 mmol, 3 eq), and then the mixture was stirred at 30 °C for 4 h. Upon completion of the reaction, the reaction mixture was quenched with water (1 mL) and was dried with using N ₂ , and then was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40mm * lOum; mobile phase: [water(10 mM NH4HCO3)- ACN] ; B%: 15%-45%, 8min) to obtain N-((S)-1-(((,S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)ami no)-3-cyclopropyl-1- xopropan2-yl)-1H-pyrazole-5-carboxamide (compound 872, 160 mg, 425.76 umol, 33.25% yield, 99.1% purity) as a white solid. MS (ESI) m/z 373.1[M+H] ⁺

[0001745] ¹ H NMR (400MHz, DMSO-d6) δ ppm 13.57 - 13.18 (m, 1H), 8.91 (d, J= 8.0 Hz, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.83 (s, 1H), 7.52 (s, 1H), 7.02 - 6.59 (m, 1H), 5.05 (q, J= 7.9 Hz, 1H), 4.48 (q, J= 7.4 Hz, 1H), 3.16 - 3.02 (m, 2H), 2.31 - 2.17 (m, 2H), 1.89 - 1.65 (m, 4H), 1.63 - 1.32 (m, 3H), 0.71 (d ,J= 6.4 Hz, 1H), 0.40 (d, J= 8.0 Hz, 2H), 0.09 (dd,J= 4.6, 14.9 Hz, 2H).

[0001746] Methyl(5-(((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3- cyclopropyl - 1 -oxopropan-2-yl)carbamoyl)- 1H-pyrazol- 1 -yl)sulfonylcarbamate (20 mg, 425.76 umol, 33.25% yield, 99.1% purity) was obtained as a white solid. MS (ESI) m/z 510.1[M+H] ⁺

[0001747] ¹ H NMR (400MHz, DMSO-d6) δ ppm 9.06 (s, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.77 (s, 1H), 7.52 (s, 1H), 7.21 (s, 1H), 7.08 (s, 1H), 7.01 - 6.92 (m, 1H), 6.77 - 6.32 (m, 2H), 5.05 (q, J= 7.9 Hz, 1H), 4.56 - 4.40 (m, 1H), 3.47 (s, 3H), 3.16 - 3.01 (m, 2H), 2.30 - 2.15 (m, 2H), 1.89 - 1.65 (m, 4H), 1.63 - 1.31 (m, 3H), 0.77 - 0.65 (m, 1H), 0.45 - 0.32 (m, 2H), 0.21 - 0.00 (m, 2H).

Example 218. Synthesis of viral protease inhibitor compound 731

Step 1: (Z)-ethyl 3-bromo-2-(hydroxyimino)propanoate

[0001748] To a solution of ethyl 3-bromo-2-oxo-propanoate (167 g, 428.18 mmol, 107.05 mL, 50% purity, 1 eq) in CHCl ₃ (800 mL) was added NH ₂ OH.HCl (32.73 g, 471.00 mmol, 1.1 eq) in H ₂ O (800 mL) under N2. The mixture was stirred at 25 °C for 16 h. Upon completion, the reaction was extracted with DCM (1000 mL * 4). The combined organic phase was washed with brine (2000 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give (Z)-ethyl 3-bromo-2-(hydroxyimino)propanoate (440 g, crude) as a white solid. MS (ESI) m/z 210.3 [M+H] ⁺ .

Step 2: l-(cyclohexylidenemethyl)pyrrolidine

[0001749] A mixture of cyclohexanecarbaldehyde (100 g, 891.51 mmol, 107.30 mL, 1 eq), pyrrolidine (82.43 g, 1.16 mol, 96.74 mL, 1.3 eq) in toluene (1.6 L) was heated to 130 °C for 14 h, and then water was removed by Dean-Stark trap. Upon completion, the reaction mixture was concentrated under reduced pressure at 55 °C to afford 1- (cyclohexylidenemethyl)pyrrolidine (420 g, crude) as a yellow oil. MS (ESI) m/z 166.2 [M+H] ⁺ .

Step 3: ethyl l-hydroxy-2-oxa-3-azaspiro[5.5]undec-3-ene-4-carboxylate [0001750] To a solution of l-(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 N ₂ . After 1 h, TEA (85.72 g, 847.08 mmol, 117.90 mL, 1 eq) was added drop-wise at - 20 °C under N ₂ . The reaction mixture was stirred at 25 °C for 12 h under N ₂ . Upon completion, the residue was poured into HC1 (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 1/1) to give a ethyl 1 -hy droxy-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] ⁺ .

Step 4: ethyl 2-azaspiro[4.5]decane-3-carboxylate

[0001751 ] To a solution of ethyl 1 -hydroxy-2-oxa-3-azaspiro[5.5]undec-3-ene-4- carboxylate (20 g, 49.73 mmol, 60% purity, 1 eq) in EtOH (150 mL) was added Raney nickel (12.00 g, 140.07 mmol, 2.82 eq) under Arz. The suspension was degassed under vacuum and purged with H ₂ (100.46 mg, 49.73 mmol, 1 eq) several times. The mixture was stirred under H ₂ (100.46 mg, 49.73 mmol, 1 eq) (50 psi) at 50 °C for 18 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to ethyl acetate :MeOH = 10/1) to give a ethyl 2- azaspiro[4.5]decane-3-carboxylate (35 g, 165.64 mmol, 33.31% yield) as a yellow oil. MS (ESI) m/z 212.2 [M+H] ⁺ .

Step 5: 2-tert-butyl 3-ethyl 2-azaspir o [4.5 ]de cane -2, 3-dicar boxy late [0001752] To a solution of ethyl 2-azaspiro[4.5]decane-3-carboxylate (35 g, 132.51 mmol, 80% purity, 1 eq) in DCM (350 mL) was added Boc ₂ O (34.70 g, 159.02 mmol, 36.53 mL, 1.2 eq) and TEA (26.82 g, 265.03 mmol, 36.89 mL, 2 e^) at 0 °C. The mixture was stirred at 25 °C for 14 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (400 mL), and extracted with ethyl acetate (200 mL * 3). The combined organic layers were washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 10/1) to give 2-tert- butyl 3-ethyl 2-azaspiro[4.5]decane-2,3-dicarboxylate (40 g, 95.05 mmol, 71.73% yield, 74% purity) as a yellow oil. MS (ESI) m/z 312.2 [M+H] ⁺ .

Step 6: 2-(tert-butoxycarbonyl)-2-azaspiro[4.5Jdecane-3-carboxylic acid

[0001753] 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 H ₂ O (120 mL) and MeOH (480 mL) was added LiOH.H ₂ O (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 H ₂ O (800 mL) and extracted with ethyl acetate (500 mL * 2). The aqueous phase were added with HC1 (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 Na ₂ SO ₄ , 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] ⁺

Step 7: tert-butyl 3-(((S)-l-methoxy-l-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2- yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylate

[0001754] To a solution of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (22.97 g, 97.05 mmol, 1.1 eq, HC1) and 2-tert-butoxycarbonyl-2-azaspiro[4.5]decane-3- carboxylic acid (25 g, 88.23 mmol, 1 eq) in DCM (400 mL) was added DMAP (21.56 g, 176.45 mmol, 2 eq) and EDCI (25.37 g, 132.34 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction was quenched by 0.5 M HC1 (400 mL) and then extracted with DCM (150 mL * 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate =

1/1 to 0/1) to give tert-butyl 3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-ca rboxylate (27 g, 47.84 mmol, 54.23% yield, 82.5% purity) as a yellow solid. MS (ESI) m/z 466.2 [M+H] ⁺

Step 8: (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2-azaspiro[4.5]decane-3- carboxamido)propanoate

[0001755] To a solution of tert- butyl 3-[[(l S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-ca rboxylate (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 (2 S)-2-(2-azaspiro[4.5 ]decane-3 -carbonyl amino)-3 - [(3 S)-2-oxo-3 -piperidyl]propanoate (25 g, crude, HC1) as a yellow solid. MS (ESI) m/z 366.3 [M+H] ⁺

Step 9: (2S)-methyl 2-(2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3 - carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[0001756] To a solution of methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (25 g, 62.20 mmol, 1 eq, HC1) and 7-chloro-lH- indole-2-carboxylic acid (13.38 g, 68.42 mmol, 1.1 eq) in DCM (400 mL) was added EDCI (17.89 g, 93.30 mmol, 1.5 eq) and DMAP (15.20 g, 124.40 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction was quenched by 0.5 M HC1 (400 mL) and then extracted with DCM (300 mL * 2). The combined organic phase was washed with brine (400 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/1 to 0/1) to give methyl (2S)-2-[[2-(7-chloro-lH-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)- 2-oxo-3- piperidyl]propanoate (25 g, 44.19 mmol, 71.05% yield, 96% purity) as a yellow solid. MS (ESI) m/z 543.3 [M+H] ⁺

Step 10: N-((S)-l-amino-l-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl) -2-(7-chloro-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide

[0001757] A solution of methyl (2S)-2-[[2-(7-chloro-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (5 g, 8.84 mmol, 96% purity, 1 eq) in NH ₃ (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 NH ₃ /MeOH, and added DCM (300 mL) (three times) was concentrated under reduced pressure to give N-[(l S)-2-amino-2-oxo-1- [[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-2-(7-chloro-lH-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] ⁺

Step 11: 2-(7-chloro-lH-indole-2-carbonyl)-N-((S)-l-cyano-2-((S)-2-ox opiperidin-3- yl)ethyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001758] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-2-(7-chloro-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3- carboxamide (12 g, 22.73 mmol, 1 eq) in DCM (200 mL) was added Burgess reagent (11.91 g, 50.00 mmol, 2.2 eq). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by addition H ₂ O (10 mL) at 20 °C, and then to remove solvent by N ₂ . The residue was purified by prep-HPLC (column: Phenomenex Titank C18 Bulk 250 * 100 mm lOu; mobile phase: [water (lOmM NH4HCO3) - ACN]; B%: 30% - 65%, 20min) to give 2-(7-chloro-lH-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-ox opiperidin- 3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide (17 g, 99.29% purity) as a yellow solid. MS (ESI) m/z 510.3 [M+H] ⁺

Step 12: 2-(7-chloro-lH-indole-2-carbonyl)-N-( ( S)-l-cyano-2-( (S)-2-oxopiperidin-3- yl)ethyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide Isomer 1:

[0001759] The desired compound was further separated by SFC (condition: column: REGIS (s,s) WHELK-Ol (250mm * 50mm, lOum); mobile phase: [0.1% NH3H ₂ O ETOH]; B%: 60%-60%, 9.5min) to give 2-(7-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 - cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-azaspiro[4.5]decane -3-carboxamide (6.1 g, 11.96 mmol, 26.31% yield) as a yellow solid. MS (ESI) m/z 510.3 [M+H] ⁺

[0001760] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.64 - 11.51 (m, 1H), 8.98 - 8.86 (m, 1H), 7.70 - 7.38 (m, 2H), 7.32 - 7.21 (m, 1H), 7.16 - 6.69 (m, 2H), 5.08 - 4.47 (m, 2H), 3.88 - 3.76 (m, 1H), 3.70 - 3.60 (m, 1H), 3.27 - 2.93 (m, 2H), 2.35 (br s, 3H), 1.88 - 1.31 (m,

16H). [0001761 ] ¹ H NMR (400 MHz, DMSO-d ₆ , 273+80K) δ = 11.28 - 11.09 (m, 1H), 8.82 - 8.62 (m, 1H), 7.73 - 7.52 (m, 1H), 7.37 - 7.22 (m, 2H), 7.20 - 6.96 (m, 2H), 5.08 - 4.86 (m, 1H), 4.70 - 4.46 (m, 1H), 3.88 - 3.78 (m, 1H), 3.70 - 3.51 (m, 1H), 3.14 - 3.09 (m, 2H), 2.40 - 2.13 (m, 3H), 1.87 - 1.37 (m, 16H).

[0001762 ] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.67 - 7.46 (m, 1H), 7.32 - 7.22 (m, 1H), 7.14 - 6.81 (m, 2H), 5.16 - 4.97 (m, 1H), 4.83 - 4.58 (m, 1H), 3.98 - 3.81 (m, 1H), 3.76 - 3.38 (m, 1H), 3.27 - 2.98 (m, 2H), 2.67 - 2.20 (m, 3H), 2.05 - 1.43 (m, 16H).

Isomer 2:

[0001763] 2-(7-Chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide (7 g, 13.72 mmol, 30.20% yield) was obtained as a yellow solid. MS (ESI) m/z 510.3 [M+H] ⁺

[0001764] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.59 - 11.47 (m, 1H), 8.98 - 8.77 (m, 1H), 7.69 - 7.63 (m, 1H), 7.54 - 7.46 (m, 1H), 7.32 - 7.23 (m, 1H), 7.18 - 6.68 (m, 2H), 5.06 - 4.84 (m, 1H), 4.80 - 4.47 (m, 1H), 3.90 - 3.78 (m, 1H), 3.74 - 3.61 (m, 1H), 3.28 - 3.00 (m, 2H), 2.33 - 2.09 (m, 1H), 2.08 - 2.06 (m, 1H), 1.88 - 1.32 (m, 16H).

[0001765] NMR (400 MHz, DMSO-d ₆ , 273+80K) δ = 11.26 - 11.02 (m, 1H), 8.74 - 8.57 (m, 1H), 7.76 - 7.51 (m, 1H), 7.32 - 7.21 (m, 2H), 7.17 - 6.93 (m, 2H), 5.07 - 4.87 (m, 1H), 4.73 - 4.51 (m, 1H), 3.87 - 3.79 (m, 1H), 3.73 - 3.52 (m, 1H), 3.08 (s, 2H), 2.29 - 2.12 (m, 3H), 1.86 - 1.38 (m, 16H).

[0001766] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.72 - 7.52 (m, 1H), 7.33 - 7.19 (m, 1H), 7.14 - 6.79 (m, 2H), 5.09 - 4.92 (m, 1H), 4.70 - 4.54 (m, 1H), 3.99 - 3.89 (m, 1H), 3.83 - 3.40 (m, 1H), 3.22 - 3.00 (m, 2H), 2.57 - 2.12 (m, 3H), 2.01 - 1.40 (m, 16H).

Example 219. Synthesis of viral protease inhibitor compound 900

Step 1: (S)-methyl2-((S)-2-(7-chloro-5-methoxy-lH-indole-2-carboxami do)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[0001767] To a solution of 7-chloro-5-methoxy- 1H-indole-2-carboxylic acid (1 g, 3.24 mmol, 85% purity, 1.1 eq, HC1) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl] propanoate (918.04 mg, 2.95 mmol, 1 eq) in DMF (15 mL) was added PyBOP (1.53 g, 2.95 mmol, 1 eq). TEA (895.02 mg, 8.85 mmol, 1.23 mL, 3 eq) in DMF (5 mL) was added, and then the mixture was stirred at - 40 °C for 2 h. Upon completion, the mixture was quenched by water (60 mL) and was extracted with DCM (20 mL * 3), then was concentration in vacuum and was purified by column (SiO ₂ , petroleum ether: ethyl acetate= 5:1 to 0:1) to obtain (S)-methyl2-((S)-2-(7- chloro-5-methoxy- 1H-indole- 2-carboxamido)-3-cyclopropylpropanamido)-3-((S)-2- oxopiperidin-3-yl)propanoate (1.5 g, 2.02 mmol, 68.62% yield, 70% purity) as a brown gum. MS (ESI) m/z 519.2 [M+H] ⁺

Step 2: N-( (S)-l-( ( (S)-l -amino- 1 -oxo-3-( (S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl-l-oxopropan-2-yl)-7-chloro-5-methoxy-lH-indole-2 -carboxamide [0001768] A solution of (S)-methyl2-((S)-2-(7-chloro-5-methoxy-1H-indole-2- carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl) propanoate (350 mg, 674.39 umol, 1 eq) in NH ₃ /MeOH (7M, 4 mL) was stirred at 50 °C for 20 h. Upon complteion, 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-cyclopro pyl-1-oxopropan-2-yl)-7- chloro-5-methoxy-1H-indole-2-carboxamide (1.3 g, crude) as a brown gum. MS (ESI) m/z 502.1 [M-H] ⁺ Step 3: 7-chloro-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)e thyl)amino)-3- cyclopropyl-l-oxopropan-2-yl)-5-methoxy-lH-indole-2-carboxam ide

[0001769 ] To a solution of 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-chl oro-5-m ethoxy- 1H-indole- 2-carboxamide (1.3 g, 2.58 mmol, 1 eq) in DCM (20 mL) was added Burgess reagent (1.84 g, 7.74 mmol, 3 eq) at 30 °C. The resulting mixture was stirred at 30 °C for 2 h. Upon completion, the mixture was quenched by water (2 mL) and was dried by blowing N ₂ . The mixture was purified by prep-HPLC (column: Waters Xbridge Cl 8 150 * 50mm * lOum; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 25%-55%, lOmin) to obtain 7-chloro-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)e thyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-5-methoxy- 1H-indole-2-carboxamide (260 mg, 535.02 umol, 20.74% yield, 100% purity) as a white solid. MS (ESI) m/z 486.1[M+H] ⁺

[0001770] ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 11.57 (s, 1H), 8.99 (d, J = 8.0 Hz, 1H), 8.65 (d, J= 7.6 Hz, 1H), 7.53 (s, 1H), 7.15 (dd, J= 2.2, 11.3 Hz, 2H), 7.00 (d, J= 2.2 Hz, 1H), 5.07 (q ,J= 8.0 Hz, 1H), 4.58 - 4.44 (m, 1H), 3.84 - 3.72 (m, 3H), 3.17 - 3.00 (m, 2H), 2.30 - 2.20 (m, 2H), 1.91 - 1.65 (m, 4H), 1.64 - 1.33 (m, 3H), 0.87 - 0.73 (m, 1H), 0.50 - 0.35 (m, 2H), 0.26 - 0.05 (m, 2H).

Example 220. Synthesis of viral protease inhibitor compound 908

Step 1: methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3S)-2-oxo -3- piperidyl ]propanoatemethyl

[0001771 ] A solution of tert-butyl 3-[[(l S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-ca rboxylate (1.5 g, 3.22 mmol, 1 eq) in HCl/MeOH (15 mL) was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to afford methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3 S)-2-oxo-3- piperidyl]propanoate (1.25 g, crude, HCI) as a white solid. MS (ESI) m/z 366.2 [M+H] ⁺

Step 2: methyl (2S)-2-[[2-(6-chloro-4-methoxy-JH-indole-2-carbonyl)-2- azaspiro[ 4.5 ]decane-3-carbonyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate

[0001772] To a solution of methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3- [(3 S)-2-oxo-3 -pi peri dyl Jpropanoate (1.25 g, 3.10 mmol, 1 eq, HC1) and 6-chloro-4- methoxy- 1 H-indole-2-carboxylic acid (700 mg, 3.10 mmol, 1 eq) in DCM (40 mL) was added DMAP (1.14 g, 9.31 mmol, 3 eq). After adding EDCI (1.78 g, 9.31 mmol, 3 eq), the mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (30mL), and then extracted with DCM (15 mL * 2). The combined organic layers were washed with HC1 (1 M) (10 mL * 2), and then the combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 0/1, dichloromethane : methanol = 10:1, (UV 254 nm)) to give methyl (2 S)-2-[ [2-(6-chloro-4- methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbon yl]amino]-3-[(3S)-2- oxo-3-piperidyl]propanoate (1.2 g, 1.96 mmol, 63.24% yield, 93.7% purity) as a yellow solid. MS (ESI) m/z 573.2 [M+H] ⁺

Step 3: N-f ( l S) -2-amino-2-oxo- 1 -[ [ ( 3S)-2-oxo-3-piperidyl ] methyl ] ethyl ]-2-( 6-chloro-4- methoxy-lH-indole-2-carbonyl)-2-azaspiro[ 4.5 ]decane-3-carboxamide

[0001773 ] A solution of methyl (2S)-2-[[2-(6-chloro-4-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate (1.1 g,

1.92 mmol, 1 eq) in NH ₃ /MeOH (7 M, 60 mL, 218.81 eq) was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove solvent to give N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]-2-(6-chloro-4-methoxy- lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (1.05 g, crude) as a yellow solid. MS (ESI) m/z 558.2 [M+H] ⁺

Step 4: 2-( 6-chloro-4-methoxy-lH-indole-2-carbonyl)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxo-3- piperidyl ] ethyl ]-2-azaspiro[ 4.5 ]decane-3 -carboxamide [0001774] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-2-(6-chloro-4-methoxy-lH-indole-2-ca rbonyl)-2- azaspiro[4.5]decane-3-carboxamide (1.04 g, 1.86 mmol, 1 eq) in DCM (20 mL) was added Burgess reagent (888.20 mg, 3.73 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* lOum; mobile phase: [water(10 mM NH4HCC>3)-ACN];B%: 50%-70%, 10 min) to give 2-(6-chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)- 2-oxo-3-piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide (500 mg, 886.03 umol, 47.54% yield, 95.7% purity) as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺ .

Step 5: 2-( 6-chloro-4-methoxy-lH-indole-2-carbonyl)-N-[ ( l S)-l-cyano-2-[ ( 3S)-2-oxo-3- piperidyl ] ethyl ]-2-azaspiro[ 4.5 ]decane-3 -carboxamide Isomer 1: [0001775] 2-(6-Chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo- 3-piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide (500 mg) was separated by SFC (column: REGIS (s,s) WHELK-01 (250mm*30mm,5um);mobile phase: [0.1%NH3H ₂ O ETOH];B%: 50%-50%,6min) to give 2-(6-chloro-4-methoxy-lH-indole-2-carbonyl)-N- [(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-azaspiro[4. 5]decane-3-carboxamide (66.7 mg, 123.01 umol, 13.29% yield, 99.6% purity) as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺ .

[0001776] 1H NMR (400MHz, DMSO-d ₆ ) δ = 11.76 - 11.61 (m, 1H), 8.88 (d, J = 8.4Hz, 1H), 7.67 - 7.33 (m, 1H), 7.14 - 6.86 (m, 2H), 6.67 - 6.48 (m, 1H), 5.06 - 4.87 (m, 1H), 4.49 (t, J = 8.8Hz, 1H), 3.92 (s, 2H), 3.88 - 3.80 (m, 1H), 3.66 (d, J = 10.3Hz, 1H), 3.33 (s, 6H), 2.38 - 2.17 (m, 2H), 2.03 - 0.83 (m, 14H)

[0001777] ¹ H NMR (400MHZ, DMSO-d ₆ , 273+80K) δ = 11.46 (s, 1H), 8.71 (s, 1H), 7.27 (s, 1H), 7.09 (s, 2H), 6.55 (s, 1H), 4.97 (s, 1H), 4.61 (s, 1H), 3.92 (s, 2H), 3.85 (d, J = 10.4Hz, 1H), 3.61 (s, 1H), 3.08 (s, 6H), 2.38 - 2.12 (m, 2H), 2.01 - 1.02 (m, 14H)

Isomer 2:

[0001778] 2-(6-Chloro-4-methoxy-lH-indole-2-carbonyl)-N-[(l S)-1-cyano-2-[(3S)-2-oxo- 3-piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide (111.6 mg, 206.65 umol,

22.32% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺ .

[0001779] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.76 - 11.64 (m, 1H), 8.81 (d, J = 8.4Hz, 1H), 7.53 - 7.41 (m, 1H), 7.06 (s, 1H), 6.97 (s, 1H), 6.65 - 6.51 (m, 1H), 5.04 - 4.86 (m, 1H), 4.58 - 4.38 (m, 1H), 3.92 (s, 2H), 3.84 (d, J = 9.8Hz, 1H), 3.76 - 3.57 (m, 1H), 3.33 (s, 6H), 2.24 - 2.11 (m, 2H), 1.88 - 1.10 (m, 14H)

[0001780] 1H NMR (400MHz, DMSO-d ₆ , 273+80K) δ = 11.48 (s, 1H), 8.64 (s, 1H), 7.23 (s, 1H), 7.09 (s, 1H), 6.93 (s, 1H), 6.56 (s, 1H), 4.97 (s, 1H), 4.59 (s, 1H), 3.93 (s, 2H), 3.85 (d, J = 10.8Hz, 1H), 3.65 (s, 1H), 3.08 (s, 6H), 2.20 (s, 2H), 2.01 - 1.23 (m, 14H)

Example 221. Synthesis of viral protease inhibitor compound 1057

Step 1: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[[4-[2-(2-methoxyethoxy)ethoxy ]-JH-indole-2- carbonyl ] amino ]propanoyl ] amino ]-3-[( 3S)-2-oxo-3-piperidyl ]propanoate

[0001781 ] To a mixture of 4-[2-(2-methoxy ethoxy )ethoxy]- 1 H-indole-2-carboxylic acid (500 mg, 1.79 mmol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (684.99 mg, 1.97 mmol, 1.1 eq, HC1) in DCM (9 mL) and DMF (3 mL) was added DMAP (656.15 mg, 5.37 mmol, 3 eq) and EDCI (686.39 mg, 3.58 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 diluted with H ₂ O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (15 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/l to 0/1) to give methyl (2S)-2- [[(2S)-3-cyclopropyl-2-[[4-[2-(2-methoxy ethoxy )ethoxy]-lH-indole-2- carbonyl]amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (850 mg, 1.48 mmol, 82.91% yield) as a yellow solid. MS (ESI) m/z 573.3 [M+H] ⁺

Step 2: N-f ( l S)-2-[[( 1 S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ] methyl ]ethyl]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-[2-(2-methoxyethoxy)ethox y]-lH-indole-2-carboxamide

[0001782 ] A mixture of methyl (2 S)-2-[ [(2 S)-3 -cy clopropy l-2-[ [4-[2-(2- methoxy ethoxy )ethoxy]-lH-indole-2-carbonyl]amino]propanoyl]amino]-3-[(3S) -2-oxo-3- piperidyl]propanoate (850 mg, 1.41 mmol, 95% purity, 1 eq) in N¾ /MeOH (7 M, 25 mL, 124.10 eq) was stirred at 55 °C for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[(l S)-2-[[(l S)-2-amino-2-oxo-1- [[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropylm ethyl)-2-oxo-ethyl]-4-[2- (2-methoxy ethoxy )ethoxy]- 1 H-indole-2-carboxamide (781 mg, 1.22 mmol, 86.41% yield, 87% purity) as a yellow solid. MS (ESI) m/z 558.3 [M+H] ⁺

Step 3: N-f ( l S)-2-[[ ( l S)-l-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl ]amino]-l- (cyclopropylmethyl)-2-oxo-ethyl]-4-[2-(2-methoxyethoxy)ethox y]-JH-indole-2-carboxamide

[0001783] A mixture of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-[2-(2- methoxyethoxy)ethoxy]-lH-indole-2-carboxamide (730 mg, 1.14 mmol, 87% purity, 1 eq) in DCM (10 mL) was added Burgess reagent (542.82 mg, 2.28 mmol, 2 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition; column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(10 mMNH4HC03)-ACN];B%: 20%-50%, 8min) to give N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-[2-(2-methoxy ethoxy )ethoxy]-lH-indole-2- carboxamide (230 mg, 426.22 umol, 37.42% yield) as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺

[0001784] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.56 (s, 1H), 8.89 (d, J=8.2 Hz, 1H), 8.58 (d,J=7.5 Hz, 1H), 7.52 (br s, 1H), 7.39 (d, >=1.5 Hz, 1H), 7.11 - 6.99 (m, 2H), 6.50 (d, J=7.5 Hz, 1H), 5.10 - 5.01 (m, 1H), 4.49 - 4.41 (m, 1H), 4.21 (t, J=4.4 Hz, 2H), 3.86 - 3.79 (m, 2H), 3.63 (dd, J=3.7, 5.7 Hz, 2H), 3.49 (dd, J=3.7, 5.5 Hz, 2H), 3.26 (s, 3H), 3.13 - 3.03 (m, 2H), 2.36 - 2.20 (m, 2H), 1.90 - 1.76 (m, 3H), 1.75 - 1.65 (m, 1H), 1.62 - 1.50 (m, 1H), 1.49 - 1.34 (m, 2H), 0.88 - 0.75 (m, 1H), 0.48 - 0.33 (m, 2H), 0.24 - 0.07 (m, 2H)

Example 221a. Synthesis of viral protease inhibitor compound 822

Step 1: methyl (Z)-2-azido-3-(2-chloro-3-fluoro-phenyl)prop-2-enoate

[0001785] 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 H2060 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 Na ₂ SO ₄ filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=l/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.

Step 2: methyl 4-chloro-5-fluoro-lH-indole-2-carboxylate

[0001786 ] A mixture of methyl (Z)-2-azido-3-(2-chloro-3-fluoro-phenyl)prop-2-enoate (2.3 g, 9.00 mmol, 1 eq) in xylene (25 mL) was stirred at 170 °C for 1 h. Upon completion, the reaction mixture was filtered to give methyl 4-chloro-5-fluoro- 1 H-indole- 2-carboxylate (1.4 g, 6.15 mmol, 68.36% yield) as a white solid. Step 3: 4-chloro-5-fluoro-lH-indole-2-carboxylic acid

[0001787] A mixture of methyl 4-chloro-5-fluoro- 1 H-indole-2-carboxylate (1.4 g, 6.15 mmol, 1 eq) in THF (7 mL) and H ₂ O (7 mL) was added LiOH.H ₂ O (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 acidly by 1M HC1 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 Na2S04, filtered and concentrated under reduced pressure to give 4-chloro-5-fluoro-lH-indole-2-carboxylic acid (1 g, 4.68 mmol, 76.12% yield) as a white solid. (ESI) m/z 211.9 [M-H] ⁺

Step 4: methyl (2S)-2-[[(2S)-2-[(4-chloro-5-fluoro-lH-indole-2-carbonyl)ami no]-3- cyclopropyl-propanoyl ] amino ]-3-[ ( 3S)-2-oxo-3-piperidyl ]propanoate [0001788] To a mixture of 4-chloro-5-fluoro-lH-indole-2-carboxylic acid (500 mg, 2.34 mmol, 1 eq) and methyl (2 S)-2-[ [(2 S)-2-amino-3 -cy clopropy 1-propanoy 1 ]amino]-3 -[(3 S)- 2-oxo-3-piperidyl]propanoate (895.68 mg, 2.57 mmol, 1.1 eq, HC1) in DCM (10 mL) and DMF (3 mL) was added DMAP (857.96 mg, 7.02 mmol, 3 eq) and EDCI (897.50 mg, 4.68 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 diluted with H2030 mL and extracted with EA 60 mL (20 mL * 3). The combined organic layers were washed with brine 30 mL (30 mL * 1), dried over Na2S04, filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=5/l to 0/1) to give methyl (2 S)-2-[ [(2 S)-2-[(4-chloro-5 -fluoro- 1 H- indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[( 3S)-2-oxo-3- piperidyljpropanoate (800 mg, 1.58 mmol, 67.41% yield) as a white solid. MS (ESI) m/z 505.0 [M-H] ⁺

Step 5: N-f ( l S)-2-[[( l S)-2-amino-2-oxo-l-[[( 3S)-2-oxo-3-piperidyl ]methyl ]ethyl]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-4-chloro-5-fluoro-lH-ind ole-2-carboxamide

[0001789] A mixture of methyl (2S)-2-[[(2S)-2-[(4-chloro-5-fluoro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3-piperidyl]propanoate (800 mg, 1.58 mmol, 1 eq) in NH ₃ /MeOH (7 M, 20 mL, 88.72 eq) was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]me thyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-chloro-5-fluoro-lH-indole -2-carboxamide (730 mg, 1.35 mmol, 85.57% yield, 91% purity) as a white solid. MS (ESI) m/z 492.2 [M+H] ⁺

Step 6: 4-chloro-N-[(lS)-2-[[(lS)-l-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]amino]-l-

(cyclopropylmethyl)-2-oxo-ethyl]-5-fluoro-lH-indole-2-car boxamide

[0001790] A mixture of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-chloro-5-fluoro- lH-indole-2-carboxamide (730 mg, 1.26 mmol, 85% purity, 1 eq) in DCM (20 mL) was added Burgess reagent (1.05 g, 4.41 mmol, 3.5 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude. The crude was purified by prep- HPLC (neutral condition; column: Phenomenex Gemini-NX C1875*30mm*3um;mobile phase: [water(10mM NH4HC03)-ACN];B%: 25%-55%,8min) to give 4-chloro-N-[(1S)- 2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo- ethyl]-5-fluoro-lH-indole-2-carboxamide (300 mg, 633.01 umol, 50.19% yield) as a white solid. MS (ESI) m/z 474.1 [M+H]

[0001791 ] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ = 12.06 (br s, 1H), 8.94 (d, J=8.2 Hz, 1H), 8.81 (d, J=7.5 Hz, 1H), 7.54 (br s, 1H), 7.47 (s, 1H), 7.40 (dd, J=4.0, 9.0 Hz, 1H), 7.23 (t, J=9.4 Hz, 1H), 5.11 - 5.03 (m, 1H), 4.51 - 4.42 (m, 1H), 3.09 (br s, 2H), 2.31 - 2.20 (m, 2H), 1.92 - 1.76 (m, 3H), 1.76 - 1.64 (m, 1H), 1.56 (br d, J=3.3 Hz, 1H), 1.51 - 1.33 (m, 2H), 0.88 - 0.76 (m, 1H), 0.49 - 0.35 (m, 2H), 0.26 - 0.05 (m, 2H)

Example 222. Synthesis of viral protease inhibitor compound 824

[0001792] Step 1: (Z)-methyl 2-azido-3-(2-chloro-4-fluorophenyl)acrylate

[0001793] To a solution of NaOMe (13.63 g, 252.27 mmol, 4 eq) in MeOH (50 mL), then 2-chloro-4-fluoro-benzaldehyde (10 g, 63.07 mmol, 1 eq) and methyl 2-azidoacetate (30.49 g, 264.89 mmol, 4.2 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 filtered and concentrated under reduced pressure to give methyl (Z)-2-azido-3-(2-chloro-4-fluoro- phenyl)prop-2-enoate (7 g, crude) as a yellow solid.

[0001794] Step 2: methyl 4-chloro-6-fluoro- 1 H-indole-2-carboxylate

[0001795] 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 (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 8/1) to give methyl 4-chloro-6-fluoro- 1 H-indole-2- carboxylate (2 g, 8.79 mmol, 37.44% yield) as a yellow solid. MS (ESI) m/z 228.1 [M+H] ⁺ .

[0001796] Step 3: 4-chloro-6-fluoro- 1 H-indole-2-carboxylic acid [0001797] To a solution of methyl 4-chloro-6-fluoro-lH-indole-2-carboxylate (2 g, 8.79 mmol, 1 eq) in THF (20 mL) and H ₂ O (10 mL) was added LiOH.H ₂ O (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 HC1 was added, adjust pH = 3, then was filtered and concentrated under reduced pressure to give 4-chloro-6-fluoro-lH-indole-2-carboxylic acid (1.6 g, crude) as a yellow solid. MS (ESI) m/z 214.0 [M+H] ⁺ .

[0001798] Step 4: (S)-methyl 2-((S)-2-(4-chloro-6-fluoro-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[0001799 ] To a solution of 4-chloro-6-fluoro-lH-indole-2-carboxylic acid (1 g, 4.68 mmol, 1 eq), methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) -2-oxo-3- piperidyljpropanoate (1.63 g, 4.68 mmol, 1 eq, HC1), DMAP (1.72 g, 14.05 mmol, 3 eq) in DCM (10 mL), then EDCI (1.80 g, 9.36 mmol, 2 eq) was added. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O 35 mL at 20 °C, and then extracted with DCM (35 mL * 3). The combined organic layers were washed with 1M HC1 (40 mL * 2), then the combined organic layers were washed with brine (40 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 0/1) to give methyl (2S)-2-[[(2S)-2-[(4-chloro-6- fluoro-lH-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]a mino]-3-[(3S)-2-oxo-3- pi peri dy 1 ] propanoat e (1.1 g, 2.17 mmol, 46.35% yield, 100% purity) as a yellow solid. MS (ESI) m/z 507.2 [M+H] ⁺ .

[0001800] Step 5: N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)prop an-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-chloro-6-fluoro- lH-indole-2-carboxamide

[0001801 ] To a solution of methyl (2S)-2-[[(2S)-2-[(4-chloro-6-fluoro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3-piperidyl]propanoate (1.06 g, 2.09 mmol, 1 eq) in NH ₃ /MeOH (7 M, 20 mL, 66.96 eq). The mixture was stirred at 20 °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-et hyl]-4-chloro-6-fluoro- 1 H-indole-2-carboxamide (1 g, crude) as a yellow solid. MS (ESI) m/z 492.2 [M+H] ⁺ .

[0001802] Step 6: 4-chloro-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-6-fluoro-lH- indole-2-carboxamide

[0001803] To a solution of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-chloro-6-fluoro- 1 H-indole-2-carboxamide (980 mg, 1.99 mmol, 1 eq) in DCM (10 mL) was added BURGESS REAGENT (949.46 mg, 3.98 mmol, 2 eq). The mixture was stirred at 30 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150 *50mm *10um; mobile phase: [water(10mM NH4HC03)-ACN];B%: 35%- 60%,10min) to give 4-chloro-N-[( 1 S)-2-[ [( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3 - piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6- fluoro-lH-indole-2- carboxamide (375 mg, 791.26 umol, 39.72% yield, 100% purity) as a white solid. MS (ESI) m/z 474.1 [M+H] ⁺ .

[0001804] ¹ H NMR (400MHZ, DMSO-d6) δ = 12.04 (s, 1H), 8.94 (d, J=8.1 Hz, 1H), 8.77 (d, J=7.5 Hz, 1H), 7.53 ( s, 1H), 7.45 (s, 1H), 7.15 (d, J=9.4 Hz, 2H), 5.07 (d, J=7.9 Hz, 1H), 4.46 (d, J=5.7 Hz, 1H), 3.16 - 2.98 (m, 2H), 2.26 (d, J=9.0 Hz, 2H), 1.97 - 1.63 (m, 4H), 1.46 (s, 3H), 0.81 (dd, J=5.7, 7.7 Hz, 1H), 0.41 (dd, J=3.5, 7.5 Hz, 2H), 0.26 - 0.03 (m, 2H).

Example 223. Synthesis of viral protease inhibitor compound 828

[0001805] Step 1: 7-chloro-6-fluoro- 1 H-indole

[0001806] 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 N ₂ . The mixture was stirred at -40 °C for 2 h under N ₂ . Upon completion, the reaction was quenched by addition NH4CI (500 mL) and then extracted with EtOAc (300 mL * 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by column chromatography (SiO ₂ , EtOAc :MEOH = 10: 1) to give product 7-chloro-6-fluoro- 1 H-indole (4.8 g, 25.47 mmol, 44.72% yield, 90% purity) as yellow oil. MS (ESI) m/z 170.0 [M+H] ⁺

[0001807] Step 2 : tert-butyl 7-chloro-6-fluoro-indole- 1 -carboxylate [0001808] To a mixture of 7-chloro-6-fluoro- 1 H-indole (4.8 g, 28.30 mmol, 1 eq) in DCM (50 mL) was added Boc ₂ O (6.80 g, 31.14 mmol, 7.15 mL, 1.1 eq), TEA (3.44 g, 33.97 mmol, 4.73 mL, 1.2 eq) and DMAP (691.60 mg, 5.66 mmol, 0.2 eq) at 20 °C under N ₂ . The mixture was stirred at 20 °C for 1.5 h. Upon completion, the reaction mixture was poured into water (50 mL) and extracted with DCM (40 mL * 2). The combined organic layers were concentrated under reduced pressure and was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 50/1 to 20/1) to give product tert- butyl 7-chloro-6-fluoro-indole- 1 -carboxylate (6 g, 22.25 mmol, 78.60% yield) as white solid. MS (ESI) m/z 270.0 [M+H] ⁺ [0001809] Step 3: l-tert-butoxycarbonyl-7-chloro-6-fluoro-indole-2-carboxylic acid

[0001810) 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 N ₂ . The mixture was stirred at -60 °C for 2 h, then the above solution wasadded 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 N ₂ and stirred for 10 min. The aqueous phase was added 1 M HC1 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 Na ₂ SO ₄ , filtered and concentrated in vacuum. It was triturated with Petroleum etherEthyl acetate = 50: 1 (100 mL) to give product l-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] ⁺

[0001811 ] Step 4: 7-chloro-6-fluoro- 1 H-indole-2-carboxylic acid

[0001812] A solution of 1 -tert-butoxycarbonyl-7-chloro-6-fluoro-indole-2-carboxylic acid (4.3 g, 13.71 mmol, 1 eq) in HCl/EtOAc (4 M, 50 mL, 14.59 eq) was stirred at 30 °C for 40 h. Upon completion, the reaction mixture was concentrated under pressure reduced to get the crude product 7-chloro-6-fluoro- 1 H-indole-2-carboxylic acid (2.9 g, crude) as white solid. MS (ESI) m/z 212.0 [M+H] ⁺

[0001813] Step 5: methyl (2S)-2-[[(2S)-2-[(7-chloro-6-fluoro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3-piperidyl]propanoate

[0001814] To a solution of 7-chloro-6-fluoro-lH-indole-2-carboxylic acid (0.7 g, 3.28 mmol, 1.5 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (759.97 mg, 2.18 mmol, 1 eq, HC1) in DCM (7 mL) was added EDCI (837.67 mg, 4.37 mmol, 2 eq), DMAP (800.77 mg, 6.55 mmol, 3 eq). The solution was stirred at 20 °C, for 1 h. Upon completion, the mixture was quenched by addition H ₂ O (40 mL) and extracted with DCM (10 mL * 4). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/1 to 0/1 and then DCM:MeOH = 5:1) to give product methyl (2 S)-2-[ [(2 S)-2-[(7-chloro-6-fluoro- 1 H- indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[( 3S)-2-oxo-3- piperidyl]propanoate (0.8 g, 1.50 mmol, 68.62% yield, 95% purity) as yellow solid. MS (ESI) m/z 505.1 [M+H] ⁺

[0001815] Step 6: N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-7-chloro-6-fluoro- 1 H-indole-2-carboxamide

[0001816] The methyl (2S)-2-[[(2S)-2-[(7-chloro-6-fluoro-lH-indole-2-carbonyl)ami no]-3- cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate (0.78 g, 1.54 mmol, 1 eq) in NH ₃ /MEOH (15 mL) was stirred at 50 °C for 24 h. Upon completion, the reaction mixture was concentrated under pressure reduced to give the product N-[(1S)-2-[[(1S)-2- amino-2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2- oxo-ethyl]-7-chloro-6-fluoro-lH-indole-2-carboxamide (0.75 g, crude) as white solid. MS (ESI) m/z 492.2 [M+H] ⁺

[0001817] Step 7: 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6- fluoro-lH-indole-2- carboxamide

[0001818] TheN-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-7-chloro-6-fluoro- lH-indole-2-carboxamide (0.7 g, 1.31 mmol, 92% purity, 1 eq) in DCM (10 mL) was add BURGESS REAGENT (935.91 mg, 3.93 mmol, 3 eq). The mixture was stirred at 30 °C for 12 h. Upon completion, the reaction was quenched with water (2 mL) and blow-dried with N ₂ and was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um;mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN];B%: 25%- 55%,10min) to give product 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6- fluoro-lH-indole-2- carboxamide (0.23 g, 480.45 umol, 36.70% yield, 99% purity) as white solid. MS (ESI) m/z 474.1 [M+H] ⁺

[0001819] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.99 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 7.5 Hz, 1H), 7.66 (dd, J = 4.9, 8.7 Hz, 1H), 7.53 (br s, 1H), 7.29 (s, 1H), 7.18 - 7.07 (m, 1H), 5.07 (q, J = 7.9 Hz, 1H), 4.59 - 4.42 (m, 1H), 3.18 - 3.04 (m, 2H), 2.32 - 2.18 (m, 2H), 2.07 (s, 1H), 1.93 - 1.76 (m, 3H), 1.71 (dt, J = 4.0, 8.9 Hz, 1H), 1.63 - 1.34 (m, 3H), 0.89 - 0.74 (m, 1H), 0.53 - 0.36 (m, 2H), 0.24 - 0.16 (m, 1H), 0.15 - 0.06 (m, 1H).

Example 224. Synthesis of viral protease inhibitor compound 830

[0001820] Step 1: tert-butyl 7-chloro-5-fluoro- 1 H-indole- 1 -carboxylate

[0001821 ] To a solution of 7-chloro-5-fluoro-l H-indole (4.5 g, 26.54 mmol, 1 eq) and TEA (3.22 g, 31.84 mmol, 4.43 mL, 1.2 eq) in DCM (20 mL) was added DMAP (648.36 mg, 5.31 mmol, 0.2 eq) and Boc ₂ O (6.37 g, 29.19 mmol, 6.71 mL, 1.1 eq) under N ₂ , then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 100 mL, and then extracted with DCM 150 ml (50 mL * 3). The combined organic layers were washed with brine (50 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum etherEthyl acetate = 1:0 to 15:1) to give the product tert-butyl 7-chloro-5-fluoro-indole- 1 -carboxylate (6 g, 21.13 mmol, 79.65% yield, 95% purity) as a yellow oil. [0001822] Step 2: 1 -(tert-butoxycarbonyl)-7-chloro-5-fluoro- 1 H-indole-2-carboxylic acid

[0001823] 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 N ₂ . 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 N ₂ and stirred for 10 min. The aqueous phase was added 1 M HC1 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 Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give the product l-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.

[0001824] Step 3: 7-chloro-5-fluoro-lH-indole-2-carboxylic acid

[0001825] To a solution of l-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-lH-indole-2- carboxylic acid (660 mg, crude, HC1) as a yellow solid.

[0001826] Step 4: (S)-methyl 2-((S)-2-(7-chloro-5-fluoro-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[0001827] To a solution of 7-chloro-5-fluoro-lH-indole-2-carboxylic acid (660 mg, 2.64 mmol, 1 eq, HC1) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3- [(3S)-2-oxo-3-piperidyl]propanoate (1.07 g, 3.43 mmol, 1.3 eq) in DMF (5 mL) and DCM (20 mL), and then DMAP (967.38 mg, 7.92 mmol, 3 eq) and EDCI (1.01 g, 5.28 mmol, 2 eq) was added, then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate=5: 1 to 0: 1) to give the product methyl (2S)-2-[[(2S)-2-[(7-chloro-5- fluoro-lH-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]a mino]-3-[(3S)-2-oxo-3- piperidyl]propanoate (770 mg, 1.41 mmol, 53.52% yield, 93% purity) as a yellow solid. MS (ESI) m/z 507.2 [M+H] ⁺ .

[0001828] Step 5: (S)-methyl 2-((S)-2-(7-chloro-5-fluoro-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[0001829] To a solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-5-fluoro-lH-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- l-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1-(cyclopropy lmethyl)-2-oxo-ethyl]-7- chloro-5-fluoro-lH-indole-2-carboxamide (720 mg, crude) as a yellow solid. MS (ESI) m/z 492.2 [M+H] ⁺ .

[0001830] Step 6: 7-chloro-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-5-fluoro-lH- indole-2-carboxamide

[0001831] To a solution of N-[(l S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-7-chloro-5-fluoro- 1 H-indole-2-carboxamide (660 mg, 1.34 mmol, 1 eq) in DCM (15 mL) and BURGESS REAGENT (639.44 mg, 2.68 mmol, 2 eq) was added, and then the mixture was stirred at 30 °C for 4.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150 * 50mm * lOum; mobile phase: [water (lOmM NH4HCO3) - ACN]; B%: 30% - 60%, lOmin) to give the product 7-chloro-N-[( 1 S)-2-[[( 1 S)- 1 -cyano-2-[(3 S)- 2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-e thyl]-5-fluoro-lH-indole- 2-carboxamide (232.57 mg, 490.73 umol, 36.58% yield, 100% purity) as a white solid. MS (ESI) m/z 474.2 [M+H] ⁺ .

[0001832] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.87 (s, 1H), 9.00 (d, J = 7.9 Hz, 1H), 8.74 (br d, J = 7.6 Hz, 1H), 7.53 (br s, 1H), 7.47 (dd, J = 2.2, 9.3 Hz, 1H), 7.33 (dd, J = 2.2, 9.3 Hz, 1H), 7.26 (s, 1H), 5.07 (br d, J = 7.8 Hz, 1H), 4.51 (s, 1H), 3.15 - 3.04 (m, 2H), 2.25 (br t, J = 8.7 Hz, 2H), 1.88 - 1.75 (m, 3H), 1.74 - 1.67 (m, 1H), 1.39 - 1.57 (s, 3H), 0.86 - 0.76 (m, 1H), 0.48 - 0.37 (m, 2H), 0.23 - 0.07 (m, 2H)

Example 225. Synthesis of viral protease inhibitor compound 832

[0001833] Step 1: (Z)-methyl 2-azido-3-(5-chloro-2-fluorophenyl)acrylate

[0001834] 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 H ₂ O 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 Na ₂ SO ₄ filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum etherEthyl 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.

[0001835] Step 2: methyl 7-chloro-4-fluoro- 1 H-indole-2-carboxylate

[0001836] To a solution of methyl (Z)-2-azido-3 -(5 -chloro-2-fluoro-pheny 1 )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- 1 H-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] ⁺ .

[0001837] Step 3: 7-chloro-4-fluoro-lH-indole-2-carboxylic acid

[0001838] To a solution of methyl 7-chloro-4-fluoro-lH-indole-2-carboxylate (1.5 g, 6.59 mmol, 1 eq) THF (10 mL) and H ₂ O (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 H ₂ O 100 mL at 0 °C, and then HC1 (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the product 7-chloro-4-fluoro-lH-indole-2-carboxylic acid (1.4 g, crude) as a white solid.

[0001839] Step 4: 7-chloro-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-fluoro-lH- indole-2-carboxamide

[0001840] To a solution of 7-chloro-4-fluoro-lH-indole-2-carboxylic acid (100 mg, 468.18 umol, 1.30 eq) and (2S)-2-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl ]-3- cyclopropyl-propanamide (200 mg, 359.26 umol, 50% purity, 1 eq) in DMF (2 mL) and DCM (5 mL), and then DMAP (131.67 mg, 1.08 mmol, 3 eq) and EDCI (137.74 mg, 718.52 umol, 2 eq) was added, then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 30mm * lOum; mobile phase: [water (lOmM NH4HCO3) - ACN]; B%: 30%-50%, 8 min) to give the product 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2- [(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2 -oxo-ethyl]-4-fluoro-lH- indole-2-carboxamide (112.98 mg, 238.39 umol, 66.36% yield, 100% purity) as a white solid. MS (ESI) m/z 474.2 [M+H] ⁺ .

[0001841 ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.12 (br s, 1H), 9.10 - 8.97 (m, 1H), 8.79 (d, J = 7.2 Hz, 1H), 7.55 (br s, 1H), 7.36 - 7.33 (m, 1H), 7.33 - 7.26 (m, 1H), 6.90 (dd, J = 8.6, 9.6 Hz, 1H), 5.13 - 4.98 (m, 1H), 4.58 - 4.47 (m, 1H), 3.14 - 3.03 (m, 2H), 2.30 - 2.17 (m, 2H), 1.88 - 1.67 (m, 4H), 1.61 - 1.38 (m, 3H), 0.86 - 0.77 (m, 1H), 0.48 - 0.38 (m, 2H), 0.24 - 0.18 (m, 1H), 0.14 - 0.08 (m, 1H)

Example 226. Synthesis of viral protease inhibitor compound 840

[0001842] Step 1: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,6-dichloro-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate

[0001843 ] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1 g, 2.87 mmol, 1 eq, HCI) and 4,6-dichloro-lH-indole-2-carboxylic acid (661.37 mg, 2.87 mmol, 1 eq) in DCM (40 mL), then DMAP (1.05 g, 8.62 mmol, 3 eq) was added, and then EDCI (1.65 g, 8.62 mmol, 3 eq) was added. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 30 mL, and then extracted with DCM 40 mL (20 mL * 2). The combined organic layers were washed with HCI (1 M) 30 mL (15 mL * 2), the combined organic layers were washed with brine 30 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 3/1 to 0/1) to give methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,6-dichloro-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (1 g, 1.85 mmol, 64.46% yield, 97% purity) as a white solid. MS (ESI) m/z 523.1 [M+H] ⁺

[0001844] Step 2: N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4,6-dichloro-lH- indole-2-carboxamide [0001845] To a solution of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,6-dichloro-lH-indole- 2-carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl] propanoate (960 mg, 1.83 mmol, 1 eq) in NH ₃ /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-et hyl]-4,6-dichloro-lH- indole-2-carboxamide (820 mg, crude) as a white solid. MS (ESI) m/z 508.1 [M+H] ⁺

[0001846] Step 3: 4,6-dichloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH -indole-2-carboxamide

[0001847] 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-et hyl]-4,6-dichloro-lH- indole-2-carboxamide (800 mg, 1.57 mmol, 1 eq) in DCM (15 mL), then BURGES SRE AGENT (749.98 mg, 3.15 mmol, 2 eq) was added. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge CIS 150*50mm* 10um;mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN];B%: 40%-60%,10min), to give 4,6-dichloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH -indole-2-carboxamide (213.1 mg, 434.56 umol, 27.62% yield, 100% purity) as a white solid. MS (ESI) m/z 490.1 [M+H] ⁺

[0001848] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.11 (s, 1H), 8.95 (d, J = 8.4Hz, 1H), 8.84 (d, J = 7.4Hz, 1H), 7.53 (s, 1H), 7.44 (d, J = 17.4Hz, 2H), 7.24 (d, J = 1.8Hz, 1H), 5.13 - 5.01 (m, 1H), 4.52 - 4.41 (m, 1H), 3.19 - 3.00 (m, 2H), 2.35 - 2.18 (m, 2H), 1.97 - 1.63 (m, 4H), 1.61 - 1.33 (m, 3H), 0.88 - 0.75 (m, 1H), 0.51 - 0.32 (m, 2H), 0.25 - 0.05 (m,

2H)

Example 227. Synthesis of viral protease inhibitor compound 856

[0001849] Step 1: 4-(trifluoromethyl)- 1 H-indole-2-carboxylic acid

[0001850 ] To a solution of ethyl 4-(trifluoromethyl)- 1 H-indole-2-carboxylate (800 mg,

3.11 mmol, 1 eq) in THF (10 mL), H ₂ 0 (5 mL) was added LiOH.H ₂ O (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 HCI (1M, aq). The mixture was extracted with EtOAc (100 * 3 mL). The combined organiclayer was dried over Na ₂ SO ₄ , filtered, concentrated to give product 4- (trifluoromethyl)- 1 H-indole-2-carboxylic acid (700 mg, crude) was white solid. MS (ESI) m/z 230.0 [M+H] ⁺

[0001851 ] Step 2: (S)-methyl 2-((S)-3-cyclopropyl-2-(4-(trifluoromethyl)-lH-indole-2- carboxamido)propanamido)-3-((S)-2-oxopiperidin-3-yl)propanoa te

[0001852] To a solution of 4-(trifluoromethyl)- 1 H-indole-2-carboxylic acid (650 mg, 2.84 mmol, 1 eq) in DCM (20 mL) was added (S)-methyl 2-((S)-2-amino-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e (986.64 mg, 2.84 mmol, 1 eq, HCI), DMAP (1.04 g, 8.51 mmol, 3 eq), EDCI (1.09 g, 5.67 mmol, 2 eq) and the mixture was stirred at 25 °C for 1 h. Upon completion, the reaction was quenched by addition H ₂ O (200 mL) and then extracted with EtOAc (100 mL * 3). The combined organic layers were washed with (brine 100 mL), dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure and was purified by column chromatography (SiO ₂ , EtOAc/MeOH = 1/0 to 10/1) to give product (S)-methyl 2-((S)-3-cyclopropyl-2-(4- (trifluoromethyl)-lH-indole-2-carboxamido)propanamido)-3-((S )-2-oxopiperidin-3- yl)propanoate (800 mg, 1.50 mmol, 52.83% yield, 97.87% purity) as yellow solid. MS (ESI) m/z 523.2 [M+H] ⁺

[0001853] Step 3: N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)prop an-2- yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-4-(trifluoromethyl)- lH-indole-2- carboxamide

[0001854] To a solution of (S)-methyl 2-((S)-3-cyclopropyl-2-(4-(trifluoromethyl)-lH- indole-2-carboxamido)propanamido)-3-((S)-2-oxopiperidin-3-yl )propanoate (700 mg, 1.34 mmol, 1 eq) in ammonia (7 M, 40 mL, 209.01 eq) was stirred at 50 °C for 10 h. Upon completion, the reaction was concentrated in the vacuum to give crude product N- ((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan -2-yl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-4-(trifluoromethyl)- 1 H-indole-2-carboxamide (690 mg, crude) as white solid. MS (ESI) m/z 508.2 [M+H] ⁺

[0001855] Step 4: N-((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-4-(trifluoromethyl)- 1 H-indole-2-carboxamide

[0001856] To a solution of N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-(tri fluoromethyl)-lH-indole- 2-carboxamide (670 mg, 1.32 mmol, 1 eq) in DCM (30 mL) was added BURGESS REAGENT (943.82 mg, 3.96 mmol, 3 eq) and the mixture was stirred at 25 °C for 4 h. Upon completion, the reaction was concentrated in the vacuum and was purified by prep- HPLC (column: Waters Xbridge C18 150 * 50mm * lOum; mobile phase: [water(10mM NH ₄ HC03)-ACN];B%: 30%-60%,10min) to give prodcut N-((S)-1-(((S)-1-cyano-2-((S)- 2-oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2 -yl)-4-(trifluoromethyl)- lH-indole-2-carboxamide (200 mg, 408.59 umol, 30.95% yield, 100% purity) as white solid. MS (ESI) m/z 490.1 [M+H] ⁺

[0001857] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.14 (br s, 1H), 8.97 - 8.95 (m, 1H), 8.88 - 8.86 (m, 1H), 7.75 7.71 (m, 1H), 7.54 (s, 2H), 7.45 - 7.43 (m, 1H), 7.37 - 7.31 (m, 1H), 5.11 - 5.03 (m, 1H), 4.52 - 4.45 (m, 1H), 3.15 - 3.04 (m, 2H), 2.35 - 2.21 (m, 2H), 1.93 - 1.76 (m, 3H), 1.76 - 1.64 (m, 1H), 1.62 - 1.51 (m, 1H), 1.49 - 1.34 (m, 2H), 0.84 - 0.81 (m, 1H), 0.48 - 0.36 (m, 2H), 0.26 - 0.07 (m, 2H). Example 228. Synthesis of viral protease inhibitor compound 896

[0001858] Step 1: methyl (2 S)-2-amino-3 -[(3 S)-2-oxopy rroli din-3 -y 1 ]propanoate

[0001859] A mixture of methyl (2 S)-2-(tert-butoxy carbonyl amino)-3 -[(3 S)-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, HC1) as yellow oil. MS (ESI) m/z 187.1 [M+H] ⁺ .

[0001860] Step 2 : tert-butyl 3-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxyla te

[0001861 ] A mixture of methyl (2S)-2-amino-3-[(3 S)-2-oxopyrrolidin-3-yl]propanoate (2 g, 8.98 mmol, 1 eq, HC1) in DCM (20 mL) and DMF (2 mL) then added 2-tert- butoxy carbony 1-2-azaspi ro[4.5 ]decane-3 -carboxyl ic acid (2.80 g, 9.88 mmol, 1.1 eq), T3P (11.43 g, 17.96 mmol, 10.68 mL, 50% purity, 2 eq) and TEA (5.45 g, 53.89 mmol, 7.50 mL, 6 eq) was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , PE:EA = 4/1-0/1) to get the product tert-butyl 3-[[(l S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxyla te (2.5 g, 4.43 mmol, 49.31% yield, 80% purity) as white solid. MS (ESI) m/z 452.3 [M+H] ⁺ .

[0001862] Step 3: methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate

[0001863] A mixture of tert-butyl 3-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxyla te (2.1 g, 3.72 mmol, 80% purity, 1 eq) in HCl/MeOH (4 M, 25 mL, 26.88 eq) was stirred at 20 °C for 3 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 methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3 S)-2- oxopyrrolidin-3-yl]propanoate (1.4 g, crude, HC1) as white oil. MS (ESI) m/z 352.2 [M+H] ⁺ .

[0001864] Step 4: methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate

[0001865] A mixture of methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3 S)- 2-oxopyrrolidin-3-yl]propanoate (1.4 g, 3.61 mmol, 1 eq, HC1) in DCM (20 mL) then added 7-chloro-5-methoxy-lH-indole-2-carboxylic acid (1.06 g, 4.69 mmol, 1.3 eq), DMAP (1.10 g, 9.02 mmol, 2.5 eq) and EDCI (1.38 g, 7.22 mmol, 2 eq) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , PE:EA = 2/1-0/1) to get the product methyl (2S)-2-[[2-(7- chloro-5-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane -3-carbonyl]amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (1.5 g, 2.68 mmol, 74.34% yield) as white solid. MS (ESI) m/z 559.2 [M+H] ⁺ . [0001866 ] Step 5 : N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3-yl]methyl]ethyl]-2-

(7-chloro-5-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5] decane-3-carboxamide

[0001867] A mixture of methyl (2S)-2-[[2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidi n-3-yl]propanoate (1.46 g, 2.61 mmol, 1 eq) in NH ₃ /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]e thyl]-2-(7- chloro-5-methoxy-lH-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] ⁺ .

[0001868] Step 6: 2-(7-chloro-5-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)- 2-oxopyrrolidin-3-yl]ethyl]-2-azaspiro[4.5]decane-3-carboxam ide

[0001869] A mixture of N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-2-(7-chloro-5-methoxy-lH-indole-2-carbonyl) -2-azaspiro[4.5]decane-3- carboxamide (1.35 g, 2.11 mmol, 85% purity, 1 eq) in DCM (15 mL) added BURGESS REAGENT (1.51 g, 6.33 mmol, 3 eq) was stirred at 30 °C for 1 h. Upon completion, the mixture were quenched with water (1 mL) and blow-dried with N ₂ . The residue was purified by prep-HPLC (column: Waters X bridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 35% - 65%, 8 min), which was further separated by SFC (column: REGIS(S, S) WHELK-01 (250 mm * 25 mm, 10 um); mobile phase: [Neu-ETOH]; B%: 60% - 60%, 12 min) to get the product 2-(7-chloro-5- methoxy-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-[(3S)-2-oxop yrrolidin-3-yl]ethyl]-2- azaspiro[4.5]decane-3-carboxamide (322.82 mg, 613.70 umol, 29.10% yield) as white solid. MS (ESI) m/z 526.2 [M+H] ⁺ .

[0001870] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.12 (d, J=1.7 Hz, 1H), 7.02 (s, 1H), 6.97 (br d, J=1.8 Hz, 1H), 5.12 - 5.00 (m, 1H), 4.62 (dd, J=7.9, 9.7 Hz, 1H), 3.92 (brd, J=10.3 Hz, 1H), 3.86 - 3.33 (m, 5H), 3.30 - 3.26 (m, 1H), 2.77 - 2.55 (m, 1H), 2.52 - 2.23 (m, 3H), 1.98 - 1.67 (m, 3H), 1.62 - 1.41 (m, 10H). [0001871 ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.07 (br d, J=1.1 Hz, 1H), 8.72 (br d, J=7.5 Hz, 1H), 7.44 (br d, J=0.7 Hz, 1H), 7.12 (br s, 1H), 6.97 (s, 2H), 4.92 (br s, 1H), 4.60 (br s, 1H), 3.85 - 3.77 (m, 4H), 3.61 (br s, 1H), 3.14 (br s, 2H), 2.43 - 2.21 (m, 2H), 2.20 - 1.89 (m, 2H), 1.80 (br s, 1H), 1.72 - 1.58 (m, 2H), 1.57 - 1.35 (m, 10H).

[0001872 ] To get the product 2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-N-[(1S)-1- cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-azaspiro[4.5]dec ane-3-carboxamide (289.32 mg, 550.01 umol, 26.08% yield) as white solid. MS (ESI) m/z 526.2 [M+H] ⁺ .

[0001873] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.12 (d, J=2.0 Hz, 1H), 7.04 (s, 1H), 6.99 - 6.93 (m, 1H), 5.06 - 4.97 (m, 1H), 4.63 (dd, J=7.9, 9.5 Hz, 1H), 3.94 (br d, J=10.4 Hz, 1H), 3.88 - 3.68 (m, 4H), 3.30 - 2.73 (m, 2H), 2.68 - 2.10 (m, 4H), 1.94 - 1.69 (m, 3H), 1.62 - 1.40 (m, 10H).

[0001874] ¹ H NMR (400 MHz, DMSO-d6) δ = 11.46 - 10.49 (m, 1H), 8.67 (br d, J=6.6 Hz, 1H), 7.44 (br s, 1H), 7.21 - 7.07 (m, 1H), 6.98 (s, 2H), 5.06 - 4.83 (m, 1H), 4.59 (br dd, J=2.1, 4.1 Hz, 1H), 3.80 (s, 4H), 3.70 - 3.44 (m, 1H), 3.22 - 3.10 (m, 2H), 2.25 (s, 4H), 1.82 (br s, 1H), 1.68 (br d, J=10.4 Hz, 2H), 1.59 - 1.33 (m, 10H).

Example 229. Synthesis of viral protease inhibitor compound 1059

[0001875] Step 1: (2S)-2-amino-3-(2,2-difluorocyclopropyl)propanoic acid

[0001876] A mixture of (2S)-2-amino-3-(2,2-difluorocyclopropyl)propanoic acid (630 mg, 3.13 mmol, 1 eq, HC1) in HCl/MeOH (4 M, 6 mL, 7.68 eq) was stirred at 80 °C for 2 h. Upon completion, the mixture was concentrated under the reduced pressure to give methyl(2S)-2-amino-3-(2,2-difluorocyclopropyl)propanoate (700 mg, crude, HC1) as a yellow oil.

[0001877] Step 2: (2S)-methyl 3-(2,2-difluorocyclopropyl)-2-(4-methoxy-lH-indole-2- carboxamido)propanoate

[0001878] To a solution of methyl (2S)-2-amino-3-(2,2-difluorocyclopropyl)propanoate (700 mg, 3.25 mmol, 1 eq, HC1) and 4-methoxy- 1 H-indole-2-carboxylic acid (930.98 mg, 4.87 mmol, 1.5 eq) in DCM (15 mL) and DMF (3 mL) was added DMAP (793.21 mg, 6.49 mmol, 2 eq) and EDCI (1.24 g, 6.49 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (30 mL), and then extracted with EA (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether:Ethyl acetate = 10: 1 to 0: 1) to give methyl (2S)-3-(2,2-difluorocyclopropyl)-2-[(4- methoxy- 1 H-indole-2-carbonyl)amino]propanoate (1 g, 2.84 mmol, 87.43% yield) as a yellow oil. MS (ESI) m/z 353.1 [M+H] ⁺

[0001879] Step 3: (2S)-3-(2,2-difluorocyclopropyl)-2-(4-methoxy-lH-indole-2- carboxamido)propanoic acid

[0001880 ] To a solution of methyl (2S)-3-(2,2-difluorocyclopropyl)-2-[(4-methoxy-lH- indole-2-carbonyl)amino]propanoate (1 g, 2.84 mmol, 1 eq) in THF (10 mL) and H ₂ O (3 mL) was added LiOH.H ₂ O (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 H ₂ O (30 mL), and then added aq. HC1 (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (2S)-3-(2,2- difluorocyclopropyl)-2-[(4-methoxy-lH-indole-2-carbonyl)amin o]propanoic acid (1 g, crude) as a yellow solid. MS (ESI) m/z 339.1 [M+H] ⁺

[0001881 ] Step 4: (2S)-methyl2-((2S)-3-(2,2-difluorocyclopropyl)-2-(4-methoxy- lH- indole-2-carboxamido)propanamido)-3-((S)-2-oxopiperidin-3-yl )propanoate

[0001882 ] To a solution of (2S)-3-(2,2-difluorocyclopropyl)-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoic acid (1 g, 2.96 mmol, 1 eq) and methyl (2S)-2-amino-3-[(3 S)- 2-oxo-3-piperidyl]propanoate (887.81 mg, 3.75 mmol, 1.27 eq, HC1) in DCM (15 mL) and DMF (3 mL) was added DMAP (722.23 mg, 5.91 mmol, 2 eq) and EDCI (1.13 g,

5.91 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (30 mL), and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum etherEthyl acetate = 10: 1 to 0: 1) to give methyl (2S)-2-[[(2S)-3-(2,2-difluorocyclopropyl)-2-[(4-methoxy-lH-i ndole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (1 g, 1.92 mmol, 64.99% yield) as a yellow solid. MS (ESI) m/z 521.2 [M+H] ⁺ [0001883] Step 5: N-((2S)- 1 -(((S)- 1 -amino- 1 -oxo-3 -((S)-2-oxopiperidin-3-yl)propan-2- yl)amino)-3-(2,2-difluorocyclopropyl)-1-oxopropan-2-yl)-4-me thoxy-lH-indole-2- carboxamide

[0001884] methyl(2S)-2-[[(2S)-3-(2,2-difluorocyclopropyl)-2-[(4-methox y-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (1 g, 1.92 mmol, 1 eq) in NH ₃ /MeOH (7 M, 15 mL, 54.66 eq) was stirred at 80 °C for 16 h. Upon completion, the mixture was concentrated under the reduced pressure to give N-[(1S)-2- [[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl ]amino]-1-[(2,2- difluorocyclopropyl)methyl]-2-oxo-ethyl]-4-methoxy-lH-indole -2-carboxamide (1 g, crude) as a brown solid. MS (ESI) m/z 506.2 [M+H] ⁺

[0001885] Step 6: N-((2S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)ami no)-3-(2,2- difluorocyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[0001886] To a solution of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-[(2,2-difluorocyclopropyl)me thyl]-2-oxo-ethyl]-4- methoxy-lH-indole-2-carboxamide (1 g, 1.98 mmol, 1 eq) in DCM (15 mL) was added BURGESS REAGENT (1.41 g, 5.93 mmol, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150 * 50 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 25%-50%, 10 min) to give N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-[(2,2- difluorocyclopropyl)methyl]-2-oxoethyl]-4-methoxy- lH-indole-2-carboxamide (0.6 g, 1.23 mmol, 62.22% yield) as a yellow solid. MS (ESI) m/z 488.2 [M+H] ⁺

[0001887] Step 7: N-((2S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)ami no)-3-(2,2- difluorocyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[0001888] N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1-[(2,2- difluorocyclopropyl)methyl]-2-oxoethyl]-4-methoxy- lH-indole-2-carboxamide (0.6 g, 1.23 mmol) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 um); mobile phase: [0.1% NH3H ₂ O IPA]; B%: 46% - 46%, 7 min) to give N- [(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino ]-1-[(2,2- difluorocyclopropyl)methyl]-2-oxoethyl]-4-methoxy- lH-indole-2-carboxamide Isomer 1 (210 mg, 429.91 umol, 34.93% yield, 99.8% purity) as a white solid. MS (ESI) m/z 488.2 [M+H] ⁺

[0001889] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.27 - 7.26 (m, 1H), 7.17 - 7.15 (m, 1H), 7.13 - 7.04 (m, 1H), 6.52 - 6.50 (m, 1H), 5.14 - 5.09 (m, 1H), 4.61 - 4.56 (m, 1H), 3.93 (s, 3H), 3.23 - 3.21 (m, 2H), 2.46 - 2.42 (m, 2H), 1.96 - 1.95 (m, 1H), 1.93 - 1.92 (m, 3H), 1.85 - 1.70 (m, 3H), 1.56 - 1.44 (m, 2H), 1.22 - 1.12 (m, 1H)

[0001890] To give N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1- [(2,2-difluorocyclopropyl)methyl]-2-oxoethyl]-4-methoxy-lH-i ndole-2-carboxamide Isomer 2 (210 mg, 429.05 umol, 34.86% yield, 99.6% purity) as a white solid. MS (ESI) m/z 488.2 [M+H] ⁺

[0001891 ] 1H NMR (400 MHZ, MeOD-d ₄ ) δ = 7.32 - 7.24 (m, 1H), 7.20 - 7.11 (m, 1H), 7.13 - 7.05 (m, 1H), 6.53 - 6.51 (m, 1H), 5.14 - 5.00 (m, 1H), 4.66 -4.61 (m, 1H), 3.94 (s, 3H), 3.20 - 3.19 (m, 2H), 2.43 - 2.25 (m, 2H), 1.95 - 1.90 (m, 4H), 1.85 - 1.63 (m, 3H), 1.56 - 1.44 (m, 2H), 1.22 - 1.03 (m, 1H)

Example 230. Synthesis of viral protease inhibitor compound 1155

[0001892] Step 1: tert-butyl (2S,4S)-4-methoxy-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo- 3-piperidyl]methyl]ethyl]carbamoyl]-4-(trifluoromethyl)pyrro lidine-1-carboxylate

[0001893] To a solution of (2S,4S)-1-tert-butoxycarbonyl-4-methoxy-4-

(trifluoromethyl)pyrrolidine-2-carboxylic acid (0.5 g, 1.60 mmol, 1.2 eq), methyl (2S)-2- amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (314.82 mg, 1.33 mmol, 1 eq, HC1), EDCI (509.94 mg, 2.66 mmol, 2 eq) in DCM (5 mL) was added DMAP (487.48 mg, 3.99 mmol, 3 eq) and the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (100 mL) and extracted with DCM (15 mL * 4). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/1 to 0/1 and then DCM:MeOH = 5:1) to give product tert-butyl (2S,4S)-4-methoxy-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-4-(trifluoromethyl)pyrroli dine- 1 -carboxylate (0.9 g, 1.27 mmol, 95.60% yield, 70% purity) as yellow oil. MS (ESI) m/z 496.2 [M+H] ⁺

[0001894] Step 2: methyl (2S)-2-[[(2S,4S)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2- carbony 1 ]amino]-3 -[(3 S)-2-oxo-3 -piperidyl ]propanoate [0001895] To a solution of tert-butyl (2S,4S)-4-methoxy-2-[[(1S)-2-methoxy-2-oxo-1- [[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-4-(trifluor omethyl)pyrrolidine-1- carboxylate (0.8 g, 1.61 mmol, 1 eq) in HCl/MeOH (4 M, 9 mL, 22.30 eq) was stirred at 20 °C for 1 h. Upon completion, the reaction was concentrated under pressure reduced to give crude product methyl (2S)-2-[[(2S,4S)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.65 g, crude, HC1) as yellow oil. MS (ESI) m/z 396.1 [M+H] ⁺

[0001896] Step 3: methyl (2S)-2-[[(2S,4S)-4-methoxy-1-(4-methoxy-lH-indole-2- carbonyl)-4-(trifluoromethyl)pyrrolidine-2-carbonyl]amino]-3 -[(3S)-2-oxo-3- piperidyl]propanoate

[0001897 ] To a solution of methyl (2S)-2-[[(2S,4S)-4-methoxy-4-

(trifluoromethyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2- oxo-3-piperidyl]propanoate (0.65 g, 1.51 mmol, 1 eq, HC1), 4-methoxy-lH-indole-2-carboxylic acid (345.32 mg, 1.81 mmol, 1.2 eq) in DCM (5 mL) was added DMAP (551.67 mg, 4.52 mmol, 3 eq) and EDCI (577.10 mg, 3.01 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction was quenched by addition H ₂ O (80 mL) and extracted with DCM (10 mL * 4). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/1 to 0/1) to give the product methyl (2S)-2-[[(2S,4S)-4- methoxy- 1 -(4-methoxy- 1 H-indole-2-carbonyl)-4-(trifluoromethyl)pyrrolidine-2- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.65 g, crude) as yellow oil. MS (ESI) m/z 569.2 [M+H] ⁺

[0001898] Step 4: (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-4-methoxy- 1 -(4-methoxy- lH-indole-2-carbonyl)-4- (trifluoromethyl)pyrrolidine-2-carboxamide

[0001899] To a solution of methyl (2S)-2-[[(2S,4S)-4-methoxy-l -(4-methoxy- lH-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 NH ₃ /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- lH-indole-2-carbonyl)-4- (trifluoromethyl)pyrrolidine-2-carboxamide (0.5 g, crude) as yellow solid. MS (ESI) m/z 554.2 [M+H] ⁺

[0001900] Step 5: (2S,4S)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-4-m ethoxy-1- (4-methoxy-lH-indole-2-carbonyl)-4-(trifluoromethyl)pyrrolid ine-2-carboxamide

[0001901 ] To a solution of (2S,4S)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-4-methoxy- 1 -(4-methoxy- lH-indole-2-carbonyl)-4- (trifluoromethyl)pyrrolidine-2-carboxamide (0.5 g, 812.96 umol, 90% purity, 1 eq) in DCM (8 mL) was added BURGESS REAGENT (581.21 mg, 2.44 mmol, 3 eq) and the mixture was stirred at 30 °C for 4 h. Upon completion, the mixture were quenched with water(1.5 mL) and blow-dried with N ₂ and was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HCO3)- ACN];B%: 25%-50%,8min) to give product (2S,4S)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-4-methoxy-1-(4-methoxy-lH-indole-2-carbonyl )-4- (trifluoromethyl)pyrrolidine-2-carboxamide (0.21 g, 392.15 umol, 48.24% yield, 100% purity) as white solid. MS (ESI) m/z 536.2 [M+H] ⁺

[0001902] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ = 7.25 - 7.13 (m, 1H), 7.05 (br d, J = 8.2 Hz, 2H), 6.63 - 6.40 (m, 1H), 5.36 - 4.89 (m, 2H), 4.47 - 4.04 (m, 2H), 4.02 - 3.79 (m, 3H), 3.45 (br s, 3H), 3.26 - 2.90 (m, 2H), 2.86 - 2.50 (m, 2H), 2.49 - 2.14 (m, 2H), 2.04 - 1.04 (m, 5H).

Example 231. Synthesis of viral protease inhibitor compound 1053

[0001903] Step 1: 01-tert-butyl02-methyl(2S,4E)-4-(dimethylaminomethylene)-5-o xo- pyrrolidine-1 ,2-dicarboxylae

[0001904] A mixture of Ol-tert-butyl 02-methyl (2S)-5-oxopyrrolidine- 1 ,2-dicarboxylate (282 g, 1.16 mol, 1 eq), l-tert-butoxy-N,N,N',N'-tetramethyl-methanediamine (303.06 g, 1.74 mol, 359.08 mL, 1.5 eq) in DME (282 mL) was stirred at 75 °C for 3 h. Upon completion, the mixture was cooled to 0 °C and then filtered, the filter cake was concentrated under the reduced pressure to give the product 01-tert-butyl02- methyl(2S,4E)-4-(dimethylaminomethylene)-5-oxo-pyrrolidine- 1 ,2-dicarboxylae(272 g, crude) as a white solid. [0001905] Step 2: 01-tert-butyl 02-methyl (2S)-4-methylene-5-oxo-pyrrolidine-l,2- dicarboxylate

[0001906] To a solution of 01-tert-butyl 02-methyl (2S,4E)-4-(dimethylaminomethylene)- 5-oxo-pyrrolidine-l,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. NH4CI (2500 mL) and then extracted with EA (1000 mL * 3). The combined organic layers were washed with brine (2000 mL), dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 1/1) to give the product. The product Ol- tert-butyl 02-methyl (2S)-4-methylene-5-oxo-pyrrolidine- 1,2-dicarboxylate (35 g,

137.11 mmol, 58.44% yield) was obtained as a white solid.

[0001907] Step 3: dimethyl (2S)-2-(tert-butoxycarbonylamino)-4-methylene-pentanedioate

[0001908] To a solution of Ol-tert-butyl 02-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 NH4CI (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] ⁺

[0001909] Step 4: dimethyl (2S)-2-(tert-butoxycarbonylamino)-4-(2-methyl-2-nitro- propyl)pentanedioate

[0001910] To a solution of dimethyl (2S)-2-(tert-butoxycarbonylamino)-4-methylene- pentanedioate (34 g, 118.34 mmol, 1 eq) and 2-nitropropane (11.60 g, 130.17 mmol,

11.69 mL, 1.1 eq) in ACN (350 mL) was added DBU (21.62 g, 142.01 mmol, 21.40 mL, 1.2 eq). The solution was stirred for 2 h at 20 °C. Upon completion, the solution was concentrated to give crude. The crude was purified by column (SiO ₂ , PE:EA = 20: 1 to 1:1) to give product compound dimethyl (2S)-2-(tert-butoxycarbonylamino)-4-(2- methyl-2-nitro-propyl)pentanedioate (30 g, 79.70 mmol, 67.35% yield) as a white solid. MS (ESI) m/z 277.1 [M+H-100] ⁺

[0001911 ] Step 5 : methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5,5-dimethyl-2-oxo- pyrrolidin-3-yl)propanoate

[0001912] To a solution of dimethyl (2S)-2-(tert-butoxycarbonylamino)-4-(2-methyl-2- nitro-propyl)pen tanedioate (26 g, 69.08 mmol, 1 eq) in IPA (250 mL) was added Pd/C (24.54 g, 20.72 mmol, 10% purity, 0.3 eq) under N2. The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 40 °C for 15 h. Upon completion, the mixture was filtered and concentrated to give crude compound. The crude was purified by column(SiO ₂ , PE:EA = 20: 1 to 0: 1) to give product methyl (2S)-2-(tert-butoxycarbony lamino)-3-(5, 5-dimethyl -2-oxo-pyrrolidin-3- yl)propanoate (14.6 g, 46.44mmol, 67.23%) as a white solid and continue purified by SFC (column: DAICEL CHIRALPAK IC(250mm*50mm,10um);mobile phase: [0.1%NH ₃ H _Z O IPA];B%: 30%-30%,11.5min) to give BB7 methyl (2S)-2-(tert- butoxycarbonylamino)-3-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)p ropanoate (4.8 g, 15.27 mmol, 32.65% yield) as a white solid. MS (ESI) m/z 315.2 [M+H] ⁺

[0001913] Step 6: methyl (2S)-2-amino-3-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)propanoat e

[0001914] 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, HC1) as a white solid and used directly for the next step.

[0001915] Step 7: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoyl]amino]-3-(5,5- dimethyl-2-oxo-pyrrolidin-3-yl)propanoate

[0001916] To a solution of methyl (2S)-2-amino-3-(5,5-dimethyl-2-oxo-pyrrolidin-3- yl)propanoate (370 mg, 1.48 mmol, 1 eq, HC1) in DCM (10 mL) and DMF (5 mL) was added DMAP (360.58 mg, 2.95 mmol, 2 eq) and (2S)-2-(tert-butoxycarbonylamino)-3- cyclopropyl-propanoic acid (372.18 mg, 1.62 mmol, 1.1 eq) and EDCI (565.80 mg, 2.95 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was diluted with H ₂ O (60 mL) and extracted with EA (60 mL * 3) and concentrated to give crude. The crude was purified by column (SiO ₂ , PE:EA = 10: 1 to 0: 1) to give compound methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-pro panoyl] amino]-3- (5,5-dimethyl-2-oxo-pyrrolidin-3-yl)propanoate (550 mg, 1.29 mmol, 87.59% yield) as a yellow oil. MS (ESI) m/z 426.2 [M+H] ⁺

[0001917] Step 8: methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(5,5- dimethyl-2-oxo- pyrrolidin -3-yl)propanoate

[0001918] A solution of methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbony lamino)-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, HC1) as a white solid.

[0001919] Step 9: methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino] -3- cyclopropyl-propanoyl] amino]-3-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)propanoate

[0001920] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-(5, 5-dimethyl -2-oxo-pyrrolidin-3-yl)propanoate (450 mg, 1.24 mmol, 1 eq, HC1) in DCM (10 mL) and DMF (5 mL) was added DMAP (303.85 mg, 2.49 mmol, 2 eq) and 7-chloro-lH-indole-2-carboxylic acid (243.24 mg, 1.24 mmol, 1 eq) and EDCI (476.79 mg, 2.49 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the solution was diluted with H ₂ O (60 mL) and extracted with EA (70 mL * 3) and washed with brine (100 mL * 2) and concentrated to give crude. The crude was purified by column (SiO ₂ , PE:EA = 3:1 to 0:1) to give product methyl (2S)-2-[[(2S)-2- [(7-chloro-lH-indole-2-carbonyl) amino]-3-cyclopropyl-propanoyl]amino]-3-(5,5- dimethyl-2-oxo-pyrrolidin-3-yl)propanoate (550 mg, 1.09 mmol, 87.93% yield) as a white solid. MS (ESI) m/z 503.2 [M+H] ⁺

[0001921 ] Step 10: 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-lH-indole- 2-carboxamide [0001922] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]- 3 -cyclopropyl- propanoyl]amino]-3-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)propa noate (550 mg, 1.09 mmol, 1 eq) in NH ₃ /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-(cyclopropy lmethyl)-2-oxo-ethyl]-7- chloro-lH-indole-2-carboxamide (530 mg, crude) was obtained as a white solid. MS (ESI) m/z 488.2 [M+H] ⁺

[0001923] Step 11: 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-(5,5-dimethyl-2-oxo-pyrr olidin-3- yl)ethyl]amino] -1-(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide

[0001924] To a solution of 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-lH- indole- 2-carboxamide (530 mg, 1.09 mmol, 1 eq) in DCM (20 mL) was added BURGESS REAGENT (517.65 mg, 2.17 mmol, 2 eq). The mixture was stirred at 20 °C for 2.5 h. Upon the reaction was completion, the solution was washed with H ₂ O (30 mL) and the organic phase was blowed dry with N ₂ to give crude. The crude was purified by neutral pre-HPLC (Waters Xbridge C 18 150 * 50mm * 10um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 30%-70%,10min) to give product. MS (ESI) m/z 470.2 [M+H] ⁺

[0001925] 7-chloro-N-[(l S)-2-[[( 1 S)- 1 -cyano-2-(5,5-dimethyl-2-oxo-pyrrolidin-3- yl)ethyl]amino] -1-(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide (330 mg, 702.18 umol, 64.65% yield) was obtained as a white solid.

[0001926] ¹ H NMR (400MHZ, DMSO-d ₆ ) Shift = 11.56 (br s, 1H), 8.89 (d, J=7.9 Hz, 1H), 8.60 (d, J=7.5 Hz, 1H), 7.70 (s, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.12 (s, 1H), 6.95 (t, J=7.8 Hz, 1H), 4.95 - 4.76 (m, 1H), 4.46 - 4.20 (m, 1H), 2.52 - 2.44 (m, 1H), 2.12 - 1.99 (m, 1H), 1.88 (dd, J=8.6, 12.2 Hz, 1H), 1.76 - 1.60 (m, 2H), 1.45 - 1.33 (m, 2H), 1.03 (s, 3H), 0.95 (s, 3H), 0.76 - 0.62 (m, 1H), 0.38 - 0.25 (m, 2H), 0.14 - -0.06 (m, 2H).

Example 232. Synthesis of viral protease inhibitor compound 1111

[0001927] Step 1: methyl (2S)-2-amino-3-(6,6-dimethyl-2-oxo-3-piperidyl)propanoate

[0001928 ] methyl (2S)-2-(tert-butoxycarbonylamino)-3-(6,6-dimethyl-2-oxo-3- piperidyl)propanoate (20 mg, 60.90 umol, 1 eq) was added HCl/MeOH (4 M, 5 mL, 328.40 eq). The mixture 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 used next step directly. Compound methyl (2S)-2-amino-3-(6,6-dimethyl-2-oxo-3- piperidyl)propanoate (16 mg, 57.41 umol, 94.27% yield, 95% purity, HCI) was obtained as a colourless oil.

[0001929] Step 2: tert-butyl 3-[[(1S)-1-[(6,6-dimethyl-2-oxo-3-piperidyl)methyl]-2- methoxy-2-oxo-ethy 1 ] carbamoyl]-2-azaspiro[4.5]decane-2-carboxylate

[0001930 ] To a mixture of 2-tert-butoxycarbonyl-2-azaspiro[4.5]decane-3-carboxylic acid (171.25 mg, 604.35 umol, 1 eq) and methyl (2S)-2-amino-3-(6,6-dimethyl-2-oxo-3- piperidyl)propanoate (160 mg, 604.35 umol, 1 eq, HCI) in DMF (3 mL) and DCM (6 mL) was added EDCI (231.71 mg, 1.21 mmol, 2 eq) and DMAP (147.67 mg, 1.21 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O 20 mL and extracted with DCM 50 mL (25 mL * 2). The combined organic layers were washed with BRINE 20 mL (20 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=7/l to 1/1) to get the compound tert-butyl 3-[[(1S)-1-[(6,6-dimethyl-2-oxo-3-piperidyl)methyl]-2-methox y-2- oxo-ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxylate ( 195 mg, 395.03 umol, 65.36% yield, N/A purity) as a colourless oil.

[0001931 ] Step 3 : methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-(6,6- dimethyl-2-oxo-3-piperidyl) propanoate

[0001932] tert-butyl 3-[[(1S)-1-[(6,6-dimethyl-2-oxo-3-piperidyl)methyl]-2-methox y-2- oxo-ethy 1 ]carbamoy 1 ] -2-azaspiro[4.5]decane-2-carboxylate (170 mg, 344.38 umol, 1 eq) was added HCl/MeOH (4 M, 17.00 mL, 197.45 eq). The mixture 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 used next step directly. Compound methyl (2S)-2-(2- azaspiro[4.5]decane-3-carbonylamino)-3-(6,6-dimethyl-2-oxo-3 - piperidyl)propanoate (145 mg, 320.36 umol, 93.03% yield, 95% purity, HC1) was obtained as a colourless oil.

[0001933] Step 4: methyl (2S)-3-(6,6-dimethyl-2-oxo-3-piperidyl)-2-[[2-(4-methoxy-lH- indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]propanoate

[0001934] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (64.47 mg, 337.23 umol, 1 eq) and methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-(6,6-dimeth yl- 2-oxo-3-piperidyl)propanoate (145 mg, 337.23 umol, 1 eq, HC1) in DCM (6 mL) and DMF (3 mL) was added DMAP (82.40 mg, 674.45 umol, 2 eq) and EDCI (129.29 mg, 674.45 umol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O 30 mL and extracted with EA 100 mL (50 mL *

2). The combined organic layers were washed with BRINE 50 mL (50 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (DCM: MeOH = 10: 1) to get the compound methyl (2S)-3-(6,6-dimethyl-2-oxo-3-piperidyl)-2-[[2-(4-methoxy-lH- indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]propanoate (200 mg, 335.28 umol, 99.42% yield, 95% purity) as a yellow oil. MS (ESI) m/z 567.3 [M+H] ⁺ [0001935] Step 5: N-[( 1 S)-2-amino- 1 -[(6,6-dimethyl-2-oxo-3 -piperidyl)methyl]-2-oxo- ethyl]-2-(4-methoxy- lH-indole-2 -carbonyl)-2-azaspiro[4.5 ]decane-3 -carboxamide

[0001936] To a mixture of methyl (2S)-3-(6,6-dimethyl-2-oxo-3-piperidyl)-2-[[2-(4- methoxy-lH-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]propanoat e (200 mg, 352.93 umol, 1 eq) was added NH ₃ /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-[(l S)-2-amino-1-[(6,6-dimethyl-2-oxo-3-piperidyl) methyl]-2-oxo-ethyl]-2- (4-methoxy- 1 H-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] ⁺

[0001937] Step 6: N-[(1S)-1-cyano-2-(6,6-dimethyl-2-oxo-3-piperidyl)ethyl]-2-( 4- methoxy-lH-indole-2-carbonyl) -2-azaspiro[4.5]decane-3-carboxamide

[0001938] To a mixture of N-[(1S)-2-amino-1-[(6,6-dimethyl-2-oxo-3-piperidyl)methyl]-2 - oxo-ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5 ]decane-3-carboxamide (190 mg, 344.41 umol, 1 eq) in DCM (2 mL) was added BURGESS REAGENT (164.15 mg, 688.81 umol, 2 eq). The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was diluted with H ₂ O 5 mL and extracted with DCM 10 mL (5 mL * 2).

The combined organic layers were concentrated by blow-drying to give a residue. The residue was purified by prep-HPLC (neutral condition) (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 30%- 60%, 10 min) to give desired compound (80 mg) as a white solid. The white solid was spereted by SFC (column: REGIS(S, S)WHELK-01(250mm*25mm,10um);mobile phase: [Neu-ETOH];B%: 60%-60%,7min) to get the Isomers 1, 2, 3 & 4. The mixture (Isomers 2 &3) was separated by SFC (column: REGIS(S,S)WHELK- 01(250mm*25mm,10um);mobile phase: [Neu-MeOH];B%: 50%-50%,15min). MS (ESI) m/z 534.2 [M+H] ⁺

[0001939] Isomer 1 : Compound N-[(1S)-1-cyano-2-(6,6-dimethyl-2-oxo-3- piperidyl)ethyl]-2-(4-methoxy-lH-indole-2- carbonyl)-2-azaspiro[4.5]decane-3- carboxamide (13 mg, 24.36 umol, 7.07% yield, 100% purity) was obtained as a white solid.

[0001940] ¹ H NMR (400MHz, DMSO-d6) δ = 11.29 (br s, 1H), 8.69 (br s, 1H), 7.28 - 6.72

(m, 4H), 6.52 (d, J=7.7 Hz, 1H), 4.99 (br s, 1H), 4.78 - 4.46 (m, 1H), 3.95 - 3.82 (m, 4H), 3.73 - 3.40 (m, 1H), 2.34 - 2.04 (m, 3H), 1.89 - 1.31 (m, 16H), 1.13 (br d, J=10.6 Hz, 6H)

[0001941 ] Isomer 2 : Compound N-[( 1 S)- 1 -cyano-2-(6,6-dimethyl-2-oxo-3- piperidyl)ethyl]-2-(4-methoxy-lH-indole-2- carbonyl)-2-azaspiro[4.5]decane-3- carboxamide (17 mg, 31.86 umol, 9.25% yield, 100% purity) was obtained as a white solid.

[0001942] ¹ H NMR (400MHz, DMSO-d6) δ = 11.31 (br s, 1H), 8.64 (br s, 1H), 7.25 - 6.75 (m, 4H), 6.52 (d, J=7.7 Hz, 1H), 4.99 (q, J=8.0 Hz, 1H), 4.61 (br s, 1H), 4.01 - 3.80 (m, 4H), 3.66 (br s, 1H), 2.30 - 1.94 (m, 3H), 1.92 - 1.31 (m, 16H), 1.12 (d, J=6.4 Hz, 6H)

[0001943 ] Isomer 3 : Compound N-[( 1 S)- 1 -cyano-2-(6,6-dimethyl-2-oxo-3- piperidyl)ethyl]-2-(4-methoxy-lH-indole-2- carbonyl)-2-azaspiro[4.5]decane-3- carboxamide (14 mg, 26.23 umol, 7.62% yield, 100% purity) was obtained as a white solid.

[0001944] ¹ H NMR (400MHz, DMSO-d6) δ = 11.30 (br s, 1H), 8.92 - 8.52 (m, 1H), 7.41 -

6.74 (m, 4H), 6.52 (br d, J=7.3 Hz, 1H), 4.94 (br s, 1H), 4.63 (br s, 1H), 4.03 - 3.78 (m, 4H), 3.73 - 3.44 (m, 1H), 2.35 - 2.04 (m, 3H), 1.93 - 1.32 (m, 16H), 1.14 (s, 6H)

[0001945] Isomer 4: Compound N-[(1S)-1-cyano-2-(6,6-dimethyl-2-oxo-3- piperidyl)ethyl]-2-(4-methoxy-lH-indole-2- carbonyl)-2-azaspiro[4.5]decane-3- carboxamide (28 mg, 52.23 umol, 15.16% yield, 99.538% purity) was obtained as a white solid.

[0001946] ¹ H NMR (400MHz, DMSO-d6) δ = 11.31 (br s, 1H), 8.69 (br s, 1H), 7.27 - 6.77 (m, 4H), 6.53 (d, J=7.5 Hz, 1H), 4.94 (br s, 1H), 4.61 (br s, 1H), 4.06 - 3.83 (m, 4H), 3.66 (br s, 1H), 2.32 - 1.98 (m, 3H), 1.83 - 1.32 (m, 16H), 1.13 (d, J=18.1 Hz, 6H)

Example 233. Synthesis of viral protease inhibitor compound 3069

[0001947] Step 1: (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)-5,5- dimethyl-2-oxopyrrolidin-3-yl)propanoate

[0001948] A solution of (S)-methyl 2-((S)-2-((tert-butoxy carbonyl) amino)-4,4- dimethylpentanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-y l)propanoate (400 mg, 905.88 umol, 1 eq) in HCI/MeOH (5 mL) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give methyl (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)-5,5-dimethyl- 2- oxopyrrolidin-3-yl)propanoate (330 mg, crude, HC1) as a white solid. MS (ESI) m/z 342.2 [M+H] ⁺ .

[0001949] Step 2: (6S,9S,12S)-methyl 6-(tert-butyl)-12-(((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)methyl)-2,2-dimethyl-9-neopentyl-4,7, 10-trioxo-3-oxa-5,8, 11 - triazatridecan- 13-oate

[0001950] To a solution of (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (330 mg, 873.23 umol, 1 eq, HC1) and (S)- 2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (201.97 mg, 873.23 umol, 1 eq) in DCM (10 mL), was added DMAP (320.05 mg, 2.62 mmol, 3 eq) and EDCI (502.20 mg, 2.62 mmol, 3 eq). The mixture was stirred at 30 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (10 mL), and then extracted with DCM (5 mL * 2). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (6S,9S, 12S)-methyl 6- (tert-butyl)-12-(((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)meth yl)-2,2-dimethyl-9- neopentyl-4,7, 10-trioxo-3-oxa-5,8, 11 -triazatridecan- 13-oate (450 mg, crude) as a white solid. MS (ESI) m/z 555.4 [M+H] ⁺ .

[0001951] Step 3: tert-butyl ((S)-1-(((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)-1-oxopropan-2-yl)amino)-4,4-dimethyl-1-o xopentan-2-yl)amino)- 3 ,3-dimethyl- 1 -oxobutan-2-yl)carbamate

[0001952] A solution of (6S,9S,12S)-methyl 6-(tert-butyl)-12-(((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)methyl)-2,2-dimethyl-9-neopentyl-4,7,10-t rioxo-3-oxa-5,8,ll- triazatri decan- 13-oate (400 mg, 721.09 umol, 1 eq) in NH ₃ /MeOH (7 M, 8.00 mL, 77.66 eq) was stirred at 65 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give tert-butyl ((S)-1-(((S)-1-(((S)-1-amino- 3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2-yl)amino)-4, 4-dimethyl- 1 - oxopentan-2-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (430 mg, crude) as a white solid. MS (ESI) m/z 540.4 [M+H] ⁺ .

[0001953] Step 4: (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-dim ethylpentanamide

[0001954] A solution of tert-butyl ((S)-1-(((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)-1-oxopropan-2-yl)amino)-4,4-dimethyl-1-o xopentan-2-yl)amino)- 3 ,3-dimethyl- 1 -oxobutan-2-yl)carbamate (410 mg, 759.67 umol, 1 eq) in HCl/EtOAc (4 M, 189.92 uL, 1 eq) was stirred at 25 °C for 1 h. Upon completion, the resulting solution was concentrated in vacuum (40 °C) to give (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-di methy lpentanamide (340 mg, crude) as a white solid. MS (ESI) m/z 440.3 [M+H] ⁺ [0001955] Step 5: (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-trifluoroacetam ido)butanamido)-4,4- dimethylpentanamide

[0001956] 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 H ₂ O (10 mL), adjusted to pH~8 with NaHCO ₃ and then extracted with EtOAc (10 mL * 2). The combined organic phase was dried over Na ₂ SO ₄ , 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-dimethylpentanam ide (290 mg, crude) as a white solid. MS (ESI) m/z 536.3 [M+H] ⁺

[0001957] Step 6: (S)-N-((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl) ethyl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamido)-4, 4-dimethylpentanamide

[0001958] To a solution of (S)-N-((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl) - l-oxopropan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacet amido)butanamido)-4,4- dimethylpentanamide (290 mg, 541.45 umol, 1 eq) in DCM (3 mL) was added BURGESS REAGENT (258.06 mg, 1.08 mmol, 2 eq) then the mixture was stirred at 25 °C for 3 h. Upon completion, the resulting solution was quenched with H ₂ O (0.3 mL), then was concentrated in vacuum (25 °C). The residue was purified by prep-HPLC (column: Phenomenex Gemini -NX C18 75 * 30 mm * 3 um; mobile phase: [water(10 mM NH4HCO3)- ACN] ; B%: 30%-60%, 8 min) to give (S)-N-((S)-1-cyano-2-((R)-5,5- dimethyl-2-oxopyrrolidin-3-yl)ethyl)-2-((S)-3,3-dimethyl-2-( 2,2,2- trifluoroacetamido)butanamido)-4,4-dimethylpentanamide (75.94 mg, 146.72 umol, 27.10% yield, 100% purity) as a white solid. MS (ESI) m/z 518.3 [M+H] ⁺ . [0001959] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 4.96 - 4.91 (m, 1H), 4.46 - 4.37 (m, 2H), 2.78 - 2.64 (m, 1H), 2.37 - 2.27 (m, 1H), 2.22 - 2.14 (m, 1H), 1.95 - 1.84 (m, 1H), 1.74 - 1.59 (m, 3H), 1.29 (s, 3H), 1.23 (s, 3H), 1.00 - 0.96 (m, 18H)

Example 234. Synthesis of viral protease inhibitor compound 3129

[0001960] Step 1: (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[0001961 ] A mixture of methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (1 g, 3.80 mmol, 90% purity, 1 eq, HC1) and (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoic acid (1.03 g, 4.18 mmol, 1.1 eq) in DCM (10 mL) was added DMAP (1.16 g, 9.51 mmol, 2.5 eq), EDCI (1.46 g, 7.60 mmol, 2 eq) at 0 °C, then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (5 mL), and then diluted with H ₂ O (10 mL) and extracted with DCM 60 mL (30 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 0:1 to 10: 1) to give (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanamid o)-3-((S)-2-oxopiperidin- 3-yl)propanoate (1.14 g, 2.32 mmol, 61.01% yield, 87% purity) as yellow solid. MS (ESI) m/z 428.2 [M+H] ⁺ .

[0001962] Step 2: tert-butyl ((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan - 2-yl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)carbamate

[0001963] A solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate (1 g, 2.03 mmol, 87% purity, 1 eq) in NH ₃ /MeOH (7 M, 15 mL, 51.60 eq) was stirred at 60 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give tert- butyl ((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan -2-yl)amino)-4,4- dimethyl-1-oxopentan-2-yl)carbamate (1 g, crude) as a yellow solid. MS (ESI) m/z 413.2 [M+H] ⁺ .

[0001964] Step 3: (S)-2-amino-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl) propan- 2-yl)-4,4-dimethylpentanamide

[0001965] A solution of tert-butyl ((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamat e (1 g, 2.01 mmol, 83% purity, 1 eq) in HCl/EtOAc (4 M, 8.30 mL, 16.50 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (S)-2- amino-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan -2-yl)-4,4- dimethylpentanamide (800 mg, crude) as a yellow solid. MS (ESI) m/z 313.2 [M+H] ⁺ .

[0001966] Step 4: tert-butyl ((S)-1-(((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)amino)-3, 3-dimethyl- 1 -oxobutan- 2-yl)carbamate

[0001967 ] To a mixture of (S)-2-amino-N-((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)-4,4-dimethylpentanamide (700 mg, 1.57 mmol, 78% purity, 1 eq, HC1) and (2S)-2-(tert-butoxycarbonylamino)-3, 3-dimethyl-butanoic acid (433.33 mg, 1.87 mmol, 1.2 eq) in DCM (10 mL) was added DMAP (478.01 mg, 3.91 mmol, 2.5 eq), EDCI (600.05 mg, 3.13 mmol, 2 eq) at 0 °C, then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with 1 N HC1 (10 mL), then washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 0:1 to 10: 1) to give tert-butyl ((S)- 1 -(((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)- 2-oxopiperidin-3-yl)propan-2-yl)amino)-4,4-dimethyl-1-oxopen tan-2-yl)amino)-3,3- dimethyl- 1 -oxobutan-2-yl)carbamate (400 mg, 684.83 umol, 43.76% yield, 90% purity) as yellow solid. MS (ESI) m/z 526.4 [M+H] ⁺ .

[0001968] Step 5: (S)-N-((S)-1 -amino- 1 -oxo-3 -((S)-2-oxopi peridin-3-yl)propan-2-yl)-2- ((S)-2-amino-3,3-dimethylbutanamido)-4,4-dimethylpentanamide

[0001969] A mixture of tert-butyl ((S)- 1 -(((S)- 1 -(((S)- 1 -amino- 1 -oxo-3 -((S)-2- oxopiperidin-3-yl)propan-2-yl)amino)-4,4-dimethyl-1-oxopenta n-2-yl)amino)-3,3- dimethyl- 1 -oxobutan-2-yl)carbamate (300 mg, 513.62 umol, 90% purity, 1 eq) in HCl/EtOAc (4 M, 2.70 mL, 21.03 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (S)-N-((S)- 1 -amino- 1 - oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-2-((S)-2-amino-3 ,3-dimethylbutanamido)- 4,4-dimethylpentanamide (240 mg, crude, HC1) as yellow solid. MS (ESI) m/z 426.4 [M+H] ⁺ .

[0001970] Step 6: (S)-N-((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamido)-4, 4-dimethylpentanamide

[0001971 ] To a mixture of (S)-N-((S)- 1 -amino- 1 -oxo-3 -((S)-2-oxopiperidin-3-yl)propan-2- yl)-2-((S)-2-amino-3,3-dimethylbutanamido)-4,4-dimethylpenta namide (280 mg, 484.82 umol, 80% purity, 1 eq, HC1) in DCM (3 mL) was added DIEA (187.98 mg, 1.45 mmol, 253.34 uL, 3 eq) and TFAA (152.74 mg, 727.23 umol, 101.15 uL, 1.5 eq) at 0 °C, then the mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (3 mL) and extracted with DCM (3 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH =

100:1 to 10:1) to give (S)-N-((S)- 1 -amino- 1 -oxo-3 -((S)-2-oxopiperidin-3-yl)propan-2-yl)- 2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanamido)- 4,4-dimethylpentanamide (280 mg, crude) as yellow solid. MS (ESI) m/z 522.3 [M+H] ⁺ . [0001972] Step 7: (S)-N-((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2-((S)- 3,3- dimethyl-2-(2,2,2-trifluoroacetamido)butanamido)-4,4-dimethy lpentanamide

[0001973] To a mixture of (S)-N-((S)- 1 -amino- 1 -oxo-3 -((S)-2-oxopiperidin-3-yl)propan-2- yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanami do)-4,4- dimethylpentanamide (270 mg, 414.13 umol, 80% purity, 1 eq) in DCM (3 mL) was added BURGESS REAGENT (197.38 mg, 828.27 umol, 2 eq) and stirred at 25 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.4 mL) at 20 °C, and then concentrated under reduced pressure (<30 °C) to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 um; mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 30%-60%, 10 min) to give (S)-N-((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2-((S)- 3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanamido)-4,4-dimethylpentanamide (104.51 mg, 207.54 umol, 50.12% yield, 100% purity) as white solid. MS (ESI) m/z 504.2 [M+H] ⁺ .

[0001974] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.09 (br s, 1H), 8.95 (d ,J= 8.1 Hz, 1H), 8.37 (d,J = 7.8 Hz, 1H), 7.52 (br s, 1H), 5.02 - 4.87 (m, 1H), 4.39 (br s, 1H), 4.33 (br d ,J = 6.5 Hz, 1H), 3.15 - 3.00 (m, 2H), 2.37 - 2.29 (m, 1H), 2.22 - 2.12 (m, 1H), 1.85 - 1.66 (m, 3H), 1.64 - 1.44 (m, 3H), 1.42 - 1.30 (m, 1H), 0.96 - 0.78 (m, 18H)

Example 235. Synthesis of viral protease inhibitor compound 3065 [0001975] Step 1: (6S,9S,12S)-methyl 6-(tert-butyl)-9-(cyclopropylmethyl)-12-(((R)-5,5- dimethyl-2-oxopyrrolidin-3-yl)methyl)-2,2-dimethyl-4,7,10-tr ioxo-3-oxa-5,8,ll- triazatridecan- 13-oate

[0001976] To a mixture of methyl (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)- 3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (404.97 mg, 1.75 mmol, 1.2 eq) in DCM (3 mL) was added (600 mg, 1.46 mmol, 88% purity, 1 eq, HC1), DMAP (534.77 mg, 4.38 mmol, 3 eq) and EDCI (559.43 mg, 2.92 mmol, 2 eq), then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addtion into water (1 mL), and then extracted with DCM (3 mL * 3). The combined organic layers were washed with HC1 (1M, 3 mL), then washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column (SiO ₂ , DCM:MeOH = 100: 1 to 10: 1) to give (6S,9S, 12S)-methyl 6-(tert-butyl)-9- (cyclopropylmethyl)-12-(((R)-5,5-dimethyl-2-oxopyrrolidin-3- yl)methyl)-2,2-dimethyl- 4,7, 10-trioxo-3-oxa-5,8, 11 -triazatridecan- 13-oate (550 mg, 969.97 umol, 66.48% yield, 95% purity) as white solid. MS (ESI) m/z 539.3 [M+H] ⁺ .

[0001977] Step 2: tert-butyl ((S)-1-(((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)amino)- 3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0001978] A mixture of (6S,9S, 12S)-methyl 6-(tert-butyl)-9-(cyclopropylmethyl)- 12-(((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl)-2,2-dimethyl-4,7,1 0-trioxo-3-oxa-5,8,ll- triazatri decan- 13-oate (550 mg, 969.97 umol, 95% purity, 1 eq) in NH ₃ /MeOH (7 M, 5 mL, 39.70 eq) was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl ((S)-1-(((S)-1-(((S)-1-amino-3- ((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 - oxopropan-2-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (520 mg, crude) as white solid. MS (ESI) m/z 524.3 [M+H] ⁺ .

[0001979] Step 3: (S)-2-amino-N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-y l)-3 ,3 - dimethylbutanamide [0001980] A mixture of tert-butyl ((S)-1-(((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)amino)- 3 ,3-dimethyl- 1 -oxobutan-2-yl)carbamate (500 mg, 954.81 umol, 1 eq) in HC1/EA (4 M, 10 mL) was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give (S)-2-amino-N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl- 2-oxopyrrolidin-3-yl)-1-oxopropan-2-yl)amino)-3-cyclopropyl- 1-oxopropan-2-yl)-3,3- dimethylbutanamide (350 mg, crude, HC1) as white solid. MS (ESI) m/z 424.2 [M+H] ⁺ .

[0001981 ] Step 4: (S)-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolid in-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-3,3-dimethyl -2-(2,2,2- trifluoroacetamido)butanamide

[ 0001982 ] A mixture of (S)-2-amino-N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-y l)-3 ,3 - dimethylbutanamide (300 mg, 586.94 umol, 90% purity, 1 eq, HC1) in DCM (1 mL) was added TFAA (160.26 mg, 763.03 umol, 106.13 uL, 1.3 eq) and DIEA (227.57 mg, 1.76 mmol, 306.70 uL, 3 eq) at 0 °C, then stirred at 20 °C for 1 h. Upon completion, the mixture was quenched with water (1 mL) and concentrated under reduced pressure to give a residue (<30 °C). The residue was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um;mobile phase: [water( NH ₄ HCO ₃ )-ACN];B%: 30%-60%, 12 min) to give (S)-N-((S)- 1 -(((S)- 1 -cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)ethyl)amino) - 3-cyclopropyl-1-oxopropan-2-yl)-3,3-dimethyl-2-(2,2,2-triflu oroacetamido)butanamide (40.23 mg, 77.08 umol, 13.13% yield, 96.1% purity) as white solid. MS (ESI) m/z 502.2 [M+H] ⁺ .

[0001983] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.16 - 9.03 (m, 1H), 8.98 - 8.85 (m, 1H), 8.41 - 8.30 (m, 1H), 7.94 - 7.80 (m, 1H), 5.00 - 4.82 (m, 1H), 4.47 - 4.37 (m, 1H), 4.28 - 4.20 (m, 1H), 2.22 - 2.11 (m, 1H), 2.02 - 1.93 (m, 1H), 1.80 - 1.62 (m, 2H), 1.54 (dd,J= 10.1, 12.3 Hz, 1H), 1.39 - 1.28 (m, 1H), 1.25 - 1.20 (m, 1H), 1.20 - 1.16 (m, 3H), 1.10 (s, 3H), 0.93 (s, 9H), 0.76 - 0.62 (m, 1H), 0.46 - 0.29 (m, 2H), 0.17 - 0.01 (m, 2H)

Example 236. Synthesis of viral protease inhibitor compound 3071a

[0001984] Step 1: methyl (2S)-2-[[6-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]-6-azaspiro[3.4] octane-7-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]propanoate

[0001985] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3, 3-dimethyl-butanoic acid (206.60 mg, 893.27 umol, 1.1 eq) and methyl (2S)-2-(6-azaspiro[3.4]octane-7- carbonylamino)-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]pr opanoate (350 mg, 812.06 umol, 90% purity, 1 eq, HCI) in DCM (10 mL) was added DMAP (297.63 mg, 2.44 mmol, 3 eq) and EDCI (311.35 mg, 1.62 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O 20 mL and extracted with DCM 45 mL (15 mL * 3). The combined organic layers were washed with brine 20 mL (20 mL * 1), dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1 to 0/1) to give methyl (2S)-2-[[6-[(2S)-2- (tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6-azaspiro [3.4]octane-7- carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]p ropanoate (300 mg, 494.06 umol, 60.84% yield, 93% purity) as a white solid. MS (ESI) m/z 565.3 [M+H] ⁺ [0001986] Step2: tert-butyl N-[(1S)-1-[7-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2- oxo-ethyl]carbamoyl]-6-azaspiro[3.4]octane-6-carbonyl]-2,2- dimethyl-propyl]carbamate

[0001987] A solution of methyl (2S)-2-[[6-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-6-azaspiro[3.4]octane-7-carbonyl]amino]-3 -[(3R)-5,5-dimethyl-2- oxo-pyrrolidin-3-yl]propanoate (300 mg, 531.24 umol, 1 eq) in NH ₃ /MeOH (7 M, 15.00 mL, 197.65 eq) was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl N-[(1S)-1-[7-[[(1S)-2-amino-1- [[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethy l]carbamoyl]-6- azaspiro[3.4]octane-6-carbonyl]-2,2-dimethyl-propyl]carbamat e (290 mg, crude) as a white solid. MS (ESI) m/z 550.3 [M+H] ⁺

[0001988] Step 3: 6-[(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-azaspiro[3.4]octane-7 - carboxamide

[0001989] A mixture of tert-butyl N-[(1S)-1-[7-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2- oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]carbamoyl]-6-azaspir o[3.4]octane-6-carbonyl]- 2,2-dimethyl-propyl]carbamate (200 mg, 338.37 umol, 93% purity, 1 eq) in HCl/EtOAc (4 M, 4.65 mL, 54.97 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 6-[(2S)-2-amino-3,3-dimethyl- butanoyl]-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrol idin-3-yl]methyl]-2-oxo- ethyl]-6-azaspiro[3.4]octane-7-carboxamide (176 mg, crude, HC1) as a yellow solid.

[0001990] Step 4: N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl] methyl]- 2-oxo-ethyl]-6-[(2S)-3,3 -dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6- azaspiro[34]octane-7-carboxamide

[0001991 ] A mixture of 6-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[(1S)-2-amino-1- [[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethy l]-6-azaspiro[3.4]octane-7- carboxamide (120 mg, 246.89 umol, 1 eq, HC1) in DCM (2 mL) was added DIPEA (95.73 mg, 740.67 umol, 129.01 uL, 3 eq) and TFAA (103.71 mg, 493.78 umol, 68.68 uL, 2 eq) at 0 °C, the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched by addition NaHCOs 4 mL at 25 °C, and extracted with DCM 6 mL (2 mL * 3). The combined organic layers were washed with brine 6 mL (3 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give N-[( 1 S)-2-amino- 1 - [[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethy l]-6-[(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6-azaspiro[3 4]octane-7-carboxamide (130 mg, crude) as a yellow solid. MS (ESI) m/z 546.3 [M+H] ⁺

[0001992] Step 5: N-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]e thyl]-6- [(2S)-3,3-dimethyl-2- [(2,2,2-trifluoroacetyl)amino]butanoyl]-6-azaspiro[3.4]octan e-7- carboxamide

[0001993] A mixture ofN-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]ethyl]-6-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)ami no]butanoyl]-6- azaspiro[3.4]octane-7-carboxamide (180 mg, 170.59 umol, 50% purity, 1 eq) in DCM (5 mL) was added Burgess reagent (121.96 mg, 511.77 umol, 3 eq), the mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition;column: Waters Xbridge BEH C18 100*30mm* 10um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 35%-65%,8min) to give desired product (50 mg) as a white solid, which was further separated by SFC (condition: column: REGIS(S,S)WHELK-01(250mm*25mm,10um);mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 35%-35%,15min) to give N-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]ethyl]-6-[(2S)-3,3-dimethyl-2-[(2,2,2-triflu oroacetyl)amino]butanoyl]-6- azaspiro[3.4]octane-7-carboxamide ( Isomer 1, 20 mg, 37.53 umol, 22.00% yield, 99% purity) as a white solid. MS (ESI) m/z 528.2 [M+H] ⁺

[0001994] NMR (400 MHz, DMSO-d ₆ ) δ = 9.36 - 9.14 (m, 1H), 8.83 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 4.98 - 4.84 (m, 1H), 4.51 (s, 1H), 4.18 (t, J = 8.0 Hz, 1H), 3.87 (d, J = 9.9 Hz, 1H), 3.49 (d, J = 10.1 Hz, 1H), 2.62 - 2.56 (m, 1H), 2.29 - 2.09 (m, 2H), 2.06 - 1.80 (m, 7H), 1.77 - 1.67 (m, 2H), 1.58 - 1.50 (m, 1H), 1.20 - 1.06 (m, 6H), 1.05 - 0.87 (m, 9H) [0001995] To give N-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]e thyl]-6- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6-azaspiro[3.4]octane-7- carboxamide (Isomer 2, 20 mg, 37.30 umol, 21.87% yield, 98.4% purity) as a white solid. MS (ESI) m/z 528.2 [M+H] ⁺

[0001996] ¹ H NMR (400 MHz, DMSO-d6) δ = 9.54 - 9.35 (m, 1H), 8.56 (d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 5.04 - 4.87 (m, 1H), 4.67 (br d, J = 8.2 Hz, 1H), 4.19 (t, J = 7.4 Hz, 1H), 3.83 (d, J = 10.4 Hz, 1H), 3.60 (d, J = 10.1 Hz, 1H), 2.52 (br s, 1H), 2.25 (dd, J = 8.3, 12.5 Hz, 1H), 2.10 - 1.68 (m, 10H), 1.58 - 1.44 (m, 1H), 1.23 - 1.08 (m, 6H), 0.97 (s,

9H).

Example 237. Synthesis of viral protease inhibitor compound 3039a

[0001997] Step 1: methyl 6-azaspiro[3.4]octane-7-carboxylate

[0001998 ] 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, HCI) was obtained as a brown solid. The crude product was used directly in next step. [0001999] Step 2: methyl 6-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]- 6- azaspiro[34]octane-7-carboxylate

[0002000] To a solution of methyl 6-azaspiro[3 ,4]octane-7-carboxylate (240 mg, 1.17 mmol, 1 eq, HC1) 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 HC1 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , 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]o ctane-7-carboxylate (300 mg, 784.33 umol, 67.22% yield, assumed 100% purity) as a colorless oil.

[0002001] Step 3: 6-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]- 6- azaspiro[34]octane-7-carboxylic acid

[0002002] 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 H ₂ O (0.5 mL) was added LiOH.H ₂ O (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 H ₂ O 20 mL. Then seperated the aquire phase adjusted pH=l by 1 M HC1 and extracted with EtOAc 15 mL (5 mL * 3). The combined organic layers were washed with sat. NaHCO3 5 mL, dried over Na ₂ SO ₄ , 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.

[0002003] Step 4: tert-butyl N-[(l S)-1-[7-[[(l S)-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 [0002004] To a solution of 6-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]- 6-azaspiro[3.4]octane-7-carboxylic acid (210 mg, 569.93 umol, 1 eq) and (2S)-2-amino- 3-[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]propanamide (112.41 mg, 569.93 umol, 1 eq) in DMF (2 mL) was added PyBOP (296.59 mg, 569.93 umol, 1 eq) and TEA (115.34 mg, 1.14 mmol, 158.66 uL, 2 eq) in DMF (1 mL) at -20 °C. Then the reaction was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O 20 mL and extracted with EtOAc 30 mL (10 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 50/1 to 0/1, 10% MeOH) give the compound of tert-butyl N-[(l S)-1-[7-[[(l S)-2-amino-2-oxo-1- [[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yllmethyllethyllcarbamo yll-6-azaspiro[3.4]octane- 6-carbonyl]-2,2-dimethyl-propyl]carbamate (175 mg, 319.53 umol, 56.06% yield, assumed 100% purity) was obtained as a white oil.

[0002005] Step 5: 6-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[( 1 S)-2-amino-2-oxo- 1 - [[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]methyl]ethyl]-6-azas piro[3.4]octane-7- carboxamide

[0002006] To a solution of tert-butyl N-[(l S)-1-[7-[[(l S)-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, 2HC1) as a white solid. The crude product was used directly in next step.

[0002007] Step 6: N-[( 1 S)-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-trifluoroace tyl)amino]butanoyl]-6- azaspiro[34]octane-7-carboxamide

[0002008] 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, 2HC1) 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 H ₂ O 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 Na ₂ SO ₄ , 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]octan e-7-carboxamide (110 mg, crude) as brown solid. The crude product was used directly in next step.

[0002009] Step 7: N-[(1S)-1-cyano-2-[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]eth yl]-6- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6-azaspiro[3.4]octane-7- carboxamide

[0002010] To a solution ofN-[(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-trifluoroa cetyl)amino]butanoyl]-6- azaspiro[3.4]octane-7-carboxamide (110 mg, 202.36 umol, 1 eq) in DCM (5 mL) was added BURGESS REAGENT (106.09 mg, 445.20 umol, 2.2 eq). Then the reaction was stirred at 25 °C for 16 h. Upon completion, the reaction was blow-dried by N ₂ . The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water( NH ₄ HCO ₃ )-ACN];B%: 35%-55%,8min), and prep-HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [water(FA)- ACN];B%: 45%-75%,8min) to give N-[(1S)-1-cyano-2-[(6R)-5-oxo-4- azaspiro[2.4]heptan-6-yl]ethyl]-6-[(2S)-3,3-dimethyl-2-[(2,2 ,2- trifluoroacetyl)amino]butanoyl]-6-azaspiro[3.4]octane-7-carb oxamide (Isomer 1, 10 mg, 18.63 umol, 9.21% yield, 97.9% purity) as white solid. MS (ESI) m/z 526.1 [M+H] ⁺ .

[0002011 ] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.41 (br d, J = 9.0 Hz, 1H), 8.56 (d, J = 8.3

Hz, 1H), 7.83 (s, 1H), 5.03 - 4.80 (m, 1H), 4.67 (d, J = 8.8 Hz, 1H), 4.19 (t, J = 7.3 Hz, 1H), 3.83 (d, J = 10.3 Hz, 1H), 3.61 (d, J = 10.3 Hz, 1H), 2.58 - 2.52 (m, 1H), 2.25 (dd, J = 8.3, 12.5 Hz, 1H), 2.11 - 1.92 (m, 5H), 1.91 - 1.75 (m, 6H), 0.97 (s, 9H), 0.79 - 0.69 (m, 1H), 0.63 - 0.48 (m, 3H). [0002012] To give N-[(1S)-1-cyano-2-[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]eth yl]-6- [(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl] -6-azaspiro[3.4]octane-7- carboxamide (Isomer 2, 20 mg, 34.40 umol, 17.00% yield, 90.4% purity) as white solid. MS (ESI) m/z 526.2 [M+H] ⁺ .

[0002013] ¹ H NMR (400 MHz, DMSO-d6) δ = 9.35 (br d, J = 7.1 Hz, 1H), 8.89 (d, J = 8.7 Hz, 1H), 7.73 (s, 1H), 5.04 - 4.82 (m, 1H), 4.52 (br d, J = 5.9 Hz, 1H), 4.18 (t, J = 8.1 Hz, 1H), 3.88 (d, J = 9.9 Hz, 1H), 3.49 (d, J = 10.0 Hz, 1H), 2.76 - 2.68 (m, 1H), 2.28 - 2.15 (m, 2H), 2.05 - 1.92 (m, 4H), 1.86 (br d, J = 2.8 Hz, 4H), 1.80 - 1.65 (m, 2H), 1.00 (s, 9H), 0.79 - 0.67 (m, 1H), 0.63 - 0.47 (m, 3H).

Example 238. Synthesis of viral protease inhibitor compound 3133

[0002014] Step 1: tert-butyl ((S)-l -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2- yl)carbamate

[0002015] A mixture of methyl (2 S)-2-(tert-butoxy carbonyl amino)-3 -[(3 S)-2-oxo-3 - piperidyl]propanoate (5 g, 16.65 mmol, 1 eq) in NH ₃ /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-[( 1 S)-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] ⁺

[0002016] Step 2: (S)-2-amino-3-((S)-2-oxopiperidin-3-yl)propanamide

[0002017] A mixture of tert-butyl N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-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] ⁺

[0002018] Step 3: methyl ((4-(tert-butyl)phenyl)(2-((4,4-difluorocyclohexyl)amino)-1- (5- fluoropyridin-3-yl)-2-oxoethyl)carbamoyl)-L-prolinate

[0002019] To a solution of (2S)-2-amino-3-[(3 S)-2-oxo-3-piperidyl]propanamide (0.5 g, 2.26 mmol, 1 eq, HC1) and ( 1 R,2 S, 5 S)-3 -[(2 S)-2-(tert-butoxy carbony lamino)-3 ,3 - dimethyl -butanoyl]-6,6-dimethyl-3-azabicyclo[3.1 0]hexane-2-carboxylic acid (831.06 mg, 2.26 mmol, 1 eq) in DMF (10 mL) was added PyBOP (1.29 g, 2.48 mmol, 1.1 eq) and then added Et3N (456.46 mg, 4.51 mmol, 627.86 uL, 2 eq). The mixture was stirred at -30 °C for 2 h. Upon completion, the combined reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (40 mL * 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate/MeOH = 20/1/0 to 0/0/1) to give tert-butyl N-[( 1 S)- 1 -[( 1 R,2 S, 5 S)-2-[[( 1 S)-2- amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoy l]-6,6-dimethyl-3- azabicyclo[3.1 0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (290 mg, 541.37 umol, 24.00% yield) as a light yellow solid. MS (ESI) m/z 436.2 [M-100+H] ⁺ [0002020] Step 4: ( 1 R,2S, 5 S)-N-((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2- yl)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azab icyclo[3.1 0]hexane-2- carboxamide

[0002021 ] A mixture of tert-butyl N-[(l S)-1-[(lR,2S,5S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)- 2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-6,6-dimethyl-3-aza bicyclo[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 (lR,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-azabic yclo[3.1.0]hexane-2- carboxamide (300 mg, crude, HC1) was obtained as a yellow solid and used directly next step.

[0002022] Step 5: (lR,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)p ropan-2- yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl )-6,6-dimethyl-3- azabicyclo[3.1 0]hexane-2-carboxamide

[0002023] To a solution of (lR,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-N-[(l S)-2- amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-6,6-dim ethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide (0.2 g, 423.71 umol, 1 eq, HC1) in DCM (10 mL) was added DIEA (164.29 mg, 1.27 mmol, 221.41 uL, 3 eq) and TFAA (102.34 mg,

487.27 umol, 67.78 uL, 1.15 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. Upon completion, the combined reaction mixture was poured into aq. NaHCO ₃ (20 mL) and extracted with DCM (10 mL * 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (lR,2S,5S)-N-[(1S)-2-amino-2- oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-[(2S)-3,3-dim ethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1 0]hexane-2-carboxamide (294 mg, crude) as a yellow solid which was used directly next step. MS (ESI) m/z 532.2 [M+H] ⁺ [0002024] Step 6: (lR,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]- 3-[(2S)- 3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-d imethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide

[0002025] To a solution of ( 1 R,2S,5 S)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3 - piperidyl]methyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifl uoroacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1 0]hexane-2-carboxamide (194 mg, 364.96 umol, 1 eq) in DCM (10 mL) was added methoxycarbonyl-(triethylammonio)sulfonyl-azanide (260.91 mg, 1.09 mmol, 3 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by water (0.5 mL) at 20 °C, and the system was blow- dried with N ₂ to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250 * 50 mm * lOum; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30% - 50%, 10 min) to give (lR,2S,5S)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroace tyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1 0]hexane-2-carboxamide (60.22 mg, 117.26 umol, 32.13% yield, 100% purity) as a white solid. MS (ESI) m/z 514.2 [M+H] ⁺

[0002026] ¹ H NMR (400MHZ, DMSO-d ₆ ) δ = 9.41 (br d,J= 7.2 Hz, 1H), 8.99 (d, J= 8.3 Hz, 1H), 7.51 (s, 1H), 5.01 (ddd, J= 5.9, 8.4, 10.2 Hz, 1H), 4.44 - 4.38 (m, 1H), 4.16 (s, 1H), 3.90 (dd, J= 5.5, 10.3 Hz, 1H), 3.68 (d, J= 10.5 Hz, 1H), 3.12 - 3.05 (m, 2H), 2.37 - 2.19 (m, 2H), 1.85 (br dd,J= 3.7, 12.7 Hz, 1H), 1.79 - 1.66 (m, 2H), 1.60 - 1.52 (m, 2H), 1.43 - 1.33 (m, 1H), 1.29 (d,J= 7.7 Hz, 1H), 1.02 (s, 3H), 0.99 (s, 9H), 0.84 (s, 3H).

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

Step 1 : (S)-methyl 2-(((benzyloxy)carbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)pr opanoate [0001] To a solution of methyl (2 S)-2-amino-3 -[(3 S)-2-oxo-3 -piperidy 1 ]propanoate (10 g, 38.02 mmol, 90% purity, 1 eq, HC1) in IPA (100 mL) was added a solution of pH=l 1 of NaOH (4 M, 10.00 mL, 1.05 eq) and NaHCOs (194.40 g, 2.31 mol, 90.00 mL, 60.86 eq) at 0 °C. Then benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (10.42 g,

41.83 mmol, 1.1 eq) was added. The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was poured into H ₂ O 100 mL at 20 °C, and then extracted with EtOAc (lOOmL * 3). The combined organic layers were washed with brine (100 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=80/l to 30/1) to give methyl (2S)-2- (benzyloxycarbonylamino)-3-[(3S)-2-oxo-3-piperidyl]propanoat e (10.5 g, 31.40 mmol, 82.59% yield) as a yellow oil.

Step 2: benzyl ((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)ca rbamate [0002] A solution of methyl (2S)-2-(benzyloxycarbonylamino)-3-[(3S)-2-oxo-3- piperidyl]propanoate (10 g, 14.95 mmol, 1 eq) in NH ₃ /MeOH (7 M, 50 mL, 23.41 eq) was stirred at 65 °C for 48 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove MeOH to give benzyl N-[(1S)-2-amino-2-oxo-1- [[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamate (9.55 g, crude) as a yellow solid.

Step 3: benzyl ((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)carbamate

[0003] To a solution of benzyl N-[(l S)-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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=l/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.

Step 4: (S)-2-amino-3-((S)-2-oxopiperidin-3-yl)propanenitrile [0004] To a solution of benzyl N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]carbamate (300 mg, 995.55 umol, 1 eq) in IPA (6 mL) was added Pd(OH)2 (699.05 mg, 995.55 umol, 20% purity, 1 eq). The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM/MeOH=l/0 to 80/1) to give (2S)-2-amino-3-[(3S)-2- oxo-3-piperidyl]propanenitrile (147 mg, 820.24 umol, 82.39% yield, 93.3% purity) as a white solid. MS (ESI) m/z 168.1 [M+H] ⁺ . ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 4.11 (t, J = 7.9 Hz, 1H), 3.30 - 3.23 (m, 2H), 2.56 - 2.45 (m, 1H), 2.27 - 2.15 (m, 1H), 2.03 (d, J = 3.0, 6.3, 12.9 Hz, 1H), 1.92 - 1.84 (m, 1H), 1.81 - 1.70 (m, 2H), 1.64 - 1.51 (m, 1H).

Example 240. Synthesis of viral protease inhibitor compound 247

Step 1: (S)-2-amino-3-(lH-indol-3-yl)propanamide

[0005] A solution of methyl (2S)-2-amino-3-(lH-indol-3-yl)propanoate (20 g, 78.52 mmol, 1 eq, HCI) in NH ₃ /MeOH (7 M, 200.00 mL, 17.83 eq) was stirred at 80 °C for 38 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (S)-2-amino-3-(lH-indol-3-yl)propanamide (17 g, crude) as a yellow solid. MS (ESI) m/z 204.1 [M+H] ⁺ .

Step 2: (2S)-2-amino-3-(2-oxoindolin-3-yl)propanamide

[0006] To a mixture of (2S)-2-amino-3-(lH-indol-3-yl)propanamide (17 g, 83.64 mmol, 1 eq) in AcOH (170 mL) was slowly added a mixture of HC1 (12 M, 27.88 mL, 4 eq) and DMSO (9.80 g, 125.47 mmol, 9.80 mL, 1.5 eq), and then the mixture was stirred at 20 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove HC1 and AcOH, then was quenched by addition NH3.H ₂ O until adjust to pH>8 at 20 °C. The residue was purified by prep-HPLC (column: Xtimate C18 lOu 250 mm* 80 mm; mobile phase:

[water(0.05%NH ₃ H ₂ 0+ 10 mM NH ₄ HCO ₃ )-ACN]; B%: 0%-20%, 30 min) to give (2S)-2-amino-3-(2-oxoindolin-3-yl)propanamide (3.0 g, 10.95 mmol, 13.09% yield, 80% purity) as yellow solid. MS (ESI) m/z 220.2 [M+H] ⁺ .

Step 3: 4-methoxy- 1 H-indole-2-carbonyl chloride

[0007] To a mixture of 4-methoxy- 1 H-indole-2-carboxylic acid (10 g, 52.31 mmol, 1 eq) in DCM (100 mL) was added (COCl)z (26.56 g, 209.22 mmol, 18.31 mL, 4 eq) and DMF (191.16 mg, 2.62 mmol, 201.22 uL, 0.05 eq), then was stirred at 40 °C for 5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give 4-methoxy- 1 H-indole-2-carbonyl chloride (11 g, crude) as brown solid.

Step 4: (S)-3-cyclopropyl-2-(4-methoxy-lH-indole-2-carboxamido)propa noic acid [0008] To a mixture of (2S)-2-amino-3-cyclopropyl-propanoic acid (9.49 g, 73.46 mmol, 1.4 eq) in DCM (100 mL) and sat.NazCO ₃ (50 mL) was drop wise added a solution of 4-methoxy- lH-indole-2-carbonyl chloride (11 g, 52.47 mmol, 1 eq) in DCM (100 mL) at 25 °C. Then the mixture was stirred at 25 °C for 0.5 h. The reaction mixture was adjusted with 1 N HC1 to pH=l, then extracted with DCM (50 mL* 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and puri fired with prep-HPLC(column : Phenomenex luna C18 (250* 70 mm, 15 um); mobile phase: [water(0.05%HC1)-ACN] ; B%: 23%-53%, 27 min) to give (S)-3-cyclopropyl-2-(4-methoxy-lH-indole-2-carboxamido)propa noic acid (8.0 g, 23.82 mmol, 45.39% yield, 90% purity) as yellow solid. MS (ESI) m/z 303.1 [M+H] ⁺ . Step 5 : N-( 1 -(((2S)-1 -amino- 1 -oxo-3-(2-oxoindolin-3-yl)propan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[0009] To a solution of (2S)-2-amino-3-(2-oxoindolin-3-yl)propanamide (2 g, 7.30 mmol, 80% purity, 1 eq) in DCM (20 mL) and DMF (5 mL) was added (2S)-3- cyclopropyl-2-[(4-methoxy-lH-indole-2-carbonyl)amino]propano ic acid (2.75 g, 7.30 mmol, 90% purity, 1 eq, HC1), DIEA (1.89 g, 14.60 mmol, 2.54 mL, 2 eq), HOBt (1.97 g, 14.60 mmol, 2 eq), and then EDCI (2.80 g, 14.60 mmol, 2 eq) at 0 °C. The mixture was then stirred at 20 °C for 2 h. The reaction mixture was quenched by addition H ₂ O (1 mL) at 20 °C, then concentrated under reduced pressure and purified by prep-HPLC (column: Phenomenex luna C18 (250* 70 mm, 15 um); mobile phase: [water(0.05% HC1)-ACN]; B%: 22%-52%, 27 min) to give N-(l-(((2S)-1-amino-1- oxo-3-(2-oxoindolin-3-yl)propan-2-yl)amino)-3-cyclopropyl-1- oxopropan-2-yl)-4- methoxy- 1 H-indole-2-carboxamide (2.5 g, 4.87 mmol, 66.67% yield, 98% purity) as yellow solid. MS (ESI) m/z 504.2 [M+H] ⁺ .

Step 6: N-( 1 -((( 1 S)- 1 -cyano-2-(2-oxoindolin-3-yl)ethyl)amino)-3-cyclopropyl- 1 -oxopropan- 2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[00010] To a mixture of N-( 1 -(((2S)- 1 -amino- 1 -oxo-3 -(2-oxoindolin-3-yl)propan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-methoxy-lH-indol e-2-carboxamide (2.5 g, 4.87 mmol, 98% purity, 1 eq) in DCM (25 mL) was added Burgess reagent (3.48 g, 14.60 mmol, 3 eq) and stirred at 20 °C for 2 h. Then was added Burgess reagent (3.48 g, 14.60 mmol, 3 eq) and stirred at 20 °C for 2 h. The reaction mixture was quenched by addition H ₂ O (2.5 mL) at 20 °C, then concentrated under reduced pressure (<30°C) and purified by prep-HPLC (column: Agela DuraShell C18250* 70 mm* 10 um; mobile phase: [ water(0.225%F A)- ACN] ; B%: 30%-60%, 20 min) to give N-( 1 -((( 1 S)- 1 -cy ano-2-(2-oxoindolin-3-yl)ethyl)amino)-3-cy clopropyl- 1 - oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide (800 mg, 1.59 mmol, 32.65% yield, 96.4% purity) as white solid. MS (ESI) m/z 486.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.55 (br d, J = 11.0 Hz, 1H), 10.52 (br d, J = 18.5 Hz, 1H),

9.13 - 8.94 (m, 1H), 8.51 (br d, J = 6.9 Hz, 1H), 7.36 (br s, 1H), 7.33 - 7.24 (m, 1H), 7.22 - 7.15 (m, 1H), 7.13 - 7.05 (m, 1H), 7.02 - 6.91 (m, 2H), 6.84 (br t, J = 6.1 Hz, 1H), 6.50 (br d, J = 7.0 Hz, 1H), 5.32 - 5.02 (m, 1H), 4.59 - 4.40 (m, 1H), 3.88 (br s, 3H), 3.52 - 3.46 (m, 1H), 2.41 - 2.15 (m, 2H), 1.90 - 1.67 (m, 1H), 1.64 - 1.35 (m, 1H), 0.91 - 0.70 (m, 1H), 0.53 - 0.31 (m, 2H), 0.27 - 0.00 (m, 2H)

Example 241. Synthesis of viral protease inhibitor compound 689

Step 1: (S)-methyl 2-((S)-3-cyclopropyl-2-(4-methoxy-lH-indole-2- carboxamido)propanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin -3-yl)propanoate

[00011] A solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (150 mg, 460.97 umol, 1 eq), 4- methoxy- 1 H-indole-2-carboxylic acid (105.76 mg, 553.16 umol, 1.2 eq) in DCM (5 mL) was added DMAP (112.63 mg, 921.94 umol, 2 eq) and EDCI (132.55 mg,

691.45 umol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 10 mL, and then extracted with DCM (10 mL * 3). The combined organic layers were washed with brine 15 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give methyl (2S)-2- [[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2-carbonyl)amin o]propanoyl]amino]- 3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (125 mg, 248.21 umol, 53.85% yield, 99% purity) as yellow oil. MS (ESI) m/z 499.2 [M+H] ⁺ .

Step 2 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-methoxy-lH-indol e-2-carboxamide

[00012] A solution of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-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 NfhMeOH (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 NH ₃ MeOH. 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-lH-indole-2-carbo xamide (105 mg, crude) as a white solid. MS (ESI) m/z 484.2 [M+H] ⁺ .

Step 3 : N-((S)- 1 -(((S)- 1 -cyano-2-((R)-5, 5-dimethyl -2-oxopyrrolidin-3-yl)ethyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[00013] To a solution of N-[(1S)-2-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmet hyl)-2-oxo-ethyl]-4- methoxy- 1 H-indole-2-carboxamide (105 mg, 217.14 umol, 1 eq) in DCM (5 mL) was added Burgess reagent (113.84 mg, 477.71 umol, 2.2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the DCM was removed under N ₂ . The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 30 mm * 10 um; mobile phase: [water (10 mM NH4HCO3)- ACN] ; 35%-65%, 10 min) to give N-[(1S)- 2-[[( 1 S)- 1 -cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]ethyl]amin o]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide (26 mg,

55.85 umol, 25.72% yield, 100% purity) as a white solid. MS (ESI) m/z 466.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.55 (s, 1H), 8.91 (d, J = 8.2 Hz, 1H), 8.51 (br d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.36 (d, J = 1.3 Hz, 1H), 7.13 - 7.06 (m, 1H), 7.03 - 6.98 (m, 1H), 6.50 (d, J = 7.7 Hz, 1H), 5.00 - 4.92 (m, 1H), 4.49 - 4.41 (m, 1H), 3.88 (s, 3H), 2.64 - 2.55 (m, 1H), 2.22 - 2.13 (m, 1H), 1.99 (dd, J = 8.5, 12.3 Hz, 1H), 1.89 - 1.70 (m, 2H), 1.57 - 1.42 (m, 2H), 1.19 - 1.03 (m, 6H), 0.80 (br dd, J = 6.0, 7.3 Hz, 1H), 0.47 - 0.33 (m, 2H), 0.25 - 0.03 (m, 2H)

Example 242. Synthesis of viral protease inhibitor compound 731

Step 1: tert-butyl 3-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2- yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylate

[00014] To a mixture of 2-tert-butoxycarbonyl-2-azaspiro[4.5]decane-3-carboxylic acid (200 mg, 564.65 umol, 80% purity, 1 eq) in DCM (3 mL) was added methyl (2S)-2- amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (133.65 mg, 564.65 umol, 1 eq, HC1), DMAP (206.95 mg, 1.69 mmol, 3 eq) and EDCI (216.49 mg, 1.13 mmol, 2 eq) at 0 °C, then stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by the addition of water (3 mL), and then was extracted with DCM (3 mL * 3). The combined organic layers were washed with HC1 (1M, 3 mL), then washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10:1) to afford tert-butyl 3-(((S)- 1 -methoxy- 1 -oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylat e (200 mg, 429.57 umol, 76.08% yield) as yellow solid. MS (ESI) m/z 466.2 [M+H] ⁺ .

Step 2: (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2-azaspiro[4.5]decane-3- carboxamido)propanoate [00015] A mixture of (tert-butyl 3 -(((S)- 1 -methoxy- 1 -oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylat e(200 mg, 386.61 umol, 90% purity, 1 eq) in HCl/MeOH (4 M, 2.67 mL, 27.59 eq) at 0 °C was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2- azaspiro[4.5]decane-3-carboxamido)propanoate (170 mg, crude, HC1) as yellow solid. MS (ESI) m/z 366.1 [M+H] ⁺ .

Step 3: (2S)-methyl 2-(2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3 - carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[00016] To a mixture of methyl (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2- azaspiro[4.5]decane-3-carboxamido)propanoate (172 mg, 427.94 umol, 1 eq, HC1) in DCM (3 mL) was added 7-chloro-lH-indole-2-carboxylic acid (83.71 mg, 427.94 umol, 1 eq), DMAP (156.84 mg, 1.28 mmol, 3 eq) and EDCI (164.07 mg, 855.88 umol, 2 eq) at 0 °C, and then the resulting mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by the addition of water (3 mL), and then extracted with DCM (3 mL * 3). The combined organic layers were washed with HC1 (1M, 3 mL), then washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10:1) to give (2S)-methyl 2-(2-(7-chloro-lH-indole- 2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamido)-3-((S)-2-ox opiperidin-3- yl)propanoate (100 mg, 178.80 umol, 41.78% yield, 97.1% purity) as yellow solid.

MS (ESI) m/z 543.2 [M+H] ⁺ .

Step 4 : N-((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-2-(7-chloro- 1 H- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide

[00017] To a mixture of methyl (2S)-2-[[2-(7-chloro-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3 S)-2-oxo-3-piperidyl]propanoate ( 100 mg, 184.14 umol, 1 eq) was added NH ₃ /MeOH (7 M, 3 mL, 114.04 eq), and then the resulting mixture was stirred at 65 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-amino-2-oxo-1-[[(3S)-2- oxo-3-piperidyl]methyl]ethyl]-2-(7-chloro-lH-indole-2-carbon yl)-2- azaspiro[4.5]decane-3-carboxamide (90 mg, crude) as yellow solid. MS (ESI) m/z 528.2 [M+H] ⁺

Step 5: 2-(7-chloro-lH-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-ox opiperidin-3-yl)ethyl)- 2-azaspiro[4.5]decane-3-carboxamide

[00018] To a mixture of N-((S)- 1 -amino- 1 -oxo-3 -((S)-2-oxopiperidin-3-yl)propan-2-yl)- 2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-ca rboxamide (80 mg, 151.50 umol, 1 eq) in DCM (3 mL) was added Burgess reagent (72.21 mg, 303.01 umol, 2 eq) and stirred at 25 °C for 2 h. Upon completion, the mixture was quenched with water (1 mL) and concentrated under reduced pressure to give a residue (<30 °C). The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water(10mM NH4HCC>3)-ACN];B%: 35%- 65%, 8min) to give 2-(7-chloro-lH-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2- oxopiperidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide (4 mg, 7.47 umol, 4.93% yield, 95.2% purity) as white solid. MS (ESI) m/z 510.1 [M+H] ⁺ . 1H NMR (400 MHz, METHANOL-iM) δ = 7.63 (br d, J = 7.9 Hz, 1H), 7.33 - 7.21 (m, 1H), 7.20 - 6.75 (m, 2H), 5.16 - 5.05 (m, 1H), 4.73 - 4.55 (m, 1H), 3.99 - 3.83 (m, 1H),

3.72 (br d, J = 10.5 Hz, 1H), 3.28 - 2.93 (m, 2H), 2.73 - 2.39 (m, 2H), 2.39 - 2.23 (m, 1H), 2.03 (br s, 1H), 1.98 - 1.89 (m, 1H), 1.85 - 1.37 (m, 14H).

Example 243. Synthesis of viral protease inhibitor compound 818

Step 1 : (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanamid o) -3-((S)- 2-oxopiperidin-3-yl)propanoate

[00019] To a solution of methyl (2 S)-2-amino-3 -[(3 S)-2-oxo-3 -piperidy 1 ]propanoate (1 g, 3.80 mmol, 90% purity, 1 eq, HC1) and (2S)-2-(tert-butoxycarbonylamino)-4,4- dimethyl-pentanoic acid (932.77 mg, 3.80 mmol, 1 eq) in DCM (20 mL) was added DMAP (1.16 g, 9.51 mmol, 2.5 eq) and EDCI (1.46 g, 7.60 mmol, 2 eq), and then the mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O 50 mL and extracted with DCM (30 mL * 3). The combined organic layers were washed with bime 40 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum etherEthyl acetate = 1:0 to 0: 1) to give the methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pent anoyl]amino]-3-[(3S)- 2-oxo-3-piperidyl]propanoate (1.2 g, 2.81 mmol, 73.82% yield) as a white solid. MS (ESI) m/z 428.3 [M+H] ⁺ .

Step 2: (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((S)-2-oxopiperidi n-3- yl)propanoate

[00020] A mixture of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.2 g, 2.81 mmol, 1 eq) in HCI/MeOH (4 M, 20 mL, 28.50 eq) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the methyl (2S)- 2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo -3- piperidyl]propanoate (1 g, crude, HC1) as a white solid.

Step 3: 7-fluoro- 1 H-indole-2-carboxylic acid

[00021] To a solution of ethyl 7-fluoro- 1 H-indole-2-carboxylate (900 mg, 4.34 mmol, 1 eq) in THF (10 mL) and H ₂ O (5 mL) was added LiOH.H ₂ O (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 H ₂ O 60 mL at 0°C and added drop-wise 1M HC1 to pH = 5, and then extracted with ethyl acetate (40 mL * 3). The combined organic layers were washed with brine 30 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the 7-fluoro- 1 H-indole-2-carboxylic acid (700 mg, crude) as a yellow solid.

Step 4: (S)-methyl 2-((S)-2-(7-fluoro-lH-indole-2-carboxamido)-4,4-dimethylpent anamido)- 3-((S)-2-oxopiperidin-3-yl)propanoate

[00022] To a solution of 7-fluoro- 1 H-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, HC1) 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 H ₂ O 60 mL and extracted with DCM (40 mL * 3). The combined organic layers were washed with brine 50 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum etherEthyl acetate = 1:0 to 0: 1) to give the methyl (2S)-2-[[(2S)-2-[(7-fluoro-lH-indole-2-carbonyl)amino]-4,4-d imethyl- 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] ⁺

Step 5 : N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-4,4- dimethyl- 1 -oxopentan-2-yl)-7-fluoro- 1 H-indole-2-carboxamide

[00023] A mixture of methyl (2S)-2-[[(2S)-2-[(7-fluoro-lH-indole-2-carbonyl)amino]- 4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]prop anoate (0.8 g, 1.64 mmol, 1 eq) in NH ₃ /MeOH (7 M, 20 mL, 85.50 eq), the mixture was stirred at 30 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3 - piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-7-fluo ro-lH-indole-2- carboxamide (0.7 g, crude) as a white solid. MS (ESI) m/z 474.3 [M+H] ⁺

Step 6: N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amin o)-4,4-dimethyl-1- oxopentan-2-yl)-7-fluoro- 1 H-indole-2-carboxamide

[00024] To a solution of N-[(l S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-7-fluo ro-lH-indole-2- carboxamide (0.6 g, 1.27 mmol, 1 eq) in DCM (15 mL) was added Burgess reagent (452.92 mg, 1.90 mmol, 1.5 eq), and then the mixture was stirred at 40 °C for 1.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40mm * lOum; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 30% - 60%, 8 min) to give N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-7-fluoro-lH-i ndole-2-carboxamide (230 mg, 495.32 umol, 39.09% yield, 98.1% purity) as a white solid. MS (ESI) m/z 456.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.03 (s, 1H), 8.97 (d, J= 7.7 Hz, 1H), 8.59 (d ,J= 7.9 Hz, 1H), 7.54 (br s, 1H), 7.48 - 7.44 (m, 1H), 7.29 (d, J= 3.1 Hz, 1H), 7.07 - 6.97 (m, 2H), 5.09 - 5.01 (m, 1H), 4.59 - 4.51 (m, 1H), 3.11 - 3.02 (m, 2H), 2.30 - 2.18 (m, 2H), 1.87 - 1.77 (m, 2H), 1.76 - 1.64 (m, 3H), 1.59 - 1.48 (m,

1H), 1.44 - 1.34 (m, 1H), 0.94 (s, 9H).

Example 244. Synthesis of viral protease inhibitor compound 826

Step 1 : methyl (Z)-2-azido-3-(2-chloro-5-fluoro-phenyl)prop-2-enoate

[00025] 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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=l/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 2: methyl 4-chloro-7-fluoro-lH-indole-2-carboxylate

[00026] A mixture of methyl (Z)-2-azido-3-(2-chloro-5-fluoro-phenyl)prop-2-enoate (2.4 g, 9.39 mmol, 1 eq) in xylene (25 mL) was stirred at 170 °C for 1 h. Upon completion, the reaction mixture was filtered to give methyl 4-chloro-7 -fluoro- 1 H- indole-2-carboxylate (700 mg, 3.08 mmol, 32.76% yield) as a white solid.

Step 3: 4-chloro-7-fluoro-lH-indole-2-carboxylic acid [00027] A mixture of methyl 4-chloro-7-fluoro- 1 H-indole-2-carboxylate (700 mg, 3.08 mmol, 1 eq) in THF (4 mL) and H ₂ O (4 mL) was added LiOH.H ₂ O (258.08 mg, 6.15 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 HC1, extracted with EA 90 mL (30 mL * 3). The combined organic layers were washed with brine 45 mL (45 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 4-chloro-7-fluoro-lH-indole-2-carboxylic acid (600 mg, 2.81 mmol, 91.34% yield) as a white solid. (ESI) m/z 211.9 [M-H] ⁺

Step 4: methyl (2S)-2-[[(2S)-2-[(4-chloro-7-fluoro-lH-indole-2-carbonyl)ami no]-3- cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate

[00028] To a mixture of 4-chloro-7-fluoro-lH-indole-2-carboxylic acid (500 mg, 2.34 mmol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3- [(3S)-2-oxo-3-piperidyl]propanoate (895.68 mg, 2.57 mmol, 1.1 eq, HC1) in DCM (10 mL) and DMF (3 mL) was added DMAP (857.96 mg, 7.02 mmol, 3 eq) and EDCI (897.50 mg, 4.68 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 diluted with H ₂ O 30 mL and extracted with EA 60 mL (20 mL * 3). The combined organic layers were washed with brine 30 mL (30 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/l to 0/1) to give methyl (2S)- 2-[[(2S)-2-[(4-chloro-7-fluoro-lH-indole-2-carbonyl)amino]-3 -cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (l g, 1.97 mmol, 84.27% yield) as a white solid. MS (ESI) m/z 505.0 [M-H] ⁺

Step 5: N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]me thyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-chloro-7-fluoro-lH-indole -2-carboxamide [00029] A mixture of methyl (2S)-2-[[(2S)-2-[(4-chloro-7-fluoro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3- piperidyl]propanoate (1.21 g, 2.17 mmol, 91% purity, 1 eq) in NH ₃ /MeOH (7 M, 20 mL, 64.52 eq) was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-chloro-7-fluoro- 1 H-indole-2-carboxamide (850 mg, 1.38 mmol, 63.70% yield, 80% purity) as a white solid. MS (ESI) m/z 492.2 [M+H] ⁺

Step 6: 4-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-7-fluoro-lH-indole-2-carbox amide

[00030] A mixture of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-chloro-7-fluoro- lH-indole-2-carboxamide (780 mg, 1.27 mmol, 80% purity, 1 eq) in DCM (15 mL) was added Burgess reagent(604.57 mg, 2.54 mmol, 2 eq) in one portion at 25 °C. The mixture was stirred at 40 °C for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition;column: Waters Xbridge C18 150*50mm* 10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 30%-60%,10min ) to give 4-chloro-N-[(l S)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-7-fluoro-lH-indole-2-carbox amide (250 mg,

527.51 umol, 41.59% yield) as a white solid. MS (ESI) m/z 474.1 [M+H], ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.48 (br s, 1H), 8.96 (d, J=7.9 Hz, 1H), 8.79 (d, J=7.5 Hz, 1H), 7.54 (br s, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.14 - 7.02 (m, 2H), 5.07 (q, J=7.8 Hz, 1H), 4.55 - 4.44 (m, 1H), 3.17 - 3.00 (m, 2H), 2.31 - 2.20 (m, 2H), 1.91 - 1.65 (m,

4H), 1.57 (br d, J=3.7 Hz, 1H), 1.52 - 1.34 (m, 2H), 0.89 - 0.75 (m, 1H), 0.49 - 0.35 (m, 2H), 0.26 - 0.05 (m, 2H)

Example 245. Synthesis of viral protease inhibitor compound 834 & 836

Step 1 : ethyl (Z)-2-azido-3-(4-chloro-3-fluoro-phenyl)prop-2-enoate

[00031] To a solution of NaOMe (6.81 g, 126.14 mmol, 2 eq) in MeOH (70 mL) was added 4-chloro-3-fluoro-benzaldehyde (10 g, 63.07 mmol, 1 eq) and ethyl 2- azidoacetate (17.10 g, 132.44 mmol, 15.13 mL, 2.1 eq) in MeOH (100 mL) at -10 °C. Upon completion, the mixture was stirred at 20 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove MeOH. The reaction mixture was quenched by addition H ₂ O 100 mL, and extracted with ethyl acetate 100 mL (50 mL * 2). The combined organic layers were dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 10/1, Petroleum etherEthyl acetate = 5:1, (12)) to give ethyl (Z)-2-azido-3 -(4-chloro- 3 -fluoro-pheny 1 )prop-2-enoate (8.9 g, 29.70 mmol, 47.10% yield, 90% purity) as a yellow solid. MS (ESI) m/z 256.02 [M+H] ⁺

Step 2: methyl 6-chloro-7-fluoro- 1 H-indole-2-carboxylate and methyl 6-chloro-5-fluoro- 1 H- indole-2-carboxylate [00032] To a solution of ethyl (Z)-2-azido-3-(4-chloro-3-fluoro-phenyl)prop-2-enoate (4 g, 14.83 mmol, 1 eq) in xylene (40 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 (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 5/1, Petroleum etherEthyl acetate = 5:1, (UV 254 nm)) to give mixture of methyl 6-chloro-7-fluoro-lH-indole-2-carboxylate (2.85 g, 5.61 mmol, 37.82% yield, 44.8% purity) and methyl 6-chloro-5-fluoro-lH-indole- 2-carboxylate (2.85 g, 6.41 mmol, 43.22% yield, 51.2% purity) as a yellow solid. MS (ESI) m/z 228.01 [M+H] ⁺

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

[00033] To a solution of methyl 6-chloro-7-fluoro-lH-indole-2-carboxylate (1 g, 1.97 mmol, 44.8% purity, 1 eq) and methyl 6-chloro-5-fluoro-lH-indole-2-carboxylate (1 g, 2.25 mmol, 51.2% purity, 1.14 eq) in THF (10 mL) and H ₂ O (5 mL) was added LiOH.H ₂ O (247.76 mg, 5.90 mmol, 3 eq). The mixture was stirred at 60 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove THF, then the reaction mixture was addition HC1 (1 M) until pH = 3, and then extracted with EA 10 mL. The combined organic layers were washed with brine 10 mL, filtered and concentrated under reduced pressure to give 6-chloro-7-fluoro-lH- indole-2-carboxylic acid (680 mg, crude) and 6-chloro-5-fluoro-lH-indole-2- carboxylic acid (680 mg, crude) as a yellow solid. MS (ESI) m/z 214.00 [M+H] ⁺

Step 4: methyl (2S)-2-[[(2S)-2-[(6-chloro-7-fluoro-lH-indole-2-carbonyl)ami no]-3- cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate and methyl (2S)-2- [[(2S)-2-[(6-chloro-5-fluoro-lH-indole-2-carbonyl)amino]-3-c yclopropyl-propanoyl]amino]- 3-[(3S)-2-oxo-3-piperidyl]propanoate

[00034] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (l.l g, 3.16 mmol, 1 eq, HC1) and 6-chloro-7-fluoro-lH-indole-2-carboxylic acid (405.28 mg, 758.98 umol, 63.67 uL, 40% purity, 0.24 eq) and 6-chloro-5-fluoro-lH-indole-2-carboxylic acid (270.19 mg, 758.98 umol, 60% purity, 0.24 eq) in DCM (45 mL), then DMAP (1.16 g, 9.49 mmol, 3 eq) was added, and then EDCI (1.82 g, 9.49 mmol, 3 eq) was added. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 30 mL, and then extracted with DCM 40 mL (20 mL * 2). The combined organic layers were washed with HC1 (1 M) 30 mL (15 mL * 2), the combined organic layers were washed with brine 30 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 3/1 to 0/1, Dichloromethane:Methanol = 10:1,(UV 254 nm)) to give methyl (2S)-2-[[(2S)-2-[(6- chloro-7-fluoro-lH-indole-2-carbonyl)amino]-3-cyclopropyl-pr opanoyl]amino]-3- [(3 S)-2-oxo-3 -piperidyl]propanoate (850 mg, 685.76 umol, 21.68% yield, 40.9% purity) and methyl (2S)-2-[[(2S)-2-[(6-chloro-5-fluoro-lH-indole-2-carbonyl)ami no]- 3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pro panoate (850 mg, 989.24 umol, 31.28% yield, 59% purity) as a yellow solid. MS (ESI) m/z 507.17 [M+H] ⁺ .

Step 5: N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]me thyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-7-fluoro-lH-indole -2-carboxamide and N-[(1S)- 2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-5-fluoro-lH-indole -2-carboxamide [00035] A solution of methyl (2S)-2-[[(2S)-2-[(6-chloro-7-fluoro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3- piperidyl]propanoate (830 mg, 669.63 umol, 40.9% purity, 1 eq) and methyl (2S)-2- [[(2S)-2-[(6-chloro-5-fluoro-lH-indole-2-carbonyl)amino]-3-c yclopropyl- propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (830.00 mg, 965.97 umol, 59% purity, 1.44 eq) in NH ₃ /MeOH (7 M, 4.08 mL, 42.68 eq) was stirred at 65 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent and afford N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-6-chloro-7-fluoro- lH-indole-2-carboxamide (800 mg, crude) and N-[(1S)-2-[[(1S)-2-amino-2-oxo-1- [[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-6- chloro-5-fluoro- 1 H-indole-2-carboxamide (800 mg, crude) as a yellow solid. MS (ESI) m/z 492.17 [M+H] ⁺ . Step 6: 6-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-7-fluoro-lH-indole-2-carbox amide and 6-chloro-N-[(l S)- 2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-ox o- ethyl]-5-fluoro-lH-indole-2-carboxamide

[00036] 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-et hyl]-6-chloro-7-fluoro- 1 H-indole-2-carboxamide (780 mg, 635.81 umol, 40.1% purity, 1 eq) and N-[(1S)-2- [[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl ]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-5-fluoro-lH-indole -2-carboxamide (780.00 mg, 948.16 umol, 59.8% purity, 1.49 eq) in DCM (18 mL) was added with Burgess reagent (303.04 mg, 1.27 mmol, 2 eq). The mixture was stirred at 30 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um;mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN];B%: 40%- 65%,10min) to give 6-chloro-N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-7-fluoro- lH-indole-2- carboxamide (500 mg, 422.01 umol, 66.37% yield, 40% purity) and 6-chloro-N-[(1S)- 2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2- oxo-ethyl]-5-fluoro-lH-indole-2-carboxamide (500 mg, 633.01 umol, 99.56% yield, 60% purity) as a yellow solid. MS (ESI) m/z 474.16 [M+H] ⁺ .

Step 7: 6-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-7-fluoro-lH-indole-2-carbox amide and 6-chloro-N-[(l S)- 2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-ox o- ethyl]-5-fluoro-lH-indole-2-carboxamide

[00037] 6-chloro-N-[(l S)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]-l - (cyclopropylmethyl)-2-oxo-ethyl]-5-fluoro-lH-indole-2-carbox amide (500 mg) was separated by SFC column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [0.1%NH3H20 MEOH];B%: 38%-38%,6min) to give 6-chloro-N-[(1S)-2- [[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyc lopropylmethyl)-2-oxo- ethyl]-7-fluoro-lH-indole-2-carboxamide (109.43 mg, 230.21 umol, 54.55% yield, 99.7% purity) as a white solid. MS (ESI) m/z 474.16 [M+H] ⁺ . 1H NMR (400 MHz, DMSO-d ₆ ) δ = 0.04 - 0.29 (m, 2H), 0.30 - 0.52 (m, 2H), 0.71 - 0.90 (m, 1H), 1.32 - 1.63 (m, 3H), 1.65 - 1.90 (m, 4H), 2.16 - 2.37 (m, 2H), 2.97 - 3.18 (m, 2H), 4.41 - 4.55 (m, 1H), 4.97 - 5.13 (m, 1H), 7.13 (d,J= 8.56Hz, 1H), 7.34 (d, J= 3.06Hz, 1H), 7.43 - 7.58 (m, 2H), 8.65 (d ,J= 7.46Hz, 1H), 8.97 (d ,J= 7.95Hz, 1H), 12.31 (s, 1H)

Example 246. Synthesis of viral protease inhibitor compound 844

Step 1 : (Z)-methyl 2-azido-3-(4-bromo-2-methoxyphenyl)acrylate

[00038] To a solution of NaOMe (1.00 g, 18.60 mmol, 2 eq) in MeOH (10 mL) was added 4-bromo-2-methoxy-benzaldehyde (2 g, 9.30 mmol, 1 eq) and ethyl 2- azidoacetate (2.40 g, 18.60 mmol, 2.13 mL, 2 eq) in MeOH (50 mL) at 0 °C. The mixture was stirred at 20 °C for 18 h. Upon the reaction completion, the mixture was concentration in vacuum, was added with water (150 mL) and then extracted with EtOAc (50 mL * 3). The resulting mixture was concentrated in vacuum and purified by column (SiO ₂ , PE:EA =1 :0 to 10: 1) to afford (Z)-methyl 2-azido-3-(4-bromo-2- methoxyphenyl)acrylate (1.6 g, 5.13 mmol, 55.12% yield) as a yellow solid.

Step 2: methyl 6-bromo-4-methoxy- 1 H-indole-2-carboxylate

[00039] 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] ⁺

Step 3: 6-bromo-4-methoxy-lH-indole-2-carboxylic acid

[00040] 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 H ₂ O (6 mL) was added LiOH.H ₂ O (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~l with 1M HC1 (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] ⁺

Step 4: (S)-methyl2-((S)-2-(6-bromo-4-methoxy-lH-indole-2-carboxamid o)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[00041] To a solution of 6-bromo-4-methoxy-1H-indole-2-carboxylic acid (480 mg, 1.78 mmol, 1.2 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3- [(3S)-2-oxo-3-piperidyl] propanoate (461.16 mg, 1.48 mmol, 1 eq) in DMF (20 mL) was added TEA (449.60 mg, 4.44 mmol, 618.43 uL, 3 eq) and PyBop (770.73 mg,

1.48 mmol, 1 eq) in DMF (1 mL), and then the mixture was stirred at -40 °C for 2 h. Upon the reaction completion, the mixture was quenched by water (30 mL) and was extracted with DCM (10 mL * 3), then concentrated in vacuum and purified by column (SiO ₂ , PE:EA = 1 : 1 to 0: 1 to DCM:MeOH = 10: 1) to afford (S)-methyl 2-((S)- 2-(6-bromo-4-methoxy-1H-indole-2 -carboxamido)-3-cyclopropylpropanamido)-3- ((S)-2-oxopiperidin-3-yl)propanoate (800 mg, 993.90 umol, 67.11% yield, 70% purity) as a yellow gum. MS (ESI) m/z 563.2 [M-H] ⁺

Step 5 : N-((S)-1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-6-bromo-4-methoxy- 1 H-indole-2-carboxamide [00042] A solution of (S)-methyl 2-((S)-2-(6-bromo-4-methoxy-1H-indole-2 - carboxamido)-3-cyclopropylpropanamido)-3-((S)-2-oxopiperidin -3-yl) propanoate (200 mg, 354.96 umol, 1 eq) in NH ₃ /MeOH (7M, 20 mL) was stirred at 50 °C for 8 h. Upon the reaction complteion, the mixture was concentrated in vacuum to obtained N- ((S)- 1 -(((S)- 1 -amino-1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-6-bromo-4-methoxy-1H-indole-2-carboxamide (600 mg, crude) as a white solid.

Step 6: 6-bromo-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)et hyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[00043] To a solution of N-((S)- 1 -(((S)- 1 -amino-1 -oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)amino)- 3-cyclopropyl-1-oxopropan-2-yl)-6-bromo-4-methoxy-1H- indole-2-carboxamide (580 mg, 1.06 mmol, 1 eq) in DCM (8 mL) was added burgess reagent (756.07 mg, 3.17 mmol, 3 eq), and then the resulting mixture was stirred at 30 °C for 1 h. Upon the reaction completion, the mixture was quenched by water (1 mL) and was dried by blowing N ₂ and was purified by prep-HPLC (column: Waters Xbridge C18 150 * 50mm * lOum; mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 30% - 60%, 10 min) to obtained 6-bromo-N-((S)- 1 -(((S)- 1 -cy ano-2-((5)-2- oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-4-methoxy- 1 H- indole-2-carboxamide (130 mg, 227.94 umol, 21.55% yield, 93% purity) as a white solid. MS (ESI) m/z 530.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ ppm 11.72 (d, J = 1.9 Hz, 1H), 8.90 (d, J= 8.1 Hz, 1H), 8.57 (d, J= 7.5 Hz, 1H), 7.52 (s, 1H), 7.38 (d, J= 1.5 Hz, 1H), 7.19 (s, 1H), 6.66 (d ,J= 1.3 Hz, 1H), 5.06 (q, J= 8.1 Hz, 1H), 4.49 - 4.39 (m, 1H), 3.91 (s, 3H), 3.14 - 3.02 (m, 2H), 2.30 - 2.21 (m, 2H), 1.88 - 1.75 (m, 3H), 1.74 - 1.66 (m, 1H), 1.62 - 1.51 (m, 1H), 1.49 - 1.32 (m, 2H), 0.86 - 0.74 (m,

1H), 0.46 - 0.35 (m, 2H), 0.24 - 0.05 (m, 2H).

Example 247. Synthesis of viral protease inhibitor compound 846

Step 1 : (Z)-methyl 2-azido-3-(5-bromo-2-methoxyphenyl)acrylate

[00044] 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 H ₂ O 100 mL and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with solvent brine (100 mL * 2), dried over Na ₂ SO ₄ 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.

Step 2: methyl 7-bromo-4-methoxy- 1 H-indole-2-carboxylate

[00045] 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- 1 H-indole-2-carboxylate (100 mg, crude) as a yellow solid.

Step 3: 7-bromo-4-methoxy- 1 H-indole-2-carboxylic acid [00046] To a solution of methyl 7-bromo-4-methoxy-lH-indole-2-carboxylate (100 mg, 351.98 umol, 1 eq) in THF (7 mL) and H ₂ 0 (3.5 mL) was added LiOH.H ₂ O (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 HC1 was added, adjust pH to 3, then was filtered and concentrated under reduced pressure to give 7-bromo-4-methoxy- 1 H-indole-2-carboxylic acid (50 mg, crude) as a yellow solid.

Step 4: (S)-methyl 2-((S)-2-(7-bromo-4-methoxy-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[00047] To a solution of 7-bromo-4-methoxy- 1 H-indole-2-carboxylic acid (500 mg, 1.85 mmol, 1 eq), methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-[(3S) - 2-oxo-3-piperidyl]propanoate (772.74 mg, 2.22 mmol, 1.2 eq, HC1), DMAP (678.51 mg, 5.55 mmol, 3 eq) in DCM (10 mL) was added EDCI (709.80 mg, 3.70 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O 30 mL at 20 °C, and then extracted with DCM (35 mL * 3). The combined organic layers were washed with brine (35 mL *2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 50/1 to 10/1) to give methyl (2S)-2-[[(2S)-2-[(7-bromo-4-methoxy-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3- piperidyl]propanoate (460 mg, 816.41 umol, 44.10% yield) as a yellow solid.

Step 5 : 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-4-methoxy- 1 H-indole-2-carboxamide

[00048] To a solution of methyl (2S)-2-[[(2S)-2-[(7-bromo-4-methoxy-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3- piperidyl]propanoate (450 mg, 798.67 umol, 1 eq) in NH ₃ /MeOH (7 M, 18 mL, 157.76 eq). The mixture was stirred at 65 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove MeOH to give N-[(1S)- 2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-7-bromo-4-methoxy-lH-indole -2-carboxamide (430 mg, crude) as a yellow solid. MS (ESI) m/z 548.1 [M+H] ⁺ . Step 6: 7-bromo-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)et hyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[00049] 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-et hyl]-7-bromo-4- methoxy- 1 H-indole-2-carboxamide (420 mg, 765.82 umol, 1 eq) in DCM (5 mL) was added Burgess reagent (365.00 mg, 1.53 mmol, 2 eq). The mixture was stirred at 30 °C for 3 h. Upon completion, the reaction mixture was poured into H ₂ O 20 mL at 20 °C, and then extracted with DCM (25 mL * 3). The combined organic layers were washed with brine (20mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18200*40mm* 10um;mobile phase: [ water(0.2%F A)- ACN] ;B% : 30%-70%,8min) to give 7-bromo-N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4- methoxy-lH-indole-2- carboxamide (95.7 mg, 180.43 umol, 23.56% yield, 100% purity) as a white solid. MS (ESI) m/z 530.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.46 (d, J = 1 ,5Hz,

1H), 8.98 (d ,J= 7.9Hz, 1H), 8.72 (d ,J= 7.6Hz, 1H), 7.52 (s, 1H), 7.35 (d ,J= 8.2Hz, 1H), 7.28 (d,J= 2.1Hz, 1H), 6.54 (d,J= 8.3Hz, 1H), 5.07 (d,J= 7.9Hz, 1H), 4.51 (d, J= 6.2Hz, 1H), 3.89 (s, 3H), 3.17 - 3.00 (m, 2H), 2.26 (t ,J= 8.7Hz, 2H), 1.81 (dd,7 = 8.5, 14.2Hz, 4H), 1.49 (s, 3H), 0.89 - 0.73 (m, 1H), 0.52 - 0.36 (m, 2H), 0.25 - 0.04 (m, 2H).

Example 248. Synthesis of viral protease inhibitor compound 850

Step 1: 7-bromo-6-fluoro- 1 H-indole

[00050] 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 N ₂ . The reaction mixture was stirred at -40 °C for another 1.5 hr. Upon completion, the residue was poured into NH4CI aq (200 mL) under N ₂ and 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 NazS04, filtered andconcentrated in vacuum. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 10/1) to give 7- bromo-6-fluoro- 1 H-indol e (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] ⁺ .

Step 2: tert-butyl 7-bromo-6-fluoro- 1 H-indole- 1 -carboxylate

[00051] To a solution of 7-bromo-6-fluoro- 1 H-indole (2.4 g, 11.21 mmol, 1 eq) and TEA (1.36 g, 13.46 mmol, 1.87 mL, 1.2 eq) in DCM (25 mL) was added Boc ₂ O (2.69 g, 12.33 mmol, 2.83 mL, 1.1 eq) and DMAP (273.98 mg, 2.24 mmol, 0.2 eq). The mixture was stirred at 25 °C for 2 hr. Upon completion, the reaction mixture was quenched by addition H ₂ O 40 mL, and extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 10/1) to give tert-butyl 7-bromo-6-fluoro-indole- 1 -carboxylate (3 g, 8.88 mmol, 79.20% yield, 93% purity) was obtained as a yellow oil. MS (ESI) m/z 313.0 [M+H] ⁺ .

Step 3: 7-bromo-1-(tert-butoxycarbonyl)-6-fluoro-lH-indole-2-carboxy lic acid

[00052] To a solution of tert-butyl 7-bromo-6-fluoro-indole-l -carboxylate (3 g, 9.55 mmol, 1 eq) in THF (30 mL) was added LDA (2 M, 5.25 mL, 1.1 eq) drop-wise at - 60 °C under N ₂ . The reaction mixture was stirred at -60 °C for 0.5 h, then the above solution was added into drikold (21.01 g, 1.00 eq). The reaction mixture was stirred at 25 °C for another 1 hrs. Upon completion, the reaction mixture was poured into H ₂ O (80 mL) under N ₂ and stirred for 10 min. The aqueous phase was added with 1M HC1 to adjust pH~2 at 0 °C and extracted with ethyl acetate (40 mL * 3). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm, 15 um); mobile phase: [water (0.2%FA)-ACN]; B%: 40%-70%, 20 min) to give 7-bromo-1-tert-butoxycarbonyl-6-fluoro-indole-2- carboxylic acid (900 mg, 2.51 mmol, 26.31% yield, N/A purity) was obtained as a white solid.MS (ESI) m/z 357.0 [M+H] ⁺ .

Step 4: 7-bromo-6-fluoro-lH-indole-2-carboxylic acid

[00053] 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 H ₂ O (40 mL) and extracted with EtOAc (25 mL * 4). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Compound 7-bromo-6-fluoro-lH-indole-2-carboxylic acid (650 mg, crude) was obtained as a yellow solid. MS (ESI) m/z 256.9 [M+H] ⁺ .

Step 5: (S)-methyl 2-((S)-2-(7-bromo-6-fluoro-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[00054] To a solution of 7-bromo-6-fluoro-lH-indole-2-carboxylic acid (650 mg, 2.52 mmol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3- [(3S)-2-oxo-3-piperidyl]propanoate (876.18 mg, 2.52 mmol, 1 eq, HC1) in DCM (25 mL) was added DMAP (615.47 mg, 5.04 mmol, 2 eq) and EDCI (724.33 mg, 3.78 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction was quenched by H ₂ O 60 mL slowly and then extracted with DCM (30mL * 3). The combined organic phase was washed with brine (45 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 3/1 to 0/1) to afford methyl (2S)-2-[[(2S)-2-[(7-bromo-6-fluoro-lH-indole-2-carbonyl) amino]-3- cyclopropyl-propanoyl] amino]-3-[(3S)-2-oxo-3-piperidyl] propanoate (0.75 g, 1.29 mmol, 51.30% yield, 95% purity) was obtained as a yellow solid. MS (ESI) m/z 550.1 [M+H] ⁺ .

Step 6 : 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-6-fluoro- 1 H-indole-2-carboxamide

[00055] A solution of methyl (2S)-2-[[(2S)-2-[(7-bromo-6-fluoro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3- piperidyl]propanoate (800 mg, 1.45 mmol, 1 eq) in NILMeOH (7 M, 40 mL, 192.99 eq) was stirred at 65 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove DCM to give N-[(1S)-2-[[(1S)-2- amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]amino]-1 -(cyclopropylmethyl)- 2-oxo-ethyl]-7-bromo-6-fluoro-lH-indole-2-carboxamide (730 mg, crude) was obtained as a brown solid. MS (ESI) m/z 535.1 [M+H] ⁺ .

Step 7: 7-bromo-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)et hyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-6-fluoro- 1 H-indole-2-carboxamide

[00056] To a solution of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-7-bromo-6- fluoro- 1 H-indole-2-carboxamide (730 mg, 1.36 mmol, 1 eq) in DCM (15 mL) was added Burgess reagent (648.64 mg, 2.72 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under N ₂ at 25 °C. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (0.05%NH3H ₂ O+10mM NH4HCO3)- ACN]; B%: 40%-55%, 8min) to give 7 -bromo-N-[( 1 S)-2-[ [( 1 S)- 1 -cy ano-2-[(3 S)-2- oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-eth yl]-6-fluoro-lH- indole-2-carboxamide (235 mg, 453.34 umol, 33.31% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 517.1 [M+H] ⁺ . 1H NMR (400 MHz, DMSO- ck) δ = 11.72 - 11.49 (m, 1H), 9.11 - 8.90 (m, 1H), 8.55 - 8.37 (m, 1H), 7.67 - 7.49 (m, 2H), 7.06 - 6.93 (m, 1H), 6.68 - 6.60 (m, 1H), 5.17 - 5.04 (m, 1H), 4.65 - 4.55 (m, 1H), 3.17 - 3.00 (m, 2H), 2.37 - 2.19 (m, 2H), 1.94 - 1.66 (m, 4H), 1.62 - 1.32 (m,

3H), 0.84 - 0.72 (m, 1H), 0.52 - 0.37 (m, 2H), 0.21 - 0.05 (m, 2H).

Example 249. Synthesis of viral protease inhibitor compound 854

Step 1 : (Z)-ethyl 2-azido-3-(5-bromo-2-fluorophenyl)acrylate and (Z)-methyl 2-azido-3-(5- bromo-2-fluorophenyl)acrylate

[00057] 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 H ₂ O 100 mL and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine 100 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , 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 .

Step 2: ethyl 7-bromo-4-fluoro- 1 H-indole-2-carboxylate and methyl 7-bromo-4-fluoro- 1 H- indole-2-carboxylate

[00058] A mixture of ethyl (Z)-2-azido-3-(5-bromo-2-fluoro-phenyl)prop-2-enoate (1.6 g, 5.09 mmol, 1 eq) and methyl (Z)-2-azido-3-(5-bromo-2-fluoro-phenyl)prop-2- enoate (1.6 g, 5.33 mmol, 1.05 eq) in xylene (30 mL) 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 (SiO ₂ , Petroleum etherEthyl acetate = 1:0 to 100: 1) to afford ethyl 7-bromo-4-fluoro- 1 H-indole-2- carboxylate (0.35 g, 1.22 mmol, 24.02% yield) as a white solid and methyl 7-bromo- 4-fluoro- 1 H-indole-2-carboxylate (0.35 g, 1.29 mmol, 25.26% yield) as a white solid.

Step 3: 7-bromo-4-fluoro- 1 H-indole-2-carboxylic acid

[00059] To a solution of ethyl 7-bromo-4-fluoro- 1 H-indole-2-carboxylate (250 mg, 873.83 umol, 1 eq) in THF (6 mL) and H ₂ 0 (3 mL) was added LiOH.H ₂ O (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 H ₂ O 60 mL at 0 °C, 1M HC1 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to get the product 7-bromo- 4-fluoro- 1 H-indole-2-carboxylic acid (200 mg, crude) was obtained as a white solid. MS (ESI) m/z 255.9 [M-H] ⁺ .

[00060] To a solution of methyl 7-bromo-4-fluoro- 1 H-indole-2-carboxylate (350 mg, 1.29 mmol, 1 eq) in THF (6 mL) and H ₂ 0 (3 mL), then LiOH.H ₂ O (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 H ₂ O 60 mL at 0 °C and added drop- wise 1M HC1 to pH = 5, and then extracted with EtOAc (40 mL * 3). The combined organic layers were washed with brine 30 mL, dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to get the product 7 -bromo-4-fluoro- 1 H-indole- 2-carboxylic acid (300 mg, crude) was obtained as a white solid. Step 4: (S)-methyl 2-((S)-2-(7-bromo-4-fluoro-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[00061] To a solution of 7-bromo-4-fluoro- 1 H-indole-2-carboxylic acid (500 mg, 1.94 mmol, 1 eq) and methyl (2 S)-2-[ [(2 S)-2-amino-3 -cy clopropy 1-propanoy 1 ]amino]-3 - [(3 S)-2-oxo-3 -piperidyl]propanoate (876.18 mg, 2.52 mmol, 1.30 eq, HC1) in DCM (10 mL), then DMAP (710.16 mg, 5.81 mmol, 3 eq) and EDCI (742.91 mg, 3.88 mmol, 2 eq) was added, the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 60 mL at 0 °C, and then extracted with DCM (40 mL * 3). The combined organic layers were washed with brine 60 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ethenEthyl acetate = 1 :0 to 0: 1) to get the product methyl (2S)-2-[[(2S)-2-[(7-bromo-4-fluoro- lH-indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3 -[(3S)-2-oxo-3- piperidyl]propanoate (600 mg, 1.09 mmol, 56.16% yield) as a white solid. MS (ESI) m/z 551.1 [M+H] ⁺

Step 5 : 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-4-fluoro- 1 H-indole-2-carboxamide

[00062] A solution of methyl (2S)-2-[[(2S)-2-[(7-bromo-4-fluoro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo -3- piperidyl]propanoate (0.6 g, 1.09 mmol, 1 eq) in NH ₃ /MeOH (7 M, 30.00 mL, 192.99 eq) was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get 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-bromo-4- fluoro-lH-indole-2-carboxamide (550 mg, crude) was obtained as a white solid. MS (ESI) m/z 536.1 [M+H] ⁺ .

Step 6: 7-bromo-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)et hyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-4-fluoro- 1 H-indole-2-carboxamide

[00063] 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-et hyl]-7-bromo-4- fluoro-lH-indole-2-carboxamide (550 mg, 1.03 mmol, 1 eq) in DCM (20 mL) was added burgess reagent (488.70 mg, 2.05 mmol, 2 eq), and then the mixture was stirred at 40 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (lOmM NH4HCO3) - ACN]; B%: 30% - 60%, 8 min) to ge the product 7-bromo-N-[(l S)-2-[[(l S)-1-cyano- 2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-(cyclopropylmethyl) -2-oxo-ethyl]-4-fluoro- 1 H-indole-2-carboxamide (230 mg, 443.69 umol, 43.27% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 518.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.76 (br s, 1H), 9.01 (d ,J= 7.9 Hz, 1H), 8.84 (d ,J= 7.5 Hz, 1H), 7.53 (br s, 1H), 7.48 - 7.40 (m, 1H), 7.34 (s, 1H), 6.94 - 6.79 (m, 1H), 5.15 - 5.02 (m, 1H), 4.60 - 4.46 (m, 1H), 3.17 - 3.00 (m, 2H), 2.31 - 2.17 (m, 2H), 1.90 - 1.66 (m, 4H), 1.63 - 1.35 (m, 3H), 0.91 - 0.75 (m, 1H), 0.53 - 0.38 (m, 2H), 0.24 - 0.17 (m, 1H), 0.15 - 0.07 (m, 1H).

Example 250. Synthesis of viral protease inhibitor compound 858

Step 1: (S)-methyl 2-((S)-2-(4-cyano-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[00064] To a mixture of (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((S)- 2-oxopiperidin-3-yl)propanoate (1.05 g, 2.40 mmol, 80% purity, 1.1 eq, HC1) in DCM (4 mL) and DMF (1 mL) was added 4-cyano-lH-indole-2-carboxylic acid (500 mg, 2.69 mmol, 1 eq). After the addition of EDCI (1.03 g, 5.37 mmol, 2 eq) and DMAP (984.36 mg, 8.06 mmol, 3 eq) at 0 °C, the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by the addition of water (3 mL), and then extracted with DCM (3 mL * 2). The combined organic layers were washed with HC1 (1M, 3 mL), then washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , DCM:MeOH = 100: 1 to 10: 1) to give (S)-methyl 2-((S)-2-(4-cyano- lH-indole-2-carboxamido)-3-cyclopropylpropanamido)-3-((S)-2- oxopiperidin-3- yl)propanoate (750 mg, 1.49 mmol, 55.32% yield, 95% purity) as yellow solid. MS (ESI) m/z 480.1 [M+H] ⁺ .

Step 2 : N-((S)-1-(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-4-cyano- 1 H-indole-2-carboxamide

[00065] A mixture of (S)-methyl 2-((S)-2-(4-cyano- 1 H-indole-2-carboxamido)-3 - cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e (700 mg, 1 eq) in NH ₃ /MeOH (7 M, 5 mL, 745.93 eq) was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (N-((S)-1-(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3-cyclopr opyl- 1 - oxopropan-2-yl)-4-cy ano- 1 H-indole-2-carboxamide (670 mg, crude) as yellow solid. MS (ESI) m/z 465.2 [M+H] ⁺ .

Step 3 : 4-cyano-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)et hyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)- 1 H-indole-2-carboxamide

[00066] To a mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-cyano-lH- indole-2-carboxamide (670 mg, 1.37 mmol, 95% purity, 1 eq) in DCM (10 mL) was added burgess reagent (979.63 mg, 4.11 mmol, 3 eq) and stirred at 20 °C for 14 h. Upon completion, the mixture was quenched with water (1 mL) and concentrated under reduced pressure to give a residue (<30 °C). The residue was purified by prep- HPLC (column: Waters Xbridge C18 150* 50 mm* 10 um; mobile phase: [water (lOmM NH4HCO3)- ACN] ; B%: 30%-55%, 10 min) to give 4-cyano-N-((S)-1-(((S)-1- cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl- 1-oxopropan-2-yl)-lH- indole-2-carboxamide (40.4 mg, 90.48 umol, 6.60% yield, 100% purity) as off-white solid. MS (ESI) m/z 447.1 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.84 - 7.68 (m, 1H), 7.60 - 7.46 (m, 1H), 7.46 - 7.39 (m, 1H), 7.39 - 7.29 (m, 1H), 5.18 - 5.01 (m, 1H), 4.66 - 4.48 (m, 1H), 3.29 - 3.15 (m, 2H), 2.57 - 2.27 (m, 2H), 2.05 - 1.46 (m, 7H), 1.01 - 0.73 (m, 1H), 0.61 - 0.45 (m, 2H), 0.28 - 0.11 (m, 2H)

Example 245. Synthesis of viral protease inhibitor compound 864

Step 1: 5-chloro- lH-pyrrole-2-carboxylic acid

[00067] To a mixture of methyl 5-chloro- 1 H-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 H ₂ O (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- lH-pyrrole-2-carboxylic acid (500 mg, crude) as yellow oil. MS (ESI) m/z 146.0 [M+H] ⁺ .

Step 2: (S)-methyl 2-((S)-2-(5-chloro-lH-pyrrole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[00068] To a mixture of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3-[(3S)-2-oxo-3-piperidyl]propanoate (1.49 g, 3.44 mmol, 80% purity, 1 eq, HC1) in DMF (1 mL) and DCM (4 mL) was added 5-chloro- 1 H-pyrrole-2-carboxylic acid (500 mg, 3.44 mmol, 1 eq), and then DMAP (1.26 g, 10.31 mmol, 3 eq) and EDCI (1.32 g, 6.87 mmol, 2 eq) were added at 0 °C, then the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was quenched by the addition ofo water (10 mL), and then extracted with DCM (10 mL * 3). The combined organic layers were washed with HC1 (1M, 10 mL), then washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 100: 1 to 10: 1) to give (S)- methyl 2-((S)-2-(5-chloro-lH-pyrrole-2-carboxamido)-3-cyclopropylpr opanamido)-3- ((S)-2-oxopiperidin-3-yl)propanoate (300 mg, 683.52 umol, 19.90% yield) as yellow solid. MS (ESI) m/z 439.1 [M+H] ⁺ .

Step 3 : N-((S)-1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-5-chloro- 1 H-pyrrole-2-carboxamide

[00069] A mixture of methyl (2S)-2-[[(2S)-2-[(5-chloro-lH-pyrrole-2-carbonyl)amino]- 3-cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pro panoate (300 mg, 683.52 umol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 102.41 eq) was stirred at 80 °C for 30 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)- 3-cyclopropyl-1-oxopropan-2-yl)-5-chloro-lH-pyrrole-2-carbox amide (280 mg, crude) as yellow solid. MS (ESI) m/z 424.1 [M+H] ⁺ .

Step 4: 5-chloro-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)e thyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)- 1 H-pyrrole-2-carboxamide

[00070] To a mixture of N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-5-chloro-lH- pyrrole-2-carboxamide (220 mg, 467.10 umol, 90% purity, 1 eq) in DCM (3 mL) was added burgess reagent (333.94 mg, 1.40 mmol, 3 eq) and then the resulting mixture was stirred at 25 °C for 4 h. Upon completion, the mixture was quenched with water (1 mL) and concentrated under reduced pressure to give a residue (<30 °C). The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150* 40 mm* 10 um; mobile phase: [water(10mM NH4HCO3)- ACN] ; B%: 20%-50%, 8 min) to give 5-chloro-N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)e thyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)- 1 H-pyrrole-2-carboxamide (30.49 mg, 75.12 umol, 16.08% yield, 100% purity) as white solid. MS (ESI) m/z 406.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.36 (s, 1H), 9.10 - 8.81 (m, 1H), 8.13 - 8.03 (m, 1H),

7.52 (br s, 1H), 6.96 - 6.50 (m, 1H), 6.45 - 6.02 (m, 1H), 5.17 - 4.88 (m, 1H), 4.49 - 4.31 (m, 1H), 3.15 - 3.01 (m, 2H), 2.29 - 2.14 (m, 2H), 1.88 - 1.66 (m, 4H), 1.61 - 1.48 (m, 1H), 1.47 - 1.25 (m, 2H), 0.84 - 0.63 (m, 1H), 0.53 - 0.24 (m, 2H), 0.20 - 0.01 (m, 2H)

Example 251. Synthesis of viral protease inhibitor compound 868

Step 1: ethyl 5-chloro-lH-imidazole-2-carboxylate

[00071] To a solution of ethyl lH-imidazole-2-carboxylate (5 g, 35.68 mmol, 1 eq) in DMF (150 mL) was added acetic acid (1 mL) drop wise, 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , PE:EA = 1:0 to 65:35) to get product ethyl 5-chloro- 1 H-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] ⁺ .

Step 2: 5-chloro- lH-imidazole-2-carboxylic acid

[00072] To a mixture of ethyl 5-chloro- lH-imidazole-2-carboxylate (2.5 g, 10.02 mmol, 70% purity, 1 eq) in THF (30 mL) and H ₂ O (10 mL) and MeOH (3 mL) was added LiOH.H ₂ O (1.05 g, 25.06 mmol, 2.5 eq). The mixture was stirred at 40 °C for 24 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (TFA column: Waters X bridge C18 150 * 50 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 1% - 15%, 10 min) to get the product 5-chloro-lH-imidazole-2-carboxylic acid (1.0 g, 6.82 mmol, 68.08% yield) as white solid. MS (ESI) m/z 145.1 [M+H] ⁺ .

Step 3 : (2S)-2-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl ]-3-cyclopropyl- propanamide

[00073] A mixture of tert-butyl N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]car bamate (2.1 g, 5.55 mmol, 1 eq) in EA (12 mL) was added HC1/EA (4 M, 12 mL, 8.65 eq). The mixture was stirred 20 °C for 1 h. Upon completion, the mixture was concentrated under reduced pressure to give a residue, then was dissolved with ethyl acetate (20 mL * 3) and concentrated under reduced pressure to get the product (2 S)-2-amino-N-[( 1 S)- 1 - cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-3-cyclopropyl-propana mide (1.7 g, crude, HC1) as white solid. MS (ESI) m/z 279.1 [M+H] ⁺ .

Step 4: 5-chloro-N-[2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-lH-imidazole-2-carboxamide

[00074] To a solution of 5-chloro-lH-imidazole-2-carboxylic acid (800 mg, 5.46 mmol, 2.02 eq) in DMF (20 mL) was added HOBt (729.67 mg, 5.40 mmol, 2 eq), EDCI (1.04 g, 5.40 mmol, 2 eq) and (2S)-2-amino-N-[( 1 S)-l -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]-3-cyclopropyl-propanamide (1.7 g, 2.70 mmol, 50% purity, 1 eq, HC1). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with EA (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters X bridge C18 150 * 50 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 15% - 45%, 10 min) to get the product 5-chloro-N-[(1S)-2-[[(1S)-1- cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]- lH-imidazole-2-carboxamide (500 mg, 1.23 mmol, 45.51% yield) as white solid. MS (ESI) m/z 407.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.59 (br s, 1H), 8.96 - 8.79 (m, 1H), 8.42 - 8.28 (m, 1H), 7.52 (br s, 1H), 7.40 (s, 1H), 5.11 - 4.88 (m, 1H), 4.53 - 4.35 (m, 1H), 3.07 (br s, 2H), 2.32 - 2.10 (m, 2H), 1.81 (br s, 4H), 1.62 - 1.34 (m, 3H), 0.78 - 0.63 (m, 1H), 0.39 (br d, J = 7.8 Hz, 2H), 0.21 - 0.05 (m, 2H).

[00075] 5-chloro-N-[2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl ]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-imidazole-2-carboxamide (300 mg, 737.34 umol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IF (250 mm * 30 mm, 10 um); mobile phase: [0.1% NH3H ₂ O ETOH]; B%: 27% - 27%, 9 min) to afford 5-chloro-N-[2-[[( 1 S)-l -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]-l - (cyclopropylmethyl)-2-oxo-ethyl]-lH-imidazole-2-carboxamide Isomer 1 (197.02 mg, 484.24 umol, 65.67% yield) as white solid. MS (ESI) m/z 407.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.47 (br s, 1H), 8.85 (br d, J = 8.0 Hz, 1H), 8.40 (br d, J = 8.0 Hz, 1H), 7.52 (br s, 1H), 7.43 (s, 1H), 5.17 - 4.92 (m, 1H), 4.54 - 4.25 (m, 1H), 3.09 (br s, 2H), 2.34 - 2.18 (m, 2H), 1.88 - 1.65 (m, 4H), 1.62 - 1.31 (m, 3H), 0.70 (br s, 1H), 0.39 (br d, J = 7.6 Hz, 2H), 0.19 - 0.00 (m, 2H).

[00076] To afforad 5-chloro-N-[2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH -imidazole-2- carboxamide (10.42 mg, 25.61 umol, 3.47% yield) as white solid. MS (ESI) m/z 407.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.44 (br s, 1H), 8.86 (br d, J = 7.6 Hz, 1H), 8.35 (br d, J = 8.0 Hz, 1H), 7.52 (br s, 1H), 7.42 (s, 1H), 5.11 - 4.95 (m, 1H),

4.51 - 4.38 (m, 1H), 3.09 (br s, 2H), 2.26 - 2.08 (m, 2H), 1.89 - 1.66 (m, 4H), 1.63 - 1.34 (m, 3H), 0.69 (br s, 1H), 0.38 (br s, 2H), 0.09 (br d, J = 13.7 Hz, 2H).

[00077] To afford 5-chloro-N-[2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH -imidazole-2- carboxamide (39.82 mg, 97.87 umol, 13.27% yield) as white solid. MS (ESI) m/z 407.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 13.45 (br s, 1H), 8.92 (br d, J = 7.2 Hz, 1H), 8.41 - 8.32 (m, 1H), 7.53 (br s, 1H), 7.43 (s, 1H), 5.07 - 4.83 (m, 1H), 4.45 (br d, J = 5.4 Hz, 1H), 3.09 (br s, 2H), 2.35 - 2.12 (m, 2H), 1.92 - 1.67 (m, 4H), 1.65 - 1.35 (m, 3H), 0.70 (br s, 1H), 0.38 (br s, 2H), 0.09 (br d, J = 16.8 Hz, 2H).

Example 252. Synthesis of viral protease inhibitor compound 870

Step 1: tert-butyl ((S)-1-(((S)-1 -amino- l-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)- 3-cyclopropyl-1-oxopropan-2-yl)carbamate

[00078] A solution of methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbony lamino)-3 - cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate (5 g, 12.15 mmol, 1 eq) in NH ₃ /MeOH (7 M, 50 mL, 28.80 eq) was stirred at 65 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give tert-butyl N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]carbamate (4.8 g, crude) as a yellow solid. MS (ESI) m/z 397.2 [M+H] ⁺ .

Step 2: tert-butyl ((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino) -3- cyclopropyl- 1 -oxopropan-2-yl)carbamate

[00079] To a solution of tert-butyl N-[(l S)-2-[[( 1 S)-2-ami no-2-oxo- 1 -[ [(3 S)-2-oxo-3 - piperidyl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate = 1/0 to 0/1) to give tert-butyl N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]car bamate (4.3 g, 11.36 mmol, 93.85% yield) as a white solid. MS (ESI) m/z 379.2 [M+H] ⁺ .

Step 3 : (S)-2-amino-N-((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl) -3- cyclopropylpropanamide

[00080] A solution of tert-butyl N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]car bamate (2.5 g, 6.61 mmol, 1 eq) in EA (10 mL) and HCl/EtOAc (4 M, 10 mL, 6.06 eq) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue to give (2S)-2-amino-N-[(1S)-1-cyano-2- [(3S)-2-oxo-3-piperidyl]ethyl]-3-cyclopropyl-propanamide (2 g, crude, HC1) as a white solid. MS (ESI) m/z 279.1 [M+H] ⁺ .

Step 4: N-((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 -cyclopropyl- 1 - oxopropan-2-yl)-lH-imidazole-2-carboxamide

[00081] To a solution of lH-imidazole-2-carboxylic acid (267.03 mg, 2.38 mmol, 1 eq ), (2S)-2-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl ]-3-cyclopropyl- propanamide (1.5 g, 2.38 mmol, 50% purity, 1 eq, HC1), DMAP (873.15 mg, 7.15 mmol, 3 eq) in DCM (10 mL) was added EDCI (913.42 mg, 4.76 mmol, 2 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 10%-40%,10min) to give N-[(1S)-2-[[(1S)-1- cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]- lH-imidazole-2-carboxamide (130 mg, 293.22 umol, 12.31% yield, 84% purity) as a white solid. MS (ESI) m/z 373.1 [M+H] ⁺ .

Step 5 : N-( 1 -((( 1 S)- 1 -cyano-2-(2-oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl- 1 - oxopropan-2-yl)-lH-imidazole-2-carboxamide

[00082] N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1-

(cyclopropylmethyl)-2-oxo-ethyl]-lH-imidazole-2-carboxami de (130 mg, 293.22 umol, 12.31% yield, 84% purity) was separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [Neu-MeOH] ;B% : 45%- 45%,12min) to afford N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH -imidazole-2- carboxamide (14.9 mg, 40.01 umol, 11.46% yield, 100% purity) as a white solid. MS (ESI) m/z 373.2 [M+H] ⁺ . ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.40 - 7.00 (m, 2H), 5.23 - 5.05 (m, 1H), 4.51 (t, J= 7.0Hz, 1H), 3.27 - 3.17 (m, 2H), 2.55 - 2.35 (m, 2H), 2.06 - 1.62 (m, 6H), 1.60 - 1.44 (m, 1H), 0.90 - 0.76 (m, 1H), 0.60 - 0.44 (m, 2H), 0.26 - 0.07 (m, 2H)

[00083] To give N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-imidazole-2-carboxamide (27.3 mg, 72.20 umol, 20.69% yield, 98.5% purity) as a white solid. MS (ESI) m/z 373.2 [M+H] ⁺ . ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.43 - 7.01 (m, 2H), 5.06 (t, J= 7.3Hz, 1H), 4.56 (dd, J= 6.2, 7.4Hz, 1H), 3.29 - 3.19 (m, 2H), 2.48 - 2.39 (m, 1H), 2.34 (td, J= 6.7, 13.8Hz, 1H), 2.01 - 1.66 (m, 6H), 1.62 - 1.50 (m, 1H), 0.89 - 0.75 (m, 1H), 0.56 - 0.42 (m, 2H), 0.24 - 0.10 (m, 2H).

[00084] To give N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-imidazole-2-carboxamide (12.5 mg, 32.59 umol, 9.34% yield, 97.1% purity) as a white solid. MS (ESI) m/z 373.2 [M+H] ⁺ . ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.33 - 7.09 (m, 2H), 5.15 - 5.03 (m, 1H), 4.53 (d, J= 6.0, 7.3Hz, 1H), 3.26 - 3.21 (m, 2H), 2.44 - 2.27 (m, 2H), 2.04 - 1.96 (m, 1H), 1.93 - 1.77 (m, 3H), 1.76 - 1.68 (m, 2H), 1.59 - 1.51 (m, 1H), 0.89 - 0.76 (m, 1H), 0.56 - 0.45 (m, 2H), 0.23 - 0.12 (m, 2H)

[00085] To give N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-imidazole-2-carboxamide (5.5 mg, 13.32 umol, 3.82% yield, 90.2% purity) as a white solid. MS (ESI) m/z 373.2 [M+H] ⁺ . ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ = 7.35 - 7.05 (m, 2H), 5.11 (t, J= 1.2Hz, 1H), 4.55 (t, J= 6.9Hz, 1H), 3.27 - 3.21 (m, 2H), 2.50 - 2.32 (m, 2H), 2.06 - 1.98 (m, 1H), 1.97 - 1.81 (m, 3H), 1.79 - 1.68 (m, 2H), 1.63 - 1.56 (m, 1H), 1.65 - 1.53 (m, 1H), 0.88 - 0.77 (m, 1H), 0.52 (d, J= 7.8Hz, 2H), 0.23 - 0.09 (m, 2H).

Example 253. Synthesis of viral protease inhibitor compound 896

Step 1: methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate

[00086] A mixture of methyl (2S)-2-(tert-butoxycarbonylamino)-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (2.6 g, 9.08 mmol, 1 eq) in HCI/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, HCI) as yellow oil. MS (ESI) m/z 187.1 [M+H] ⁺ .

Step 2: tert-butyl 3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxyla te

[00087] To a mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (2 g, 8.98 mmol, 1 eq, HCI) in DCM (20 mL) and DMF (2 mL) was added 2-tert- butoxycarbonyl-2-azaspiro[4.5]decane-3-carboxylic acid (2.80 g, 9.88 mmol, 1.1 eq), T3P (11.43 g, 17.96 mmol, 10.68 mL, 50% purity, 2 eq) and TEA (5.45 g, 53.89 mmol, 7.50 mL, 6 eq) was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , PE:EA = 4/1-0/1) to get the product tert-butyl 3-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2- oxopyrrolidin-3-yl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]de cane-2-carboxylate (2.5 g, 4.43 mmol, 49.31% yield, 80% purity) as white solid. MS (ESI) m/z 452.3 [M+H] ⁺ .

Step 3: methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3S)-2-oxo pyrrolidin-3- yl]propanoate

[00088] A mixture of tert-butyl 3-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxopyrrolidin-3- yl]methyl]ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxyla te (2.1 g, 3.72 mmol, 80% purity, 1 eq) in HCl/MeOH (4 M, 25 mL, 26.88 eq) was stirred at 20 °C for 3 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 methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)- 3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (1.4 g, crude, HC1) as white oil. MS (ESI) m/z 352.2 [M+H] ⁺ .

Step 4: methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3S)-2-oxo pyrrolidin-3- yl]propanoate

[00089] A mixture of methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3S)- 2-oxopyrrolidin-3-yl]propanoate (1.4 g, 3.61 mmol, 1 eq, HC1) in DCM (20 mL) was added with 7-chloro-5-methoxy-lH-indole-2-carboxylic acid (1.06 g, 4.69 mmol, 1.3 eq), DMAP (1.10 g, 9.02 mmol, 2.5 eq) and EDCI (1.38 g, 7.22 mmol, 2 eq), and then the resulting mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , PE:EA = 2/1-0/1) to obtain methyl (2S)-2-[[2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)- 2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxopyrroli din-3-yl]propanoate (1.5 g, 2.68 mmol, 74.34% yield) as white solid. MS (ESI) m/z 559.2 [M+H] ⁺ .

Step 5: N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]e thyl]-2-(7-chloro-5- methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbox amide [00090] A mixture of methyl (2S)-2-[[2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxopyrrolidi n-3-yl]propanoate (1.46 g, 2.61 mmol, 1 eq ) in NH ₃ /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-lH-indole-2-carbony l)-2- azaspiro[4.5]decane-3-carboxamide (1.35 g, crude) as yellow oil. MS (ESI) m/z 544.2 [M+H] ⁺ .

Step 6: 2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-N-[(l S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl]-2-azaspiro[4.5]decane-3-carboxamid e

[00091] To a mixture of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]ethyl]-2-(7-chloro-5-methoxy-lH-indole-2-carbonyl) -2- azaspiro[4.5]decane-3-carboxamide (1.35 g, 2.11 mmol, 85% purity, 1 eq) in DCM (15 mL) was added burgess reagent (1.51 g, 6.33 mmol, 3 eq) = at 30 °C for 1 h.

Upon completion, the mixture were quenched with water (1 mL) and blow-dried with N ₂ . The residue was purified by prep-HPLC (column: Waters X bridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 35% - 65%, 8 min), which was further separated by SFC (column:

REGIS(S, S) WHELK-01 (250 mm * 25 mm, 10 um); mobile phase: [Neu-ETOH]; B%: 60% - 60%, 12 min) to get the product 2-(7-chloro-5-methoxy-lH-indole-2- carbonyl)-N-[(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl ]-2- azaspiro[4.5]decane-3-carboxamide (322.82 mg, 613.70 umol, 29.10% yield) as white solid. MS (ESI) m/z 526.2 [M+H] ⁺ .

[00092] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.12 (d, J=1.7 Hz, 1H), 7.02 (s, 1H), 6.97 (br d, J=1.8 Hz, 1H), 5.12 - 5.00 (m, 1H), 4.62 (dd, J=7.9, 9.7 Hz, 1H), 3.92 (br d, J=10.3 Hz, 1H), 3.86 - 3.33 (m, 5H), 3.30 - 3.26 (m, 1H), 2.77 - 2.55 (m, 1H), 2.52 - 2.23 (m, 3H), 1.98 - 1.67 (m, 3H), 1.62 - 1.41 (m, 10H).

[00093] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.07 (br d, J=1.1 Hz, 1H), 8.72 (br d, J=7.5 Hz, 1H), 7.44 (br d, J=0.7 Hz, 1H), 7.12 (br s, 1H), 6.97 (s, 2H), 4.92 (br s, 1H), 4.60 (br s, 1H), 3.85 - 3.77 (m, 4H), 3.61 (br s, 1H), 3.14 (br s, 2H), 2.43 - 2.21 (m, 2H), 2.20 - 1.89 (m, 2H), 1.80 (br s, 1H), 1.72 - 1.58 (m, 2H), 1.57 - 1.35 (m,

10H).

[00094] To get the product 2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-N-[(1S)-1- cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-2-azaspiro[4.5]dec ane-3-carboxamide (289.32 mg, 550.01 umol, 26.08% yield) as white solid. MS (ESI) m/z 526.2 [M+H] ⁺ .

[00095] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.12 (d, J=2.0 Hz, 1H), 7.04 (s, 1H), 6.99 - 6.93 (m, 1H), 5.06 - 4.97 (m, 1H), 4.63 (dd, J=7.9, 9.5 Hz, 1H), 3.94 (br d, J=10.4 Hz, 1H), 3.88 - 3.68 (m, 4H), 3.30 - 2.73 (m, 2H), 2.68 - 2.10 (m, 4H), 1.94 - 1.69 (m,

3H), 1.62 - 1.40 (m, 10H).

[00096] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.46 - 10.49 (m, 1H), 8.67 (br d, J=6.6 Hz, 1H), 7.44 (br s, 1H), 7.21 - 7.07 (m, 1H), 6.98 (s, 2H), 5.06 - 4.83 (m, 1H), 4.59 (br dd, J=2.1, 4.1 Hz, 1H), 3.80 (s, 4H), 3.70 - 3.44 (m, 1H), 3.22 - 3.10 (m, 2H), 2.25 (s, 4H), 1.82 (br s, 1H), 1.68 (br d, J=10.4 Hz, 2H), 1.59 - 1.33 (m, 10H).

Example 254. Synthesis of viral protease inhibitor compound 910

Step 1 : ethyl 2-((diphenylmethylene)amino)-4-methylpent-4-enoate

[00097] 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) drop wise (-0.5 h) at -78 °C under N ₂ , 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) drop wise 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 Na ₂ SO ₄ , concentrated in vacuum and purified by column (SiO ₂ , 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] ⁺

Step 2: ethyl 2-amino-4-methylpent-4-enoate

[00098] A solution of ethyl 2-((diphenylmethylene)amino)-4-methylpent-4-enoate (9 g, 28.00 mmol, 1 eq) in aq. HC1 (2 M, 140.01 mL, 10 eq) was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was concentrated in vacuum to obtained ethyl 2-amino-4-methylpent-4-enoate (9 g, crude) as a yellow gum. MS (ESI) m/z 158.2 [M+H] ⁺

Step 3: ethyl 2-(((benzyloxy)carbonyl)amino)-4-methylpent-4-enoate

[00099] To a solution of ethyl 2-amino-4-methylpent-4-enoate (9 g, 28.62 mmol, 1 eq) in THF (100 mL) was added sat.NazCO ₃ (7.21 g, 68.06 mmol, 14.84 uL, 2.38 eq) (adjust pH=8), and then benzyl carbonochloridate (9.77 g, 57.25 mmol, 8.14 mL, 2 eq) was added. The resulting mixture was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was concentrated in vacuum, then was added H ₂ O (500 mL) and extracted with EA (150 mL * 3). The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , purified by column (SiO ₂ , PE:EA = 60: 1 to 40: 1) and repurified by prep-HPLC (column: Xtimate C18 lOu 250mm * 80mm; mobile phase: [water (lOmM NH4HCO3)- ACN] ; B%: 30%-65%,30min) to obtained ethyl 2- (((benzyloxy)carbonyl)amino)- 4-methylpent-4-enoate (3.4 g, 10.50 mmol, 36.69% yield, 90% purity) as a yellow oil. MS (ESI) m/z 292.1 [M+H] ⁺

Step 4: ethyl 2-(((benzyloxy)carbonyl)amino)-3-( 1 -methylcyclopropyl)propanoate

[000100] To a solution of ZnEtz (1 M, 14.27 mL, 4.16 eq) in DCM (50 mL) at 0 °C under N ₂ was added diiodomethane (3.79 g, 14.17 mmol, 1.14 mL, 4.13 eq) in DCM (25 mL) drop wise, then the mixture was stirred at 0 °C under N ₂ for 0.5 h, then was added ethyl 2-(((benzyloxy)carbonyl)amino)- 4-methylpent-4-enoate (l g, 3.43 mmol, 1 eq) in DCM (25 mL) at 0 °C. The mixture was stirred at 20 °C for 48 h. Upon the reaction completion, the mixture was poured into aq. HC1 (30 mL, 1 M) at 0 °C, then was extracted with DCM (10 mL * 3), the organic phase was dried with Na ₂ SO ₄ , concentrated in vacuum and purified by column (SiO ₂ , PE:EA = 60: 1 to 30: 1) to obtained ethyl 2-(((benzyloxy)carbonyl)amino)-3-(l-methylcyclopropyl)propan oate (800 mg, 2.36 mmol, 68.69% yield, 90% purity) as a yellow oil. MS (ESI) m/z 306.1 [M+H] ⁺

Step 5: 2-(((benzyloxy)carbonyl)amino)-3-(l-methylcyclopropyl)propan oic acid [000101] To a solution of ethyl 2-(((benzyloxy) carbonyl) amino)-3-(l- methylcyclopropyl) propanoate (800 mg, 2.62 mmol, 1 eq) in THF (5 mL) and H ₂ O (5 mL) was added LiOH.H ₂ O (329.81 mg, 7.86 mmol, 3 eq), the mixture was stirred at 30 °C for 16 h. Upon the reaction completion, the mixture was adjust pH=l with aq.HCl (1M, 10 mL) and was extracted with ethyl acetate (5 mL * 2). The resulting mixture was concentrated in vacuum to obtained 2-(((benzyloxy)carbonyl)amino)-3- (l-methylcyclopropyl)propanoic acid (700 mg, crude) as a light yellow oil. MS (ESI) m/z 276.1 [M-H] ⁺

Step 6: (2S)-methyl 2-(2-(((benzyloxy)carbonyl)amino)-3-( 1 - methylcyclopropyl)propanamido)-3-((S)-2-oxopiperidin-3-yl)pr opanoate [000102] A solution of 2-(((benzyloxy)carbonyl)amino)-3-( 1 - methylcyclopropyl)propanoic acid (600 mg, 2.16 mmol, 1 eq) in ACN (1 mL) was added methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl]propanoate (614.54 mg, 2.60 mmol, 1.2 eq, HC1), [chloro(dimethylamino)methylene]-dimethyl- ammonium;hexafluorophosphate (910.59 mg, 3.25 mmol, 1.5 eq), then 1- methylimidazole (532.90 mg, 6.49 mmol, 517.37 uL, 3 eq), the mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with DCM (10 mL * 3). The combined organic layers were washed with 1 N HC1 (10 mL), then washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 0: 1 to 10: 1) to give (2S)-methyl 2-(2- (((benzyloxy)carbonyl)amino)-3-(l-methylcyclopropyl)propanam ido)-3-((S)-2- oxopiperidin-3-yl)propanoate (1.1 g, 1.80 mmol, 82.98% yield, 75% purity) as yellow solid. MS (ESI) m/z 460.2 [M+H] ⁺ .

Step 7: benzyl (l-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-y l)amino)-3-(l- methylcyclopropyl)- 1 -oxopropan-2-yl)carbamate

[000103] A solution of (2S)-methyl 2-(2-(((benzyloxy)carbonyl)amino)-3-(l- methylcyclopropyl)propanamido)-3-((S)-2-oxopiperidin-3-yl)pr opanoate (1 g, 1.63 mmol, 75% purity, 1 eq) in NH ₃ /MeOH (7 M, 10.71 mL, 45.95 eq) was stirred at 30 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give benzyl (l-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)amino)-3-(l-methylcyclopropyl)-1-oxopropan-2- yl)carbamate (1 g, crude) as yellow solid. MS (ESI) m/z 445.2 [M+H] ⁺ .

Step 8 : 2-amino-N-((S)- 1 -amino- 1 -oxo-3 -((S)-2-oxopiperidin-3-yl)propan-2-yl)-3-( 1 - methylcyclopropyl)propanamide

[000104] A solution of benzyl (l-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan- 2-yl)amino)-3-(l-methylcyclopropyl)-1-oxopropan-2-yl)carbama te (1 g, 2.25 mmol, 1 eq) in IPA (20 mL) was added HC1 (12 M, 243.71 uL, 1.3 eq), Pd/C (1 g, 833.33 umol, 10% purity, 0.37 eq) under N ₂ . The suspension was degassed under vacuum and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi) at 25 °C for 1 h. Upon completion, the reaction mixture was filtered through celatom then concentrated under reduced pressure to give 2-amino-N-((S)-l -amino- l-oxo-3-((S)-2- oxopiperidin-3-yl)propan-2-yl)-3-(l-methylcyclopropyl)propan amide (680 mg, crude) as yellow solid. MS (ESI) m/z 311.2 [M+H] ⁺ .

Step 9 : N-( 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3-( 1 - methylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[000105] To a solution of 2-amino-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)-3-(l-methylcyclopropyl)propanamide (680 mg, 1.96 mmol, 1 eq, HC1) in DCM (7 mL) was added 4-methoxy-lH-indole-2-carboxylic acid (449.78 mg, 2.35 mmol, 1.2 eq), DMAP (718.54 mg, 5.88 mmol, 3 eq), then EDCI (751.65 mg, 3.92 mmol, 2 eq) at 0 °C, the mixture was then stirred at 25 °C for 2 h. Upon completion, the mixture was quenched with water (10 mL) and extracted with DCM (10 mL* 3). The organic layers were washed with IN HC1 (10 mL) and then brine (20 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH =

0: 1 to 10: 1) to give N-(l-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2 - yl)amino)-3-( 1 -methylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2- carboxamide (550 mg, 1.02 mmol, 52.21% yield, 90% purity) as yellow solid. MS (ESI) m/z 484.2 [M+H] ⁺ . Step 10 : N-( 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-( 1 - methylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[000106] A mixture of N-( 1 -(((S)- 1 -amino- 1 -oxo-3 -((S)-2-oxopiperidin-3-yl)propan-2- yl)amino)-3-( 1 -methylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2- carboxamide (550 mg, 1.02 mmol, 90% purity, 1 eq) in DCM (1 mL) was added burgess reagent (731.85 mg, 3.07 mmol, 3 eq) and stirred at 25 °C for 3 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (0.5 mL) at 20 °C, and then concentrated under reduced pressure (<30 °C) to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 250*50mm*10um;mobile phase: [water(10mM NH ₄ HCO ₃ )-ACN];B%: 30%- 55%,10min) to give N-(l-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 - ( 1 -methylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide (250 mg, 531.64 umol, 51.93% yield, 99% purity) as white solid. MS (ESI) m/z 466.2 [M+H] ⁺ .

Step 11 : N-( 1 -(((S)-l -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-( 1 - methylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide [000107] N-(1-(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-( 1 - methylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide (250 mg, 531.64 umol, 99% purity, 1 eq) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm* 30 mm, 10 um); mobile phase: [Neu-ETOH]; B%: 50% - 50%, 15 min) to give N-(l-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 - ( 1 -methylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide (63.08 mg, 135.50 umol, 25.49% yield, 100% purity) as white solid. MS (ESI) m/z 466.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.58 (br s, 1H), 8.96 (br d ,J= 8.1 Hz, 1H), 8.43 (br d,J= 7.8 Hz, 1H), 7.52 (br s, 1H), 7.33 (s, 1H), 7.09 (t, J= 7.9 Hz, 1H), 7.01 (d ,J= 8.3 Hz, 1H), 6.50 (d ,J= 7.6 Hz, 1H), 5.10 - 5.01 (m, 1H), 4.66 - 4.57 (m, 1H), 3.88 (s, 3H), 3.13 - 3.02 (m, 2H), 2.32 - 2.20 (m, 2H), 1.86 - 1.72 (m, 3H), 1.72 - 1.51 (m, 3H), 1.39 (br d, J = 11.0 Hz, 1H), 1.07 (s, 3H), 0.56 - 0.49 (m, 1H), 0.29 - 0.23 (m, 1H), 0.23 - 0.12 (m, 2H)

[000108] To give N-(l-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 -(l- methylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide (85.13 mg, 182.86 umol, 34.40% yield, 100% purity) as white solid. MS (ESI) m/z 466.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.60 (br s, 1H), 8.95 (br d, J = 8.1 Hz, 1H), 8.45 (br d, J = 8.4 Hz, 1H), 7.53 (br s, 1H), 7.34 (s, 1H), 7.10 (t, J = 7.9 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 5.09 - 5.00 (m, 1H), 4.70 - 4.62 (m, 1H), 3.89 (s, 3H), 3.13 - 3.03 (m, 2H), 2.25 - 2.14 (m, 2H), 1.89 - 1.69 (m, 4H), 1.65 - 1.50 (m, 2H), 1.48 - 1.36 (m, 1H), 1.05 (s, 3H), 0.59 - 0.50 (m, 1H), 0.27 - 0.20 (m, 1H), 0.19 - 0.11 (m, 2H)

Example 255. Synthesis of viral protease inhibitor compound 912

Step 1 : ethyl 2-((diphenylmethylene)amino)-5-methylhex-4-enoate

[000109]To a solution of ethyl 2-(benzhydrylideneamino) acetate (5 g, 18.70 mmol, 1 eq) in THF (50 mL) was added LiHMDS (1M, 20.57 mL, 1.1 eq) at -78 °C, stirred 30 min, and then l-bromo-3-methyl-but-2-ene (2.79 g, 18.70 mmol, 2.16 mL, 1 eq) was added. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O 50 mL at 20 °C, and then extracted with EtOAc (60 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 1/0 to 30/1) to give ethyl 2-(benzhydrylideneamino)-5-methyl-hex-4-enoate (3 g, 8.94 mmol, 47.82% yield) as a yellow oil. MS (ESI) m/z 336.2 [M+H] ⁺ .

Step 2: ethyl 2-amino-5-methylhex-4-enoate

[000110] A solution of ethyl 2-(benzhydrylideneamino)-5-methyl-hex-4-enoate (2.7 g, 8.05 mmol, 1 eq) in HC1 (2 M, 27 mL, 6.71 eq) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove H ₂ O to give ethyl 2-amino-5-methyl-hex-4-enoate (1.3 g, crude, HC1) as a white solid.

Step 3: ethyl 2-(((benzyloxy)carbonyl)amino)-5-methylhex-4-enoate

[000111] To a solution of ethyl 2-amino-5-methyl-hex-4-enoate (900 mg, 5.26 mmol, 1 eq) in IPA (10 mL) was added NazCO ₃ (1.39 g, 13.14 mmol, 9 mL, 2.5 eq) and NaOH (210.22 mg, 5.26 mmol, 1 mL, 1 eq) to adjust pH to 11 at 0 °C, and then benzyl (2,5- dioxopyrrolidin-1-yl) carbonate (1.44 g, 5.78 mmol, 1.1 eq) was added. The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was poured into H ₂ O 30 mL at 20 °C, and then extracted with EtOAc (35 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to give ethyl 2-(benzyloxycarbonylamino)-5- methyl-hex-4-enoate (1.3 g, crude) as a yellow solid. MS (ESI) m/z 306.1 [M+H] ⁺ .

Step 4: ethyl 2-(((benzyloxy)carbonyl)amino)-3-(2,2-dimethylcyclopropyl)pr opanoate [000112] To a solution of ethyl 2-(benzyloxycarbonylamino)-5-methyl-hex-4-enoate (1.2 g, 2.75 mmol, 70% purity, 1 eq) in DCM (20 mL) and ZnEtz (1 M, 6.88 mL, 2.5 eq) at -40 °C, stirred 10 min, then CH2I2 (1.47 g, 5.50 mmol, 443.83 uL, 2 eq) was added. The mixture was stirred at 20 °C for 15 h 50 min. Upon completion, the reaction mixture was quenched by addition NH4CI 30 mL at 20 °C, and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over NazSC^, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 80/1 to 40/1) to give ethyl 2-(benzyloxycarbonylamino)-3-(2,2- dimethylcyclopropyl)propanoate (1 g, crude) as a yellow oil. MS (ESI) m/z 320.2 [M+H] ⁺ .

Step 5: 2-(((benzyloxy)carbonyl)amino)-3-(2,2-dimethylcyclopropyl)pr opanoic acid [000113] To a solution of ethyl 2-(benzyloxycarbonylamino)-3-(2,2- dimethylcyclopropyl)propanoate ( 1 g, 3.13 mmol, 1 eq) in THF (9 mL) and H ₂ O (3 mL) was added LiOH.H ₂ O (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 HC1 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 2- (benzyloxycarbonylamino)-3-(2,2-dimethylcyclopropyl)propanoi c acid (1.1 g, crude) as a yellow oil.

Step 6: (2S)-methyl 2-(2-(((benzyloxy)carbonyl)amino)-3-(2,2- dimethylcyclopropyl)propanamido)-3-((S)-2-oxopiperidin-3-yl) propanoate [000114] To a solution of 2-(benzyloxycarbonylamino)-3-(2,2- dimethylcyclopropyl)propanoic acid (1.08 g, 3.71 mmol, 1 eq), methyl (2S)-2-amino- 3-[(3S)-2-oxo-3-piperidyl]propanoate (1.75 g, 7.41 mmol, 2 eq, HC1) in DCM (10 mL) was added DMAP (1.13 g, 9.27 mmol, 2.5 eq), then EDCI (1.42 g, 7.41 mmol, 2 eq) was added. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O 50 mL at 20 °C, and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM:MeOH = 1/0 to 80/1) to give methyl (2S)-2-[[2-(benzyloxycarbonylamino)-3-(2,2- dimethylcyclopropyl)propanoyl]amino]-3-[(3S)-2-oxo-3-piperid yl]propanoate (1.5 g, 3.17 mmol, 85.45% yield) as a yellow solid. MS (ESI) m/z 474.2 [M+H] ⁺ .

Step 7: benzyl ( 1 -(((S)-l -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3-(2,2- dimethylcyclopropyl)- 1 -oxopropan-2-yl)carbamate

[000115] A solution of methyl (2S)-2-[[2-(benzyloxycarbonylamino)-3-(2,2- dimethylcyclopropyl)propanoyl]amino]-3-[(3S)-2-oxo-3-piperid yl]propanoate (1.5 g, 3.17 mmol, 1 eq) in NH ₃ /MEOH (7 M, 15.00 mL, 33.15 eq) was stirred at 65 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove MeOH to give benzyl N-[2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-[(2,2-dimethylcyclopropyl)me thyl]-2-oxo- ethyl]carbamate (1.45 g, crude) as a yellow solid. MS (ESI) m/z 459.2 [M+H] ⁺ .

Step 8: 2-amino-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)prop an-2-yl)-3-(2,2- dimethylcyclopropyl)propanamide

[000116] To a solution of benzyl N-[2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-[(2,2-dimethylcyclopropyl)me thyl]-2-oxo- ethyl]carbamate (1.45 g, 3.16 mmol, 1 eq) in i-PrOH (15 mL) was added HC1 (12 M, 263.51 uL, 1 eq), then Pd/C (1.45 g, 3.16 mmol, 20% purity, 1 eq) was added. The mixture was stirred at 20 °C for 3 h under H ₂ . Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give (2S)-2-[[2-amino-3-(2,2- dimethylcyclopropyl)propanoyl]amino]-3-[(3S)-2-oxo-3-piperid yl]propanamide (1 g, crude) as a yellow solid. MS (ESI) m/z 325.2 [M+H] ⁺ .

Step 9: N-( 1 -(((S)-l -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3-(2,2- dimethylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide [000117] To a solution of (2S)-2-[[2-amino-3-(2,2- dimethylcyclopropyl)propanoyl]amino]-3-[(3S)-2-oxo-3-piperid yl]propanamide (990 mg, 3.05 mmol, 1 eq), 4-methoxy- 1 H-indole-2-carboxylic acid (700.10 mg, 3.66 mmol, 1.2 eq) in DCM (10 mL) was added DMAP (932.03 mg, 7.63 mmol, 2.5 eq), then EDCI (1.17 g, 6.10 mmol, 2 eq) was added. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O 25 mL at 20 °C, and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (25 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM: MeOH = 100/0 to 95/5) to give N-[2-[[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-[(2,2-dimethylcyclopropyl)me thyl]-2-oxo-ethyl]-4- methoxy- 1 H-indole-2-carboxamide (1.01 g, 2.03 mmol, 66.52% yield) as a yellow solid. MS (ESI) m/z 498.2 [M+H] ⁺ . Step 10: N-(l -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-(2,2- dimethylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide [000118] To a solution of N-[2-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]amino]-1-[(2,2-dimethylcyclopropyl)me thyl]-2-oxo-ethyl]-4- methoxy- 1 H-indole-2-carboxamide (1 g, 2.01 mmol, 1 eq) in DCM (10 mL) was added burgess reagent (957.85 mg, 4.02 mmol, 2 eq). The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was poured into H ₂ O 30 mL at 20 °C, and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over NazSC> ₄ filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250*50mm* 10um;mobile phase: [water(10mM NH4HCO3)- ACN] ;B% : 35%-65%,10min) to give N-[2-[[(1S)-1-cyano-2-[(3S)-2-oxo- 3-piperidyl]ethyl]amino]-1-[(2,2-dimethylcyclopropyl)methyl] -2-oxo-ethyl]-4- methoxy- 1 H-indole-2-carboxamide (280 mg, 583.86 umol, 29.05% yield, 100% purity) as a white solid. MS (ESI) m/z 480.2 [M+H] ⁺ .

Step 11 : N-(l-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 -(2,2- dimethylcyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide [000119]N-[2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl] amino]-1-[(2,2- dimethylcyclopropyl)methyl]-2-oxo-ethyl]-4-methoxy-lH-indole -2-carboxamide (280 mg, 583.86 umol, 29.05% yield, 100% purity) was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [Neu-IPA];B%: 30%-50%,18min) to give N-[2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-1-[(2,2-dimethylcyclopropyl)methyl]-2 -oxo-ethyl]-4- methoxy- 1 H-indole-2-carboxamide (55 mg, 113.31 umol, 19.41% yield, 98.8% purity) as a white solid. MS (ESI) m/z 480.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD- d ₄ ) δ = 7.26 (s, 1H), 7.19 - 7.10 (m, 1H), 7.07 - 6.98 (m, 1H), 6.51 (d ,J= 7.2 Hz, 1H), 5.17 - 5.08 (m, 1H), 4.58 - 4.46 (m, 1H), 3.93 (s, 3H), 3.27 - 3.15 (m, 2H), 2.55 - 2.39 (m, 2H), 2.08 - 1.89 (m, 3H), 1.86 - 1.66 (m, 3H), 1.56 - 1.45 (m, 1H), 1.26 - 0.96 (m, 6H), 0.71 - 0.58 (m, 1H), 0.50 (d, J= 2.5, 4.5 Hz, 1H), 0.14 - 0.01 (m, 1H).

[000120] To give N-[2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1-[(2,2- dimethylcyclopropyl)methyl]-2-oxo-ethyl]-4-methoxy-lH-indole -2-carboxamide (155 mg, 322.56 umol, 55.25% yield, 99.8% purity) as a white solid. MS (ESI) m/z 480.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.27 (s, 1H), 7.19 - 7.11 (m, 1H), 7.04 (d,J= 8.3 Hz, 1H), 6.52 (d, J= 7.7 Hz, 1H), 5.06 (d,J= 6.2, 10.0 Hz, 1H), 4.59 (d, J = 5.8, 84 Hz, 1H), 3.93 (s, 3H), 3.22 - 3.11 (m, 2H), 2.40 (d,J= 6.2, 10.2, 13.8 Hz, 1H), 2.33 - 2.22 (m, 1H), 2.12 - 2.02 (m, 1H), 2.00 - 1.85 (m, 2H), 1.84 - 1.73 (m, 2H), 1.61 (d, J= 2.4 Hz, 1H), 1.49 (d, J= 11.0 Hz, 1H), 1.14 - 1.07 (m, 3H), 1.07 - 0.99 (m, 3H), 0.69 - 0.58 (m, 1H), 0.48 (d, J = 4.3, 8.7 Hz, 1H), 0.14 - 0.03 (m, 1H).

Example 256. Synthesis of viral protease inhibitor compound 918

Step 1: (1 S,3aR,7aS)-tert-butyl l-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan- 2-yl)carbamoyl)hexahydro-lH-isoindole-2(3H)-carboxylate

[000121] To a solution of (lS,3aR,7aS)-2-tert-butoxycarbonyl-l,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, HC1) in DCM (5 mL) and DMF (1.5 mL) was added DMAP (612.36 mg, 5.01 mmol, 3 eq) and EDCI (640.58 mg, 3.34 mmol, 2 eq), then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 50 mL at 0 °C, and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum etherEthyl acetate = 5: 1 to 0: 1) to give the product tert-butyl ( 1 S,3aR,7aS)- 1 -[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-l,3,3a,4,5,6,7,7a-octahydr oisoindole-2- carboxylate (680 mg, 1.36 mmol, 81.12% yield, 90% purity) as a white solid. MS (ESI) m/z 452.2 [M+H] ⁺ .

[000122] Step 2: (S)-methyl 2-((lS,3aR,7aS)-octahydro-lH-isoindole-1-carboxamido)-3- ((S)-2-oxopiperidin-3-yl)propanoate hydrochloride

[000123] To a solution of tert-butyl (lS,3aR,7aS)-1-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2- oxo-3-piperidyl]methyl]ethyl]carbamoyl]-l,3,3a,4,5,6,7,7a-oc tahydroisoindole-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- [[(lS,3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydro-lH-isoindole-1-ca rbonyl]amino]-3-[(3S)- 2-oxo-3-piperidyl]propanoate (580 mg, crude, HC1) as a white solid.

[000124] Step 3: (S)-methyl 2-((lS,3aR,7aS)-2-(4-methoxy-lH-indole-2- carbonyl)octahydro-lH-isoindole-1-carboxamido)-3-((S)-2-oxop iperidin-3- yl)propanoate

[000125] To a solution of 4-methoxy-lH-indole-2-carboxylic acid (371.62 mg, 1.94 mmol, 1.3 eq) and methyl (2S)-2-[[(lS,3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydro-lH- isoindole-1-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propan oate (580 mg, 1.50 mmol, 1 eq, HC1) in DCM (15 mL) and DMF (3 mL) was added DMAP (548.02 mg, 4.49 mmol, 3 eq) and EDCI (573.27 mg, 2.99 mmol, 2 eq), then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 50 mL at 0 °C, and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether:Ethyl acetate = 5:1 to 0:1) to give the product methyl (2S)-2-[[(lS,3aR,7aS)-2-(4-methoxy-lH-indole-2- carbonyl)-l,3,3a,4,5,6,7,7a-octahydroisoindole-1-carbonyl]am ino]-3-[(3S)-2-oxo-3- piperidyl]propanoate (710 mg, 1.26 mmol, 84.18% yield, 93% purity) as a yellow solid. MS (ESI) m/z 525.2 [M+H] ⁺ .

[000126] Step 4: ( 1 S,3aR,7aS)-N-((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopi peri din-3 -yl)propan- 2-yl)-2-(4-methoxy- 1 H-i ndole-2-carbony l)octahy dro- 1 H-isoindole- 1 -carboxamide

[000127] To a solution of methyl (2 S)-2-[ [( 1 S, 3 aR, 7aS)-2-(4-methoxy- 1 H-indole-2- carbonyl)-l,3,3a,4,5,6,7,7a-octahydroisoindole-1-carbonyl]am ino]-3-[(3S)-2-oxo-3- piperidyl]propanoate (710 mg, 1.35 mmol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 51.72 eq) and then mixture was stirred at 40 °C fo 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product (lS,3aR,7aS)-N- [(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl] -2-(4-methoxy-lH- indole-2-carbonyl)-l,3,3a,4,5,6,7,7a-octahydroisoindole-1-ca rboxamide (640 mg, crude) as a white solid. MS (ESI) m/z 510.2 [M+H] ⁺ .

[000128] Step 5: (lS,3aR,7aS)-N-((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl )-2-(4- methoxy- 1 H-indole-2-carbonyl)octahydro- 1 H-isoindole- 1 -carboxamide

[000129] To a solution of (lS,3aR,7aS)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)-l ,3,3a,4,5,6,7,7a- octahydroisoindole- 1 -carboxamide (640 mg, 1.26 mmol, 1 eq) and BURGESS REAGENT (598.57 mg, 2.51 mmol, 2 eq) in DCM (10 mL), and the mixture was stirred at 30 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150 * 50 mm * 10 um; mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 25% - 55%, 10 min) to give the product (lS,3aR,7aS)-N- [(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-(4-methoxy- lH-indole-2-carbonyl)- l,3,3a,4,5,6,7,7a-octahydroisoindole-1-carboxamide (450 mg, 906.26 umol, 72.16% yield, 99% purity) as a white solid. MS (ESI) m/z 492.2 [M+H] ⁺ . [000130] Step 6: 2-(5-chloro-4-methoxy-lH-indole-2-carbonyl)-N-((S)-1-cyano-2 -((S)-2- oxopiperidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide

[000131] 2-(5-chloro-4-methoxy-lH-indole-2-carbonyl)-N-((S)-1-cyano-2 -((S)-2- oxopiperidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide was purified by SFC (column: REGIS(S,S) WHELK-Ol(250 mm * 25 mm, 10 um); mobile phase: [0.1% NH3H ₂ O MEOH]; B%: 50% - 50%, 4 min) to give the product (3aR,7aS)-N-[(1S)-1- cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-(4-methoxy-lH-indol e-2-carbonyl)- l,3,3a,4,5,6,7,7a-octahydroisoindole-1-carboxamide Isomer 1 (136.17 mg, 277.00 umol, 30.26% yield, 100% purity) as a white solid MS (ESI) m/z 492.2 [M+H] ⁺ .

[000132] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.56 (s, 1H), 9.30 - 8.85 (m, 1H), 7.54 (br s, 1H), 7.15 - 7.07 (m, 1H), 7.07 - 6.95 (m, 2H), 6.52 (d, J = 7.6 Hz, 1H), 5.06 (br d, J = 7.7 Hz, 1H), 4.58 - 4.20 (m, 1H), 4.06 - 3.94 (m, 1H), 3.91 - 3.81 (m, 3H), 3.78 (br dd, J = 5.8, 9.8 Hz, 1H), 3.15 - 2.89 (m, 2H), 2.45 - 2.37 (m, 1H), 2.31 - 2.11 (m, 3H), 1.46 (br d, J = 3.5 Hz, 13H).

[000133] To give the product (3aR,7aS)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)-l,3,3a,4 ,5,6,7,7a- octahydroisoindole-1 -carboxamide Isomer 2 (161.76 mg, 329.06 umol, 35.95% yield, 100% purity) as a white solid. MS (ESI) m/z 492.2 [M+H] ⁺ .

[000134] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.62 - 11.55 (m, 1H), 9.15 - 8.84 (m, 1H), 7.55 - 7.39 (m, 1H), 7.15 - 7.09 (m, 1H), 7.06 - 6.97 (m, 2H), 6.61 - 6.50 (m, 1H), 5.05 (br d, J = 8.1 Hz, 1H), 4.47 - 4.24 (m, 1H), 4.00 (dd, J = 7.1, 9.7 Hz, 1H), 3.90 - 3.83 (m, 3H), 3.82 - 3.75 (m, 1H), 3.08 (br s, 2H), 2.44 - 2.37 (m, 1H), 2.24 (br d, J = 7.1 Hz, 3H), 1.83 - 1.32 (m, 13H).

Example 257. Synthesis of viral protease inhibitor compound 930

Step 1: tert-butyl 3-[[(1S)-1-[(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methyl]-2-me thoxy-2-oxo- ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxylate

[000135] To a mixture of methyl (2S)-2-amino-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]propanoate (750.00 mg, 2.99 mmol, 1 eq, HC1) and 2-tert-butoxycarbonyl-2- azaspiro[4.5]decane-3-carboxylic acid (932.40 mg, 3.29 mmol, 1.1 eq) in DCM (10 mL) and DMF (3 mL) was added DMAP (1.10 g, 8.97 mmol, 3 eq) and EDCI (1.15 g, 5.98 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 diluted with H ₂ O 30 mL and extracted with EA 60 mL (20 mL * 3). The combined organic layers were washed with brine 30 mL (30 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/l to 0/1) to give tert-butyl 3- [[(1S)-1-[(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methyl]-2-meth oxy-2-oxo- ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carboxylate (1.2 g, 2.50 mmol, 83.64% yield) as a yellow oil. MS (ESI) m/z 480.3 [M+H] ⁺ Step 2: methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-(5,5-dimeth yl-2-oxo- pyrrolidin-3-yl)propanoate

[000136] A mixture of tert-butyl 3-[[(1S)-1-[(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methyl]- 2-methoxy-2-oxo-ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-car boxylate (1.2 g, 2.50 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- (2-azaspiro[4.5]decane-3-carbonylamino)-3-(5,5-dimethyl-2-ox o-pyrrolidin-3- yl)propanoate (1 g, 2.40 mmol, 96.09% yield, HC1) as a yellow solid.

Step 3: methyl (2S)-2-[[2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]de cane-3- carbonyl]amino]-3-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)propan oate

[000137] To a mixture of 7-chloro- 1 H-indole-2-carboxylic acid (427.50 mg, 2.19 mmol, 1 eq) and methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-(5,5-dimeth yl-2- oxo-pyrrolidin-3-yl)propanoate (1 g, 2.40 mmol, 1.1 eq, HC1) in DCM (12 mL) and DMF (3 mL) was added DMAP (801.02 mg, 6.56 mmol, 3 eq) and EDCI (837.95 mg, 4.37 mmol, 2 eq), the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O 30 mL and extracted with EA 60 mL (20 mL * 3). The combined organic layers were washed with brine 30 mL (30 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/l to 0/1) to give methyl (2S)-2-[[2-(7-chloro-lH-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-(5,5-dim ethyl-2-oxo- pyrrolidin-3-yl)propanoate (700 mg, 1.26 mmol, 57.49% yield) as a white solid. MS (ESI) m/z 557.3[M+H] ⁺

Step 4: N-[(l S)-2-amino-1-[(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methyl]-2- oxo-ethyl]-2-(7- chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxa mide

[000138] A mixture of methyl (2S)-2-[[2-(7-chloro-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-(5,5-dimethyl-2-oxo- pyrrolidin-3- yl)propanoate (700 mg, 1.26 mmol, 1 eq) in NH ₃ /MeOH (7 M, 105.00 mL, 334.25 eq) was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-amino-1-[(5,5-dimethyl-2-oxo-pyrrolidin-3- yl)methyl]-2-oxo-ethyl]-2-(7-chloro-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3- carboxamide (660 mg, 1.22 mmol, 96.90% yield) as a white solid. MS (ESI) m/z 542.3 [M+H] ⁺

Step 5: 2-(7-chloro- 1 H-indole-2-carbonyl)-N-[( 1 S)-1-cyano-2-(5,5-dimethyl-2-oxo- pyrrolidin-3-yl)ethyl]-2-azaspiro[4.5]decane-3-carboxamide

[000139] A mixture of N-[(1S)-2-amino-1-[(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methy l]- 2-oxo-ethyl]-2-(7-chloro-lH-indole-2-carbonyl)-2-azaspiro[4. 5]decane-3- carboxamide (660 mg, 1.03 mmol, 85% purity, 1 eq) in DCM (10 mL) was added Burgess reagent (863.22 mg, 3.62 mmol, 3.5 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 8 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (neutral condition; column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HCC>3)-ACN];B%: 40%- 60%,8min) to give desired compound (270 mg, yield 49%, purity 100%) as a white solid, which was further separated by SFC (condition: column: DAICEL CHIRALPAK IC(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O ETOH];B%: 43%-43%,7min ) to give 2-(7-chloro-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-(5,5- dimethyl-2-oxo-pyrrolidin-3-yl)ethyl]-2-azaspiro[4.5]decane- 3-carboxamide (100 mg, 190.82 umol, 18.44% yield) as a white solid. MS (ESI) m/z 524.2[M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.66 - 11.45 (m, 1H), 8.95 (d, J= 8.2 Hz, 1H), 7.81 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.14 (s, 1H), 7.11 - 6.97 (m, 1H), 4.99 - 4.75 (m, 1H), 4.50 (t ,J= 8.6 Hz, 1H), 3.83 (br d ,J= 10.1 Hz, 1H), 3.66 (d,J= 10.4 Hz, 1H), 2.76 - 2.64 (m, 1H), 2.29 - 2.13 (m, 2H), 1.99 (dd, J= 8.6, 11.9 Hz, 1H), 1.82 - 1.66 (m, 1H), 1.65 - 1.28 (m, 12H), 1.18 - 1.07 (m, 3H), 1.02 (s, 3H)

Example 258. Synthesis of viral protease inhibitor compound 934

Step 1: benzyl N-[l-(hydroxymethyl)cyclopropyl]carbamate

[000140] 350 mL of a buffer-pH=l 1 (Saturated NaHCO ₃ adjusted with 4 M NaOH to pH=l 1) 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 H ₂ O 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 Na ₂ SO ₄ , 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-[l- (hydroxymethyl)cyclopropyl]carbamate (35 g, 142.37 mmol, 62.02% yield, 90% purity) was obtained as a white solid.

Step 2: benzyl N-( 1 -formylcyclopropyl) carbamate

[000141] To a mixture of benzyl N-[ 1 -(hydroxymethyl) cyclopropyl] carbamate (13 g, 58.76 mmol, 1 eq) in toluene (130 mL) and DMSO (130.00 g, 1.66 mol, 130.00 mL, 28.32 eq) was added TFA (3.35 g, 29.38 mmol, 2.18 mL, 0.5 eq) and pyridine (4.65 g, 58.76 mmol, 4.74 mL, 1 eq) and DCC (36.37 g, 176.27 mmol, 35.66 mL, 3 eq). The mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was filtered and diluted with EA 100 mL and washed with H ₂ O 300 mL (100 mL * 3). The combined organic layers were washed with brine 100 mL (100 mL * 1), and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 8/1 to 5/1) to give benzyl N-( 1 -formylcyclopropyl) carbamate (9 g, 39.00 mmol, 66.37% yield, 95% purity) as a white solid.

Step 3: benzyl N-[l-[(E)-2-methoxy vinyl] cyclopropyl] carbamate

[000142] 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 N ₂ . Upon completion, the reaction mixture was diluted with H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 30/1 to 10/1) to give benzyl N-[l-[(E)-2-methoxy vinyl] 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] ⁺

Step 4: benzyl N-[l-(2-oxoethyl)cyclopropyl]carbamate [000143] To a mixture of benzyl N-[l-[(E)-2-methoxy vinyl] cyclopropyl] carbamate (1.9 g, 7.68 mmol, 1 eq) in THF (20 mL) was added HC1 (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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 5/1). Compound benzyl N-[l-(2-oxoethyl) cyclopropyl] carbamate (1.3 g, 5.02 mmol, 65.28% yield, 90% purity) was obtained as a white solid.

Step 5: Ol-tert-butyl 02-methyl (2S)-4-[2-[l-(benzyloxycarbonylamino)cyclopropyl]-1- hydroxy- ethyl]-5-oxo-pyrrolidine- 1 ,2-dicarboxylate

[000144]To a mixture of Ol-tert-butyl 02-methyl (2S)-5-oxopyrrolidine-l, 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 N ₂ . The mixture was stirred at -60 °C for 30 min, and then benzyl N-[l-(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 Ol-tert-butyl 02-methyl (2S)-4-[2-[l- (benzyloxycarbonylamino) cyclopropyl]-! -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] ⁺

Step 6: Ol-tert-butyl 02-methyl(2S,4E)-4-[2-[l-

(benzyloxycarbonylamino)cyclopropyl]ethylidene]- 5-oxo-pyrrolidine- 1 ,2-dicarboxylate [000145] To a mixture of Ol-tert-butyl 02-methyl (2S)-4-[2-[l-

(benzyloxycarbonylamino)cyclopropyl]-1-hydroxy-ethyl]-5-o xo-pyrrolidine-l,2- dicarboxylate (900 mg, 1.89 mmol, 1 eq) in DCM (20 mL) was added burgess reagent (1.35 g, 5.67 mmol, 3 eq) at 25 °C.The mixture was stirred at 40 °C for 16 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 10/1 to 3/1). Compound Ol-tert-butyl 02- methyl(2S,4E)-4-[2-[l-(benzyloxycarbonylamino)cyclopropyl]et hylidene]-5-oxo- pyrrolidine-1 ,2-dicarboxylate (420 mg, 824.42 umol, 43.65% yield, 90% purity) was obtained as a colorless oil. MS (ESI) m/z 459.2 [M+H] ⁺

Step 7: Ol-tert-butyl 02-methyl (2S)-4-[2-(l-aminocyclopropyl)ethyl]-5-oxo-pyrrolidine- 1,2-dicarboxylate

[000146] To a mixture of Ol-tert-butyl 02-methyl (2S,4E)-4-[2-[l-

(benzyloxycarbonylamino)cyclopropyl]ethylidene]-5-oxo-pyr rolidine-l,2- dicarboxylate (700 mg, 1.53 mmol, 1 eq) in i-PrOH (10 mL) was added Pd/C (300 mg, 1.53 mmol, 10% purity, 1.00 eq). The mixture was stirred at 25 °C for 1 h under H ₂ (3.08 mg, 1.53 mmol, 1 eq) at 15 Psi. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue and used next step directly. Compound Ol-tert-butyl 02-methyl (2S)-4-[2-(l-aminocyclopropyl)ethyl]- 5-oxo-pyrrolidine-l,2-dicarboxylate (400 mg, crude) was obtained as a colourless oil.

Step 8: methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-oxo-4-azaspiro[2.5]oc tan-6- yl)propanoate

[000147] To a mixture of Ol-tert-butyl 02-methyl (2S)-4-[2-(l-aminocyclopropyl)ethyl]- 5-oxo-pyrrolidine-l,2-dicarboxylate (350 mg, 1.07 mmol, 1 eq) in MeOH (5 mL) and CHCl ₃ (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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue and used next step directly. The residue was purified by column chromatography (SiO ₂ , 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.

Step 9: methyl (2S)-2-amino-3-(5-oxo-4-azaspiro [2.5] octan-6-yl) propanoate

[000148] To methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-oxo-4-azaspiro[2.5]oc tan-6- yl)propanoate (170 mg, 520.85 umol, 1 eq) was added HCl/MeOH (4 M, 42.50 mL, 326.39 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 (2 S)-2-amino-3 -(5 -oxo-4- azaspiro [2.5] octan-6-yl) propanoate (136 mg, crude, HC1) was obtained as colourless oil.

Step 10: methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbony lamino)-3 -cy clopropy 1- propanoyl]amino]- 3-(5-oxo-4-azaspiro[2.5]octan-6-yl)propanoate

[000149] To a mixture of methyl (2 S)-2-ami no-3 -(5 -oxo-4-azaspiro[2.5 ]octan-6- yl)propanoate (136 mg, 517.64 umol, 1 eq, HC1) and (2S)-2-(tert- butoxycarbonylamino)-3-cyclopropyl-propanoic acid (118.68 mg, 517.64 umol, 1 eq) in DCM (9 mL) was added DMAP (126.48 mg, 1.04 mmol, 2 eq) and EDCI (198.46 mg, 1.04 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O 20 mL and extracted with EA 40 mL (20 mL * 2). The combined organic layers were washed with brine 20 mL (20 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5:1/1 to 1/1). Compound methyl (2 S)-2-[ [(2 S)-2-(tert-butoxy carbony lamino)-3 - cyclopropyl-propanoyl]amino]-3-(5-oxo-4-azaspiro[2.5]octan-6 -yl)propanoate (186 mg, 403.86 umol, 78.02% yield, 95% purity) was obtained as a colourless oil. MS (ESI) m/z 438.3 [M+H] ⁺

Step 11: methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(5-ox o-4- azaspiro[2.5 ] octan-6-y l)propanoate

[000150] 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-ox o- 4-azaspiro[2.5] octan-6-yl)propanoate (138 mg, crude, HC1) was obtained as a white solid.

[000151] Step 12: methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]-3- cyclopropyl-propanoyl] amino]-3-(5-oxo-4-azaspiro[2.5]octan-6-yl)propanoate [000152] To a mixture of 7-chloro- 1 H-indole-2-carboxylic acid (72.20 mg, 369.11 umol,

1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(5-ox o-4- azaspiro[2.5]octan-6-yl)propanoate (138 mg, 369.11 umol, 1 eq, HC1) in DCM (5 mL) was added EDCI (141.52 mg, 738.22 umol, 2 eq) and DMAP (90.19 mg, 738.22 umol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O 20 mL and extracted with EA 40 mL (20 mL * 2). The combined organic layers were washed with brine 20 mL (20 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 3/1 to 1/1). Compound methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-(5-oxo-4-az aspiro[2.5]octan-6- yl)propanoate (150 mg, 282.52 umol, 76.54% yield, 97% purity) was obtained as a colourless oil. MS (ESI) m/z 515.2 [M+H] ⁺

Step 13 : N-[(l S)-2-[[(l S)-2-amino-2-oxo-1-[(5-oxo-4-azaspiro[2.5]octan-6- yl)methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4- methoxy-lH-indole-2- carboxamide

[000153] A solution of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-(5-oxo-4-azaspiro[2.5]octa n-6-yl)propanoate (130 mg, 254.61 umol, 1 eq) in NH ₃ /MeOH (7 M, 13.16 mL, 361.91 eq) was stirred at 60 °C for 48 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-2-oxo-1-[(5-oxo-4-azaspiro[2.5]octan-6-yl)methyl]ethyl ]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide (120 mg, 217.93 umol, 85.59% yield, 90% purity) was obtained as a white solid. MS (ESI) m/z 500.2 [M+H] ⁺

Step 14: 7-chloro-N-[(l S)-2-[[(l S)-1-cyano-2-(5-oxo-4-azaspiro[2.5]octan-6- yl)ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole -2-carboxamide [000154] To a mixture of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[(5-oxo-4- azaspiro[2.5]octan-6-yl)methyl]ethyl]amino]-1-(cyclopropylme thyl)-2-oxo-ethyl]-7- chloro-lH-indole-2-carboxamide (120 mg, 240.01 umol, 1 eq) in DCM (6 mL) was added burgess reagent (114.39 mg, 480.01 umol, 2 eq). The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was diluted with H ₂ O 5 mL and extracted with DCM 10 mL (5 mL * 2). The combined organic layers were concentrated by blow-drying to give a residue. The residue was purified by neutral prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (lOmM NH4HCO3)- ACN] ; B%: 30%-55%, 10 min) to get the mixture 50 mg. The 50 mg mixture was purified by SFC (column: DAICEL CHIRALPAK IF (250mm*30mm,10um);mobile phase: [0.1%NH3H ₂ O ETOH];B%: 40%-40%,12min). Compound 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-(5-oxo-4-azaspiro[2.5]oc tan-6- yl)ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]- 1 H-indole-2-carboxamide ( 12 mg, 24.65 umol, 10.27% yield, 99% purity) was obtained as white solid. MS (ESI) m/z 482.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.73 (br s, 1H), 9.02 (d, J = 8.1 Hz, 1H), 8.72 (d ,J= 7.7 Hz, 1H), 7.67 - 7.57 (m, 2H), 7.35 - 7.29 (m, 1H), 7.26 (s, 1H), 7.07 (t ,J= 7.8 Hz, 1H), 5.09 (q, J = 8.0 Hz, 1H), 4.59 - 4.47 (m, 1H), 2.40 - 2.21 (m, 2H), 1.98 - 1.71 (m, 4H), 1.63 - 1.33 (m, 3H), 0.88 - 0.65 (m, 2H), 0.61 - 0.37 (m, 5H), 0.26 - 0.03 (m, 2H).

[000155] 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-(5-oxo-4-azaspiro[2.5]oc tan-6- yl)ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]- 1 H-indole-2-carboxamide (4 mg, 8.30 umol, 3.46% yield) were obtained as white solid. MS (ESI) m/z 482.1 [M+H] ⁺ .

1 H NMR (400 MHz, DMSO-d ₆ ) δ = 11.73 (br d,J= 1.8 Hz, 1H), 9.04 (br d, J= 7.5 Hz, 1H), 8.75 (br d ,J= 7.9 Hz, 1H), 7.71 - 7.54 (m, 2H), 7.35 - 7.23 (m, 2H), 7.07 (t, J= 7.8 Hz, 1H), 5.02 (q, J= 7.2 Hz, 1H), 4.61 - 4.51 (m, 1H), 2.35 - 2.26 (m, 2H), 2.01 - 1.91 (m, 1H), 1.87 - 1.71 (m, 3H), 1.67 - 1.40 (m, 3H), 0.88 - 0.65 (m, 2H),

0.62 - 0.37 (m, 5H), 0.26 - 0.06 (m, 2H).

Example 259. Synthesis of viral protease inhibitor compound 936

Step 1: Ol-tert-butyl 02-methyl (2S)-4-[[l-(benzyloxycarbonylamino)cyclopropyl]-hydroxy- methyl]-5-oxo-pyrrolidine- 1 ,2-dicarboxylate

[000156] To a solution of benzyl N-(l-formylcyclopropyl)carbamate (1.80 g, 8.22 mmol,

1 eq) in THF (30 mL) was added LiHMDS (1 M, 10.69 mL, 1.3 eq) at -60°C. The solution was stirred for 1 h at -60°C. Ol-tert-butyl 02-methyl (2S)-5-oxopyrrolidine- 1 ,2-dicarboxylate (2000 mg, 8.22 mmol, 1 eq) was added. The solution was stirred for 2.5 h at -60 °C. Upon completion, the solution was quenched with H ₂ O(60mL) and extracted with EA(50mL*3) and concentrated to give crude Ol-tert-butyl 02-methyl (2S)-4-[[l-(benzyloxycarbonylamino)cyclopropyl]-hydroxy-meth yl]-5-oxo- pyrrolidine-l,2-dicarboxylate (3.3 g, crude) as a yellow oil. The crude was used directly for the next step. MS (ESI) m/z 463.2 [M+H] ⁺

Step 2: Ol-tert-butyl 02-methyl (2S,4E)-4-[[l-

(benzyloxycarbonylamino)cyclopropyl]methylene]-5-oxo-pyrr olidine-l,2-dicarboxylate [000157] To a solution of Ol-tert-butyl 02-methyl (2S)-4-[[l-

(benzyloxycarbonylamino)cyclopropyl]-hydroxy-methyl]-5-ox o-pyrrolidine-l,2- dicarboxylate (3300 mg, 7.14 mmol, 1 eq) in DCM (50 mL) was added burgess reagent (5.10 g, 21.41 mmol, 3 eq) at 20 °C. The solution was stirred for 10 h at 40°C. Upon completion, the solution was concentrated to give crude. The crude was purified by column (SiO ₂ , PE: EA=10: 1 to 0: 1) to give product Ol-tert-butyl 02-methyl (2S,4E)-4-[[l-(benzyloxycarbonylamino)cyclopropyl]methylene] -5-oxo-pyrrolidine- 1,2-dicarboxylate (1.9 g, 4.27 mmol, 59.91% yield) as a yellow. MS (ESI) m/z 445.1 [M+H] ⁺

Step 3: Ol-tert-butyl 02-methyl (2S)-4-[(l-aminocyclopropyl)methyl]-5-oxo-pyrrolidine- 1,2-dicarboxylate

[000158] To a solution of Ol-tert-butyl 02-methyl (2S,4E)-4-[[l-

(benzyloxycarbonylamino)cyclopropyl]methylene]-5-oxo-pyrr olidine-l,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 N ₂ atmosphere. The suspension was degassed and purged with H ₂ for 3 times. The mixture was stirred under H ₂ (15 psi ) at 25 °C for 2 h. Upon completion, the mixture was filtered and concentrated to give crude Ol-tert-butyl 02-methyl (2S)-4-[(l-aminocyclopropyl)methyl]-5-oxo- pyrrolidine-l,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] ⁺

Step 4: methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-oxo-4-azaspiro[2.4]he ptan-6- yl)propanoate

[000159] To a solution of Ol-tert-butyl 02-methyl (2S)-4-[(l-aminocyclopropyl)methyl]- 5-oxo-pyrrolidine-l,2-dicarboxylate (950 mg, 3.04 mmol, 1 eq) in MeOH (15 mL) and CHCl ₃ (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 H ₂ O (50mL) and extracted with EA (50mL*3) and concentrated to give crude. The crude was purified by column (SiO ₂ , PE: EA=10: 1 to 0: 1) to give product methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5-oxo-4-azaspiro[2.4]he ptan-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] ⁺

Step 5: methyl (2S)-2-amino-3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate [000160] 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, HC1) as a white solid. The crude was used directly for the next step. MS (ESI) m/z 213.2 [M+H] ⁺

Step 6: methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-pro panoyl]amino]- 3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate

[000161] To a solution of methyl (2S)-2-amino-3-(5-oxo-4-azaspiro[2.4]heptan-6- yl)propanoate (207 mg, 832.31 umol, 1 eq, HC1) in DCM (7 mL) was added DMAP (203.37 mg, 1.66 mmol, 2 eq) and (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl- propanoic acid (200.37 mg, 873.92 umol, 1.05 eq) and EDCI (319.11 mg, 1.66 mmol, 2 eq). The solution was stirred for 2 h at 20 °C. Upon completion, the solution was diluted with H ₂ O (40mL) and extracted with EA (50mL*3) and concentrated to give crude. The crude was purified by column (SiO ₂ , PE: EA=10: 1 to 0: 1) to give product methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-pro panoyl]amino]- 3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate (290 mg, 684.77 umol, 82.27% yield) as a white solid. MS (ESI) m/z 424.2 [M+H] ⁺

Step 7: methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]-3-(5-ox o-4- azaspiro[2.4]heptan-6-yl)propanoate

[000162] 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-aza spiro[2.4]heptan-6- yl)propanoate (245 mg, crude, HC1) as a white solid. The crude was used directly for the next step. MS (ESI) m/z 324.2 [M+H] ⁺

Step 8: methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]-3-cyc lopropyl- propanoyl]amino]-3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propano ate

[000163] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-(5-oxo-4-azaspiro[2.4]heptan-6-yl)propano ate (240 mg, 666.95 umol, 1 eq, HC1) in DCM (6 mL) was added DMAP(162.96 mg, 1.33 mmol, 2 eq) and 7-chloro-lH-indole-2-carboxylic acid (130.46 mg, 666.95 umol, 1 eq) and EDCI (255.71 mg, 1.33 mmol, 2 eq). The solution was stirred for 1 h at 25 °C Upon completion, The solution was diluted with H ₂ O (60mL) and extracted with EA(50mL*3) and concentrated to give crude. The crude was purified by column (SiO ₂ , PE:EA=10: 1 to 0: 1) to give product methyl (2S)-2-[[(2S)-2-[(7-chloro-lH- indole-2-carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-(5 -oxo-4- azaspiro[2.4]heptan-6-yl)propanoate (185 mg, 369.28 umol, 55.37% yield) as an off- yellow solid. MS (ESI) m/z 501.2 [M+H]+

Step 9: N-[(l S)-2-[[(l S)-2-amino-2-oxo-l -[(5-oxo-4-azaspiro[2.4]heptan-6- yl)methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-7- chloro-lH-indole-2- carboxamide

[000164] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-lH-indole-2-carbonyl)amino]- 3-cyclopropyl-propanoyl]amino]-3-(5-oxo-4-azaspiro[2.4]hepta n-6-yl)propanoate (185 mg, 369.28 umol, 1 eq) in NH ₃ /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 crudeN-[(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-lH-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]+

Step 10: 7-chloro-N-[(l S)-2-[[(l S)-1-cyano-2-(5-oxo-4-azaspiro[2.4]heptan-6- yl)ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole -2-carboxamide [000165] To a solution of N-[( 1 S)-2-[[( 1 S)-2-amino-2-oxo- 1 -[(5-oxo-4- azaspiro[2.4]heptan-6-yl)methyl]ethyl]amino]-1-(cyclopropylm ethyl)-2-oxo-ethyl]-7- chloro-lH-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(SiO ₂ , PE:EA=0: 1) to give product(70mg) and continued to purified by SFC to give product

[000166] 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-(5-oxo-4-azaspiro[2.4]he ptan-6- yl)ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-lH-indole -2-carboxamide (27 mg, 57.70 umol, 18.09% yield, 100% purity) as a white solid and 7-chloro-N-[(1S)-2- [[(1S)-1-cyano-2-(5-oxo-4-azaspiro[2.4]heptan-6-yl)ethyl]ami no]-1- (cyclopropylmethyl)-2-oxo-ethyl]-lH-indole-2-carboxamide (5 mg, 10.36 umol, 3.25% yield, 97% purity) as a white solid. SFC method(neutral) column:

REGIS(S,S) WHELK-01 (250mm*25mm, 10um);mobile phase: [Neu-IPA];B%: 45%- 45%,6min. MS (ESI) m/z 468.2 [M+H] ⁺ Isomer 1 : ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.72 (br s, 1H), 9.02 (d, J= 8.1 Hz, 1H), 8.72 (d, J= 7.5 Hz, 1H), 7.80 (s, 1H), 7.63 (dd, J= 0.8, 8.0 Hz, 1H), 7.33 - 7.24 (m, 2H), 7.07 (t, J= 7.8 Hz, 1H), 5.01 - 4.93 (m, 1H), 4.55 - 4.47 (m, 1H), 3.50 - 3.37 (m, 1H), 3.33 - 3.27 (m, 1H), 2.68 - 2.59 (m, 1H), 2.56 - 2.51 (m, 1H), 2.20 (ddd, J= 5.7, 9.1, 13.7 Hz, 1H), 2.01 - 1.76 (m, 4H), 1.50 (ddd, J= 6.2, 7.6, 14.0 Hz, 1H), 1.03 (d, J= 6.1 Hz, 1H), 0.86 - 0.76 (m, 1H), 0.76 - 0.67 (m, 1H), 0.58 - 0.48 (m, 3H), 0.48 - 0.38 (m, 2H), 0.23 - 0.15 (m, 1H), 0.15 - 0.07 (m, 1H)

[000167] Isomer 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.74 (br s, 1H), 9.09 (d, J = 7.7 Hz, 1H), 8.76 (d, J= 7.7 Hz, 1H), 7.85 (s, 1H), 7.63 (d,J= 7.5 Hz, 1H), 7.32 (d ,J= 7.4 Hz, 1H), 7.26 (s, 1H), 7.07 (t, J= 7.8 Hz, 1H), 4.96 (d, J= 7.2 Hz, 1H), 4.58 (br d, J= 6.1 Hz, 1H), 3.56 - 3.38 (m, 2H), 2.58 (br s, 1H), 2.55 - 2.52 (m, 1H), 2.32 - 2.23 (m, 1H), 2.12 - 2.05 (m, 1H), 2.03 - 1.93 (m, 1H), 1.88 - 1.73 (m, 2H), 1.54 (s, 1H), 1.23 (br s, 1H), 1.03 (d, J= 6.1 Hz, 1H), 0.80 (br s, 1H), 0.77 - 0.71 (m, 1H), 0.61 - 0.48 (m, 3H), 0.48 - 0.39 (m, 2H), 0.19 (br d, J= 2.4 Hz, 1H), 0.12 (br d, J= 2.4 Hz,

1H)

Example 260. Synthesis of viral protease inhibitor compound 1059

Step 1 : N-(l-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 -(2,2- difluorocyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[000168] N-[(1S)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-1-[(2, 2- difluorocyclopropyl)methyl]-2-oxoethyl]-4-methoxy-1H-indole- 2-carboxamide (210 mg) was separated by SFC (column: DAICEL CHIRALPAK IE (250 mm * 30 mm,

10 um); mobile phase: [Heptane-EtOH]; B%: 40%-80%, 19 min) to give N-( I-(((S)- 1- cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-(2,2-difluor ocyclopropyl)-1- oxopropan-2-yl)-4-methoxy- 1H-indole-2-carboxamide Isomer 1 (50 mg, 102.56 umol, 100% purity) as a white solid. MS (ESI) m/z 488.1 [M+H] ^{+ 1} H NMR (400 MHz, MeOD-d ₄ ) δ = 7.27 (s, 1H), 7.20 - 7.10 (m, 1H), 7.04 - 7.02 (m, 1H), 6.52 - 6.50 (m, 1H), 5.17 - 5.08 (m, 1H), 4.60 - 4.56 (m, 1H), 3.93 (s, 3H), 3.26 - 3.18 (m, 2H), 2.53 - 2.37 (m, 2H), 2.49 - 2.40 (m, 1H), 2.04 - 1.88 (m, 3H), 1.87 - 1.64 (m,

3H), 1.58 - 1.43 (m, 2H), 1.18 - 1.05 (m, 1H).

[000169] Another purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 15%-55%, 8 min) to give N-(l -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-(2,2- difluorocyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1H-indole-2-carboxamide Isomer 2 (25 mg, 47.03 umol, 91.7% purity) as a white solid. MS (ESI) m/z 488.1 [M+H] ^{+ 1} H NMR (400 MHz, MeOD-d ₄ ) δ = 7.27 (s, 1H), 7.20 - 7.11 (m, 1H), 7.04 - 7.02 (m,

1H), 6.52 - 6.50 (m, 1H), 5.18 - 5.06 (m, 1H), 4.62 - 4.59 (m, 1H), 3.93 (s, 3H), 3.26 - 3.17 (m, 2H), 2.52 - 2.37 (m, 2H), 2.23 - 2.10 (m, 1H), 2.02 - 1.88 (m, 3H), 1.86 - 1.76 (m, 1H), 1.75 - 1.62 (m, 2H), 1.59 - 1.44 (m, 2H), 1.21 - 1.09 (m, 1H).

Example 261. Synthesis of viral protease inhibitor compound 1059

Step 1 : N-(l-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 -(2,2- difluorocyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[000170] N-[( 1 S)-2-[[( 1 S)- 1 -cyano-2-[(3S)-2-oxo-3 -piperidyl]ethyl]amino]- 1 -[(2,2- difluorocyclopropyl)methyl]-2-oxoethyl]-4-methoxy-1H-indole- 2-carboxamide (210 mg) was separated by SFC (column: DAICEL CHIRALPAK IE (250 mm * 30 mm,

10 um); mobile phase: [Heptane-EtOH]; B%: 40%-70%, 20 min) to give N-( !-(((£)- 1- cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-(2,2-difluor ocyclopropyl)-1- oxopropan-2-yl)-4-methoxy-1H-indole-2-carboxamide Isomer 2 2 (50 mg, 102.15 umol, 99.6% purity) as a white solid. MS (ESI) m/z 488.1 [M+H] ^{+ 1} H NMR (400 MHz, MeOD-d ₄ ) δ = 7.27 (s, 1H), 7.18 - 7.16 (m, 1H), 7.04 - 7.02 (m, 1H), 6.53 - 6.51 (m, 1H), 5.08 - 5.04 (m, 1H), 4.64 - 4.60 (m, 1H), 3.98 (s, 3H), 3.20 - 3.19 (m, 2H), 2.39 - 2.33 (m, 2H), 2.31 - 2.05 (m, 5H), 2.01 - 1.96 (m, 2H), 1.72 - 1.43 (m,

2H), 1.18 - 1.09 (m, 1H).

[000171] Another purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 15%-55%, 8 min) to give N-(l-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 -(2,2- difluorocyclopropyl)- 1 -oxopropan-2-yl)-4-methoxy- 1H-indole-2-carboxamide Isomer 2 1 (50 mg, 102.56 umol, 100% purity) as a white solid. MS (ESI) m/z 488.1 [M+H] ^{+ 1} H NMR (400 MHz, MeOD-d ₄ ) δ = 7.27 (s, 1H), 7.20 - 7.11 (m, 1H), 7.04 - 7.02 (m, 1H), 6.52 - 6.50 (m, 1H), 5.18 - 5.06 (m, 1H), 4.62 - 4.59 (m, 1H), 3.93 (s, 3H), 3.26 - 3.17 (m, 2H), 2.52 - 2.37 (m, 2H), 2.23 - 2.10 (m, 1H), 2.02 - 1.88 (m, 3H), 1.86 - 1.76 (m, 1H), 1.75 - 1.62 (m, 2H), 1.59 - 1.44 (m, 2H), 1.16 - 1.12 (m, 1H).

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

Step 1: (R)-2-(4-methoxy-lH-indole-2-carboxamido)-3-(trimethylsilyl) propanoic acid [000172] A solution of tert-butyl (2R)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-3- trimethylsilyl-propanoate (30 mg, 76.82 umol, 1 eq) in DCM (1.2 mL) was cooled to 0 °C, and then TFA/H ₂ O 10: 1 (0.8 mL) was added dropwise 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 Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 80 * 40 mm * 3 um; mobile phase: [water (0.04%HC1 )- ACN] ; B%: 32%-58%, 7 min) to give (2R)-2- [(4-methoxy-lH-indole-2-carbonyl)amino]-3-trimethylsilyl-pro panoic acid (2.74 mg, 8.19 umol, 10.67% yield, 100% purity) as a white solid. MS (ESI) m/z 335.1 [M+H] ^{+ 1} H NMR (400MHz, CDCl ₃ ^ 5 = 9.81 - 9.58 (s, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.09 - 7.02 (m, 2H), 6.60 (br d, J=7.9 Hz, 1H), 6.51 (d, J=7.8 Hz, 1H), 4.94 - 4.74 (m, 1H), 3.96 (s, 3H), 1.37 (dd, J=5.6, 14.7 Hz, 1H), 1.16 (br dd, J=9.7, 14.7 Hz, 1H), 0.11 (s,

9H)

Example 263. Synthesis of viral protease inhibitor compound 1083

Step 1: methyl (2S)-2-amino-3-(4-methyl-lH-indol-3-yl)propanoate

[000173] To (2S)-2-amino-3-(4-methyl-lH-indol-3-yl)propanoic acid (500 mg, 2.29 mmol, 1 eq) was added HCI/MeOH (4 M, 25.00 mL, 43.65 eq) in one portion at 20 °C under N ₂ . The mixture was stirred at 20 °C for 12 h. Upon completion, the reaction mixture was concentrated to get the product. Methyl (2S)-2-amino-3-(4-methyl-lH- indol-3-yl) propanoate (550 mg, 2.05 mmol, 89.33% yield, HC1) was obtianed as the purple solid and used directly next step. MS (ESI) m/z 233.1 [M+H] ⁺ 1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.03 (br s, 1 H), 8.49 (br s, 4 H), 7.09 - 7.22 (m, 2 H), 6.92 (t,J= 7.61 Hz, 1 H), 6.71 (d, J= 7.06 Hz, 1 H), 4.11 (brt, J= 7.28 Hz, 1 H), 3.65 (s,

3 H), 3.39 - 3.48 (m, 1 H), 3.27 (br d ,J= 8.16 Hz, 1 H), 2.59 (s, 3 H)

Step 2: (2S)-2-amino-3-(4-methyl-lH-indol-3-yl) propanamide

[000174] To methyl (2S)-2-amino-3-(4-methyl-lH-indol-3-yl)propanoate (550 mg, 2.05 mmol, 1 eq, HC1) was added NH ₃ /MeOH (7 M, 20.00 mL, 68.41 eq) in one portion at 20 °C under N ₂ . 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-lH-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] ⁺ Step 3: (2S)-2-amino-3-(4-methyl-2-oxo-indolin-3-yl)propanamide

[000175] To a mixture of (2S)-2-amino-3-(4-methyl-lH-indol-3-yl)propanamide (490 mg, 2.26 mmol, 1 eq) in AcOH (10 mL) was added the solution ofDMSO (264.32 mg, 3.38 mmol, 264.32 uL, 1.5 eq) and HC1 (12 M, 751.77 uL, 4 eq) in one portion at 20 °C under N ₂ . The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was added the water (10 mL) and concentrated to 10 mL. The crude product was purified by pre-HPLC (column: Phenomenex luna C18250*50 mm*10 um; mobile phase: [water (0.04%HC1 )- ACN] ; B%: 1% - 30%,10min). (2S)-2-amino- 3-(4-methyl-2-oxo-indolin-3-yl) propanamide (124 mg, crude, HC1) was obtained as light green solid. MS (ESI) m/z 234.1 [M+H] ⁺

Step 4: N-[(1S)-2-[[(1S)-2-amino-1-[(4-methyl-2-oxo-indolin-3-yl)met hyl]-2-oxo- ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH -indole-2-carboxamide [000176] To a mixture of (2S)-2-amino-3-(4-methyl-2-oxo-indolin-3-yl)propanamide (120 mg, 514.43 umol, 1 eq) and (2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoic acid (194.41 mg, 514.43 umol, 80% purity, 1 eq) in DMF (1.2 mL) was added PyBop (267.71 mg, 514.43 umol, 1 eq) and TEA (156.17 mg,

1.54 mmol, 214.81 uL, 3 eq) at -30 °C under N ₂ . The mixture was stirred at -30 °C for 2 h. Upon completion, the reaction mixture was quenched by addition water (10 mL) at 20 °C, and then diluted with DCM (10 mL) and extracted with DCM (5 mL * 2). The combined organic layers were concentrated under reduced pressure to give a residue. The crude product was purified by pre-TLC. N-[( 1 S)-2-[[( 1 S)-2-amino- 1 -[(4- methyl-2-oxo-indolin-3-yl)methyl]-2-oxo-ethyl]amino]-1-(cycl opropylmethyl)-2-oxo- ethyl]-4-methoxy- 1 H-indole-2-carboxamide (130 mg, crude) was obtained as the light yellow solid. MS (ESI) m/z 518.2 [M+H] ⁺

Step 5 : N-[(l S)-2-[[( 1 S)- 1 -cyano-2-(4-methyl-2-oxo-indolin-3-yl)ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo- ethyl]-4-methoxy- 1 H-indole-2-carboxamide

[000177] To a mixture of N-[(l S)-2-[[(l S)-2-amino-1-[(4-methyl-2-oxo-indolin-3- yl)methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-methoxy-lH- indole-2-carboxamide (130 mg, 251.17 umol, 1 eq) in DCM (20 mL) was added Burgess reaction (179.57 mg, 753.51 umol, 3 eq) in one portion at 20 °C under N ₂ . The mixture was stirred at 20 °C for 12 h. Upon completion, the reaction mixture was added the water (5 mL) and stirred for 20 min. Then the reaction mixture was concentrated to get the crude product. The crude product was purified by pre-HPLC (column: Waters Xb ridge BEH C18 100*25 mm*5 um; mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 30% - 60%, 10 min). N-[(1S)-2-[[(1S)-1-cyano-2-(4-methyl- 2-oxo-indolin-3-yl)ethyl]amino]-1-(cyclopropylmethyl)-2-oxo- ethyl ]-4-methoxy- 1 H- indole-2-carboxamide (55 mg, 110.10 umol, 43.83% yield) was obtained as white solid. MS (ESI) m/z 500.2 [M+H] ⁺

Step 6: N-[2-[[(1S)-1-cyano-2-(4-methyl-2-oxo-indolin-3-yl)ethyl]ami no]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide

[000178] The product was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [0.1% NH3.H ₂ O EtOH]; B%: 55%-55%, 20 min). Isomer 1 : N-[2-[[(1S)-1-cyano-2-(4-methyl-2-oxo-indolin-3-yl)ethyl]ami no]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy- lH-indole-2-carboxamide (10.8 mg, 21.34 umol, 19.38% yield, 98.7% purity) was obtained as the white solid. MS (ESI) m/z 500.2 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.57 (s, 1 H) 10.41 - 10.59 (m, 1 H) 8.95 (m, 1 H) 8.42 - 8.59 (m, 1 H) 7.36 (m, 1 H) 7.05 - 7.14 (m, 2 H) 6.99 (br d, J= 8.33 Hz, 1 H) 6.73 - 6.82 (m, 1 H) 6.66 (m, 1 H) 6.50 (d,J= 7.89 Hz, 1 H) 4.99 - 5.14 (m, 1 H) 4.38 - 4.54 (m, 1 H) 3.88 (s, 3 H) 3.50 - 3.65 (m, 1 H) 3.50 - 3.65 (m, 1 H) 2.62 - 2.72 (m, 1 H) 2.28 (d,J= 12.93 Hz, 2 H) 2.17 (m, 1 H) 1.92 - 2.04 (m, 1 H) 1.71 - 1.87 (m, 1 H) 1.43 - 1.61 (m, 2 H) 0.73 - 0.88 (m, 1 H) 0.33 - 0.49 (m, 2 H) 0.02 - 0.25 (m, 2 H)

[000179] Isomer 2: N-[2-[[(1S)-1-cyano-2-(4-methyl-2-oxo-indolin-3-yl)ethyl]ami no]-1- (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide (17.2 mg, 34.29 umol, 31.15% yield, 99.6% purity) was obtained as the white solid.. MS (ESI) m/z 500.2 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.55 (br d ,J= 1.53 Hz, 1 H) 10.40 - 10.54 (m, 1 H) 8.93 (m, 1 H) 8.48 (m, 1 H) 7.34 (m, 1 H) 7.03 - 7.14 (m, 2 H) 6.98 (br d, J= 8.11 Hz, 1 H) 6.71 - 6.79 (m, 1 H) 6.64 (m, 1 H) 6.45 - 6.52 (m, 1 H) 4.97 - 5.10 (m, 1 H) 4.36 - 4.53 (m, 1 H) 3.86 (s, 3 H) 3.49 - 3.64 (m, 1 H) 2.57 - 2.64 (m, 1 H) 2.26 (d ,J= 12.94 Hz, 3 H) 2.16 (m, 1 H) 1.96 (m, 1 H) 1.70 - 1.84 (m, 1 H) 1.44 - 1.57 (m, 1 H) 0.77 (m, 1 H) 0.34 - 0.44 (m, 2 H) 0.04 - 0.22 (m, 2 H)

Example 264. Synthesis of viral protease inhibitor compound 1085

Step 1: methyl (2S)-2-amino-3-(5-methyl-lH-indol-3-yl)propanoate

[000180] A mixture of (2S)-2-amino-3-(5-methyl-lH-indol-3-yl)propanoic acid (1 g, 4.58 mmol, 1 eq) in HCI/MeOH (4 M, 20 mL) was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-amino-3-(5-methyl-lH-indol-3-yl)propanoate (1.1 g, 4.09 mmol, 89.33% yield, HCI) as a yellow solid.

Step 2: (2S)-2-amino-3-(5-methyl-lH-indol-3-yl)propanamide

[000181] A mixture of methyl (2S)-2-amino-3-(5-methyl-lH-indol-3-yl)propanoate (1.1 g, 4.74 mmol, 1 eq) in NH ₃ /MeOH (7 M, 34.71 mL, 51.30 eq) was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (2S)-2-amino-3-(5-methyl-lH-indol-3-yl)propanamide (1 g, 4.60 mmol, 97.19% yield) as a yellow solid. MS (ESI) m/z 218.1 [M+H] ⁺

Step 3: (2S)-2-amino-3-(5-methyl-2-oxo-indolin-3-yl)propanamide

[000182] A mixture ofDMSO (539.43 mg, 6.90 mmol, 539.43 uL, 1.5 eq) and HCI (12 M, 1.53 mL, 4 eq) was added to a mixture of (2S)-2-amino-3-(5-methyl-lH-indol-3- yl)propanamide (1 g, 4.60 mmol, 1 eq) in AcOH (10 mL), the mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was purified by prep-HPLC (HC1 condition; column: Welch Xtimate C18 100*25mm*3um;mobile phase: [water(0.04%HCl)-ACN];B%: 1%-I0%,8min) to give (2S)-2-amino-3-(5-methyl-2- oxo-indolin-3-yl)propanamide (370 mg, 682.05 umol, 14.82% yield, 43% purity) as a yellow solid. MS (ESI) m/z 234.0 [M+H] ⁺

Step 4: N-[(1S)-2-[[(1S)-2-amino-1-[(5-methyl-2-oxo-indolin-3-yl)met hyl]-2-oxo- ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH -indole-2-carboxamide [000183] To a solution of (2S)-2-amino-3-(5-methyl-2-oxo-indolin-3-yl)propanamide (370 mg, 682.05 umol, 43% purity, 1 eq) and (2 S)-3 -cyclopropyl -2-[(4-methoxy- 1 H- indole-2-carbonyl)amino]propanoic acid (226.82 mg, 750.26 umol, 1.1 eq) in DCM (5 mL) and DMF (2 mL) was added DMAP (249.98 mg, 2.05 mmol, 3 eq) and EDCI (261.50 mg, 1.36 mmol, 2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O 10 mL and extracted with EA 18 mL (6 mL * 3). The combined organic layers were washed with brine 9 mL (9 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by prep-TLC (SiO ₂ , EAMeOH = 10:1) to give N-[(1S)-2-[[(1S)-2-amino-1-[(5-methyl-2-oxo-indolin-3-yl)met hyl]-2-oxo- ethyljamino]- 1 -(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy- 1 H-indole-2- carboxamide (150 mg, 289.81 umol, 42.49% yield) as a white solid. MS (ESI) m/z 518.2 [M+H] ⁺

Step 5: N-[(l S)-2-[[( 1 S)- 1 -cyano-2-(5-methyl-2-oxo-indolin-3-yl)ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide

[000184] A mixture of N-[(l S)-2-[[(l S)-2-amino-1-[(5-methyl-2-oxo-indolin-3- yl)methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-methoxy-lH- indole-2-carboxamide (120 mg, 185.48 umol, 80% purity, 1 eq) in DCM (2 mL) was added Burgess reagent (88.40 mg, 370.96 umol, 2 eq) in one portion. The mixture was stirred at 40 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep- HPLC (neutral condition; column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HCC>3)-ACN];B%: 30%- 60%,8min) to give N-[(l S)-2-[[(l S)-1-cyano-2-(5-methyl-2-oxo-indolin-3- yl)ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy -lH-indole-2- carboxamide (30 mg, 60.05 umol, 32.38% yield) as a white solid. MS (ESI) m/z 500.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ = 11.62 - 11.48 (m, 1H), 10.47 - 10.30 (m, 1H), 9.12 - 8.89 (m, 1H), 8.58 - 8.45 (m, 1H), 7.37 (br d, J= 6.7 Hz, 1H), 7.19 - 7.04 (m, 2H), 7.02 - 6.95 (m, 2H), 6.77 - 6.63 (m, 1H), 6.55 - 6.15 (m, 1H), 5.25 - 5.02 (m, 1H), 4.58 - 4.40 (m, 1H), 3.89 (d, J= 3.3 Hz, 3H), 3.51 - 3.38 (m, 1H), 2.32 - 2.13 (m, 5H), 1.87 - 1.70 (m, 1H), 1.59 - 1.39 (m, 1H), 0.80 (br s, 1H), 0.50 - 0.28 (m, 2H), 0.27 - -0.03 (m, 2H)

Example 265. Synthesis of viral protease inhibitor compound 1087

Step 1: methyl (2S)-2-amino-3-(6-methyl-lH-indol-3-yl)propanoate

[000185] To (2S)-2-amino-3-(6-methyl-lH-indol-3-yl)propanoic acid (1.00 g, 4.58 mmol, 1 eq) was added HCl/MeOH (4 M, 50.00 mL, 43.65 eq) in one portion at 20 °C under N ₂ . The mixture was stirred at 20 °C for 12 h. Upon completion, the reaction mixture was concentrated to get Methyl (2S)-2-amino-3-(6-methyl-lH-indol-3-yl) propanoate (1.15 g, crude, HCI) as the light yellow solid and used directly next step. MS (ESI) m/z 233.1 [M+H] ⁺

Step 2: (2S)-2-amino-3-(6-methyl-lH-indol-3-yl)propanamide

[000186] Methyl (2S)-2-amino-3-(6-methyl-lH-indol-3-yl) propanoate (1.15 g, 4.28 mmol, 1 eq, HCI) was dissolved in NH ₃ /MeOH (7 M, 20 mL, 32.72 eq) at 20 °C. The mixture was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was cooled to 20 °C and concentrated to get the product. (2S)-2-amino-3-(6-methyl-lH- indol-3-yl) propanamide (1.1 g, crude) was obtained as the light yellow solid and used directly next step. MS (ESI) m/z 218.1 [M+H] ⁺

Step 3: (2S)-2-amino-3-(6-methyl-2-oxo-indolin-3-yl)propanamide

[000187] To a solution of (2S)-2-amino-3-(6-methyl-lH-indol-3-yl)propanamide (1.08 g, 4.97 mmol, 1 eq) in AcOH (10 mL) was added drop wise the solution of DMSO (582.58 mg, 7.46 mmol, 582.58 uL, 1.5 eq) and HC1 (12 M, 1.66 mL, 4 eq) at 20 °C under N ₂ . The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was added the saturated sodium bicarbonate aqueous solution to pH~6. The product was purified by prep-HPLC (column: Phenomenex luna C18250*50mm*10 um; mobile phase: [water (0.04%HC1) -ACN]; B%: l%-30%, lOmin) to give (2S)-2- amino-3-(6-methyl-2-oxo-indolin-3-yl)propanamide (0.22 g, 754.50 umol, 15.18% yield, 80% purity) as the green solid. MS (ESI) m/z 234.1 [M+H] ⁺

Step 4: N-[(1S)-2-[[(1S)-2-amino-1-[(6-methyl-2-oxo-indolin-3-yl)met hyl]-2-oxo- ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH -indole-2-carboxamide [000188] To a mixture of (2S)-2-amino-3-(6-methyl-2-oxo-indolin-3-yl)propanamide (200.00 mg, 857.39 umol, 1 eq) and (2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoic acid (324.01 mg, 857.39 umol, 80% purity, 1 eq) in DMF (0.5 mL) was added PyBop (446.18 mg, 857.39 umol, 1 eq) and TEA (260.28 mg, 2.57 mmol, 358.01 uL, 3 eq) in one portion at -30 °C under N ₂ . The mixture was stirred at -30 °C for 2 h. Upon completion, the reaction mixture was quenched by addition water (20 mL) at 20 °C, and then diluted with DCM (20 mL) and extracted with DCM (10 mL * 2). The combined organic layers were concentrated under reduced pressure to give N-[(l S)-2-[[(l S)-2-amino-1-[(6-methyl-2-oxo-indolin-3- yl)methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-methoxy-lH- indole-2-carboxamide (200 mg, crude) as the light yellow oil. MS (ESI) m/z 518.2 [M+H] ⁺

Step 5 : N-[(l S)-2-[[( 1 S)- 1 -cyano-2-(6-methyl-2-oxo-indolin-3-yl)ethyl]amino]- 1 - (cyclopropylmethyl)-2-oxo-ethyl]-4-methoxy-lH-indole-2-carbo xamide

[000189] To a mixture of N-[(l S)-2-[[(l S)-2-amino-1-[(6-methyl-2-oxo-indolin-3- yl)methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-methoxy-lH- indole-2-carboxamide (100 mg, 193.21 umol, 1 eq) in DCM (20 mL) was added Burgess reagent (138.13 mg, 579.63 umol, 3 eq) in one portion at 25 °C under N ₂ .

The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was added the water (5 mL) and stirred for 20 min. Then the reaction mixture was concentrated to get the crude product. The crude protuct was purified by pre-HPLC (column: Waters Xbridge BEH C18 100*25mm*5um; mobile phase: [water (lOmM NH4HCO3)- ACN] ; B%: 30%-60%, 10min) to giveN-[(1S)-2-[[(1S)-1-cyano-2-(6- methyl-2-oxo-indolin-3-yl)ethyl]amino]-1-(cyclopropylmethyl) -2-oxo-ethyl]-4- methoxy-lH-indole-2-carboxamide (2.11 mg, 4.20 umol, 2.17% yield, 99.4% purity) as white solid. MS (ESI) m/z 500.2 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ = 11.67 - 11.47 (m, 1H), 10.52 - 10.34 (m, 1H), 9.11 - 8.93 (m, 1H), 8.59 - 8.44 (m,

1H), 7.40 - 7.31 (m, 1H), 7.18 - 7.03 (m, 2H), 7.01 - 6.94 (m, 1H), 6.82 - 6.70 (m,

1H), 6.64 (d, J= 7.2 Hz, 1H), 6.54 - 6.45 (m, 1H), 5.19 - 5.01 (m, 1H), 4.53 - 4.41 (m, 1H), 3.91 - 3.83 (m, 3H), 3.49 - 3.36 (m, 1H), 2.31 (br d, J= 2.0 Hz, 5H), 1.85 - 1.68 (m, 1H), 1.59 - 1.38 (m, 1H), 0.86 - 0.70 (m, 1H), 0.44 - 0.28 (m, 2H), 0.24 - -0.01 (m, 2H).

Example 266. Synthesis of viral protease inhibitor compound 1091 Step 1: (S)-methyl 2-amino-3-(4-chloro-lH-indol-3-yl)propanoate

[000190] A mixture of (2S)-2-amino-3-(4-chloro-lH-indol-3-yl)propanoic acid (1 g, 4.19 mmol, 1 eq) in HCl/MeOH (4 M, 20 mL, 19.09 eq) was stirred at 25 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the methyl (2S)-2-amino-3-(4-chloro-lH-indol-3-yl)propanoate (1 g, crude) as a yellow solid. MS (ESI) m/z 251.1 [M-H] ⁺ .

Step 2: (S)-2-amino-3-(4-chloro-lH-indol-3-yl)propanamide

[000191] A solution of methyl (2S)-2-amino-3-(4-chloro-lH-indol-3-yl)propanoate (1 g, 3.96 mmol, 1 eq) in NH ₃ /MeOH (7 M, 20.00 mL, 35.38 eq) was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the (2S)-2-amino-3-(4-chloro-lH-indol-3-yl)propanamide (0.9 g, crude) as a yellow solid. MS (ESI) m/z 238.1 [M+H] ⁺ .

Step 3: (2S)-2-amino-3-(4-chloro-2-oxoindolin-3-yl)propanamide

[000192] To a solution of (2S)-2-amino-3-(4-chloro-lH-indol-3-yl)propanamide (500 mg, 2.10 mmol, 1 eq) in t-BuOH (6 mL), EtOH (4 mL) and AcOH (2 mL), then BLAH; pyridin-1-ium (672.78 mg, 2.10 mmol, 1 eq) was added, the mixture was stirred at 20 °C for 3 h, then AcOH (2 mL) and Zn (1.05 g, 15.99 mmol, 7.6 eq) was added, the mixture was stirred at 20 °C for 15 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C 1880 * 40 mm * 3 um; mobile phase: [water (0.04% HC1) - ACN]; B%: 1% - 25%, 7 min) to give the (2S)-2-amino- 3-(4-chloro-2-oxo-indolin-3-yl)propanamide (35 mg, 137.97 umol, 6.56% yield) was obtained as a white solid. MS (ESI) m/z 254.1 [M+H] ⁺ .

Step 4: N-((2S)-1-(((2S)- 1 -amino-3-(4-chloro-2-oxoindolin-3-yl)- 1 -oxopropan-2-yl)amino)- 3-cyclopropyl-1-oxopropan-2-yl)-4-methoxy-lH-indole-2-carbox amide

[000193] To a solution of (2S)-2-amino-3-(4-chloro-2-oxo-indolin-3-yl)propanamide (30 mg, 103.40 umol, 1 eq, HC1) and (2S)-3-cyclopropyl-2-[(4-methoxy-lH-indole-2- carbonyl)amino]propanoic acid (40.64 mg, 134.42 umol, 1.3 eq) in DMF (1 mL) was added Py-Bop (53.81 mg, 103.40 umol, 1 eq) was cooled to -30 °C, then EtsN (31.39 mg, 310.19 umol, 43.17 uL, 3 eq) in DMF (0.5 mL) was added drop-wise, the mixture was stirred at -30 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 20 mL at 0 °C, and then extracted with DCM (10 mL * 3). The combined organic layers were washed with brine 15 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (S1O2, EtOAc:MeOH = 20: 1) to give the N-[( 1 S)-2-[[( 1 S)-2-amino- 1 - [(4-chloro-2-oxo-indolin-3-yl)methyl]-2-oxo-ethyl]amino]-1-( cyclopropylmethyl)-2- oxo-ethyl]-4-methoxy-lH-indole-2-carboxamide (35 mg, 65.06 umol, 62.92% yield) was obtained as a white solid. MS (ESI) m/z 538.2 [M+H] ⁺ .

Step 5 : N-((2S)- 1 -((( 1 S)-2-(4-chloro-2-oxoindolin-3-yl)-1-cyanoethyl)amino)-3-cycl opropyl- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[000194] To a sloution of N-[( 1 S)-2-[[( 1 S)-2-amino- 1 -[(4-chloro-2-oxo-indolin-3- yl)methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-et hyl]-4-methoxy-lH- indole-2-carboxamide (35 mg, 65.06 umol, 1 eq) in DCM (2 mL) was added burgess reagent (31.01 mg, 130.11 umol, 2 eq), then the mixture was stirrred at 20 °C for 12 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 0.5 mL, concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C1875 * 30mm * 3um; mobile phase:

[water (0.2% FA) - ACN]; B%: 30% - 60%, 8 min) to give the N-[(1S)-2-[[(1S)-2-(4- chloro-2-oxo-indolin-3-yl)- 1 -cyano-ethyl]amino]- 1 -(cyclopropylmethyl)-2-oxo- ethy 1 ]-4-methoxy- 1 H-indole-2-carboxamide (4 mg, 7.69 umol, 11.82% yield, 100% purity) was obtained as a yellow solid. MS (ESI) m/z 520.1 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.29 - 7.23 (m, 1H), 7.21 - 7.10 (m, 2H), 7.07 - 6.95 (m, 2H), 6.88 - 6.65 (m, 1H), 6.55 - 6.49 (m, 1H), 5.28 - 4.53 (m, 1H), 3.93 (d, J = 2.6 Hz, 3H),

3.85 - 3.72 (m, 1H), 3.01 - 2.85 (m, 1H), 2.62 - 2.28 (m, 1H), 1.88 - 1.78 (m, 1H),

1.70 - 1.55 (m, 1H), 1.41 - 1.26 (m, 1H), 0.95 - 0.76 (m, 1H), 0.58 - 0.39 (m, 2H),

0.27 - 0.09 (m, 2H).

Example 267. Synthesis of viral protease inhibitor compound 1101

Step 1: (S)-methyl 2-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate

[000195] A solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(5,5-dimethyl-2-oxo- pyrrolidin-3-yl)propanoate (500.00 mg, 1.59 mmol, 1 eq) in HCI/MeOH (4 M, 10.00 mL, 25.15 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product methyl (2S)-2-amino-3- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (390 mg, crude, HC1) as a white solid.

Step 2: (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanamid o)-3-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate

[000196] 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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum etherEthyl 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] ⁺ .

Step 3: (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)-5,5-dimethyl- 2- oxopyrrolidin-3-yl)propanoate

[000197] To a solution of methyl (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4- dimethyl-pentanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrroli din-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, HC1) as a white solid.

Step 4: (S)-methyl 3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((S)-2-(4-methox y-lH- indole-2-carboxamido)-4,4-dimethylpentanamido)propanoate

[000198] To a solution of methyl (2 S)-2-[ [(2 S)-2-amino-4,4-dimethy 1-pentanoy 1 ]ami no]- 3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (190 mg, 502.77 umol, 1 eq, HC1) and 4-methoxy- 1 H-indole-2-carboxylic acid (124.96 mg, 653.60 umol, 1.3 eq) in DCM (4 mL) and DMF (1 mL), and then DMAP (184.27 mg, 1.51 mmol, 3 eq) and EDCI (192.76 mg, 1.01 mmol, 2 eq) was added, then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 50 mL at 0 °C, and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give the product methyl (2S)-3-[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]-2-[[(2S)-2-[(4-methoxy-lH-indole-2-carbonyl )amino]-4,4-dimethyl- pentanoyl]amino]propanoate (200 mg, 349.78 umol, 69.57% yield, 90% purity) as a yellow solid. MS (ESI) m/z 515.2 [M+H] ⁺ .

Step 5 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5, 5-dimethyl -2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide [000199] A solution of methyl (2S)-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]-2-[[(2S)- 2-[(4-methoxy-lH-indole-2-carbonyl)amino]-4,4-dimethyl- pentanoyl]amino]propanoate (200 mg, 388.64 umol, 1 eq) in NH ₃ /MeOH (7 M, 5 mL, 90.06 eq) was stirred at 40 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product N-[( 1 S)- 1 -[[( 1 S)-2-amino- 1 - [[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethy l]carbamoyl]-3,3- dimethyl-butyl]-4-methoxy-lH-indole-2-carboxamide (190 mg, crude) as a white solid. MS (ESI) m/z 500.2 [M+H] ⁺ .

Step 6: N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3 -yl)ethyl)amino)-4,4- dimethyl- 1 -oxopentan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[000200] To a solution of N-[(1S)-1-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]carbamoyl]-3,3-dimethyl- butyl]-4-methoxy-lH- indole-2-carboxamide (160 mg, 320.26 umol, 1 eq) in DCM (3 mL) and burgess reagent (91.58 mg, 384.31 umol, 1.2 eq) was added, and then the mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 10 u 250 mm * 80 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%:25% - 55%, 35 min) to give the product N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]ethyl]carbamoyl]-3, 3-dimethyl-butyl]-4- methoxy- 1 H-indole-2-carboxamide (67.35 mg, 139.85 umol, 43.67% yield, 100% purity) as a white solid. MS (ESI) m/z 482.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d6) δ = 11.54 (d, J = 1.6 Hz, 1H), 8.87 (d, J = 8.2 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 7.81 (s, 1H), 7.33 (d, J = 1.5 Hz, 1H), 7.12 - 7.06 (m, 1H), 7.03 - 6.98 (m, 1H), 6.50 (d, J = 7.6 Hz, 1H), 4.98 - 4.89 (m, 1H), 4.51 (dt, J = 3.6, 8.5 Hz, 1H), 3.88 (s, 3H), 2.60 - 2.54 (m, 1H), 2.17 (dt, J = 4.8, 9.0 Hz, 1H), 1.95 (dd, J = 8.6, 12.2 Hz, 1H), 1.83 - 1.72 (m, 2H), 1.71 - 1.63 (m, 1H), 1.49 (t, J = 11.6 Hz, 1H), 1.14 (s, 3H), 1.02 (s, 3H), 0.93 (s, 9H)

Example 268. Synthesis of viral protease inhibitor compound 1103

Step 1: (S)-methyl 3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((S)-2-azaspiro[ 4.5]decane- 3-carboxamido)propanoate hydrochloride

[000201] 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]d ecane-2-carboxylate (400 mg, 834.01 umol, 1 eq) in HCI/MeOH (4 M, 5 mL, 23.98 eq) 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]p ropanoate (340 mg, crude, HC1) as a white solid.

Step 2: (S)-methyl 3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((S)-2-(4-methox y-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamido)propa noate

[000202] To a solution of 4-methoxy- 1 H-indole-2-carboxylic acid (170.98 mg, 894.33 umol, 1.2 eq) and methyl (2S)-2-[[(3S)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (310 mg, 745.28 umol, 1 eq, HC1) in DCM (15 mL) and DMF (3 mL) was added DMAP (273.15 mg, 2.24 mmol, 3 eq) and EDCI (285.74 mg, 1.49 mmol, 2 eq), then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (50 mL) at 0 °C, and then extracted with DCM (50 mL * 3). The combined organic layers were washed with brine (50 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1 to 0/1) to give the product methyl (2S)-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]-2-[[(3S)-2- (4-methoxy-lH- indole-2-carbonyl)-2-azaspiro[4.5 ]decane-3 -carbonyl ]amino]propanoate (320 mg, 561.65 umol, 75.36% yield, 97% purity) as a yellow solid. MS (ESI) m/z 553.2 [M+H] ⁺ .

Step 3 : (S)-N-((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl) -1-oxopropan-2-yl)-2- (4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-car boxamide

[000203] To a solution of methyl (2S)-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]-2- [[(3 S)-2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane- 3- carbonyl]amino]propanoate (320 mg, 579.02 umol, 1 eq) in NH ₃ /MeOH (7 M, 5.00 mL, 60.45 eq) was stirred at 60 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product (3 S)-N-[( 1 S)-2-amino- 1 - [[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethy l]-2-(4-methoxy-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (310 mg, crude) as a yellow solid. MS (ESI) m/z 538.3 [M+H] ⁺ .

Step 4: (S)-N-((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl) ethyl)-2-(4-methoxy- lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide

[000204] A solution of (3S)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin- 3- yl]methyl]-2-oxo-ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)-2 -azaspiro[4.5]decane- 3 -carboxamide (310 mg, 501.63 umol, 87% purity, 1 eq) and burgess reagent (239.09 mg, 1.00 mmol, 2 eq) in DCM (5 mL) was stirred at 30 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 30 mm * 10 um; mobile phase: [water(10 mM NH4HCO3) - ACN]; B%: 35% - 65%, 8 min) to give the product (3S)-N-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3 - yl]ethyl]-2-(4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5] decane-3-carboxamide (115.37 mg, 222.02 umol, 44.26% yield, 100% purity) as a white solid. MS (ESI) m/z 520.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.53 (s, 1H), 8.89 (d, J= 8.1 Hz, 1H), 7.81 (s, 1H), 7.15 - 7.08 (m, 1H), 7.02 (d, J= 8.3 Hz, 1H), 6.94 (d, J= 1.2 Hz, 1H), 6.52 (d, J= 7.7 Hz, 1H), 4.96 - 4.89 (m, 1H), 4.50 (t, J= 8.5 Hz, 1H), 3.89 (s, 3H), 3.87 - 3.79 (m, 1H), 3.67 (d,J= 10.4 Hz, 1H), 2.26 - 2.11 (m, 2H), 2.00 (dd, J= 8.4, 12.0 Hz, 1H), 1.78 - 1.70 (m, 1H), 1.63 - 1.31 (m, 13H), 1.14 (s, 3H), 1.08 - 1.00 (m, 3H).

Example 269. Synthesis of viral protease inhibitor compound 1105

Step 1: tert-butyl 7-[[(1S)-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl] -2-methoxy-2- oxo-ethyl]carbamoyl]-6-azaspiro[3.4]octane-6-carboxylate

[000205] To a mixture of methyl (2S)-2-amino-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]propanoate (450 mg, 2.10 mmol, 1 eq) and 6-tert-butoxycarbonyl-6- azaspiro[3.4]octane-7-carboxylic acid (589.83 mg, 2.31 mmol, 1.1 eq) in DCM (10 mL), was added DMAP (769.75 mg, 6.30 mmol, 3 eq) and EDCI (805.24 mg, 4.20 mmol, 2 eq), the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O 25 mL and extracted with DCM 45 mL (15 mL * 3). The combined organic layers were washed with brine 20 mL (20 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1 to 0/1) to give tert-butyl 7-[[(1S)-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-methoxy-2-oxo-ethyl]carbamoyl]-6-a zaspiro[3.4]octane-6- carboxylate (0.9 g, 1.79 mmol, 85.41% yield, 90% purity) as a yellow solid. MS (ESI) m/z 452.3 [M+H] ⁺

Step2 : methyl (2S)-2-(6-azaspiro[34]octane-7-carbonylamino)-3-[(3R)-5,5-di methyl-2-oxo- pyrrolidin-3-yl]propanoate

[000206] A mixture of tert-butyl 7-[[(1S)-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]methyl]-2-methoxy-2-oxo-ethyl]carbamoyl]-6-azaspiro[3.4]o ctane-6-carboxylate (0.9 g, 1.79 mmol, 90% purity, 1 eq) in HCl/MeOH (4M, 15 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-[(3R)-5,5- dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (800 mg, crude, HC1) as a white solid.

Step 3: methyl (2S)-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]-2-[[6-(4-me thoxy-lH- indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carbonyl]amino]pr opanoate

[000207] A mixture of methyl (2S)-2-(6-azaspiro[3.4]octane-7-carbonylamino)-3-[(3R)- 5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (386.00 mg, 995.10 umol, 1 eq, HC1) and 4-methoxy-lH-indole-2-carboxylic acid (199.76 mg, 1.04 mmol, 1.05 eq) in DCM (10 mL) was added DMAP (364.71 mg, 2.99 mmol, 3 eq) and EDCI (381.53 mg, 1.99 mmol, 2 eq), and then the mixture was stirred at 25 °C for 2 h under N ₂ atmosphere. Upon completion, the reaction mixture was diluted with H ₂ O 20 mL and extracted with EA 45 mL (15 mL * 3). The combined organic layers were washed with brine 20 mL (20 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1 to 0/1) to give methyl (2S)-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]-2-[[6-(4-me thoxy-lH-indole-2- carbonyl)-6-azaspiro[3.4]octane-7-carbonyl]amino]propanoate (390 mg, 691.37 umol, 69.48% yield, 93% purity) as a yellow solid. MS (ESI) m/z 525.3 [M+H] ⁺

Step 4: N-[(l S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methy l]-2-oxo-ethyl]- 6-(4-methoxy- 1 H-indole-2-carbonyl)-6-azaspiro[3 4]octane-7-carboxamide

[000208] A mixture of methyl (2S)-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]-2-[[6-(4- methoxy-lH-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carbon yl]amino]propanoate (370 mg, 705.29 umol, 1 eq) in NH ₃ /MeOH(7 M, 15 mL, 148.88 eq) was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]methyl]-2-oxo-ethyl]-6-(4-methoxy-lH-indole-2-carbonyl)-6 -azaspiro[3.4]octane- 7-carboxamide (320 mg, 571.43 umol, 81.02% yield, 91% purity) as a yellow solid. MS (ESI) m/z 510.3 [M+H] ⁺

Step 5: N-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]e thyl]-6-(4-methoxy- lH-indole-2-carbonyl)-6-azaspiro[3.4]octane-7-carboxamide

[000209] A mixture ofN-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]methyl]-2-oxo-ethyl]-6-(4-methoxy-lH-indole-2-carbonyl)-6 -azaspiro[3.4]octane- 7-carboxamide (320 mg, 571.43 umol, 91% purity, 1 eq) in DCM (10 mL) was added Burgess reagent (272.36 mg, 1.14 mmol, 2 eq), and the resulting mixture was stirred at 20 °C for 5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC ( neutral condition;column: Phenomenex Gemini -NX C 18 75*30mm*3um;mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN];B%: 30%-60%,8min) to give desired compound 200 mg as a white solid, which was further separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O IPA];B%: 52%-52%,12min) to give N-[( 1 S)- 1 -cyano-2-[(3R)-5, 5-dimethyl-2-oxo- pyrrolidin-3-yl]ethyl]-6-(4-methoxy-lH-indole-2-carbonyl)-6- azaspiro[3.4]octane-7- carboxamide Isomer 1 (90 mg, 181.62 umol, 31.78% yield, 99.2% purity) as a white solid. MS (ESI) m/z 492.1 [M+H] ⁺

[000210] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.55 (s, 1H), 8.83 (d ,J= 8.2 Hz, 1H), 7.82 (s, 1H), 7.16 - 7.07 (m, 1H), 7.05 - 6.94 (m, 2H), 6.52 (d, J= 7.7 Hz, 1H), 4.93 (q, J = 8.1 Hz, 1H), 4.45 (t ,J= 7.4 Hz, 1H), 4.04 - 3.69 (m, 5H), 2.70 - 2.56 (m, 1H), 2.35 - 2.25 (m, 1H), 2.21 - 1.69 (m, 10H), 1.50 (brt, 11.5 Hz, 1H), 1.20 - 0.85 (m, 6H).

[000211] ¹ H NMR (400 MHz, DMSO-d ₆ , 273+80K) δ = 11.39 - 11.15 (m, 1H), 8.83 - 8.51 (m, 1H), 7.66 - 7.53 (m, 1H), 7.17 - 7.02 (m, 2H), 7.01 - 6.88 (m, 1H), 6.53 (d ,J = 7.7 Hz, 1H), 4.99 - 4.86 (m, 1H), 4.64 - 4.44 (m, 1H), 4.05 - 3.82 (m, 5H), 2.54 (br s, 1H), 2.39 - 2.25 (m, 1H), 2.20 - 1.73 (m, 10H), 1.61 - 1.42 (m, 1H), 1.23 - 1.03 (m,

6H). [000212] To give N-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]e thyl]-6- (4-methoxy- 1 H-indole-2-carbonyl)-6-azaspiro[3 4]octane-7-carboxamide Isomer 2 (100 mg, 203.43 umol, 35.60% yield, 100% purity) as a white solid. MS (ESI) m/z 492.1 [M+H] ⁺

[000213] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.69 - 11.46 (s, 1H), 8.74 (d, J = 8.2 Hz, 1H), 7.87 - 7.66 (m, 1H), 7.17 - 7.09 (m, 1H), 7.06 - 6.95 (m, 2H), 6.60 - 6.40 (m, 1H), 5.00 - 4.74 (m, 1H), 4.45 (t, J= 7.2 Hz, 1H), 3.98 (q ,J= 10.1 Hz, 2H), 3.93 - 3.77 (m, 3H), 2.49 - 2.41 (m, 1H), 2.28 (br dd, J= 8.0, 12.2 Hz, lH), 2.14 (br dd,J = 4.0, 9.3 Hz, 2H), 2.05 - 1.80 (m, 7H), 1.80 - 1.67 (m, 1H), 1.50 (brt, J= 11.5 Hz, 1H), 1.20 - 1.02 (m, 6H).

[000214] ¹ H NMR (400 MHz, DMSO-d ₆ , 273+80K) δ = 11.35 - 11.25 (m, 1H), 8.59 (br d, J= 5.5 Hz, 1H), 7.56 (br s, 1H), 7.18 - 7.03 (m, 2H), 7.02 - 6.89 (m, 1H), 6.53 (d ,J = 7.7 Hz, 1H), 4.98 - 4.88 (m, 1H), 4.63 - 4.49 (m, 1H), 4.02 - 3.88 (m, 5H), 2.49 - 2.42 (m, 1H), 2.36 - 2.26 (m, 1H), 2.21 - 2.10 (m, 2H), 2.08 - 1.85 (m, 8H), 1.58 - 1.46 (m, 1H), 1.25 - 1.01 (m, 6H).

Example 270. Synthesis of viral protease inhibitor compound 1115

Step 1: (S)-methyl 2-((S)-2-(7-chloro-5-methoxy-lH-indole-2-carboxamido)-3 cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin- 3-yl)propanoate [000215] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl] propanoate (150 mg, 414.52 umol, 1 eq, HC1) and 7-chloro-5-methoxy-lH-indole-2-carboxylic acid (140.29 mg, 621.78 umol, 1.5 eq) in DCM (4 mL) was added DMAP (101.28 mg, 829.04 umol, 2 eq) and EDCI (119.20 mg, 621.78 umol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 40 mL, and then extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10: 1) to give methyl (2S)-2-[[(2S)-2-[(7-chloro-5- methoxy- 1 H-indole-2-carbonyl) amino]-3-cyclopropyl-propanoyl] amino]-3-[(3R)-5, 5-dimethyl-2-oxo-pyrrolidin-3-yl] propanoate (198 mg, 360.33 umol, 86.93% yield, 97% purity) as a yellow solid. MS (ESI) m/z 532.2 [M+H] ⁺ .

Step 2 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-7-chloro-5-methoxy -lH-indole-2-carboxamide.

[000216] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-5-methoxy-lH-indole-2- carbonyl) amino]-3-cyclopropyl-propanoyl] amino]-3-[(3R)-5, 5-dimethyl-2-oxo- pyrrolidin-3-yl] propanoate (160 mg, 300.18 umol, 1 eq) in NH3MeOH (7 M, 10 mL, 233.19 eq) was stirred at 65 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give crude product N-[(1S)-2-[[(1S)-2-amino- l-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-et hyl]amino]-l (cyclopropylmethyl)-2-oxo-ethyl]-7-chloro-5-methoxy-lH-indol e-2-carboxamide (166.1 mg, crude) as a yellow solid. MS (ESI) m/z 517.2 [M+H] ⁺ .

Step 3: 7-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyr rolidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-5-methoxy-lH -indole-2-carboxamide.

[000217] A solution of N-[(l S)-2-[[(l S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin- 3-yl]methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo- ethyl]-7-chloro-5- methoxy- 1 H-indole-2-carboxamide (140 mg, 270.27 umol, 1 eq) in DCM (4 mL) was added burgess reagent (141.69 mg, 594.59 umol, 2.2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was remove DCM under N ₂ .

The residue was purified by prep-HPLC (column: Waters Xb ridge BEH Cl 8 100*30mm*10um; mobile phase: [water (lOmM NH ₄ HCO ₃ )-ACN]; B%: 30%-60%, 8min) to give 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo - pyrrolidin-3-yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-eth yl]-5-methoxy-lH- indole-2-carboxamide (45 mg, 90.00 umol, 33.30% yield, 100% purity) as a white solid. MS (ESI) m/z 499.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.67 - 11.34 (m, 1H), 9.06 - 8.96 (m, 1H), 8.69 - 8.62 (m, 1H), 7.90 - 7.79 (m, 1H), 7.19 - 7.11 (m, 2H), 7.02 - 6.96 (m, 1H), 5.02 - 4.92 (m, 1H), 4.57 - 4.45 (m, 1H), 3.82 -

3.73 (m, 3H), 2.63 - 2.54 (m, 1H), 2.26 - 2.12 (m, 1H), 2.03 - 1.95 (m, 1H), 1.86 -

1.73 (m, 2H), 1.58 - 1.44 (m, 2H), 1.16 - 1.12 (m, 3H), 1.09 - 1.05 (m, 3H), 0.85 -

0.77 (m, 1H), 0.51 - 0.38 (m, 2H), 0.26 - 0.16 (m, 1H), 0.14 - 0.06 (m, 1H).

Example 271. Synthesis of viral protease inhibitor compound 1119

Step 1: (S)-methyl 3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((S)-2-azaspiro[ 4.5]decane- 3-carboxamido)propanoate hydrochloride

[000218] To a solution of tert-butyl (3S)-3-[[(1S)-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin- 3 -y 1 ]methy 1 ]-2-methoxy-2-oxo-ethy 1 ]carbamoy 1 ] -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, HC1) as a white solid. Step 2: (S)-methyl 2-((S)-2-(6-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]deca ne-3- carboxamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)propan oate

[000219] To a solution of methyl (2S)-2-[ [(3 S)-2-azaspiro[4.5 ]decane-3 -carbony 1 ]amino]- 3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (310 mg, 745.28 umol, 1 eq, HC1) and 6-chloro-lH-indole-2-carboxylic acid (174.93 mg, 894.33 umol, 1.2 eq) in DCM (10 mL) and DMF (3 mL), and then DMAP (273.15 mg, 2.24 mmol, 3 eq) and EDCI (285.74 mg, 1.49 mmol, 2 eq) was added, then the mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H2030 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum etherEthyl acetate = 5: 1 to 0: 1) to gieve the product (2S)-2-[[(3S)-2-(6-chloro-lH-indole-2-carbonyl)-2-azaspiro[4 .5]decane-3- carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]p ropanoate (420 mg, 467.44 umol, 62.72% yield, 62% purity) as a yellow solid. MS (ESI) m/z 557.2 [M+H] ⁺ .

Step 3 : (S)-N-((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl) -1-oxopropan-2-yl)-2- (6-chloro-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carb oxamide

[000220] To a solution of methyl (2S)-2-[[(3S)-2-(6-chloro-lH-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 NH ₃ /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-ethy l]-2-(6-chloro-lH- 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] ⁺ .

Step 4: (S)-2-(6-chloro-lH-indole-2-carbonyl)-N-((S)-1-cyano-2-((R)- 5,5-dimethyl-2- oxopyrrolidin-3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamid e

[000221] To a solution of (3S)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin- 3-yl]methyl]-2-oxo-ethyl]-2-(6-chloro-lH-indole-2-carbonyl)- 2-azaspiro[4.5]decane- 3-carboxamide (400 mg, 553.44 umol, 75% purity, 1 eq) in DCM (5 mL) was added burgess reagent (791.32 mg, 3.32 mmol, 6 eq), and then the mixture was stirred at 30 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 45%-75%, 8 min) to give the product (3S)-2-(6-chloro-lH- indole-2-carbonyl)-N-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-ox o-pyrrolidin-3- yl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide (80.38 mg, 153.38 umol, 27.71% yield, 99.7% purity) as a white solid. MS (ESI) m/z 524.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.62 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.09 - 6.99 (m, 2H), 5.06 - 4.94 (m, 1H), 4.61 (dd, J = 7.7, 9.8 Hz, 1H), 3.99 (br d, J = 10.2 Hz, 1H), 3.72 (d, J = 10.3 Hz, 1H), 2.97 (br dd, J = 5.0, 8.7 Hz, 1H), 2.51 - 2.34 (m, 1H), 2.30 (br dd, J = 7.7, 12.3 Hz, 1H), 2.16 (dd, J = 8.5, 12.3 Hz, 1H), 1.91 - 1.81 (m, 1H), 1.74 (dd, J = 10.2, 12.4 Hz, 1H), 1.67 - 1.37 (m, 11H), 1.22 (s, 3H), 1.13 - 0.80 (m, 3H).

Example 272. Synthesis of viral protease inhibitor compound 1121

Step 1 : (S)-methyl3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((S)-2 -azaspiro[4.5]decane-3- carboxamido)propanoate

[000222] A solution of (S)-tert-butyl 3 -(((S)-3 -((R)-5 , 5 -dimethy 1 -2-oxopy rrolidin-3 -y 1 )- 1 - methoxy- 1 - oxopropan-2-yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylat e (350 mg, 729.76 umol, 1 eq) in HCI/MeOH (4 M,4 mL) was stirred at 20 °C for 1 h. Upon the reaction completion, the reaction mixture was concentrated in vacuum to obtained (S)-methyl 3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((S)-2-azaspiro[ 4.5]decane-3- carboxamido)propanoate (280 mg, crude) as a white solid. MS (ESI) m/z 380.2 [M+H] ⁺

Step 2 : (S)-methyl2-((S)-2-(7-chloro-4-methoxy- 1 H-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carboxamido)-3-((R)-5,5-dimethyl-2-oxo pyrrolidin-3-yl)propanoate [000223] To a solution of (S)-methyl 3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((S)-2- azaspiro[4.5 ]decane-3 -carboxamido)propanoate (280 mg, 673.15 umol, 1 eq, HC1) in DCM (2 mL) was added 7-chloro-4-m ethoxy- 1H-indole-2-carboxylic acid (182.26 mg, 807.78 umol, 1.2 eq), DMAP (205.60 mg, 1.68 mmol, 2.5 eq) and EDCI (258.09 mg, 1.35 mmol, 2 eq), the mixture was stirred at 20 °C for 1 h. Upon the reaction completion, the reaction mixture was quenched by addition of water (5 mL), and then extracted with DCM (2 mL * 3). The combined organic layers were washed with HC1 (1M, 3 mL), then was adjusted pH~7 with sat.NaHCO ₃ (2 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuum and was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10:1) to obtained (S)-methyl 2-((S)-2-(7-chloro-4-methoxy-1H-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxamido)-3-((R)-5,5-di methyl-2- oxopyrrolidin-3-yl)propanoate (300 mg, 510.98 umol, 75.91% yield) as a yellow solid. MS (ESI) m/z 587.3 [M+H] ⁺

Step 3 : (S)-N-((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl) -1-oxopropan-2-yl)-2- (7-chloro-4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]dec ane-3-carboxamide

[000224] A solution of (S)-methyl 2-((S)-2-(7-chloro-4-methoxy-1H-indole-2-carbonyl)- 2-azaspiro[4.5] decane-3-carboxamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3- yl)propanoate (300 mg, 510.98 umol, 1 eq) in NH ₃ /MeOH (7 M, 5 mL) was stirred at 50 °C for 20 h. Upon the reaction completion, the mixture was concentrated in vacuum to obtained (S)-N-((S)- 1 -amino-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)- 1 - oxopropan-2-yl)-2-(7-chloro-4-methoxy-1H-indole-2-carbonyl)- 2- azaspiro[4.5]decane-3-carboxamide (260 mg, crude) as a yellow solid. MS (ESI) m/z 572.3 [M+H] ⁺

[000225] Step 4: (S)-2-(7-chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-((S)- 1 -cy ano-2- ((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)ethyl)-2-azaspiro[4.5 ]decane-3-carboxamide [000226] To a solution of (S)-N-((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopynOlidin-3-yl)- l-oxopropan-2-yl)-2-(7-chloro-4-methoxy-1H-indole-2-carbonyl )-2- azaspiro[4.5]decane-3-carboxamide (260 mg, 461.46 umol, 1 eq) in DCM (2 mL) was added burgess reagent (329.91 mg, 1.38 mmol, 3 eq) and stirred at 30 °C for 1.5 h. Upon the reaction completion, the mixture was quenched by water (1 mL) and was dried by blowing N ₂ and was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 25mm * Sum; mobile phase: [water (10mMNH ₄ HCO ₃ )-ACN]; B%: 30%- 65%, lOmin) to obtained (S)-2-(7-chloro-4-methoxy-1H-indole-2-carbonyl)-N-((S)-1- cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)ethyl)-2-azas piro[4.5]decane-3- carboxamide (61.15 mg, 110.36 umol, 23.92% yield, 100% purity) as a white solid. MS (ESI) m/z 554.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.12 - 10.96 (m, 1H), 8.79 - 8.63 (m, 1H), 7.63 - 7.51 (m, 1H), 7.22 (s, 1H), 7.05 - 6.91 (m, 1H), 6.61 -

6.53 (m, 1H), 4.96 - 4.86 (m, 1H), 4.67 - 4.51 (m, 1H), 3.95 - 3.88 (m, 3H), 3.87 -

3.78 (m, 1H), 3.70 - 3.54 (m, 1H), 2.65 - 2.55 (m, 1H), 2.30 - 2.09 (m, 2H), 1.85 -

1.74 (m, 1H), 1.71 - 1.62 (m, 1H), 1.60 - 1.33 (m, 12H), 1.21 - 1.14 (m, 3H), 1.12 -

1.03 (m, 3H).

Example 273. Synthesis of viral protease inhibitor compound 1123

Stepl : (S)-methyl 2-((S)-2-(7-chloro-4-methoxy-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin- 3-yl)propanoate

[000227] To a solution of (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate hydrochloride (130 mg, 359.25 umol, 1.1 eq, HC1) in DCM (5 mL) was added 7-chloro-4-methoxy-lH-indole-2-carboxylic acid (73.69 mg, 326.59 umol, 1 eq), DMAP (119.70 mg, 979.78 umol, 3 eq) and EDCI (125.22 mg, 653.19 umol, 2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction was quenched by H ₂ O (20 mL), and was extracted with DCM (10 mL * 3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na ₂ SO ₄ , filtered, concentrated in vacuum and purified by prep- TLC (SiO ₂ , DCM:MeOH = 10:1) to give product (S)-methyl 2-((S)-2-(7-chloro-4- methoxy-lH-indole-2-carboxamido)-3-cyclopropylpropanamido)-3 -((R)-5,5- dimethyl-2-oxopyrrolidin-3-yl)propanoate (150 mg, 281.42 umol, 86.17% yield) as yellow solid. MS (ESI) m/z 533.2 [M+H] ⁺

Step2 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-l -oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-7-chloro-4-methoxy -lH-indole-2-carboxamide [000228] A solution of (S)-methyl 2-((S)-2-(7-chloro-4-methoxy- 1 H-indole-2- carboxamido)-3-cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2 -oxopyrrolidin-3- yl)propanoate (150 mg, 281.42 umol, 1 eq) in ammonia (in MeOH solution, 7 M, 20 mL, 497.48 eq) was stirred at 30 °C for 10 h. Upon completion, the reaction was concentrated in the vacuum to give product N-((S)- 1 -(((S)- 1 -amino-3 -((R)-5,5- dimethyl-2-oxopyrrolidin-3-yl)-1-oxopropan-2-yl)amino)-3-cyc lopropyl-1- oxopropan-2-yl)-7-chloro-4-methoxy- 1 H-indole-2-carboxamide (130 mg, crude) as yellow solid. MS (ESI) m/z 518.2 [M+H] ⁺

Step3 : 7-chloro-N-((S)- 1 -(((S)- 1 -cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-methoxy-lH -indole-2-carboxamide [000229] To a solution of N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3- yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-7-chloro-4-methoxy- 1 H-indole-2-carboxamide (130 mg, 250.96 umol, 1 eq) in DCM (10 mL) was added burgess reagent (179.42 mg, 752.89 umol, 3 eq) and the mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated in the vacuum and purified by prep-HPLC (column: Phenomenex Gemini -NX 80* 40 mm* 3 um; mobile phase: [water (10 mM NH4HCO3)- ACN]; B%: 20%-50%, 8 min) to give product 7-chloro- N-((S)- 1 -(((S)- 1 -cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)ethyl)amino) -3- cyclopropyl- 1 -oxopropan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide (40 mg, 80.00 umol, 31.88% yield, 100% purity) as white solid. MS (ESI) m/z 500.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ = 8.99 - 8.97 (m, 1H), 8.67 - 8.65 (m, 1H), 7.82 (s,

1H), 7.29 - 7.16 (m, 2H), 6.57 - 6.55(m, 1H), 4.99 - 4.93 (m, 1H), 4.56 - 4.37 (m, 1H), 3.89 (s, 3H), 2.61 (br s, 1H), 2.23 - 2.12 (m, 1H), 2.01 - 1.97 (m, 1H), 1.87 - 1.72 (m, 2H), 1.55 - 1.43 (m, 2H), 1.15 (s, 3H), 1.07 (s, 3H), 0.83 - 0.81 (m, 1H), 0.44 - 0.42 (m, 2H), 0.25 - 0.05 (m, 2H)

Example 274. Synthesis of viral protease inhibitor compound 1131

Step 1 : (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)-5,5-dimethyl- 2- oxopyrrolidin-3-yl)propanoate

[000230] 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 (260 mg, 588.82 umol, 1 eq) in HCI/MeOH (4 M, 5 mL, 33.97 eq) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the procduct methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (210 mg, crude, HC1) as a white solid.

Step 2: (S)-methyl 2-((S)-2-(7-chloro-4-methoxy- 1 H-indole-2-carboxamido)-4,4- dimethylpentanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-y l)propanoate

[000231] To a solution of methyl (2 S)-2-[ [(2 S)-2-amino-4,4-dimethy 1-pentanoy 1 ]ami no]- 3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (210 mg, 555.69 umol, 1 eq, HC1) and 7-chloro-4-methoxy- 1 H-indole-2-carboxylic acid (162.99 mg, 722.40 umol, 1.3 eq) in DCM (5 mL) and DMF (1.5 mL), was added with DMAP (203.67 mg, 1.67 mmol, 3 eq) and EDCI (213.05 mg, 1.11 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 H ₂ O 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, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM: MeOH = 10: 1) to give the product methyl (2S)-2-[[(2S)-2- [(7-chloro-4-methoxy-lH-indole-2-carbonyl)amino]-4,4-dimethy l-pentanoyl]amino]- 3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (270 mg, 393.40 umol, 70.79% yield, 80% purity) as a yellow solid. MS (ESI) m/z 549.2 [M+H] ⁺ .

Step 3 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-7-chloro-4-methoxy- 1 H-indole-2-carboxamide [000232] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-4-methoxy-lH-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3R)-5,5-di methyl-2-oxo- pyrrolidin-3-yl]propanoate (270.00 mg, 491.75 umol, 1 eq) in NH ₃ /MeOH (7 M, 5 mL, 71.17 eq), was stirred at 40 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product N-[(1S)-1-[[(1S)-2- amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2- oxo-ethyl]carbamoyl]- 3,3-dimethyl-butyl]-7-chloro-4-methoxy-lH-indole-2-carboxami de (240 mg, crude) as a yellow solid. MS (ESI) m/z 534.2 [M+H] ⁺ .

Step 4: 7-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyr rolidin-3- yl)ethyl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide [000233] To a solution of N-[(1S)-1-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]carbamoyl]-3,3-dimethyl- butyl]-7-chloro-4- methoxy- 1 H-indole-2-carboxamide (240 mg, 373.00 umol, 83% purity, 1 eq) in DCM (5 mL) was added burgess reagent (222.22 mg, 932.50 umol, 2.5 eq), and then the mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 lOu 250 mm * 80 mm; mobile phase: [water(10 mM NH4HCO3)- ACN] ; B%: 25%-55%, 35 min) to give the product 7-chloro-N- [(1S)-1-[[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin -3-yl]ethyl]carbamoyl]- 3,3-dimethyl-butyl]-4-methoxy-lH-indole-2-carboxamide (107.95 mg, 207.10 umol, 55.52% yield, 99% purity) as a white solid. MS (ESI) m/z 516.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ =11.67 (br s, 1H), 8.99 (d, J= 7.9 Hz, 1H), 8.64 (d ,J= 7.9 Hz, 1H), 7.82 (s, 1H), 7.27 (s, 1H), 7.20 (d , J= 8.1 Hz, 1H), 6.55 (d, J= 8.3 Hz, 1H), 4.94 (br d, J = 7.5 Hz, 1H), 4.54 (br d, J = 6.8 Hz, 1H), 3.88 (s, 3H), 2.58 - 2.53 (m, 1H), 2.21 - 2.14 (m, 1H), 1.94 (dd, J= 8.4, 12.2 Hz, 1H), 1.77 (td, J= 3.3, 6.4 Hz, 1H), 1.72 (br d, J= 6.4 Hz, 2H), 1.49 (t, J= 11.4 Hz, 1H), 1.13 (s, 3H), 1.01 (s, 3H), 0.94 (s, 9H)

Example 275. Synthesis of viral protease inhibitor compound 1133

Step 1 : 2-[(Z)-[(2R)-2-hydroxy-2,6,6-trimethyl-norpinan-3-ylidene]am ino]acetate

[000234] To a solution of tert-butyl 2-aminoacetate (5.75 g, 43.84 mmol, 1.47 eq) and (2R)-2-hydroxy-2,6,6-trimethyl-norpinan-3-one (5 g, 29.72 mmol, 1 eq) in toluene (135 mL) was added BF ₃ .Et ₂ O (513.39 mg, 3.62 mmol, 446.43 uL, 1.22e ^'1 eq) at 20 °C. Then the reaction was stirred at 120 °C for 12 h in the presence with a Dean- Stark trap. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 50/1 to 5/1, 1% TEA) to give tert-butyl 2-[(Z)-[(2R)-2-hydroxy-2,6,6-trimethyl- norpinan-3-ylidene]amino]acetate (6 g, 21.32 mmol, 71.74% yield) as a yellow oil. Step 2: tert-butyl (2R)-2-[(Z)-[(2R)-2-hydroxy-2,6,6-trimethyl-norpinan-3-ylide ne]amino]-3- trimethylsilyl-propanoate

[000235] 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]am ino]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 coolled 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 Na ₂ SO ₄ , filtered and concnetrated in vacuo to dryness. The residue was purified by column chromatography (SiO ₂ , 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.

Step 3: tert-butyl (2R)-2-amino-3-trimethylsilyl-propanoate

[000236] 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 combained, dried over Na ₂ SO ₄ , 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

Step 4: tert-butyl (2R)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-3-trimethylsi lyl- propanoate [000237] To a solution of 4-methoxy- 1 H-indole-2-carboxylic acid (380 mg, 1.99 mmol, 1 eq) in DMF (5 mL) was added tert-butyl (2R)-2-amino-3-trimethylsilyl-propanoate (380 mg, 1.75 mmol, 8.79e-l eq), EDCI (495.34 mg, 2.58 mmol, 1.3 eq), TEA (603.38 mg, 5.96 mmol, 829.96 uL, 3 eq). Then the reaction was added HOBt (349.14 mg, 2.58 mmol, 1.3 eq) at -10-0 °C for 10 min. Then the reaction was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (100 mL) and extracted with EA 150 mL (50 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was pruified by column (SiO ₂ , PE/EA = 10/1 to 1/1) to give tert-butyl (2R)-2- [(4-methoxy-lH-indole-2-carbonyl)amino]-3-trimethylsilyl-pro panoate (600 mg, 1.54 mmol, 77.29% yield, assumed 100% purity) as a white solid.

Step 5: (2R)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-3-trimethylsi lyl-propanoic acid [000238] To a solution of tert-butyl (2R)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-3- trimethylsilyl-propanoate (300 mg, 768.15 umol, 1 eq) in DCM (3 mL) was added TFA/H ₂ O (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 H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue of (2R)-2- [(4-methoxy-lH-indole-2-carbonyl)amino]-3-trimethylsilyl-pro panoic acid (300 mg, crude) as a yellow oil.

Step 6: N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-2-oxo-1- (trimethylsilylmethyl)ethyl]-4-methoxy-lH-indole-2-carboxami de Isomer 1 & N-[(lR)-2- [[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-2-oxo- 1-(trimethylsilylmethyl)ethyl]- 4-methoxy-lH-indole-2-carboxamide Isomer 2

[000239] To a solution of (2R)-2-[(4-methoxy-lH-indole-2-carbonyl)amino]-3- trimethylsilyl-propanoic acid (230 mg, 687.71 umol, 1 eq) and (2S)-2-amino-3-[(3S)- 2-oxo-3-piperidyl]propanenitrile (114.99 mg, 687.71 umol, 1 eq) in DMF (3 mL) was added PyBop (357.88 mg, 687.71 umol, 1 eq) and TEA (139.18 mg, 1.38 mmol,

191.44 uL, 2 eq) in DMF (1 mL) at -20 °C. Then the reaction was stirred at -20 °C for 2 h. Upon completion, the reaction was diluted with MeCN (2 mL), filtered. The residue was purified by prep-HPLC (column: Phenomenex Luna C 18 75*30mm*3um;mobile phase: [ water(0.2%F A)- ACN] ;B% : 40%-70%,8min) to give ~70 mg epimerisomers. Then the residue was seperated by SFC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [0.1%NH ₃ H ₂ O MEOH];B%: 30%-30%,15min) to give N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]amino]-2-oxo-1-(trimethylsilylmethyl)ethyl]- 4-methoxy-lH-indole-2- carboxamide Isomer 1 (20 mg, 40.53 umol, 5.89% yield, 98% purity) as a white solid. MS (ESI) m/z 484.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.23 (s, 1H), 7.19 - 7.10 (m, 1H), 7.03 (d ,J= 8.2 Hz, 1H), 6.52 (d ,J= 7.7 Hz, 1H), 5.04 (dd,J= 6.3, 9.9 Hz, 1H), 4.60 (t ,J= 8.0 Hz, 1H), 3.94 (s, 3H), 3.21 - 3.11 (m, 2H), 2.45 - 2.23 (m, 2H), 2.05 - 1.95 (m, 1H), 1.90 (td, J= 6.8, 13.6 Hz, 1H), 1.82 (dt, J= 3.9, 9.0 Hz,

1H), 1.73 - 1.60 (m, 1H), 1.57 - 1.43 (m, 1H), 1.25 - 1.15 (m, 2H), 0.10 (s, 9H).

[000240] To give N-[(lR)-2-[[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]ami no]-2- oxo-1-(trimethylsilylmethyl)ethyl]-4-methoxy-lH-indole-2-car boxamide Isomer 2 (70 mg, 144.74 umol, 21.05% yield, 100% purity) as a white solid. MS (ESI) m/z 484.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.23 (s, 1H), 7.19 - 7.10 (m, 1H), 7.02 (d, J= 8.3 Hz, 1H), 6.51 (d, J= 7.6 Hz, 1H), 5.09 (dd, J= 6.1, 9.8 Hz, 1H), 4.61 (t,J = 7.9 Hz, 1H), 3.93 (s, 3H), 3.22 - 3.17 (m, 2H), 2.52 - 2.37 (m, 2H), 2.02 - 1.88 (m,

2H), 1.83 - 1.74 (m, 1H), 1.72 - 1.60 (m, 1H), 1.57 - 1.42 (m, 1H), 1.21 (d, J= 8.0 Hz, 2H), 0.16 - 0.05 (m, 9H).

Example 276. Synthesis of viral protease inhibitor compound 1135

Stepl : (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-cyclopropylprop anoic acid

[000241] 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 CH ₃ I (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 H ₂ O (200 mL) and was adjusted pH = 1 with HCI (1 M), and extracted with ethyl acetate (150 mL * 3). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na ₂ SO ₄ , 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] ⁺

Step2 : (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[000242] To a solution of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3- cyclopropylpropanoic acid (6.17 g, 25.36 mmol, 1 eq) in DCM (100 mL) was added (S)-methyl 2-amino-3-((S)-2-oxopiperidin-3-yl)propanoate (6.60 g, 27.90 mmol, 1.1 eq, HC1), was added DMAP (9.29 g, 76.08 mmol, 3 eq) and EDCI (9.72 g, 50.72 mmol, 2 eq), and then the mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was quenched by H ₂ O (200 mL) and was extracted with DCM (200 mL * 3). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum and was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/10 to 0/1) to give product (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e (7 g, 16.45 mmol, 64.87% yield) as yellow oil. MS (ESI) m/z 426.3 [M+H] ⁺

Step3 : tert-butyl ((S)-l -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)- 3-cyclopropyl-1-oxopropan-2-yl)(methyl)carbamate

[000243] To a solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e (1.02 g, 2.40 mmol, 1 eq) in AMMONIA (7 M, 40 mL, 116.81 eq) was stirred at 30 °C for 10 h. Upon completion, the reaction was concentrated in the vacuum to give crude product tert- butyl ((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)(methyl)carbamate (990 mg, crude) as yellow solid. MS (ESI) m/z 411.3 [M+H] ⁺

Step4: (S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2 -yl)-3-cyclopropyl-2- (methylamino)propanamide; (S)-methyl 2-((S)-3-cyclopropyl-2- (methylamino)propanamido)-3-((S)-2-oxopiperidin-3-yl)propano ate

[000244] To a solution of tert-butyl ((S)- 1 -(((S)- 1 -amino- 1 -oxo-3 -((S)-2-oxopiperidin-3 - yl)propan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)(methyl)carbamate (990 mg, 2.41 mmol, 1 eq) in HCl/MeOH (30 mL) was stirred at 25 °C for 1 h. Upon completion, the reaction was concentrated in the vacuum to give crude product (S)-N- ((S)- 1 -amino- 1 -oxo-3 -((S)-2-oxopiperidin-3-yl)propan-2-yl)-3 -cyclopropyl-2- (methylamino)propanamide (1.1 g, crude, 30% purity) as yellow solid (S)-methyl 2- ((S)-3-cyclopropyl-2-(methylamino)propanamido)-3-((S)-2-oxop iperidin-3- yl)propanoate (1.1 g, crude, 60% purity) as yellow solid. MS (ESI) m/z 311.2 [M+H] ⁺ , MS (ESI) m/z 326.2 [M+H] ⁺ Step5 : N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)prop an-2-yl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-4-methoxy-N-methyl- 1 H-indole-2-carboxamide

[000245] To a solution of (S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2 - yl)-3-cyclopropyl-2-(methylamino)propanamide (1 g, 966.52 umol, 30% purity, 1 eq), 4-methoxy- 1 H-indole-2-carboxylic acid (184.78 mg, 966.52 umol, 1 eq) in DCM (30 mL) was added DMAP (354.24 mg, 2.90 mmol, 3 eq), EDCI (370.56 mg, 1.93 mmol, 2 eq) and the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction was quenched by H ₂ O (200 mL), and was extracted with DCM (100 mL * 3). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum and was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give product N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3 -((S)-2- oxopiperidin-3-yl)propan-2-yl)amino)-3 -cyclopropyl- 1 -oxopropan-2-yl)-4-methoxy- N-methyl-lH-indole-2-carboxamide (90 mg, 186.12 umol, 19.26% yield) as yellow solid. MS (ESI) m/z 484.2 [M+H] ⁺

Step6 : N-((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 -cyclopropyl- 1 - oxopropan-2-yl)-4-methoxy-N-methyl- 1 H-indole-2-carboxamide

[000246] To a solution of N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-meth oxy-N-methyl-lH- indole-2-carboxamide (86 mg, 177.85 umol, 1 eq) in DCM (3 mL) was added burgess reagent (127.15 mg, 533.54 umol, 3 eq) and the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction was concentrated in the vacuum and was purified by prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [water(0.2%FA)-ACN];B%: 20%-50%,8min) to give product N-((S)-1-(((S)-1-cyano- 2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl-1-oxop ropan-2-yl)-4- methoxy-N-methyl-lH-indole-2-carboxamide (35 mg, 75.18 umol, 42.27% yield, 100% purity) as white solid. MS (ESI) m/z 466.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ = 11.60 (br s, 1H), 8.87 (br s, 1H), 7.56 (br s, 1H), 7.15 - 7.07 (m, 1H), 7.05 - 6.99 (m, 1H), 6.91 (br s, 1H), 6.52 - 6.50 (m, 1H), 5.13 - 4.96 (m, 2H), 3.87 (s, 3H), 3.09 (br s, 2H), 2.23 (br s, 2H), 1.96 - 1.77 (m, 3H), 1.74 - 1.71 (m, 1H), 1.66 - 1.34 (m, 3H), 0.80 - 0.02 (m, 5H)

Example 277. Synthesis of viral protease inhibitor compound 1137

Stepl : (S)-methyl 2-((S)-3-cyclopropyl-2-(methylamino)propanamido)-3-((S)-2- oxopiperidin-3-yl)propanoate

[000247] To a solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e (2 g, 4.70 mmol, 1 eq) in HCI/MeOH (50 mL) was stirred at 25 °C for 3 h. Upon completion, the reaction was concentrated in the vacuum to give crude product (S)-methyl 2-((S)-3- cyclopropyl-2-(methylamino)propanamido)-3-((S)-2-oxopiperidi n-3-yl)propanoate (2 g, crude) as yellow solid. MS (ESI) m/z 326.2 [M+H] ⁺

Step2 : (S)-methyl 2-((S)-2-(7-chloro-N-methyl- 1 H-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e [000248] To a solution of (S)-methyl 2-((S)-3-cyclopropyl-2-

(methylamino)propanamido)-3-((S)-2-oxopiperidin-3-yl)prop anoate (1 g, 2.76 mmol,

1 eq, HCI) in DCM (30 mL) was added 7-chloro-lH-indole-2-carboxylic acid (540.54 mg, 2.76 mmol, 1 eq), DMAP (1.01 g, 8.29 mmol, 3 eq), EDCI (1.06 g, 5.53 mmol, 2 eq) and the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction was quenched by H ₂ O (200 mL), and was extracted with DCM (100 mL * 3). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum and was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/9 to 0/1) to give product (S)-methyl 2-((S)-2-(7-chloro-N-methyl- 1 H-indole-2-carboxamido)-3 - cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e (530 mg, 1.05 mmol, 38.13% yield) as yellow solid. MS (ESI) m/z 503.2 [M+H] ⁺

Step3: N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)prop an-2-yl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-7-chloro-N-methyl- 1 H-indole-2-carboxamide [000249] A solution of (S)-methyl 2-((S)-2-(7-chloro-N-methyl- 1 H-indole-2- carboxamido)-3-cyclopropylpropanamido)-3-((S)-2-oxopiperidin -3-yl)propanoate (530 mg, 1.05 mmol, 1 eq) in ammonia (7 M, 30 mL, 199.30 eq) was stirred at 30 °C for 10 h. Upon completion, the reaction was concentrated in the vacuum to give crude prodcut 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-chloro-N-methyl- lH-indole-2- carboxamide (440 mg, crude) as yellow solid. MS (ESI) m/z 488.2 [M+H] ⁺

Step4 : N-((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 -cyclopropyl- 1 - oxopropan-2-yl)-4-(trifluoromethyl)-lH-indole-2-carboxamide

[000250] To a solution of 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-chlo ro-N-methyl-lH- indole-2-carboxamide (440 mg, 901.68 umol, 1 eq) in DCM (15 mL) was added burgess reagent (644.62 mg, 2.71 mmol, 3 eq) and the mixture was stirred at 25 °C for 4 h. Upon completion, the reaction was concentrated in the vacuum and was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HC03 )- ACN] ;B% : 30%-60%,8min) to give product 7- chloro-N-((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3 - cyclopropyl- 1 -oxopropan-2-yl)-N-methyl- 1 H-indole-2-carboxamide (220 mg, 468.12 umol, 51.92% yield, 100% purity) as white solid. MS (ESI) m/z 470.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ = 11.93 - 11.60 (m, 1H), 8.90 (br s, 1H), 7.57 (br s,

2H), 7.28 - 7.26 (m, 1H), 7.08 - 7.04 (m, 1H), 7.02 - 6.57 (m, 1H), 5.12 - 5.02 (m,

1H), 5.00 - 4.71 (m, 1H), 3.30 - 3.16 (m, 2H), 3.13 - 2.93 (m, 3H), 2.30 - 2.16 (m,

2H), 1.95 - 1.39 (m, 7H), 0.84 - 0.18 (m, 5H).

[000251] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.34 (br s, 1H), 8.73 - 8.71 (m, 1H), 7.61 - 7.59 (m, 1H), 7.35 - 7.23 (m, 2H), 7.10 - 7.02 (m, 1H), 6.87 (br s, 1H), 5.07 - 5.01 (m, 1H), 4.93 (br s, 1H), 3.14 (br s, 5H), 2.34 - 2.19 (m, 2H), 1.98 - 1.81 (m, 3H), 1.80 - 1.56 (m, 3H), 1.51 - 1.44 (m, 1H), 0.71 (br s, 1H), 0.53 - 0.37 (m, 1H), 0.53 - 0.37 (m, 1H), 0.19 - 0.04 (m, 2H)

Example 278. Synthesis of viral protease inhibitor compound 1141

Step 1: 7-chloro-2-(trichloromethyl)-lH-benzo[d]imidazole

[000252] 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. NaHCOs (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 Na ₂ SO ₄ 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] ⁺

Step 2: methyl 7-chloro-lH-benzo[d]imidazole-2-carboxylate

[000253] To a solution of 7-chloro-2-(trichloromethyl)-1H-benzimidazole (3 g, 11.11 mmol, 1 eq) in MeOH (40 mL) was added NazCO ₃ (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] ⁺

Step 3: 7-chloro-lH-benzo[d]imidazole-2-carboxylic acid

[000254] To a solution of methyl 7-chloro-1H-benzimidazole-2-carboxylate (3 g, 14.24 mmol, 1 eq) in THF (20 mL) and H ₂ O (5 mL) was added LiOH.H ₂ O (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 IN HC1 (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 Na ₂ SO ₄ , 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] ⁺

Step 4: (S)-methyl2-((S)-3-cyclopropyl-2-(methylamino)propanamido)-3 -((S)-2- oxopiperidin-3-yl)propanoate

[000255] A mixture of methyl (2S)-2-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]-3- cyclopropyl-propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propa noate (1 g, 2.35 mmol, 1 eq) in HCl/MeOH (4 M, 20 mL, 59.57 eq) was stirred at 20 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressure to give the product methyl (2S)-2-[[(2S)-3-cyclopropyl-2-(methylamino)propanoyl]amino]- 3- [(3S)-2-oxo-3-piperidyl]propanoate (0.8 g, crude, HC1) as a yellow solid. MS (ESI) m/z 326.2 [M+H] ⁺

Step 5 : (S)-methyl2-((S)-2-(7-chloro-N-methyl- 1 H-benzo[d]imidazole-2-carboxamido)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e [000256] To a solution of methyl(2S)-2-[[(2S)-3-cyclopropyl-2-

(methylamino)propanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]p ropanoate (700 mg, 1.93 mmol, 1 eq, HC1) and 7-chloro-1H-benzimidazole-2-carboxylic acid (456.35 mg, 2.32 mmol, 1.2 eq) in DMF (20 mL) was added DMAP (472.65 mg, 3.87 mmol, 2 eq) and EDCI (741.67 mg, 3.87 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (30 mL), and then extracted with EA (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 5/1 to 0/1) to give the product methyl(2S)-2-[[(2S)-2-[(7-chloro- 1H-benzimidazole-2-carbonyl)-methyl-amino]-3-cyclopropylprop anoyl]amino]-3- [(3S)-2-oxo-3-piperidyl]propanoate (0.5 g, 992.11 umol, 51.29% yield) as a yellow solid. MS (ESI) m/z 504.2 [M+H] ⁺

Step 6: 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-chloro-N-methyl- 1 H-benzo[d]imidazole-2-carboxamide [000257] A mixture of methyl(2S)-2-[[(2S)-2-[(7-chloro-1H-benzimidazole-2-carbonyl )- methyl-amino]-3-cyclopropylpropanoyl]amino]-3-[(3S)-2-oxo-3- piperidyl]propanoate (450 mg, 892.90 umol, 1 eq) in NH ₃ /MeOH (7 M, 10 mL, 78.40 eq) was stirred at 30 °C for 16 h. Upon completion, the mixture was concentrated under the 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-et hyl]-7-chloro-N- methyl-1H-benzimidazole-2-carboxamide (400 mg, crude) as a yellow solid. MS (ESI) m/z 489.2 [M+H] ⁺

Step 7 : 7-chloro-N-((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-N-methyl- 1 H-benzo[d]imidazole-2-carboxamide [000258] 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-et hyl]-7-chloro-N- methyl-1H-benzimidazole-2-carboxamide (200 mg, 409.03 umol, 1 eq) in DCM (10 mL) was added burgess reagent (194.95 mg, 818.05 umol, 2 eq). The mixture was stirred at 20 °C for 4 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water(10 mM NH4HCO3) - ACN]; B%: 30% - 60%, 8 min) to give the product 7-chl oro-N- [(1S)-2- [[( 1 S)- 1 -cy ano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]- 1 -(cyclopropylmethyl)-2- oxoethyl]-N-methyl-1H-benzimidazole-2-carboxamide (50 mg, 106.17 umol, 12.98% yield, 100% purity) as a white solid. MS (ESI) m/z 471.2 [M+H] ^{+ 1} H NMR (400 MHz, MeOD-d ₄ ) δ = 7.72 - 7.48 (s, 1H), 7.45 - 7.25 (m, 3H), 5.92 (dd, J = 5.8, 9.2 Hz, 1H), 5.32 - 5.17 (m, 1H), 5.14 - 4.94 (m, 1H), 3.62 - 3.55 (m, 1H), 3.20 (dd,J= 4.6, 8.8 Hz, 3H), 3.07 (s, 3H), 2.57 - 2.33 (m, 3H), 2.12 - 1.92 (m, 4H), 1.88 - 1.77 (m, 2H), 1.74 - 1.46 (m, 4H), 0.62 - 0.39 (m, 3H), 0.35 - 0.10 (m, 3H), 0.009 - 0.037 (m, 1H).

Example 279. Synthesis of viral protease inhibitor compound 1143

Step 1 : (S)-tert-butyl3-(((S)- 1 -methoxy- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2- yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylate

[000259] To a solution of (S)-2-(tert-butoxycarbonyl)-2-azaspiro[4.5]decane-3-carboxyl ic acid (300 mg, 846.97 umol, 80% purity, 1 eq) in DCM (8 mL) was added (S)-methyl 2-amino-3-((S)-2-oxopiperidin-3-yl)propanoate (169.59 mg, 846.97 umol, 1 eq), and then DMAP (310.42 mg, 2.54 mmol, 3 eq) and EDCI (324.73 mg, 1.69 mmol, 2 eq) were added at 0 °C, then the mixture was stirred at 20 °C for 1 h. Upon the reaction completion, the reaction mixture was quenched by addition of water (10 mL), and extracted with DCM (3 mL * 3). The combined organic layers were washed with HC1 (1 M, 4 mL), then was adjusted pH~7 with sat. NaHCOs (4 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuum and was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10:1) to obtained (S)-tert-buty 13-(((S)- 1 -m ethoxy- 1 -oxo-3 -((S)-2- oxopiperidin-3-yl)propan-2-yl)carbamoyl)-2-azaspiro[4.5]deca ne-2-carboxylate (268 mg, 575.62 umol, 67.96% yield) as a yellow solid. MS (ESI) m/z 466.3 [M+H] ⁺

Step 2: (S)-methyl3-((S)-2-oxopiperidin-3-yl)-2-((S)-2-azaspiro[4.5] decane-3- carboxamido)propanoate

[000260] A solution of (S)-tert-butyl 3-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3-yl) propan-2-yl)carbamoyl)-2-azaspiro[4.5]decane-2-carboxylate (240 mg, 515.48 umol,

1 eq) in HCl/MeOH (4 M, 4 mL) at 0 °C, the mixture was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was concemtration in vacuum to obtained (S)-methyl3-((S)-2-oxopiperidin-3-yl)-2-((S)- 2-azaspiro[4.5]decane-3- carboxamido)propanoate (180 mg, crude, HC1) as a yellow solid. MS (ESI) m/z 366.2 [M+H] ⁺

Step 3 : (S)-methyl2-((S)-2-(5-methoxy-lH-indole-2-carbonyl)-2-azaspi ro[4.5]decane-3- carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000261] A mixture of (S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-((S)-2- azaspiro[4.5]decane-3-carboxamido)propanoate (180 mg, 447.84 umol, 1 eq, HC1) in DCM (4 mL) was added 5-methoxy-1H-indole-2-carboxylic acid (85.62 mg, 447.84 umol, 1 eq), and then was added DMAP (109.43 mg, 895.69 umol, 2 eq) and EDCI (128.78 mg, 671.76 umol, 1.5 eq) at 20 °C, the mixture was stirred at 20 °C for 1 h. Upon the reaction completion, the reaction mixture was quenched by addition of water (10 mL), and then extracted with DCM (3 mL * 3). The combined organic layers were washed with HC1 (1 M, 4 mL), then was adjusted pH~7 with sat. NaHCO ₃ (4 mL), dried over Na ₂ SO ₄ , filtered and concentration in vacuum and was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to obtained (S)-methyl2-((S)-2-(5-methoxy- lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamido)-3 -((S)-2-oxopiperidin- 3-yl)propanoate (220 mg, 408.44 umol, 91.20% yield) as a yellow solid. MS (ESI) m/z 539.3 [M+H] ⁺

Step 4: (S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2 -yl)-2-(5-methoxy-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide [000262] A solution of (S)-methyl 2-((S)-2-(5-m ethoxy- 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 NH ₃ /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-azasp iro[4.5]decane-3- carboxamide (150 mg, crude) as a yellow solid. MS (ESI) m/z 524.3 [M+H] ⁺

Step 5: (S)-N-((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2-(5-me thoxy-lH-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxamide

[000263] To a solution of (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, 286.47 umol, 1 eq) in DCM (3 mL) was added burgess reagent (204.80 mg, 859.40 umol, 3 eq) and stirred at 30 °C for 1.5 h. Upon the reaction completion, the reaction mixture was quenced by water (1 mL) and was dried by blowing N ₂ and was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 25mm * Sum; mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 30%-60%, lOmin) to obtained (S)-N-((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-2-(5-methoxy- 1H-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (10.54 mg, 20.85 umol, 7.28% yield, 100% purity) as a white solid. MS (ESI) m/z 506.2 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.44 - 11.33 (m, 1H), 9.11 - 8.84 (m, 1H), 7.58 - 7.41 (m, 1H),

7.36 - 7.24 (m, 1H), 7.15 (d ,J= 1.5 Hz, 1H), 6.98 - 6.92 (m, 1H), 6.89 - 6.76 (m, 1H), 4.89 (s, 1H), 4.54 - 4.45 (m, 1H), 3.94 - 3.84 (m, 1H), 3.75 (s, 3H), 3.72 (s, 1H), 2.88 (s, 2H), 2.30 - 2.23 (m, 1H), 2.22 - 2.14 (m, 1H), 2.03 - 1.82 (m, 1H), 1.81 - 1.63 (m, 2H), 1.59 - 1.12 (m, 14H).

[000264] ¹ H NMR (400 MHz, DMSO-d ₆ , 273+80K) δ ppm 11.14 (s, 1H), 8.72 (s, 1H), 7.35 (d ,J= 9.0 Hz, 1H), 7.27 (s, 1H), 7.09 (s, 1H), 6.86 (dd, J= 1.9, 8.9 Hz, 2H), 5.03 - 4.91 (m, 1H), 4.69 - 4.54 (m, 1H), 3.89 (d, J= 11.0 Hz, 1H), 3.78 (s, 3H), 3.66 - 3.51 (m, 1H), 2.30 - 2.10 (m, 3H), 1.86 - 1.62 (m, 4H), 1.59 - 1.36 (m, 14H).

Example 280. Synthesis of viral protease inhibitor compound 1145

Step 1: (2S)-methyl 3-((S)-2-oxopiperidin-3-yl)-2-(2-azaspiro[4.5]decane-3- carboxamido)propanoate hydrochloride

[000265] 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-ca rboxylate (3.5 g, 7.52 mmol, 1 eq) in HCl/MeOH (4 M, 50 mL, 26.60 eq) 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-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3 S)-2-oxo-3- piperidyl]propanoate (3 g, crude, HC1) was obtained as a white solid.

Step 2: (2S)-methyl 2-(2-(5-chloro-4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4. 5]decane- 3-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000266] To a solution of methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3- [(3S)-2-oxo-3-piperidyl]propanoate (1.59 g, 3.96 mmol, 9.92 e-1 eq, HC1) and 5- chloro-4-methoxy- 1 H-indole-2-carboxylic acid (900 mg, 3.99 mmol, 1 eq) in DCM (15 mL) and DMF (5 mL) was added DMAP (1.46 g, 11.97 mmol, 3 eq) and EDCI (1.53 g, 7.98 mmol, 2 eq) at 0 °C, and then the resulting mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 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, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum etherEthyl acetate = 5:1 to 0:1) to give the product methyl (2S)-2-[[2-(5-chloro-4-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5 ]decane-3 -carbony 1 ]amino]-3 -[(3 S)-2-oxo-3-piperidyl]propanoate (2 g, 3.35 mmol, 83.99% yield, 96% purity) as a yellow solid. MS (ESI) m/z 573.2 [M+H] ⁺ .

Step 3 : N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl) -2-(5-chloro-4- methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbox amide

[000267] A solution of methyl (2S)-2-[[2-(5-chloro-4-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3 S)-2-oxo-3-piperidyl]propanoate ( 1.95 g, 3.40 mmol, 1 eq) in NH ₃ /MeOH (7 M, 50 mL, 102.86 eq) stirred at 40 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethy l]-2- (5-chloro-4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]dec ane-3-carboxamide (1.8 g, crude) as a white solid. MS (ESI) m/z 558.2 [M+H] ⁺ .

Step 4 : 2-(5-chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-((S)- 1 -cyano-2-((S)-2-oxopiperidin- 3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide

[000268] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-2-(5-chloro-4-methoxy-lH-indole-2-ca rbonyl)-2- azaspiro[4.5 ]decane-3 -carboxamide (1.80 g, 3.23 mmol, 1 eq) in DCM (25 mL) was added burgess reagent (2.31 g, 9.68 mmol, 3 eq), and then the resulting mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Xtimate C18 lOu 250 mm * 80mm;mobile phase: [water (lOmM NH4HCO3) - ACN]; B%: 25%-55%, 35 min) to give the product 2-(5-chloro-4- methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]-2- azaspiro[4.5]decane-3-carboxamide (1.5 g, 2.75 mmol, 85.25% yield, 99% purity) as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺ . Step 5 : 2-(5-chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-((S)- 1 -cyano-2-((S)-2-oxopiperidin- 3-yl)ethyl)-2-azaspiro[4.5]decane-3-carboxamide

[000269] 2-(5-chloro-4-methoxy-lH-indole-2-carbonyl)-N-[(1S)-1-cyano- 2-[(3S)-2-oxo- 3-piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide (1.5 g) was separated by SFC (column: REGIS(S, S)WHELK-01(250 mm * 25 mm, 10 um); mobile phase:

[0.1% NH3H ₂ O MEOH]; B%: 50%-50%, 4 min) to give the product 2-(5-chloro-4- methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]-2- azaspiro[4.5]decane-3-carboxamide Isomer 1 (308.55 mg, 569.62 umol, 20.51% yield, 99.7% purity) as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺ .

[000270] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.23 - 6.86 (m, 3H), 5.09 - 5.00 (m, 1H), 4.63 (dd, J = 8.0, 9.5 Hz, 1H), 4.10 - 4.02 (m, 3H), 3.94 (br s, 1H), 3.80 (d, J= 10.3 Hz, 1H), 3.23 - 3.01 (m, 2H), 2.42 - 2.05 (m, 3H), 2.01 - 1.38 (m, 16H)

[000271] To give the product 2-(5-chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 - cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-azaspiro[4.5]decane -3-carboxamide Isomer 2 (269.63 mg, 499.27 umol, 17.98% yield, 100% purity) as a white solid. MS (ESI) m/z 540.2 [M+H] ⁺ .

[000272] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.25 - 6.82 (m, 3H), 5.11 (dd, J = 5.7, 10.5 Hz, 1H), 4.62 (dd, J= 7.9, 9.6 Hz, 1H), 4.01 (s, 3H), 4.00 - 3.82 (m, 1H), 3.75 (d,J = 10.1 Hz, 1H), 3.28 - 3.05 (m, 2H), 2.62 - 1.69 (m, 7H), 1.68 - 1.33 (m, 12H)

Example 281. Synthesis of viral protease inhibitor compound 1147

Step 1: methyl (2S)-2-[[2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piperi dyl]propanoate

[000273] A mixture of methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3-[(3S)- 2-oxo-3-piperidyl]propanoate (1.4 g, 3.48 mmol, 1 eq, HCI) in DCM (20 mL) then added 7-chloro-5-methoxy- 1 H-indole-2-carboxylic acid (1.2 g, 5.32 mmol, 1.53 eq), DMAP (1.06 g, 8.71 mmol, 2.5 eq) and EDCI (1.34 g, 6.97 mmol, 2 eq) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , PE:EA = 2:1 to 0:1) to get product methyl (2S)-2-[[2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-2-azasp iro[4.5]decane-3- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1.3 g, 2.27 mmol, 65.13% yield) as yellow solid. MS (ESI) m/z 573.2 [M+H] ⁺ .

[000274] Step 2: N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethy l]-2-(7- chloro-5-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane -3-carboxamide

[000275] A mixture of methyl (2S)-2-[[2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3 S)-2-oxo-3-piperidyl]propanoate ( 1.26 g, 2.20 mmol, 1 eq) in NH ₃ /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-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3 - piperidyl]methyl]ethyl]-2-(7-chloro-5-methoxy-lH-indole-2-ca rbonyl)-2- azaspiro[4.5]decane-3-carboxamide (1.2 g, crude) as yellow solid. MS (ESI) m/z 558.3 [M+H] ⁺ .

[000276] Step 3: 2-(7-chloro-5-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)- 2-oxo-3-piperidyl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide

[000277] A mixture of N-[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]- 2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]d ecane-3-carboxamide (1.20 g, 2.15 mmol, 1 eq) in DCM (20 mL) added BURGESS REAGENT (1.49 g, 6.24 mmol, 2.9 eq) was stirred at 30 °C for 1 h. Upon completion, the mixture were quenched with water (1 mL) and blow-dried with N ₂ . The residue was purified by prep-HPLC (column: Waters X bridge C18 150 * 50 mm * lOum; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 35% - 65%, 10 min), which was further separated by SFC (column: REGIS (S,S)WHELK-01 (250 mm * 25 mm, 10 um); mobile phase: [Neu - MeOH]; B%: 60% - 60%, 7 min) to get the product 2-(7-chloro- 5-methoxy-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-[(3S)-2-ox o-3-piperidyl]ethyl]- 2-azaspiro[4.5]decane-3-carboxamide Isomer 1 (251.52 mg, 465.73 umol, 21.66% yield) as white oil. MS (ESI) m/z 540.3 [M+H] ⁺ .

[000278] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.12 (d, J=1.8 Hz, 1H), 7.02 (s, 1H), 6.98 - 6.91 (m, 1H), 5.17 - 4.94 (m, 1H), 4.61 (s, 1H), 3.95 - 3.85 (m, 1H), 3.85 - 3.76 (m, 3H), 3.70 (br d, J=10.4 Hz, 1H), 3.29 - 3.13 (m, 2H), 2.64 - 2.23 (m, 3H), 2.09 - 1.87 (m, 2H), 1.82 - 1.68 (m, 2H), 1.64 - 1.39 (m, 12H).

[000279] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.05 (br s, 1H), 8.72 (br d, J=7.5 Hz, 1H), 7.28 (br s, 1H), 7.12 (br s, 1H), 6.97 (s, 2H), 4.97 (br s, 1H), 4.60 (br s, 1H), 3.80 (s, 4H), 3.61 (br s, 1H), 3.08 - 3.03 (m, 1H), 2.49 - 2.47 (m, 1H), 2.45 - 2.08 (m, 3H), 2.00 - 1.62 (m, 4H), 1.59 - 1.32 (m, 12H).

[000280] To get the product 2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-N-[(1S)-1- cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-azaspiro[4.5]decane -3-carboxamide Isomer 2 (366.62 mg, 678.86 umol, 31.57% yield) as white solid. MS (ESI) m/z 540.3 [M+H] ⁺ .

[000281] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.01 (br s, 1H), 8.67 (br s, 1H), 7.25 (br s, 1H), 7.20 - 7.09 (m, 1H), 6.98 (s, 2H), 4.98 (br d, J = 7.1 Hz, 1H), 4.59 (br s, 1H), 3.80 (s, 4H), 3.62 (br s, 1H), 3.12 - 3.10 (m, 1H), 3.08 - 3.06 (m, 1H), 2.50 - 2.47 (m, 2H), 2.20 (br s, 3H), 1.83 (br s, 2H), 1.67 (br d, J = 11.5 Hz, 2H), 1.57 - 1.33 (m,

12H).

[000282] ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.13 (d, J = 2.1 Hz, 1H), 7.04 (s, 1H), 7.00 - 6.93 (m, 1H), 5.01 (dd, J = 6.2, 10.2 Hz, 1H), 4.62 (dd, J = 7.8, 9.8 Hz, 1H), 3.94 (br d, J = 10.4 Hz, 1H), 3.84 - 3.72 (m, 4H), 3.23 - 3.02 (m, 2H), 2.45 - 2.22 (m, 3H), 2.04 - 1.85 (m, 2H), 1.84 - 1.68 (m, 2H), 1.65 - 1.50 (m, 7H), 1.44 (br d, J = 10.1 Hz,

5H).

Example 282. Synthesis of viral protease inhibitor compound 1149

Step 1 : (Z)-methyl 2-azido-3-(4-chloro-2-methoxyphenyl)acrylate

[000283] 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 H ₂ O (100 mL), and then extracted with EA (30 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na ₂ SO ₄ filtered and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO ₂ , 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.

Step 2: methyl 6-chloro-4-methoxy- 1 H-indole-2-carboxylate

[000284] Methyl (Z)-2-azido-3-(4-chloro-2-methoxy-phenyl) prop-2-enoate (7.60 g, 28.40 mmol, 1 eq) in xylene (80 mL) was stirred at 170 °C for 2 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The crude product was triturated with PE (10 mL) at 0 °C for 20 min affording methyl 6-chloro- 4-methoxy-1H-indole-2-carboxylate (4 g, 16.69 mmol, 58.77% yield) as a white solid. MS (ESI) m/z 240.1 [M+H] ⁺

Step 3 : (S)-methyl2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethyl pentanamido)-3-((S)-2- oxopiperidin-3-yl)propanoate

[000285] To a solution of (2S)-2-(tert-butoxycarbonylamino)-4, 4-dimethyl-pentanoic acid (1 g, 4.08 mmol, 1 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3-piperidyl] propanoate (1.16 g, 4.89 mmol, 1.2 eq, HC1) in DCM (20 mL) was added DMAP (996.01 mg, 8.15 mmol, 2 eq) and EDCI (1.56 g, 8.15 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (30 mL), and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give methyl(2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-4,4-dimethyl-pentanoyl]amino]-3-[(3S)-2 -oxo-3- piperidyl]propanoate (1 g, crude) as a yellow solid. MS (ESI) m/z 428.3 [M+H] ⁺

Step 4: (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((S)-2-oxopiperidi n-3- yl)propanoate

[000286] Methyl(2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethy l- pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (1 g, 2.34 mmol, 1 eq) was added with HCl/MeOH (4 M, 10 mL, 17.10 eq), and then the mixture was stirred at 20 °C for 1 h. Upon completion, the mixture was concentrated under the reduced pressure to give methyl (2S)-2-[[(2S)-2 -amino-4, 4-dimethyl-pentanoyl]amino]-3- [(3 S)-2 -oxo-3 -pi peri dy 1 ] propanoate (0.8 g, crude, HC1) as a yellow solid. MS (ESI) m/z 328.2 [M+H] ⁺

Step 5: 6-chloro-4-methoxy-lH-indole-2-carboxylic acid

[000287] A mixture of methyl 6-chloro-4-methoxy-1H-indole-2-carboxylate (4 g, 16.69 mmol, 1 eq) in THF (30 mL) and H ₂ O (10 mL) was added LiOH.H ₂ O (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 H ₂ O (50 mL), and then added aq. HC1 (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 Na ₂ SO ₄ , 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] ⁺

Step 6 : (S)-methyl2-((S)-2-(6-chloro-4-methoxy- 1 H-indole-2-carboxamido)-4,4- dimethylpentanamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000288] To a mixture of methyl(2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3S)-2-oxo-3-piperidyl]propanoate (0.8 g, 2.20 mmol, 1 eq, HC1) and 6-chloro-4- methoxy-1H-indole-2-carboxylic acid (744.08 mg, 3.30 mmol, 1.5 eq) in DCM (20 mL) was added DMAP (537.18 mg, 4.40 mmol, 2 eq) and EDCI (842.93 mg, 4.40 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (30 mL), and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 10: 1 to 0: 1) to give methyl(2S)-2-[[(2S)-2-[(6-chloro-4-methoxy-1H-indole-2-carbo nyl)amino]-4,4- dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoa te (1 g, 1.87 mmol, 85.01% yield) as a white solid. MS (ESI) m/z 535.2 [M+H] ⁺

Step 7 : N-((S)-1-(((S)- 1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)amino)-4,4- dimethyl- 1 -oxopentan-2-yl)-6-chloro-4-methoxy- 1 H-indole-2-carboxamide

[000289]Methyl(2S)-2-[[(2S)-2-[(6-chloro-4-methoxy-1H-ind ole-2-carbonyl)amino]-4,4- dimethyl-pentanoyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoa te (1 g, 1.87 mmol, 1 eq) in NH ₃ /MeOH (7 M, 15 mL, 56.18 eq) was stirred at 80 °C for 16 h. Upon completion, the mixture was concentrated under the reduced pressure to give N-[(1S)- l-[[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]eth yl]carbamoyl]-3,3- dimethyl-butyl]-6- chloro-4-methoxy-1H-indole-2-carboxamide (0.8 g, crude) as a white solid. MS (ESI) m/z 520.2 [M+H] ⁺

Step 8 : 6-chloro-N-((S)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)-4,4- dimethyl- 1 -oxopentan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide

[000290] To a solution of N-[( 1 S)- 1 -[[( 1 S)-2-amino-2-oxo- 1 -[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-6-chlo ro-4-methoxy-1H- indole-2-carboxamide (700 mg, 1.35 mmol, 1 eq) in DCM (10 mL) was added burgess reagent (962.35 mg, 4.04 mmol, 3 eq). The mixture was stirred at 20 °C for 8 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xb ridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 35% - 65%, 8 min) to give 6-chloro-N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]carbamoyl]-3,3-dimethyl-butyl]-4-methoxy-1H- indole-2-carboxamide (230 mg, 458.16 umol, 34.04% yield, 100% purity) as a white solid. MS (ESI) m/z 502.1 [M+H] ⁺

[000291] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.72 (br s, 1H), 8.88 (d ,J= 8.2 Hz, 1H), 8.53 (br d, J= 7.8 Hz, 1H), 7.51 (br s, 1H), 7.35 (s, 1H), 7.04 (s, 1H), 6.55 (d, J= 1.6 Hz, 1H), 5.14 - 4.93 (m, 1H), 4.51 - 4.48 (m, 1H), 3.91 (s, 3H), 3.16 - 2.99 (m, 2H), 2.32 - 2.17 (m, 2H), 1.88 - 1.73 (m, 3H), 1.71 - 1.62 (m, 2H), 1.59 - 1.46 (m, 1H), 1.44 - 1.31 (m, 1H), 0.93 (s, 9H)

Example 283. Synthesis of viral protease inhibitor compound 1151

H

Step 1: tert-butyl (5R)-5-[[( 1 S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-l,3-azasiloli dine-1-carboxylate

[000292] To a mixture of (5R)-1-tert-butoxy carbonyl-3, 3-dimethyl-l,3-azasilolidine-5- carboxylic acid (300 mg, 1.16 mmol, 1 eq ) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3- piperidyl]propanoate (301.15 mg, 1.27 mmol, 1.1 eq, HCI) in DCM (6 mL) and DMF (2 mL) was added DMAP (423.91 mg, 3.47 mmol, 3 eq) and EDCI (443.46 mg, 2.31 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 diluted with H ₂ O 22 mL and extracted with EA 45 mL (15 mL * 3). The combined organic layers were washed with brine 20 mL (20 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/l to 0/1) to give tert-butyl (5R)-5-[[(1S)-2-methoxy- 2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-3,3 -dimethyl-l,3- azasilolidine-1-carboxylate (500 mg, 1.13 mmol, 97.89% yield) as a yellow oil. (ESI) m/z 442.3 [M+H] ⁺

Step 2: methyl (2S)-2-[[(5R)-3,3-dimethyl-l,3-azasilolidine-5-carbonyl]amin o]-3-[(3S)-2- oxo-3-piperidyl]propanoate

[000293] A mixture of tert-butyl (5R)-5-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3,3-dimethyl-l,3-azasiloli dine-1-carboxylate (500 mg, 1.13 mmol, 1 eq) in HCl/MeOH (5 mL) was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-[[(5R)-3,3-dimethyl-l,3-azasilolidine-5-carbonyl]amin o]-3-[(3S)-2- oxo-3-piperidyl]propanoate (420 mg, 1.11 mmol, 98.15% yield, HC1) as a white solid.

Step 3: methyl (2S)-2-[[(5R)-1-(4-methoxy-lH-indole-2-carbonyl)-3,3-dimethy l-l,3- azasilolidine-5-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate

[000294]To a mixture of 4-methoxy-lH-indole-2-carboxylic acid (193.15 mg, 1.01 mmol, 1 eq) and methyl (2S)-2-[[(5R)-3,3-dimethyl-l,3-azasilolidine-5- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.42 g, 1.11 mmol, 1.1 eq, HC1) in DCM (4 mL) and DMF (1 mL) was added DMAP (370.27 mg, 3.03 mmol, 3 eq) and EDCI (387.34 mg, 2.02 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 diluted with H ₂ O 25 mL and extracted with EA 45 mL (15 mL * 3). The combined organic layers were washed with brine 20 mL (20 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The crude was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=5/l to 0/1) to give methyl (2S)-2-[[(5R)-1-(4-methoxy-lH-indole-2-carbonyl)-3,3-dimethy l-l,3- azasilolidine-5-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]pr opanoate (450 mg, 874.39 umol, 86.55% yield) as a yellow solid. (ESI) m/z 515.2 [M+H] ⁺

Step 4: (5R)-N-[(1 S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-1- (4-methoxy- lH-indole-2-carbonyl)-3,3-dimethyl-l,3-azasilolidine-5-carbo xamide

[000295] A mixture of methyl (2S)-2-[[(5R)-1-(4-methoxy-lH-indole-2-carbonyl)-3,3- dimethyl-l,3-azasilolidine-5-carbonyl]amino]-3-[(3S)-2-oxo-3 -piperidyl]propanoate (750 mg, 1.46 mmol, 1 eq) in NH ₃ /MeOH(7 M, 40 mL, 192.13 eq) was stirred at 25 °C for 48 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (5R)-N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]- 1 -(4-methoxy- lH-indole-2-carbonyl)-3, 3-dimethyl- 1,3- azasilolidine-5-carboxamide (720 mg, 1.44 mmol, 98.88% yield) as a yellow solid. MS (ESI) m/z 500.2 [M+H] ⁺

Step 5 : (5R)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3 -piperidyl]ethyl]- 1 -(4-methoxy- 1 H-indole-2- carbonyl)-3,3-dimethyl-l,3-azasilolidine-5-carboxamide

[000296] A mixture of (5R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]- 1 -(4-methoxy- lH-indole-2-carbonyl)-3, 3-dimethyl- 1,3- azasilolidine-5-carboxamide (640 mg, 922.28 umol, 72% purity, 1 eq) in DCM (10 mL) was added Burgess reagent (549.47 mg, 2.31 mmol, 2.5 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 16 hours. Upon completion, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude was purified by prep-HPLC (FA condition; column: Phenomenex Luna Cl 8 200*40mm*10um;mobile phase: [water(0.2%FA)-ACN];B%: 35%-75%,8min) to give (5R)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]- 1 -(4-methoxy- 1 H- indole-2-carbonyl)-3,3-dimethyl-l,3-azasilolidine-5-carboxam ide (190 mg, 394.50 umol, 42.77% yield) as a yellow solid. MS (ESI) m/z 482.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ = 11.47 (br s, 1H), 8.78 (br d, J= 6.7 Hz, 1H), 7.52 (br s, 1H),

7.19 - 6.97 (m, 3H), 6.50 (d, J= 7.6 Hz, 1H), 5.01 (q, J= 7.9 Hz, 2H), 3.88 (br s, 3H), 3.35 (br s, 1H), 3.28 - 3.17 (m, 1H), 3.08 (br s, 2H), 2.31 - 2.10 (m, 2H), 1.99 - 1.47 (m, 4H), 1.44 - 1.16 (m, 2H), 0.98 (br d,J= 14.8 Hz, 1H), 0.33 - 0.15 (m, 6H)

Example 284. Synthesis of viral protease inhibitor compound 1153

Step 1: tert-butyl 3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-2-aza-5-silaspiro[4.4]nona ne-2-carboxylate [000297] To a solution of 2-tert-butoxycarbonyl-2-aza-5-silaspiro[4.4]nonane-3- carboxylic acid (0.7 g, 2.45 mmol, 1 eq) and methyl (2 S)-2-amino-3 - [(3 S)-2-oxo-3 - piperidyl]propanoate (580.52 mg, 2.45 mmol, 1 eq, HC1) in DCM (8 mL) was added DMAP (898.90 mg, 7.36 mmol, 3 eq) and EDCI (940.33 mg, 4.91 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (30 mL) and extracted with DCM (10 mL * 4). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by column chromatography (SiO ₂ , Petroleum etherEthyl acetate = 2:1 to 1:1 to 0:1) to give product tert-butyl 3-[[(1S)-2-methoxy- 2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-2-aza-5- silaspiro[4.4]nonane-2-carboxylate (0.8 g, 1.37 mmol, 55.80% yield, 80% purity) as yellow oil. MS (ESI) m/z 468.3 [M+H] ⁺ Step 2: methyl (2S)-2-(2-aza-5-silaspiro[4.4]nonane-3-carbonylamino)-3-[(3S )-2-oxo-3- piperidyl]propanoate

[000298] A solution of tert-butyl 3-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-2-aza-5-silaspiro[4.4]nona ne-2-carboxylate (0.75 g, 1.28 mmol, 80% purity, 1 eq) in HCl/MeOH (4 M, 24.00 mL, 74.82 eq) was stirred at 20 °C for 2 h. Upon completion, the reaction was concentrated under pressure reduced to give crude product methyl (2S)-2-(2-aza-5-silaspiro[4.4]nonane-3- carbonylamino)-3-[(3S)-2-oxo-3-piperidyl]propanoate (0.5 g, crude, HC1) as yellow oil. MS (ESI) m/z 368.1 [M+H] ⁺

Step 3: methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)-2-aza-5-silaspir o[4.4]nonane-3- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate

[000299] To a solution of methyl (2S)-2-(2-aza-5-silaspiro[4.4]nonane-3-carbonylamino)- 3-[(3S)-2-oxo-3-piperidyl]propanoate (0.5 g, 1237.71 umol, 1 eq, HC1) and 4- methoxy- 1 H-indole-2-carboxylic acid (236.63 mg, 1237.71 umol, 1 eq) in DCM (10 mL) was added DMAP (453.63 mg, 1.49 mmol, 3 eq) and EDCI (474.53 mg, 1.49 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction was quenched by addition H ₂ O (80 mL) and extracted with DCM (15 mL * 6). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 9/1 to 4/1 tol/1 to 0/1 and then Dichloromethane/Methanol = 10/1) to give the product methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)-2-aza- 5-silaspiro[4.4]nonane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-pip eridyl]propanoate (0.527 g, 274.89 umol, 89.59% yield, 85% purity) as yellow oil. MS (ESI) m/z 541.3 [M+H] ⁺

Step 4: N-[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-2- (4-methoxy-lH- indole-2-carbonyl)-2-aza-5-silaspiro[4.4]nonane-3-carboxamid e

[000300] A solution of methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)-2-aza-5- silaspiro[4.4]nonane-3-carbonyl]amino]-3-[(3S)-2-oxo-3-piper idyl]propanoate (0.47 g, 869.27 umol, 1 eq) in NH ₃ /MeOH (1 mL, 7M) was stirred at 20 °C for 42 h. Upon completion, the reaction was concentrated under pressure reduced to get the crude product N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethy l]-2-(4- methoxy-lH-indole-2-carbonyl)-2-aza-5-silaspiro[4.4]nonane-3 -carboxamide (0.45 g, crude) as yellow solid. MS (ESI) m/z 526.3 [M+H] ⁺

Step 5: N-[(l S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]-2-(4-methoxy- 1 H-indole-2- carbonyl)-2-aza-5-silaspiro[4.4]nonane-3-carboxamide

[000301] A solution of N-[(l S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]- 2-(4-methoxy-lH-indole-2-carbonyl)-2-aza-5-silaspiro[4.4]non ane-3-carboxamide (0.46 g, 875.07 umol, 1 eq) in DCM (5 mL) was added burgess reagent (625.62 mg, 2.63 mmol, 3 eq). The mixture was stirred at 30 °C for 6 h. Upon completion, the mixture were quenched with water (3 mL) and blow-dried with N ₂ and was purified by prep-HPLC (column: Kromasil C18 (250*50mm*10 um);mobile phase: [water(10mM NH4HCO3)- ACN] ; B%: 35%-55%,10min) to give product N-[(1S)-1- cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-(4-methoxy-lH-indol e-2-carbonyl)-2-aza-5- silaspiro[4.4]nonane-3-carboxamide Isomer 1 (57 mg, 111.16 umol, 12.70% yield, 99% purity) as white solid. MS (ESI) m/z 508.1 [M+H] ^{+ 1} H NMR (400MHz, DMSO- ck) δ = 11.52 (s, 1H), 8.86 (brd, J= 7.2 Hz, 1H), 7.51 (br s, 1H), 7.17 - 7.00 (m, 3H), 6.51 (d ,J= 7.7 Hz, 1H), 5.00 - 4.99 (m, 1H), 5.09 - 4.94 (m, 1H), 3.88 (s, 3H), 3.51 - 3.42 (m, 1H), 3.08 (br s, 2H), 2.31 - 2.10 (m, 2H), 1.89 - 1.70 (m, 3H), 1.70 - 1.46 (m, 6H), 1.46 - 1.33 (m, 2H), 1.01 (br d,J= 15.2 Hz, 1H), 0.92 - 0.64 (m, 4H).

[000302] Get the product N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-2-(4- methoxy-lH-indole-2-carbonyl)-2-aza-5-silaspiro[4.4]nonane-3 -carboxamide Isomer 2 (47 mg, 91.66 umol, 10.47% yield, 99% purity) as white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.48 (br s, 1H), 8.84 (br d ,J= 7.3 Hz, 1H), 7.52 (br s, 1H), 7.19 - 7.00 (m, 3H), 6.50 (d ,J= 7.7 Hz, 1H), 5.16 - 4.91 (m, 2H), 3.88 (s, 3H), 3.52 - 3.41 (m, 1H), 3.07 (br s, 2H), 2.31 - 2.19 (m, 2H), 1.88 - 1.73 (m, 2H), 1.72 - 1.46 (m, 7H), 1.45 - 1.32 (m, 2H), 1.11 - 0.99 (m, 1H), 0.91 - 0.70 (m, 4H).

Example 285. Synthesis of viral protease inhibitor compound 1163

Step 1 : (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanamid o)-3-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate

[000303] 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, HC1) 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 Na ₂ SO ₄ , 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-di methyl-2- oxopyrrolidin-3-yl)propanoate (0.3 g, crude) was obtained as a yellow solid. MS (ESI) m/z 441.2 [M+H] ⁺ .

Step 2 (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)-5,5-dimethyl- 2- oxopyrrolidin-3-yl)propanoate [000304] A mixture of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-4,4- dimethylpentanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-y l)propanoate (0.28 g, 634.12 umol, 1 eq) in HCl/MeOH (4 mL) was stirred at 15 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (S)- methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)-5,5-dimethyl- 2- oxopyrrolidin-3-yl)propanoate (0.18 g, crude, HC1) as a yellow solid.

Step 3: (2S)-methyl 2-(2-(4-methoxy-lH-indole-2-carbonyl)-8-oxa-2-azaspiro[4.5]d ecane-3- carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[000305] To a solution of (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (0.13 g, 380.74 umol, 1 eq, HC1) in DMF (0.7 mL) and DCM (1.3 mL) was added PyBop (198.13 mg, 380.71 umol, 1 eq), and then 7-chloro-5-methoxy-lH-indole-2-carboxylic acid (85.90 mg, 380.71 umol, 1 eq) and NEts (115.58 mg, 1.14 mmol, 3 eq) was added, the solution was stirred at 15 °C for 2 h. Upon completion, the reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ethenEthyl acetate = 10: 1 to 0: 1) to give methyl (2S)-2-[[2-(4-methoxy-lH-indole-2-carbonyl)-8-oxa-2-azaspiro [4.5]decane-3- carbonyl]amino]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (0.16 g, 291.41 umol, 76.54% yield, 90% purity) as a white solid. MS (ESI) m/z 549.2 [M+H] ⁺ .

Step 4: N-((S)-1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-7-chloro-5-methoxy- 1 H-indole-2-carboxamide [000306] A mixture of (S)-methyl 2-((S)-2-(7-chloro-5-methoxy-lH-indole-2- carboxamido)-4,4-dimethylpentanamido)-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3- yl)propanoate (0.13 g, 246.88 umol, 1 eq) in NH ₃ .MeOH (7 M, 3 mL, 85.06 eq) was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)-1-oxopropan-2-yl)amino)-4,4-dimethyl-1-o xopentan-2-yl)-7- chloro-5-methoxy-lH-indole-2-carboxamide (0.12 g, crude) as a yellow oil. MS (ESI) m/z 534.2 [M+H] ⁺ . Step 5: 7-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyr rolidin-3- yl)ethyl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-5-methoxy- 1 H-indole-2-carboxamide [000307] To a solution of N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3 - yl)- 1 -oxopropan-2-yl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-7-chloro-5-methoxy- 1 H-indole-2-carboxamide (0.11 g, 205.97 umol, 1 eq) in DCM (1 mL) was added burgess reagent (147.26 mg, 617.92 umol, 3 eq), and the solution was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was quenched with water (1 mL) and air dried. The residue was purified by prep-HPLC (column: Waters Xb ridge BEH C18 100*30mm* 10um;mobile phase: [water(10mM NH4HCO ₃ )-ACN]) to give 7-chloro- N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3 -yl)ethyl)amino)-4,4- dimethyl- 1 -oxopentan-2-yl)-5-methoxy- 1 H-indole-2-carboxamide (30.00 mg, 58.14 umol, 28.22% yield, 99% purity) as a white solid. MS (ESI) m/z 516.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 7.23 - 7.08 (m, 2H), 7.08 - 6.98 (m, 1H), 6.53 (br d, J= 7.6 Hz, 1H), 5.02 (br dd, J= 5.7, 10.1 Hz, 1H), 4.72 - 4.62 (m, 2H), 4.19 - 4.03 (m, 1H), 3.98 - 3.81 (m, 4H), 3.77 - 3.62 (m, 4H), 3.29 - 3.17 (m, 1H), 2.52 - 2.20 (m, 3H), 2.02 - 1.42 (m, 8H).

Example 286. Synthesis of viral protease inhibitor compound 1167

Step 1: 7-fluoro-4-methoxy- 1 H-indole-2-carboxylic acid [000308] To a solution of ethyl 7-fl uoro-4-methoxy- 1 H-\ ndol e-2-carboxy 1 ate (200 mg, 843.08 umol, 1 eq) in THF (4 mL) and H ₂ 0 (2 mL) was added LiOH.H ₂ O (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~l with 1M HC1 (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] ⁺

Step 2: (S)-methyl2-((S)-3-cyclopropyl-2-(7-fluoro-4-methoxy-lH-indo le-2- carboxamido)propanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin -3-yl)propanoate

[000309] To a solution of (S)-methyl2-((S)-2-amino-3-cyclopropylpropanamido)-3-((R)-

5.5- dimethyl-2-oxopyrrolidin-3-yl)propanoate (150 mg, 414.52 umol, 1 eq, HC1) and 7-fluoro-4-methoxy-1H-indole-2-carboxylic acid (104.05 mg, 497.43 umol, 1.2 eq) in DCM (8 mL) was added DMAP (101.28 mg, 829.04 umol, 2 eq), then the mixture was added EDCI (158.93 mg, 829.04 umol, 2 eq), the mixture was stirred at 20 °C for 2 h. Upon the reaction completion, the mixture was filtered and was concentrated in vacuum and was purified by prep-TLC (SiO ₂ , EA = 1) to obtained (S)-methyl2-((S)-3- cyclopropyl-2-(7-fluoro-4-methoxy-1H-indole-2-carboxamido) propanamido)-3-((R)-

5.5-dimethyl-2-oxopyrrolidin-3-yl) propanoate (140 mg, 252.05 umol, 60.81% yield, 93% purity) as a yellow solid. MS (ESI) m/z 517.1 [M+H] ⁺

Step 3 : N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3 -yl)-1-oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-7-fluoro-4-methoxy -lH-indole-2-carboxamide [000310] A solution of (S)-methyl 2-((S)-3-cyclopropyl-2-(7-fluoro-4-methoxy-1H- indole-2-carboxamido) propanamido)-3-((R)-5, 5-dimethyl-2-oxopyrrolidin-3-yl) propanoate (140 mg, 271.02 umol, 1 eq) in NH ₃ /MeOH (4 mL, 7M), the mixture was stirred at 30 °C for 16 h. Upon the reaction completion, the mixture was concentrated in vacuum to obtained N-((S)-\ -(((S)- 1 -amino-3 -((R)-5,5-dimethyl-2-oxopyrrolidin- 3-yl)-1-oxopropan-2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl )-7-fluoro-4- methoxy-1H-indole-2-carboxamide (130 mg, crude) as a yellow solid. MS (ESI) m/z 502.2 [M+H] ⁺

Step 4: N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3 -yl)ethyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-7-fluoro-4-methoxy- 1 H-indole-2-carboxamide [000311] To a solution of N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3- yl)-1-oxopropan -2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-7-fluoro-4-meth oxy- 1H-indole-2-carboxamide (120 mg, 239.26 umol, 1 eq) in DCM (6 mL) was added burgess reagent (285.09 mg, 1.20 mmol, 5 eq) at 30 °C, and then the resulting mixture was stirred at 30 °C for 1 h. Upon the reaction completion, the reaction mixture was quenched by water (1 mL) and was dried by blowing N ₂ and was purified by prep- HPLC(column: Waters Xbridge C18 150 * 50mm * lOum; mobilephase: [water(10 mM NH4HCO3)- ACN] ; B%: 25%-55%, lOmin) to obtained N-((S)-1-(((5)-1-cyano-2- ((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl) ethyl)amino)-3-cyclopropyl- 1 -oxopropan-2- yl)-7-fluoro-4-methoxy-1H-indole-2-carbox amide (25 mg, 51.70 umol, 21.61% yield, 100% purity) as a white solid. MS (ESI) m/z 484.2[M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.14 - 11.90 (m, 1H), 9.03 - 8.85 (m, 1H), 8.54 (d, J= 7.4 Hz,

1H), 7.88 - 7.73 (m, 1H), 7.38 - 7.29 (m, 1H), 6.97 - 6.86 (m, 1H), 6.46 - 6.37 (m,

1H), 5.01 - 4.90 (m, 1H), 4.51 - 4.40 (m, 1H), 3.87 (s, 3H), 2.63 - 2.54 (m, 1H), 2.22 - 2.11 (m, 1H), 2.07 (s, 1H), 1.87 - 1.72 (m, 2H), 1.56 - 1.44 (m, 2H), 1.16 (s, 3H), 1.07 (s, 3H), 0.81 (s, 1H), 0.42 (d, J= 6.4 Hz, 2H), 0.24 - 0.16 (m, 1H), 0.10 (s, 1H).

Example 287. Synthesis of viral protease inhibitor compound 1173

Step 1: (S)-methyl 2-((S)-3-cyclopropyl-2-(4,5-dimethyl-lH-pyrrole-2- carboxamido)propanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin -3-yl)propanoate

[000312] To a mixture of (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (140 mg, 340.46 umol, 88% purity, 1 eq, HCI) in DCM (3 mL) was added 4,5-dimethyl-lH-pyrrole-2-carboxylic acid (56.85 mg, 408.55 umol, 1.2 eq), and then then DMAP (124.78 mg, 1.02 mmol, 3 eq) and EDCI (130.53 mg, 680.92 umol, 2 eq) were added at 0 °C. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition into water (3 mL), and then extracted with DCM (3 mL * 3). The combined organic layers were washed with HC1 (1M, 3 mL), then washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give (S)-methyl 2-((S)-3-cyclopropyl-2-(4,5-dimethyl-lH-pyrrole-2-carboxamid o)propanamido)-3- ((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (105 mg, 216.33 umol, 63.54% yield, 92% purity) as yellow solid. MS (ESI) m/z 447.1 [M+H] ⁺ .

Step 2 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4,5-dimethyl-lH-py rrole-2-carboxamide [000313] A mixture of (S)-methyl 2-((S)-3-cyclopropyl-2-(4,5-dimethyl-lH-pyrrole-2- carboxamido)propanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin -3-yl)propanoate (100 mg, 206.03 umol, 92% purity, 1 eq) in NH ₃ /MeOH (7M, 5.48 mL, 186.06 eq) was stirred at 20 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced to give N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3 - yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-4, 5-dimethyl- 1 H- pyrrole-2-carboxamide (100 mg, crude) as white solid. MS (ESI) m/z 430.1 [M-H] ⁺ .

Step 3 : N-((S)- 1 -(((S)- 1 -cyano-2-((R)-5, 5-dimethyl -2-oxopyrrolidin-3-yl)ethyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)-4, 5-dimethyl- 1 H-pyrrole-2-carboxamide

[000314] To a mixture of N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3 - yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-4, 5-dimethyl- 1 H- pyrrole-2-carboxamide (90 mg, 177.28 umol, 85% purity, 1 eq) in DCM (1 mL) was added burgess reagent (92.94 mg, 390.01 umol, 2.2 eq) and stirred at 20 °C for 14 h. Upon completion, the mixture was quenched with water (1 mL) and concentrated under reduced pressure to give a residue (<30 °C). The residue was purified by prep- HPLC (column : Phenomenex Luna C18 75*30mm*3um;mobile phase: [water(0.2%FA)-ACN];B%: 35%-65%,8min) to give N-((S)- 1 -(((S)- 1 -cyano-2- ((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)ethyl)amino)-3-cyclop ropyl-1-oxopropan-2- yl)-4,5-dimethyl-lH-pyrrole-2-carboxamide (4.27 mg, 10.12 umol, 5.71% yield, 98.0% purity) as white solid. MS (ESI) m/z 414.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMS0-d ₆ ) δ = 10.94 (br d,J= 1.5 Hz, 1H), 8.80 (d, J= 8.2 Hz, 1H), 7.81 (s, 1H), 7.77 - 7.71 (m, 1H), 6.61 (d, J = 2.6 Hz, 1H), 4.98 - 4.87 (m, 1H), 4.40 - 4.32 (m, 1H), 2.60 - 2.53 (m, 1H), 2.18 - 2.10 (m, 1H), 2.10 - 2.04 (m, 3H), 1.97 (dd, J= 8.6, 12.3 Hz, 1H), 1.90 (s, 3H), 1.80 - 1.69 (m, 2H), 1.53 - 1.44 (m, 1H), 1.43 - 1.35 (m, 1H), 1.19 - 1.12 (m, 3H), 1.06 (s, 3H), 0.80 - 0.67 (m, 1H), 0.45 - 0.31 (m, 2H), 0.18 - 0.00 (m, 2H).

Example 288. Synthesis of viral protease inhibitor compound 1175

Step 1: (S)-methyl 2-((S)-2-(4-chloro- 1 H-pyrrole-2-carboxamido)-3- cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin- 3-yl)propanoate

[000315] To a mixture of (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (150 mg, 364.78 umol, 88% purity, 1 eq, HCI) in DCM (3 mL) was added 4-chloro- 1 H-pyrrole-2-carboxylic acid (63.71 mg, 437.73 umol, 1.2 eq). Then, HOBT (98.58 mg, 729.56 umol, 2 eq), DIEA (94.29 mg, 729.56 umol, 127.08 uL, 2 eq) and EDCI (139.86 mg, 729.56 umol, 2 eq) were added at 0 °C. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition of water (3 mL), and then extracted with DCM (3 mL * 3). The combined organic layers were washed with HCI (1M, 3 mL), then washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give (S)-methyl 2-((S)-2-(4-chloro- 1 H-pyrrole-2- carboxamido)-3-cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2 -oxopyrrolidin-3- yl)propanoate (110 mg, 242.86 umol, 66.58% yield) as yellow solid. MS (ESI) m/z 451.0 [M-H] ⁺ . Step 2 : N-((S)-1-(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4-chloro-lH-pyrrol e-2-carboxamide

[000316] A mixture of (S)-methyl 2-((S)-2-(4-chloro-lH-pyrrole-2-carboxamido)-3- cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin- 3-yl)propanoate (100 mg, 220.78 umol, 100% purity, 1 eq) in NH ₃ /MeOH (7M, 3 mL, 95.12 eq) was stirred at 50 °C for 20 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-4- chloro- 1 H-pyrrole-2-carboxamide (95 mg, crude) as white solid. MS (ESI) m/z 438.2 [M+H] ⁺ .

Step 3: 4-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyr rolidin-3- yl)ethyl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)- 1 H-pyrrole-2-carboxamide

[000317] To a mixture of N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3 - yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-4-chloro- 1 H-pyrrole- 2-carboxamide (95 mg, 190.90 umol, 88% purity, 1 eq) in DCM (1 mL) was added burgess reagent (136.48 mg, 572.71 umol, 3 eq) and stirred at 20 °C for 1.5 h. Upon completion, the reaction mixture was quenched with water (1 mL) and concentrated under reduced pressure to give a residue (<30 °C). The residue was purified by prep- HPLC(column : W aters Xbridge BEH C18 100*30mm* 10um;mobile phase : [ water( 1 OmM NH4HCO3)- ACN] ;B% : 25%-55%,10min) to give 4-chloro-N- ((S)- 1 -(((S)- 1 -cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)ethyl)amino) -3- cyclopropyl- 1 -oxopropan-2-yl)- 1 H-pyrrole-2-carboxamide (28.63 mg, 68.18 umol, 35.72% yield, 100% purity) as white solid. MS (ESI) m/z 420.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.84 - 11.68 (m, 1H), 8.88 (d, J= 8.2 Hz, 1H), 8.18 (d, 7 = 7.5 Hz, 1H), 7.83 (s, 1H), 6.95 (br d, J= 7.3 Hz, 2H), 5.01 - 4.86 (m, 1H), 4.46 - 4.29 (m, 1H), 2.62 - 2.53 (m, 1H), 2.19 - 2.09 (m, 1H), 2.03 - 1.92 (m, 1H), 1.81 - 1.71 (m, 2H), 1.54 - 1.36 (m, 2H), 1.16 (s, 3H), 1.10 - 0.99 (m, 3H), 0.83 - 0.69 (m, 1H), 0.47 - 0.33 (m, 2H), 0.21 - 0.02 (m, 2H).

Example 289. Synthesis of viral protease inhibitor compound 1177

Step 1: (S)-methyl 2-((S)-2-(5-chloro-lH-pyrrole-2-carboxamido)-3- cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin- 3-yl)propanoate

[000318] To a solution of (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (150.00 mg, 460.97 umol, 1 eq, HC1) in ACN (5 mL) was added NMI (113.54 mg, 1.38 mmol, 3 eq), and then 5-chloro-lH- pyrrole-2-carboxpuriylic acid (67.09 mg, 460.97 umol, 1.0 eq) and TCFH (129.34 mg, 460.97 umol, 1 eq) was added, the solution was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was diluted with water (10 mL), extracted with EtOAc (5 mL * 3) and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex Luna 80*30mm*3um; mobile phase: [water(0.1%TFA)-ACN]). Compound (S)- methyl 2-((S)-2-(5-chloro-lH-pyrrole-2-carboxamido)-3-cyclopropylpr opanamido)-3- ((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (60.0 mg, 132.37 umol, 28.74% yield, 90% purity) was obtained as a white solid. MS (ESI) m/z 453.2 [M+H] ⁺ .

Step 2 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-5-chloro-lH-pyrrol e-2-carboxamide

[000319] A mixture of (S)-methyl 2-((S)-2-(5-chloro-lH-pyrrole-2-carboxamido)-3- cyclopropylpropanamido)-3-((R)-5, 5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (60.00 mg, 132.47 umol, 1 eq) in HCl/MeOH (4 M, 4 mL) was stirred at 60 °C for 18 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-((S)-1-(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan- 2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-5-chloro-lH-pyrr ole-2-carboxamide (50.00 mg, crude) as a white solid.

Step 3: 5-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyr rolidin-3- yl)ethyl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)- 1 H-pyrrole-2-carboxamide

[000320] To a solution of N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3 - yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-5-chloro- 1 H-pyrrole- 2-carboxamide (50.00 mg, 114.18 umol, 1 eq) in DCM (1 mL) was added burgess reagent (81.63 mg, 342.53 umol, 3 eq), and then the solution was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was quenched with water (1 mL) and air dried. The residue was purified by prep-HPLC (Waters Xbridge BEH Cl 8 100*30mm*10um; mobile phase: [water(10mM NH4HCO ₃ )-ACN]) to give 5-chloro- N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3 -yl)ethyl)amino)-3- cyclopropyl- 1 -oxopropan-2-yl)- 1 H-pyrrole-2-carboxamide (5.00 mg, 11.91 umol, 10.43% yield) as a white solid. MS (ESI) m/z 420.1 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ ppm 6.82 (d, J=3.81 Hz, 1 H) 6.03 (d, J=3.93 Hz, 1 H) 5.01 (dd, J=10.37, 5.72 Hz, 1 H) 4.45 (t, J=7.39 Hz, 1 H) 2.87 - 2.71 (m, 1 H) 2.34 (ddd, J=13.77, 10.43, 5.13 Hz, 1 H) 2.14 (dd, J=12.40, 8.46 Hz, 1 H) 1.94 - 1.76 (m, 2 H) 1.65 - 1.53 (m, 2 H) 1.25 (s, 3 H) 1.16 (s, 3 H) 0.87 - 0.72 (m, 1 H) 0.51 (d, J=8.11 Hz, 2 H) 0.22 - 0.10 (m, 2 H)

Example 290. Synthesis of viral protease inhibitor compound 1181

Step 1: (S)-methyl 2-((S)-3-cyclopropyl-2-(4,6-dichloro-lH-indole-2- carboxamido)propanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin -3-yl)propanoate [000321] To a mixture of (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (140 mg, 386.89 umol, 1 eq, HC1) in DCM (3 mL) was added 4,6-dichloro-lH-indole-2-carboxylic acid (89.00 mg, 386.89 umol, 1 eq), DMAP (141.80 mg, 1.16 mmol, 3 eq) and EDCI (148.33 mg, 773.77 umol, 2 eq), then stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition of water (3 mL), and then extracted with DCM (5 mL * 3). The combined organic layers were washed with HC1 (1M, 5 mL), then washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (Si02, DCM: MeOH = 10: 1). To give (S)-methyl 2-((S)-3-cyclopropyl-2-(4,6-dichloro-lH-indole-2-carboxamido )propanamido)-3- ((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (130 mg, 241.89 umol, 62.52% yield) as yellow solid. MS (ESI) m/z 537.2 [M+H] ⁺ .

Step 2 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-4,6-dichloro-lH-in dole-2-carboxamide

[000322] To a mixture of (S)-methyl 2-((S)-3-cyclopropyl-2-(4,6-dichloro-lH-indole-2- carboxamido)propanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin -3-yl)propanoate (110 mg, 204.68 umol, 1 eq) in HNs/MeOH (7 M, 2 mL, 68.40 eq) was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-4,6- dichloro- 1 H-indole-2-carboxamide (110 mg, crude) as white solid. MS (ESI) m/z 522.2 [M+H] ⁺ .

Step 3 : 4,6-dichloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-ox opyrrolidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-lH-indole-2- carboxamide

[000323] To a mixture of N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3 - yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-4,6-dichloro- 1 H- indole-2-carboxamide (105 mg, 180.89 umol, 90% purity, 1 eq) in DCM (2 mL) was added burgess reagent (258.64 mg, 1.09 mmol, 6 eq) then stirred at 20 °C for 2 h. Upon completion, the mixture was quenched with water (0.1 mL) and concentrated under reduced pressure to give a residue(<30 °C). The residue was purified by prep- HPLC (column: Waters Xbridge BEH C18 100* 30 mm* 10 um; mobile phase: [water(10 mM NH4HCO3)- ACN]; B%: 35%-65%, 8 min) to give 4,6-dichloro-N- ((S)- 1 -(((S)- 1 -cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)ethyl)amino) -3- cyclopropyl- 1 -oxopropan-2-yl)- 1 H-indole-2-carboxamide as white solid. MS (ESI) m/z 504.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.99 - 11.77 (m, 1H), 8.84 -

8.66 (m, 1H), 8.60 - 8.49 (m, 1H), 7.55 - 7.35 (m, 2H), 7.40 - 7.32 (m, 1H), 7.19 (d ,J

= 1.5 Hz, 1H), 5.03 - 4.88 (m, 1H), 4.64 - 4.45 (m, 1H), 2.60 - 2.54 (m, 1H), 2.28 - 2.14 (m, 1H), 2.12 - 1.99 (m, 1H), 1.90 - 1.75 (m, 2H), 1.66 - 1.51 (m, 2H), 1.22 -

1.09 (m, 6H), 0.91 - 0.73 (m, 1H), 0.48 - 0.39 (m, 2H), 0.28 - 0.03 (m, 2H)

Example 291. Synthesis of viral protease inhibitor compound 1191

Stepl : methyl (2S)-2-[[(2S)-2-[(7-chloro-6-fluoro-lH-indole-2-carbonyl)ami no]-3- cyclopropyl-propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrr olidin-3-yl]propanoate [000324] To a mixture of 7-chloro-6-fluoro- 1 H-indole-2-carboxylic acid (0.1 g, 374.54 umol, 80% purity, 1.2 eq) and methyl (2 S)-2-[ [(2 S)-2-amino-3 -cyclopropy 1- propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl] propanoate (112.94 mg, 312.12 umol, 1 eq, HC1) in DCM (3 mL) were added EDCI (119.67 mg, 624.24 umol, 2 eq) and DMAP (114.40 mg, 936.36 umol, 3 eq), and then the resulting mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (20 mL) and extracted with DCM (6 mL * 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give methyl (2S)-2-[[(2S)-2-[(7-chloro-6-fluoro-lH-indole-2-carbonyl)ami no]-3- cyclopropyl-propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrr olidin-3- yl]propanoate (0.14 g, 241.85 umol, 77.49% yield, 90% purity) as white solid. MS (ESI) m/z 521.2 [M+H] ⁺

Step2: N-[(l S)-2-[[(l S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methy l]-2- oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-7-chloro -6-fluoro-lH-indole-2- carboxamide

[000325] A solution of methyl (2S)-2-[[(2S)-2-[(7-chloro-6-fluoro-lH-indole-2- carbonyl)amino]-3-cyclopropyl-propanoyl]amino]-3-[(3R)-5,5-d imethyl-2-oxo- pyrrolidin-3-yl]propanoate (0.12 g, 230.34 umol, 1 eq) in NH ₃ /MeOH (3 mL) was stirred at 30 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to get the crude product 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]-7-chloro-6-fluoro-lH-indole -2-carboxamide (0.11 g, crude) as white solid. MS (ESI) m/z 506.2 [M+H] ⁺

Step3 : 7-chloro-N-[(l S)-2-[[(l S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6-fluoro- lH-indole-2-carboxamide [000326] To a solution of N-[(1S)-2-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmet hyl)-2-oxo-ethyl]-7- chloro-6-fluoro- 1 H-indole-2-carboxamide (0.11 g, 173.92 umol, 80% purity, 1 eq) in DCM (3 mL) was added burgess reagent (82.90 mg, 347.85 umol, 2 eq), the mixture was stirred at 30 °C for 2 h. Upon completion, the mixture were quenched with water (1 mL) and blow-dried with N ₂ and was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HCO3)- ACN];B%: 30%-60%,8min) to give the product 7-chloro-N-[(1S)-2-[[(1S)-1-cyano-2- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]ethyl]amino]-1-(cyc lopropylmethyl)-2-oxo- ethy 1 ]-6-fluoro- 1 H-indol e-2-carboxamide (0.058 g, 118.86 umol, 68.34% yield, 100% purity) as white solid. MS (ESI) m/z 488.1 [M+H] ^{+ 1} H NMR (400MHz, DMSO-d ₆ ) δ = 11.89 (br s, 1H), 9.01 (d, J = 7.9 Hz, 1H), 8.69 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H),

7.66 (dd, J = 4.8, 8.7 Hz, 1H), 7.27 (s, 1H), 7.13 (dd, J = 8.9, 10.0 Hz, 1H), 4.97 (br d, J = 7.9 Hz, 1H), 4.50 (br d, J = 6.6 Hz, 1H), 2.63 - 2.55 (m, 1H), 2.26 - 2.09 (m, 1H), 2.00 (dd, J = 8.4, 12.2 Hz, 1H), 1.90 - 1.72 (m, 2H), 1.59 - 1.44 (m, 2H), 1.15 (s, 3H), 1.07 (s, 3H), 0.90 - 0.75 (m, 1H), 0.55 - 0.35 (m, 2H), 0.25 - 0.16 (m, 1H), 0.15 - 0.07 (m, 1H).

Example 292. Synthesis of viral protease inhibitor compound 1193

Stepl : methyl (2S)-2-[[(2S)-2-[(6-chloro-5-fluoro-lH-indole-2-carbonyl)ami no]-3- cyclopropyl-propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrr olidin-3-yl]propanoate [000327] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl] propanoate (0.1 g, 276.35 umol, 1 eq, HC1) and 6-chloro-5-fluoro- 1 H-indole-2-carboxylic acid (70.83 mg, 331.62 umol, 1.2 eq) in DCM (3 mL), DMF (0.5 mL) was added EDCI (105.95 mg, 552.70 umol, 2 eq), DMAP (101.28 mg, 829.04 umol, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (30 mL) and extracted with DCM (8 mL * 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10:1) to give product methyl (2S)-2- [[(2S)-2-[(6-chloro-5-fluoro-lH-indole-2-carbonyl)amino]-3-c yclopropyl- propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl] propanoate (0.08 g, 141.27 umol, 51.12% yield, 92% purity) as white solid. MS (ESI) m/z 521.2 [M+H] ⁺

Step2: N-[(l S)-2-[[(l S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methy l]-2- oxo-ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6-chloro -5-fluoro-lH-indole-2- carboxamide [000328] The methyl (2S)-2-[[(2S)-2-[(6-chloro-5-fluoro-lH-indole-2-carbonyl)ami no]-3- cyclopropyl-propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrr olidin-3- yl]propanoate (0.07 g, 134.36 umol, 1 eq) in NH ₃ /MeOH (1 mL) was stirred at 50 °C for 12 h. Upon completion, the reaction mixture was concentrated under pressure reduced to get the crude product N-[( 1 S)-2-[[( 1 S)-2-amino- 1 -[[(3R)-5, 5-dimethyl-2- oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]amino]-1-(cyclopropy lmethyl)-2-oxo-ethyl]- 6-chloro-5-fluoro- 1 H-indole-2-carboxamide (0.05 g, crude) as white solid. MS (ESI) m/z 506.2 [M+H] ⁺

Step3 : 6-chloro-N-[(l S)-2-[[(l S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-5-fluoro- lH-indole-2-carboxamide [000329] The solution of N-[(l S)-2-[[(l S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmet hyl)-2-oxo-ethyl]-6- chloro-5-fluoro- 1 H-indole-2-carboxamide (0.03 g, 56.33 umol, 95% purity, 1 eq) in DCM (1 mL) was added burgess reagent (53.69 mg, 225.31 umol, 4 eq). The mixture was stirred at 30 °C for 1 h. Upon completion, the mixture were quenched with water (1 mL) and blow-dried with N ₂ , and was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(10mM NH4HCO3)- ACN];B%: 35%-65%,8min) to give the product 6-chloro-N-[(1S)-2-[[(1S)-1-cyano-2- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]ethyl]amino]-1-(cyc lopropylmethyl)-2-oxo- ethyl]-5-fluoro-lH-indole-2-carboxamide (0.017 g, 34.84 umol, 61.85% yield, 100% purity) as a white solid. MS (ESI) m/z 488.1 [M+H] ^{+ 1} H NMR (400MHz, DMSO-d ₆ ) δ = 7.52 (d, J = 6.4 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.17 (d, J = 0.7 Hz, 1H), 5.04 (dd, J = 5.7, 10.5 Hz, 1H), 4.54 (t, J = 7.5 Hz, 1H), 2.92 - 2.77 (m, 1H), 2.40 - 2.31 (m, 1H), 2.21 - 2.11 (m, 1H), 1.88 (br s, 2H), 1.71 - 1.55 (m, 2H), 1.26 - 1.23 (m, 3H), 1.14 (s, 3H), 0.91 - 0.77 (m, 1H), 0.59 - 0.46 (m, 2H), 0.19 (dd, J = 5.0, 10.6 Hz, 2H)

Example 293. Synthesis of viral protease inhibitor compound 1195

Step 1: (S)-methyl 2-((S)-2-(6-chloro-7-fluoro-lH-indole-2-carboxamido)-3- cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin- 3-yl)propanoate

[000330] To a mixture of (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)propanoate (140 mg, 344.19 umol, 80% purity, 1 eq) in DCM (3 mL) was added 6-chloro-7-fluoro- 1 H-indole-2-carboxylic acid (88.22 mg, 413.03 umol, 1.2 eq), DMAP (126.15 mg, 1.03 mmol, 3 eq) and EDCI (131.96 mg, 688.38 umol, 2 eq), then the resulting mixture stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition of water (1 mL), and then extracted with DCM (3 mL * 3). The combined organic layers were washed with HC1 (1M, 3 mL), then washed with brine (3 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (Si02, DCM:MeOH = 10: 1) to give (S)-methyl 2-((S)-2-(6-chloro-7-fluoro-lH-indole-2- carboxamido)-3-cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2 -oxopyrrolidin-3- yl)propanoate (140 mg, 241.85 umol, 70.27% yield, 90% purity) as yellow solid. MS (ESI) m/z 519.0 [M-H] ⁺ .

Step 2 : N-((S)-1-(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-6-chloro-7-fluoro- lH-indole-2-carboxamide [000331] To a mixture of (S)-methyl 2-((S)-2-(6-chloro-7-fluoro-lH-indole-2- carboxamido)-3-cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2 -oxopyrrolidin-3- yl)propanoate (140 mg, 241.85 umol, 90% purity, 1 eq) in NH ₃ /MeOH (7 M, 3 mL, 86.83 eq) was stirred at 60 °C for 16 h. Upon completion, The reaction mixture was concentrated under reduced pressure to give N-((S)-1-(((S)-1-amino-3-((R)-5,5- dimethyl-2-oxopyrrolidin-3-yl)-1-oxopropan-2-yl)amino)-3-cyc lopropyl-1- oxopropan-2-yl)-6-chloro-7-fluoro- 1 H-indole-2-carboxamide (140 mg, crude) as white solid. MS (ESI) m/z 504.0 [M-H] ⁺ .

Step 3: 6-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyr rolidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-7-fluoro-lH- indole-2-carboxamide

[000332] To a mixture of N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3 - yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-6-chloro-7-fluoro- 1 H- indole-2-carboxamide (130 mg, 205.55 umol, 80% purity, 1 eq) in DCM (2 mL) was added burgess reagent (146.95 mg, 616.64 umol, 3 eq), then stirred at 20 °C for 2 h. Upon completion, the mixture was quenched with water (1 mL) and concentrated under reduced pressure to give a residue (<30 °C). The residue was purified by prep- HPLC(column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(10mM NH4HCO ₃ )-ACN]; B%: 35%-65%, 10 min) to give 6-chloro-N-((S)-1- (((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)ethyl )amino)-3-cyclopropyl- l-oxopropan-2-yl)-7-fluoro-lH-indole-2-carboxamide (29.53 mg, 60.09 umol,

29.24% yield, 99.3% purity) as white solid. MS (ESI) m/z 488.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.35 - 12.19 (m, 1H), 8.99 (d, J= 7.9 Hz, 1H), 8.66 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.50 (d, J= 8.6 Hz, 1H), 7.32 (d,J= 3.1 Hz, 1H), 7.13 (dd, J= 6.4, 8.6 Hz, 1H), 5.02 - 4.90 (m, 1H), 4.53 - 4.42 (m, 1H), 2.61 - 2.54 (m,

1H), 2.22 - 2.11 (m, 1H), 1.99 (dd, J= 8.4, 12.1 Hz, 1H), 1.89 - 1.72 (m, 2H), 1.57 - 1.42 (m, 2H), 1.18 - 1.03 (m, 6H), 0.88 - 0.73 (m, 1H), 0.50 - 0.34 (m, 2H), 0.26 - 0.03 (m, 2H)

Example 294. Synthesis of viral protease inhibitor compound 1201

Step 1 : 3-chloro-5-fluoro-2-hydroxybenzaldehyde

[000333] To a solution of 2-chloro-4-fluoro-phenol (5 g, 34.12 mmol, 1 eq ) and MgCh (9.80 g, 102.93 mmol, 4.22 mL, 3.02 eq) in ACN (300 mL) was added TEA (9.45 g, 93.40 mmol, 13.00 mL, 2.74 eq), (HCHO)n (3.5 g, 34.12 mmol, 1.00 eq), the mixture was stirred at 80 °C for 60 h. Upon the reaction completion, the mixture was concentrated in vacuum and acidified with aqueous HC1 (100 mL, 3M) solution to pH~l, and extracted with EtOAc (50 mL * 3), then the organic phase was concentrated in vacuum and purified by column (SiO ₂ , PE = 1) to obtained 3-chloro- 5-fluoro-2- hydroxybenzaldehyde (5 g, 25.21 mmol, 73.88% yield, 88% purity) as a yellow solid. MS (ESI) m/z 173.1 [M-H] ⁺

Step 2: 3-chloro-5-fluoro-2-methoxybenzaldehyde [000334] 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 Na ₂ SO ₄ , 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] ⁺

Step 3: (Z)-methyl 2-azido-3-(3-chloro-5-fluoro-2-methoxyphenyl)acrylate

[000335]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 (S1O2, 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.

Step 4: methyl 5-chloro-7-fluoro-4-methoxy-lH-indole-2-carboxylate

[000336] 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.

Step 5: 5-chloro-7-fluoro-4-methoxy-lH-indole-2-carboxylic acid

[000337] 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 H ₂ O (2 mL) was added L1OH.H ₂ O (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~l with aqueous HC1 (15 mL, 1M), then was extracted with EtOAc (5 mL * 3), then was concentrated in vacuum to obtained 5 -chi oro-7 -fl uoro-4-methoxy- 1H-i ndol e-2 - carboxylic acid (250 mg, crude) as a yellow solid. MS (ESI) m/z 189.1 [M+H] ⁺ Step 6: (S)-methyl2-((S)-2-(5-chloro-7-fluoro-4-methoxy-lH-indole-2- carboxamido)-3- cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin- 3-yl)propanoate

[000338] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl-propanoyl]amino]- 3-[(3R)-5,5- dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (250 mg, 690.87 umol, 1 eq, HC1) and 5-chloro-7-fluoro-4-methoxy-1H-indole-2 -carboxylic acid (168.31 mg, 690.87 umol, 1 eq) in DCM (5 mL) was added DMAP (253.21 mg, 2.07 mmol, 3 eq) and EDCI (264.88 mg, 1.38 mmol, 2 eq), and then the resulting mixture was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was adjusted pH~l with 1M HC1 (3 mL) and was added water (6 mL), then was extracted with DCM (3 mL * 3), then the organic phase was dried with Na ₂ SO ₄ , the mixture was concentrated in vacuum and was purified by prep-TLC (SiO ₂ , EtOAc = 1) to obtained (S)-methyl2- ((S)-2-(5-chloro-7-fluoro-4-methoxy-1H-indole-2- carboxamido)-3- cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin- 3-yl) propanoate ( 180 mg, 294.01 umol, 42.56% yield, 90% purity) as a white solid. MS (ESI) m/z 551.2 [M+H] ⁺

Step 7 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-5-chloro-7-fluoro- 4-methoxy-lH-indole-2- carboxamide

[000339] A solution of (S)-methyl 2-((S)-2-(5-chloro-7-fluoro-4-methoxy-1H-indole-2- carboxamido) -3-cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolid in-3-yl) propanoate (160 mg, 290.38 umol, 1 eq) in NH ₃ /MeOH (8 mL, 7M) was stirred at 30 °C for 16 h. Upon the reaction completion, the mixture was concentrated in vacuum to obtained N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3 - yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-5-chloro-7-fluoro-4- methoxy- 1H-indole-2-carboxamide (100 mg, crude) as a yellow solid. MS (ESI) m/z 536.1 [M+H] ⁺

Step 8: 5-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyr rolidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-7-fluoro-4-m ethoxy-lH-indole-2- carboxamide

[000340] To a solution of N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3- yl)-1-oxopropan -2-yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-5-chloro-7-fluo ro-4- methoxy- 1H-indole-2-carboxamide (90 mg, 167.91 umol, 1 eq) in DCM (2 mL) was added burgess reagent (120.05 mg, 503.74 umol, 3 eq) at 30 °C, and then the resulting mixture was stirred at 30 °C for 3 h. Upon the reaction completion, the mixture was quenched by water (0.5 mL) and was dried by blowing N ₂ and was purified by prep- HPLC (column: Waters Xbridge BEH C18 100 * 25mm * Sum; mobile phase: [water (10 mM NH ₄ HCO ₃ )- ACN] ; B%: 35%-70%, 10 min) to obtained 5-chloro-N-((S)-1- (((S)-1-cyano-2-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)ethyl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-7-fluoro-4-methoxy- 1H-indole-2-carboxamide (15 mg, 28.88 umol, 17.20% yield, 99.74% purity) as a white solid. MS (ESI) m/z 518.1 [M+H] ⁺

[000341] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.36 (s, 1H), 9.07 - 8.91 (m, 1H), 8.76 - 8.63 (m, 1H), 7.84 - 7.79 (m, 1H), 7.70 - 7.32 (m, 1H), 7.17 (d, J= 10.4 Hz, 1H), 4.97 (q, J= 8.2 Hz, 1H), 4.53 - 4.43 (m, 1H), 4.03 - 3.77 (m, 3H), 2.61 - 2.54 (m, 1H), 2.21 - 2.12 (m, 1H), 2.05 - 1.96 (m, 1H), 1.89 - 1.73 (m, 2H), 1.57 - 1.43 (m, 2H), 1.19 - 1.13 (m, 3H), 1.10 - 1.04 (m, 3H), 0.87 - 0.76 (m, 1H), 0.48 - 0.38 (m, 2H), 0.24 - 0.07 (m, 2H).

[000342] ¹ H NMR (400 MHz, DMSO-d ₆ , 273+80K) δ ppm 12.05 (s, 1H), 8.71 (d ,J= 7.8 Hz, 1H), 8.44 - 8.33 (m, 1H), 7.56 - 7.49 (m, 1H), 7.44 - 7.35 (m, 1H), 7.09 (d ,J = 10.4 Hz, 1H), 5.00 - 4.93 (m, 1H), 4.60 - 4.53 (m, 1H), 4.04 - 3.81 (m, 3H), 2.63 - 2.55 (m, 1H), 2.25 - 2.16 (m, 1H), 2.14 - 2.06 (m, 1H), 1.90 - 1.75 (m, 2H), 1.69 - 1.52 (m, 2H), 1.23 - 1.17 (m, 3H), 1.16 - 1.11 (m, 3H), 0.88 - 0.79 (m, 1H), 0.50 - 0.42 (m, 2H), 0.24 - 0.09 (m, 2H).

Example 295. Synthesis of viral protease inhibitor compound 1203

Step 1 : 4-chloro-3-fluoro-2-methoxy-benzaldehyde

[000343] To a mixture of l-chloro-2-fluoro-3-methoxy-benzene (5 g, 31.14 mmol, 1 eq) in THF (100 mL) was added n-BuLi (2.5 M, 13.70 mL, 1.1 eq) in one portion at - 70 °C under N ₂ . The mixture was stirred at -70 °C for 1 h, then added DMF (18.66 g, 255.35 mmol, 19.65 mL, 8.2 eq) in THF (35 mL) at -70 °C, and then the resulting mixture was stirred at -70 °C for 1 h, then HCI (1 M, 75 mL, 2.41 eq) was added and heated to 25 °C and stirred for 16 h. -20% reactant was still, the reaction mixture was diluted with H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue.

[000344] The residue was purified by neutral prep-HPLC (column: Welch Xtimate C18 250*70mm#10um; mobile phase: [water (lOmM NH ₄ HCO ₃ )-ACN]; B%: 35%-65%, 20 min). Compound 4-chloro-3-fluoro-2-methoxy-benzaldehyde (1 g, 4.77 mmol, 15.33% yield, 90% purity) was obtained as a white solid. MS (ESI) m/z 189.0 [M+H] ⁺

Step2 : methyl (Z)-2-azido-3-(4-chloro-3-fluoro-2-methoxy-phenyl)prop-2-eno ate

[000345] To a mixture of NaOMe (229.18 mg, 4.24 mmol, 2 eq) in MeOH (8 mL) was cooled to -10 °C, a mixture 4-chloro-3-fluoro-2-methoxy-benzaldehyde (400 mg, 2.12 mmol, 1 eq) and ethyl 2-azidoacetate (547.73 mg, 4.24 mmol, 484.72 uL, 2 eq) in MeOH (4 mL) was dropwise to this solution. The mixture was stirred at 25 °C for 16 h and yellow solid was observed. Upon completion, the reaction mixture was filtered to give a residue. The residue was purified by prep-TLC (Petroleum ethenEthyl acetate = 20:1). Compound methyl (Z)-2-azido-3-(4-chloro-3-fluoro-2-methoxy- phenyl) prop-2-enoate (200 mg, 630.12 umol, 29.71% yield, 90% purity) was obtained as a white solid.

Step 3: methyl 6-chloro-5-fluoro-4-methoxy-lH-indole-2-carboxylate

[000346] A solution of methyl (Z)-2-azido-3-(4-chloro-3-fluoro-2-methoxy-phenyl)prop- 2-enoate (140 mg, 490.10 umol, 1 eq) in xylene (10 mL) was stirred at 170 °C for 4 h. -10% reactant was still. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum etherEthyl acetate = 2:1). Compound methyl 6-chloro-5-fluoro-4-methoxy-lH- indole-2-carboxylate (96 mg, 353.98 umol, 72.23% yield, 95% purity) was obtained as a white solid.

Step 4: 6-chloro-5-fluoro-4-methoxy-lH-indole-2-carboxylic acid

[000347] To a mixture of methyl 6-chloro-5-fluoro-4-methoxy-lH-indole-2-carboxylate (96 mg, 372.61 umol, 1 eq) in THF (2 mL) and H ₂ O (1 mL) was added LiOH.H ₂ O (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 HC1, and then diluted with H ₂ O 30 mL and extracted with EA 100 mL (50 mL * 2). The combined organic layers were washed with brine 50 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was used next step directly. Compound 6-chloro-5-fluoro-4-methoxy-lH-indole-2-carboxylic acid (70 mg, crude) was obtained as a yellow solid. MS (ESI) m/z 241.9 [M-H] ⁺

Step 5: methyl (2S)-2-[[(2S)-2-[(6-chloro-5-fluoro-4-methoxy-lH-indole-2-ca rbonyl)amino]- 3-cyclopropyl-propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-py rrolidin-3-yl]propanoate [000348] To a mixture of 6-chloro-5-fluoro-4-methoxy-lH-indole-2-carboxylic acid (70 mg, 287.33 umol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl] propanoate (103.98 mg, 287.33 umol, 1 eq, HC1) in DCM (6 mL) and DMF (3 mL) was added DMAP (70.21 mg, 574.67 umol, 2 eq) and EDCI (110.17 mg, 574.67 umol, 2 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O 20 mL and extracted with EA 40 mL (20 mL * 2). The combined organic layers were washed with brine 20 mL (20 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10:1). Compound methyl (2S)-2-[[(2S)- 2-[(6-chloro-5-fluoro-4-methoxy-lH-indole-2-carbonyl)amino]- 3-cyclopropyl- propanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl] propanoate (120 mg, 206.89 umol, 72.00% yield, 95% purity) was obtained as a colourless oil. MS (ESI) m/z 551.1 [M+H] ⁺

Step 6: N-[(l S)-2-[[(l S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methy l]-2- oxo-ethyl] amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-6-chloro-5-fluoro- 4-methoxy-lH- indole-2-carboxamide

[000349] A solution of methyl (2S)-2-[[(2S)-2-[(6-chloro-5-fluoro-4-methoxy-lH-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-[(l S)-2-[[(l S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmet hyl)-2-oxo-ethyl]-6- chloro-5-fluoro -4-methoxy- 1 H-indole-2-carboxamide (90 mg, crude) was obtained as a white solid. MS (ESI) m/z 536.2 [M+H] ⁺

Step 7 : 6-chloro-N-[(l S)-2-[[( 1 S)- 1 -cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-5-fluoro- 4-methoxy-lH-indole-2- carboxamide

[000350] To a mixture of N-[(1S)-2-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]amino]-1-(cyclopropylmet hyl)-2-oxo-ethyl]-6- chloro-5-fluoro-4-methoxy-lH-indole-2-carboxamide (90 mg, 167.91 umol, 1 eq) in DCM (5 mL) was added burgess reagent (80.03 mg, 335.82 umol, 2 eq). The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was diluted with H ₂ O 5 mL and extracted with DCM 10 mL (5 mL * 2). The combined organic layers were concentrated by blow-drying to give a residue. The residue was purified by neutral prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (lOmM NH4HCO3)- ACN] ; B%: 40%-70%, 10 min). Compound 6- chloro-N-[(1S)-2-[[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-p yrrolidin-3- yl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-5-fluoro- 4-methoxy-lH-indole- 2-carboxamide (52 mg, 97.18 umol, 57.87% yield, 96.8% purity) was obtained as a white solid. MS (ESI) m/z 518.1 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) δ = 11.81 (br d,J= 1.1 Hz, 1H), 8.96 (d, J= 8.1 Hz, 1H), 8.69 (d, J= 7.6 Hz, 1H), 7.82 (s, 1H), 7.57 (d, J= 0.9 Hz, 1H), 7.26 - 7.16 (m, 1H), 5.05 - 4.88 (m, 1H), 4.54 - 4.40 (m, 1H), 4.12 (d ,J= 1.3 Hz, 3H), 2.55 (br s, 1H), 2.23 - 2.11 (m, 1H), 1.98 (dd,J= 8.6, 12.3 Hz, 1H), 1.89 - 1.71 (m, 2H), 1.57 - 1.40 (m, 2H), 1.15 (s, 3H), 1.05 (s, 3H), 0.86 - 0.74 (m, 1H), 0.49 - 0.34 (m, 2H), 0.25 - 0.16 (m, 1H), 0.14 - 0.04 (m, 1H).

Example 296. Synthesis of viral protease inhibitor compound 1205 Step 1 : (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)-5,5-dimethyl- 2- oxopyrrolidin-3-yl)propanoate

[000351] HMT A (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 drop wise 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 NazSO4 and 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] ⁺ .

Step 2: 4-chloro-5-fluoro-2-methoxybenzaldehyde

[000352] 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 adeded K2CO ₃ (4.24 g, 30.65 mmol, 2 eq), then Mel (4.35 g, 30.65 mmol, 1.91 mL, 2 eq) was added drop wise 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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether: Ethyl acetate=l: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] ⁺ .

Step 3: (Z)-methyl 2-azido-3-(4-chloro-5-fluoro-2-methoxyphenyl)acrylate

[000353] 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) drop wise 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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether: Ethyl acetate=l: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] ⁺ .

Step 4: methyl 6-chloro-7-fluoro-4-methoxy-lH-indole-2-carboxylate

[000354] A solution of methyl (Z)-methyl 2-azido-3-(4-chloro-5-fluoro-2- methoxyphenyl)acrylate (390 mg, 1.37 mmol, 1 eq) in xylene (10 mL) was stirred at 170 °C for 1.5 h. Upon completion, the reaction mixture was cooled to 25 °C, solid precipitation, then filtration, the crude product was washed with PE 100 mL to give methyl 6-chloro-7-fluoro-4-methoxy-lH-indole-2-carboxylate (220 mg, 811.19 umol, 59.42% yield, 95% purity) as a white solid. MS (ESI) m/z 258.0 [M+H] ⁺ .

Step 5: 6-chloro-7-fluoro-4-methoxy-lH-indole-2-carboxylic acid

[000355] To a solution of methyl 6-chloro-7-fluoro-4-methoxy-lH-indole-2-carboxylate (200 mg, 776.26 umol, 1 eq) in THF (2 mL) and H ₂ O (0.5 mL) was added LiOH.H ₂ O (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 HC1 and then extracted with EtOAc (5 mL x 2). The combined organic phasewas dried over Na ₂ SO ₄ , filtered and concentrated to give 6-chloro-7-fluoro-4-methoxy-lH-indole-2- carboxylic acid (190 mg, crude) as a white solid. MS (ESI) m/z 244.0 [M+H] ⁺ .

Step 6: (S)-methyl 2-((S)-2-(6-chloro-7-fluoro-4-methoxy-lH-indole-2-carboxamid o)-3- cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin- 3-yl)propanoate

[000356] To a solution of 6-chloro-7-fluoro-4-methoxy-lH-indole-2-carboxylic acid (190 mg, 779.91 umol, 1 eq) in DCM (2 mL) and DMF (2 mL) was added (S)-methyl 2- ((S)-2-amino-3-cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2 -oxopyrrolidin-3- yl)propanoate (416.92 mg, 1.01 mmol, 88% purity, 1.3 eq, HC1), DMAP (285.84 mg, 2.34 mmol, 3 eq) and EDCI (299.02 mg, 1.56 mmol, 2 eq), after the addition the mixture was stirred at 25 °C for 1 h. Upon completion, the resulting solution was poured into brine (10 mL), and then extracted with EtOAc (10 mL * 2), the combined organic layers washed with citric acid (20 mL * 2), then washed with NaHCOs (10 mL), brine (10 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated to give a crude product. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=l/l to 0/1) to give (S)-methyl 2-((S)-2-(6-chloro-7-fluoro-4- methoxy-lH-indole-2-carboxamido)-3-cyclopropylpropanamido)-3 -((R)-5,5- dimethyl-2-oxopyrrolidin-3-yl)propanoate (210 mg, 381.12 umol, 48.87% yield) as a white solid. MS (ESI) m/z 551.2 [M+H] ⁺ .

Step 7 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-6-chloro-7-fluoro- 4-methoxy-lH-indole-2- carboxamide

[000357] A solution of (S)-methyl 2-((S)-2-(6-chloro-7-fluoro-4-methoxy- 1 H-indole-2- carboxamido)-3-cyclopropylpropanamido)-3-((R)-5,5-dimethyl-2 -oxopyrrolidin-3- yl)propanoate (190 mg, 344.82 umol, 1 eq) in NH ₃ /MeOH (7 M, 3.83 mL, 77.66 eq) was stirred at 65 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove solvent to give N-((S)- 1 -(((S)- 1 -amino-3 -((R)-5 , 5 - dimethyl-2-oxopyrrolidin-3-yl)-1-oxopropan-2-yl)amino)-3-cyc lopropyl-1- oxopropan-2-yl)-6-chloro-7-fluoro-4-methoxy- 1 H-indole-2-carboxamide (186 mg, crude) as a white solid. MS (ESI) m/z 536.2 [M+H] ⁺ .

Step 8: 6-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyr rolidin-3- yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-7-fluoro-4-m ethoxy-lH-indole-2- carboxamide

[000358] To a solution of N-((S)-1-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3 - yl)- 1 -oxopropan-2-yl)amino)-3-cyclopropyl- 1 -oxopropan-2-yl)-6-chloro-7-fluoro-4- methoxy- 1 H-indole-2-carboxamide (186 mg, 347.02 umol, 1 eq) in DCM (4 mL) was added Burgess reagent (165.40 mg, 694.04 umol, 2 eq), and then the mixture was stirred at 25 °C for 3 h. LCMS showed most starting material was remained, then was added Burgess reagent (82.70 mg, 347.02 umol, 1 eq) was stirred another 12 h. LCMS showed a little starting material was remained, then was added Burgess reagent (82.70 mg, 347.02 umol, 1 eq) and was stirred for another 6 h. Upon completion, the resulting solution was quenched with H ₂ O (0.5 mL), then was concentrated in vacuum (25°C). The residue was purified by prep-HPLC column: Waters Xbridge BEH C18 100*25mm*5um;mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 30%-65%,

10 min to give 6-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyr rolidin- 3-yl)ethyl)amino)-3-cyclopropyl-1-oxopropan-2-yl)-7-fluoro-4 -methoxy-lH-indole-2- carboxamide (50.52 mg, 97.53 umol, 28.11% yield, 100% purity) as a white solid. MS (ESI) m/z 518.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 8.94 (d, J = 8.2 Hz, 1H), 8.60 (d, J= 7.6 Hz, 1H), 7.82 (s, 1H), 7.37 (d, J= 2.8 Hz, 1H), 6.59 (d, J= 4.6 Hz, 1H), 5.04 - 4.88 (m, 1H), 4.54 - 4.35 (m, 1H), 3.89 (s, 3H), 2.61 - 2.53 (m, 1H), 2.21 - 2.12 (m, 1H), 1.99 (dd, J= 8.4, 12.3 Hz, 1H), 1.84 - 1.73 (m, 2H), 1.53 - 1.44 (m,

2H), 1.16 (s, 3H), 1.06 (s, 3H), 0.87 - 0.74 (m, 1H), 0.44 - 0.34 (m, 2H), 0.21 - 0.05 (m, 2H)

Example 297. Synthesis of viral protease inhibitor compound 1215

Step 1 : (Z)-methyl 2-azido-3-(4-chloro-2-methoxyphenyl)acrylate [000359] To a solution of NaOMe (9.50 g, 175.86 mmol, 2 eq) in MeOH (100 mL) was added 4-chloro-2-methoxy-benzaldehyde (15 g, 87.93 mmol, 1 eq) and ethyl 2- azidoacetate (23.84 g, 184.65 mmol, 21.10 mL, 2.1 eq) in MeOH (100 mL) at -10 °C. The mixture was stirred at 20 °C for 18 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 50 mL at 20 °C, and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 80/1) to give methyl (Z)-2-azido-3-(4-chloro-2- methoxy-phenyl)prop-2-enoate (15.5 g, 57.91 mmol, 65.86% yield) as a yellow solid.

Step 2: methyl 6-chloro-4-methoxy-lH-indole-2-carboxylate

[000360] 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-lH-indole-2-carboxylate (4 g, crude) as a white solid.

Step 3: 6-chloro-4-methoxy-lH-indole-2-carboxylic acid

[000361] To a solution of methyl 6-chloro-4-methoxy-lH-indole-2-carboxylate (4 g,

16.69 mmol, 1 eq) in THF (30 mL) and H ₂ O (10 mL) was added LiOH.H ₂ O (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 HC1 was added, adjust pH to 3, then was filtered and concentrated under reduced pressure to give 6-chloro-4-methoxy-lH-indole-2-carboxylic acid (3.5 g, crude) as a white solid.

Step 4: (lS,3aR,6aS)-2-tert-butyl 1-ethyl hexahy drocy cl openta[c]pyrrole- 1,2(1 H)- dicarboxylate

[000362] To a solution of ethyl (3S,3aS,6aR)-l,2,3,3a,4,5,6,6a- octahydrocyclopenta[c]pyrrole-3-carboxylate (1.5 g, 8.19 mmol, 1 eq), TEA (993.96 mg, 9.82 mmol, 1.37 mL, 1.2 eq) in DCM (15 mL), was added (Boc) ₂ O (2.14 g, 9.82 mmol, 2.26 mL, 1.2 eq), and then DMAP (200.01 mg, 1.64 mmol, 0.2 eq) was added. The mixture was stirred at 20 °C for 16 h. Upon completion, the reaction mixture was poured into H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 1/0 to 80/1) to give 02-tert-butyl 03-ethyl (3S,3aS,6aR)-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole-2,3-dicarboxylate (2 g, 7.06 mmol, 86.22% yield) as a colorless oil.

Step 5: (lS,3aR,6aS)-2-(tert-butoxycarbonyl)octahydrocyclopenta[c]py rrole-1-carboxylic acid

[000363] To a solution of 02-tert-butyl 03-ethyl (3S, 3aS,6aR)-3, 3a, 4,5,6, 6a-hexahydro- lH-cyclopenta[c]pyrrole-2,3-dicarboxylate (2 g, 7.06 mmol, 1 eq) in THF (15 mL) and H ₂ O (5 mL) was added LiOH.H ₂ O (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 HC1 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-lH-cyclopenta[c]pyrro le-3-carboxylic acid (1.7 g, crude) as a white solid.

Step 6: (lS,3aR,6aS)-tert-butyl l-(((S)-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-1- methoxy- 1 -oxopropan-2-yl)carbamoyl)hexahydrocyclopenta[c]pyrrole-2( 1 H)-carboxylate [000364] To a solution of (3S,3aS,6aR)-2-tert-butoxycarbonyl-3, 3a, 4,5,6, 6a-hexahydro- lH-cyclopenta[c]pyrrole-3-carboxylic acid (534.61 mg, 2.09 mmol, 1.5 eq), methyl (2S)-2-amino-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]prop anoate (350 mg, 1.40 mmol, 1 eq, HC1) in DCM (7 mL) was added DMAP (426.36 mg, 3.49 mmol, 2.5 eq), and then EDCI (535.22 mg, 2.79 mmol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was poured into H ₂ O 15 mL at 20 °C, and then extracted with DCM (20 mL * 3). The combined organic layers were washed with brine (15 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 60/1 to 40/1) to give tert-butyl (3S,3aS,6aR)-3-[[(1S)- l-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-methox y-2-oxo- ethyl]carbamoyl]-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyr role-2-carboxylate (600 mg, 1.20 mmol, 85.67% yield, 90% purity) as a yellow solid. Step 7: (S)-methyl 3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((lS,3aR,6aS)- octahydrocy clopenta[c]pyrrole- 1 -carboxamido)propanoate

[000365] A solution of tert-butyl (3S,3aS,6aR)-3-[[(1S)-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-methoxy-2-oxo-ethyl]carbamoyl]-3, 3a, 4,5,6, 6a-hexahydro- lH-cyclopenta[c]pyrrole-2-carboxylate (550 mg, 1.22 mmol, 1 eq) in HCl/MeOH (10 mL) was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove MeOH to give methyl (2S)-2- [[(3S,3aS,6aR)-l,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrro le-3-carbonyl]amino]- 3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (472 mg, crude, HC1) as a yellow solid.

Step 8: (S)-methyl 2-((lS,3aR,6aS)-2-(6-chloro-4-methoxy-lH-indole-2- carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamido)-3-((R) -5,5-dimethyl-2- oxopyrrolidin-3-yl)propanoate

[000366] To a solution of 6-chloro-4-methoxy- 1 H-indole-2-carboxylic acid (363.64 mg, 1.61 mmol, 1.2 eq), methyl (2S)-2-[[(3S,3aS,6aR)-l,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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 80/1 to 30/1) to give methyl (2S)-2-[[(3S,3aS,6aR)-2-(6-chloro-4-methoxy-lH- indole-2-carbonyl)-3, 3a, 4,5,6, 6a-hexahydro-lH-cyclopenta[c]pyrrole-3- carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]p ropanoate (650 mg, 1.16 mmol, 86.57% yield) as a yellow solid.

Step 9: (lS,3aR,6aS)-N-((S)-1-amino-3-((R)-5,5-dimethyl-2-oxopyrroli din-3-yl)-1- oxopropan-2-yl)-2-(6-chloro-4-methoxy- 1 H-indole-2- carbonyl)octahydrocyclopenta[c]pyrrole- 1 -carboxamide [000367] A solution of methyl (2S)-2-[[(3S,3aS,6aR)-2-(6-chloro-4-methoxy-lH-indole- 2-carbonyl)-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole- 3-carbonyl]amino]-3- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (650 mg, 1.16 mmol, 1 eq) in NH ₃ /MEOH (7 M, 13.00 mL, 78.27 eq) was stirred at 65 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (3S,3aS,6aR)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyr rolidin-3-yl]methyl]- 2-oxo-ethyl]-2-(6-chloro-4-methoxy-lH-indole-2-carbonyl)-3,3 a,4,5,6,6a-hexahydro- lH-cyclopenta[c]pyrrole-3-carboxamide (630 mg, crude) as a yellow solid.

Step 10: ( 1 S,3aR,6aS)-2-(6-chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-((S)- 1 -cyano-2-((R)- 5,5-dimethyl-2-oxopyrrolidin-3-yl)ethyl)octahydrocyclopenta[ c]pyrrole-1-carboxamide [000368] To a solution of (3S,3aS,6aR)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]-2-(6-chloro-4-methoxy-l H-indole-2-carbonyl)- 3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-3-carboxamid e (630 mg, 1.16 mmol, 1 eq) in DCM (12 mL) was added Burgess reagent (551.91 mg, 2.32 mmol, 2 eq). The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was poured into H ₂ O 30 mL at 20 °C, and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18250*50mm*10um;mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN];B%: 45%-75%,10min) to give (3S,3aS,6aR)- 2-(6-chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3R)-5,5- dimethyl-2-oxo-pyrrolidin-3-yl]ethyl]-3, 3a, 4,5,6, 6a-hexahydro-lH- cyclopenta[c]pyrrole-3-carboxamide (215 mg, 408.73 umol, 35.30% yield, 100% purity) as a white solid.

[000369] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.69 (s, 1H), 8.92 (d ,J= 7.9 Hz, 1H), 7.83 (s, 1H), 7.18 - 6.85 (m, 2H), 6.57 (s, 1H), 4.95 (d, J= 7.1 Hz, 1H), 4.74 - 4.30 (m,

1H), 4.16 (d ,J= 8.9 Hz, 1H), 3.97 - 3.62 (m, 4H), 3.33 - 3.26 (m, 1H), 2.95 - 2.75 (m, 1H), 2.69 - 2.57 (m, 1H), 2.23 - 1.32 (m, 10H), 1.24 - 0.68 (m, 6H)

[000370] ¹ H NMR (400 MHz, DMSO-d ₆ , 273+80k) δ = 11.37 (s, 1H), 8.85 - 8.58 (m,

1H), 7.51 (s, 1H), 7.10 (s, 1H), 6.88 (s, 1H), 6.55 (s, 1H), 5.01 - 4.88 (m, 1H), 4.49 (s, 1H), 4.08 (s, 1H), 3.92 (s, 3H), 3.74 (d, J = 4.5, 10.8 Hz, 1H), 3.00 (s, 4H), 2.88 - 2.75 (m, 1H), 2.65 - 2.54 (m, 2H), 2.22 - 2.10 (m, 1H), 2.08 - 1.92 (m, 2H), 1.90 - 1.71 (m, 3H), 1.68 - 1.58 (m, 2H), 1.57 - 1.47 (m, 2H), 1.19 (s, 3H), 1.08 (s, 3H).

Example 298. Synthesis of viral protease inhibitor compound 1219

Step 1: (1 S,2S,5R)-tert-butyl 2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan-2- yl)carbamoyl)-3-azabicyclo[3.1 0]hexane-3-carboxylate

[000371] To a solution of (1 S,2S,5R)-3-tert-butoxycarbonyl-3-azabicyclo[3.1 0]hexane-2- carboxylic acid (500 mg, 2.20 mmol, 1 eq), methyl (2S)-2-amino-3-[(3S)-2-oxo-3- piperidyl] propanoate (755.22 mg, 2.64 mmol, 70% purity, 1.2 eq) in DCM (15 mL) was added DMAP (537.58 mg, 4.40 mmol, 2 eq) and EDCI (632.66 mg, 3.30 mmol, 1.5 eq). The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (40 mL), and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (SiO ₂ , Methanol :Dichloromethane = 10:1) to give tert-butyl ( 1 S,2S,5R)-2-[[(l S)-2-methoxy-2-oxo- 1 -[[(3 S)-2-oxo-3- piperidyl]methyl]ethyl]carbamoyl]-3-azabicyclo[3.1 0]hexane-3-carboxylate (811 mg, 1.47 mmol, 66.61% yield, 74% purity) as a white solid. MS (ESI) m/z 410.2 [M+H] ⁺ .

Step 2: (S)-methyl 2-((lS,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S )-2- oxopiperidin-3-yl)propanoate

[000372] A solution of tert-butyl (IS, 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-[[(lS, 2S, 5R)-3- azabicyclo [3.1.0] hexane-2-carbonyl] amino]-3-[(3S)-2-oxo-3-piperidyl] propanoate (500 mg, crude, HC1) as a white solid. MS (ESI) m/z 310.2 [M+H] ⁺ .

Step 3: (S)-methyl 2-((lS,2S,5R)-3-(4-methoxy-lH-indole-2-carbonyl)-3- azabicyclo[3.1 0]hexane-2-carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoat e

[000373]To a solution of methyl (2S)-2-[[(lS,2S,5R)-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (800 mg, 2.59 mmol, 1 eq), 4- methoxy-lH-indole-2-carboxylic acid (494.40 mg, 2.59 mmol, 1 eq) in DCM (20 mL) was added DMAP (631.86 mg, 5.17 mmol, 2 eq) and EDCI (743.60 mg, 3.88 mmol, 1.5 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 50 mL, and then extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Ethyl acetate/MeOH = 5/1) to give methyl (2S)-2-[[(lS, 2S, 5R)-3-(4-methoxy-lH-indole-2-carbonyl)-3-azabicyclo [3.1.0] hexane-2-carbonyl] amino]-3-[(3S)-2-oxo-3-piperidyl] propanoate (810 mg, 1.59 mmol, 61.67% yield, 95% purity) as a white solid. MS (ESI) m/z 483.2 [M+H] ⁺ .

Step 4: (1 S,2S,5R)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)pro pan-2-yl)-3-(4- methoxy-lH-indole-2-carbonyl)-3-azabicyclo[3.1 0]hexane-2-carboxamide

[000374] A solution of methyl (2S)-2-[[(lS,2S,5R)-3-(4-methoxy-lH-indole-2-carbonyl)- 3-azabicyclo[3.1 0]hexane-2-carbonyl]amino]-3-[(3 S)-2-oxo-3-piperidyl]propanoate (810 mg, 1.76 mmol, 1 eq) in NH ₃ MeOH (7 M, 10 mL, 39.74 eq) was stirred at 65 °C for 14 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove HNs/MeOH, and DCM (30 mL) was added and was concentrated under reduced pressure (repeat three times) to give (1 S,2S,5R)-N-[(1 S)-2-amino-2- oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl]-3-(4-methoxy-lH -indole-2-carbonyl)- 3-azabicyclo[3.1 0]hexane-2-carboxamide (800 mg, crude) as a white solid. MS (ESI) m/z 468.2 [M+H] ⁺ .

Step 5: (lS,2S,5R)-N-((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)- 3-(4-methoxy-lH- indole-2-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide

[000375] To a solution of (lS,2S,5R)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-3-(4-methoxy-lH-indole-2-carbonyl)-3 - azabicyclo[3.1 0]hexane-2-carboxamide (810 mg, 1.73 mmol, 1 eq) in DCM (10 mL) was added burgess reagent (908.33 mg, 3.81 mmol, 2.2 eq). The mixture was stirred at 25 °C for 2 h. Upon completion, the DCM was removed under N ₂ . The residue was purified by prep-TLC (SiO ₂ , EA:MeOH = 20: 1) to give desired compound (460 mg, purity 98%) as a white solid, which was further separated by SFC (column: REGIS(S,S)WHELK-01(250 mm * 25 mm, 10 urn); mobile phase: [Neu-ETOH];

B%: 50%-50%, 7 min) to give (1 S,2S,5R)-N-[(1 S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-3-(4-methoxy-lH-indole-2-carbonyl)-3-azabic yclo[3.1.0]hexane-2- carboxamide Isomer 1 (120 mg, 266.96 umol, 15.41% yield, 100% purity) as a white solid. MS (ESI) m/z 450.2 [M+H] ⁺ .

[000376] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.55 (s, 1H), 9.43 - 8.98 (m, 1H), 7.60 - 7.46 (m, 1H), 7.11 (q ,J= 8.3 Hz, 1H), 7.06 - 6.97 (m, 1H), 6.96 - 6.59 (m, 1H), 6.55 - 6.43 (m, 1H), 5.07 (q ,J= 7.7 Hz, 1H), 4.92 - 4.63 (m, 1H), 4.18 - 3.95 (m, 2H), 3.93 - 3.78 (m, 3H), 3.14 - 2.86 (m, 2H), 2.32 - 2.14 (m, 2H), 1.83 - 1.36 (m, 6H), 1.30 - 1.01 (m, 1H), 0.89 - 0.75 (m, 1H), 0.21 (br d, J= 3.8 Hz, 1H).

[000377] ¹ H NMR (400 MHz, DMSO-d ₆ , 273+80K) δ = 11.29 (br s, 1H), 9.10 - 8.56 (m, 1H), 7.27 (br d,J= 1.3 Hz, 1H), 7.16 - 6.74 (m, 3H), 6.52 (d ,J= 7.5 Hz, 1H), 5.11 - 5.00 (m, 1H), 4.83 - 4.72 (m, 1H), 4.06 (br d, J= 9.9 Hz, 2H), 3.90 (s, 3H), 3.18 - 3.08 (m, 2H), 2.31 - 2.21 (m, 2H), 1.92 - 1.40 (m, 7H), 0.88 - 0.78 (m, 1H), 0.21 (q,7 = 4.1 Hz, 1H). [000378] To give (1 S,2S,5R)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]-3-(4- methoxy-lH-indole-2-carbonyl)-3-azabicyclo[3.1 0]hexane-2-carboxamide Isomer 2 (182 mg, 392.75 umol, 22.67% yield, 97% purity) as a white solid. MS (ESI) m/z 450.2 [M+H] ⁺ .

[000379] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.61 - 11.48 (m, 1H), 9.26 - 8.95 (m, 1H), 7.58 - 7.43 (m, 1H), 7.17 - 6.97 (m, 2H), 6.96 - 6.56 (m, 1H), 6.55 - 6.46 (m, 1H),

5.12 - 5.03 (m, 1H), 4.82 - 4.66 (m, 1H), 4.16 - 4.00 (m, 2H), 3.92 - 3.82 (m, 3H),

3.13 - 2.96 (m, 2H), 2.33 (br s, 2H), 1.88 - 1.38 (m, 7H), 0.86 - 0.74 (m, 1H), 0.25 - 0.11 (m, 1H).

[000380] ¹ H NMR (400 MHz, DMSO-d ₆ , 273+80K) δ = 11.37 - 11.24 (m, 1H), 8.99 - 8.67 (m, 1H), 7.30 - 7.22 (m, 1H), 7.15 - 7.09 (m, 1H), 7.07 - 7.02 (m, 1H), 6.96 - 6.80 (m, 1H), 6.52 (d,J= 7.7 Hz, 1H), 5.13 - 5.00 (m, 1H), 4.79 - 4.71 (m, 1H), 4.13 - 3.94 (m, 2H), 3.90 (s, 3H), 3.18 - 3.09 (m, 2H), 2.31 - 2.08 (m, 2H), 1.94 - 1.57 (m, 6H), 1.50 - 1.38 (m, 1H), 0.87 - 0.77 (m, 1H), 0.24 - 0.15 (m, 1H).

Example 299. Synthesis of viral protease inhibitor compound 1221

Step 1 : (R)-tert-butyl 2-amino-3-(trimethylsilyl)propanoate

[000381] 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 Na ₂ SO ₄ concentrated 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] ⁺

Step 2: (R)-tert-butyl 2-(6-chloro-4-methoxy-lH-indole-2-carboxamido)-3- (trimethylsilyl)propanoate

[000382] To a solution of 6-chloro-4-methoxy- 1 H-indole-2-carboxylic acid (477.45 mg, 2.12 mmol, 1 eq) in DMF (5 mL) was added tert-butyl (2R)-2-amino-3-trimethylsilyl- propanoate (460 mg, 2.12 mmol, 1 eq), EDCI (527.36 mg, 2.75 mmol, 1.3 eq), TEA (642.38 mg, 6.35 mmol, 883.61 uL, 3 eq), and HOBt (371.72 mg, 2.75 mmol, 1.3 eq) was added at 0 °C. The resulting reaction was stirred at 25 °C for 1 h. LCMS showed the reaction was not completed, then EDCI (527.36 mg, 2.75 mmol, 1.3 eq), HOBt (371.72 mg, 2.75 mmol, 1.3 eq) and TEA (363.50 mg, 3.59 mmol, 0.5 mL, 1.70 eq) was added and was stirred for 14 h further. Upon completion, the reaction mixture was diluted with H ₂ O (20 mL) and extracted with EA (20 mL * 2). The combined organic layers were washed with brine (10 mL*5), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (SiO ₂ PE/EA = 10:1) to give tert-butyl (2R)-2-[(6-chloro-4- methoxy- 1 H-indole-2-carbonyl) amino]-3-trimethylsilyl-propanoate (770 mg, 1.79 mmol, 84.76% yield, 99% purity) as a light yellow solid. MS (ESI) m/z 369.1[M+H- 56] ⁺

Step 3 : (R)-2-(6-chloro-4-methoxy-lH-indole-2-carboxamido)-3-(trimet hylsilyl)propanoic acid

[000383] To a solution of tert-butyl (2R)-2-[(6-chloro-4-methoxy- 1 H-indole-2- carbonyl)amino]-3-trimethylsilyl-propanoate (750 mg, 1.76 mmol, 1 eq) in DCM (9 mL) was added TFA/H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated in vacuum to give (2R)-2-[(6-chloro-4-methoxy- lH-indole-2-carbonyl)amino]-3-trimethylsilyl-propanoic acid (740 mg, crude) as a light yellow solid. MS (ESI) m/z 369.1[M+H] ⁺

Step 4: 6-chloro-N-((R)- 1 -(((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amino)- 1 -oxo-3- (trimethylsilyl)propan-2-yl)-4-methoxy-lH-indole-2-carboxami de

[000384] To a solution of (2R)-2-[(6-chloro-4-methoxy-lH-indole-2-carbonyl)amino]-3- trimethylsilyl-propanoic acid (100 mg, 271.09 umol, 1 eq) and (2S)-2-amino-3-[(3S)- 2-oxo-3-piperidyl]propanenitrile (67.99 mg, 406.63 umol, 1.5 eq) in DMF (2 mL) was added a solution ofPyBOP (211.61 mg, 406.63 umol, 1.5 eq) and TEA (82.29 mg, 813.26 umol, 113.20 uL, 3 eq) in DMF (2 mL) at -30 °C. Then the reaction was stirred at -30 °C for 1 h. Upon completion, the reaction mixture was quenched with water (10 mL) at -30 °C, then was extrated with EA (10 mL * 2), the combined organic phase was dried over Na ₂ SO ₄ , and concentrated. The residue was purified by prep-HPLC column: Waters Xbridge Prep OBD C 18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 40%-70%, 8 min to give the product. The residue was purified by SFC column: DAICEL CHIRALPAK AD (250 mm * 30mm, 10 um); mobile phase: [0.1% NH ₃ H ₂ O IP A]; B%: 40% - 40%, 12 min to give Isomer 1 (Rt= 1.344 min) 6-chloro-N-[( 1 R)-2-[[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3- piperidyl]ethyl]amino]-2-oxo-1-(trimethylsilylmethyl)ethyl]- 4-methoxy-lH-indole-2- carboxamide (4.39 mg, 8.40 umol, 3.10% yield, 99.1% purity) as a white solid. MS (ESI) m/z 518.1 [M+H] ⁺

[000385] 1H NMR (400MHz, MeOD-d ₄ ) δ = 7.21 (s, 1H), 7.05 (s, 1H), 6.52 (d, J=1.4 Hz, 1H), 5.08 (br dd, J=6.1, 9.8 Hz, 1H), 4.59 (t, J=7.9 Hz, 1H), 3.93 (s, 3H), 3.23 - 3.16 (m, 2H), 2.53 - 2.36 (m, 2H), 2.03 - 1.84 (m, 2H), 1.78 (dt, J=4.6, 9.0 Hz, 1H), 1.72 - 1.60 (m, 1H), 1.55 - 1.43 (m, 1H), 1.20 (d, J=7.9 Hz, 2H), 0.10 (s, 9H)

Example 300. Synthesis of viral protease inhibitor compound 1227

Step 1: methyl (2S)-2-[[2-(6-chloro-4-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2 -oxo-pyrrolidin-3- yl]propanoate

[000386] To a solution of methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (0.1 g, 240.41 umol, 1 eq, HC1) and 6-chloro-4-methoxy- 1 H-indole-2-carboxylic acid (81.37 mg, 360.62 umol, 1.5 eq) in DCM (2 mL) was added DMAP (88.11 mg, 721.23 umol, 3 eq), EDCI (92.17 mg, 480.82 umol, 2 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (10 mL) and extracted with DCM (5 mL * 4). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give methyl (2S)-2-[[2-(6-chloro-4-methoxy-lH-indole-2- carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3R)-5, 5-dimethyl-2-oxo- pyrrolidin-3-yl]propanoate (0.089 g, 128.85 umol, 53.60% yield, 85% purity) as yellow oil. MS (ESI) m/z 587.2 [M+H] ⁺

Step2: N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl] methyl]-2-oxo-ethyl]-2- (6-chloro-4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]dec ane-3-carboxamide [000387] The methyl (2S)-2-[[2-(6-chloro-4-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2 -oxo-pyrrolidin-3- yl]propanoate (0.079 g, 134.56 umol, 1 eq) in NH ₃ /MeOH (3 mL) was stirred at 60 °C for 16 h. Upon completion, the reaction mixture was concentrated under pressure reduced to get the crude product N-[( 1 S)-2-amino- 1 -[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]-2-(6-chloro-4-methoxy-l H-indole-2-carbonyl)- 2-azaspiro[4.5]decane-3-carboxamide (75 mg, crude) as yellow solid. MS (ESI) m/z 572.2 [M+H] ⁺

Step3 : (3 S)-2-(6-chloro-4-methoxy- 1 H-indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3R)-5, 5- dimethyl-2-oxo-pyrrolidin-3-yl]ethyl]-2-azaspiro[4.5]decane- 3-carboxamide

[000388] To a solution of N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]methyl]-2-oxo-ethyl]-2-(6-chloro-4-methoxy-lH-indole-2-ca rbonyl)-2- azaspiro[4.5]decane-3-carboxamide (0.075 g, 131.10 umol, 1 eq) in DCM (1 mL) was added burgess reagent (93.73 mg, 393.29 umol, 3 eq). The mixture was stirred at 30 °C for 3 h. Upon completion, the mixture were quenched with water (0.5 mL) and blow-dried with N ₂ , and was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [water(10mMNH ₄ HCO ₃ )-ACN];B%: 40%- 70%,8min) to give the product (3 S)-2-(6-chloro-4-methoxy- 1 H-indole-2-carbonyl)-N- [( 1 S)- 1 -cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]ethyl]-2- azaspiro[4.5]decane-3-carboxamide (19 mg, 34.29 umol, 26.16% yield, 100% purity) as white solid. MS (ESI) m/z 554.2 [M+H] ⁺ .

[000389] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.76 - 11.58 (m, 1H), 8.90 (d ,J= 7.9 Hz, 1H), 7.81 (s, 1H), 7.15 - 6.85 (m, 2H), 6.57 (s, 1H), 4.92 (br d, J= 6.6 Hz, 1H), 4.49 (t ,J= 8.4 Hz, 1H), 3.92 (s, 3H), 3.84 (br s, 1H), 3.67 (br d ,J= 10.4 Hz, 1H), 2.66 - 2.58 (m, 1H), 2.28 - 2.04 (m, 2H), 1.99 (dd, J= 8.3, 11.8 Hz, 1H), 1.82 - 1.68 (m, 1H), 1.61 - 1.31 (m, 12H), 1.19 - 1.06 (m, 3H), 1.06 - 0.80 (m, 3H).

[000390] NMR (400 MHz, DMSO-d ₆ , 273+80K) δ= 11.51 - 11.34 (m, 1H), 8.85 - 8.58 (m, 1H), 7.62 - 7.53 (m, 1H), 7.13 - 6.82 (m, 2H), 6.60 - 6.50 (m, 1H), 5.04 - 4.81 (m, 1H), 4.73 - 4.42 (m, 1H), 3.96 - 3.90 (m, 3H), 3.88 - 3.83 (m, 1H), 3.76 - 3.51 (m,

1H), 2.65 - 2.55 (m, 1H), 2.27 - 2.01 (m, 2H), 1.82 - 1.36 (m, 14H), 1.20 - 1.14 (m, 3H), 1.12 - 1.00 (m, 3H).

Example 301. Synthesis of viral protease inhibitor compound 1229

Stepl : methyl (2S)-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]-2-[[2-(7-fl uoro-4-methoxy- lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbonyl]amino ]propanoate

[000391] To a solution of methyl (2S)-2-(2-azaspiro[4.5]decane-3-carbonylamino)-3- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (82.86 mg, 199.20 umol, 1 eq, HCI), 7-fluoro-4-m ethoxy- 1 H-indole-2-carboxylic acid (0.05 g, 239.04 umol, 1.2 eq) in DCM (1 mL) was added DMAP (73.01 mg, 597.59 umol, 3 eq) and EDCI (76.37 mg, 398.39 umol, 2 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (15 mL) and extracted with DCM (5 mL * 5). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure and was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give product methyl (2S)-3-[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]-2-[[2-(7-fluoro-4-methoxy-lH-indole-2-carbo nyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]propanoate (0.08 g, 141.27 umol, 57.11% yield, 97% purity) as white solid. MS (ESI) m/z 571.3 [M+H] ⁺

Step2: N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl] methyl]-2-oxo-ethyl]-2- (7-fluoro-4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]dec ane-3-carboxamide

[000392] A solution of methyl (2S)-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]-2-[[2-(7- fluoro-4-methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane -3- carbonyl]amino]propanoate (0.07 g, 122.67 umol, 1 eq) in NH ₃ /MeOH (7M, 3 mL) was stirred at 50 °C for 12 h. Upon completion, the reaction mixture was concentrated under pressure reduced to get the crude product N-[( 1 S)-2-amino- 1 -[[(3R)-5, 5- dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]-2-(7-flu oro-4-methoxy-lH- indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carboxamide (0.065 g, crude) as white solid. MS (ESI) m/z 556.3 [M+H] ⁺

Step3 : N-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]e thyl]-2-(7-fluoro-4- methoxy-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane-3-carbox amide

[000393] To a solution of N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]methyl]-2-oxo-ethyl]-2-(7-fluoro-4-methoxy-lH-indole-2-ca rbonyl)-2- azaspiro[4.5]decane-3-carboxamide (0.06 g, 102.58 umol, 95% purity, 1 eq) in DCM (1 mL) was added burgess reagent (97.79 mg, 410.34 umol, 4 eq), and the resulting mixture was stirred at 30 °C for 1 h. Upon completion, the mixture were quenched with water (0.5 mL) and blow-dried with N ₂ , and purified by prep-HPLC (column: Waters Xbridge BEH C18 100*25mm*5um;mobile phase: [water(10mM NH4HCO3)- ACN];B%: 30%-65%,10min) to give the product N-[(1S)-1-cyano-2-[(3R)-5,5- dimethyl-2-oxo-pyrrolidin-3-yl]ethyl]-2-(7-fluoro-4-methoxy- lH-indole-2-carbonyl)- 2-azaspiro[4.5]decane-3-carboxamide (0.015 g, 26.67 umol, 26.00% yield, 95.6% purity) as white solid. MS (ESI) m/z 538.3 [M+H] ⁺

[000394] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.13 - 11.88 (m, 1H), 9.12 - 8.84 (m, 1H), 7.88 - 7.69 (m, 1H), 7.07 - 6.63 (m, 2H), 6.48 - 6.31 (m, 1H), 4.99 - 4.83 (m, 1H),

4.50 (t, J = 8.7 Hz, 1H), 3.90 - 3.77 (m, 4H), 3.68 (d, J = 10.3 Hz, 1H), 2.73 - 2.59 (m, 1H), 2.27 - 2.12 (m, 2H), 2.06 - 1.96 (m, 1H), 1.82 - 1.69 (m, 1H), 1.62 - 1.29 (m, 12H), 1.19 - 1.06 (m, 3H), 1.05 - 0.87 (m, 3H).

[000395] ¹ H NMR (400 MHz, DMSO-d ₆ , 273+80K) δ = 11.73 - 11.58 (m, 1H), 8.80 -

8.61 (m, 1H), 7.66 - 7.51 (m, 1H), 7.05 - 6.80 (m, 2H), 6.52 - 6.28 (m, 1H), 5.00 -

4.84 (m, 1H), 4.73 - 4.48 (m, 1H), 3.92 - 3.80 (m, 4H), 3.75 - 3.50 (m, 1H), 2.65 -

2.54 (m, 1H), 2.29 - 2.18 (m, 1H), 2.11 - 1.93 (m, 1H), 1.87 - 1.61 (m, 2H), 1.58 -

1.28 (m, 12H), 1.20 - 1.14 (m, 3H), 1.10 - 1.00 (m, 3H).

Example 302. Synthesis of viral protease inhibitor compound 1231

Step 1: methyl (2S)-2-[[(3S)-2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-2- azaspiro[4.5]decane-3-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2 -oxo-pyrrolidin-3- yl]propanoate

[000396] To a mixture of methyl (2S)-2-[[(3S)-2-azaspiro[4.5]decane-3-carbonyl]amino]- 3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (600 mg, 1.44 mmol, 1 eq, HCI) in DCM (10 mL) was added 7-chloro-5-methoxy- 1 H-indole-2-carboxylic acid (650.92 mg, 2.88 mmol, 2 eq), DMAP (440.56 mg, 3.61 mmol, 2.5 eq) and EDCI (553.05 mg, 2.88 mmol, 2 eq). The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , Petroleum ether: Ethyl acetate = 5/1 to 0/1) to get product methyl (2S)- 2-[[(3S)-2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-2-azasp iro[4.5]decane-3- carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]p ropanoate (620 mg, 844.82 umol, 58.57% yield, 80% purity) as yellow solid. MS (ESI) m/z 587.3 [M+H] ⁺ .

Step 2: (3S)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin- 3-yl]methyl]-2-oxo- ethyl]-2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-2-azaspir o[4.5]decane-3-carboxamide [000397] A mixture of methyl (2 S)-2-[ [(3 S)-2-(7 -chloro-5 -methoxy- 1 H-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 NH ₃ /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-lH-indole-2-carbonyl)-2-azaspiro[4.5]decane -3-carboxamide (480 mg, crude) as yellow solid. MS (ESI) m/z 572.3 [M+H] ⁺ .

Step 3 : (3S)-2-(7-chloro-5-methoxy-lH-indole-2-carbonyl)-N-[(l S)-1-cyano-2-[(3R)-5,5- dimethyl-2-oxo-pyrrolidin-3-yl]ethyl]-2-azaspiro[4.5]decane- 3-carboxamide

[000398] To a mixture of (3S)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin- 3-yl]methyl]-2-oxo-ethyl]-2-(7-chloro-5-methoxy-lH-indole-2- carbonyl)-2- azaspiro[4.5]decane-3-carboxamide (480 mg, 839.02 umol, 1 eq) in DCM (6 mL) was added burgess reagent (599.83 mg, 2.52 mmol, 3 eq). The mixture was stirred at 30 °C for 1 h. Upon completion, the mixture were quenched with water (1 mL) and blow-dried with N ₂ . The residue was purified by prep-HPLC (column: Waters X bridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 35% - 70%, 8 min) to get the product (3S)-2-(7-chloro-5- methoxy-lH-indole-2-carbonyl)-N-[(1S)-1-cyano-2-[(3R)-5,5-di methyl-2-oxo- pyrrolidin-3-yl]ethyl]-2-azaspiro[4.5]decane-3-carboxamide (215.9 mg, 386.54 umol, 46.07% yield, 99.2% purity) as white solid. MS (ESI) m/z 554.3 [M+H] ⁺ .

[000399] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.51 - 11.25 (m, 1H), 9.03 - 8.86 (m, 1H), 7.87 - 7.73 (m, 1H), 7.17 - 7.10 (m, 1H), 7.03 (s, 1H), 7.00 - 6.96 (m, 1H), 4.97 - 4.76 (m, 1H), 4.49 (t,J= 8.6 Hz, 1H), 3.70 - 3.86 (m, 4H), 3.63 (d ,J= 10.4 Hz, 1H), 2.78 - 2.63 (m, 1H), 2.30 - 2.11 (m, 2H), 2.04 - 1.95 (m, 1H), 1.85 - 1.68 (m, 1H), 1.64 - 1.28 (m, 12H), 1.18 - 1.08 (m, 3H), 1.05 - 0.86 (m, 3H).

Example 303. Synthesis of viral protease inhibitor compound 1237

Step 1 : (S)-methyl2-((S)-2-(6,7-dichloro-lH-indole-2-carboxamido)-4, 4- dimethylpentanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-y l)propanoate

[000400] To a solution of 6,7-dichloro-lH-indole-2-carboxylic acid (91.31 mg, 396.92 umol, 1 eq) and methyl (2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (150 mg, 396.92 umol, 1 eq, HC1) in DCM (5 mL) was added DMAP (96.98 mg, 793.85 umol, 2 eq) and EDCI (152.18 mg, 793.85 umol, 2 eq). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O (30 mL), and then extracted with EA (20 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , PE:EA = 0: 1) to give the product methyl(2S)-2-[[(2S)-2-[(6,7-dichloro-1H-indole-2-carbonyl)am ino]-4,4- dimethyl-pentanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrroli din-3-yl]propanoate (110 mg, 198.74 umol, 50.07% yield) as a yellow solid. MS (ESI) m/z 553.2 [M+H] ⁺

Step 2 : N-((S)- 1 -(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)-6,7-dichloro-lH-ind ole-2-carboxamide [000401] A mixture of methyl (2S)-2-[[(2S)-2-[(6,7-dichloro-1H-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3R)-5,5-di methyl-2-oxo- pyrrolidin-3-yl]propanoate (110 mg, 198.74 umol, 1 eq) in NH ₃ /MeOH (7 M, 7.86 mL, 276.74 eq) was stirred at 80 °C for 16 h. Upon completion, the mixture was concentrated under the reduced pressure to give the product N-[(1S)-1-[[(1S)-2- amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2- oxo-ethyl]carbamoyl]- 3,3-dimethyl-butyl]-6,7-dichloro-1H-indole-2-carboxamide (100 mg, crude) as a yellow solid. MS (ESI) m/z 538.2 [M+H] ⁺ Step 3 : 6,7-dichloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl-2-ox opyrrolidin-3- yl)ethyl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)- 1 H-indole-2-carboxamide

[000402] To a solution of N-[(1S)-1-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]carbamoyl]-3,3-dimethyl- butyl]-6,7-dichloro-1H- indole-2-carboxamide (90 mg, 167.14 umol, 1 eq) in DCM (3 mL) was added burgess reagent (79.66 mg, 334.28 umol, 2 eq). The mixture was stirred at 20 °C for 5 h. Upon completion, the mixture was concentrated under the reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 40% - 70%, 8 min) to give the product 6,7-dichloro-N-[( 1 S)- 1 -[[( 1 S)- 1 -cyano-2-[(3R)- 5,5-dimethyl-2-oxo-pyrrolidin-3-yl]ethyl]carbamoyl]-3,3- dimethyl-butyl]- 1H-indole- 2-carboxamide (20 mg, 38.24 umol, 22.88% yield, 99.5% purity) as a white solid. MS (ESI) m/z 520.2 [M+H] ^{+ 1} H NMR (400 MHz, MeOD-d ₄ ) δ = 7.56 (d ,J= 8.4 Hz, 1H), 7.27 - 7.15 (m, 2H), 5.00 (dd, J= 5.6, 10.4 Hz, 1H), 4.65 (dd, J= 4.6, 8.2 Hz, 1H), 2.78 (dd, J = 5.6, 8.2 Hz, 1H), 2.36 - 2.07 (m, 1H), 2.10 (dd,J= 8.6, 12.4 Hz, 1H), 1.95 - 1.84 (m, 2H), 1.83 - 1.74 (m, 1H), 1.65 - 1.52 (m, 1H), 1.21 (s, 3H), 1.08 (s, 3H), 1.05 - 1.01 (m, 9H).

Example 304. Synthesis of viral protease inhibitor compound 1239

Step 1 : (S)-methyl2-((S)-2-(6-chloro-4-methoxy-lH-indole-2-carboxami do)-4,4- dimethylpentanamido)-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-y l)propanoate

[000403] To a solution of methyl(2S)-2-[[(2S)-2-amino-4,4-dimethyl-pentanoyl]amino]-3- [(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (200 mg, 529.23 umol, 1 eq, HCI) and 6-chloro-4-methoxy-1H-indole-2-carboxylic acid (143.29 mg, 635.08umol, 1.2 eq) in DCM (10 mL) was added EDCI (202.91 mg, 1.06 mmol, 2 eq) and DMAP (193.97 mg, 1.59 mmol, 3 eq), the mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was diluted with H ₂ O (60 mL) and extracted with DCM (40 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH = 10: 1) to give the product methyl(2S)-2-[[(2S)-2-[(6-chloro-4-methoxy-1H-indole-2-carbo nyl)amino]- 4,4-dimethyl-pentanoyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyr rolidin-3- yl]propanoate (180 mg, 327.83 umol, 61.95% yield) as a white solid. MS (ESI) m/z 549.3 [M+H] ⁺ .

Step2 :N-((S)-1-(((S)- 1 -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-6-chloro-4-methoxy- 1 H-indole-2-carboxamide [000404] A solution of methyl(2S)-2-[[(2S)-2-[(6-chloro-4-methoxy-1H-indole-2- carbonyl)amino]-4,4-dimethyl-pentanoyl]amino]-3-[(3R)-5,5-di methyl-2-oxo- pyrrolidin-3-yl]propanoate (180.00 mg, 327.83 umol, 1 eq) in NH ₃ /MeOH (7 M, 5 mL, 106.76 eq) was stirred at 60 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the product N-[(1S)-1-[[(1S)-2- amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2- oxo-ethyl]carbamoyl]- 3,3-dimethyl-butyl]-6-chloro-4-methoxy-1H-indole-2-carboxami de (150 mg, crude) as a yellow solid. MS (ESI) m/z 534.3 [M+H] ⁺ .

Step3:6-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5,5-dimethyl -2-oxopyrrolidin-3- yl)ethyl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-4-methoxy- 1 H-indole-2-carboxamide [000405] To a solution of N-[(1S)-1-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]carbamoyl]-3,3-dimethyl- butyl]-6-chloro-4- methoxy- 1H-indole-2-carboxamide (130.00 mg, 243.42 umol, 1 eq) in DCM (6 mL) was added Burgess reagent (232.04 mg, 973.70 umol, 4 eq), the mixture was stirred at 25 °C for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 um; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 35% - 65%, 8 min) to give the product 6-chl oro-N- [(1S)-1- [[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]et hyl]carbamoyl]-3,3- dimethyl- butyl]-4-methoxy-1H-indole-2-carboxamide (30 mg, 58.14 umol, 23.88% yield, 100% purity) as a white solid. MS (ESI) m/z 516.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOD-d ₄ ) δ = 7.23 (s, 1H), 7.04 (s, 1H), 6.52 (d ,J= 1.4 Hz, 1H), 4.99 (dd, J= 5.8, 10.4 Hz, 1H), 4.63 (dd, J = 4.6, 8.3 Hz, 1H), 3.93 (s, 3H), 2.78 - 2.68 (m, 1H), 2.41 - 2.29 (m, 1H), 2.09 (dd, J= 8.6, 12.4 Hz, 1H), 1.92 - 1.75 (m, 3H), 1.62 - 1.54

(m, 1H), 1.21 (s, 3H), 1.13 - 0.96 (m, 12H) _C

Example 305. Synthesis of viral protease inhibitor compound 1249

Step 1 : (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((S)-2-oxopiperid in-3- yl)propanoate

[000406] A solution of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl) amino)-3- cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl) propanoate (5 g, 12.15 mmol, 1 eq) in HCI/MeOH (4 M, 60 mL) was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was concemtration in vacuum to obtained (S)-methyl 2-((S)- 2-amino-3-cyclopropylpropanamido)-3-((S)-2-oxopiperidin-3-yl ) propanoate (4 g, crude) as a white solid. MS (ESI) m/z 312.2 [M+H] ⁺

Step 2: (S)-methyl2-((S)-3-cyclopropyl-2-(5-(trifluoromethyl)-lH-pyr role-2- carboxamido)propanamido)-3-((S)-2-oxopiperidin-3-yl)propanoa te

[000407] To a solution of (S)-methyl 2-((S)-2-amino-3-cyclopropylpropanamido)-3-((S)- 2-oxopiperidin-3-yl)propanoate (680 mg, 1.95 mmol, 1 eq, HCI) and 5- (trifluoromethyl)-1H-pyrrole-2-carboxylic acid (350.12 mg, 1.95 mmol, 1 eq) in CH ₃ CN (8 mL) was added with NMI (481.50 mg, 5.86 mmol, 467.48 uL, 3 eq) and TCFH (548.52 mg, 1.95 mmol, 1 eq), the mixture was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was diluted with water (20 mL), and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuum and was purified by column chromatography (SiO ₂ , PE/EA = 1/0 to 0/1) then re-purified by prep-TLC (SiO ₂ , EA:MeOH = 10: 1) to obtained (S)-methyl 2-((S)-3-cyclopropyl-2- (5-(trifluoromethyl)-1H-pyrrole-2-carboxamido)propanamido)-3 -((S)-2-oxopiperidin- 3-yl)propanoate (350 mg, 740.81 umol, 37.89% yield) as a yellow solid. MS (ESI) m/z 473.2 [M+H] ⁺

Step 3 : N-((S)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)prop an-2-yl)amino)-3- cyclopropyl-1-oxopropan-2-yl)-5-(trifluoromethyl)-lH-pyrrole -2-carboxamide

[000408] A solution of (S)-methyl 2-((S)-3-cyclopropyl-2-(5-(trifluoromethyl)-1H- pyrrole-2-carboxamido)propanamido)-3-((S)-2-oxopiperidin-3-y l)propanoate (300 mg, 634.98 umol, 1 eq) in NH ₃ /MeOH (10 mL, 7M) was stirred at 25 °C for 12 h, then was stirred at 30 °C for 24 h. Upon the reaction completion, the mixture was concentrated in vacuum to obtained N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3 -((S)-2- oxopi peri din-3-yl)propan-2-yl)amino)-3 -cyclopropyl- 1 -oxopropan-2-yl)-5- (trifluoromethyl)-1H-pyrrole-2-carboxamide (330 mg, crude) as a yellow solid. MS (ESI) m/z 458.2 [M+H] ⁺

Step 4: N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amin o)-3-cyclopropyl-1- oxopropan-2-yl)-5-(trifluoromethyl)-lH-pyrrole-2-carboxamide

[000409] To a solution of N-((S)- 1 -(((S)- 1 -amino-1 -oxo-3-((S)-2-oxopiperidin-3- yl)propan-2-yl)amino) -3-cyclopropyl-1-oxopropan-2-yl)-5-(trifluoromethyl)-1H- pyrrole-2-carboxamide (300 mg, 459.07 umol, 1 eq) in DCM (5 mL) was added burgess reagent (328.20 mg, 1.38 mmol, 3 eq), and the mixture was stirred at 30 °C for 4 h. Upon the reaction completion, the mixture was quenched by water (1 mL) and was dried by blowing N ₂ and was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 * 40mm * lOum; mobile phase: [water(10 mM NH4HCO3)- ACN]; B%: 20%-50%, 8min) to obtained N-((S)- 1 -(((S)- 1 -cy ano-2-((5)-2- oxopiperidin-3-yl)ethyl)amino)-3-cyclopropyl- 1 - oxopropan-2-yl)-5- (trifluoromethyl)-1H-pyrrole-2-carboxamide (4.36 mg, 9.92 umol, 2.16% yield, 100% purity) as a white solid. MS (ESI) m/z 440.1 [M+H] ⁺

[000410] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.73 (s, 1H), 8.96 - 8.85 (m, 1H), 8.45 - 8.32 (m, 1H), 7.52 (s, 1H), 6.95 (d ,J= 3.2 Hz, 1H), 6.66 - 6.57 (m, 1H), 5.05 (q ,J = 8.0 Hz, 1H), 4.48 - 4.39 (m, 1H), 3.13 - 3.03 (m, 2H), 2.29 - 2.18 (m, 2H), 1.88 - 1.65 (m, 4H), 1.62 - 1.50 (m, 1H), 1.49 - 1.34 (m, 2H), 0.83 - 0.71 (m, 1H), 0.47 - 0.35 (m, 2H), 0.22 - 0.04 (m, 2H).

Example 306. Synthesis of viral protease inhibitor compound 1251

Step 1 : (Z)-methyl 2-azido-3-(4-fluoro-2-methoxyphenyl)acrylate

[000411] A solution of NaOMe (700.98 mg, 12.98 mmol, 2 eq) was added 4-fluoro-2- methoxy-benzaldehyde (1 g, 6.49 mmol, 1 eq), ethyl 2-azidoacetate (1.68 g, 12.98 mmol, 1.48 mL, 2 eq) in MeOH (30mL) at -10 °C was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 30 mL, and then extracted with EA (30 mL * 3). The combined organic layers were washed with brine 30 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 100/1 to 50/1) to give methyl (Z)-2-azido-3-(4-fluoro-2- methoxy-phenyl) prop-2-enoate (685 mg, 2.45 mmol, 37.83% yield, 90% purity) as a yellow solid. Step 2: methyl 6-fluoro-4-methoxy- 1 H-indole-2-carboxylate

[000412] 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-lH-indole-2- carboxylate (400 mg, crude) as a white solid. MS (ESI) m/z 224.1 [M+H] ⁺ .

Step 3: 6-fluoro-4-methoxy-lH-indole-2-carboxylic acid

[000413] A solution of methyl 6-fluoro-4-methoxy-lH-indole-2-carboxylate (400 mg, 1.79 mmol, 1 eq) in THF (8 mL) and H ₂ O (2 mL) was added LiOH.H ₂ O (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 H ₂ O 20 mL, the aqueous phase was added HC1 (1M) to pH = 3 and extracted with DCM (15 mL * 3). The combined organic layers were washed with brine 20 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 6-fluoro-4-methoxy-lH-indole-2-carboxylic acid (460 mg, crude) as a white solid. MS (ESI) m/z 210.0 [M+H] ⁺ .

Step 4: N-((S)-1-(((S)-1-cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)amin o)-3-cyclopropyl-1- oxopropan-2-yl)-6-fluoro-4-methoxy- 1 H-indole-2-carboxamide

[000414] A solution of 6-fluoro-4-methoxy-lH-indole-2-carboxylic acid (81.01 mg, 387.28 umol, 1.1 eq), (2S)-2-amino-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-3-cyclopropyl-propanamide (140 mg, 352.08 umol, 70% purity, 1 eq) in DCM (4 mL) was added DMAP (86.02 mg, 704.15 umol, 2 eq) and EDCI (101.24 mg, 528.11 umol, 1.5 eq). The mixture was stirred 25 °C for 2 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 15 mL, and then extracted with EA (15 mL * 3). The combined organic layers were washed with brine 20 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 30 mm * 10 um; mobile phase: [water (10 mM NH4HCO ₃ )-ACN]; B%: 25%-55%, 8 min) to give N-[(l S)-2-[[(l S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]amino]-1- (cyclopropylmethyl)-2-oxo-ethyl]-6-fluoro-4-methoxy-lH-indol e-2-carboxamide (20 mg, 41.75 umol, 11.86% yield, 98% purity) as a white solid. MS (ESI) m/z 470.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.64 (s, 1H), 8.89 (d, J = 8.2 Hz, 1H), 8.49 (d, J= 7.5 Hz, 1H), 7.52 (br s, 1H), 7.36 (d, J= 1.5 Hz, 1H), 6.73 (dd,J= 1.3, 9.5 Hz, 1H), 6.46 (dd, J= 2.0, 12.1 Hz, 1H), 5.10 - 5.01 (m, 1H), 4.48 - 4.40 (m, 1H), 3.90 (s, 3H), 3.15 - 3.03 (m, 2H), 2.29 - 2.22 (m, 2H), 1.87 - 1.68 (m, 4H), 1.61 - 1.35 (m, 3H), 0.85 - 0.73 (m, 1H), 0.48 - 0.34 (m, 2H), 0.25 - 0.04 (m, 2H)

Example 307. Synthesis of viral protease inhibitor compound 1253

Step 1: l-(tert-butoxycarbonyl)-4-cyclopentylpyrrolidine-2-carboxyli c acid

[000415] To a solution of 4-cyclopentylpyrrolidine-2-carboxylic acid (900 mg, 4.10 mmol, 1 eq, HCI) in DCM (20 mL) was added TEA (497.41 mg, 4.92 mmol, 684.19 uL, 1.2 eq), DMAP (100.09 mg, 819.27 umol, 0.2 eq) and (Boc) ₂ O (983.42 mg, 4.51 mmol, 1.04 mL, 1.1 eq), and then the resulting mixtrue was stirred at 20 °C for 12 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 50 mL at 0 °C, and then extracted with DCM 30 mL. The aqueous layers was added 1M HCI to pH = 4, then extracted with DCM (30 mL * 3), washed with brine 40 mL, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the 1-tert- butoxycarbonyl-4-cyclopentyl-pyrrolidine-2-carboxylic acid (750 mg, crude) as a yellow solid.

Step 2: tert-butyl 4-cyclopentyl-2-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin- 3-yl)propan- 2-yl)carbamoyl)pyrrolidine-1-carboxylate

[000416] To a solution of l-tert-butoxycarbonyl-4-cyclopentyl-pyrrolidine-2-carboxylic acid (750 mg, 2.65 mmol, 1 eq) and methyl (2S)-2-amino-3-[(3S)-2-oxo-3- piperidyl]propanoate (904.92 mg, 3.44 mmol, 90% purity, 1.3 eq, HC1) in DCM (20 mL) was added DMAP (808.38 mg, 6.62 mmol, 2.5 eq) and EDCI (1.01 g, 5.29 mmol, 2 eq), and then the mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was quenched by addition H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ethenEthyl acetate = 1 :0 to 0: 1) to give the tert-butyl 4-cyclopentyl -2-[[(1S)-2-methoxy-2-oxo-1- [[(3S)-2-oxo-3-piperidyl] methyl] ethyl] carbamoyl] pyrrolidine- 1-carboxylate (1.0 g, 2.15 mmol, 81.15% yield) as a white solid. MS (ESI) m/z 466.2 [M+H] ⁺

Step 3: (2S)-methyl 2-(4-cyclopentylpyrrolidine-2-carboxamido)-3-((S)-2-oxopiper idin-3- yl)propanoate

[000417] A mixture of tert-butyl 4-cyclopentyl-2-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo- 3-piperidyl]methyl]ethyl]carbamoyl]pyrrolidine-1-carboxylate (1 g, 2.15 mmol, 1 eq) in HCl/MeOH (4 M, 20 mL, 37.25 eq) was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the methyl (2S)- 2-[(4-cyclopentylpyrrolidine-2-carbonyl) amino]-3-[(3S)-2-oxo-3-piperidyl] propanoate (0.8 g, crude, HC1) as a white solid.

Step 4: (2S)-methyl 2-(4-cyclopentyl-1-(4-methoxy-lH-indole-2-carbonyl)pyrrolidi ne-2- carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000418] 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, HC1) and 4-methoxy-lH- 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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum etherEthyl acetate = 1:4 to 0: 1) to give the methyl (2S)-2-[[4-cyclopentyl-1-(4-methoxy-lH-indole-2- carbonyl)pyrrolidine-2-carbonyl]amino]-3-[(3S)-2-oxo-3-piper idyl]propanoate (0.9 g, 1.60 mmol, 80.59% yield, 96% purity) as a yellow solid. MS (ESI) m/z 539.3 [M+H] ⁺

Step 5 : N-((S)-1 -amino- 1 -oxo-3-((S)-2-oxopiperidin-3-yl)propan-2-yl)-4-cyclopentyl- 1 -(4- methoxy- 1 H-indole-2-carbonyl)pyrrolidine-2-carboxamide

[000419] A mixture of methyl (2S)-2-[[4-cyclopentyl-1-(4-methoxy-lH-indole-2- carbonyl) pyrrolidine-2-carbonyl] amino]-3-[(3S)-2-oxo-3-piperidyl] propanoate (0.9 g, 1.67 mmol, 1 eq) in NH ₃ /MeOH (4 M, 20 mL, 47.88 eq), the mixture was stirred at 50 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the N-[( 1 S)-2-amino-2-oxo- 1 -[[(3 S)-2-oxo-3-piperidyl] methyl] ethyl]-4-cy clopentyl- 1 -(4-methoxy- 1 H-indole-2-carbonyl) pyrrolidine-2- carboxamide (0.9 g, crude) as a white solid. MS (ESI) m/z 524.3 [M+H] ⁺

Step 6 : N-((S)- 1 -cyano-2-((S)-2-oxopiperidin-3-yl)ethyl)-4-cyclopentyl- 1 -(4-methoxy- 1 H- indole-2-carbonyl)pyrrolidine-2-carboxamide

[000420] To a solution of N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-4-cyclopentyl-1-(4-methoxy-lH-indole -2- carbonyl)pyrrolidine-2-carboxamide (850 mg, 1.62 mmol, 1 eq) in DCM (8 mL) was added burgess reagent (773.68 mg, 3.25 mmol, 2 eq), then the mixture was stirred at 25 °C for 1 h. LCMS showed -50% reactant 1 remained, then burgess reagent (386.84 mg, 1.62 mmol, 1.00 eq) was added and stirred for 2 h additional. Upon completion, the reaction was quenched with water (0.8 mL), stirred for 10 min and concentrated in vacuum (bellow 30 °C). The residue was purified by prep-HPLC(column : Waters Xbridge BEH C18250 * 50 mm * 10 um; mobile phase: [water(10 mM NH4HCO3)- ACN]; B%: 35%-75%,10 min) then was purified by SFC column: DAICEL CHIRALCEL OD(250 mm * 30 mm, 10 um); mobile phase: [Neu-MeOH]; B%: 45%-45%, 15 min to give Isomer 1 (Rt = 1.409 min), N-[(1S)-1-cyano-2-[(3S)-2-oxo- 3-piperidyl]ethyl]-4-cyclopentyl-1-(4-methoxy-lH-indole-2-ca rbonyl)pyrrolidine-2- carboxamide Isomer 1 (75.72 mg, 149.76 umol, 9.23% yield, 100% purity) as white solid. MS (ESI) m/z 506.2 [M+H] ⁺

[000421] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.21 (br s, 1H), 8.64 (br s, 1H), 7.23 - 7.04 (m, 3H), 6.89 (br s, 1H), 6.53 (d, J=7.3 Hz, 1H), 4.98 (br d, J=7.2 Hz, 1H), 4.58 (br s, 1H), 4.12 (dd, J=7.8, 10.0 Hz, 1H), 3.91 (s, 3H), 3.50 (br s, 1H), 3.10 (br s, 2H), 2.47 - 2.06 (m, 5H), 1.90 - 1.74 (m, 4H), 1.71 - 1.46 (m, 7H), 1.45 - 1.13 (m, 3H)

[000422] To give N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]-4-cyclopentyl-1-(4- methoxy- 1 H-indole-2-carbonyl) pyrrolidine-2-carboxamide Isomer 2 (98.03 mg, 193.89 umol, 11.94% yield, 100% purity) as a white solid. MS (ESI) m/z 506.2 [M+H] ⁺

[000423] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.20 (br s, 1H), 8.53 (br s, 1H), 7.09 (br dd, J=7.8, 16.0 Hz, 3H), 6.91 (br s, 1H), 6.61 - 6.43 (m, 1H), 4.97 (br s, 1H), 4.57 (br s, 1H), 4.12 (br d, J=8.8 Hz, 1H), 3.91 (br d, J=7.7 Hz, 3H), 3.53 (br s, 1H), 3.09 (br s, 2H), 2.28 - 2.02 (m, 4H), 1.90 - 1.54 (m, 12H), 1.45 - 1.11 (m, 3H)

[000424] To give N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-4-cyclopent yl-1-(4- methoxy-lH-indole-2-carbonyl)pyrrolidine-2-carboxamide Isomer 3 (250 mg, 494.46 umol, 23.04% yield, 100% purity) as a white solid. The product was re-purified by SFC (column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 um); mobile phase: [Neu-EtOH]; B%: 50%-50%, 15 min) to give N-[(1S)-1-cyano-2-[(3S)-2-oxo-3- piperidyl]ethyl]-4-cyclopentyl-1-(4-methoxy-lH-indole-2-carb onyl)pyrrolidine-2- carboxamide Isomer 3 1 (90.63 mg, 179.25 umol, 11.04% yield, 100% purity) as a white solid. MS (ESI) m/z 506.2 [M+H] ⁺

[000425] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.25 (br s, 1H), 8.62 (br s, 1H), 7.19 - 7.04 (m, 3H), 6.88 (br s, 1H), 6.52 (d, J=7.3 Hz, 1H), 5.00 (br d, J=6.4 Hz, 1H), 4.68 (br s, 1H), 4.07 (br s, 1H), 3.91 (s, 3H), 3.52 (br s, 1H), 3.10 (br s, 2H), 2.36 - 2.13 (m, 3H), 2.05 - 1.68 (m, 8H), 1.67 - 1.37 (m, 6H), 1.20 (brd, J=10.6 Hz, 2H)

[000426] To give N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl] ethyl]-4-cyclopentyl-1-(4- methoxy- 1 H-indole-2-carbonyl) pyrrolidine-2-carboxamide Isomer 3 2 (89.82 mg, 177.65 umol, 10.94% yield, 100% purity) as a white solid. MS (ESI) m/z 506.2 [M+H] ⁺

[000427] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 11.24 (br s, 1H), 8.66 (br s, 1H), 7.37 - 7.01 (m, 3H), 6.89 (br s, 1H), 6.53 (br d, J=6.7 Hz, 1H), 5.00 (br s, 1H), 4.69 (br s, 1H), 4.05 (br s, 1H), 3.90 (br d, J=4.5 Hz, 3H), 3.51 (br s, 1H), 3.11 (br s, 2H), 2.31 - 2.19 (m, 3H), 2.07 - 1.68 (m, 8H), 1.65 - 1.38 (m, 6H), 1.20 (br s, 2H).

Example 308. Synthesis of viral protease inhibitor compound 1268

Step 1: methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,7-difluoro-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(6R)-5-oxo-4-azaspiro[2.4 ]heptan-6-yl]propanoate [000428] To a solution of methyl (2S)-2-[[(2S)-2-amino-3-cyclopropyl- propanoyl]amino]-3-[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]pr opanoate (200 mg, 555.79 umol, 1 eq, HC1) in DCM (5 mL) was added 4,7-difluoro-lH-indole-2- carboxylic acid (164.35 mg, 833.69 umol, 1.5 eq), DMAP (169.75 mg, 1.39 mmol,

2.5 eq) and EDCI (213.09 mg, 1.11 mmol, 2 eq). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was acidic at pH of 4~5 with 1 M HC1 (50 mL) and extracted with DCM (30 mL * 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column (SiO ₂ , Petroleum etherEthyl acetate = 5/1 —0/1) to get product methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,7-difluoro-lH-indole-2- carbonyl)amino]propanoyl]amino]-3-[(6R)-5-oxo-4-azaspiro[2.4 ]heptan-6- yl]propanoate (100 mg, 199.00 umol, 35.81% yield) as white solid. MS (ESI) m/z 503.2 [M+H] ⁺ .

Step 2: N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(6R)-5-oxo-4-azaspiro[2.4 ]heptan-6- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4, 7-difluoro-lH-indole-2- carboxamide

[000429] To a solution of methyl (2S)-2-[[(2S)-3-cyclopropyl-2-[(4,7-difluoro-lH-indole- 2-carbonyl)amino]propanoyl]amino]-3-[(6R)-5-oxo-4-azaspiro[2 .4]heptan-6- yl]propanoate (100 mg, 199.00 umol, 1 eq) was added NH ₃ /MeOH (7 M, 2 mL, 70.35 eq). The mixture was stirred at 65 °C for 20 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- [[( 1 S)-2-amino-2-oxo- 1 -[[(6R)-5-oxo-4-azaspiro[24]heptan-6- yl]methyl]ethyl]amino]-1-(cyclopropylmethyl)-2-oxo-ethyl]-4, 7-difluoro-lH-indole- 2-carboxamide (90 mg, crude) as white solid. MS (ESI) m/z 488.2 [M+H] ⁺ .

Step 3 : N-[(l S)-2-[[( 1 S)- 1 -cyano-2-[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]ethyl]amino] - 1 - (cyclopropylmethyl)-2-oxo-ethyl]-4,7-difluoro-lH-indole-2-ca rboxamide

[000430]To a solution of N-[(1S)-2-[[(1S)-2-amino-2-oxo-1-[[(6R)-5-oxo-4- azaspiro[2.4]heptan-6-yl]methyl]ethyl]amino]-1-(cyclopropylm ethyl)-2-oxo-ethyl]- 4,7-difluoro-lH-indole-2-carboxamide (90 mg, 184.62 umol, 1 eq) in DCM (1 mL) was added burgess reagent (131.98 mg, 553.85 umol, 3 eq). The mixture was stirred at 30 °C for 1 h. Upon completion, the mixture were quenched with water (1 mL) and blow-dried with N ₂ . The residue was purified by prep-HPLC (column: Waters X bridge BEH C18 100 * 25 mm * 5 um; mobile phase: [water (NH4HCO3) - ACN]; B%: 20% - 55%, 10 min) to get the product N-[(1S)-2-[[(1S)-1-cyano-2-[(6R)-5-oxo- 4-azaspiro[2.4]heptan-6-yl]ethyl]amino]-1-(cyclopropylmethyl )-2-oxo-ethyl]-4,7- difluoro-lH-indole-2-carboxamide (10.52 mg, 21.96 umol, 11.89% yield, 98% purity) as white solid. MS (ESI) m/z 470.2 [M+H] ⁺ .

[000431] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 12.45 (s, 1H), 8.98 (d, 1H), 8.70 (d, 1H), 7.80 (s, 1H), 7.40 (d, J= 2.4 Hz, 1H), 7.06 - 6.96 (m, 1H), 6.85 - 6.76 (m, 1H), 5.04 - 4.89 (m, 1H), 4.58 - 4.43 (m, 1H), 2.70 - 2.57 (m, 1H), 2.29 - 2.15 (m, 1H), 2.01 - 1.75 (m, 4H), 1.55 - 1.38 (m, 1H), 0.90 - 0.77 (m, 1H), 0.73 - 0.68 (m, 1H),0.62 - 0.48 (s, 3H), 0.47 - 0.38 (m, 2H), 0.26 - 0.01 (m, 2H).

Example 309. Synthesis of viral protease inhibitor compound 1282

Step 1: (1 S,3aR,7aS)-tert-butyl l-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopiperidin-3-yl)propan- 2-yl)carbamoyl)hexahydro-lH-isoindole-2(3H)-carboxylate

[000432] A solution of (lS,3aR,7aS)-2-tert-butoxycarbonyl-l,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, HCI) 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 H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (SiO ₂ PE/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 NaHCO ₃ (10 mL), brine(10 mL) dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give tert-butyl (lS,3aR,7aS)-1-[[(1S)-2-methoxy-2-oxo-1-[[(3S)- 2-oxo-3-piperidyl]methyl]ethyl]carbamoyl]-l,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] ⁺

Step 2: (S)-methyl 2-((lS,3aR,7aS)-octahydro-lH-isoindole-1-carboxamido)-3-((S) -2- oxopiperidin-3-yl)propanoate hydrochloride

[000433] A solution of tert-butyl (lS,3aR,7aS)-1-[[(1S)-2-methoxy-2-oxo-1-[[(3S)-2-oxo- 3-piperidyl]methyl]ethyl]carbamoyl]-l,3,3a,4,5,6,7,7a-octahy droisoindole-2- carboxylate (500 mg, 1.11 mmol, 1 eq) in HCl/MeOH (4 M, 10 mL, 36.12 eq) was stirre at 25 °C for 1 h. Upon completion, the reaction was concentrated in vacuum to give methyl (2S)-2-[[(lS,3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydro-lH-isoindo le-1- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (430 mg, crude, HC1) as a white solid.

Step 3: (S)-methyl 2-((lS,3aR,7aS)-2-(7-chloro-lH-indole-2-carbonyl)octahydro-l H- isoindole- 1 -carboxamido)-3-((S)-2-oxopiperidin-3-yl)propanoate

[000434] To a solution of methyl (2S)-2-[[(lS,3aR,7aS)-2,3,3a,4,5,6,7,7a-octahydro-lH- isoindole-1-carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propan oate (430 mg, 1.11 mmol, 1 eq, HC1) and 7-chloro-lH-indole-2-carboxylic acid (281.88 mg, 1.44 mmol, 1.3 eq) in DMF (6 mL) and DCM (2 mL), was added EDCI (425.01 mg, 2.22 mmol, 2 eq) and DMAP (406.29 mg, 3.33 mmol, 3 eq), then the mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with H ₂ O (20 mL) at 0 °C and then extracted with EA (20 mL * 2). The combined organic layers were was washed with 15% citric acid (20 ml, * 2), the combined organic layers were washed with NaHCO ₃ (20 mL), brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO ₂ PE/EA = 0: 1) to give methyl (2S)-2-[[(lS,3aR,7aS)-2-(7- chloro-lH-indole-2-carbonyl)-l,3,3a,4,5,6,7,7a-octahydroisoi ndole-1- carbonyl]amino]-3-[(3S)-2-oxo-3-piperidyl]propanoate (440 mg, 798.45 umol, 72.03% yield, 96% purity) as a off-white solid. MS (ESI) m/z 529.2[M+H] ⁺

Step 4: (1 S,3aR,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)p ropan-2-yl)-2-(7- chloro- 1 H-indole-2-carbonyl)octahydro- 1 H-isoindole- 1 -carboxamide

[000435] A solution of methyl (2S)-2-[[(lS,3aR,7aS)-2-(7-chloro-lH-indole-2-carbonyl)- l,3,3a,4,5,6,7,7a-octahydroisoindole-1-carbonyl]amino]-3-[(3 S)-2-oxo-3- piperidyl]propanoate (440 mg, 831.72 umol, 1 eq) in NH ₃ .MeOH (7 M, 12 mL, 101.00 eq) and the mixture was stirred at 40 °C fo 24 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (lS,3aR,7aS)-N- [(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]ethyl] -2-(7-chloro-lH- indole-2-carbonyl)-l,3,3a,4,5,6,7,7a-octahydroisoindole-1-ca rboxamide (430 mg, crude) as an off-white solid. MS (ESI) m/z 514.2 [M+H] ⁺

Step 5: (lS,3aR,7aS)-2-(7-chloro-lH-indole-2-carbonyl)-N-((S)-1-cyan o-2-((S)-2- oxopiperidin-3-yl)ethyl)octahydro- lH-isoindole- 1 -carboxamide

[000436] To a solution of (lS,3aR,7aS)-N-[(1S)-2-amino-2-oxo-1-[[(3S)-2-oxo-3- piperidyl]methyl]ethyl]-2-(7-chloro-lH-indole-2-carbonyl)-l, 3,3a,4,5,6,7,7a- octahydroisoindole- 1 -carboxamide (430 mg, 836.55 umol, 1 eq) in DCM (5 mL) was added Burgess reagent (598.08 mg, 2.51 mmol, 3 eq), and then the mixture was stirred at 25 °C for 3 h. Upon completion, the residue was quenched with water (0.5 mL) and was stirred for 10 min, then was concentrated bellow 30 °C. The residue was purified by prep-HPLC (HPLC column: Phenomenex Gemini-NX 80 * 40 mm * 3 um; mobile phase: [water (10 mM NH4HCO3)- ACN] ; B%: 25%-55%, 8 min. Then was purified by SFC to give Isomer 1 (Rt = 0.878 min) (lS,3aR,7aS)-2-(7-chloro-lH- indole-2-carbonyl)-N-[( 1 S)- 1 -cyano-2-[(3 S)-2-oxo-3-piperidyl]ethyl]- l,3,3a,4,5,6,7,7a-octahydroisoindole-1-carboxamide (103.07 mg, 207.80 umol, 24.84% yield, 100% purity) as a white solid. MS (ESI) m/z 496.1 [M+H] ⁺

[000437] ¹ H NMR (400MHz, DMSO- d ₆ ) (273+80K) δ = 11.13 (br s, 1H), 8.74 (br s, 1H), 7.62 (br s, 1H), 7.31 - 7.23 (m, 2H), 7.08 (br t, J=7.8 Hz, 2H), 5.00 (br s, 1H), 4.31 (br d, J=4.4 Hz, 1H), 4.08 - 3.88 (m, 1H), 3.73 (br d, J=7.1 Hz, 1H), 3.10 (br s, 2H), 2.41 (br s, 1H), 2.23 (br s, 3H), 1.84 (br s, 2H), 1.71 (br s, 2H), 1.59 - 1.33 (m, 9H)

[000438] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.66 - 11.52 (m, 1H), 9.12 - 8.85 (m, 1H), 7.64 (d ,J= 7.8 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.32 - 7.25 (m, 1H), 7.16 (s, 1H), 7.11 - 7.01 (m, 1H), 5.11 - 4.94 (m, 1H), 4.42 - 4.19 (m, 1H), 3.98 (dd, J= 6.7, 10.0 Hz, 1H), 3.80 - 3.69 (m, 1H), 3.12 - 2.97 (m, 2H), 2.38 (br d,J= 4.5 Hz, 1H), 2.27 - 2.13 (m, 3H), 1.88 - 1.61 (m, 4H), 1.54 (br d, J= 4.8 Hz, 5H), 1.44 - 1.23 (m, 4H) [000439] And Isomer 2 (Rt = 1.583 min) (lS,3aR,7aS)-2-(7-chloro-lH-indole-2- carbonyl)-N-[(1S)-1-cyano-2-[(3S)-2-oxo-3-piperidyl]ethyl]-l ,3,3a,4,5,6,7,7a- octahydroisoindole-1 -carboxamide (99.03 mg, 199.66 umol, 23.87% yield, 100% purity) as a white solid. MS (ESI) m/z 496.1 [M+H] ⁺

[000440] ¹ H NMR (400MHz, DMSO-d ₆ ) (273+80Κ)δ = 11.11 (br s, 1H), 8.77 (br s, 1H), 7.60 (br s, 1H), 7.26 (br d, J=7.3 Hz, 2H), 7.17 - 6.98 (m, 2H), 5.00 (br s, 1H), 4.32 (br s, 1H), 3.93 (s, 1H), 3.69 (br s, 1H), 3.10 (br s, 2H), 2.44 - 2.18 (m, 4H), 1.80 (br s, 2H), 1.68 (br s, 2H), 1.54 (br s, 5H), 1.36 (br s, 4H)

[000441] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.59 (br s, 1H), 9.22 - 8.93 (m, 1H), 7.64 (d ,J= 7.8 Hz, 1H), 7.58 - 7.46 (m, 1H), 7.34 - 7.24 (m, 1H), 7.16 (s, 1H), 7.11 - 6.99 (m, 1H), 5.13 - 4.90 (m, 1H), 4.46 - 4.24 (m, 1H), 3.98 (dd,J= 6.7, 10.0 Hz, 1H), 3.78 - 3.53 (m, 1H), 3.15 - 2.91 (m, 2H), 2.43 - 2.15 (m, 4H), 1.96 - 1.75 (m, 2H), 1.70 - 1.48 (m, 7H), 1.46 - 1.24 (m, 4H)

Example 310. Synthesis of viral protease inhibitor compound 1286 Step 1: (S)-methyl 2-amino-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate hydrochloride

[000442] A solution of (S)-methyl 2-((tert-butoxy carbonyl) amino)-3-((R)-5-oxo-4- azaspiro [2.4] heptan-6-yl) propanoate (250 mg, 800.36 umol, 1 eq) in HCl/MeOH (5 mL, 4M) was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was concemtration in vacuum to obtained (S)-methyl 2-amino-3-((R)-5-oxo-4-azaspiro [2.4] heptan-6-yl) propanoate hydrochloride (200 mg, crude, HC1) as a yellow solid.

Step 2 : (S)-methyl2-((S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethyl pentanamido)-3-((R)- 5-oxo-4-azaspiro[2.4]heptan-6-yl)propanoate

[000443] To a solution of methyl (S)-methyl 2-amino-3-((R)-5-oxo-4-azaspiro

[2.4]heptan-6-yl) propanoate hydrochloride (200 mg, 804.16 umol, 1 eq, HC1) and (2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl-pentanoic acid (217.00 mg, 884.58 umol, 1.1 eq) in DCM (10 mL) was added DMAP (196.49 mg, 1.61 mmol, 2 eq) and EDCI (308.32 mg, 1.61 mmol, 2 eq) at 20 °C, the mixture was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was adjusted pH~l with aq.HCl (15 mL, 1M), then was added addition of water (10 mL) and was extracted with DCM (9 mL * 3), then the organic phase was adjusted pH~7 with sat.NaHCO ₃ (15 mL), then the organic phase was concemtration in vacuum and was purified by column (SiO ₂ , ninhydrin, PE:EA = 1:0 to 0:1) to obtained (2S)-2-[[(2S)-2-(tert- butoxycarbonylamino)-4,4-dimethyl-pentanoyl] amino]-3-[(6R)-5- oxo-4- azaspiro[2.4]heptan-6-yl] propanoate (350 mg, 732.58 umol, 91.10% yield, 92% purity) as a white solid. MS (ESI) m/z 440.2 [M+H] ⁺

Step 3 : (S)-methyl2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)-5-o xo-4- azaspiro[2.4]heptan-6-yl)propanoate

[000444] A solution of (2S)-2-[[(2S)-2-(tert-butoxycarbonylamino)-4,4-dimethyl- pentanoy 1 ]amino]-3 - [(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl] propanoate (160 mg, 364.01 umol, 1 eq) in HCl/MeOH (3 mL, 4 M) was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was concemtration in vacuum to obtained (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3- ((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl) propanoate (100 mg, crude, HC1) as a white solid. MS (ESI) m/z 340.2 [M+H] ⁺ Step 4: (S)-methyl2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)-5-o xo-4- azaspiro[2.4]heptan-6-yl)propanoate

[000445] To a solution of (S)-methyl 2-((S)-2-amino-4,4-dimethylpentanamido)-3-((R)-5- oxo-4-azaspiro[2.4] heptan-6-yl) propanoate (90 mg, 239.43 umol, 1 eq, HC1) and 7- chloro-5-methoxy-1H-indole-2-carboxylic acid (75.63 mg, 335.20 umol, 1.4 eq) in DCM (5 mL) was added DMAP (58.50 mg, 478.86 umol, 2 eq) and EDCI (91.80 mg, 478.86 umol, 2 eq), the mixture was stirred at 20 °C for 1 h. Upon the reaction completion, the mixture was added addtion water (15 mL) and was extracted with DCM (5 mL * 3), then was dried with Na ₂ SO ₄ , filtered and concemtration in vacuum and was purification by prep-TLC (SiO ₂ , EA = 1) to obtained (S)-methyl 2-((S)-2- amino-4,4-dimethylpentanamido)-3-((R)-5-oxo-4-azaspiro[2.4]h eptan-6- yl)propanoate (80 mg, 131.62 umol, 54.97% yield, 90% purity) as a white solid. MS (ESI) m/z 547.2 [M+H] ⁺

Step 5 : N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((R)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2- yl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-7-chloro-5-methoxy- 1 H-indole-2-carboxamide [000446] A solution of (S)-methyl 2-((S)-2-amino-4, 4-di methyl pentanami do)-3 -((R)- 5 - oxo-4-azaspiro [2.4] heptan-6-yl) propanoate (70 mg, 127.96 umol, 1 eq) in NH ₃ /MeOH (4 mL, 7 M) was stirred at 30 °C for 16 h. Upon the reaction completion, the mixture was concemtration in vacuum to obtained N-((S)- 1 -(((S)- 1 -amino- 1 -oxo- 3-((R)-5-oxo-4-azaspiro [2.4] heptan-6-yl) propan-2-yl) amino)-4, 4-dimethyl- 1- oxopentan-2-yl)-7-chloro-5-methoxy-1H-indole-2-carboxamide (70 mg, cmde) as a white solid. MS (ESI) m/z 532.2 [M+H] ⁺

Step 6 : 7-chloro-N-((S)- 1 -(((S)- 1 -cyano-2-((R)-5-oxo-4-azaspiro[2.4]heptan-6- yl)ethyl)amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-5-methoxy- 1 H-indole-2-carboxamide [000447] To a solution of N-((S)- 1 -(((S)- 1 -amino- 1 -oxo-3-((R)-5-oxo-4-azaspiro[2.4] heptan-6-yl) propan-2-yl) amino)-4, 4-dimethyl- 1 -oxopentan-2-yl)-7-chloro-5- methoxy- 1H-indole-2-carboxamide (60 mg, 112.78 umol, 1 eq) in DCM (2 mL) was added burgess reagent (80.62 mg, 338.33 umol, 3 eq), the mixture was stirred at 30 °C for 2 h. Upon the reaction completion, the mixture was quenched by water (0.5 mL) and was dried by blowing N ₂ and was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 25mm * Sum; mobile phase: [water (10 mM NH4HCO3)- ACN]; B%: 30%-60%, lOmin) to obtained 7-chloro-N-((S)-1-(((S)-1-cyano-2-((R)-5- oxo-4-azaspiro[2.4]heptan-6-yl)ethyl)amino) -4,4-dimethyl- l-oxopentan-2-yl)-5- methoxy- 1 H-indole-2-carboxamide (15 mg, 28.89 umol, 25.62% yield, 99% purity) as a white solid. MS (ESI) m/z 514.1 [M+H] ⁺

[000448] ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.55 (s, 1H), 9.02 (d, J = 8.0 Hz, 1H), 8.66 (d ,J= 8.0 Hz, 1H), 7.82 - 7.73 (m, 1H), 7.18 - 7.11 (m, 2H), 7.00 (d , J= 2.2 Hz, 1H), 4.95 (q, J= 7.8 Hz, 1H), 4.61 - 4.53 (m, 1H), 3.78 (s, 3H), 2.64 - 2.58 (m, 1H), 2.24 - 2.15 (m, 1H), 1.99 - 1.91 (m, 2H), 1.90 - 1.81 (m, 1H), 1.77 - 1.65 (m, 2H), 0.94 (s, 9H), 0.75 - 0.67 (m, 1H), 0.57 - 0.43 (m, 3H).

Example 311. Synthesis of viral protease inhibitor compound 3075

Step 1: tert-butyl ((S)-l -amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2- yl)carbamate

[000449] 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 NH ₃ /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.

Step 2: (S)-2-amino-3-((R)-5,5-dimethyl-2-oxopyrrolidin-3-yl)propana mide

[000450] 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]prop anamide (5.13 g, crude, HC1) as white solid and used directly for next step.

Step 3: tert-butyl ((S)-1-((lR,2S,5S)-2-(((S)-1-amino-3-((R)-5,5-dimethyl-2-oxo pyrrolidin-3- yl)-1-oxopropan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3. 1.0]hexan-3-yl)-3, 3-dimethyl- 1 -oxobutan-2-yl)carbamate

[000451] To a solution of (lR,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl - butanoyl]-6,6-dimethyl-3-azabicyclo[3.1 0]hexane-2-carboxylic acid (0.5 g, 1.36 mmol, 1 eq) and (2S)-2-amino-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3- yl]propanamide (405.57 mg, 2.04 mmol, 1.5 eq) in DMF (5 mL) was added PyBOP (776.78 mg, 1.49 mmol, 1.1 eq) and cooled to -30 °C, the mixture was added EtsN (274.62 mg, 2.71 mmol, 377.75 uL, 2 eq) at -30 °C. The mixture was stirred at -30 °C for 2 h. Upon completion, the reaction mixture was quenched by water (10 mL), and then extracted with ethyl acetate (6 mL * 2). The combined organic layers were washed with brine (10 mL * 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate = 20/1 to 0/1) to give tert-butyl N-[(1S)-1-[(lR,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, 67.03% yield) as a white solid. MS (ESI) m/z 436.2 [M+H] ⁺ Step 4: (lR,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-N-((S)-1-ami no-3-((R)-5,5- dimethyl-2-oxopyrrolidin-3-yl)- 1 -oxopropan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1 OJhexane- 2-carboxamide

[000452] A mixture of tert-butyl N-[(1S)-1-[(lR,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 ( 1 R,2 S, 5 S)-3 -[(2 S)-2-amino-3 , 3 - dimethyl-butanoyl]-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-o xo-pyrrolidin-3- yl]methyl]-2-oxo-ethyl]-6,6-dimethyl-3-azabicyclo[3.1 0]hexane-2-carboxamide (540 mg, crude, HC1) as a white solid and used directly for next step. MS (ESI) m/z 450.3 [M+H] ⁺

Step 5: (lR,2S,5S)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopiperidin-3-yl)p ropan-2-yl)-3-((S)- 3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimet hyl-3-azabicyclo[3.1 OJhexane- 2-carboxamide

[000453] To a solution of (lR,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 (0.44 g, 905.26 umol, 1 eq, HC1) in DCM (10 mL) was added DIEA (351.00 mg, 2.72 mmol, 473.04 uL, 3 eq), and cooled to 0 °C, then added TFAA (152.11 mg, 724.21 umol, 100.73 uL, 0.8 eq). The mixture was stirred at 0 °C for 1 h. Upon completion, the combined reaction mixture was poured into aq.NaHCO ₃ (20 mL) and extracted with DCM (10 mL * 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give (lR,2S,5S)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1 ,0]hexane-2- carboxamide (350 mg, crude, 70.86% yield) as a white solid and used directly for next step. MS (ESI) m/z 546.1 [M+H] ⁺ Step 6: (lR,2S,5S)-N-((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidi n-3-yl)ethyl)-3-((S)- 3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimet hyl-3-azabicyclo[3.1 OJhexane- 2-carboxamide

[000454] To a solution of ( 1 R,2S,5 S)-N-[( 1 S)-2-amino- 1 -[[(3R)-5, 5-dimethyl-2-oxo- pyrrolidin-3-yl]methyl]-2-oxo-ethyl]-3-[(2S)-3,3-dimethyl-2- [(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3. 1 0]hexane-2- carboxamide (0.3 g, 549.86 umol, 1 eq) in DCM (5 mL) was added burgess reagent (393.10 mg, 1.65 mmol, 3 eq). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched by water (0.5 mL) at 20 °C, and the system was blow-dried with N ₂ to give a residue. The residue was purified by prep- HPLC (column: Waters Xbridge BEH C18 100 * 30 mm *10 um; mobile phase: [water(10 mM NH4HCO3) - ACN]; B%: 35% - 60%, 8min) to give (1R,2S,5S)-N- [(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]eth yl]-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimet hyl-3- azabicyclo[3.1 0]hexane-2-carboxamide (91.51 mg, 173.45 umol, 31.54% yield,

100% purity) as a white solid. MS (ESI) m/z 528.2 [M+H] ⁺

[000455] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.41 (br d ,J= 7.7 Hz, 1H), 8.99 (d ,J= 8.4 Hz, 1H), 7.83 (s, 1H), 4.97 - 4.88 (m, 1H), 4.40 (br d ,J= 7.1 Hz, 1H), 4.20 - 4.14 (m, 1H), 3.90 (br dd,J= 5.5, 10.4 Hz, lH), 3.68 (br d,J= 10.6 Hz, 1H), 2.21 - 2.08 (m, 2H), 1.99 (br dd, J= 8.8, 12.3 Hz, 1H), 1.75 (ddd, J= 5.7, 10.3, 13.5 Hz, 1H), 1.59 - 1.51 (m, 2H), 1.29 (d, J= 7.7 Hz, 1H), 1.20 - 1.16 (m, 3H), 1.10 (s, 3H), 1.05 - 1.01 (m, 3H), 1.01 - 0.95 (m, 9H), 0.86 - 0.83 (m, 3H)

[000456] Step 7: (lR,2S,5S)-N-((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidi n-3- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)bu tanoyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxamide

[000457] The (lR,2S,5S)-N-((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidi n-3- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)bu tanoyl)-6,6-dimethyl-3- azabicyclo[3.1 0]hexane-2-carboxamide was further separated by SFC (column: DAICEL CHIRALPAK AD-H(250 mm * 30 mm, 5 um); mobile phase: [Neu-IPA]; B%: 5%-15%,15min) to give ( 1 R,2S, 5 S)-N-((S)- 1 -cyano-2-((R)-5,5-dimethyl-2- oxopyrrolidin-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifl uoroacetamido)butanoyl)- 6, 6-dimethyl -3-azabicyclo[3.1 0]hexane-2-carboxamide Isomer 1 (5.1 mg, 9.67 umol, 5.74% yield) as a white solid. MS (ESI) m/z 528.2 [M+H] ⁺

[000458] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.50 - 9.36 (m, 1H), 9.09 - 8.96 (m, 1H), 7.98 - 7.82 (m, 1H), 4.98 - 4.87 (m, 1H), 4.40 (br d, J= 5.5 Hz, 1H), 4.21 - 4.15 (m, 1H), 3.97 - 3.85 (m, 1H), 3.73 - 3.60 (m, 1H), 2.53 - 2.52 (m, 1H), 2.15 - 2.08 (m, 1H), 2.07 - 1.93 (m, 1H), 1.84 - 1.70 (m, 1H), 1.58 - 1.47 (m, 2H), 1.35 - 1.27 (m, 1H), 1.22 - 1.17 (m, 3H), 1.16 - 1.08 (m, 3H), 1.05 - 1.00 (m, 3H), 1.00 - 0.94 (m, 9H), 0.86 - 0.81 (m, 3H).

[000459] To give (lR,2S,5S)-N-((S)-1-cyano-2-((R)-5,5-dimethyl-2-oxopyrrolidi n-3- yl)ethyl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)bu tanoyl)-6,6-dimethyl-3- azabicyclo[3.1 0]hexane-2-carboxamide Isomer 2 (61.8 mg, 117.14 umol, 69.59% yield) as a white solid. MS (ESI) m/z 528.2 [M+H] ⁺

[000460] ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.41 (br d ,J= 7.7 Hz, 1H), 8.99 (br d ,J = 8.2 Hz, 1H), 7.84 (s, 1H), 4.96 - 4.89 (m, 1H), 4.40 (br d,J= 7.1 Hz, 1H), 4.17 (s, 1H), 3.90 (br dd,J= 5.4, 10.5 Hz, lH), 3.68 (br d,J= 10.6 Hz, 1H), 2.52 (d,J= 2.0 Hz, 1H), 2.19 - 2.10 (m, 1H), 1.99 (br dd, J= 8.7, 12.5 Hz, 1H), 1.75 (ddd, J= 5.6, 10.1, 13.3 Hz, 1H), 1.59 - 1.51 (m, 2H), 1.29 (d, J= 7.7 Hz, 1H), 1.19 - 1.16 (m, 3H), 1.10 (s, 3H), 1.02 (s, 3H), 0.98 (s, 9H), 0.86 - 0.84 (m, 3H)

Example 312. Synthesis of viral protease inhibitor compound 3073 Step 1: methyl (2S)-2-[[(3S)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimet hyl-butanoyl]- 2-azaspiro [4.5]decane-3-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyr rolidin-3- yl]propanoate

[000461] To a mixture of methyl (2S)-2-[[(3S)-2-azaspiro[4.5]decane-3-carbonyl]amino]- 3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]propanoate (200 mg, 480.82 umol, 1 eq, HC1) in DCM (10 mL) was added DMAP (117.48 mg, 961.65 umol, 2 eq), (2S)-2- (tert-butoxycarbonylamino)-3, 3-dimethyl-butanoic acid (111.21 mg, 480.82 umol, 1 eq) and EDCI (184.35 mg, 961.65 umol, 2 eq) at 25 °C.The mixture was stirred at 25 °C for 60 min. Upon completion, the reaction mixture was diluted with H ₂ O 20 mL and extracted with EA 50 mL (25 mL * 2). The combined organic layers were washed with brine 25 mL (25 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , Petroleum ether/Ethyl acetate=10/l to 1/1) to get the crude 180 mg. The residue was purified by neutral condition prep-HPLC. (column: Waters Xbridge BEH C18 100*30mm* 10um;mobile phase: [water(10mM NH4HC03)- ACN];B%: 50%-80%,10min). Compound methyl (2S)-2-[[(3S)-2-[(2S)-2-(tert- butoxycarbonylamino)-3,3-dimethyl-butanoyl]-2-azaspiro [4.5]decane-3- carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]p ropanoate (70 mg, 118.09 umol, 24.56% yield, 100% purity) was obtained as a white solid. MS (ESI) m/z 593.4 [M+H] ⁺

Step2: tert-butyl N-[(l S)-1-[(3S)-3-[[(l S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin- 3-yl]methyl] -2-oxo-ethyl]carbamoyl]-2-azaspiro[4.5]decane-2-carbonyl]-2, 2-dimethyl- propyl]carbamate

[000462] Methyl (2S)-2-[[(3S)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimet hyl- butanoyl]-2-azaspiro [4.5]decane-3-carbonyl]amino]-3-[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl]propanoate (70 mg, 118.09 umol, 1 eq) was added NH ₃ /MeOH (7 M, 14.00 mL, 829.87 eq). The mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was used next step directly. Compound tert-butyl N-[(1S)-1-[(3S)-3-[[(1S)-2- amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]-2- oxo-ethyl]carbamoyl]- 2-azaspiro[4.5]decane-2-carbonyl]-2,2-dimethyl-propyl]carbam ate (68 mg, 115.34 umol, 97.67% yield, 98% purity) was obtained as a white solid. MS (ESI) m/z 578.4 [M+H] ⁺

Step 3 : (3S)-2-[(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]-2-azaspi ro[4.5]decane-3-carboxamide [000463] Tert-butyl N-[(1S)-1-[(3S)-3-[[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo - pyrrolidin-3-yl]methyl]- 2-oxo-ethy 1 ]carbamoy 1 ]-2-azaspiro[4.5 ]decane-2-carbony 1 ]-

2.2-dimethyl-propyl]carbamate (68 mg, 117.70 umol, 1 eq) was added HCl/EtOAc (4 M, 3.78 mL, 128.39 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 (3S)-2-[(2S)-2-amino-

3.3-dimethyl-butanoyl]-N-[(1S)-2-amino-1-[[(3R)-5,5-dimet hyl-2-oxo-pyrrolidin-3- y 1 ]methy 1 ]-2-oxo-ethy 1 ]-2-azaspiro[4.5 ]decane-3 -carboxamide (60 mg, 114.37 umol, 97.18% yield, 98% purity, HC1) was obtained as a white solid.

Step 4: (3S)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin- 3-yl]methyl]-2-oxo- ethyl]-2-[(2S) -3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-2- azaspiro[4.5 ]decane-3 -carboxamide

[000464] (3S)-2-[(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]-2-azaspi ro[4.5]decane-3- carboxamide (40 mg, 77.81 umol, 1 eq, HC1) in DCM (4 mL) was added DIEA (30.17 mg, 233.42 umol, 40.66 uL, 3 eq) and TFAA (19.61 mg, 93.37 umol, 12.99 uL, 1.2 eq) at 0 °C, the mixture was stirred at 0 °C for 30 min. Upon completion, the reaction mixture was quenched by addition H ₂ O 2 mL at 0 °C, and extracted with EA 10 mL (5 mL * 2). The combined organic layers were washed with brine 5 mL (5 mL * 1), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue and used next step directly. Compound (3S)-N-[(1S)-2-amino-1-[[(3R)-5,5-dimethyl- 2-oxo-pyrrolidin-3-yl]methyl]-2-oxo-ethyl]-2-[(2S)-3,3-dimet hyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-2-azaspiro[4.5]decane-3-carb oxamide (60 mg, 73.22 umol, 94.10% yield, 70% purity) was obtained as a white solid. MS (ESI) m/z 574.2 [M+H] ⁺

Step 5: (3S)-N-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3 -yl]ethyl]-2-[(2S)-3,3- dimethyl -2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-2-azaspiro[4.5]de cane-3-carboxamide [000465] To a mixture of (3 S)-N-[( 1 S)-2-amino- 1 -[[(3R)-5, 5-dimethyl-2-oxo-pyrrolidin- 3-yl]methyl]-2-oxo-ethyl]-2-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-2-azaspiro[4.5]decane-3-carb oxamide (30 mg, 52.30 umol, 1 eq) in DCM (3 mL) was added BURGESS REAGENT (24.93 mg, 104.59 umol, 2 eq). The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was diluted with H ₂ O 5 mL and extracted with DCM 10 mL (5 mL * 2). The combined organic layers were concentrated by blow-drying to give a residue. The residue was purified by neutral condition prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (10mMNH4HCO3)-ACN]; B%: 40%- 70%, 10 min). Compound (3S)-N-[(1S)-1-cyano-2-[(3R)-5,5-dimethyl-2-oxo- pyrrolidin-3-yl] ethyl]-2-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-2-azaspiro[4.5]decane-3-carb oxamide (10 mg, 17.40 umol, 33.28% yield, 96.7% purity) was obtained as a white solid. MS (ESI) m/z 556.2 [M+H] ⁺

[000466] ¹ H NMR (400 MHz, DMSO-d6) δ = 8.98 - 8.29 (m, 2H), 7.50 (br s, 1H), 5.01 - 4.78 (m, 1H), 4.56 (s, 1H), 4.31 (br t, J= 8.6 Hz, 1H), 3.79 (br d, J= 10.1 Hz, 1H), 3.29 (br d,J= 10.0 Hz, 1H), 2.60 (br dd, J= 5.4, 8.9 Hz, 1H), 2.26 - 2.03 (m, 3H), 1.87 - 1.71 (m, 1H), 1.64 - 1.26 (m, 12H), 1.25 - 1.13 (m, 6H), 1.03 (s, 9H)

Example 313. Evaluation of antiviral activity of Compounds against COVID-19 (nCoV- 2019, SARS-CoV2) Mpro in the enzymatic assay

[0002027] 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 in E. coli and purified. The assay buffer contains 20 mM of Tris-HCl (pH 7.3), 100 mM of NaCl, 1 mM of EDTA, 5mM of TCEP and 0.1%BSA. The final concentrations of the Mpro protein and substrate are 25 nM and 25 μΜ, respectively, in the Mpro enzymatic assay. The Km of the Mpro substrate for the protease was 13.5 μΜ.

[0002028] The compounds are added to an assay plate. For 100% inhibition control (HPE, hundred percent effect), 1 μΜ 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.

[0002029] 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.

Inhibition% =[ (Sample- Average ZPE )/(Average HPE-Average ZPE)] * 100% ^{# #} HEP: Hundred percent effect controls. Containing substrate + enzyme + 1 μΜ GC376.

ZPE: Zero percent effective controls. Containing enzyme + substrate, no compound. Sample: Compound activity testing wells. Containing compound + enzyme + substrate. BG: Compound background control wells. Containing compound + substrate, no enzyme.

Example 314. Evaluation of antiviral activity of Compounds against human coronavirus (HCov) 229E and OC43 in the cytopathic effect (CPE) assays

[0002030] 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.

[0002031 ] Reagents and instruments used in this assay include luminescent cell viability assay kit CellTiter Glo (Promega) and Microplate Reader Synergy2 (BioTek).

Virus - HCoV 229E

[0002032] 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.

Virus - HCov OC43 [0002033] 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.

[0002034] 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.

[0002035] Table 3, Table 4 and Table 5 show activity data.

Table 3. Activity data for compounds.

A >30 μΜ, B > 10 μΜ and <30 μΜ, C >2 μΜ and <10 μΜ, D <2 μΜ.

Table 4. Activity data for compounds.

A > 30 μΜ, B > 10 μΜ and <30 μΜ, C >2 μΜ and <10 μΜ, D <2 μΜ.

Table 5. Activity data for compounds.

A > 30 μΜ, B > 10 μΜ and ≤30 μΜ, C ≥2 μΜ and ≤10 μΜ, D <2 μΜ.

INCORPORATION BY REFERENCE

[0002036] 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

[0002037] 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.

[0002038] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure.