Protease inhibitors, their preparation and uses

Abstract

To provide non-covalent inhibitors of proteases such as SARS-CoV-2 3CLpro, and preparations and uses of these inhibitors.SOLUTION: The disclosure provides compounds of Formula I, compositions comprising the same, and methods of using the same, including use in treating a disease and / or a symptom of a disease caused by a coronavirus.SELECTED DRAWING: Figure 1A

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present disclosure relates to compounds that inhibit proteases, such as 3C-like protease (3CLpro), compositions containing the compounds, methods of preparing the compounds, and methods of using the compounds to treat disease or symptoms of disease caused by a coronavirus, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). [Background technology]

[0002] 2. Background of the Invention The COVID-19 pandemic is caused by a novel coronavirus, SARS-CoV-2. There is a great need for drugs that specifically treat diseases caused by SARS-CoV-2 or other coronaviruses. The positive-sense RNA virus SARS-CoV-2 encodes 16 nonstructural proteins (nsps), named nsp1 to nsp16, in over 70% of its genome (Refs. 1, 2). The 16 nsps are translated into two polyproteins, pp1a and pp1ab, from which the individual nsps are generated by proteolytic cleavage. Specifically, pp1a is cleaved from nsp1 to nsp11, while pp1ab is cleaved from nsp1 to nsp10 and from nsp12 to nsp16 (Ref. 1). Cleavage is carried out by two proteases, nsp3 and nsp5, contained in the 16 nsps. nsp3 is a large protein containing several domains, among which the papain-like protease (PLpro) domain is involved in the cleavage of peptide bonds between nsp1 and 2, nsp2 and 3, and nsp3 and 4 (Ref. 1, 3). nsp5 is 3CLpro, a cysteine ​​protease that cleaves peptide bonds to release nsp4 to nsp16 (Ref. 1). 3CLpro has almost the same function in other coronaviruses.

[0003] After cleavage from pp1a and pp1ab, 3CL forms a homodimer with significantly increased protease activity and facilitates the cleavage of peptide bonds between other nsp. The catalytic center of 3CL contains a catalytic dyad composed of His41 and Cys145. The mechanism of action and protein sequence of the catalytic domain of 3CL are conserved among different coronaviruses. The sequence identity between 3CL of SARS-CoV-2 and 3CL of SARS-CoV reaches 96%.

[0004] Inhibition of the protease activity of 3CLpro blocks the release of nsp16 from nsp4, which is necessary for coronavirus replication. For example, nsp12 and nsp13, also known as RNA-dependent RNA polymerase (RdRp) and helicase, respectively, are enzymes that catalyze the replication of the viral RNA genome. Therefore, 3CLpro is a promising target for the development of anti-coronavirus drugs. Several research teams have devoted significant efforts to developing inhibitors of SARS-CoV 3CLpro and SARS-CoV-2 3CLpro. The majority of these inhibitors are covalent inhibitors optimized from peptide scaffolds (Ref. 4). A number of non-covalent inhibitors were also reported, but most of them showed poor activity in cell-free or cell-based assays. Summary of the Invention [Problem to be solved by the invention]

[0005] The present disclosure provides non-covalent inhibitors of proteases such as SARS-CoV-2 3CLpro, and the preparation and uses of these inhibitors. [Means for solving the problem]

[0006] overview One aspect of the present disclosure provides a compound selected from the compounds of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, which can be used in the treatment of a disease caused by a coronavirus and / or a symptom thereof. For example, a compound selected from the compounds of the following structural formula I: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, Ar is phenyl or 6-membered heteroaryl; Ring A is a 9- or 10-membered heteroaryl, where V 1 , V 2 , V 3 , and V 4 are each absent, -CH-, or N, V 1 , V 2 , V 3 , and V 4 may be absent, W 1 , W 2 , W 3 , and W 4 If one of is absent, V 1 , V 2 , V 3 , and V 4 None of these can be absent, W 1 , W 2 , W 3 , and W 4 are each absent, -CH-, or N, W 1 , W 2 , W 3 , and W 4 may be absent, W 1 , W2 , W 3 , and W 4 At least one of must be N, X is absent or -NR a -, or -NR a (CR b R c ) a - and Y is absent or C 3 ~C 12 carbocyclyl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, 3 ~C 12 Carbocyclyl, Y 3- to 12-membered heterocyclyl, and Y 5- to 10-membered heteroaryl each have o R 3 is substituted with a group, Z is absent or -NR d -, -(CR e R f ) b NR d - or -C(=O)NR d (CR g R h ) c -where: R a and R d is, for each occurrence, independently, hydrogen or C 1 ~C 4 is alkyl, R b , R c , R e , and R f is, for each occurrence, independently selected from hydrogen, halogen, cyano, and C 1 ~C 4 C optionally substituted with 1 to 3 groups selected from alkoxy 1 ~C 4 is alkyl, R g and R h is, for each occurrence, independently, hydrogen, or halogen, cyano, C 1 ~C 4 Alkoxy, and -C(=O)NRi R j C optionally substituted with 1 to 3 groups selected from 1 ~C 4 alkyl, where R i and R j is, for each occurrence, independently, hydrogen or C 1 ~C 4 is alkyl, a, b, and c are each independently an integer selected from 1, 2, 3, and 4; R 1 , R 2 , and R 3 For each occurrence, halogen, cyano, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 1 ~C 6 Alkoxy, -C(=O)(C 1 ~C 6 alkyl), -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) w R s , -NO 2 , -NO 2 + , -NH(=O)OH, -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) w R s , -S(=O) w NR p R q , -SO 3 - , C 3 ~C12 each independently selected from carbocyclyl, 3- to 12-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl, R 1 , R 2 , and R 3 Either one of C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 1 ~C 6 Alkoxy and -C(=O)(C 1 ~C 6 Alkyl) C 1 ~C 6 Alkyl is halogen, cyano, -C(=O)R s , -C(=O)OR s , -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) w R s , -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) w R s , -S(=O) w NR p R q , C 3 ~C 6 optionally substituted with 1 to 3 groups selected from cycloalkyl, and phenyl optionally substituted with 1 to 3 halogen atoms; R 1 , R 2 , and R 3 Either one of C 3 ~C 12Carbocyclyl, 3- to 12-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl are each independently selected from halogen, cyano, C 1 ~C 4 Alkyl, -NR p R q , and -OR s and optionally substituted with 1 to 3 groups selected from R p , R q , and R r For each occurrence, hydrogen, C 1 ~C 4 Alkyl, and C 3 ~C 6 cycloalkyl, where R p , R q , and R r Either one of C 1 ~C 4 The alkyl is optionally substituted with one to three groups selected from halogen, cyano, and -OH; R s For each occurrence, hydrogen, C 1 ~C 4 Alkyl, and C 3 ~C 6 cycloalkyl, where R p , R q , and R r Either one of C 1 ~C 4 The alkyl is optionally substituted with one to three groups selected from halogen, cyano, and -OH; w is an integer selected from 1 and 2; R 1 may, for each occurrence, be attached, valence permitting, to any of the ring atoms in any of the two monocyclic rings that are fused together to form ring A in formula I; m is an integer selected from 0, 1, 2, 3, 4, 5, and 6; n is an integer selected from 1, 2, 3, 4, and 5; o is an integer selected from 0, 1, 2, and 3. is disclosed herein.

[0007] In one aspect of the disclosure, the compound of formula I is selected from compounds 1 to 23 shown below, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

[0008] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise a compound selected from compounds 1 to 23 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt thereof. These compositions may further comprise an additional active pharmaceutical agent.

[0009] Another aspect of the disclosure provides a method of treating a disease and / or a symptom of the disease (e.g., a respiratory tract infectious disease) caused by a coronavirus, comprising administering to a subject a therapeutically effective amount of a compound of Formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of treatment comprises administering to a subject a compound selected from compounds 1 to 23 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0010] In some embodiments, the method of treatment comprises administering an additional active pharmaceutical agent to a subject in need thereof, either in the same pharmaceutical composition as a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or in a separate composition. In some embodiments, the method of treatment comprises administering a compound selected from compounds 1 to 23 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, either in the same pharmaceutical composition or in a separate composition, together with the additional active pharmaceutical agent.

[0011] Also disclosed herein is a method of reducing or inhibiting coronavirus protease activity, comprising administering to a subject a therapeutically effective amount of a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of reducing or inhibiting coronavirus protease activity comprises administering to a subject a compound selected from compounds 1 to 23 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of reducing or inhibiting the activity of a coronavirus protease comprises contacting the coronavirus or the protease with a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of reducing or inhibiting the activity of a coronavirus protease comprises contacting the coronavirus or the protease with a compound selected from compounds 1 to 23 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0012] Further disclosed herein is a method of reducing or inhibiting coronavirus replication, comprising administering to a subject a therapeutically effective amount of a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of reducing or inhibiting coronavirus replication comprises administering to a subject a compound selected from compounds 1 to 23 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of reducing or inhibiting coronavirus replication comprises contacting the coronavirus or coronavirus protease with a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of reducing or inhibiting coronavirus replication comprises contacting the coronavirus or coronavirus protease with a compound selected from compounds 1 to 23 shown below, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. [Brief description of the drawings]

[0013] [Figure 1A] FIG. 1 shows the chemical structures of three inhibitors (FIG. 1A) and two analogues of compound 2 (FIG. 1B). [Figure 1B] FIG. 1 shows the chemical structures of three inhibitors (FIG. 1A) and two analogues of compound 2 (FIG. 1B). [Figure 2A] FIG. 2 shows NMR (FIG. 2A) and mass spectrometry (FIG. 2B) characterization data for compound I-1. [Figure 2B] FIG. 2 shows NMR (FIG. 2A) and mass spectrometry (FIG. 2B) characterization data for compound I-1. [Figure 3A] FIG. 3 shows NMR (FIG. 3A) and mass spectrometry (FIG. 3B) characterization data for compound I-2(1). [Figure 3B] FIG. 3 shows NMR (FIG. 3A) and mass spectrometry (FIG. 3B) characterization data for compound I-2(1). [Figure 4] FIG. 1 shows NMR characterization data for compound 2. [Figure 5A] FIG. 5 shows NMR (FIG. 5A) and mass spectrometry (FIG. 5B) characterization data for compound 10. [Figure 5B] FIG. 5 shows NMR (FIG. 5A) and mass spectrometry (FIG. 5B) characterization data for compound 10. [Figure 6A] FIG. 6 shows NMR (FIG. 6A) and mass spectrometry (FIG. 6B) characterization data for compound 23. [Figure 6B] FIG. 6 shows NMR (FIG. 6A) and mass spectrometry (FIG. 6B) characterization data for compound 23. [Figure 7A] Figure 7 shows the inhibitory activity of the compounds in Figure 1 against SARS-CoV-2 3CLpro. Using an in vitro enzyme assay, the half maximal inhibitory concentration (IC50) of compounds 1, 2, and 8 (Figure 7A) and two analogs of compound 2, namely compounds 10 and 23 (Figure 7B), was measured. [Figure 7B] Figure 7 shows the inhibitory activity of the compounds in Figure 1 against SARS-CoV-2 3CLpro. Using an in vitro enzyme assay, the half maximal inhibitory concentration (IC50) of compounds 1, 2, and 8 (Figure 7A) and two analogs of compound 2, namely compounds 10 and 23 (Figure 7B), was measured. [Figure 8A]Crystal structure of SARS-CoV-2 3CLpro complexed with compound 2. Figure 8A shows that compound 2 (sticks) binds to the catalytic pocket of 3CLpro. The surface electrostatic potential of 3CLpro was calculated by PyMol. Figure 8B shows the interaction between compound 2 and 3CLpro. Hydrogen bonds are represented by dashed lines. [Figure 8B] Crystal structure of SARS-CoV-2 3CLpro complexed with compound 2. Figure 8A shows that compound 2 (sticks) binds to the catalytic pocket of 3CLpro. The surface electrostatic potential of 3CLpro was calculated by PyMol. Figure 8B shows the interaction between compound 2 and 3CLpro. Hydrogen bonds are represented by dashed lines. [Figure 9A] Crystal structure of SARS-CoV-2 3CLpro complexed with compound 8. Figure 9A shows that compound 8 (sticks) binds to the catalytic pocket of 3CLpro. The surface electrostatic potential of 3CLpro was calculated by PyMol. Figure 9B shows the interaction between compound 8 and 3CLpro. Hydrogen bonds are represented by dashed lines. [Figure 9B] Crystal structure of SARS-CoV-2 3CLpro complexed with compound 8. Figure 9A shows that compound 8 (sticks) binds to the catalytic pocket of 3CLpro. The surface electrostatic potential of 3CLpro was calculated by PyMol. Figure 9B shows the interaction between compound 8 and 3CLpro. Hydrogen bonds are represented by dashed lines. [Figure 10A] Crystal structure of SARS-CoV-2 3CLpro complexed with compound 1. Figure 10A shows that compound 1 (stick) binds to the catalytic pocket of 3CLpro. The surface electrostatic potential of 3CLpro was calculated by PyMol. Figure 10B shows the interaction between compound 1 and 3CLpro. Hydrogen bonds are represented by dashed lines. [Figure 10B]Crystal structure of SARS-CoV-2 3CLpro complexed with compound 1. Figure 10A shows that compound 1 (stick) binds to the catalytic pocket of 3CLpro. The surface electrostatic potential of 3CLpro was calculated by PyMol. Figure 10B shows the interaction between compound 1 and 3CLpro. Hydrogen bonds are represented by dashed lines. [Figure 11A] Figure 11A shows the anti-SARS-CoV-2 activity (Figure 11A) and cytotoxicity effect (Figure 11B) of three inhibitors in A549 cells. [Figure 11B] Figure 11A shows the anti-SARS-CoV-2 activity (Figure 11A) and cytotoxicity effect (Figure 11B) of three inhibitors in A549 cells. [Figure 12A] Figure 12 shows the anti-SARS-CoV-2 activity of three inhibitors in VeroE6 cells (Figure 12A) and Calu3 cells (Figure 12B). [Figure 12B] Figure 12 shows the anti-SARS-CoV-2 activity of three inhibitors in VeroE6 cells (Figure 12A) and Calu3 cells (Figure 12B). [Figure 13] FIG. 1 shows an alignment of the amino acid sequences of the 3CL proteases of SARS-CoV-2 (SEQ ID NO: 1), SARS-CoV (SEQ ID NO: 2), and MERS-CoV (SEQ ID NO: 3). Residues within 5 Å of compound 2 in SARS-CoV-2 3CLpro are indicated by triangles. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Detailed Description I. Definition The terms "a" or "an," when referring to a noun as used herein, encompass "at least one," and thus encompass both the singular and plural units of the noun. For example, "an additional pharmaceutical agent" means a single or two or more additional pharmaceutical agents.

[0015] The term "coronavirus" as used herein refers to a group of related RNA viruses that cause disease in mammals and birds, such as a respiratory tract infectious disease that can range from mild to fatal in humans and birds, diarrhea in cattle and pigs, and hepatitis and encephalomyelitis in mice. Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome and a nucleocapsid with helical symmetry. They have characteristic club-like spikes protruding from their surface, which in electron micrographs evoke the image of a solar corona, from which the name is derived. Deadly variants of coronaviruses include those that can cause SARS (Severe Acute Respiratory Syndrome), MERS (Middle East Respiratory Syndrome), and COVID-19 (the infectious disease caused by Severe Acute Respiratory Syndrome coronavirus 2 or SARS-CoV-2).

[0016] As used herein, the term "inhibitor" refers to an inhibitor of 3C-like protease (3CL), the major protease of coronaviruses. pro 3C-like proteases cleave coronavirus polyproteins at multiple conserved sites with glutamine-serine / glutamine-alanine / glutamine-glycine peptide bonds and are important in the processing of coronavirus replicase polyprotein P0C6U8. Other examples of coronavirus proteases include papain-like protease PLpro, which is necessary for processing viral polyproteins to generate functional replicase complexes and allow the spread of the virus.

[0017] The term "compound", when referring to a compound of the present disclosure, refers to a collection of molecules having the same chemical structure, except that there may be isotopic variations between the constituent atoms of the molecule, unless otherwise indicated as a collection of stereoisomers (e.g., a collection of racemates, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers). Thus, it is clear to those skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom as indicated also contains a smaller amount of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in the structure. The relative amount of such isotopologues in the compounds of the present disclosure depends on several factors, including, for example, the isotopic purity of the reagents used to make the compound, and the efficiency of isotope incorporation in the various synthetic steps used to prepare the compound. However, as described above, the overall relative amount of such isotopologues is less than 49.9% of the compound. In other embodiments, the overall relative amount of such isotopologues is less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5% of the compounds.

[0018] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to a hydrogen radical in a given structure being replaced with a group of the specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when two or more positions in any given structure may be substituted with two or more substituents selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present disclosure are those that result in the formation of stable or chemically feasible compounds.

[0019] The term "isotopologues" refers to species whose chemical structures differ only in their isotopic composition. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention may include compounds that differ only in the presence of one or more isotopically enriched atoms, such as the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with isotope ions. 13 C or 14 Except for the replacement with C, it is within the scope of this disclosure.

[0020] Unless otherwise indicated, the structures depicted herein are also intended to include all isomeric forms of the structures, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds of the present invention are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0021] The term "tautomer" as used herein refers to one of two or more isomers of a compound that exist together in equilibrium and readily interchange by the movement of an atom, e.g., a hydrogen atom or group, within a molecule.

[0022] As used herein, "stereoisomer" refers to enantiomers and diastereomers.

[0023] As used herein, a "deuterated derivative" refers to a compound having the same chemical structure as a reference compound, except that one or more hydrogen atoms have been replaced with a deuterium atom ("D" or " 2It will be appreciated that some variation in natural isotopic abundance will occur in the synthesized compounds depending on the origin of the chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotope substitution of the deuterated derivatives described herein, despite this variation. Thus, unless otherwise stated, when referring to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen has been replaced with deuterium at a level well above its natural isotopic abundance, which is typically about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500 (67.5% deuterium incorporation at each designated deuterium), at least 5000 (75% deuterium incorporation at each designated deuterium), at least 5500 (82.5% deuterium incorporation at each designated deuterium), at least 6000 (90% deuterium incorporation at each designated deuterium), at least 6333.3 (95% deuterium incorporation at each designated deuterium), at least 6466.7 (97% deuterium incorporation at each designated deuterium), or at least 6600 (99% deuterium incorporation at each designated deuterium).

[0024] As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0025] The term "alkyl" as used herein means a straight or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group contains 1 to 20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1 to 10 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1 to 8 aliphatic carbon atoms. In some embodiments, an alkyl group contains 1 to 6 alkyl carbon atoms. In some embodiments, an alkyl group contains 1 to 4 alkyl carbon atoms. In other embodiments, an alkyl group contains 1 to 3 alkyl carbon atoms. In still other embodiments, an alkyl group contains 1 to 2 alkyl carbon atoms. In some embodiments, an alkyl group is substituted. In some embodiments, an alkyl group is unsubstituted. In some embodiments, an alkyl group is straight or linear or unbranched. In some embodiments, an alkyl group is branched.

[0026] The term "cycloalkyl" refers to a fully saturated monocyclic C 3~8 Hydrocarbon or spirocyclic, fused, or bridged bicyclic or tricyclic C 8~14 In some embodiments, the cycloalkyl group is a substituted or unsubstituted cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted or unsubstituted cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted or unsubstituted cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted or unsubstituted cycloalkyl group. In some embodiments, the cycloalkyl group is a substituted or unsubstituted cycloalkyl group. 3 From C 12 In some embodiments, cycloalkyl is C 3 From C 8 In some embodiments, cycloalkyl is C 3 From C 6 Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentanyl, and cyclohexyl.

[0027] The term "carbocyclyl" encompasses the term "cycloalkyl" and refers to monocyclic C alkyl groups that are fully saturated or that contain one or more units of unsaturation but are partially saturated such that they are not aromatic. 3~8 Hydrocarbon or spirocyclic, fused, or bridged bicyclic or tricyclic C 8~14 refers to a hydrocarbon, with any individual ring in said bicyclic ring system having 3 to 7 members. Bicyclic carbocyclyl includes, for example, a combination of a monocyclic carbocyclic ring fused to a phenyl. In some embodiments, the carbocyclyl group is substituted. In some embodiments, the carbocyclyl group is unsubstituted. In some embodiments, the carbocyclyl is C 3 From C 12 In some embodiments, the carbocyclyl is 3 From C 10 In some embodiments, the carbocyclyl is 3 From C 8 It is a carbocyclyl.

[0028] The term "alkenyl" as used herein refers to a straight or branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, an alkenyl group is substituted. In some embodiments, an alkenyl group is unsubstituted. In some embodiments, an alkenyl group is straight, linear, or unbranched. In some embodiments, an alkenyl group is branched.

[0029] The term "heterocyclyl" as used herein means a non-aromatic (i.e., fully saturated or containing one or more units of unsaturation but partially saturated as in the case of a non-aromatic), monocyclic, or spirocyclic, fused, or bridged bicyclic or tricyclic ring system in which one or more ring members are independently selected heteroatoms. Bicyclic heterocyclyls include, for example, the following combinations of monocyclic rings: monocyclic heteroaryl fused to a monocyclic heterocyclyl; monocyclic heterocyclyl fused to another monocyclic heterocyclyl; monocyclic heterocyclyl fused to a phenyl; monocyclic heterocyclyl fused to a monocyclic carbocyclyl / cycloalkyl; and monocyclic heteroaryl fused to a monocyclic carbocyclyl / cycloalkyl. In some embodiments, a "heterocyclyl" group contains 3 to 14 ring members, where one or more ring members are heteroatoms independently selected from, for example, oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, a heterocyclic ring has at least one unsaturated carbon-carbon bond. In some embodiments, a heterocyclic ring has at least one unsaturated carbon-nitrogen bond. In some embodiments, a heterocyclic ring has one heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, a heterocyclic ring has one heteroatom that is a nitrogen atom. In some embodiments, a heterocyclic ring has one heteroatom that is an oxygen atom. In some embodiments, a heterocyclic ring has two heteroatoms each independently selected from nitrogen and oxygen. In some embodiments, a heterocyclic ring has three heteroatoms each independently selected from nitrogen and oxygen. In some embodiments, a heterocyclic ring is substituted. In some embodiments, a heterocyclic ring is unsubstituted. In some embodiments, the heterocyclyl is a 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl is a 3- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 4- to 9-membered heterocyclyl, e.g., a 4- to 9-membered heterocyclyl containing at least one N atom and optionally at least one O atom.In some embodiments, the heterocyclyl is a 5- to 10-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- to 8-membered heterocyclyl. In some embodiments, the heterocyclyl is a 5- or 6-membered heterocyclyl. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl. Non-limiting examples of monocyclic heterocyclyls include piperidinyl, piperazinyl, tetrahydropyranyl, azetidinyl, tetrahydrothiophenyl 1,1-dioxide, and the like.

[0030] The term "heteroatom" means one or more of oxygen, sulfur, and nitrogen, including any oxidized form of nitrogen or sulfur; the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in the case of N-substituted pyrrolidinyl).

[0031] As used herein, the term "unsaturated" means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a situation in which not all of the available valence bonds in a compound are satisfied by substituents, thus causing the compound to contain one or more double or triple bonds.

[0032] The term "alkoxy," as used herein, refers to an alkyl group, as defined above, in which one carbon of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is linked between two carbon atoms.

[0033] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.

[0034] As used herein, a "cyano" or "nitrile" group refers to --C.ident.N.

[0035] As used herein, "aromatic ring" refers to a carbocyclic or heterocyclic ring containing a conjugated planar ring system with a delocalized π-electron orbital composed of [4n+2] p-orbital electrons, where n is an integer from 0 to 6. A "non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the requirements set forth above for aromatic rings and can be either fully saturated or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, which are further defined below.

[0036] The term "aryl," used alone or as part of a larger moiety, as in "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic or spirocyclic, fused, or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, in which all rings are aromatic rings containing only carbon atoms, and in which each ring in a bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C 6 ) and naphthyl (C 10 ) ring. In some embodiments, an aryl group is substituted. In some embodiments, an aryl group is unsubstituted.

[0037] The term "heteroaryl" refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Bicyclic heteroaryls include, for example, the following combinations of monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to phenyl. Non-limiting examples of bicyclic heteroaryls are isoquinolinyl, quinolinyl, quinazolinyl, phthalazinyl, purinyl, and 1H-pyrrolo[2,3-c]pyridinyl. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected from, for example, nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has one heteroatom. In some embodiments, the heteroaryl group has two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic ring system having 5 ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having 6 ring members. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl is a 3- to 12-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 3- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 8-membered heteroaryl. In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. Non-limiting examples of monocyclic heteroaryls are pyridinyl, pyrimidinyl, thiophenyl, thiazolyl, isoxazolyl, and the like.

[0038] Non-limiting examples of suitable solvents that may be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or “methylene chloride” (CH2 Cl 2 ), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et 2 O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0039] Non-limiting examples of suitable bases that may be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K 2 CO 3 ), N-methylmorpholine (NMM), triethylamine (Et 3 N;TEA), diisopropyl-ethylamine (i-Pr 2 EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH) and sodium methoxide (NaOMe; NaOCH 3 ).

[0040] Pharmaceutically acceptable salts of the disclosed compounds are disclosed herein. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0041] The term "pharmaceutically acceptable" as used herein refers to a component that is suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" refers to any non-toxic salt that is capable of imparting, directly or indirectly, the compound of the present disclosure upon administration to a recipient. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al., J. Pharmaceutical Sciences, 1977, Vol. 66, pp. 1-19.

[0042] Acids commonly used to form pharma-ceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharma- ceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexyrate-1,5-diol, hexyrate-1,6-diol, hexyrate-1,7-diol, hexyrate-1,8-diol, hexyrate-1,9-diol, hexyrate-1,10-diol, hexyrate-1,11-diol, hexyrate-1,2-diol, hexyrate-1,3-diol, hexyrate-1,4-diol, hexyrate-1,5-diol, hexyrate-1,6-diol, hexyrate-1,7-diol, hexyrate-1,8-diol, hexyrate-1,9-diol, hexyrate-1,11-diol, hexyrate-1,1 ...13-diol, hexyrate-1,4-diol, hexyrate-1,4-diol, hexy ,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and other salts. In some embodiments, pharma- ceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, as well as those formed with organic acids such as maleic acid.

[0043] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1~4 Alkyl) 4The present disclosure also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cations formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate, and arylsulfonate. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0044] The term "subject" refers to animals, including humans.

[0045] The term "therapeutically effective amount" refers to an amount of a compound that produces the desired effect for which the compound is administered (e.g., amelioration of coronavirus-caused disease and / or symptoms, reduction in severity of coronavirus-caused disease and / or symptoms, and / or reduction in progression of coronavirus-caused disease and / or symptoms). The exact amount of a therapeutically effective amount depends on the purpose of the treatment and can be determined by the skilled artisan using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0046] As used herein, the term "treatment" and its cognates refer to slowing or stopping disease progression. As used herein, "treatment" and its cognates include, but are not limited to, complete or partial remission, cure of a disease caused by coronavirus, reducing the risk of disease and / or symptoms of disease caused by coronavirus. Improvement or reduction in severity of any of these symptoms can be determined according to methods and techniques known in the art.

[0047] The terms "about" and "approximately," when used in connection with numbers, such as percentages, include the specified number as well as a range of numbers (eg, a percentage range) recognized by one of ordinary skill in the art.

[0048] II. Compounds and Compositions In a first embodiment, the compound of the present disclosure has the following structural formula I: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, Ar is phenyl or 6-membered heteroaryl; Ring A is a 9- or 10-membered heteroaryl, where V 1 , V 2 , V 3 , and V 4 are each absent, -CH-, or N, V 1 , V 2 , V 3 , and V 4 may be absent, W 1 , W 2 , W 3 , and W 4 If one of is absent, V 1 , V 2 , V 3 , and V 4 None of these can be absent, W 1 , W 2 , W 3 , and W 4 are each absent, -CH-, or N, W 1 , W 2 , W 3 , and W 4 may be absent, W 1 , W 2 , W 3 , and W4 At least one of must be N, X is absent or -NR a -, or -NR a (CR b R c ) a - and Y is absent or C 3 ~C 12 carbocyclyl, 3- to 12-membered heterocyclyl, or 5- to 10-membered heteroaryl, 3 ~C 12 Carbocyclyl, Y 3- to 12-membered heterocyclyl, and Y 5- to 10-membered heteroaryl each have o R 3 is substituted with a group, Z is absent or -NR d -, -(CR e R f ) b NR d - or -C(=O)NR d (CR g R h ) c -where: R a and R d is, for each occurrence, independently, hydrogen or C 1 ~C 4 is alkyl, R b , R c , R e , and R f is, for each occurrence, independently selected from hydrogen, halogen, cyano, and C 1 ~C 4 C optionally substituted with 1 to 3 groups selected from alkoxy 1 ~C 4 is alkyl, R g and R h is, for each occurrence, independently, hydrogen, or halogen, cyano, C 1 ~C 4 Alkoxy, and -C(=O)NR i R jC optionally substituted with 1 to 3 groups selected from 1 ~C 4 alkyl, where R i and R j is, for each occurrence, independently, hydrogen or C 1 ~C 4 is alkyl, a, b, and c are each independently an integer selected from 1, 2, 3, and 4; R 1 , R 2 , and R 3 For each occurrence, halogen, cyano, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 1 ~C 6 Alkoxy, -C(=O)(C 1 ~C 6 alkyl), -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) w R s , -NO 2 , -NO 2 + , -NH(=O)OH, -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) w R s , -S(=O) w NR p R q , -SO 3 - , C 3 ~C 12each independently selected from carbocyclyl, 3- to 12-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl, R 1 , R 2 , and R 3 Either one of C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, and C 1 ~C 6 Alkoxy and -C(=O)(C 1 ~C 6 Alkyl) C 1 ~C 6 Alkyl is halogen, cyano, -C(=O)R s , -C(=O)OR s , -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s , -NR p C(=O)OR s , -NR p C(=O)NR q R r , -NR p S(=O) w R s , -OR s , -OC(=O)R s , -OC(=O)OR s , -OC(=O)NR p R q , -S(=O) w R s , -S(=O) w NR p R q , C 3 ~C 6 optionally substituted with 1 to 3 groups selected from cycloalkyl, and phenyl optionally substituted with 1 to 3 halogen atoms; R 1 , R 2 , and R 3 Either one of C 3 ~C 12Carbocyclyl, 3- to 12-membered heterocyclyl, phenyl, and 5- to 10-membered heteroaryl are each independently selected from halogen, cyano, C 1 ~C 4 Alkyl, -NR p R q , and -OR s and optionally substituted with 1 to 3 groups selected from R p , R q , and R r For each occurrence, hydrogen, C 1 ~C 4 Alkyl, and C 3 ~C 6 cycloalkyl, where R p , R q , and R r Either one of C 1 ~C 4 The alkyl is optionally substituted with one to three groups selected from halogen, cyano, and -OH; R s For each occurrence, hydrogen, C 1 ~C 4 Alkyl, and C 3 ~C 6 cycloalkyl, where R p , R q , and R r Either one of C 1 ~C 4 The alkyl is optionally substituted with one to three groups selected from halogen, cyano, and -OH; w is an integer selected from 1 and 2; R 1 may, for each occurrence, be attached, valence permitting, to any of the ring atoms in any of the two monocyclic aromatic rings that are fused together to form ring A in formula I; m is an integer selected from 0, 1, 2, 3, 4, 5, and 6; n is an integer selected from 1, 2, 3, 4, and 5; o is an integer selected from 0, 1, 2, and 3. It is.

[0049] In one embodiment, in Formula I, Ar is phenyl, pyridinyl, or pyrimidinyl, each of which is selected from m R 1 In one embodiment, in formula I, Ar is optionally substituted with m R 1 and all other variables not specifically defined herein are as defined in the first embodiment.

[0050] In one embodiment, in Formula I, ring A is isoquinolinyl, quinolinyl, quinazolinyl, phthalazinyl, purinyl, or 1H-pyrrolo[2,3-c]pyridinyl, each of which is selected from m R 1 All other variables that are optionally substituted with groups and not specifically defined herein are as defined in the first embodiment.

[0051] In one embodiment, in formula I, ring A is selected from m R 1 isoquinolinyl optionally substituted with a group, V 1 , V 2 , V 3 , and V 4 are all -CH-, W 2 is N, W 1 , W 3 , and W 4 is -CH-, All other variables not specifically defined herein are as defined above.

[0052] In one embodiment, in formula I, ring A is selected from m R 1 quinolinyl optionally substituted with a group, V 1 , V 2 , V 3, and V 4 are all -CH-, W 1 is N, W 2 , W 3 , and W 4 is -CH-, All other variables not specifically defined here are as defined in the first embodiment.

[0053] In one embodiment, in formula I, ring A is selected from m R 1 quinazolinyl optionally substituted by a group, V 1 , V 2 , V 3 , and V 4 are all -CH-, W 2 is -CH-, W 1 , W 3 , and W 4 is N, All other variables not specifically defined here are as defined in the first embodiment.

[0054] In one embodiment, in formula I, ring A is selected from m R 1 phthalazinyl optionally substituted with a group, V 1 , V 2 , V 3 , and V 4 are all -CH-, W 1 is -CH-, W 2 , W 3 , and W 4 is N, All other variables not specifically defined here are as defined in the first embodiment.

[0055] In one embodiment, in formula I, ring A is selected from m R 1 purinyl optionally substituted with a group, V 1 and V 3 are all N and V 2 and V 4 is -CH-; or V 1 and V 3 are all -CH- and V 2 and V 4 is N, W 1 is absent, W 2 is -CH-, W 1 and W 3 is N, All other variables not specifically defined here are as defined in the first embodiment.

[0056] In one embodiment, in formula I, ring A is selected from m R 1 purinyl optionally substituted with a group, V 1 is absent, V 3 is -CH-, V 2 and V 4 is N, W 1 and W 3 is -CH- and W 2 and W 4 is N; or, W 1 and W 3 is N and W 2 and W 4 is -CH-, All other variables not specifically defined here are as defined in the first embodiment.

[0057] In one embodiment, in formula I, ring A is selected from m R 1 1H-pyrrolo[2,3-c]pyridinyl optionally substituted with a group, V 4 is absent, V 1 is N, V2 and V 3 is -CH-, W 3 is N, W 1 , W 2 , and W 4 is -CH-, All other variables not specifically defined here are as defined in the first embodiment.

[0058] In one embodiment, in formula I, ring A is selected from m R 1 1H-pyrrolo[2,3-c]pyridinyl optionally substituted with a group, V 4 is absent, V 3 is N, V 1 and V 2 is -CH-, W 2 is N, W 1 , W 3 , and W 4 is -CH-, All other variables not specifically defined here are as defined in the first embodiment.

[0059] In one embodiment, in formula I, ring A is selected from m R 1 1H-pyrrolo[2,3-c]pyridinyl optionally substituted with a group, V 3 is N, V 1 , V 2 , and V 4 is -CH-, W 1 is absent, W 2 is N, W 3 and W 4 is -CH-, All other variables not specifically defined here are as defined in the first embodiment.

[0060] In a second embodiment, the compound of the present disclosure has the following structural formula II: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in the preceding embodiments.

[0061] In a third embodiment, the compound of the present disclosure has the following structural formula IIIa: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0062] In a fourth embodiment, the compound of the present disclosure has the following structural formula IVa: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, R b and R c is, for each occurrence, independently selected from hydrogen, halogen, cyano, and C 1 ~C 4 C optionally substituted with 1 to 3 groups selected from alkoxy 1 ~C 2 is alkyl, a is an integer selected from 1 and 2; All other variables not specifically defined herein are as defined in any one of the preceding embodiments. It is.

[0063] In a fifth embodiment, the compound of the present disclosure has the following structural formula Va: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein n is an integer selected from 1, 2, 3, and 4, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0064] In a sixth embodiment, in the compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Y is C 3 ~C 12 cycloalkyl or 3- to 12-membered heterocyclyl, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0065] In a seventh embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R a , R b , R c , R d , R e , and R f is, for each occurrence, independently, hydrogen or C 1 ~C 2 is alkyl, R g and R h is, for each occurrence, independently, hydrogen or -C(=O)NR i R j Optionally replaced by C 1 ~C 2 alkyl, where R i and R j is, for each occurrence, independently, hydrogen or C 1 ~C2 is alkyl, a, b, and c are each independently an integer selected from 1 and 2; All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0066] In an eighth embodiment, the compound of the present disclosure has the following structural formula IIIb-1: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, Y is C 3 ~C 10 is cycloalkyl, o is an integer selected from 0 and 1; All other variables not specifically defined herein are as defined in any one of the preceding embodiments. It is.

[0067] In a ninth embodiment, the compound of the present disclosure has the following structural formula IVb-1: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, Y is C 3 ~C 6 is cycloalkyl, n is an integer selected from 1, 2, 3, and 4; All other variables not specifically defined herein are as defined in any one of the first, sixth, seventh, and eighth embodiments. It is.

[0068] In a tenth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, Y is cyclohexyl, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0069] In an eleventh embodiment, the compound of the present disclosure has the following structural formula IIIb-2: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, Y is a 3- to 10-membered heterocyclyl containing at least one N atom and optionally at least one other heteroatom selected from O and S; At least one of T and U is N; o is an integer selected from 0, 1, and 2; All other variables not specifically defined herein are as defined in any one of the preceding embodiments. It is.

[0070] In a twelfth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, X is absent, -NH-, or -NHCH 2 - and Z is absent, -NH-, -[CH(CH(CH 3 ) 2 ]NH-, or -C(=O)NHCH[(CONHCH 3 )CH 2 ]-- and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0071] In a thirteenth embodiment, the compound of the present disclosure has the following structural formula IVb-2: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, Y is a 4- to 9-membered heterocyclyl containing at least one N atom and optionally at least one O atom; At least one of T and U is N; R 2’ is halogen, cyano, -NO 2 + , -NH(=O)OH, or -SO 3 - and n is an integer selected from 1, 2, 3, and 4; o is an integer selected from 0 and 1; All other variables not specifically defined herein are as defined in any one of the preceding embodiments. It is.

[0072] In a fourteenth embodiment, the compound of the present disclosure has the following structural formula Vb-2: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0073] In a fifteenth embodiment, in the compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the disclosure, Y is azetidinyl, piperidinyl, piperazinyl, 2,7-diazaspiro[4.4]nonanyl, octahydrocyclopenta[c]pyrrolyl, 2-oxa-6-azaspiro[3.4]octanyl, or octahydro-1H-isoindolyl, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0074] In a sixteenth embodiment, the compound of the present disclosure has the following structural formula IIIc: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, R 2’ is halogen, cyano, -NO 2 + , -NH(=O)OH, or -SO 3 - and n is an integer selected from 1, 2, 3, and 4; All other variables not specifically defined herein are as defined in any one of the preceding embodiments. It is.

[0075] In a seventeenth embodiment, the compound of the present disclosure has the following structural formula IVc: [ka] or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, R 2’’ is halogen or C 1 ~C 4 is alkyl, R 2’’’ is -C(=O)NR p Rq where: R p and R q are each independently hydrogen or C 1 ~C 4 is alkyl, All other variables not specifically defined herein are as defined in any one of the preceding embodiments. It is.

[0076] In an eighteenth embodiment, a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, wherein: R 2’’ is F, Cl, Br or C 1 ~C 2 is alkyl, R 2’’’ is -C(=O)NR p R q where: R p and R q are each independently hydrogen or C 1 ~C 2 is alkyl, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0077] In a nineteenth embodiment, a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, wherein: R 2’’ -Br or -CH 3 and R 2’’’ is -C(=O)NHCH 3 and All other variables not specifically defined here are as defined in any one of the seventeenth and eighteenth embodiments.

[0078] In a twentieth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 For each occurrence, halogen, cyano, C1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy, -C(=O)(C 1 ~C 4 alkyl), -C(=O)NR p R q , -NR p R q , and -OR s are independently selected from R 1 C 1 ~C 4 Alkyl and C 1 ~C 4 Alkoxy and -C(=O)(C 1 ~C 4 Alkyl) C 1 ~C 4 Alkyl is independently halogen, cyano, or -OR. s and optionally substituted with 1 to 3 groups selected from R p and R q For each occurrence, hydrogen and C 1 ~C 2 each independently selected from alkyl, R s For each occurrence, hydrogen and C 1 ~C 2 independently selected from alkyl, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0079] In a twenty-first embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 For each occurrence, F, Cl, Br, C 1 ~C 2 Alkyl, and -OR s are independently selected from R 1 C 1 ~C 2 The alkyl is optionally substituted with 1 to 3 halogen groups; Rs For each occurrence, hydrogen and C 1 ~C 2 independently selected from alkyl, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0080] In a twenty-second embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 1 is independently selected for each occurrence from F and -OH, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0081] In a twenty-third embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 3 For each occurrence, halogen, cyano, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy, -C(=O)(C 1 ~C 4 alkyl), -C(=O)NR p R q , -NR p R q , -OR s and phenyl, R 3 C 1 ~C 4 Alkyl and C 1 ~C 4 Alkoxy and -C(=O)(C 1 ~C 4 Alkyl) C 1 ~C 4 Alkyl is halogen, cyano, -OR s and phenyl optionally substituted with 1 to 3 halogen atoms; R 3 The phenyl in 1 ~C2 optionally substituted with 1 to 3 groups selected from alkyl; R p and R q For each occurrence, hydrogen and C 1 ~C 2 each independently selected from alkyl, R s For each occurrence, hydrogen and C 1 ~C 2 independently selected from alkyl, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0082] In a twenty-fourth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 3 For each occurrence, F, Cl, Br, C 1 ~C 2 Alkyl, -OR s and phenyl, R 3 C 1 ~C 2 the alkyl is optionally substituted with one to three groups selected from halogen, cyano, and phenyl optionally substituted with one to three halogen atoms; R s For each occurrence, hydrogen and C 1 ~C 2 independently selected from alkyl, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0083] In a twenty-fifth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 3 is independently selected for each occurrence from -OH, phenyl, and 2,4-dichloro-1-methylbenzene, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0084] In a twenty-sixth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 2 For each occurrence, halogen, cyano, C 1 ~C 4 Alkyl, C 1 ~C 4 Alkoxy, -C(=O)(C 1 ~C 4 alkyl), -C(=O)NR p R q , -NR p R q , -NO 2 , -NO 2 + , -NH(=O)OH, -OR s , and -SO 3 - are independently selected from R 2 C 1 ~C 4 Alkyl and C 1 ~C 4 Alkoxy and -C(=O)(C 1 ~C 4 Alkyl) C 1 ~C 4 Alkyl is halogen, cyano, -OR s and optionally substituted with 1 to 3 groups selected from R p and R q For each occurrence, hydrogen and C 1 ~C 2 each independently selected from alkyl, R s For each occurrence, hydrogen and C 1 ~C 2 independently selected from alkyl, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0085] In a twenty-seventh embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R2 For each occurrence, F, Cl, Br, cyano, C 1 ~C 2 Alkyl, -C(=O)NR p R q , -NO 2 , -NO 2 + , -NH(=O)OH, -OR s , and -SO 3 - are independently selected from R 2 C 1 ~C 2 The alkyl is optionally substituted with 1 to 3 halogen groups; R p and R q For each occurrence, hydrogen and -CH 3 are each independently selected from R s For each occurrence, hydrogen and C 1 ~C 2 independently selected from alkyl, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0086] In a twenty-eighth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 2 For each occurrence, Br, -CH 3 , -C(=O)NHCH 3 , -NO 2 + , -NH(=O)OH, and -SO 3 - All other variables independently selected from and not specifically defined herein are as defined in any one of the preceding embodiments.

[0087] In a twenty-ninth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 2 For each occurrence, halogen, cyano, C 1 ~C 4Alkyl, C 1 ~C 4 Alkoxy, -C(=O)(C 1 ~C 4 alkyl), -C(=O)NR p R q , -NR p R q , and -OR s are independently selected from R 2 C 1 ~C 4 Alkyl and C 1 ~C 4 Alkoxy and -C(=O)(C 1 ~C 4 Alkyl) C 1 ~C 4 Alkyl is halogen, cyano, -OR s and optionally substituted with 1 to 3 groups selected from R p and R q For each occurrence, hydrogen and C 1 ~C 2 each independently selected from alkyl, R s For each occurrence, hydrogen and C 1 ~C 2 independently selected from alkyl, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0088] In a thirtieth embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 2 For each occurrence, F, Cl, Br, cyano, C 1 ~C 2 Alkyl, -C(=O)NR p R q , and -OR s are independently selected from R 2 C 1 ~C 2 The alkyl is optionally substituted with 1 to 3 halogen groups; R p and R q For each occurrence, hydrogen and -CH 3 are each independently selected from R s For each occurrence, hydrogen and C 1 ~C 2 independently selected from alkyl, All other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0089] In a thirty-first embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the present disclosure, R 2 For each occurrence, Br, -CH 3 , and -C(=O)NHCH 3 All other variables independently selected from and not specifically defined herein are as defined in any one of the preceding embodiments.

[0090] In a thirty-second embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the disclosure, m is an integer selected from 0 and 1, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0091] In a thirty-third embodiment, in a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of the disclosure, m is an integer selected from 1 and 2, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0092] In certain embodiments, at least one compound of the present disclosure is selected from compounds 1 to 23 depicted in Table 1, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing. [Table 1-1] [Table 1-2] [Table 1-3]

[0093] Another aspect of the disclosure provides a pharmaceutical composition comprising at least one compound selected from a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of said compounds or said tautomers, or pharma- ceutically acceptable salts of the foregoing, and at least one pharma- ceutically acceptable carrier.

[0094] In some embodiments, the pharma- ceutically acceptable carrier is selected from a pharma- ceutically acceptable vehicle and a pharma-ceutically acceptable adjuvant. In some embodiments, the pharma-ceutically acceptable carrier is selected from a pharma-ceutically acceptable filler, a disintegrant, a surfactant, a binder, and a lubricant.

[0095] It is also understood that the pharmaceutical composition of the present disclosure can be used in combination therapy; that is, the pharmaceutical composition described herein can further comprise an additional active pharmaceutical agent. Alternatively, the pharmaceutical composition comprises a compound selected from the compounds of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of said compounds or said tautomers, or pharma- ceutically acceptable salts of the foregoing. The pharmaceutical composition comprising any of the foregoing can be administered as a separate composition, simultaneously with, before, or after a composition comprising an additional active pharmaceutical agent.

[0096] As described above, the pharmaceutical composition disclosed herein comprises a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be selected from adjuvants and vehicles. The pharmaceutically acceptable carrier used herein can be selected from, for example, any solvent, diluent, other liquid vehicle, dispersing aid, suspending aid, surface active agent, isotonicity agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the specific dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, for example, by producing any undesirable biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharma- ceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethylcellulose), and the like. sodium cellulose, ethylcellulose, and cellulose acetate), powdered tragacanth, agave, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, releasing agents, coating agents, sweeteners, flavorings, fragrances, preservatives, and antioxidants.

[0097] III. Methods of Treatment and Uses In another aspect of the disclosure, the compounds, tautomers, deuterative derivatives, or pharma- ceutically acceptable salts described herein, e.g., compounds of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in treating disease and / or disease symptoms caused by a coronavirus. In another aspect, disclosed herein is the use of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt as described herein, e.g., a compound of Formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease and / or a symptom of the disease caused by a coronavirus. In yet another aspect, disclosed herein is a method of treating a disease and / or a symptom of a disease in a subject, comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt described herein, e.g., a compound of Formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof.

[0098] In some embodiments, the coronavirus-caused disease is a respiratory tract infection. In some embodiments, the coronavirus-caused disease is severe acute respiratory syndrome. In one embodiment, the coronavirus-caused disease is COVID-19. In one embodiment, the disease is caused by a coronavirus that is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In some embodiments, the coronavirus-caused disease symptoms are selected from fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or generalized pain, headache, new loss of taste or smell, sore throat, nasal congestion or runny nose, nausea or vomiting, diarrhea, persistent chest pain or pressure, new confusion, awakening or inability to stay awake, bluish lips or face, and combinations thereof.

[0099] In another aspect of the disclosure, the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts described herein, e.g., compounds of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in reducing or inhibiting the activity of coronavirus protease. In another aspect, disclosed herein is the use of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt as described herein, e.g., a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for reducing or inhibiting the activity of a coronavirus protease. In yet another aspect, disclosed herein is a method of reducing or inhibiting coronavirus protease activity, comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt described herein, e.g., a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof.In yet another aspect, disclosed herein is a method of reducing or inhibiting the activity of a coronavirus protease, comprising contacting said coronavirus or said protease with a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described herein, such as a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof. In one embodiment, the coronavirus protease is a 3C-like protease. In one embodiment, the coronavirus is SARS-CoV-2.

[0100] In another aspect of the disclosure, the compounds, tautomers, deuterated derivatives, or pharma- ceutically acceptable salts described herein, e.g., compounds of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in reducing or inhibiting coronavirus replication. In another aspect, disclosed herein is the use of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt as described herein, e.g., a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for reducing or inhibiting coronavirus replication. In yet another aspect, disclosed herein is a method of reducing or inhibiting coronavirus replication, comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt described herein, e.g., a compound of Formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, a tautomer thereof, a deuterated derivative of the compound or the tautomer, or a pharma- ceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof. In yet another aspect, disclosed herein is a method of reducing or inhibiting coronavirus replication, comprising contacting said coronavirus or coronavirus protease with a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt described herein, e.g., a compound of Formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof.In one embodiment, the coronavirus protease is a 3C-like protease. In one embodiment, the coronavirus is SARS-CoV-2.

[0101] A compound of Formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, may be administered once daily, twice daily, or three times daily, e.g., for the treatment of disease and / or symptoms of disease caused by a coronavirus, e.g., SARS-CoV-2.

[0102] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, is administered once daily, twice daily, or three times daily.

[0103] The compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of the compound or the tautomers, or pharma- ceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, may be administered, for example, orally, parenterally, sublingually, topically, rectally, nasally, bucally, intravaginally, transdermally, by patch, pump administration, or via an implanted reservoir, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration may be by continuous infusion over a selected period of time. Other dosage forms contemplated in the present disclosure are as described in International Patent Applications Nos. WO2013 / 075083, WO2013 / 075084, WO2013 / 078320, WO2013 / 120104, WO2014 / 124418, WO2014 / 151142, and WO2015 / 023915. EXAMPLES

[0104] In order that the disclosure set forth herein may be more fully understood, the following examples are disclosed herein. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any manner.

[0105] Example 1 Screening for 3CLpro inhibitors A series of non-covalent binders of SARS-CoV-2 3CLpro were identified by affinity screening and then scored by docking them into the substrate-binding pocket of 3CLpro; three of these molecules that ranked highly in the molecular docking studies were synthesized (Figure 1A).

[0106] Example 2 Synthesis of exemplary compounds The compounds of the disclosure can be made according to standard chemical practices or as described herein, including the following synthetic schemes and descriptions for the preparation of a compound selected from the compounds of formula I, IIa, IIb-1, IIb-2, IIc, IIIa, IIIb-1, IIIb-2, IIIc, IVa, or IVb-2, compounds 1 to 23, tautomers thereof, deuterated derivatives of the compounds or tautomers, or pharma- ceutically acceptable salts of the foregoing.

[0107] General Scheme Compounds of formula I can be prepared using the exemplary synthetic procedures illustrated in General Schemes A through D below. Variables not specifically defined in General Schemes A through D, such as R 1 , R 2 , R 3 , V 1 , V 2 , V 3 , V 4 , W 1 , W 2 , W 3 , W 4 , m, n, and o, etc. are as defined in formula I in the present disclosure.

[0108] General Scheme A [ka]

[0109] General Scheme B [ka]

[0110] General Scheme C [ka]

[0111] General Scheme D [ka]

[0112] The reagents and conditions for steps a to d illustrated in General Schemes A to D are: (a) DIPEA, dimethylformamide (DMF), 80 °C, 16 h; (b) 3M hydrogen chloride-ethyl acetate (HCl EA), CH 2 Cl 2 , 1 hour; (c) HATU, DIPEA, DMF, room temperature, 12 hours.

[0113] Compound 2 and analogues Compounds 10, 18, 19, 20, 21, 22, 23 Using compound 2 and its analogs (e.g., compounds 10, 18, 19, 23) as representative examples, the process for preparing compounds of formula I includes the general reaction steps described in Scheme 1. The wavy bonds shown in the molecules in Scheme 1, such as compounds I-2 and I-3, [ka] The stereochemistry of the bond is undefined, as in compounds 18 and 19 (e.g., [ka] which means [ka] (which may be a racemic mixture of) or, as in the case of compounds 2, 10, and 23 [ka] Additional compound 2 analogs, such as compounds 20, 21, and 22, can be prepared by modifying the synthetic procedure depicted in Scheme 1, as described further below.

[0114] Scheme 1: Preparation of compounds 2, 10, 18, 19, and 23 [ka]

[0115] The reagents and conditions for steps a through d illustrated in Scheme 1 and described further below are: (a) 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), CH 2 Cl 2 or dichloromethane (DCM), 0 °C, 2 h; (b) DIPEA, dimethylformamide (DMF), 80 °C, 16 h; (c) 3M hydrogen chloride-ethyl acetate (HCl EA), CH 2 Cl 2 , 1 hour; (d) HATU, DIPEA, DMF, room temperature, 12 hours.

[0116] Step a: Synthesis of N-methyl-5-bromo-2-fluoro-3-nitrobenzamide (I-1) A solution of 5-bromo-2-fluoro-3-nitrobenzoic acid (0.8 g, 3.80 mmol) in dichloromethane (20 mL) was stirred at 0° C. Then, HATU (2.0 g, 5.25 mmol), DIPEA (1.88 ml, 11.4 mmol) and methylamine hydrochloride (0.31 g, 4.5 mmol) were added to the reaction. The mixture was stirred at 0° C. for 2 hours, when the mixture became clear. The mixture was extracted three times with dichloromethane and the combined organic layers were washed with saturated brine solution. The organic phase was then washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under vacuum. Finally, the mixture was purified by chromatography to give compound I-1 as a yellow solid (0.8 g, 76% yield). 1 H NMR (500 MHz, CDCl 3) δ 8.48 (dd, J = 5.5, 2.5 Hz, 1H), 8.26 (dd, J = 6.5, 2.5 Hz, 1H), 6.62 (s, 1H), 3.07 (d, J = 4.8 Hz, 3H). ESI-MS: m / z 276.87 [M+H] + NMR and mass spectrometry characterization data for compound I-1 are presented in Figures 2A and 2B.

[0117] Step b: Synthesis of tert-butyl-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)carbamate (I-2) A solution of compound I-1 (0.8 g, 2.9 mmol) in DMF (15 mL) was stirred at room temperature. tert-Butyl ((1S,2R)-2-aminocyclohexyl)carbamate (0.75 g, 3.5 mmol) (the corresponding stereoisomer of this reagent can be used to synthesize the stereoisomer of compound I-2 (1)) and DIPEA (1.44 ml, 8.7 mmol) were then added to the reaction. The mixture was warmed to 80° C. and stirred for 16 hours. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with saturated brine solution. The organic phase was then washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo to give compound I-2(1) as a yellow solid without further purification. Yellow Solid. [ka]

[0118] 1H NMR (600 MHz, DMSO) δ 8.64 (d, J = 4.5 Hz, 1H), 8.17 (d, J = 2.4 Hz, 1H), 8.06 (d, J = 9.9 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 6.87 (d, J = ESI-MS: m / z 371.00 [M-Boc+H] + . The NMR and mass spectrometry characterization data for compound I-2(1) are presented in Figures 3A and 3B.

[0119] Step c: Synthesis of 2-(2-aminocyclohexyl)amino)-5-bromo-N-methyl-3-nitrobenzamide hydrochloride (I-3) A solution of compound I-2(1) (90 mg, 0.19 mmol) (or corresponding stereoisomer) in anhydrous dichloromethane (6 mL) was stirred at room temperature. Then, HCl (4 mL, 3 M in ethyl acetate) was added. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to give compound I-3 as a yellow solid without further purification.

[0120] Step d: Synthesis of N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)iso-quinoline-4-carboxamide (compound 2), N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-7-hydroxyisoquinoline-4-carboxamide (compound 10), or N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)-5-hydroxyisoquinoline-4-carboxamide (compound 23) A solution of the corresponding isoquinoline-4-carboxylic acid (1 equiv.) and HATU (1.5 equiv.) in anhydrous DMF (6 mL) was stirred at room temperature. Compound I-3 and DIPEA (5.0 equiv.) were then added. The mixture was stirred at room temperature overnight. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with saturated brine solution. The organic phase was then washed with anhydrous Na 2 SO 4 The mixture was then dried at 40° C. and concentrated under vacuum. Finally, the mixture was purified by chromatography to give compound 2, compound 10, or compound 23 as a yellow solid (yield 30%-80%):

[0121] Compound 2: 1 H NMR (600 MHz, DMSO-d 6 ) δ 9.37 (s, 1H), 8.69 (d, J = 4.5 Hz, 1H), 8.64 (d, J = 8.6 Hz, 1H), 8.47 (s, 1H), 8.19-8.15 (m, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.80 (m, 1H), 7.75-7.69 (m, 2H), 4.34 (s, 1H), 3.76 (d, J = 3.0 Hz, 1H), 2.76 (d, J = 4.6 Hz, 3H), 1.81-1.72 (m, 2H), 1.69-1.49 (m, 4H), 1.46-1.30 (m, 2H). NMR spectral data of compound 2 is presented in Figure 4.

[0122] Compound 10: 1 H NMR (500 MHz, CDCl 3) δ 10.62 (s, 1H), 9.10 (s, 1H), 8.53 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.87 (d, J = 10.9 Hz, 1H), 7.56 (m, 2H), 7.49 (m, 1H), 7.33-7.27 (m, 2H), 6.90 (d, J = 4.5 Hz, 1H), 4.33 (d, J = 7.2 Hz, 1H), 3.99 (d, J = 5.8 Hz, 1H), 2.98 (d, J = 4.8 Hz, 3H), 2.03-1.48 (m, 8H). ESI-MS: m / z 542.00 [M+H] + NMR and mass spectrometry characterization data for compound 10 are presented in Figures 5A and 5B.

[0123] Compound 23: 1 H NMR (500 MHz, CDCl 3 ) δ 10.66 (s, 1H), 9.13 (s, 1H), 8.56 (s, 1H), 8.02 (s, 1H), 7.88 (d, J = 10.2 Hz, 1H), 7.56 (m, 3H), 7.35 (m, 2H), 6.91 (s, 1H), 4.32 (s, 1H), 3.98 (s, 1H), 2.98 (d, J = 4.3 Hz, 3H), 2.03-1.46 (m, 8H). ESI-MS: m / z 542.00 [M+H] + NMR and mass spectrometry characterization data for compound 23 are presented in Figures 6A and 6B.

[0124] compound 20 Compound 20 can be prepared by modifying the synthesis illustrated in Scheme 1 and described above, i.e., in step b, using commercially available tert-butyl (2-amino-3-hydroxycyclohexyl)carbamate or its stereoisomer instead of tert-butyl-2-aminocyclohexyl)carbamate (0.75 g, 3.5 mmol) or its corresponding stereoisomer, and reacting with compound I-1 in the presence of DIPEA and dimethylformamide (DMF) at 80° C. for 16 hours. All other reagents and conditions are the same as those for the preparation of compounds 2, 10, 18, 19, and 23 described above.

[0125] Compounds 21 and 22 Compounds 21 and 22 can be prepared by modifying the synthesis illustrated in Scheme 1, i.e., by using a different compound as the starting material in step a (i.e., 5-bromo-2-fluoro-3-sulfobenzoic acid (for compound 21) or 5-bromo-3-cyano-2-fluorobenzoic acid (for compound 22), both of which are commercially available, instead of 5-bromo-2-fluoro-3-nitrobenzoic acid). All other reagents and conditions are the same as for the preparation of compounds 2, 10, 18, 19, and 23 described above.

[0126] compound 1 Compound 1 or its analogs can be prepared using the procedures illustrated in general Scheme 2. The preparation of the compounds is shown in Scheme 3 below.

[0127] Scheme 2: General steps a and b for the preparation of compound 1 and its analogues [ka]

[0128] Scheme 3: Preparation of Compound 1 [ka]

[0129] The reagents and conditions for steps a to d illustrated in Scheme 3 are as follows: (a) 3M HCl EA, DCM, 1 h; (b) HATU, DIPEA, DCM, 0 °C, 2 h; (c) DIPEA, DMF, 80 °C, 16 h; (d) HATU, DIPEA, DMF, room temperature, 12 h.

[0130] Compounds 7, 8, and 11 Compounds 7, 8, and 11 can be prepared using the procedures illustrated in Scheme 4 below.

[0131] Scheme 4: Preparation of compounds 7, 8, and 11 [ka]

[0132] The reagents and conditions for steps a to c illustrated in Scheme 4 are as follows: (a) HATU, DIPEA, or DCM, 0° C., 2 h; (b) DIPEA, DMF, 80° C., 16 h; (c) HATU, DIPEA, DMF, rt, 12 h.

[0133] Compounds 3 and 4 Compounds 3 and 4 can be prepared using the procedures illustrated in Scheme 5 below.

[0134] Scheme 5: Preparation of compounds 3 and 4 [ka]

[0135] The reagents and conditions for steps a to c depicted in Scheme 5 are as follows: (a) HATU, DIPEA, or DCM, 0° C., 2 h; (b) DIPEA, DMF, 80° C., 16 h; (c) HATU, DIPEA, DMF, rt, 12 h.

[0136] Compounds 5 and 6 Compounds 5 and 6 can be prepared using the procedures illustrated in Scheme 6 below.

[0137] Scheme 6: Preparation of compounds 5 and 6 [ka]

[0138] The reagents and conditions for steps a to d illustrated in Scheme 6 are as follows: (a) HATU, DIPEA, or DCM, 0 °C, 2 h; (b) DIPEA, DMF, 80 °C, 16 h; (c) 3M HCl EA, DCM, 1 h; (d) HATU, DIPEA, DMF, room temperature, 12 h.

[0139] Compounds 9, 12, 15, and 16 Compounds 9, 12, 15, and 16 can be prepared using the procedures illustrated in Scheme 7 below.

[0140] Scheme 7: Preparation of compounds 9, 12, 15, and 16 [ka]

[0141] The reagents and conditions for steps a and b depicted in Scheme 7 are: (a) HATU, DIPEA, or DCM, 0° C., 2 h; (b) HATU, DIPEA, DMF, rt, 12 h.

[0142] Compounds 13 and 17 Compounds 13 and 17 can be prepared using the procedures illustrated in Scheme 8 below.

[0143] Scheme 8: Preparation of compounds 13 and 17 [ka]

[0144] The reagents and conditions for steps a to c illustrated in Scheme 8 are as follows: (a) HATU, DIPEA, or DCM, 0° C., 2 h; (b) DIPEA, DMF, 80° C., 16 h; (c) HATU, DIPEA, DMF, rt, 12 h.

[0145] compound 14 Compound 14 can be prepared using the procedures illustrated in Scheme 9 below.

[0146] Scheme 9: Preparation of compound 14 [ka]

[0147] The reagents and conditions for steps a to d illustrated in Scheme 9 are as follows: (a) HATU, DIPEA, or DCM, 0 °C, 2 h; (b) DIPEA, DMF, 80 °C, 16 h; (c) 3M HCl EA, DCM, 1 h; (d) HATU, DIPEA, DMF, room temperature, 12 h.

[0148] Example 3 In vitro enzyme assay results The ability of the three compounds in Figure 1A to inhibit 3CLpro was tested using a fluorescence resonance energy transfer (FRET)-based continuous kinetics assay. The fluorescent peptide Dabcyl-KTSAVLQ↓SGFRKM-E(Edans) (SEQ ID NO: 4) was used as a substrate for purified 3CLpro. After cleavage by 3CLpro, the fragment SGFRKM-E(Edans) (SEQ ID NO: 5) was released, and its fluorescence could be monitored at excitation and emission wavelengths of 355 nm and 538 nm, respectively.

[0149] The final concentrations of 3CLpro and fluorogenic substrate (Dabcyl-KTSAVLQ↓SGFRKM-E(Edans) (SEQ ID NO: 4) were 100 nM and 100 μM, respectively. Briefly, 15 μL of recombinant 3CLpro (0.4 μM) in assay buffer (20 mM HEPES 7.4, 150 mM NaCl, 0.01% Triton X-100, 1 mM DTT) was incubated with 1.5 μL of serial dilutions of each compound at room temperature for 1 h. A 384-well plate (Corning, CLS3575) was pre-warmed at 30° C. for 5 min. Then, 11 μL of the 3CLpro / inhibitor mixture was transferred to the 384-well plate. The reaction was started by adding 29 μL of fluorogenic substrate (138 μM in assay buffer). The reaction was then incubated at room temperature for 1 h with Thermo Varioskan Fluorescence signals were immediately measured every minute at 30° C. using a LUX plate reader at excitation of 355 nm and emission of 538 nm.

[0150] IC of compounds 1, 2, and 8 50 were 165.1 nM, 64.6 nM and 49.5 nM, respectively (Figure 7A).

[0151] Two analogs of compound 2, compounds 10 and 23 (FIG. 1B), were synthesized and tested. One of the two analogs, compound 23, had an IC similar to that of compound 2. 50 was shown (Figure 7B).

[0152] Example 4 structural biology research To understand the manner in which the compounds disclosed herein bind to 3CLpro and inhibit its enzymatic activity, certain inhibitors were co-crystallized with SARS-CoV-2 3CLpro. 3CLpro was overexpressed in E. coli and purified to homogeneity following the protocol used in the production of SARS-CoV 3CLpro (Ref.5). Prior to crystallization, a 10 mg / mL stock solution of purified SARS-CoV-2 3CLpro in a buffer containing 20 mM HEPES pH 7.4 and 150 mM NaCl was incubated with 1.5 mM of the inhibitor for 2 hours at room temperature, and the precipitate was then removed by centrifugation. For crystallization, 0.2 μL of 3CLpro / inhibitor complex was mixed with 0.2 μL of well buffer from a commercial crystallization kit. Crystals were grown at 20 °C in 96-well plates using the sitting drop vapor diffusion method. Diffraction data were collected at 100K on a Rigaku XtaLAB Synergy Custom diffractometer and solved by molecular replacement using Phaser-MR (Ref.6) in the Phenix software suite (Ref.7). The crystal structure of SARS-CoV-2 3CLpro (PDB code: 6Y2E) was used as the initial model. The structure of the 3CLpro / inhibitor complex was manually refined using Coot (Ref.8) and Phenix (Ref.7).

[0153] The crystal structure of the 3CL / compound 2 complex was determined by molecular replacement and refined to 1.83 Å. Compound 2 formed a 1:1 complex with 3CL. In the crystal structure, one molecule of compound 2 bound to the catalytic pocket of 3CL, thereby competitively inhibiting the binding of the 3CL substrate (Figure 8A). Three hydrogen bonds were formed between compound 2 and 3CL: the first hydrogen bond was between the nitrogen atom in the isoquinoline ring of compound 2 and the side chain of His163; the second hydrogen bond was between the carbonyl group attached to the isoquinoline ring and the side chain of Asn142; the third hydrogen bond was between the carbonyl oxygen in the methylcarbamoyl group of compound 2 and the main chain amide of Glu166 (Figure 8B). In addition to hydrogen bonding, amino-π interactions between the phenyl ring and the side chain of Gln189 may also contribute to the potency of compound 2; the strong electron-withdrawing ability of the nitro group may cause the aromatic ring to carry a positive charge, thus significantly enhancing this interaction (Ref. 9).

[0154] The crystal structure of the 3CL / compound 8 complex was refined to 1.9 Å (FIG. 9A). Compound 8 was found to bind to 3CL similarly to the binding of compound 2 (FIG. 9B), suggesting that the isoquinoline and nitrophenyl rings are important for the interaction with 3CL, while the linker region between them keeps them in the proper position.

[0155] The crystal structure of the 3CL / compound 1 complex was refined to 1.69 Å (FIG. 10A). The isoquinoline ring of compound 1 binds to a pocket in 3CL surrounded by residues Asn142, His163, and Glu166, similar to the binding of the isoquinoline ring of compound 2. The hydroxyl group in the isoquinoline ring forms an additional hydrogen bond with the side chain of Asn142, contributing to the binding between compound 1 and 3CL. The dichlorobenzyl group interacts with the side chain of His41 by π-π stacking.

[0156] Example 5 Anti-SARS-CoV-2 activity of 3Clpro inhibitors in cellular assays The anti-SARS-CoV-2 activity of compounds 1, 2, and 8 was measured in three different cell lines, including A549, VeroE6, and Calu3 cell lines. Nanoluciferase severe respiratory syndrome coronavirus 2 (SARS-CoV-2-Nluc), which was generated by integrating nanoluciferase gene into the SARS-CoV-2 genome, was used to infect host cells, and then antiviral assays were performed according to the method in (Ref.10). Cytotoxicity assays were also performed according to the method in (Ref.10).

[0157] A549 is a cancerous human alveolar epithelial cell line. The most potent compound in A549 cells was compound 2, followed by compound 8 and compound 1, with their IC 50 The values ​​were 12.43 nM, 38.77 nM and 848.0 nM, respectively (Figure 11A). The cytotoxic effects of these compounds in A549 cells were also evaluated. Cells were treated with serially diluted stock solutions of these compounds for 3 days. The 50% cytotoxic concentration (CC 50 ) was greater than 20 μM (FIG. 11B).

[0158] 3CLpro inhibitors, especially compound 2, also demonstrated high potency in inhibiting SARS-CoV-2 replication in VeroE6 cells (Figure 12A) and Calu3 cells (Figure 12B).

[0159] The above test results showed that several non-covalent small molecule inhibitors of SARS-CoV-2 3CLpro, such as compounds 1, 2, and 8, effectively blocked coronavirus replication in host cells. As an example, compound 2 showed high potency in both cell-free enzyme assays and cell-based anti-SARS-CoV-2 assays. Compound 2 and its analogs, such as but not limited to compounds 10, 18, and 23, can be used to treat diseases or symptoms of diseases caused by coronaviruses, such as COVID-19.

[0160] Sequence analysis showed that the residues surrounding compound 2 are highly conserved in SARS-CoV 3CLpro and MERS-CoV 3CLpro (Figure 13 and Table 2), suggesting that compound 2 and its analogs could be pan-inhibitors of coronavirus 3CL proteases.

[0161] [Table 2]

[0162] References 1. AR Fehr, S. Perlman, Coronaviruses: an overview of their replication and pathogenesis. Methods Mol. Biol. 1282, 1-23 (2015). 2. P. Zhou et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 579, 270-273 (2020). 3. J. Lei, Y. Kusov, R. Hilgenfeld, Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein. Antiviral Res. 149, 58-74 (2018). 4. T. Pillaiyar, M. Manickam, V. Namasivayam, Y. Hayashi, S.-H. Jung, An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy. J. Med. Chem. 59, 6595-6628 (2016). 5. X. Xue et al., Production of authentic SARS-CoV M(pro) with enhanced activity: application as a novel tag-cleavage endopeptidase for protein overproduction. J. Mol. Biol.366, 965-975 (2007). 6. A. J. McCoy et al., Phaser crystallographic software. J Appl Crystallogr. 40, 658-674 (2007). 7. D. Liebschner et al., Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr D Struct Biol. 75, 861-877 (2019). 8. P. Emsley, B. Lohkamp, W. G. Scott, K. Cowtan, Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486-501 (2010). 9. H. Wang, W. Wang, W. J. Jin, σ-Hole Bond vs π-Hole Bond: A Comparison Based on Halogen Bond. Chem. Rev. 116, 5072-5104 (2016). 10. X. Xie et al., A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19. Nat Commun. 11, 5214-11 (2020).

[0163] From this disclosure and the claims, it will be readily apparent to those skilled in the art that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the disclosure, as defined in the following claims.

Claims

1. The compound of formula IIIc: 【Chemistry 1】 or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, X is absent, -NH-, or -NHCH ２ - and Z is absent, -NH-, -CH(CH(CH ３ ) ２ )NH-, -C(=O)NHCH[(CONHCH ３ ) ]CH ２ - or CH(C ２ H ５ ) CH ２ NH-, Y is C ３ ~C ６ cycloalkyl, azetidinyl, piperidinyl, piperazinyl, 2,7-diazaspiro[4.4]nonanyl, octahydrocyclopenta[c]pyrrolyl, 2-oxa-6-azaspiro[3.4]octanyl, or octahydro-1H-isoindolyl, each of which has o R ３ is substituted with a group, R １ Or R ２ For each occurrence, halogen, cyano, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C １ ~C ６ Alkoxy, -C(=O)(C １ ~C ６ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (=O) ｗ R ｓ , -NO ２ , -OR ｓ , -OC(=O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , -S(=O) ｗ N.R. ｐ R ｑ , or -SO ３ － are each independently selected from R ３ For each occurrence, halogen, cyano, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C １ ~C ６ Alkoxy, -C(=O)(C １ ~C ６ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (=O) ｗ R ｓ , -NO ２ , -OR ｓ , -OC(=O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , -S(=O) ｗ N.R. ｐ R ｑ , -SO ３ － or phenyl, R １ , R ２ , or R ３ Any one of the C １ ~C ６ Alkyl, the C ２ ~C ６ alkenyl, and the C １ ~C ６ Alkoxy and -C(=O)(C １ ~C ６ alkyl) １ ~C ６ Alkyl is independently halogen, cyano, -C(=O)R ｓ , -C(=O)OR ｓ , -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (=O) ｗ R ｓ , -OR ｓ , -OC(=O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , -S(=O) ｗ N.R. ｐ R ｑ and optionally substituted with 1 to 3 groups selected from R ３ The phenyl in each of the above formulas is selected from halogen, cyano, C １ ~C ２ optionally substituted with 1 to 3 groups selected from alkyl, or -OH; R ｐ , R ｑ , and R ｒ For each occurrence, hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, where R ｐ , R ｑ , and R ｒ Any one of the C １ ~C ４ The alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; R ｓ For each occurrence, hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, where w is an integer selected from 1 and 2; R １ may be attached to any of the ring atoms in the isoquinoline in formula IIIc, for each occurrence, valence permitting; R ２’ is cyano, -NO ２ , or -SO ３ － and m is an integer selected from 0, 1, 2, 3, 4, 5, or 6; n is an integer selected from 1, 2, 3, or 4; and o is an integer selected from 0, 1, 2, and 3.

2. Structural formula Va: 【Chemistry 2】 or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, Here, -(R ｂ CR ｃ ) ａ - is -CH(C ２ H ５ ) CH ２ - or -CH(C ２ H ５ ) CH ２ CH ２ - and R １ Or R ２ For each occurrence, halogen, cyano, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C １ ~C ６ Alkoxy, -C(=O)(C １ ~C ６ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (=O) ｗ R ｓ , -NO ２ , -OR ｓ , -OC(=O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , -S(=O) ｗ N.R. ｐ R ｑ , or -SO ３ － are each independently selected from R ｐ , R ｑ , and R ｒ For each occurrence, hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, where R ｐ , R ｑ , and R ｒ Any one of the C １ ~C ４ The alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; R ｓ For each occurrence, hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, where w is an integer selected from 1 and 2; R １ may be attached to any of the ring atoms in the isoquinoline in formula Va, for each occurrence, valence permitting; m is an integer selected from 0, 1, 2, 3, 4, 5, or 6; n is an integer selected from 1, 2, 3, or 4; and o is an integer selected from 0, 1, 2, and 3.

3. The following structural formula IVb-1: 【Chemistry 3】 or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, Y is C ３ ~C ６ is cycloalkyl, n is an integer selected from 1, 2, 3, and 4.

2. The compound of claim 1 ,

4. 4. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 1 or 3, wherein Y is cyclohexyl.

5. The following structural formula IIIb-2: 【Chemistry 4】 or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, X is absent, -NH-, or -NHCH ２ - and Z is absent, -NH-, -CH(CH(CH ３ ) ２ )NH-, -C(=O)NHCH[(CONHCH ３ ) ]CH ２ - or CH(C ２ H ５ ) CH ２ NH-, However, it is absent when both X and Z are absent; Y is a 3- to 10-membered heterocyclyl containing at least one N atom and optionally at least one other heteroatom selected from O and S; At least one of T and U is N; R １ Or R ２ For each occurrence, halogen, cyano, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C １ ~C ６ Alkoxy, -C(=O)(C １ ~C ６ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (=O) ｗ R ｓ , -NO ２ , -OR ｓ , -OC(=O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , -S(=O) ｗ N.R. ｐ R ｑ , or -SO ３ － are each independently selected from R ３ For each occurrence, halogen, cyano, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C １ ~C ６ Alkoxy, -C(=O)(C １ ~C ６ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (=O) ｗ R ｓ , -NO ２ , -OR ｓ , -OC(=O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , -S(=O) ｗ N.R. ｐ R ｑ , -SO ３ － or phenyl, R ３ The phenyl in each of the above formulas is selected from halogen, cyano, C １ ~C ２ optionally substituted with 1 to 3 groups selected from alkyl, or -OH; R ｐ , R ｑ , and R ｒ For each occurrence, hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, where R ｐ , R ｑ , and R ｒ Any one of the C １ ~C ４ The alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; R ｓ For each occurrence, hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, where w is an integer selected from 1 and 2; R １ may, for each occurrence, be attached to any of the ring atoms in the isoquinoline in formula IIIb-2, valence permitting; m is an integer selected from 0, 1, 2, 3, 4, 5, or 6; n is an integer selected from 1, 2, 3, or 4; and o is an integer selected from 0, 1, and 2.

6. The following structural formula IVb-2: 【Chemistry 5】 or a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing, Z is absent, -NH-, -CH(CH(CH ３ ) ２ )NH-, -C(=O)NHCH[(CONHCH ３ ) ]CH ２ - or CH(C ２ H ５ ) CH ２ NH-, Y is a 4- to 9-membered heterocyclyl containing at least one N atom and optionally at least one O atom; At least one of T and U is N; R ２’ is cyano, -NO ２ , or -SO ３ － and R １ Or R ２ For each occurrence, halogen, cyano, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C １ ~C ６ Alkoxy, -C(=O)(C １ ~C ６ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (=O) ｗ R ｓ , -NO ２ , -OR ｓ , -OC(=O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , -S(=O) ｗ N.R. ｐ R ｑ , or -SO ３ － are each independently selected from R ３ For each occurrence, halogen, cyano, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C １ ~C ６ Alkoxy, -C(=O)(C １ ~C ６ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ C(=O)OR ｓ , -NR ｐ C(=O)NR ｑ R ｒ , -NR ｐ S (=O) ｗ R ｓ , -NO ２ , -OR ｓ , -OC(=O)R ｓ , -OC(=O)OR ｓ , -OC(=O)NR ｐ R ｑ , -S(=O) ｗ R ｓ , -S(=O) ｗ N.R. ｐ R ｑ , -SO ３ － or phenyl, R ３ The phenyl in each of the above formulas is selected from halogen, cyano, C １ ~C ２ optionally substituted with 1 to 3 groups selected from alkyl, or -OH; R ｐ , R ｑ , and R ｒ For each occurrence, hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, where R ｐ , R ｑ , and R ｒ Any one of the C １ ~C ４ The alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and -OH; R ｓ For each occurrence, hydrogen, C １ ~C ４ Alkyl, and C ３ ~C ６ cycloalkyl, where w is an integer selected from 1 and 2; R １ may, for each occurrence, be attached to any of the ring atoms in the isoquinoline in formula IVb-2, valence permitting; m is an integer selected from 0, 1, 2, 3, 4, 5, or 6; n is an integer selected from 1, 2, 3, and 4; and o is an integer selected from 0 and 1.

7. The following structural formula Vb-2: 【Chemistry 6】 7. The compound of claim 6, which is a compound of the formula:

8. 7. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 1 or 6, wherein Y is azetidinyl, piperidinyl, piperazinyl, 2,7-diazaspiro[4.4]nonanyl, octahydrocyclopenta[c]pyrrolyl, 2-oxa-6-azaspiro[3.4]octanyl, or octahydro-1H-isoindolyl.

9. R ２ The phenyl substituted with has the structure: 【Chemistry 7】 having Here R ２’’ is a halogen or C １ ~C ４ is alkyl, R ２’’’ is -C(=O)NR ｐ R ｑ where: R ｐ and R ｑ are each independently hydrogen or C １ ~C ４ 8. The compound of any one of claims 1, 3, 5-7, wherein R is alkyl, a tautomer thereof, a deuterated derivative of said compound or said tautomer, or a pharma- ceutically acceptable salt of the foregoing.

10. R ２’’ is F, Cl, Br or C １ ~C ２ is alkyl, R ２’’’ is -C(=O)NR ｐ R ｑ where: R ｐ and R ｑ are each independently hydrogen or C １ ~C ２ is alkyl, 10. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 9.

11. R ２’’ is Br or -CH ３ and R ２’’’ -C(=O)NHCH ３ That is, 10. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 9.

12. R １ For each occurrence, halogen, cyano, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, -C(=O)(C １ ~C ４ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ and -OR ｓ are independently selected from R １ The above C １ ~C ４ Alkyl and the C １ ~C ４ Alkoxy and -C(=O)(C １ ~C ４ alkyl) １ ~C ４ Alkyl is independently halogen, cyano, or -OR ｓ and optionally substituted with 1 to 3 groups selected from R ｐ and R ｑ For each occurrence, hydrogen and C １ ~C ２ are each independently selected from alkyl, R ｓ For each occurrence, hydrogen and C １ ~C ２ independently selected from alkyl, A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of claims 1, 3, 5-7.

13. R １ For each occurrence, F, Cl, Br, C １ ~C ２ Alkyl, and -OR ｓ are independently selected from R １ The above C １ ~C ２ the alkyl is optionally substituted with 1 to 3 halogen groups; R ｓ For each occurrence, hydrogen and C １ ~C ２ independently selected from alkyl, 13. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 12.

14. R １ 14. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 13, wherein, for each occurrence, is independently selected from F and -OH.

15. R ３ For each occurrence, halogen, cyano, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, -C(=O)(C １ ~C ４ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -OR ｓ and phenyl, R ３ The above C １ ~C ４ Alkyl and the C １ ~C ４ Alkoxy and -C(=O)(C １ ~C ４ alkyl) １ ~C ４ Each of the alkyl groups is selected from halogen, cyano, -OR ｓ and phenyl optionally substituted with 1 to 3 halogen atoms; R ３ wherein the phenyl is selected from halogen, cyano, and C １ ~C ２ optionally substituted with 1 to 3 groups selected from alkyl; R ｐ and R ｑ For each occurrence, hydrogen and C １ ~C ２ are each independently selected from alkyl, R ｓ For each occurrence, hydrogen and C １ ~C ２ independently selected from alkyl, A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of claims 1, 3, 5-7.

16. R ３ For each occurrence, F, Cl, Br, C １ ~C ２ Alkyl, -OR ｓ and phenyl, R ３ The above C １ ~C ２ the alkyl is optionally substituted with 1 to 3 groups selected from halogen, cyano, and phenyl optionally substituted with 1 to 3 halogen atoms; R ｓ For each occurrence, hydrogen and C １ ~C ２ independently selected from alkyl, A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of claims 1, 3, 5-7.

17. R ３ 17. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 16, wherein, for each occurrence, is independently selected from: --OH, phenyl, and 2,4-dichloro-1-methylbenzene.

18. R ２ For each occurrence, halogen, cyano, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, -C(=O)(C １ ~C ４ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ , -NO ２ , -OR ｓ , and -SO ３ － are independently selected from R ２ The above C １ ~C ４ Alkyl and the C １ ~C ４ Alkoxy and -C(=O)(C １ ~C ４ alkyl) １ ~C ４ Alkyl is independently halogen, cyano, or -OR ｓ and optionally substituted with 1 to 3 groups selected from R ｐ and R ｑ For each occurrence, hydrogen and C １ ~C ２ are each independently selected from alkyl, R ｓ For each occurrence, hydrogen and C １ ~C ２ independently selected from alkyl, A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of claims 1, 3, 5-7.

19. R ２ For each occurrence, F, Cl, Br, cyano, C １ ~C ２ Alkyl, -C(=O)NR ｐ R ｑ , -NO ２ , -OR ｓ , and -SO ３ － are independently selected from R ２ The above C １ ~C ２ the alkyl is optionally substituted with 1 to 3 halogen groups; R ｐ and R ｑ For each occurrence, hydrogen and -CH ３ are each independently selected from R ｓ For each occurrence, hydrogen and C １ ~C ２ independently selected from alkyl, 20. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 18.

20. R ２ For each occurrence, Br, -CH ３ , -C(=O)NHCH ３ , and -SO ３ － 20. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 19, independently selected from:

21. R ２ For each occurrence, halogen, cyano, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, -C(=O)(C １ ~C ４ alkyl), -C(=O)NR ｐ R ｑ , -NR ｐ R ｑ and -OR ｓ are independently selected from R ２ The above C １ ~C ４ Alkyl and the C １ ~C ４ Alkoxy and -C(=O)(C １ ~C ４ alkyl) １ ~C ４ Alkyl is independently halogen, cyano, or -OR ｓ and optionally substituted with 1 to 3 groups selected from R ｐ and R ｑ For each occurrence, hydrogen and C １ ~C ２ are each independently selected from alkyl, R ｓ For each occurrence, hydrogen and C １ ~C ２ independently selected from alkyl, 8. A compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt according to any one of claims 3, 6, and 7.

22. R ２ For each occurrence, F, Cl, Br, cyano, C １ ~C ２ Alkyl, -C(=O)NR ｐ R ｑ and -OR ｓ are independently selected from R ２ The above C １ ~C ２ the alkyl is optionally substituted with 1 to 3 halogen groups; R ｐ and R ｑ For each occurrence, hydrogen and -CH ３ are each independently selected from R ｓ For each occurrence, hydrogen and C １ ~C ２ independently selected from alkyl, 22. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 21.

23. R ２ For each occurrence, Br, -CH ３ and -C(=O)NHCH ３ 23. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of claim 22, independently selected from:

24. 8. The compound, tautomer, deuterated derivative, or pharma- ceutically acceptable salt of any one of claims 1, 3, 5-7, wherein m is an integer selected from 0 and 1.

25. The compound is 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 2. The compound of claim 1, which is selected from:

26. 26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 and at least one pharma- ceutically acceptable carrier.

27. 27. Use of a compound according to any one of claims 1 to 25 or a pharmaceutical composition according to claim 26 for the manufacture of a medicament for the treatment of a disease or a symptom of a disease caused by a coronavirus.

28. 28. The use according to claim 27, wherein the disease is a respiratory tract infectious disease.

29. 29. The use according to claim 28, wherein the respiratory tract infectious disease is severe acute respiratory syndrome.

30. 28. The use of claim 27, wherein the symptom is selected from fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or generalized aches and pains, headache, new loss of taste or smell, sore throat, stuffy or runny nose, nausea or vomiting, diarrhea, persistent pain or pressure in the chest, new confusion, awakening or inability to stay awake, bluish lips or face, and combinations thereof.

31. The use according to any one of claims 27 to 30, wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

32. Use of a compound according to any one of claims 1 to 25 or a pharmaceutical composition according to claim 26 for the manufacture of a medicament for reducing or inhibiting the activity of a coronavirus 3C-like protease.

33. 33. The use according to claim 32, wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

34. 27. Use of a compound according to any one of claims 1 to 25 or a pharmaceutical composition according to claim 26 for the manufacture of a medicament for reducing or inhibiting the replication of coronavirus.

35. 35. The use according to claim 34, wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

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