Protease inhibitors, their preparation and uses

Abstract

This disclosure provides compounds of Formula I, compositions comprising the same, and methods of using the same, including use in treating illness and / or symptoms caused by coronaviruses.

Description

Invention Field

[0001] This disclosure relates to compounds that inhibit proteases such as 3C-like protease (3CLpro), compositions comprising said compounds, methods for preparing said compounds, and methods for using said compounds to treat disease or symptoms caused by coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Background of the Invention

[0002] The COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. There is a great need for drugs specifically designed to treat diseases caused by SARS-CoV-2 or other coronaviruses. The positive-sense RNA virus SARS-CoV-2 has over 70% of its genome encoding 16 non-structural proteins (NSPS), named nsp1 to nsp16 (1,2). These 16 NSPS are translated into two polyproteins, pp1a and pp1ab, which are cleaved by proteolytic cleavage to produce individual NSPS. Specifically, pp1a is cleaved into nsp1 to nsp11, while pp1ab is cleaved into nsp1 to nsp10 and nsp12 to nsp16 (1). Cleavage is carried out by two proteases included in the 16 NSPS—nsp3 and nsp5. Nsp3 is a large protein containing several domains, among which the papain-like protease (PLpro) domain is responsible for cleaving the peptide bonds between nsp1 and 2, between nsp2 and 3, and between nsp3 and 4 (1,3). Nsp5 is 3CLpro, a cysteine ​​protease that cleaves peptide bonds to release nsp4 through nsp16 (1). 3CLpro has almost the same function in other coronaviruses.

[0003] After cleaving itself from pp1a and pp1ab, 3CLpro forms a homodimer with significantly increased protease activity, promoting the cleavage of peptide bonds between other nsps. At the catalytic center of 3CLpro, there exists a catalytic dimmer composed of His41 and Cys145. The working mechanism of the catalytic domain and the protein sequence of 3CLpro are conserved among different coronaviruses. The sequence identity between SARS-CoV-2 3CLpro and SARS-CoV 3CLpro reaches 96%.

[0004] Inhibiting the protease activity of 3CLpro would block the release of nsp4 to nsp16, which are essential 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 developing anti-coronavirus drugs. Several research groups have devoted significant effort to developing inhibitors of SARS-CoV 3CLpro and SARS-CoV-2 3CLpro. Most of these inhibitors are covalent inhibitors optimized with peptide scaffolds (4). A large number of non-covalent inhibitors have also been reported; however, most of them have shown only poor activity in cell-free or cell-based assays.

[0005] This disclosure provides non-covalent inhibitors of proteases such as SARS-CoV-2 3CLpro, as well as the preparation and uses of these inhibitors. Invention Summary

[0006] One aspect of this disclosure provides compounds selected from formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, their tautomers, deuterated derivatives of said compounds or said tautomers, or pharmaceutically acceptable salts thereof, which may be used to treat disease and / or symptoms caused by coronaviruses. For example, compounds of formula I are disclosed herein:

[0007]

[0008] Formula I

[0009] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt, wherein:

[0010] Ar is a phenyl or a 6-membered heteroaryl group;

[0011] Ring A is a 9- or 10-membered heteroaryl group, wherein:

[0012] V 1 V 2 V 3 and V 4 Each is either non-existent, -CH-, or N; where:

[0013] V 1 V 2 V 3 and V 4 At most one of them can be absent; and

[0014] When W 1 W2 W 3 and W 4 If one of them does not exist, then V 1 V 2 V 3 and V 4 None of them can be absent;

[0015] W 1 W 2 W 3 and W 4 Each is either non-existent, -CH-, or N; where:

[0016] W 1 W 2 W 3 and W 4 At most one of them can be absent; and

[0017] W 1 W 2 W 3 and W 4 At least one of them must be N;

[0018] X indicates non-existence, -NR a –or -NR a (CR b R c ) a -;

[0019] Y represents non-existent, C3-C 12 Carbocyclic, 3- to 12-membered heterocyclic, or 5- to 10-membered heteroaryl; wherein the C3-C of Y 12 The carbocyclic group, the 3- to 12-membered heterocyclic group of Y, and the 5- to 10-membered heteroaryl group of Y are each enclosed by o R. 3 Group substitution;

[0020] Z indicates non-existence, -NR d -、-(CR e R f ) b NR d -or-C(=O)NR d (CR g R h ) c -;in:

[0021] R a and R d Each of them is independently hydrogen or C1-C4 alkyl;

[0022] R b R c Re and R f Each time it appears, it is independently hydrogen or optionally substituted with one to three groups selected from halogen, cyano and C1-C4 alkoxy groups;

[0023] R g and R h Each time it appears, it is independently hydrogen or optionally surrounded by 1 to 3 groups selected from halogens, cyano groups, C1-C4 alkoxy groups, and -C(=O)NR groups. i R j C1-C4 alkyl groups substituted with groups; wherein:

[0024] R i and R j Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0025] a, b, and c are each an independent integer selected from 1, 2, 3, and 4;

[0026] R 1 R 2 and R 3 Each time it appears, it is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)(C1-C6 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 -NO2, -NO2 + -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 -SO3 - C3-C 12Carbocyclic, 3- to 12-membered heterocyclic, phenyl, and 5- to 10-membered heteroaryl; wherein:

[0027] R 1 R 2 and R 3 The C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 alkoxy groups of any one of them, as well as the C1-C6 alkyl group of -C(=O)(C1-C6 alkyl), are each optionally substituted by one to three groups selected from the following: halogen, cyano, -C(=O)R k -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 C3-C6 cycloalkyl groups and phenyl groups optionally substituted with 1 to 3 halogen atoms;

[0028] R 1 R 2 and R 3 C3-C of any one of them 12 The carbocyclic group, 3 to 12-membered heterocyclic group, phenyl group, and 5 to 10-membered heteroaryl group are each optionally surrounded by 1 to 3 groups selected from halogen, cyano, C1-C4 alkyl, -NR p R q and -OR s Substitution of groups;

[0029] R p R q and R r Each of the following is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl groups; wherein:

[0030] Rp R q and R r Any one of the C1-C4 alkyl groups may be optionally substituted with 1 to 3 groups selected from halogen, cyano and -OH;

[0031] R s Each of the following is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl groups; wherein:

[0032] R p R q and R r Any one of the C1-C4 alkyl groups may be optionally substituted with 1 to 3 groups selected from halogen, cyano and -OH;

[0033] w is an integer selected from 1 and 2; and

[0034] R 1 Each time it appears, it can be attached to any ring atom on one of the two monocycles of ring A in formula I, provided that the valence allows it; and

[0035] m is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

[0036] n is an integer selected from 1, 2, 3, 4, and 5; and

[0037] o is an integer selected from 0, 1, 2, and 3.

[0038] In one aspect of this disclosure, the compounds of Formula I are selected from compounds 1 to 23 shown below, their tautomers, deuterated derivatives of the compounds or the tautomers, or the aforementioned pharmaceutically acceptable salts.

[0039] In some embodiments, this disclosure provides pharmaceutical compositions comprising compounds of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise compounds selected from compounds 1 to 23 shown below, their tautomers, said compounds or deuterated derivatives of said tautomers, or the aforementioned pharmaceutically acceptable salts. These compositions may further comprise additional active pharmaceutical agents.

[0040] Another aspect of this disclosure provides a method for treating disease and / or symptoms of disease caused by coronaviruses (e.g., respiratory infectious diseases), 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, its tautomers, deuterated derivatives of said compound or said tautomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the aforementioned. In some embodiments, the treatment method comprises administering to a subject a compound selected from compounds 1 to 23 shown below, their tautomers, said compound or deuterated derivatives of said tautomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the aforementioned.

[0041] In some embodiments, the treatment method includes administering to a subject in need of the compound, in the same pharmaceutical composition as, or in a separate composition of, a compound of formula I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, its tautomers, deuterated derivatives of said compound or said tautomers, or the aforementioned pharmaceutically acceptable salts. In some embodiments, the treatment method includes administering a compound selected from compounds 1 to 23, their tautomers, said compound or deuterated derivatives of said tautomers, or the aforementioned pharmaceutically acceptable salts, with a separate active agent in the same pharmaceutical composition or in a different composition.

[0042] This document also discloses methods for reducing or inhibiting the activity of coronavirus proteases, 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, its tautomers, deuterated derivatives of said compound or said tautomers, or the aforementioned pharmaceutically acceptable salts, or a pharmaceutical composition comprising any of the aforementioned. In some embodiments, the method for reducing or inhibiting coronavirus protease activity comprises administering to a subject a compound selected from compounds 1 to 23 shown below, their tautomers, deuterated derivatives of said compound or said tautomers, or the aforementioned pharmaceutically acceptable salts, or a pharmaceutical composition comprising any of the aforementioned. In some embodiments, the method of reducing or inhibiting the protease activity of coronaviruses 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, its tautomers, deuterated derivatives of said compound or said tautomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the aforementioned. In some embodiments, the method of reducing or inhibiting the protease activity of coronaviruses comprises contacting the coronavirus or the protease with a compound selected from compounds 1 to 23 listed below, its tautomers, said compound or deuterated derivatives of said tautomers, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the aforementioned.

[0043] This document further discloses methods for reducing or inhibiting coronavirus replication, including 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, its tautomers, deuterated derivatives of said compound or said tautomers, or the aforementioned pharmaceutically acceptable salts, or a pharmaceutical composition comprising any of the aforementioned. In some embodiments, the method for reducing or inhibiting coronavirus replication includes administering to a subject a compound selected from compounds 1 to 23 shown below, their tautomers, said compound or deuterated derivatives of said tautomers, or the aforementioned pharmaceutically acceptable salts, or a pharmaceutical composition comprising any of the aforementioned. In some embodiments, the method for reducing or inhibiting coronavirus replication involves contacting the coronavirus or the 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, its tautomers, deuterated derivatives of the compound or its tautomers, or the aforementioned pharmaceutically acceptable salts, or a pharmaceutical composition comprising any of the aforementioned pharmaceutical compositions. In some embodiments, the method for reducing or inhibiting coronavirus replication involves contacting the coronavirus or the coronavirus protease with a compound selected from compounds 1 to 23 listed below, its tautomers, the compound or its tautomers, deuterated derivatives of the compound or its tautomers, or the aforementioned pharmaceutically acceptable salts, or a pharmaceutical composition comprising any of the aforementioned pharmaceutical compositions. Brief description of the attached diagram

[0044] Figure 1A and 1B Three inhibitors were shown ( Figure 1A ) and two analogues of compound 2 ( Figure 1B The chemical structure of ).

[0045] Figure 2A and 2B The NMR spectrum of compound I-1 is shown. Figure 2A ) and mass spectrometry ( Figure 2B Characterization data.

[0046] Figure 3A and 3B The NMR spectrum of compound I-2(1) is shown. Figure 3A ) and mass spectrometry ( Figure 3B Characterization data.

[0047] Figure 4 The NMR characterization data of compound 2 are shown.

[0048] Figure 5A and 5B The NMR spectrum of compound 10 is shown. Figure 5A) and mass spectrometry ( Figure 5B Characterization data.

[0049] Figure 6A and 6B The NMR spectrum of compound 23 is shown. Figure 6A ) and mass spectrometry ( Figure 6B Characterization data.

[0050] Figure 7A and 7B The inhibitory activity of the compounds in Figure 1 against SARS-CoV-2 3CLpro is shown. The half-maximal inhibitory concentrations (IC50) of compounds 1, 2, and 8 were determined using in vitro enzyme assays. 50 ) ( Figure 7A The half-maximum inhibitory concentration (MCMC) of compound 10 and two analogues of compound 2, namely compounds 10 and 23. Figure 7B ).

[0051] Figure 8A and 8B The crystal structure of the complex of SARS-CoV-2 3CLpro and compound 2 is shown. Figure 8A Compound 2 (rod-shaped) is shown to be bound into the catalytic bag of 3CLpro. The surface electrostatic potential of 3CLpro is calculated using PyMol. Figure 8B This shows the interaction between compounds 2 and 3CLpro. The dashed lines represent hydrogen bonds.

[0052] Figure 9A and 9B The crystal structure of the complex of SARS-CoV-2 3CLpro and compound 8 is shown. Figure 9A Compound 8 (rod-shaped) is shown to be bound into the catalytic bag of 3CLpro. The surface electrostatic potential of 3CLpro is calculated using PyMol. Figure 9B This shows the interaction between compound 8 and 3CLpro. The dashed lines represent hydrogen bonds.

[0053] Figure 10A and 10B The crystal structure of the complex of SARS-CoV-2 3CLpro and compound 1 is shown. Figure 10A Compound 1 (rod-shaped) is shown to be bound into the catalytic bag of 3CLpro. The surface electrostatic potential of 3CLpro is calculated using PyMol. Figure 10B This shows the interaction between compound 1 and 3CLpro. Dashed lines represent hydrogen bonds.

[0054] Figure 11A and 11B The three inhibitors were shown to have anti-SARS-CoV-2 activity in A549 cells. Figure 11A ) and cytotoxic effects ( Figure 11B).

[0055] Figure 12A and 12B The three inhibitors were shown to have an effect on VeroE6 cells ( Figure 12A ) and Calu3 cells ( Figure 12B The anti-SARS-CoV-2 activity in )

[0056] Figure 13 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) are shown in alignment. Residuals of compound 2 within 5 Å in SARS-CoV-2 3CLpro are represented by triangles.

[0057] Detailed description of the invention

[0058] I. Definition

[0059] When referring to nouns, the terms "a" or "an" as used in this article encompass the expression "at least one," thus covering both singular and plural units of the noun. For example, "another medicine" refers to one, two, or more other medicines.

[0060] As used in this article, the term "coronavirus" refers to a related group of RNA viruses that cause diseases in mammals and birds, such as respiratory infectious diseases commonly seen in humans and birds, ranging from mild to fatal 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 helical symmetry nucleocapsid. They have characteristic rod-shaped spikes protruding from their surface, which, in electron micrographs, evoke the shape of a solar corona, from which they derive their name. Fatal coronaviruses include those that can encompass SARS (Severe Acute Respiratory Syndrome), MERS (Middle East Respiratory Syndrome), and COVID-19 (a contact-related infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2).

[0061] As used herein, the term "inhibitor" refers to a small organic chemical molecule compound (≤10 kDa) that has the ability to reduce or inhibit the expression of any one or more proteases of coronaviruses as defined above, and / or reduce or inhibit their activity (e.g., by blocking the active site of the protease), said proteases including but not limited to 3C-like proteases (3CL). proOr 3CLpro, or formally known as C30 endopeptidase (which is the main protease of coronaviruses). The 3C-like protease cleaves the coronavirus polyprotein at multiple conserved sites with glutamine-serine / glutamine-alanine / glutamine-glycine peptide bonds and is important in the processing of the coronavirus replicase polyprotein P0C6U8. Other examples of coronavirus proteases include papain-like protease PLpro, which is required to process viral polyproteins to produce a functional replicase complex and enable viral transmission.

[0062] The term "compound," when referring to the compounds of this disclosure, means a collection of molecules having the same chemical structure, unless otherwise specified as a collection of stereoisomers (e.g., a collection of racemic compounds, a collection of cis / trans stereoisomers, or a collection of (E) and (Z) stereoisomers), except that isotopic variations may exist in the constituent atoms of the molecules. Therefore, it will be apparent to those skilled in the art that a compound represented by a specific chemical structure containing a designated deuterium atom will also contain a smaller amount of isotopes having hydrogen atoms at one or more of the designated deuterium positions in said structure. The relative amount of such isotopes in the compounds of this disclosure will depend on a number of factors, including, for example, the isotopic purity of the reagents used to prepare the compound and the efficiency of isotopic incorporation in the various synthetic steps used to prepare the compound. However, as described above, the total relative amount of such isotopes will be less than 49.9% of the compound. In other embodiments, the total relative amount of such isotopes will be 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 compound.

[0063] As used herein, “optionally substituted” may be used interchangeably with the phrase “substituted or unsubstituted.” Generally, the term “substituted” refers to the substitution of a hydrogen group in a given structure by a group containing a specified substituent. Unless otherwise stated, an “optionally substituted” group may have a substituent at each substituted position of that group, and when more than one position in any given structure may be substituted by more than one substituent selected from the specified group, the substituent may be the same or different at each position. The combinations of substituents contemplated in this disclosure are those that result in the formation of stable or chemically viable compounds.

[0064] The term "isotope" refers to a class of compounds whose chemical structures differ only in their isotopic composition. Additionally, unless otherwise stated, the structures described herein also mean compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention, except that hydrogen is replaced by deuterium or tritium, or carbon is replaced by... 13 C or 14 All substitutions for C are within the scope of this disclosure.

[0065] Unless otherwise stated, the structures described herein also include all isomers of that structure, 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. Therefore, geometric and conformational mixtures of the compounds of this invention are within the scope of this disclosure. Unless otherwise stated, all tautomers of the compounds of this disclosure are within the scope of this disclosure.

[0066] As used herein, the term "tautomer" refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by the migration of atoms such as hydrogen atoms or intramolecular groups.

[0067] As used in this article, “stereoisomer” refers to enantiomers and diastereomers.

[0068] As used herein, "deuterated derivative" refers to a compound having the same chemical structure as the reference compound, but with one or more hydrogen atoms replaced by deuterium atoms ("D" or "Deuterated"). 2 Compounds with H” substitution. It should be recognized that, depending on the source of the chemical materials used in the synthesis, there are some variations in the natural isotope abundance in the synthesized compounds. Despite such variations, the concentration of naturally enriched stable hydrogen isotopes is small and insignificant compared to the stable isotope substitution degree of the deuterated derivatives described herein. Therefore, unless otherwise stated, when referring to the compounds of this disclosure as “deuterated derivatives,” at least one hydrogen atom is substituted with deuterium at a level much higher than its natural isotope abundance, which is typically about 0.015%. In some embodiments, the deuterated derivatives disclosed herein have an isotope enrichment factor of at least 3500 (52.5% deuterium doping in each specified deuterium) and at least 4500 per deuterium atom. (67.5% deuterium doping in each specified deuterium), at least 5000 (75% deuterium doping in each specified deuterium), at least 5500 (82.5% deuterium doping in each specified deuterium), at least 6000 (90% deuterium doping in each specified deuterium), at least 6333.3 (95% deuterium doping in each specified deuterium), at least 6466.7 (97% deuterium doping in each specified deuterium), or at least 6600 (99% deuterium doping in each specified deuterium).

[0069] As used in this article, the term "isotope enrichment factor" refers to the ratio of the isotopic abundance of a particular isotope to its natural abundance.

[0070] As used herein, the term "alkyl" refers to a fully saturated linear or branched, substituted or unsubstituted hydrocarbon chain. Unless otherwise stated, an alkyl group contains 1 to 20 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 10 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1 to 8 aliphatic carbon atoms. In some embodiments, the alkyl group contains 1 to 6 alkyl carbon atoms. In some embodiments, the alkyl group contains 1 to 4 alkyl carbon atoms. In other embodiments, the alkyl group contains 1 to 3 alkyl carbon atoms. And, in still other embodiments, the alkyl group contains 1 to 2 alkyl carbon atoms. In some embodiments, the alkyl group is substituted. In some embodiments, the alkyl group is unsubstituted. In some embodiments, the alkyl group is linear, straight-chain, or unbranched. In some embodiments, the alkyl group is branched.

[0071] The term "cycloalkyl" refers to a fully saturated monocyclic C 3-8 Hydrocarbons or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 Hydrocarbons, wherein any single ring in the binary ring system has 3-7 members. In some embodiments, the cycloalkyl group is substituted. In some embodiments, the cycloalkyl group is unsubstituted. In some embodiments, the cycloalkyl group is C3-C6. 12 Cycloalkyl. In some embodiments, the cycloalkyl group is a C3-C8 cycloalkyl group. In some embodiments, the cycloalkyl group is a C3-C6 cycloalkyl group. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0072] The term "carbocycloyl" encompasses the term "cycloalkyl" and refers to a monocyclic C 3-8 Hydrocarbons or spirocyclic, fused or bridged bicyclic or tricyclic C 8-14 Hydrocarbons that are fully or partially saturated because they contain one or more unsaturated units, but are not aromatic, wherein any single ring in the bicyclic ring system has 3-7 members. Bicyclic carbocyclic groups include combinations of monocyclic carbocyclic rings fused to, for example, a phenyl group. In some embodiments, the carbocyclic group is substituted. In some embodiments, the carbocyclic group is unsubstituted. In some embodiments, the carbocyclic group is C3-C. 12 Carbocyclic group. In some embodiments, the carbocyclic group is C3-C. 10 Carbocyclic group. In some embodiments, the carbocyclic group is a C3-C8 carbocyclic group.

[0073] As used herein, the term "alkenyl" refers to a linear or branched, substituted or unsubstituted hydrocarbon chain containing one or more double bonds. In some embodiments, the alkenyl group is substituted. In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is linear, straight-chain, or unbranched. In some embodiments, the alkenyl group is branched.

[0074] As used herein, the term "heterocyclic group" refers to a non-aromatic (i.e., fully saturated or partially saturated, as it contains one or more unsaturated units, but is not aromatic), monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system, wherein one or more ring members are independently selected heteroatoms. Bicyclic heterocyclic groups include, for example, combinations of the following monocyclic groups: a monocyclic heteroaryl fused to a monocyclic heterocyclic group; a monocyclic heterocyclic group fused to another monocyclic heterocyclic group; a monocyclic heterocyclic group fused to a phenyl group; a monocyclic heterocyclic group fused to a monocyclic carbocyclic / cycloalkyl group; and a monocyclic heteroaryl group fused to a monocyclic carbocyclic / cycloalkyl group. In some embodiments, the "heterocyclic group" contains 3 to 14 ring members, wherein one or more ring members are independently selected from, for example, heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. In some embodiments, the heterocycle has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocycle has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocycle has one heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocycle has one nitrogen atom. In some embodiments, the heterocycle has one oxygen atom. In some embodiments, the heterocycle has two heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle has three heteroatoms, each independently selected from nitrogen and oxygen. In some embodiments, the heterocycle is substituted. In some embodiments, the heterocycle is unsubstituted. In some embodiments, the heterocyclic group is a 3- to 12-membered heterocyclic group. In some embodiments, the heterocyclic group is a 3- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a 4- to 9-membered heterocyclic group, for example, a 4- to 9-membered heterocyclic group containing at least one N atom and optionally at least one O atom. In some embodiments, the heterocyclic group is a 5- to 10-membered heterocyclic group. In some embodiments, the heterocyclic group is a 5- to 8-membered heterocyclic group. In some embodiments, the heterocyclic group is a 5- or 6-membered heterocyclic group. In some embodiments, the heterocyclic group is a 6-membered heterocyclic group. Non-limiting examples of monocyclic heterocyclic groups include piperidinyl, piperazinyl, tetrahydropyranyl, azacyclic butyl, tetrahydrothiophene 1,1-dioxide, etc.

[0075] The term "heteroatom" refers to one or more of oxygen, sulfur, and nitrogen, including any oxidized form of nitrogen or sulfur; any basic nitrogen in a heterocyclic ring in a quaternized form or a substituted nitrogen, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolealkyl), or NR. + (e.g., in N-substituted pyrroleyl groups).

[0076] As used herein, the term "unsaturated" refers to a portion having one or more unsaturated units or a degree of unsaturation. Degree of unsaturation is the state in which not all active valence bonds in a compound are satisfied by substituents, thus the compound contains one or more double or triple bonds.

[0077] As used herein, the term "alkoxy" refers to an alkyl group as defined above, wherein one carbon atom of the alkyl group is replaced by an oxygen ("alkoxy") atom, provided that the oxygen atom is attached between two carbon atoms.

[0078] The term "halogen" includes F, Cl, Br, and I, which are fluorine, chlorine, bromine, and iodine, respectively.

[0079] As used in this article, the "cyano" or "nitrile" group refers to -C≡N.

[0080] As used herein, "aromatic ring" refers to a carbon ring or heterocyclic ring containing a conjugated planar ring system with delocalized π-electron orbitals consisting of [4n+2] p-orbital electrons, where n is an integer from 0 to 6. "Non-aromatic" rings refer to carbon rings or heterocyclic rings that do not meet the above requirements for aromatic rings and may be fully or partially saturated. Non-limiting examples of aromatic rings include aromatic rings and heteroaromatic rings as further defined below.

[0081] The term "aryl" as used alone or as part of a larger part, such as in "arylalkyl," "arylalkoxy," or "aryloxyalkyl," refers to a monocyclic or spirocyclic, fused, or bridged bicyclic or tricyclic ring system having a total of five to fourteen ring members, wherein each ring in the system is an aromatic ring containing only carbon atoms, and wherein each ring in the bicyclic or tricyclic ring system contains 3 to 7 ring members. Non-limiting examples of aryl groups include phenyl (C6) and naphthyl (C4). 10 The aryl group is substituted in some embodiments. In some embodiments, the aryl group is unsubstituted.

[0082] The term "heteroaryl" refers to a monocyclic or spirocyclic, fused or bridged bicyclic or tricyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, the 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 heteroaryl includes, for example, combinations of the following monocyclic rings: a monocyclic heteroaryl fused to another monocyclic heteroaryl; and a monocyclic heteroaryl fused to a phenyl group. Non-limiting examples of bicyclic heteroaryl are isoquinolinyl, quinolinyl, quinazolinyl, phthalazinyl, purineyl, and 1H-pyrrolo[2,3-c]pyridyl. 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 is a monocyclic ring system having five ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having six ring members. In some embodiments, the heteroaryl group is unsubstituted. In some embodiments, the heteroaryl group is a 3- to 12-membered heteroaryl group. In some embodiments, the heteroaryl group is a 3- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 3- to 8-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 8-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. Non-limiting examples of monocyclic heteroaryl groups are pyridyl, pyrimidinyl, phenylthio, thiazolyl, isoxazolyl, etc.

[0083] Non-limiting examples of suitable solvents that may be used in this disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or “methylene chloride” (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropanol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0084] Non-limiting examples of suitable bases that may be used in this disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropylethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0085] This article discloses pharmaceutically acceptable salts of the disclosed compounds. The salts of the compounds are 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.

[0086] As used herein, the term "medicinal" means, within reasonable medical judgment, a component suitable for contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. "Medicinal salt" means any non-toxic salt that, when administered to a recipient, can directly or indirectly provide the compounds of this disclosure. Suitable medicinal salts are, for example, those disclosed by SM Berge et al. in J. Pharmaceutical Sciences, 1977, 66, pp. 1–19.

[0087] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as p-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, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Therefore, such medicinal salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, decanoates, heptanoates, propynylates, oxalates, malonates, succinates, caprylates, sebacic acid, fumarates, maleates, and butyn-1,4-dicarboxylic acid. Salts, hexyn-1,6-diacidates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolate, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and salts formed with organic acids such as maleic acid.

[0088] Pharmaceutically usable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. This disclosure also contemplates the quaternization of any basic nitrogen-containing group in the compounds disclosed herein. Suitable non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Further non-limiting examples of pharmaceutically usable salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Other suitable non-limiting examples of pharmaceutically usable salts include benzenesulfonates and glucosamine salts.

[0089] The term "subject" refers to animals that include humans.

[0090] The term "therapeutic effective amount" refers to the amount of a compound that produces the intended effect of its application (e.g., improvement of disease and / or symptoms caused by coronavirus, reduction of the severity of disease and / or symptoms caused by coronavirus, and / or slowing of the progression of disease and / or symptoms caused by coronavirus). The precise amount of a therapeutic effective amount will depend on the therapeutic purpose and can be determined by those skilled in the art using known techniques (see, for example, Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0091] As used herein, the term "treatment" and its cognates refer to slowing or stopping the progression of disease. As used herein, "treatment" and its cognates include, but are not limited to, complete or partial remission, cure of disease caused by coronavirus, and reduction of the risk of symptoms of disease caused by coronavirus. Improvement or reduction in the severity of any of these symptoms can be evaluated according to methods and techniques known in the art.

[0092] The terms “about” and “approximately” when used in conjunction with figures such as percentages include, as specified, figures, as well as ranges of figures recognized by those skilled in the art (e.g., percentage ranges).

[0093] II. Compounds and Compositions

[0094] In the first embodiment, the compound disclosed herein is a compound of structural formula I:

[0095]

[0096] Formula I

[0097] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt, wherein:

[0098] Ar is phenyl or 6-membered heteroaryl;

[0099] Ring A is a 9- or 10-membered heteroaryl group, wherein:

[0100] V 1 V 2 V 3 and V 4 Each is either non-existent, -CH-, or N; where:

[0101] V 1 V 2 V 3 and V 4 At most one of them can be absent; and

[0102] When W 1 W 2 W 3 and W 4 If one of them does not exist, then V 1 V 2 V 3 and V 4 None of them can be absent;

[0103] W 1 W 2 W 3 and W 4 Each is either non-existent, -CH-, or N; where:

[0104] W 1 W 2 W 3 and W 4 At most one of them can be absent; and

[0105] W 1 W 2 W 3 and W 4 At least one of them must be N;

[0106] X indicates non-existence, -NR a –or -NR a (CR b R c ) a -;

[0107] Y represents non-existent, C3-C 12 Carbocyclic, 3- to 12-membered heterocyclic, or 5- to 10-membered heteroaryl; wherein the C3-C of Y 12 The carbocyclic group, the 3- to 12-membered heterocyclic group of Y, and the 5- to 10-membered heteroaryl group of Y are each enclosed by o R. 3 Group substitution;

[0108] Z indicates non-existence, -NR d -、-(CR e R f ) b NR d -or-C(=O)NR d (CR g R h ) c -;in:

[0109] R a and R d Each of them is independently hydrogen or C1-C4 alkyl;

[0110] Rb R c R e and R f Each time it appears, it is independently hydrogen or optionally substituted with one to three groups selected from halogen, cyano and C1-C4 alkoxy groups;

[0111] R g and R h Each time it appears, it is independently hydrogen or optionally surrounded by 1 to 3 groups selected from halogens, cyano groups, C1-C4 alkoxy groups, and -C(=O)NR groups. i R j C1-C4 alkyl groups substituted with groups; wherein:

[0112] R i and R j Each time it appears, it is independently either hydrogen or a C1-C4 alkyl group; and

[0113] a, b, and c are each an independent integer selected from 1, 2, 3, and 4;

[0114] R 1 R 2 and R 3 Each time it appears, it is independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, -C(=O)(C1-C6 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 -NO2, -NO2 + -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 -SO3 - C3-C12 Carbocyclic, 3- to 12-membered heterocyclic, phenyl, and 5- to 10-membered heteroaryl; wherein:

[0115] R 1 R 2 and R 3 The C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 alkoxy groups of any one of them, as well as the C1-C6 alkyl group of -C(=O)(C1-C6 alkyl), are each optionally substituted by one to three groups selected from the following: halogen, cyano, -C(=O)R k -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 C3-C6 cycloalkyl groups and phenyl groups optionally substituted with 1 to 3 halogen atoms;

[0116] R 1 R 2 and R 3 C3-C of any one of them 12 The carbocyclic group, 3 to 12-membered heterocyclic group, phenyl group, and 5 to 10-membered heteroaryl group are each optionally surrounded by 1 to 3 groups selected from halogen, cyano, C1-C4 alkyl, -NR p R q and -OR s Substitution of groups;

[0117] R p R q and R r Each of the following is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl groups; wherein:

[0118] R p R q and R r The C1-C4 alkyl group of any one of them is optionally substituted by 1 to 3 groups selected from halogen, cyano and -OH;

[0119] R s Each of the following is independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl groups; wherein:

[0120] R p R q and R r The C1-C4 alkyl group of any one of them is optionally substituted by 1 to 3 groups selected from halogen, cyano and -OH;

[0121] w is an integer selected from 1 and 2; and

[0122] R 1 Each time it appears, it can be attached to any ring atom on one of the two monocyclic aromatic rings of ring A in formula I, fused together, provided that the valence allows it; and

[0123] m is an integer selected from 0, 1, 2, 3, 4, 5, and 6;

[0124] n is an integer selected from 1, 2, 3, 4, and 5; and

[0125] o is an integer selected from 0, 1, 2, and 3.

[0126] In one embodiment of Formula I, Ar is phenyl, pyridyl, or pyrimidinyl, each optionally surrounded by m R groups. 1 Group substitution; and all other variables not specifically defined herein as defined in the first embodiment. In one embodiment of Formula I, Ar is optionally replaced by m R groups. 1 A phenyl group substituted with a radical; and all other variables not specifically defined herein as defined in the first embodiment.

[0127] In one embodiment of Formula I, ring A is isoquinolinyl, quinolinyl, quinazolinyl, phthalazinyl, purinyl, or 1H-pyrrolo[2,3-c]pyridyl, each optionally surrounded by m R groups. 1 Group substitution; and all other variables not specifically defined herein are as defined in the first embodiment.

[0128] In one embodiment of Equation I, ring A is optionally divided by m R. 1 Isoquinolinyl groups substituted with functional groups, wherein:

[0129] V 1 V 2 V 3and V 4 Both are -CH-;

[0130] W 2 For N; and

[0131] W 1 W 3 and W 4 -CH-;

[0132] Furthermore, all other variables not specifically defined here are as defined above.

[0133] In one embodiment of Equation I, ring A is optionally divided by m R. 1 A quinolinyl group substituted with a functional group, wherein:

[0134] V 1 V 2 V 3 and V 4 All are -CH-;

[0135] W 1 For N; and

[0136] W 2 W 3 and W 4 -CH-;

[0137] Furthermore, all other variables not specifically defined here are as defined in the first implementation scheme.

[0138] In one embodiment of Equation I, ring A is optionally divided by m R. 1 The quinazolinyl group is substituted with a functional group, wherein

[0139] V 1 V 2 V 3 and V 4 All are -CH-;

[0140] W 2 For -CH-; and

[0141] W 1 W 3 and W 4 Let N be the number of people in the group.

[0142] Furthermore, all other variables not specifically defined here are as defined in the first implementation scheme.

[0143] In one embodiment of Equation I, ring A is optionally divided by m R. 1 A group-substituted phthalazine group, wherein:

[0144] V 1 V2 V 3 and V 4 All are –CH-;

[0145] W 1 For -CH-; and

[0146] W 2 W 3 and W 4 Let N be the number of people in the group.

[0147] Furthermore, all other variables not specifically defined here are as defined in the first implementation scheme.

[0148] In one embodiment of Equation I, ring A is optionally divided by m R. 1 A purine group substituted with a radical, wherein:

[0149] V 1 and V 3 Both are N and V 2 and V 4 For -CH-; or alternatively, V 1 and V 3 Both are -CH- and V 2 and V 4 Let N be the number of people in the group.

[0150] W 1 It does not exist;

[0151] W 2 For -CH-; and

[0152] W 1 and W 3 Let N be the number of people in the group.

[0153] Furthermore, all other variables not specifically defined here are as defined in the first implementation scheme.

[0154] In one embodiment of Equation I, ring A is optionally divided by m R. 1 A purine group substituted with a radical, wherein:

[0155] V 1 It does not exist;

[0156] V 3 -CH-;

[0157] V 2 and V 4 Let N be the number of people in the group.

[0158] W 1 and W 3 For -CH- and W 2 and W 4 For N; or alternatively, W1 and W 3 For N and W 2 and W 4 -CH-;

[0159] Furthermore, all other variables not specifically defined here are as defined in the first implementation scheme.

[0160] In one implementation of Equation I, ring A is arbitrarily divided by m R. 1 The group-substituted 1H-pyrrolo[2,3-c]pyridyl group, wherein:

[0161] V 4 It does not exist;

[0162] V 1 Let N be the number of people in the group.

[0163] V 2 and V 3 -CH-;

[0164] W 3 Let N be the number of people in the group.

[0165] W 1 W 2 and W 4 -CH-;

[0166] Furthermore, all other variables not specifically defined here are as defined in the first implementation scheme.

[0167] In one implementation of Equation I, ring A is arbitrarily divided by m R. 1 The group-substituted 1H-pyrrolo[2,3-c]pyridyl group, wherein:

[0168] V 4 It does not exist;

[0169] V 3 Let N be the number of people in the group.

[0170] V 1 and V 2 -CH-;

[0171] W 2 Let N be the number of people in the group.

[0172] W 1 W 3 and W 4 -CH-;

[0173] Furthermore, all other variables not specifically defined here are as defined in the first implementation scheme.

[0174] In one implementation of Equation I, ring A is arbitrarily divided by m R.1 The group-substituted 1H-pyrrolo[2,3-c]pyridyl group, wherein:

[0175] V 3 Let N be the number of people in the group.

[0176] V 1 V 2 and V 4 -CH-;

[0177] W 1 It does not exist;

[0178] W 2 Let N be the number of people in the group.

[0179] W 3 and W 4 -CH-;

[0180] Furthermore, all other variables not specifically defined here are as defined in the first implementation scheme.

[0181] In the second embodiment, the compound of this disclosure has one of the following structural formulas II:

[0182]

[0183] Formula II

[0184] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; and wherein all other variables not specifically defined herein are as defined in the foregoing embodiments.

[0185] In the third embodiment, the compounds of this disclosure have one of the following structural formulas IIIa:

[0186]

[0187] Formula IIIa

[0188] Its tautomers, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0189] In the fourth embodiment, the compound of this disclosure has one of the following structural formulas IVa:

[0190]

[0191] Formula IVa

[0192] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; wherein:

[0193] R b and R c Each time it appears, it is independently hydrogen or a C1-C2 alkyl group optionally substituted with one to three groups selected from halogen, cyano, and C1-C4 alkoxy groups; and

[0194] a is an integer selected from 1 and 2;

[0195] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0196] In the fifth embodiment, the compound of this disclosure has the following structural formula Va:

[0197]

[0198] Va

[0199] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; 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 of the foregoing embodiments.

[0200] In the sixth embodiment, in the compounds, tautomers, tritium derivatives, or pharmaceutically acceptable salts of this disclosure, Y is C3-C. 12 Cycloalkyl or 3- to 12-membered heterocyclic groups; and all other variables not specifically defined herein are those defined in any of the foregoing embodiments.

[0201] In the seventh embodiment, in the compounds, tautomers, tritium derivatives, or pharmaceutically acceptable salts of this disclosure:

[0202] R a R b R c R d R e and R f Each of them is independently hydrogen or C1-C2 alkyl;

[0203] R g and R h Each time it appears, it is independently hydrogen or optionally -C(=O)NR. i R j Substituted C1-C2 alkyl groups; wherein:

[0204] R i and R j Each time it appears, it is independently either hydrogen or a C1-C2 alkyl group; and

[0205] a, b, and c are each an independent integer selected from 1 and 2;

[0206] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0207] In the eighth embodiment, the compound of this disclosure has the following structural formula IIIb-1:

[0208]

[0209] Formula IIIb-1

[0210] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; wherein:

[0211] Y is C3-C 10 cycloalkyl; and

[0212] o is an integer selected from 0 and 1;

[0213] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0214] In the ninth embodiment, the compound of this disclosure has the following structural formula IVb-1:

[0215]

[0216] Formula IVb-1

[0217] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; wherein:

[0218] Y is a C3-C6 cycloalkyl group; and

[0219] n is an integer selected from 1, 2, 3, and 4;

[0220] Furthermore, all other variables not specifically defined here are those defined in any of the first, sixth, seventh, and eighth implementation schemes.

[0221] In the tenth embodiment, Y is cyclohexyl in the compounds, tautomers, tritium derivatives or pharmaceutically acceptable salts of this disclosure; and all other variables not specifically defined herein are defined in any of the foregoing embodiments.

[0222] In the eleventh embodiment, the compound of this disclosure has the following structural formula IIIb-2:

[0223]

[0224] Formula IIIb-2

[0225] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; wherein:

[0226] Y is a 3- to 10-membered heterocyclic group containing at least one N atom and optionally at least one other heteroatom selected from O and S;

[0227] At least one of T and U is N; and

[0228] o is an integer selected from 0, 1, and 2;

[0229] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0230] In the twelfth embodiment, in the compounds, tautomers, tritium derivatives, or pharmaceutically acceptable salts of this disclosure:

[0231] X is non-existent, -NH-, or -NHCH2-; and

[0232] Z is non-existent, -NH-, -[CH(CH(CH3)2]NH- or -C(=O)NHCH[(CONHCH3)CH2]-; and all other variables not specifically defined here are as defined in any of the foregoing embodiments.

[0233] In the thirteenth embodiment, the compound of this disclosure has the following structural formula IVb-2:

[0234]

[0235] Formula IVb-2

[0236] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; wherein:

[0237] Y is a 4- to 9-membered heterocyclic group containing at least one N atom and optionally at least one O atom;

[0238] At least one of T and U is N;

[0239] R 2’ Halogen, cyano, -NO2 + -NH(=O)OH or -SO3 - ;

[0240] n is an integer selected from 1, 2, 3, and 4; and

[0241] o is an integer selected from 0 and 1;

[0242] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0243] In the fourteenth embodiment, the compound of this disclosure has the following structural formula Vb-2:

[0244]

[0245] Formula Vb-2

[0246] Its tautomers, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0247] In the fifteenth embodiment, in the compounds, tautomers, tritium derivatives or pharmaceutically acceptable salts of this disclosure, Y is azacyclobutane, piperidinyl, piperazine, 2,7-diazaspiro[4.4]nonyl, octahydrocyclopentane[c]pyrrole, 2-oxa-6-azaspiro[3.4]octyl or octahydro-1H-isoindolyl; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0248] In the sixteenth embodiment, the compound of this disclosure has the following structural formula IIIc:

[0249]

[0250] Formula IIIc

[0251] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; wherein:

[0252] R 2’ Halogen, cyano, -NO2 + -NH(=O)OH or -SO3 - ;and

[0253] n is an integer selected from 1, 2, 3, and 4;

[0254] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0255] In the seventeenth embodiment, the compound of this disclosure has the following structural formula IVc:

[0256]

[0257] Formula IVc

[0258] Its tautomer, the compound or a deuterated derivative of the tautomer, or the aforementioned pharmaceutically acceptable salt; wherein:

[0259] R 2’’ It is a halogen or a C1-C4 alkyl group; and

[0260] R 2’’’ -C(=O)NR p R q ;in

[0261] R p and R q Each is independently hydrogen or C1-C4 alkyl;

[0262] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0263] In the eighteenth embodiment, among the compounds, tautomers, tritium derivatives, or pharmaceutically acceptable salts of this disclosure, wherein:

[0264] R 2’’ It is F, Cl, Br or C1-C2 alkyl; and

[0265] R 2’’’ -C(=O)NR p R q ;in:

[0266] R p and R q Each is independently hydrogen or C1-C2 alkyl;

[0267] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0268] In the nineteenth embodiment, among the compounds, tautomers, tritium derivatives, or pharmaceutically acceptable salts of this disclosure, wherein:

[0269] R 2’’ For Br or -CH3; and

[0270] R 2’’’ It is -C(=O)NHCH3;

[0271] Furthermore, all other variables not specifically defined here are as defined in either of the seventeenth and eighteenth implementation schemes.

[0272] In the twentieth embodiment, R is present in the compounds, tautomers, tritium derivatives, or pharmaceutically acceptable salts of this disclosure. 1Each time it appears, it is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), -C(=O)NR p R q -NR p R q and -OR s ,in:

[0273] R 1 The C1-C4 alkyl and C1-C4 alkoxy groups and the C1-C4 alkyl group of -C(=O)(C1-C4 alkyl) are each optionally composed of 1 to 3 groups selected from halogen, cyano and -OR. s Substitution of groups;

[0274] R p and R q Each time it appears, it is independently selected from hydrogen and C1-C2 alkyl groups; and

[0275] R s Each time it appears, it is independently selected from hydrogen and C1-C2 alkyl; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0276] In the twenty-first embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, R 1 Each occurrence is independently selected from F, Cl, Br, C1-C2 alkyl groups and -OR. s ,in:

[0277] R 1 The C1-C2 alkyl group is optionally substituted with 1 to 3 halogen groups; and

[0278] R s Each of the two groups is independently selected from hydrogen and C1-C2 alkyl groups in each occurrence;

[0279] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0280] In the twenty-second embodiment, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure. 1 Each occurrence is independently selected from F and -OH; and all other variables not specifically defined here are as defined in any of the foregoing embodiments.

[0281] In the twenty-third embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, R 3Each time it appears, it is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), -C(=O)NR p R q -NR p R q -OR s and phenyl; wherein:

[0282] R 3 The C1-C4 alkyl and C1-C4 alkoxy groups and the C1-C4 alkyl group of -C(=O)(C1-C4 alkyl) are each optionally substituted by 1 to 3 groups selected from the following groups: halogen, cyano and -OR. s , and phenyl groups optionally substituted with 1 to 3 halogen atoms;

[0283] R 3 The phenyl group is optionally substituted with 1 to 3 groups selected from halogen, cyano and C1-C2 alkyl groups;

[0284] R p and R q Each time it appears, it is independently selected from hydrogen and C1-C2 alkyl groups; and

[0285] R s Each time it appears, it is independently selected from hydrogen and C1-C2 alkyl groups.

[0286] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0287] In the twenty-fourth embodiment, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure. 3 Each occurrence is independently selected from F, Cl, Br, C1-C2 alkyl, -OR s and phenyl; wherein:

[0288] R 3 The C1-C2 alkyl group is optionally substituted with 1 to 3 phenyl groups selected from halogens, cyano groups, and optionally substituted with 1 to 3 halogen atoms; and

[0289] R s Each of the two groups is independently selected from hydrogen and C1-C2 alkyl groups in each occurrence;

[0290] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0291] In the twenty-fifth embodiment, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure. 3Each time it appears, it is independently selected from -OH, phenyl, and 2,4-dichloro-1-toluene; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0292] In the twenty-sixth embodiment, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure. 2 Each time it appears, it is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), -C(=O)NR p R q -NR p R q -NO2, -NO2 + -NH(=O)OH, -OR s and -SO3 - ;in:

[0293] R 2 The C1-C4 alkyl and C1-C4 alkoxy groups and the C1-C4 alkyl group of -C(=O)(C1-C4 alkyl) are each optionally composed of 1 to 3 groups selected from halogen, cyano and -OR. s Substitution of groups;

[0294] R p and R q Each time it appears, it is independently selected from hydrogen and C1-C2 alkyl groups; and

[0295] R s Each time it appears, it is independently selected from hydrogen and C1-C2 alkyl;

[0296] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0297] In the twenty-seventh embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, R 2 Each time it appears, it is independently selected from F, Cl, Br, cyano, C1-C2 alkyl, -C(=O)NR. p R q -NO2, -NO2 + -NH(=O)OH, -OR s and -SO3 - ;in:

[0298] R 2 The C1-C2 alkyl group is optionally substituted with 1 to 3 halogen groups;

[0299] R p and R qEach time it appears, it is independently selected from hydrogen and -CH3; and

[0300] R s Each time it appears, it is independently selected from hydrogen and C1-C2 alkyl;

[0301] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0302] In the twenty-eighth embodiment, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure. 2 Each time it appears, it is independently selected from Br, -CH3, -C(=O)NHCH3, -NO2. + -NH(=O)OH and -SO3 - Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0303] In the twenty-ninth embodiment, R is present in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure. 2 Each time it appears, it is independently selected from halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)(C1-C4 alkyl), -C(=O)NR p R q -NR p R q and -OR s ,in:

[0304] R 2 The C1-C4 alkyl and C1-C4 alkoxy groups and the C1-C4 alkyl group of -C(=O)(C1-C4 alkyl) are each optionally composed of 1 to 3 groups selected from halogen, cyano and -OR. s Substitution of groups;

[0305] R p and R q Each time it appears, it is independently selected from hydrogen and C1-C2 alkyl groups; and

[0306] R s Each time it appears, it is independently selected from hydrogen and C1-C2 alkyl;

[0307] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0308] In the thirtieth embodiment, R is present in the compounds, tautomers, tritium derivatives, or pharmaceutically acceptable salts of this disclosure. 2 Each time it appears, it is independently selected from F, Cl, Br, cyano, C1-C2 alkyl, -C(=O)NR.p R q and -OR s ;in:

[0309] R 2 The C1-C2 alkyl group is optionally substituted with 1 to 3 halogen groups;

[0310] R p and R q Each time it appears, it is independently selected from hydrogen and -CH3; and

[0311] R s Each time it appears, it is independently selected from hydrogen and C1-C2 alkyl;

[0312] Furthermore, all other variables not specifically defined here are as defined in any of the foregoing implementation schemes.

[0313] In the thirty-first embodiment, in the compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts of this disclosure, R 2 Each occurrence is independently selected from Br, -CH3, and -C(=O)NHCH3; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0314] In the thirty-second embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of this disclosure, m is an integer selected from 0 and 1; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0315] In the thirty-third embodiment, in the compounds, tautomers, deuterated derivatives or pharmaceutically acceptable salts of this disclosure, m is an integer selected from 1 and 2; and all other variables not specifically defined herein are as defined in any of the foregoing embodiments.

[0316] In some embodiments, at least one compound of this disclosure is selected from compounds 1 to 23 depicted in Table 1, their tautomers, tritium derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts.

[0317] Table 1. Compounds 1 to 23

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330] Another aspect of this disclosure provides a pharmaceutical composition comprising at least one compound selected from formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts, and at least one pharmaceutically acceptable carrier.

[0331] In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable mediators and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, adhesives, and lubricants.

[0332] It should also be understood that the pharmaceutical compositions of this disclosure can be used in combination therapies; that is, the pharmaceutical compositions described herein may further include additional active pharmaceutical agents. Alternatively, the pharmaceutical composition may comprise a compound selected from formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts. A pharmaceutical composition comprising any of the aforementioned compounds may be administered as a standalone composition concurrently with, before, or after a composition comprising additional active pharmaceutical agents.

[0333] As described above, the pharmaceutical compositions disclosed herein include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers can be selected from excipients and mediators. Pharmaceutically acceptable carriers as used herein can be selected from, for example, any and all solvents, diluents, other liquid mediators, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants, suitable for a desired specific dosage form. Remington: The Science and PRactice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and JC Boylan, eds., 1988–1999, Marcel Dekker, New York, discloses various carriers for formulating pharmaceutical compositions and known techniques for preparing them. The use of any conventional carrier is considered within the scope of this disclosure, except where it is incompatible with the compounds of this disclosure (e.g., by producing any undesirable biological effects or interacting with any other component of the pharmaceutical composition in a harmful manner). Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), mixtures of metaglycerides of saturated vegetable fatty acids, water, salts, and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., carboxylic acid). Sodium methylcellulose, ethylcellulose, and cellulose acetate), tragacanth powder, malt, 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, ethanol, phosphate buffer, non-toxic and compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavoring agents, aroma agents, preservatives, and antioxidants.

[0334] III. Treatment methods and uses

[0335] In another aspect of this disclosure, compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts as described herein, including compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, are used to treat disease and / or symptoms of disease caused by coronaviruses. In another aspect, this document discloses the use of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts as described herein, including compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of a medicament for treating diseases and / or symptoms or illnesses caused by coronaviruses. In another aspect, this document discloses a method for treating diseases and / or disease symptoms in subjects, comprising administering a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof.

[0336] In some embodiments, the disease caused by the coronavirus is a respiratory infection. In some embodiments, the disease caused by the coronavirus is severe acute respiratory syndrome. In one embodiment, the disease caused by the coronavirus is COVID-19. In one embodiment, the disease is caused by a coronavirus, specifically severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In some embodiments, the symptoms of the disease caused by the coronavirus are selected from fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, nasal congestion or runny nose, nausea or vomiting, diarrhea, persistent chest pain or chest pressure, new confusion, inability to wake up or remain awake, bluish lips or face, and combinations thereof.

[0337] In another aspect of this disclosure, compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts as described herein, including compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, are used to reduce or inhibit the activity of proteases of coronaviruses. In another aspect, this document discloses the use of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts as described herein, including compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of the compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of medicaments for reducing or inhibiting coronavirus protease activity. In another aspect, this document discloses methods for reducing or inhibiting the activity of coronavirus proteases, comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof. In another aspect, this document discloses methods for reducing or inhibiting the activity of coronavirus proteases, comprising contacting a subject with the coronavirus or the protease as described herein with compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts, including compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of the compounds or their tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof. In one embodiment, the coronavirus protease is a 3C-like protease. In one embodiment, the coronavirus is SARS-CoV-2.

[0338] In another aspect of this disclosure, compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts as described herein, including compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, are used to reduce or inhibit the replication of coronaviruses. In another aspect, this document discloses the use of compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts as described herein, including compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of medicaments for reducing or inhibiting coronavirus replication. In another aspect, this document discloses methods for reducing or inhibiting coronavirus replication, comprising administering to a subject a therapeutically effective amount of a compound, tautomer, deuterated derivative, or pharmaceutically acceptable salt as described herein, including compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof. In another aspect, this document discloses methods for reducing or inhibiting coronavirus replication, the methods comprising contacting a subject with a coronavirus or a protease of the coronavirus using compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts as described herein, said compounds, tautomers, deuterated derivatives, or pharmaceutically acceptable salts comprising compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts or pharmaceutical compositions thereof. In one embodiment, the coronavirus protease is a 3C-like protease. In one embodiment, the coronavirus is SARS-CoV-2.

[0339] Compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, may be administered once daily, twice daily or three times daily, for example, to treat disease and / or symptoms caused by coronaviruses such as SARS-CoV-2.

[0340] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of 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, their tautomers, deuterated derivatives of said compounds or tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, are administered once daily, twice daily or three times daily.

[0341] Compounds of formulas I, II, IIIa, IIIb-1, IIIb-2, IIIc, IVa, IVb-1, IVb-2, IVc, Va, or Vb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts, or pharmaceutical compositions thereof, may be administered, for example, or via oral, parenteral, sublingual, topical, rectal, nasal, sublingual, vaginal, transdermal, patch, pump, or via an implanted reservoir, and the pharmaceutical composition is formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical administration modes. Parenteral administration may be a continuous infusion over a selected time period. Other forms of application considered in this disclosure are as described in international patent applications WO2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO2014 / 151142 and WO 2015 / 023915. Example

[0342] To provide a fuller understanding of the disclosure herein, the following embodiments are provided. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting the scope of this disclosure in any way.

[0343] Example 1. Screening of 3CLpro inhibitors

[0344] A series of non-covalent conjugates of SARS-CoV-23 CLpro were identified through affinity screening, and then scored by docking them to the substrate binding bag of 3CLpro; three of these molecules that ranked highly in molecular docking studies were synthesized. Figure 1A ).

[0345] Example 2. Synthesis of an exemplary compound

[0346] The compounds disclosed herein may be prepared according to standard chemical practice or as described herein, including the following synthetic schemes and descriptions of compounds selected from formulas I, IIa, IIb-1, IIb-2, IIc, IIIa, IIIb-1, IIIb-2, IIIc, IVa or IVb-2, compounds 1 to 23, their tautomers, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable salts.

[0347] General Plan

[0348] Compounds of Formula I can be prepared using the exemplary synthetic methods described in the following general schemes A through D. Variables not specifically defined in general schemes A through D, such as R, are excluded. 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 are as defined in Equation I in this disclosure.

[0349] General Plan A

[0350]

[0351] General Option B

[0352]

[0353] General Scheme C

[0354]

[0355] General Scheme D

[0356]

[0357] The reagents and conditions for steps a to d as described in general schemes A to D are: (a) DIPEA, dimethylformamide (DMF), 80 °C, 16 h; (b) 3 M hydrogen chloride-ethyl acetate (HCl·EA), CH2Cl2, 1 h; (c) HATU, DIPEA, DMF, room temperature, 12 h.

[0358] Compound 2 and similar compounds 10, 18, 19, 20, 21, 22, 23

[0359] Using compound 2 and its analogues (e.g., compounds 10, 18, 19, 23) as representative examples, the method for preparing compounds of formula I includes the general reaction steps as described in Scheme 1. The molecules in Scheme 1, as shown in compounds I-2 and I-3, have wavy bonds ( The stereochemistry of the bond may be uncertain (e.g., It can be and (racemic mixtures), such as in compounds 18 and 19, or For example, in compounds 2, 10, and 23. Other compound 2 analogues, such as compounds 20, 21, and 22, can be prepared by modifying the synthetic method described in Scheme 1, as further described below.

[0360] Scheme 1: Preparation of compounds 2, 10, 18, 19, and 23

[0361]

[0362] The reagents and conditions for steps a to d as described in Scheme 1 and further described below are: (a) 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), CH2Cl2 or dichloromethane (DCM), 0˚C, 2 h; (b) DIPEA, dimethylformamide (DMF), 80 ˚C, 16 h; (c) 3 M ethyl hydrochloride (HCl·EA), CH2Cl2, 1 h; (d) HATU, DIPEA, DMF, room temperature, 12 h.

[0363] Step a: Synthesis of N-methyl-5-bromo-2-fluoro-3-nitrobenzamide (I-1)

[0364] 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 mixture. The mixture was stirred at 0 °C for 2 hours until it became clear. The mixture was extracted three times with dichloromethane, and the combined organic layers were washed with a saturated brine solution. The organic phase was then dried over anhydrous Na₂SO₄ and concentrated under vacuum. Finally, the mixture was purified by chromatography to give compound I-1 (0.8 g, 76% yield) as a yellow solid. 1 H NMR (500 MHz, CDCl3) 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] + The NMR and mass spectrometry characterization data of compound I-1 are presented in... Figure 2A and 2B middle.

[0365] Step b: Synthesis of tert-butyl 2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)carbamate (I-2)

[0366] A solution of compound I-1 (0.8 g, 2.9 mmol) in DMF (15 mL) was stirred at room temperature. Then, 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 added to the reaction mixture. The mixture was heated 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 saline solution. The organic phase was then dried over anhydrous Na₂SO₄ and concentrated under vacuum to give compound I-2(1) as a yellow solid, requiring no further purification.

[0367]

[0368] Compound I-2(1)

[0369] 1H NMR (600 MHz, DMSO) δ 8.64 (d, J = 4.5 Hz, 1H), 8.17 (d, J = 2.4Hz, 1H), 8.06 (d, J = 9.9 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 6.87 (d, J = 9.0Hz, 1H), 3.72 (s, 1H), 3.51 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H), 1.54 (m, 4H), 1.41-1.15 (m, 13H). ESI-MS: m / z 371.00 [M-Boc+H] + The NMR and mass spectrometry characterization data of compound I-2(1) are presented in Figure 3A and 3B middle.

[0370] Step c: Synthesis of 2-(2-aminocyclohexyl)amino)-5-bromo-N-methyl-3-nitrobenzamide hydrochloride (I-3)

[0371] A solution of compound I-2(1) (90 mg, 0.19 mmol) (or the 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 hours. The mixture was concentrated under vacuum to give compound I-3 as a yellow solid, requiring no further purification.

[0372] Step d: Synthesis of N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)isoquinoline-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)

[0373] At room temperature, a solution of the corresponding isoquinoline-4-carboxylic acid (1 equivalent) and HATU (1.5 equivalent) in anhydrous DMF (6 mL) was stirred. Then, compound I-3 and DIPEA (5.0 equivalent) were added. The mixture was stirred overnight at room temperature. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated brine. The organic phase was then dried over anhydrous Na₂SO₄ and concentrated under vacuum. Finally, the mixture was purified by chromatography to give compound 2, compound 10, or compound 23 as a yellow solid (30%–80% yield).

[0374] Compound 2: 1 H NMR (600 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.69 (d, J = 4.5Hz, 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). The NMR spectra of compound 2 are presented in... Figure 4 middle.

[0375] Compound 10: 1 H NMR (500 MHz, CDCl3) 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 of compound 10 are presented in Figure 5A and 5B middle.

[0376] Compound 23: 1 H NMR (500 MHz, CDCl3) 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] + The NMR and mass spectrometry characterization data of compound 23 are presented in... Figure 6A and 6B middle.

[0377] Compound 20

[0378] Compound 20 can be prepared by the synthesis described in modified Scheme 1 and as described above, i.e., by reacting compound I-1 with commercially available tert-butyl (2-amino-3-hydroxycyclohexyl)carbamate or its stereoisomer in step b in the presence of DIPEA and dimethylformamide (DMF) at 80 °C for 16 h. All other reagents and conditions are the same as those for the preparation of compounds 2, 10, 18, 19 and 23 as described above.

[0379] Compounds 21 and 22

[0380] Compounds 21 and 22 can be prepared by modifying the synthesis described in Scheme 1, i.e., by using different compounds as starting materials 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) instead of 5-bromo-2-fluoro-3-nitrobenzoic acid, both of which are commercially available). All other reagents and conditions are the same as those for the preparation of compounds 2, 10, 18, 19, and 23 as described above.

[0381] Compound 1

[0382] Compound 1 or its analogues can be prepared using the method described in general scheme 2. The preparation of the compound is shown in scheme 3 below.

[0383] Scheme 2: General steps a and b for the preparation of compound 1 and its analogues

[0384]

[0385] Option 3: Preparation of Compound 1

[0386]

[0387] The reagents and conditions for steps a to d as described in Scheme 3 are: (a) 3 M 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.

[0388] Compounds 7, 8 and 11

[0389] Compounds 7, 8 and 11 can be prepared using the method described in Scheme 4 below.

[0390] Scheme 4: Preparation of compounds 7, 8 and 11

[0391]

[0392] The reagents and conditions for steps a to c as described in Scheme 4 are: (a) HATU, DIPEA, or DCM, 0 ˚C, 2 h; (b) DIPEA, DMF, 80 ˚C, 16 h; (c) HATU, DIPEA, DMF, room temperature, 12 h.

[0393] Compounds 3 and 4

[0394] Compounds 3 and 4 can be prepared using the method described in Scheme 5 below.

[0395] Option 5: Preparation of compounds 3 and 4

[0396]

[0397] The reagents and conditions for steps a to c as described in Scheme 5 are: (a) HATU, DIPEA, or DCM, 0 ˚C, 2 h; (b) DIPEA, DMF, 80 ˚C, 16 h; (c) HATU, DIPEA, DMF, room temperature, 12 h.

[0398] Compounds 5 and 6

[0399] Compounds 5 and 6 can be prepared using the method described in Scheme 6 below.

[0400] Scheme 6: Preparation of compounds 5 and 6

[0401]

[0402] The reagents and conditions for steps a through d as described in Scheme 6 are: (a) HATU, DIPEA, or DCM, 0 ˚C, 2 h; (b) DIPEA, DMF, 80 ˚C, 16 h; (c) 3 M HCl·EA, DCM, 1 h; (d) HATU, DIPEA, DMF, room temperature, 12 h.

[0403] Compounds 9, 12, 15 and 16

[0404] Compounds 9, 12, 15 and 16 can be prepared using the method described in Scheme 7 below.

[0405] Scheme 7: Preparation of compounds 9, 12, 15 and 16

[0406]

[0407] The reagents and conditions for steps a and b as described in Scheme 7 are: (a) HATU, DIPEA, or DCM, 0 ˚C, 2 h; (b) HATU, DIPEA, DMF, room temperature, 12 h.

[0408] Compounds 13 and 17

[0409] Compounds 13 and 17 can be prepared using the method described in Scheme 8 below.

[0410] Scheme 8: Preparation of compounds 13 and 17

[0411]

[0412] The reagents and conditions for steps a to c as described in Scheme 8 are: (a) HATU, DIPEA, or DCM, 0 ˚C, 2 h; (b) DIPEA, DMF, 80 ˚C, 16 h; (c) HATU, DIPEA, DMF, room temperature, 12 h.

[0413] Compound 14

[0414] Compound 14 can be prepared using the method described in Scheme 9 below.

[0415] Scheme 9: Preparation of Compound 14

[0416]

[0417] The reagents and conditions for steps a to d as described in Scheme 9 are: (a) HATU, DIPEA, or DCM, 0 ˚C, 2 h; (b) DIPEA, DMF, 80 ˚C, 16 h; (c) 3 M HCl·EA, DCM, 1 h; (d) HATU, DIPEA, DMF, room temperature, 12 h.

[0418] Example 3. Results of in vitro enzyme assay

[0419] The continuous kinetics were tested using fluorescence resonance energy transfer (FRET) based measurements. Figure 1A The ability of three compounds to inhibit 3CLpro was investigated. 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.

[0420] 3CLpro and fluorescent substrate (Dabcyl-KTSAVLQ↓SGFRK) The final concentrations of ME(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 serially diluted solutions of each compound at room temperature for 1 hour. The 384-well plate (Corning, CLS3575) was preheated for 5 minutes at 30 °C, and then 11 μL of the 3CLpro / inhibitor mixture was transferred to the 384-well plate. The reaction was initiated by adding 29 μL of the fluorescent substrate (138 μM in assay buffer). Subsequently, the fluorescence signal was immediately measured every 1 minute at 30 °C using a Thermol Varioskan LUX plate reader at an excitation wavelength of 355 nm and an emission wavelength of 538 nm.

[0421] IC50 of compounds 1, 2 and 8 50 The values ​​were 165.1 nM, 64.6 nM, and 49.5 nM, respectively. Figure 7A ).

[0422] Two analogues of compound 2, compounds 10 and 23, were synthesized and tested. Figure 1BOne of the two analogues, compound 23, exhibits similar IC values ​​to compound 2. 50 ( Figure 7B ).

[0423] Example 4. Structural Biology Research

[0424] To understand how the compounds disclosed herein bind to and inhibit the enzymatic activity of 3CLpro, certain inhibitors were co-crystallized with SARS-CoV-2 3CLpro. 3CLpro was overexpressed in E. coli and purified to homogeneity according to the protocol (5) for the production of SARS-CoV 3CLpro. Prior to crystallization, 10 mg / mL of the purified SARS-CoV-2 3CLpro stock solution 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 h at room temperature, and the precipitate was removed by centrifugation. For crystallization, 0.2 μL of the 3CLpro / inhibitor complex was mixed with 0.2 μL of well buffer from a commercial crystallization kit. Crystals were grown in 96-well plates at 20 °C using sitting-drop vapor diffusion. Diffraction data were collected at 100 K on a Rigaku XtaLAB Synergy Custom diffractometer and resolved by molecular substitution using Phaser-MR (6) in the Phenix software suite (7). The crystal structure of SARS-CoV-2 3CLpro (PDB code: 6Y2E) was used as the initial model. The 3CLpro / inhibitor complex structure was artificially refined using Coot(8) and Phenix(7).

[0425] The crystal structure of the 3CLpro / compound 2 complex was determined by molecular substitution and refined to 1.83 Å. Compound 2 forms a 1:1 complex with 3CLpro. In the crystal structure, one molecule of compound 2 is bound to the catalytic pocket of 3CLpro, thus competitively inhibiting the binding of the 3CLpro substrate. Figure 8A Three hydrogen bonds are formed between compound 2 and 3CLpro: the first is between the nitrogen atom in the isoquinoline ring of compound 2 and the side chain of His163; the second is between the carbonyl group attached to the isoquinoline ring and the side chain of Asn142; and the third is 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, the amino-π interaction between the benzene ring and the side chain of Gln189 also contributes to the effectiveness of compound 2; the strong electron-withdrawing ability of the nitro group gives the aromatic ring a positive charge, thus significantly enhancing this interaction (9).

[0426] The crystal structure of the 3CLpro / compound 8 complex was refined to 1.9 Å. Figure 9A Compound 8 was found to bind to 3CLpro, similar to compound 2. Figure 9B This indicates that the isoquinoline ring and the nitrophenyl ring are important for the interaction with 3CLpro, while the junction region between them keeps them in the proper position.

[0427] The crystal structure of the 3CLpro / compound 1 complex was refined to 1.69 Å. Figure 10A The isoquinoline ring of compound 1 binds to a pouch in 3CLpro surrounded by residues Asn142, His163, and Glu166, similar to the binding of the isoquinoline ring in compound 2. The hydroxyl groups on the isoquinoline ring form additional hydrogen bonds with the side chain of Asn142, facilitating the binding between compound 1 and 3CLpro. The dichlorobenzyl group interacts with the side chain of His41 via π-π stacking.

[0428] Example 5. Anti-SARS-CoV-2 activity of 3Clpro inhibitor in cell assays

[0429] The anti-SARS-CoV-2 activities of compounds 1, 2, and 8 were measured in three different cell lines, including A549, VeroE6, and Calu3. Host cells were infected with nanoluciferase-derived severe respiratory syndrome coronavirus 2 (SARS-CoV-2-Nluc), produced by incorporating the nanoluciferase gene into the SARS-CoV-2 genome, followed by antiviral assays as described in (10). Cytotoxicity assays were also performed as described in (10).

[0430] A549 is a cancerous human alveolar epithelial cell line. The most effective compound in A549 cells is compound 2, followed by compound 8 and compound 1, with IC50 values ​​of [missing information]. 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 for three days with stock solutions of these compounds in serially diluted forms. 50% cytotoxic concentrations (CC) of all these compounds were calculated. 50 All are greater than 20 μM. Figure 11B ).

[0431] 3CLpro inhibitors, particularly compound 2, have also shown efficacy in VeroE6 cells ( Figure 12A ) and Calu3 cells ( Figure 12B It has high efficacy in inhibiting SARS-CoV-2 replication.

[0432] The test results above show that several non-covalent small molecule inhibitors of SARS-CoV-2 3CLpro, such as compounds 1, 2, and 8, effectively block coronavirus replication in host cells. For example, compound 2 showed high potency in both cell-free enzyme assays and cell-based anti-SARS-CoV-2 assays. Compound 2 and its analogues, such as, but not limited to, compounds 10, 18, and 23, may be used to treat diseases or symptoms caused by coronaviruses such as COVID-19.

[0433] Sequence analysis showed that the residues surrounding compound 2 were highly conserved in SARS-CoV 3CLpro and MERS-CoV 3CLpro. Figure 13 (and Table 2), indicating that compound 2 and its analogues may be pan-inhibitors of coronavirus 3CL protease.

[0434] Table 2. Examples of coronavirus 3CLpro protein sequences

[0435] References

[0436] 1.AR Fehr, S. Perlman, Coronaviruses: an overview of their replication and pathogenesis. Methods Mol. Biol. 1282, 1–23 (2015).

[0437] 2.P. Zhou et al., A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 579, 270–273 (2020).

[0438] 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).

[0439] 4.T. Pillaiyar, M. Manickam, V. Namasivayam, Y. Hayashi, S.-H. Jung,An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CLProtease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy. J. Med.Chem. 59, 6595–6628 (2016).

[0440] 5.X. Xue et al., Production of authentic SARS-CoV M(pro) withenhanced activity: application as a novel tag-cleavage endopeptidase forprotein overproduction. J. Mol. Biol. 366, 965–975 (2007).

[0441] 6.A. J. McCoy et al., Phaser crystallographic software. J ApplCrystallogr. 40, 658–674 (2007).

[0442] 7.D. Liebschner et al., Macromolecular structure determination usingX-rays, neutrons and electrons: recent developments in Phenix. ActaCrystallogr D Struct Biol. 75, 861–877 (2019).

[0443] 8.P. Emsley, B. Lohkamp, W. G. Scott, K. Cowtan, Features anddevelopment of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501(2010).

[0444] 9.H. Wang, W. Wang, WJ Jin, σ-Hole Bond vs π-Hole Bond: AComparison Based on Halogen Bond. Chem. Rev. 116, 5072–5104 (2016).

[0445] 10.

[0446] Those skilled in the art will readily recognize from this disclosure and the claims that various changes, modifications and variations may be made therein without departing from the spirit and scope of this disclosure as defined in the following claims.

Claims

1. A compound of the following structural Formula IVc: ###0001### Formula IVc or a pharmaceutically acceptable salt thereof; wherein: X is -NH-, Y is cyclohexyl, Z is absent, m is an integer selected from 0 and 1 ; and o is an integer of 0.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: ###0002### Formula IVc 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: ###0003### Formula IVc m is an integer of 0. R 1 is independently at each occurrence -OR s , wherein R s is hydrogen; 4. A compound having the structure: ###0004### 5. A compound, wherein the compound is selected from the group consisting of: ###0005### Compound 2 ###0006### Compound 10 and pharmaceutically acceptable salts thereof.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. R 2’’ R is halogen; and R 2’’’ -C(=O)NR p R q ; wherein R p and R q are each independently hydrogen or C1-C4alkyl; 7. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for the manufacture of a medicament for the treatment of a disease caused by a coronavirus, wherein the disease is a respiratory infectious disease; wherein the symptoms are selected from the group consisting of fever or chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, 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, inability to wake or stay awake, bluish lips or face, and combinations thereof; wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

8. The use according to claim 7, wherein the respiratory infectious disease is severe acute respiratory syndrome.

9. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6, for the manufacture of a medicament for reducing or inhibiting the activity of a protease of a coronavirus, or a medicament for reducing or inhibiting the replication of a coronavirus, wherein the protease is a 3C-like protease; wherein the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). R 1 is -OH, m is an integer of 1, R 2’’ is F, CI or Br; and R 2’’’ is -C(=O)NHCH3. ​ R 2’’ is F, CI or Br; and R 2’’’ -C(=0)NHCH3; ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

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