Anti-coronavirus compounds, their compositions and uses

Abstract

The present disclosure relates to compounds that exhibit activity in inhibiting 3-chymotrypsin-like protease, pharmaceutical compositions containing such compounds, and methods of treating viral infections by administering such compounds or pharmaceutical compositions.

Description

[0001] This application is a divisional application of a Chinese patent application with the application number 202280075597.9, the filing date of December 29, 2022, and the invention title of "Anti-coronavirus Compounds and Their Compositions and Uses". The original application is the national phase application of an international application with the international application number PCT / CN2022 / 143464. This international application claims the priority of international applications PCT / CN2021 / 142604 filed on December 29, 2021, and PCT / CN2022 / 101118 filed on June 24, 2022. Field of the Invention

[0002] The present disclosure generally relates to compounds that are active in inhibiting 3-chymotrypsin-like protease and pharmaceutical compositions containing such compounds, as well as methods of treatment by administering such compounds or pharmaceutical compositions containing such compounds. Background Art

[0003] Coronaviruses are highly prone to mutate into epidemic variants. Despite the approval of multiple vaccines since the outbreak of SARS-CoV-2, vaccinated individuals still face the risk associated with the emergence of immune escape mutants. Therefore, it is very important to develop antiviral drugs to combat existing and emerging coronaviruses.

[0004] Coronavirus 3-chymotrypsin-like protease (3CLpro; also known as "main protease" or "Mpro") is an attractive drug target because it plays an important role in processing the polyproteins translated from viral RNA. It cleaves two large overlapping polyproteins, pp1a and pp1ab, at more than 11 sites, generating the essential non-structural proteins required for viral replication and pathogenesis. The Cys145-His41 catalytic dyad located in the crevice between domain I and domain II of 3CLpro facilitates this cleavage process. The Cys145-His41 catalytic dyad and the substrate binding site are highly conserved among different species of coronaviruses, including Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) that emerged in 2002 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) that emerged in 2012. Therefore, 3CLpro inhibitors are a promising broad-spectrum antiviral agent for coronavirus infections and other related diseases.

[0005] Pfizer has developed two 3CLpro inhibitors, PF-07304814 and PF-07321332 (nirmatrelvir). Even when combined with an oxidase inhibitor, PF-07304814 still exhibits rather low oral bioavailability and low tolerance to oxidase. PF-07321332 does not overcome the problem of low tolerance to oxidase, so it needs to be co-administered with the oxidase inhibitor ritonavir tablets to effectively combat SARS-CoV-2.

[0006] Therefore, there is a need in the art to develop improved compounds that exhibit inhibitory activity against 3CLpro, particularly 3CLpro inhibitors with good oral bioavailability and high tolerance to oxidase. Summary of the Invention

[0007] The present disclosure provides compounds capable of inhibiting 3-chymotrypsin-like protease, pharmaceutical compositions comprising these compounds, and methods of using such compounds or pharmaceutical compositions to treat viral infections.

[0008] In one aspect, the present disclosure provides a compound having the formula (I’):

[0009]

[0010] or a pharmaceutically acceptable salt thereof,

[0011] wherein

[0012] R 1 and R 2 are each independently hydrogen, halogen, or alkyl, the alkyl being optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or

[0013] R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, or alkyl;

[0014] optionally substituted by one or more R a substituents;

[0015] each R a is selected from halogen, hydroxy, cyano, amino, alkyl, alkenyl, alkynyl, or haloalkyl, or

[0016] two R aTogether with the carbon atoms to which they are attached, form a cycloalkyl or heterocyclic group, which cycloalkyl or heterocyclic group may optionally be substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl;

[0017] L is selected from *-L 1 - or *-L 2 -(CH 2 ) q -L 3 -

[0018] L 1 and L 2 are each independently selected from the group consisting of: a bond, *-N(R b )-, *-O-, *-S-, *-CR b =CR c -*, -C≡C-, *-S(O)-, *-SO 2 - *-Z-C(O)-Z- and wherein the *-end of L is connected to the *-end of ;

[0019] L 3 is selected from a bond, -N(R b )-, -O-, -S-, -CR b =CR c -*, -C≡C-, -S(O)- or -SO 2 -

[0020] each V is independently selected from CR b or N, each Z is independently selected from a bond, -CR b R c -*, -O- or -N(R b )-; R b and R c are each independently selected from hydrogen, halogen, alkyl or haloalkyl;

[0021] Ring A is a 5- or 6-membered heterocyclic group;

[0022] each R 3 is independently hydrogen, halogen or alkyl, said alkyl being optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, alkenyl or alkynyl, or

[0023] one or two pairs of R 3 together with the carbon atoms to which they are attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, alkyl, alkenyl or alkynyl;

[0024] R 4 is a warhead capable of covalently binding to 3CL protease;

[0025] G is C or Si;

[0026] R 5A 、R 5B and R 6 are each independently selected from hydrogen, halogen, -OR d , alkyl, haloalkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclic group, alkylaryl or alkylheteroaryl, wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclic group, alkylaryl and alkylheteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, amino, alkyl, alkoxy or haloalkyl, and R d is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkylaryl, alkylcycloalkyl, alkylheterocyclic group, alkylheteroaryl, cycloalkyl, heterocyclic group, aryl and heteroaryl; or

[0027] R 5A and R 5B together with the G atom to which they are attached form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic group are optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl; or

[0028] R 5B and R 6 together with the atoms to which they are attached form a cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein the cycloalkyl, heterocyclic group, aryl or heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl;

[0029] R 7 is -R 7-1 -R 7-2 wherein R 7-1 is selected from a bond, -C(O)O-**, -C(O)-**, -C(O)N(R b )-** or -SO 2 -**, R 7-2Selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, alkenylcycloalkyl, alkenylheterocycloalkyl, alkenylaryl, alkenylheteroaryl, heteroalkylaryl, heteroalkylheteroaryl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkoxy, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, alkenylcycloalkyl, alkenylheterocycloalkyl, alkenylaryl, alkenylheteroaryl, heteroalkylaryl, heteroalkylheteroaryl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, alkyl, alkoxy, haloalkyl or -C(O)CF 3 wherein R 7-1 the **terminus is attached to R 7-2 ;

[0030] R 8 is selected from hydrogen, halogen, alkyl or haloalkyl; or

[0031] R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, the heterocycloalkyl group being optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl;

[0032] R 9 is selected from hydrogen, methyl or ethyl;

[0033] m is 0, 1, 2, 3 or 4;

[0034] n is 0, 1, 2, 3 or 4;

[0035] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and

[0036] q is 0, 1 or 2.

[0037] In another aspect, there is provided a compound having formula (I) or (II):

[0038]

[0039]

[0040] or a pharmaceutically acceptable salt thereof.

[0041] In yet another aspect, there is provided a compound having formula (III):

[0042]

[0043] or a pharmaceutically acceptable salt thereof.

[0044] In yet another aspect, provided are compounds having formula (IIIa) or (IIIb):

[0045]

[0046] or a pharmaceutically acceptable salt thereof.

[0047] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0048] In another aspect, the present disclosure provides a method for treating a viral infection in a patient in need thereof, which comprises administering to the subject an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0049] In another aspect, the present disclosure provides a method for inhibiting 3-chymotrypsin-like protease in a subject in need thereof, which comprises administering to the subject in need thereof an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

[0050] In another aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating a viral infection.

[0051] In another aspect, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure for treating a viral infection. DETAILED DESCRIPTION

[0052] For a detailed description, reference is made to certain embodiments of the present disclosure, examples of which are illustrated in the accompanying structures and formulas. Although the present disclosure will be described in conjunction with the enumerated embodiments, it should be understood that it is not intended that the present disclosure be limited to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, or equivalents, which may be included within the scope of the present disclosure as defined by the claims. Those skilled in the art will recognize many methods or substances for practicing the present disclosure that are similar or equivalent to those described herein. The present disclosure is in no way limited to the methods or substances described. In the event of a difference or conflict between one or more of the incorporated references and similar materials (including, but not limited to, defined terms, term usage, techniques, etc.) and the present application, the present disclosure shall prevail. All references, patents, and patent applications cited in the present disclosure are hereby incorporated by reference in their entirety.

[0053] It should be understood that certain features of the present disclosure that are described in the context of different embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure that are described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination. It must be noted that, unless the context clearly dictates otherwise, as used in the specification and the appended claims, the singular forms "a / an" and "the" include their plural forms. Thus, for example, reference to "a compound" includes a plurality of compounds.

[0054] Definition

[0055] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of the present disclosure, chemical elements are identified according to the Periodic Table, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry and specific functional groups and reactivity are described in Organic Chemistry, Thomas Sorrell, 2nd Edition, University Science Books, Sausalito, 2006; Smith and March, March's Advanced Organic Chemistry, 6th Edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd Edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th Edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of which are incorporated herein by reference.

[0056] Throughout the present disclosure, linking substituents are described. In particular, each linking substituent is intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R")- includes both -NR(CR'R")- and -(CR'R")NR-. In cases where a linking group is explicitly required by the structure, the Markush variables recited for the group are to be understood as linking groups. By way of example, if the structure requires a linking group and the Markush group definition of the variable lists "alkyl", then it is to be understood that the "alkyl" represents a linking alkylene group.

[0057] When a bond to a substituent is shown crossing a bond to two atoms in a linked ring, then the substituent may be bonded to any atom on the ring. When a listed substituent does not indicate the atom to which the substituent is bonded to the remainder of a given formula compound, then the substituent may be bonded via any atom in the formula. Combinations of substituents and / or variables are permissible only if the combination results in a stable compound.

[0058] When a "*" is shown adjacent to an atom of a compound, it indicates that the compound contains the atom as an asymmetric center of (R) or (S) stereoconfiguration.

[0059] When any variable (e.g., R i ) appears more than once in any component of a compound or in a formula, its definition at each occurrence is independent of its definition at each other occurrence. Thus, by way of example, if a group is shown to be substituted with 0 - 2 R i moieties, then the group may optionally be substituted with up to two R i moieties, and R i is independently selected at each occurrence from the definitions for R i . Also, combinations of substituents and / or variables are permissible only if the combination results in a stable compound.

[0060] As used herein, the term "C i-j " indicates a range of carbon atom numbers, where i and j are integers, and the range of carbon atom numbers includes the endpoints (i.e., i and j) and each integer point therebetween, and where j is greater than i. By way of example, C 1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C 1-12 " indicates 1 to 12, particularly 1 to 10, particularly 1 to 8, particularly 1 to 6, particularly 1 to 5, particularly 1 to 4, particularly 1 to 3, or particularly 1 to 2 carbon atoms.

[0061] As used herein, whether used as part of another term or independently, the term "alkyl" refers to a saturated straight-chain or branched-chain hydrocarbon group, which may optionally and independently be substituted with one or more of the substituents described below. The term "C i-j alkyl" refers to an alkyl group having from i to j carbon atoms. In some embodiments, the alkyl group contains from 1 to 10 carbon atoms. In some embodiments, the alkyl group contains from 1 to 9 carbon atoms. In some embodiments, the alkyl group contains from 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of "C 1-10 alkyl" include (but are not limited to) methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. Examples of "C 1-6 alkyl" are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, and the like.

[0062] As used herein, the term "alkylcycloalkyl" refers to an alkyl group linked to a cycloalkyl group, including –alkyl-cycloalkyl and alkyl-cycloalkyl-. In some embodiments, alkylcycloalkyl refers to –alkyl-cycloalkyl.

[0063] As used herein, the term "alkylheterocyclyl" refers to an alkyl group linked to a heterocyclyl group, including –alkyl-heterocyclyl and alkyl-heterocyclyl-. In some embodiments, alkylheterocyclyl refers to –alkyl-heterocyclyl.

[0064] As used herein, the term "alkylaryl" refers to an alkyl group linked to an aryl group, including –alkyl-aryl and alkyl-aryl-. In some embodiments, alkylaryl refers to –alkyl-aryl.

[0065] As used herein, the term "alkylcycloalkyl" refers to an alkyl group linked to an aryl group, including –alkyl-cycloalkyl and alkyl-cycloalkyl-. In some embodiments, alkylcycloalkyl refers to –alkyl-cycloalkyl.

[0066] As used herein, the term "alkylheteroaryl" refers to an alkyl group linked to a heteroaryl group, including –alkyl-heteroaryl and alkyl-heteroaryl-. In some embodiments, alkylheteroaryl refers to –alkyl-heteroaryl.

[0067] As used herein, whether as part of another term or used independently, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon group having at least one carbon-carbon double bond, which may optionally and independently be substituted with one or more substituents described herein, and includes groups having "cis" and "trans" conformations, or alternatively, "E" and "Z" conformations. In some embodiments, the alkenyl contains 2 to 12 carbon atoms. In some embodiments, the alkenyl contains 2 to 11 carbon atoms. In some embodiments, the alkenyl contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkenyl contains 2 carbon atoms. Examples of alkenyl include (but are not limited to) ethylenyl / vinyl, propenyl (allyl), butenyl, pentenyl, 1-methyl-2-but-1-enyl, 5-hexenyl, and the like.

[0068] As used herein, the term "alkenylcycloalkyl" refers to an alkenyl group linked to a cycloalkyl group, including –alkenyl-cycloalkyl and alkenyl-cycloalkyl-. In some embodiments, alkenylcycloalkyl refers to –alkenyl-cycloalkyl.

[0069] As used herein, the term "alkenylheterocyclyl" refers to an alkenyl group linked to a heterocyclyl group, including –alkenyl-heterocyclyl and alkenyl-heterocyclyl-. In some embodiments, alkenylheterocyclyl refers to –alkenyl-heterocyclyl.

[0070] As used herein, the term "alkenylaryl" refers to an alkenyl group linked to an aryl group, including –alkenyl-aryl and alkenyl-aryl-. In some embodiments, alkenylaryl refers to –alkenyl-aryl.

[0071] As used herein, the term "alkenylheteroaryl" refers to an alkenyl group linked to a heteroaryl group, including –alkenyl-heteroaryl and alkenyl-heteroaryl-. In some embodiments, alkenylheteroaryl refers to –alkyl-heteroaryl.

[0072] As used herein, the term "alkoxy", whether as part of another term or used independently, refers to an alkyl group linked to oxygen (-O-alkyl). In some embodiments, the alkoxy contains 1 to 10 carbon atoms. In some embodiments, the alkoxy contains 1 to 9 carbon atoms. In some embodiments, the alkoxy contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkoxy include but are not limited to methoxy, ethoxy, isopropoxy, and the like.

[0073] Whether used as part of another term or independently, as used herein, the term "alkynyl" refers to a straight-chain or branched-chain hydrocarbyl group having at least one carbon-carbon triple bond, which may optionally and independently be substituted with one or more substituents described herein. In some embodiments, the alkynyl group contains 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms. In some embodiments, the alkynyl group contains 2 to 11 carbon atoms, 2 to 10 carbon atoms, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbon atoms, 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms, and in some embodiments, the alkynyl group contains 2 carbon atoms. Examples of alkynyl groups include (but are not limited to) ethynyl, 1-propynyl, 2-propynyl, etc.

[0074] As used herein, the term "amino" refers to -NH 2 group. The amino group may also be substituted with one or more groups such as alkyl, aryl, carbonyl, or other amino groups.

[0075] Whether used as part of another term or independently, as used herein, the term "aryl" refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 12 ring members. Examples of "aryl" include (but are not limited to) phenyl, biphenyl, naphthyl, anthracenyl, etc., which may bear one or more substituents. As used herein, groups in which an aromatic ring is fused to one or more additional rings are also included within the scope of the term "aryl". In the case of polycyclic ring systems, only one ring needs to be aromatic (e.g., 2,3-dihydroindole), although all rings may be aromatic (e.g., quinoline). The second ring may also be fused or bridged. Examples of polycyclic aryl groups include (but are not limited to) benzofuranyl, indanyl, phthalimido, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, etc. The aryl group may be substituted at one or more ring positions with substituents as described above.

[0076] As used herein, whether used as part of another term or independently, the term "cycloalkyl" refers to a monovalent non-aromatic, saturated or partially unsaturated monocyclic and polycyclic ring system, wherein all ring atoms are carbon and the ring system contains at least three ring-forming carbon atoms. In some embodiments, the cycloalkyl may contain 3 to 12 ring-forming carbon atoms, 3 to 10 ring-forming carbon atoms, 3 to 9 ring-forming carbon atoms, 3 to 8 ring-forming carbon atoms, 3 to 7 ring-forming carbon atoms, 3 to 6 ring-forming carbon atoms, 3 to 5 ring-forming carbon atoms, 4 to 12 ring-forming carbon atoms, 4 to 10 ring-forming carbon atoms, 4 to 9 ring-forming carbon atoms, 4 to 8 ring-forming carbon atoms, 4 to 7 ring-forming carbon atoms, 4 to 6 ring-forming carbon atoms, 4 to 5 ring-forming carbon atoms. The cycloalkyl can be saturated or partially unsaturated. The cycloalkyl can be substituted. In some embodiments, the cycloalkyl can be a saturated cycloalkyl. In some embodiments, the cycloalkyl can be a partially unsaturated cycloalkyl containing at least one double bond or triple bond in its ring system. In some embodiments, the cycloalkyl can be monocyclic or polycyclic. Examples of monocyclic cycloalkyls include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of polycyclic cycloalkyls include (but are not limited to) adamantyl, norbornyl, fluorenyl, spiro-pentadienyl, spiro[3.6]-decyl, bicyclo[1,1,1]pentenyl, bicyclo[2,2,1]heptenyl, etc.

[0077] As used herein, the term "cyano" refers to -CN.

[0078] As used herein, the term "halogen" refers to an atom selected from fluorine (fluorine / fluoro), chlorine (chlorine / chloro), bromine (bromine / bromo) and iodine (iodine / iodo).

[0079] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogens. In some embodiments, the haloalkyl may contain 1 to 6 carbon atoms. In some embodiments, the haloalkyl may contain 1 to 4 carbon atoms. In some embodiments, the haloalkyl may contain 1 to 3 carbon atoms. Examples of haloalkyls include but are not limited to trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromomethyl, tribromomethyl and tetrafluoroethyl.

[0080] As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur, phosphorus or silicon, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen (including N-oxides).

[0081] As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one carbon atom is replaced by a heteroatom selected from N, O, S, P, or Si. The heteroalkyl group can be a carbon group or a heteroatom group (i.e., the heteroatom can be in the middle or at the end of the group), and is optionally and independently substituted by one or more substituents described herein. The term "heteroalkyl" includes alkoxy radicals and heteroalkoxy radicals.

[0082] As used herein, the term "heteroalkylaryl" refers to a heteroalkyl group attached to an aryl group, including –heteroalkyl-aryl and heteroalkyl-aryl-. In some embodiments, the heteroalkylaryl refers to –heteroalkyl-aryl.

[0083] As used herein, the term "heteroalkylcycloalkyl" refers to a heteroalkyl group attached to a cycloalkyl group, including –heteroalkyl-cycloalkyl and heteroalkyl-cycloalkyl-. In some embodiments, the heteroalkylcycloalkyl refers to –heteroalkyl-cycloalkyl.

[0084] As used herein, the term "heteroalkylheteroaryl" refers to a heteroalkyl group attached to a heteroaryl group, including –heteroalkyl-heteroaryl or heteroalkyl-heteroaryl-. In some embodiments, the heteroalkylheteroaryl refers to –heteroalkyl-heteroaryl.

[0085] As used herein, the term "heteroaryl" refers to an aryl group that has one or more heteroatoms in addition to carbon atoms. The heteroaryl group can be monocyclic. Examples of monocyclic heteroaryl groups include (but are not limited to) thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, benzofuranyl, and pteridinyl. The heteroaryl group also includes polycyclic groups in which a heteroaromatic ring is fused with one or more aryl groups, cycloaliphatic groups, or heterocyclic groups, where the linking group or point of attachment is on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include (but are not limited to) indolyl, isoindolyl, benzothienyl, benzofuranyl, benzo[1,3]dioxolyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0086] As used herein, the term "heterocyclic group" refers to a saturated or partially unsaturated carbocyclic group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, etc., and the remaining ring atoms are carbon, and one or more of the ring atoms may optionally be independently substituted with one or more substituents. In some embodiments, the heterocyclic group is a saturated heterocyclic group. In some embodiments, the heterocyclic group is a partially unsaturated heterocyclic group having one or more double bonds in its ring system. In some embodiments, the heterocyclic group may contain any oxidized form of carbon, nitrogen or sulfur and any quaternized form of basic nitrogen. "Heterocyclic group" also includes groups in which the heterocyclic group is fused to a saturated, partially unsaturated or fully unsaturated (i.e., aromatic) carbocyclic or heterocyclic ring. Where possible, the heterocyclic group may be carbon-linked or nitrogen-linked. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. By way of example, a group derived from pyrrole may be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked). Additionally, a group derived from imidazole may be imidazol-1-yl (nitrogen-linked) or imidazol-3-yl (carbon-linked).

[0087] In some embodiments, the term "3- to 12-membered heterocyclic group" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic or polycyclic heterocyclic ring system having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Fused, spiro, and bridged ring systems are also included within the scope of this definition. Examples of monocyclic heterocyclic groups include (but are not limited to) oxetanyl, 1,1-dioxothietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperazinyl, piperidinyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidinonyl, pyrazinonyl, pyrimidinonyl, pyridazonyl, pyrrolidinyl, triazinonyl, etc. Examples of fused heterocyclic groups include (but are not limited to) phenyl-fused or pyridyl-fused rings, such as quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromenyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, [1,2,3]triazolo[4,3-a]pyridyl, etc. Examples of spiro heterocyclic groups include (but are not limited to) spiropyranyl, spirooxazinyl, etc. Examples of bridged heterocyclic groups include (but are not limited to) morphanyl, hexamethylenetetramine, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.

[0088] As used herein, the term "hydroxy" refers to -OH.

[0089] As used herein, the term "partially unsaturated" refers to a group that includes at least one double bond or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (i.e., fully unsaturated) moieties.

[0090] As used herein, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. It is understood that "substitution" or "substituted" includes the implicit limitation that the substitution is consistent with the allowable valences of the atoms being substituted and that the substitution results in a stable or chemically feasible compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, etc. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the specified groups, the substituents at each position may be the same or different. One of ordinary skill in the art will understand that, where appropriate, the substituents themselves may be substituted. Unless specifically stated as "unsubstituted", a chemical moiety referred to herein is understood to include substituted variants. By way of example, reference to an "aryl" or "aryl" moiety implicitly includes both substituted and unsubstituted variants.

[0091] Compound

[0092] The present disclosure provides novel compounds of formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for making the compounds, pharmaceutical compositions containing them, and various uses of the disclosed compounds.

[0093] In one aspect, the present disclosure provides a compound having formula (I'):

[0094]

[0095] or a pharmaceutically acceptable salt thereof,

[0096] wherein

[0097] R 1 and R 2 are each independently hydrogen, halogen, or alkyl, the alkyl being optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, or

[0098] R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, or alkyl;

[0099] optionally substituted by one or more R a substituents;

[0100] each R aSelected from halogen, hydroxy, cyano, amino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0101] two Rs a together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group, which cycloalkyl or heterocyclic group may optionally be substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl;

[0102] L is selected from *-L 1 -, or *-L 2 -(CH 2 ) q -L 3 -,

[0103] L 1 and L 2 each independently is selected from the group consisting of: a bond, *-N(R b )-, *-O-, *-S-, *-CR b =CR c -*, -C≡C-, *-S(O)-, *-SO 2 - *-Z-C(O)-Z- and wherein the *-end of L is connected to the *-end of;

[0104] L 3 is selected from a bond, -N(R b )-, -O-, -S-, -CR b =CR c -*, -C≡C-, -S(O)- or -SO 2 -

[0105] each V is independently selected from CR b or N, each Z is independently selected from a bond, -CR b R c -*, -O- or -N(R b )-;

[0106] R b and R c each independently is selected from hydrogen, halogen, alkyl or haloalkyl;

[0107] Ring A is a 5- or 6-membered heterocyclic group;

[0108] each R 3 is independently hydrogen, halogen or alkyl, said alkyl being optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, alkenyl or alkynyl, or

[0109] one pair or two pairs of Rs 3Each together with the carbon atom to which it is attached forms a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, alkyl, alkenyl or alkynyl;

[0110] R 4 is a warhead capable of covalently binding to 3CL protease;

[0111] G is C or Si;

[0112] R 5A 、R 5B and R 6 are each independently selected from hydrogen, halogen, -OR d , alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclic, alkylaryl or alkylheteroaryl, wherein the cycloalkyl, heterocyclic, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclic, alkylaryl and alkylheteroaryl groups are optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, alkyl, alkoxy or haloalkyl, and R d is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkylaryl, alkylcycloalkyl, alkylheterocyclic, alkylheteroaryl, cycloalkyl, heterocyclic, aryl and heteroaryl; or

[0113] R 5A and R 5B together with the G atom to which they are attached form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl; or

[0114] R 5B and R 6 together with the atom to which they are attached form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl;

[0115] R 7 is -R 7-1 -R 7-2 wherein R 7-1 is selected from a bond, -C(O)O-**, -C(O)-**, -C(O)N(R b )-** or -SO 2 -**, R 7-2Selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, alkenylcycloalkyl, alkenylheterocycloalkyl, alkenylaryl, alkenylheteroaryl, heteroalkylaryl, heteroalkylheteroaryl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, alkoxy, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl, alkenylcycloalkyl, alkenylheterocycloalkyl, alkenylaryl, alkenylheteroaryl, heteroalkylaryl, heteroalkylheteroaryl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino, alkyl, alkoxy, haloalkyl or -C(O)CF 3 wherein R 7-1 the **terminus is attached to R 7-2 ;

[0116] R 8 is selected from hydrogen, halogen, alkyl or haloalkyl; or

[0117] R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocycloalkyl group, the heterocycloalkyl group being optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl;

[0118] R 9 is selected from hydrogen, methyl or ethyl;

[0119] m is 0, 1, 2, 3 or 4;

[0120] n is 0, 1, 2, 3 or 4;

[0121] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8; and

[0122] q is 0, 1 or 2.

[0123] In another aspect, there is provided a compound having formula (I) or (II):

[0124]

[0125] or a pharmaceutically acceptable salt thereof, wherein L, R 1 -R 4 、R 5A 、R 5B 、R 6 、R 7 、m, n and p are as defined above.

[0126] In some embodiments, R 1 and R 2 are each independently hydrogen, halogen or alkyl.

[0127] In some embodiments, R 1 and R 2 are both hydrogen.

[0128] In some embodiments, R 1 and R 2 are both alkyl. In certain embodiments, R 1 and R 2 are both methyl.

[0129] In some embodiments, R 1 and R 2 are each independently hydrogen or halogen.

[0130] In some embodiments, 1 one of R 2 and the other is halogen. In certain embodiments, 1 one of R 2 and the other is hydrogen and the other is fluorine.

[0131] In some embodiments, R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl group, which cycloalkyl group is optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl.

[0132] In certain embodiments, R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropyl group, which cyclopropyl group is optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl.

[0133] In some embodiments, is optionally substituted with one or more R a and each R a is independently selected from halogen, alkyl or haloalkyl. In certain embodiments, each R a is independently fluorine, methyl, ethyl, propyl or trifluoromethyl.

[0134] In some embodiments, is optionally substituted with one or more Ra, and two Ra together with the carbon atom to which they are attached form a cycloalkyl group, which cycloalkyl group is optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl. In certain embodiments, two R a together with the carbon atom to which they are attached form a cyclopropyl group, which cyclopropyl group is optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, amino or alkyl.

[0135] In some embodiments, L is *-L 1 -, and L 1 is a bond.

[0136] In certain embodiments, is selected from

[0137] In some embodiments, L is *-L 1 -, and L 1 is *-N(R b ). In certain embodiments, R b is selected from hydrogen, halogen, alkyl, or haloalkyl. In certain embodiments, R b is selected from hydrogen, fluorine, methyl, or trifluoromethyl.

[0138] In certain embodiments, is selected from the group consisting of:

[0139]

[0140] In some embodiments, L is *-L 1 -, and L 1 is *-O-.

[0141] In certain embodiments, is selected from the group consisting of:

[0142]

[0143] In some embodiments, L is *-L 1 -, and L 1 is *-S-.

[0144] In certain embodiments, is selected from

[0145] In some embodiments, L is *-L 1 -, and L 1 is *-CR b =CR c -. In certain embodiments, R b and R c are each independently hydrogen or alkyl. In certain embodiments, R b and R c are each independently hydrogen or methyl. In certain embodiments, R b and R c are both hydrogen. In certain embodiments, R b and R care both methyl. In certain embodiments, R b and R c one of which is hydrogen and the other is methyl.

[0146] In certain embodiments, is selected from the group consisting of:

[0147]

[0148]

[0149] wherein the wavy line directly connected to the double bond indicates that the double bond is in the E or Z configuration.

[0150] In some embodiments, L is *-L 2 -(CH 2 ) q -L 3 -, where L 2 is *-O-, L 3 is -CR b =CR c -.

[0151] In certain embodiments, is selected from

[0152] In some embodiments, L is *-L 2 -(CH 2 ) q -L 3 -, where L 2 is *-CR b =CR c -, and L 3 is -O-.

[0153] In certain embodiments, is selected from

[0154] In some embodiments, L is *-L 1 -, and L 1 is *-C≡C-.

[0155] In certain embodiments, is selected from

[0156] In some embodiments, L is *-L 1 -, and L 1 is *-S(O)-.

[0157] In certain embodiments, selected from

[0158] In some embodiments, L is *-L 1 -, and L 1 is *-SO 2 -.

[0159] In certain embodiments, selected from

[0160] In some embodiments, L is *-L 1 -, and L 1 is In certain embodiments, Z is -CR b R c -, -O-, or -N(R b )-, where R b and R c are each independently hydrogen or alkyl.

[0161] In certain embodiments, selected from

[0162] In some embodiments, L is *-L 1 -, and L 1 is *-Z-C(O)-Z-. In certain embodiments, Z is -CR b R c -, -O-, or -N(R b )-, where R b and R c are each independently hydrogen, alkyl, or haloalkyl. In certain embodiments, R b and R c are each independently hydrogen, methyl, or trifluoromethyl.

[0163] In certain embodiments, selected from the group consisting of:

[0164]

[0165]

[0166] In some embodiments, selected from the group consisting of:

[0167]

[0168] In some embodiments, ring A is selected from wherein X, Y, W, and T are each independently selected from -C-, -N-, or -O-, and wherein each of which optionally contains a double bond.

[0169] In some embodiments, each R 3 is independently hydrogen, halogen, or alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from halogen.

[0170] In some embodiments, one or two pairs of Rs 3 each together with the carbon atom to which they are attached form a cycloalkyl or aryl group, wherein the cycloalkyl and aryl groups are optionally substituted with one or more groups independently selected from halogen or alkyl.

[0171] In some embodiments, ring A is selected from the group consisting of

[0172]

[0173] In certain embodiments, each R 3 is independently hydrogen, halogen, or alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from halogen, hydroxy, or cyano.

[0174] In certain embodiments, a pair of Rs 3 together with the carbon atom to which they are attached form a cycloalkyl group, wherein the cycloalkyl group is optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, or alkyl.

[0175] In some embodiments, ring A is selected from the group consisting of:

[0176]

[0177]

[0178] In some embodiments, ring A is selected from the group consisting of

[0179]

[0180] In certain embodiments, each R 3 is independently hydrogen, halogen, or alkyl, wherein the alkyl is optionally substituted with one or more groups independently selected from halogen, hydroxy, or cyano.

[0181] In certain embodiments, one or two pairs of Rs 3 each together with the carbon atom to which they are attached form a cycloalkyl or aryl group, wherein the cycloalkyl and aryl groups are optionally substituted with one or more groups independently selected from halogen or alkyl.

[0182] In some embodiments, Ring A is selected from the group consisting of

[0183]

[0184]

[0185] In some embodiments, Ring A is selected from the group consisting of

[0186] In some embodiments, Ring A is selected from the group consisting of

[0187] In some embodiments, Ring A is selected from the group consisting of

[0188] In some embodiments, Ring A is selected from the group consisting of

[0189] In some embodiments, Ring A is selected from the group consisting of

[0190] In some embodiments, Ring A is selected from the group consisting of

[0191] In some embodiments, Ring A is selected from the group consisting of

[0192] In some embodiments, Ring A is selected from the group consisting of

[0193] In some embodiments, Ring A is selected from the group consisting of

[0194] In some embodiments, Ring A is selected from the group consisting of

[0195] In some embodiments, Ring A is selected from the group consisting of

[0196]

[0197] In some embodiments, Ring A is selected from the group consisting of

[0198]

[0199] In some embodiments, Ring A is selected from the group consisting of

[0200] In some embodiments, Ring A is selected from the group consisting of

[0201] In some embodiments, Ring A is selected from the group consisting of

[0202] In some embodiments, Ring A is selected from the group consisting of

[0203] In some embodiments, R 4 is selected from the group consisting of:

[0204]

[0205]

[0206] In some embodiments, R 5A , R 5B and R 6 are each independently selected from hydrogen, -OR d , alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, alkylaryl or alkylheteroaryl, wherein the cycloalkyl, aryl, heteroaryl, alkylaryl and alkylheteroaryl are optionally substituted with one or more groups independently selected from halogen, alkyl or haloalkyl.

[0207] In certain embodiments, is selected from the group consisting of:

[0208]

[0209]

[0210]

[0211] In some embodiments, R 5A and R 5BTogether with the G atoms to which they are attached, form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more groups independently selected from halogen or alkyl.

[0212] In certain embodiments, G is C, and is selected from the group consisting of:

[0213]

[0214] In certain embodiments, G is Si, and is selected from the group consisting of:

[0215]

[0216] In some embodiments, R 5A is hydrogen, and R 5B and R 6 together with the atoms to which they are attached, form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally substituted by one or more groups independently selected from halogen or alkyl.

[0217] In certain embodiments, is selected from the group consisting of:

[0218]

[0219]

[0220] In some embodiments, R 7 is –R 7-1 -R 7-2 ; R 7-1 is a bond, and R 7-2 is selected from alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted by one or more groups independently selected from halogen, hydroxy, cyano, alkyl, alkoxy or haloalkyl.

[0221] In certain embodiments, R 7-2 is selected from

[0222] -CH 3 、-CH 2 CH 3 、-CF 2 CF 3 and -CH 2 CF 3 .

[0223] In some embodiments, R 7-1 is -C(O)O-**, and R 7-2 is selected from alkyl, haloalkyl, alkylcycloalkyl, alkylaryl, cycloalkyl, aryl or heteroaryl, wherein said alkyl, alkylcycloalkyl, alkylaryl and cycloalkyl, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, alkyl, alkoxy or haloalkyl.

[0224] In certain embodiments, R 7 is selected from the group consisting of:

[0225]

[0226]

[0227] In some embodiments, R 7 is –R 7-1 -R 7-2 wherein R 7-1 is -C(O)-**, and R 7-2 is selected from alkyl, haloalkyl, alkylcycloalkyl, alkylaryl, alkenylaryl, heteroalkylcycloalkyl, heteroalkylaryl, heteroalkylheteroaryl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, alkylaryl, alkenylaryl, heteroalkylaryl, heteroalkylheteroaryl, cycloalkyl, heterocyclic, aryl or heteroaryl are optionally substituted with one or more groups independently selected from halogen, hydroxy, carbonyl, alkyl, alkoxy or haloalkyl.

[0228] In certain embodiments, R 7 is selected from the group consisting of:

[0229]

[0230] In some embodiments, R 7 is –R 7-1 -R 7-2 wherein R 7-1 is -C(O)N(R b )-**, and R 7-2 is selected from alkyl, haloalkyl, alkylcycloalkyl, alkylaryl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, alkylcycloalkyl, alkylaryl, cycloalkyl, heterocyclic, aryl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, alkyl, alkoxy or haloalkyl.

[0231] In certain embodiments, R 7 is selected from the group consisting of:

[0232]

[0233] In some embodiments, R 7 is –R 7-1 -R 7-2 , R 7-1 is -SO 2 -**, and R 7-2 is selected from alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from halogen, alkyl, alkoxy, or haloalkyl.

[0234] In certain embodiments, R 7 is selected from the group consisting of:

[0235]

[0236] In some embodiments, R 7 is –R 7-1 -R 7-2 , R 7-1 is a bond, and R 7-2 is hydrogen.

[0237] In certain embodiments, R 7 is -NH 2 .

[0238] In some embodiments, R 7 and R 8 , together with the nitrogen atom to which they are attached, form a heterocyclic group, which is optionally substituted with one or more groups independently selected from halogen, hydroxy, cyano, amino, or alkyl.

[0239] In certain embodiments, the heterocyclic group formed by R 7 and R 8 , together with the nitrogen atom to which they are attached, is selected from the group consisting of:

[0240]

[0241] In some embodiments, the present disclosure provides a compound of formula (III):

[0242]

[0243] or a pharmaceutically acceptable salt thereof, wherein L, G, R 5A , R 5B , R 6 , R 7 , m, and n are as defined above.

[0244] In some embodiments, the present disclosure provides a compound of formula (IIIa) or (IIIb):

[0245]

[0246] or a pharmaceutically acceptable salt thereof, wherein L, R 5A , R 5B , R 6 , R 7 , m and n are as defined above.

[0247] In some embodiments, the present disclosure provides a compound of formula (Ia):

[0248]

[0249] or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the present disclosure provides a compound of formula (Ia'):

[0251]

[0252] or a pharmaceutically acceptable salt thereof.

[0253] In yet another aspect, the present disclosure provides a compound having a chemical formula selected from the group consisting of:

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273] or a pharmaceutically acceptable salt thereof, wherein the wavy line directly attached to the double bond indicates that the double bond is in the E or Z configuration.

[0274] The compounds provided herein are described with reference to general chemical formulas and specific compounds. In addition, the disclosed compounds can exist in many different forms or derivatives, all of which are within the scope of the present disclosure. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, solvated forms, amorphous forms, different crystalline forms or polymorphs.

[0275] Depending on the substituent selection, the disclosed compounds may contain one or more asymmetric centers and can thus exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds provided herein may have asymmetric carbon centers and can thus have the (R) or (S) stereoconfiguration at the carbon asymmetric centers. Accordingly, the compounds of the present disclosure can be in the form of individual enantiomers, diastereomers or geometric isomers, or can be in the form of a mixture of stereoisomers.

[0276] As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non - superimposable mirror images of each other. The term "diastereomers" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties and reactivity.

[0277] When a particular enantiomer is preferred, in some embodiments it may be provided as being substantially free of the opposite enantiomer and may also be referred to as "optically enriched". As used herein, "optically enriched" means that a compound consists of a significantly greater proportion of one enantiomer. In certain embodiments, the compound consists of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound consists of at least about 95%, 98% or 99% by weight of the preferred enantiomer. The preferred enantiomer can be separated from the racemic mixture by any method known to those skilled in the art, such as by chromatography or crystallization, by synthesis using stereochemically homogeneous starting materials or by stereoselective synthesis. Optionally, derivatization may be carried out prior to the separation of the stereoisomers. The separation of a mixture of stereoisomers may be carried out at an intermediate step during the synthesis of the compounds provided herein or it may be carried out on the final racemic product. The absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, which is derivatized, if necessary, with a reagent containing a stereocenter of known configuration. Alternatively, the absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H. et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, page 268 (ed. E.L. Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0278] In some embodiments, a mixture of diastereomers is provided, such as a mixture of diastereomers enriched in one of the diastereomers by 51% or more, including for example one of the diastereomers being 60% or more, 70% or more, 80% or more or 90% or more.

[0279] In some embodiments, unless otherwise indicated, the compounds provided herein may have one or more double bonds present as Z or E isomers. Additionally, the present disclosure also encompasses the compounds in the form of individual isomers that are substantially free of other isomers and, alternatively, in the form of mixtures of multiple isomers (e.g., racemic mixtures of enantiomers).

[0280] The compounds of the present disclosure may also exist in different tautomeric forms, and all such forms are encompassed within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via a low energy barrier. For example, prototropic tautomers (also known as proton-transfer tautomers) include interconversions via proton migration, such as keto-enol, amide-imidic acid, lactam-lactim, imine-enamine isomerization, and cyclic forms, where the proton can occupy two or more positions in a heterocyclic system (e.g., 1H-imidazole and 3H-imidazole, 1H-1,2,4-triazole, 2H-1,2,4-triazole, and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole). Valence tautomers include interconversions via rearrangement of some of the bonding electrons. Tautomers may be in equilibrium or locked in one form by appropriate substitution. Unless otherwise specified, the compounds of the present disclosure identified by name or structure as a particular tautomeric form are intended to include other tautomeric forms.

[0281] The present disclosure also intends to include all isotopes of the atoms in the compounds. Isotopes of an atom include atoms having the same atomic number but different mass numbers. For example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of the present disclosure also mean to include their isotopes, such as (but not limited to) 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18 F, 19 F, 35 Cl, 37 Cl, 79Br, 81 Br, 124 I, 127 I and 131 I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 C. Isotope-enriched compounds of formula (I) can be prepared by conventional techniques well known to those skilled in the art or by methods similar to those described in the protocols and examples herein, using appropriate isotope-enriched reagents and / or intermediates without undue experimentation.

[0282] The compounds of the present disclosure can be formulated into pharmaceutically acceptable salts or are in the form of pharmaceutically acceptable salts. Unless otherwise specified, the compounds provided herein include pharmaceutically acceptable salts of such compounds.

[0283] As used herein, the term "pharmaceutically acceptable" indicates that the substance or composition is chemically and / or toxicologically compatible with the other components of the formulation and / or the individual being treated therewith.

[0284] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of the free acids and bases of the designated compounds and are not otherwise undesirable biologically. Pharmaceutically acceptable salt forms contemplated include (but are not limited to) monosalts, disalts, trisalts, tetrasalts, etc. Pharmaceutically acceptable salts are non-toxic at the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of the compound without preventing it from exerting its physiological action. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

[0285] Pharmaceutically acceptable salts include acid addition salts such as those containing: sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, mesylate, esylate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, and quinate. Pharmaceutically acceptable salts can be obtained from acids such as: hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.

[0286] When acidic functional groups (such as carboxylic acid or phenol) are present, pharmaceutically acceptable salts also include base addition salts, such as those containing: benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc. See, for example, Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Wiley-VCH, Weinheim, Germany, 2002. Such salts can be prepared using the appropriate corresponding base.

[0287] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of a compound can be dissolved in a suitable solvent (such as an aqueous solution containing the appropriate acid or a water-alcohol solution), and then separated by evaporation of the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosyl acids (such as glucuronic acid or galacturonic acid), α-hydroxy acids (such as citric acid or tartaric acid), amino acids (such as aspartic acid or glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid or ethanesulfonic acid), etc.

[0288] Similarly, if a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treating the free acid with an inorganic base or an organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include organic salts derived from amino acids (such as L-glycine, L-lysine, and L-arginine), ammonia, primary amines, secondary amines, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine, piperidine, morpholine, or piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0289] It should also be understood that the compounds of the present disclosure may exist in unsolvated forms, solvated forms (e.g., hydrated forms), and solid forms (e.g., crystalline or polymorphic forms), and the present disclosure is intended to cover all such forms.

[0290] As used herein, the terms “solvate” or “solvated form” refer to a solvate addition form containing a stoichiometric or non-stoichiometric amount of a solvent. Some compounds have a tendency to form solvates by entrapping a fixed molar ratio of solvent molecules in the crystalline solid state. If the solvent is water, the resulting solvate is a hydrate; and if the solvent is an alcohol, the resulting solvate is an alcoholate. Hydrates are formed by the combination of one or more water molecules with the molecules of a substance, where the water retains its molecular state as H 2 O. Examples of solvents that form solvates include (but are not limited to) water, isopropyl alcohol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

[0291] As used herein, the terms “crystal form,” “crystalline form,” “polymorphic form,” and “polymorph” are used interchangeably and refer to crystal structures in which a compound (or its salt or solvate) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. The recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystal form to predominate. The crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0292] The present disclosure is also intended to include all isotopes of the atoms in the compounds. Isotopes of an atom include atoms having the same atomic number but different mass numbers. By way of example, unless otherwise specified, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, or iodine in the compounds of the present disclosure are also meant to include their isotopes, such as (but not limited to) 1 H, 2 H, 3 H, 11 C, 12 C, 13 C, 14 C, 14 N, 15 N, 16 O, 17 O, 18 O, 31 P, 32 P, 32 S, 33 S, 34 S, 36 S, 17 F, 18F, 19 F, 35 Cl, 37 Cl, 79 Br, 81 Br, 124 I, 127 I and 131 I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes 12 C and 13 C.

[0293] Synthesis of the compound

[0294] The synthesis of the compounds provided herein (including their pharmaceutically acceptable salts) is illustrated in the synthetic schemes in the examples. The compounds provided herein can be prepared using any known organic synthesis techniques and can be synthesized according to any of a variety of possible synthetic routes, and thus, these schemes are illustrative only and are not intended to limit other possible methods that can be used to prepare the compounds provided herein. In addition, the steps in the schemes are for better illustration and can be changed as appropriate. Examples of synthesizing the compounds in the examples are for research and for possible submission to regulatory agencies.

[0295] The reactions for preparing the compounds of the present disclosure can be carried out in a suitable solvent, which can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, for example, at a temperature within the range from the freezing temperature to the boiling temperature of the solvent. The specified reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, the suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0296] The preparation of the compounds of the present disclosure may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons, Inc., New York (1999); P. Kocienski, Protecting Groups, Georg Thieme Verlag, 2003; and Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5th Edition, Wiley, 2014, all of which are incorporated herein by reference in their entirety.

[0297] The reaction can be monitored according to any suitable method known in the art. For example, it can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy (IR), spectrophotometry (e.g., UV-visible light), mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). Those skilled in the art can purify the compounds by a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs, J. Combi. Chem., 2004, 6(6), 874 - 883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.

[0298] The known starting materials of the present disclosure can be synthesized by using or according to methods known in the art, or can be purchased from commercial suppliers. Analytical grade solvents and commercially available reagents are used without further purification unless otherwise indicated.

[0299] Unless otherwise specified, the reactions of the present disclosure are carried out under a positive pressure of nitrogen or argon or in an anhydrous solvent using a dry tube, and the reaction flask is typically equipped with a rubber septum for introducing substrates and reagents via a syringe. Glassware is dried and / or heat-dried.

[0300] For illustrative purposes, the following Examples section shows synthetic routes and key intermediates for preparing the compounds of the present disclosure. Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of the invention. Although specific starting materials and reagents are depicted, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. Additionally, many of the compounds prepared by the methods described below can be further modified according to the present disclosure using conventional chemical reactions well known to those skilled in the art.

[0301] Use of the compound

[0302] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is capable of inhibiting 3CL. Accordingly, the compounds of the present disclosure or pharmaceutically acceptable salts thereof can be used as drugs, particularly as therapeutic or prophylactic agents active against various viruses. In some embodiments, the compounds of the present disclosure are therapeutic or prophylactic agents active against caliciviruses, picornaviruses, and coronaviruses.

[0303] As used herein, the term "therapy" is intended to have its ordinary meaning, i.e., treating a disease in order to relieve, in whole or in part, one, some, or all of its symptoms, or to correct or counteract the underlying pathology, thereby achieving a beneficial or desired clinical outcome. For the purposes of the present disclosure, beneficial or desired clinical outcomes include (but are not limited to): relief of symptoms, reduction in the degree of the disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or amelioration of the disease condition, and remission (partial or complete), whether detectable or not. "Therapy" can also mean an extension of the survival period compared to what would be expected in the absence of therapy. Situations that require therapy include those in which a condition or disorder is already present, those that are predisposed to a condition or disorder, or those for the purpose of preventing a condition or disorder. Unless otherwise specifically indicated, the term "therapy" also encompasses prevention. The terms "therapeutic" and "therapeutically" should be construed correspondingly.

[0304] The term "treatment" is used synonymously with "therapy". Similarly, the term "treatment" can be considered "administering therapy", where "therapy" is as defined herein.

[0305] As used herein, the term "prevention" is intended to have its ordinary meaning and includes primary prevention for preventing the development of a disease and secondary prevention for temporarily or permanently protecting a patient against disease exacerbation or worsening or the development of new disease-related symptoms when the disease has already developed.

[0306] In yet another aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof for treating a viral infection.

[0307] In yet another aspect, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure in the preparation of a medicament for treating a viral infection.

[0308] In yet another aspect, it has surprisingly been found that the compounds provided herein exhibit high tolerance to oxidases. This enables the compounds provided herein to resist oxidative metabolism in vivo, thereby showing greater metabolic stability, such as an increased in vivo half-life or a reduced dosage requirement.

[0309] In some embodiments, the compounds provided herein can be administered to a subject in need thereof without the co-administration of an oxidase inhibitor, such as ritonavir or cobicistat.

[0310] Pharmaceutical composition

[0311] For administration purposes, in some embodiments, the compounds provided herein are administered in the form of the original chemical substance or formulated into a pharmaceutical composition.

[0312] Thus, in another aspect, there is provided a pharmaceutical composition comprising one or more compounds of the present disclosure or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the pharmaceutical composition of the present disclosure comprises a compound selected from any one of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present disclosure comprises a first compound selected from any one of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof and one or more additional compounds of the same formula, provided that the first compound and the additional compounds are not the same molecule.

[0314] As used herein, the term "pharmaceutical composition" refers to a formulation containing a molecule or compound of the present disclosure in a form suitable for administration to an individual.

[0315] In some embodiments, the pharmaceutical composition of the present disclosure comprises a therapeutically effective amount of one or more compounds of formulas (I) to (VII) or a pharmaceutically acceptable salt thereof.

[0316] As used herein, the term "therapeutically effective amount" refers to an amount of a molecule, compound, or composition comprising the molecule or compound that treats, ameliorates, or prevents a identified disease or condition or shows a detectable therapeutic or inhibitory effect. The effectiveness can be detected by any assay method known in the art. The precise effective amount for an individual will depend upon the individual's body weight, size, and health condition; the nature and extent of the condition; the rate of administration; the particular therapeutic agent or combination of therapeutic agents selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0317] In another aspect, there is provided a pharmaceutical composition comprising one or more molecules or compounds of the present disclosure or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0318] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient suitable for preparing a pharmaceutical composition that is generally safe, non-toxic, and otherwise desirable both biologically and in other respects, and includes excipients acceptable for veterinary as well as for human pharmaceutical use. As used herein, "pharmaceutically acceptable excipient" includes one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent".

[0319] The particular excipient used will depend upon the means and purpose for administering the compounds of the present disclosure. Solvents are generally selected based on solvents recognized as safe by those skilled in the art for administration to mammals, including humans. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), etc. and mixtures thereof.

[0320] In some embodiments, suitable excipients can include buffering agents such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butanol, or benzyl alcohol; alkyl parabens such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, dextrin, or substituted dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (such as Zn-protein complexes); and / or nonionic surfactants such as TWEEN TM , PLURONICS TM or polyethylene glycol (PEG).

[0321] In some embodiments, suitable excipients can include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifying agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide optimal presentation of the drug (i.e., the compounds of the present disclosure or their pharmaceutical compositions) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament). The active pharmaceutical ingredient can also be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules in colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or in coarse emulsions, respectively. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th Edition, Osol, A. Ed. (1980). "Liposomes" are small vesicles containing various types of lipids, phospholipids, and / or surfactants, which are suitable for delivering drugs (such as the compounds disclosed herein and optionally chemotherapeutic agents) to mammals, including humans. The components of liposomes are typically arranged in a bilayer form, similar to the lipid arrangement of biological membranes.

[0322] The pharmaceutical compositions provided herein can be in any form that permits the composition to be administered to an individual (including but not limited to a human) and is formulated to be compatible with the intended route of administration.

[0323] Multiple routes are contemplated for the pharmaceutical compositions provided herein, and thus the pharmaceutical compositions provided herein may be supplied in bulk or unit dosage forms depending on the intended route of administration. For example, for oral, buccal, and sublingual administration, powders, suspensions, granules, lozenges, pills, capsules, softgels, and cachets are acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions, and solutions are acceptable as liquid dosage forms. For parenteral administration, emulsions and suspensions are acceptable as liquid dosage forms, and powders suitable for reconstitution with a suitable solution are acceptable as solid dosage forms. For inhalation administration, solutions, sprays, dry powders, and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions, and patches may be acceptable dosage forms. For vaginal administration, vaginal suppositories, tampons, creams, gels, pastes, foams, and sprays may be acceptable dosage forms.

[0324] The amount of the active ingredient in the unit dosage form of the composition is a therapeutically effective amount and varies depending on the particular treatment involved. As used herein, the term "therapeutically effective amount" refers to the amount of a molecule, compound, or composition comprising the molecule or compound that treats, ameliorates, or prevents the identified disease or condition or exhibits a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for an individual will depend on the individual's weight, size, and health; the nature and extent of the condition; the rate of administration; the therapeutic agent or combination of therapeutic agents selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician.

[0325] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oral administration formulation.

[0326] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a lozenge formulation. Pharmaceutically acceptable excipients suitable for lozenge formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate, or calcium carbonate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid, or talc; preservatives such as ethyl paraben or propyl paraben; and antioxidants such as ascorbic acid. The lozenge formulations may be uncoated or coated to regulate their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance, in either case using conventional coating agents and procedures well known in the art.

[0327] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin); or in the form of soft gelatin capsules, wherein the active ingredient is mixed with water or an oil (such as peanut oil, liquid paraffin, or olive oil).

[0328] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an aqueous suspension, which generally contains the active ingredient in finely powdered form and one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersing agents or wetting agents, such as lecithin, or condensation products of alkylene oxides with fatty acids (such as polyoxyethylene stearate), or condensation products of ethylene oxide with long-chain aliphatic alcohols (such as heptadecaethyleneoxyhexadecanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (such as polyoxyethylene sorbitan monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (such as polyoxyethylene dehydrated sorbitan monooleate). The aqueous suspension may also contain one or more preservatives (such as ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), coloring agents, flavoring agents, and / or sweetening agents (such as sucrose, saccharin, or aspartame).

[0329] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oily suspension, which typically contains the suspended active ingredient in a vegetable oil (such as peanut oil, castor oil, olive oil, sesame oil, or coconut oil) or a mineral oil (such as liquid paraffin). The oily suspension may also contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents (such as those described above) and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by adding antioxidants (such as ascorbic acid).

[0330] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or a mixture of any of these oils. Suitable emulsifying agents may be, for example, naturally occurring gums, such as acacia gum or tragacanth gum; naturally occurring phospholipids, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (such as dehydrated sorbitan monooleate) and condensation products of said partial esters with ethylene oxide (such as polyoxyethylene dehydrated sorbitan monooleate). The emulsion may also contain sweetening agents, flavoring agents, and preservatives.

[0331] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweetening agents, such as glycerol, propylene glycol, sorbitol, aspartame, or sucrose; demulcents; preservatives; flavoring agents, and / or coloring agents.

[0332] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for parenteral administration.

[0333] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol or prepared as a lyophilized powder. Acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid may also be used in the preparation of injectables.

[0334] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for inhalational administration.

[0335] In certain embodiments, the pharmaceutical compositions of the present disclosure may be in the form of aqueous and non - aqueous (e.g., in a fluorocarbon propellant) aerosols, which contain any suitable solvent and optionally other compounds such as (but not limited to) stabilizers, antimicrobial agents, antioxidants, pH regulators, surfactants, bioavailability modifiers, and combinations thereof. The carrier and stabilizer vary with the requirements of the particular compound, but generally include non - ionic surfactants (Tweens, Pluronics, or polyethylene glycols), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols.

[0336] In some embodiments, the pharmaceutical compositions of the present disclosure may be in the form of a formulation for topical or transdermal administration.

[0337] In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oleaginous solutions or suspensions, which may generally be obtained by formulating the active ingredient with conventional topically acceptable excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0338] In certain embodiments, the pharmaceutical compositions provided herein may be formulated in the form of a transdermal skin patch well - known to those of ordinary skill in the art.

[0339] In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present disclosure. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences", Mack Publishing Co., Easton, PA (1991), "Remington: The Science and Practice of Pharmacy", edited by the University of the Sciences in Philadelphia, 21st Edition, Lippincott Williams & Wilkins (2005), which are hereby incorporated by reference.

[0340] In some embodiments, the pharmaceutical compositions of the present disclosure may be formulated into unit dosage forms. The term "unit dosage form" refers to physically discrete units suitable for single dosage administration to a human individual and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. The amount of the compounds provided herein in unit dosage form will vary depending on the condition to be treated, the individual to be treated (e.g., the age, weight and response of the individual), the particular route of administration, the actual compound being administered and its relative activity, and the severity of the individual's symptoms.

[0341] In some embodiments, the dosage of the pharmaceutical composition of the present disclosure can be from 0.001 to 1000 mg / kg body weight per day, for example, from 0.001 to 1000 mg / kg body weight per day, from 0.001 to 900 mg / kg body weight per day, from 0.001 to 800 mg / kg body weight per day, from 0.001 to 700 mg / kg body weight per day, from 0.001 to 600 mg / kg body weight per day, from 0.001 to 500 mg / kg body weight per day, from 0.001 to 400 mg / kg body weight per day, from 0.001 to 300 mg / kg body weight per day, from 0.001 to 200 mg / kg body weight per day, from 0.001 to 100 mg / kg body weight per day, from 0.001 to 50 mg / kg body weight per day, from 0.001 to 40 mg / kg body weight per day, from 0.001 to 30 mg / kg body weight per day, from 0.001 to 20 mg / kg body weight per day, from 0.001 to 10 mg / kg body weight per day, from 0.001 to 5 mg / kg body weight per day, from 0.001 to 1 mg / kg body weight per day, from 0.001 to 0.5 mg / kg body weight per day, from 0.001 to 0.4 mg / kg body weight per day, from 0.001 to 0.3 mg / kg body weight per day, from 0.001 to 0.2 mg / kg body weight per day, from 0.001 to 0.1 mg / kg body weight per day, from 0.005 to 0.1 mg / kg body weight per day, from 0.01 to 0.1 mg / kg body weight per day, from 0.02 to 0.1 mg / kg body weight per day, from 0.03 to 0.1 mg / kg body weight per day, from 0.04 to 0.1 mg / kg body weight per day, from 0.05 to 0.1 mg / kg body weight per day, from 0.06 to 0.1 mg / kg body weight per day, from 0.07 to 0.1 mg / kg body weight per day, from 0.08 to 0.1 mg / kg body weight per day, or from 0.09 to 0.1 mg / kg body weight per day. In some cases, a dosage below the lower limit of the foregoing range may be sufficient, while in other cases, larger doses can be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day. For other information regarding the route of administration and dosage regimen, see Volume 5, Chapter 25.3 in Comprehensive Medicinal Chemistry (Corwin Hansch; Editor-in-Chief of the Editorial Board), Pergamon Press 1990, which is specifically incorporated herein by reference.

[0342] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration. In some embodiments, a unit dose for oral administration contains one or more of the compounds provided herein in the following amounts: from about 1 mg to about 1000 mg, such as from about 5 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 15 mg to about 1000 mg, from about 20 mg to about 1000 mg, from about 25 mg to about 1000 mg, from about 30 mg to about 1000 mg, from about 40 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 60 mg to about 1000 mg, from about 70 mg to about 1000 mg, from about 80 mg to about 1000 mg, from about 90 mg to about 1000 mg, from about 100 mg to about 1000 mg, from about 200 mg to 1000 mg, from about 300 mg to about 1000 mg, from about 400 mg to about 1000 mg, from about 500 mg to about 1000 mg, from about 1 mg to 500 mg, from about 10 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 300 mg to about 500 mg, from about 400 mg to about 500 mg, such as about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, etc. In some embodiments, depending on the severity of the individual's symptoms, the dosage unit may be administered to the individual 1 to 6 times per day.

[0343] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for oral administration in a treatment having a duration greater than 1 week, greater than 2 weeks, greater than 3 weeks, greater than 1 month, greater than 2 months, greater than 3 months, greater than 4 months, greater than 5 months, greater than 6 months, greater than 7 months, greater than 8 months, greater than 9 months, greater than 10 months, greater than 11 months, greater than 1 year or even longer.

[0344] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for parenteral administration, such as by intravenous, subcutaneous, or intramuscular injection. In some embodiments, a unit dose for parenteral administration contains one or more of the compounds provided herein in an amount of from about 0.1 mg to about 500 mg of one or more of the compounds provided herein, such as from about 0.2 mg to about 500 mg, from about 0.3 mg to about 500 mg, from about 0.4 mg to about 500 mg, from about 0.5 mg to about 500 mg, from about 1 mg to about 500 mg, from about 5 mg to about 500 mg, from about 10 mg to about 500 mg, from about 20 mg to about 500 mg, from about 30 mg to about 500 mg, from about 40 mg to about 500 mg, from about 50 mg to about 500 mg, from about 0.5 mg to about 400 mg, from about 0.5 mg to about 300 mg, from about 0.5 mg to about 200 mg, from about 0.5 mg to about 100 mg, from about 0.5 mg to about 90 mg, from about 0.5 mg to about 80 mg, from about 0.5 mg to about 70 mg, from about 0.5 mg to about 60 mg, from about 0.5 mg to about 50 mg, from about 0.5 mg to about 40 mg, from about 1 mg to about 90 mg, from about 5 mg to about 90 mg, from about 10 mg to about 80 mg, from about 20 mg to about 70 mg, from about 30 mg to about 60 mg, or from about 40 mg to about 50 mg, such as about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, etc.

[0345] In some embodiments, a pharmaceutical composition intended for administration by injection can be prepared by combining one or more of the compounds of the present disclosure with sterile distilled water, sesame oil, peanut oil, or an aqueous solution of propylene glycol to form a solution. In some embodiments, the pharmaceutical composition can contain a surfactant or other solubilizing excipient, which is added to facilitate the formation of a homogeneous solution or suspension. In some embodiments, the pharmaceutical composition can further contain one or more additional reagents selected from the group consisting of wetting agents, suspending agents, preservatives, buffering agents, and isotonic agents.

[0346] In some embodiments, a pharmaceutical composition intended for administration by injection can be administered using a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the pharmaceutical composition provided herein.

[0347] In another aspect, there is also provided a veterinary composition comprising one or more of the molecules or compounds of the present disclosure or a pharmaceutically acceptable salt thereof and a veterinary carrier. The veterinary carrier is a substance suitable for the purpose of administering the composition and can be a solid, liquid or gaseous substance that is originally inert or acceptable in the veterinary field and is compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally or by any other desired route.

[0348] The pharmaceutical or veterinary composition can be packaged in a variety of ways depending on the method used to administer the drug. For example, an article for dispensing can include a container in which a composition in a suitable form is deposited. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container can also include a tamper-proof assembly to prevent easy access to the contents of the package. Additionally, a label describing the contents of the container is attached to the container. The label can also include appropriate warnings. The composition can be packaged in unit dose or multi-dose containers (e.g., sealed ampoules and vials) and can be stored under a lyophilized (freeze-dried) condition, requiring only the immediate addition of a sterile liquid carrier (e.g., water) for injection before use. Ready-to-use injection solutions and suspensions are prepared from sterile powders, granules and lozenges of the previously described types.

[0349] In another aspect, there is also provided a pharmaceutical composition comprising one or more of the compounds of the present disclosure or a pharmaceutically acceptable salt thereof as a first active ingredient and a second active ingredient.

[0350] In some embodiments, the second active ingredient has an activity complementary to the compounds provided herein such that they do not have an adverse effect on each other. The ingredients are preferably present in combination in amounts effective for the intended purpose.

[0351] In some embodiments, the second active ingredient can be an antibiotic, protease inhibitor, antiviral agent, anti-inflammatory agent, immunomodulator, kinase inhibitor, antimetabolite, lysosomotropic agent, M2 proton channel blocker, polymerase inhibitor (e.g., EIDD-2801), neuraminidase inhibitor, reverse transcriptase inhibitor, viral entry inhibitor, integrase inhibitor, interferon (e.g., type I, type II and type III) or nucleoside analogue.

[0352] In some embodiments, the second active ingredient is an antibiotic. In some embodiments, the antibiotic can be selected from penicillin antibiotics, quinolone antibiotics, tetracycline antibiotics, macrolide antibiotics, lincosamide antibiotics, cephalosporin antibiotics, or RNA synthetase inhibitors. In some embodiments, the antibiotic is selected from azithromycin, vancomycin, metronidazole, gentamicin, colistin, fidaxomicin, telavancin, oritavancin, dalbavancin, daptomycin, cephalexin, cefuroxime, cefadroxil, cefazolin, cefalotin, cefaclor, cefamandole, cefoxitin, cefprozil, ceftobiprole, ciprofloxacin, levofloxacin, ofloxacin, gatifloxacin, moxifloxacin, norfloxacin, tetracycline, minocycline, oxytetracycline, doxycycline, amoxicillin, ampicillin, penicillin V, dicloxacillin, carbenicillin, methicillin, ertapenem, doripenem, imipenem / cilastatin, meropenem, amikacin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, ceftazidime, cefibuten, cefozopime, ceftriaxone, cefoxotin, and streptomycin. In some embodiments, the antibiotic is azithromycin.

[0353] In some embodiments, the second active ingredient can be a protease inhibitor. In some embodiments, the protease inhibitor can be selected from nafamostat, camostat, gabexate, ε-aminocaproic acid, aprotinin, amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir.

[0354] In some embodiments, the second active ingredient can be an antiviral agent. In some embodiments, the antiviral agent can be selected from ribavirin, favipiravir, ST-193, oseltamivir, zanamivir, peramivir, danoprevir, ritonavir, remdesivir, cobicistat, elvitegravir, emtricitabine, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate, abacavir, dolutegravir, efavirenz, elbasvir, ledipasvir, glecaprevir, sofosbuvir, bictegravir, dasabuvir, lamivudine, atazanavir, obitrovir, lamivudine, stavudine, nevirapine, rilpivirine, paritaprevir, simeprevir, daclatasvir, grazoprevir, pibrentasvir, adefovir, amprenavir, amprenavir proximate, alaviromycin, anti-goat antibody, balapiravir, cabotegravir, cytarabine, ecoliever, epigallocatechin gallate, etravirine, fostemsavir, gemcitabine, griffithsin, imunovir, indinavir, maraviroc, metisazone, MK-2048, nelfinavir, nevirapine, nitazoxanide, norvir, plerixafor, PRO 140, raltegravir, pyramidine, saquinavir, telbivudine, TNX-355, valacyclovir, VIR-576, and zalcitabine.

[0355] In some embodiments, the second active ingredient can be an anti-inflammatory agent. In some embodiments, the anti-inflammatory agent can be selected from antihistamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modifiers (e.g., montelukast, zafirlukast, pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., β-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium cromoglycate, 5-lipoxygenase inhibitors (zyflo), DPI antagonists, DP2 antagonists, PI3Kδ inhibitors, GGK inhibitors, LP (lysophospholipid) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors, bronchodilators (e.g., muscarinic antagonists, β-2 agonists), methotrexate and similar agents; monoclonal antibody therapies, such as anti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapies, e.g., etanercept and similar agents; antigen-nonspecific immunotherapies (e.g., interferons or other cytokines / chemokines, chemokine receptor modifiers such as CCR3, CCR4 or CXCR2 antagonists, other cytokine / chemokine agonists or antagonists, TLR agonists and similar reagents), suitable anti-infective agents (including antibacterial agents, antifungal agents, anthelmintics, antimalarials, antiprotozoals and antituberculosis agents).

[0356] In some embodiments, the second active ingredient can be an immunomodulator. In some embodiments, the immunomodulator can be selected from anti-PD-1 or anti-PDL-1 therapeutic agents, including pembrolizumab, nivolumab, atezolizumab, durvalumab, BMS-936559, or avelumab, anti-TIM3 (anti-HAVcr2) therapeutic agents (including but not limited to TSR-022 or MBG453), anti-LAG3 therapeutic agents (including but not limited to relatlimab, LAG525, or TSR-033), anti-4-1BB (anti-CD37, anti-TNFRSF9), CD40 agonist therapeutic agents (including but not limited to SGN-40, CP-870,893, or R07009789), anti-CD47 therapeutic agents (including but not limited to Hu5F9-G4), anti-CD20 therapeutic agents, anti-CD38 therapeutic agents, STING agonist (including but not limited to ADU-S100, MK-1454, ASA404, or amide benzimidazole), anthracyclines (including but not limited to doxorubicin or mitoxantrone), demethylating agents (including but not limited to azacitidine or decitabine), other immunomodulatory therapeutic agents (including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone). In some embodiments, the additional therapeutic agent is a β2-adrenergic receptor agonist, including but not limited to vilanterol, salmeterol, albuterol, formoterol, carmoterol, fenoterol, cimaterol, indacaterol, naminterol, clenbuterol, pirbuterol, flubuterol, reproterol, bambuterol, indacaterol, terbutaline, and salts thereof, such as the xinafoate (1-hydroxy-2-naphthoate) salt of salmeterol, the sulfate salt of albuterol, or the fumarate salt of formoterol.

[0357] In some embodiments, the second active ingredient can be a kinase inhibitor. In some embodiments, the kinase inhibitor can be selected from erlotinib, gefitinib, neratinib, afatinib, osimertinib, lapatinib, crizotinib, brigatinib, ceritinib, alectinib, lorlatinib, everolimus, sirolimus, abemaciclib, LEE011, palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, sunitinib, axitinib, dasatinib, imatinib, nilotinib, ponatinib, idelalisib, ibrutinib, Loxo 292, larotrectinib, and quizartinib.

[0358] Method for treating diseases

[0359] In another aspect, the present disclosure provides a method for treating a viral infection in a patient in need thereof, the method comprising administering an effective amount of any of the compounds described herein.

[0360] In some embodiments, the viral infection is from a virus selected from the group consisting of: RNA virus, DNA virus, coronavirus, papillomavirus, pneumovirus, picornavirus, influenza virus, adenovirus, cytomegalovirus, polyomavirus, poxvirus, rhinovirus, norovirus, flavivirus, alphavirus, Ebola virus, measles virus, enterovirus, orthopneumovirus, lentivirus, arenavirus, herpesvirus, and hepadnavirus. In certain embodiments, the viral infection is a coronavirus infection. In some embodiments, the viral infection is a coronavirus selected from the group consisting of: 229E alpha coronavirus, NL63 alpha coronavirus, OC43 beta coronavirus, HKU1 beta coronavirus, Middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV), and SARS-CoV-2 (COVID-19). In certain embodiments, the viral infection is SARS-CoV-2.

[0361] In some embodiments, the viral infection is from a virus selected from the group consisting of: calicivirus, MD145, murine norovirus, swine vesicular exanthema virus, rabbit hemorrhagic disease virus, swine teschovirus, bovine coronavirus, feline infectious peritonitis virus, EV-68 virus, EV-71 virus, poliovirus, norovirus, human rhinovirus (HRV), hepatitis A virus (HAV), and foot-and-mouth disease virus (FMDV).

[0362] In some embodiments, the viral infection is an arenavirus infection. In certain embodiments, the arenavirus is selected from the group consisting of: Junin virus, Lassa virus, Lujo virus, Machupo virus, and Sabia virus. In some embodiments, the viral infection is an influenza infection. In certain embodiments, the influenza is influenza H1N1, H3N2, or H5N1.

[0363] In some embodiments, the methods described herein can inhibit viral replication spread, replication, assembly, or release, or minimize the expression of viral proteins. In one embodiment, methods of inhibiting viral spread, methods of inhibiting viral replication, methods of minimizing the expression of viral proteins, or methods of inhibiting viral release are described herein, including administering to a patient infected with the virus a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, and / or contacting a cell infected with the virus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0364] In some embodiments, the methods described herein do not include administering an oxidase inhibitor to a subject. In certain embodiments, the methods described herein do not include co-administering ritonavir or cobicistat in combination with any of the compounds described herein.

[0365] In yet another aspect, the present disclosure provides a method for inhibiting a 3-chymotrypsin-like protease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound provided herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0366] Examples

[0367] For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the present disclosure and are only intended to present methods of practicing the present disclosure. Those skilled in the art will recognize that the chemical reactions can be readily adapted to prepare many other compounds of the present disclosure, and alternative methods for preparing the compounds of the present disclosure are considered to be within the scope of the present disclosure. For example, the synthesis of non-illustrative compounds according to the present disclosure can be successfully carried out with modifications that will be apparent to those skilled in the art, such as by appropriately protecting interfering groups, by utilizing other suitable reagents and structural units known in the art in addition to those described, and / or by making routine modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered applicable to the preparation of other compounds of the present disclosure.

[0368] Example 1

[0369] Example 1.1 Synthesis of Intermediates s1 and s2

[0370]

[0371] Step 1: Synthesis of s1-2

[0372] A mixture of (S)-1-tert-butyl 4-methyl 2-aminosuccinate hydrochloride (100.0 g, 0.42 mol), 9-bromo-9-phenylfluorene (161.8 g, 0.5 mol, 1.2 eq), and K 3 PO 4 (178.1 g, 0.84 mol, 2 eq) in CH 3 NO 2 (1000 mL) was stirred at 35 °C for 16 h. After cooling to ambient temperature, the reaction mixture was filtered to remove salts. The filtrate was diluted with CH 3 OH (20 mL), and the resulting solution was stirred at ambient temperature for 1 h. The mixture was concentrated by evaporation, and the residue was purified by silica gel column chromatography, eluting with hexane and EtOAc in a 10:1 volume ratio to afford the compound s1-2 as a viscous oil (157 g, 85%).

[0373] MS(ESI+)[(M+H) + 444.20

[0374] 11H NMR (400 MHz, CDCl 3 ) δ 7.69 - 7.65 (m, 2H), 7.41–7.19 (m, 11H), 3.65 (s, 3H), 3.35 (br s, 1H), 2.86 (dd, J=5.6, 12.8 Hz, 1H), 2.45 (dd, J=5.6, 14.8 Hz, 1H), 2.30 (dd, J=5.6, 14.8 Hz, 1H), 1.24 (s, 9H).

[0375] Step 2: Synthesis of s1-3

[0376] At -78 °C and under N 2 , within 30 minutes, a solution of KHMDS (525 mL, 1 M THF solution) was added to a solution of compound s1-2 (157 g, 0.35 mol) in anhydrous THF (1000 mL). After 30 minutes, the reaction mixture was warmed to -40 °C, and then MeI (0.25 mL, 0.525 mol) was slowly added. Then the mixture was stirred at 0 °C for 1.5 h. Subsequently, the reaction mixture was cooled again to -78 °C, and another portion of KHMDS (525 mL, 1 M THF solution) and MeI (0.25 mL, 0.525 mol) were added in the same manner as above. After the addition of MeI, the reaction mixture was stirred at 0 °C for 16 h. The reaction was quenched with saturated NH 4 Cl (500 mL) and H 2 O (500 mL). The mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel chromatography, eluting with a 3% EtOAc / hexane solution in hexane, to give compound s1-3 (121 g, 72%) as a colorless oil.

[0377] MS (ESI+) [(M + H) + 472.30

[0378] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.68 - 7.65 (m, 2H), 7.41 - 7.20 (m, 11H), 3.53 (s, 3H), 2.85 - 2.77 (m, 1H), 1.17 (s, 3H), 1.11 (s, 9H), 1.05 (s, 3H).

[0379] Step 3: Synthesis of s1-4

[0380] Under a nitrogen atmosphere, a solution of compound s1-3 (121 g, 0.26 mol) in anhydrous DCM (1000 mL) was cooled to -78 °C. Then a hexane solution of DIBAL-H (770 mL, 1 M THF solution) was added to the above solution over 40 minutes. After stirring at -78 °C for 30 minutes, saturated Rochelle salt (500 mL) was added to quench the reaction, followed by the addition of Et 2 O (200 mL). The mixture was warmed to ambient temperature and stirred for 15 minutes. The aqueous layer was extracted twice with Et 2 O. The combined organic extracts were washed with brine, dried over anhydrous MgSO 4 and concentrated to give crude compound s1-4 (86 g) as an oil, which was used directly in the next step without further purification.

[0381] MS (ESI+)[(M+H) + 444.2

[0382] 1 H NMR (400 MHz, CDCl 3 ) δ 7.69 - 7.66 (m, 2H), 7.46 (d, J = 8.0 Hz, 1H), 7.36 - 7.11 (m, 10H), 3.27 (s, 2H), 1.12 (s, 9H), 0.98 (s, 3H), 0.65 (s, 3H).

[0383] Step 4: Synthesis of s1-5

[0384] To a solution of compound s1-4 (86 g, 0.19 mol) in a mixed solvent of methanol (450 mL) and acetic acid (30 mL) was added wet 10% Pd / C (9 g), and H 2 was added to the resulting suspension three times, and the mixture was stirred overnight at ambient temperature under H 2 (1 atm). The reaction mixture was filtered through diatomaceous earth, and the catalyst was washed with MeOH. The combined filtrates were concentrated. The residue was partitioned between 300 mL of H 2 O and 300 mL of Et 2 O. The organic layer was washed with 100 mL of 0.5 M H 3 PO 4 , and the aqueous layer was adjusted to pH 9 with saturated Na 2 CO 3 and then extracted with DCM (3 × 200 mL). The organic layer was dried and evaporated to give crude compound s1-5 (29.6 g) in about 85% yield, which was used in the next step without further purification.

[0385] MS (ESI+)[(M+H)+ 204.10

[0386] 1 H NMR(400MHz,CDCl 3 )δ3.60 - 3.57(m,1H),3.32–3.28(m,2H),2.64(br s,2H),1.45(s,9H),0.98(s,3H),0.87(s,3H).

[0387] Step 5: Synthesis of s1

[0388] To a stirred solution of compound s1-5 (29.6 g, 0.15 mol) and pyridine (17.3 g, 0.22 mmol) in 500 mL of MeCN at 0 °C was added dropwise a solution of benzyloxycarbonyl chloride (29.8 g, 0.17 mmol) in 80 mL of MeCN, and the mixture was stirred at 0 °C for 90 minutes. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried and evaporated, and the residue was purified by silica gel chromatography, eluting with a hexane solution of 10% EtOAc, to give compound s1 (29.1 g).

[0389] MS(ESI+)[M+Na] + =360.20

[0390] 1 H NMR(400MHz,CDCl 3 )δ:7.41 - 7.33(m,5H),5.68(d,J=8.5Hz,1H),5.20 - 5.08(m,2H),4.27(d,J=8.5Hz,1H),3.59(dd,J=5.3,9.5Hz,1H),3.45(dd,J=5.3,12.0Hz,1H),3.11(dd,J=9.8,11.8Hz,1H),1.51(s,9H),1.13(s,3H),0.78(s,3H).

[0391] Step 6: Synthesis of s2

[0392] At 0 °C, DMP (25.1 g, 59.2 mmol) was added to a solution of compound s1 (10.0 g, 29.6 mmol) in DCM (100 mL), and the mixture was stirred at 0 °C - 20 °C for 2 hours. The reaction was quenched with saturated NaHCO 3 (50 mL) and Na 2 S 2 O 3 (50 mL), and then stirred at 20 °C for an additional 0.5 hour. The two phases were separated, and the organic layer was passed through Na 2SO 4 Dry, filter and concentrate. Then purify the residue by silica gel chromatography (PE:EA = 2:1) to obtain compound s2 as a white solid (8.4 g, 85%).

[0393] 1 HNMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 7.38–7.29 (m, 5H), 5.42 (d, J = 8 Hz, 1H), 5.14 - 5.12 (m, 2H), 4.42 (d, J = 8 Hz, 1H), 1.42 (s, 9H), 1.09 (s, 3H), 0.99 (s, 3H).

[0394] LC-MS [M+Na] + = 358.2

[0395] Example 1.2 Synthesis of Intermediate s3

[0396]

[0397] Step 1: Synthesis of s3-1

[0398] Add NaHMDS (1 M, 19.1 mL) to a solution of methyl(triphenyl)phosphonium bromide (6.8 g, 19.1 mmol) in THF (50 mL) at 0 °C. Stir the mixture at 0 °C for 1 h. Then add a solution of compound s2 (3.2 g, 9.5 mmol) in THF (20 mL) dropwise to the above reaction mixture. Stir the mixture at 25 °C for 3 h. TLC shows that compound s2 is completely consumed and a major new spot with lower polarity is detected. Quench the reactant with saturated NH 4 Cl (100 mL). Separate the two phases, and extract the aqueous phase with EA (100 mL * 3) at 0 °C. Wash the combined organic layers with 100 mL of brine, dry over Na 2 SO 4 dry, filter and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography ( 40 g Flash silica gel column, eluent is 0% - 40% ethyl acetate / petroleum ether gradient, at 40 mL / min) to obtain compound s3-1 as a colorless oil (2.5 g, 78%).

[0399] 11H NMR (400 MHz, chloroform-d) δ = 7.34 - 7.20 (m, 5H), 5.78 (dd, J = 10.8, 17.2 Hz, 1H), 5.22 - 5.02 (m, 3H), 5.01 - 4.90 (m, 2H), 4.03 (d, J = 9.2 Hz, 1H), 1.36 (s, 9H), 1.05 - 0.99 (m, 6H).

[0400] Step 2: Synthesis of s3

[0401] At 0 °C, 9-BBN (0.5 M, 10.8 mL) was slowly added to a solution of compound s3-1 (600 mg, 1.8 mmol) in THF (20 mL) over 10 minutes. The resulting clear solution was stirred at 25 °C for 10 hours. The mixture solution was cooled to 0 °C, then saturated Na 2 CO 3 (5 mL) was added, followed by H 2 O 2 (1.59 mL, 16.6 mmol, 30% purity). The mixture was stirred at 0 °C for 2 hours. LC-MS showed that compound s3-1 was completely consumed and a major peak with the desired mass was detected. The mixture was quenched by adding sodium sulfite (100 mL of a 10 wt% solution) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica chromatography ( 40 g Silica gel flash column, eluent: 0% - 30% THF / petroleum ether gradient, at 40 mL / min) to give compound s3 (430 mg, 68%) as a colorless oil.

[0402] LCMS: [M+H] + = 352.4

[0403] 1 1H NMR (500 MHz, CDCl3) δ = 7.29 - 7.18 (m, 5H), 5.67 (br d, J = 9.6 Hz, 1H), 5.05 - 4.96 (m, 2H), 4.18 (br d, J = 9.8 Hz, 1H), 3.72 - 3.60 (m, 2H), 2.17 - 1.88 (m, 1H), 1.62 - 1.51 (m, 1H), 1.37 (s, 9H), 0.94 - 0.84 (m, 6H).

[0404] Example 1.3 Synthesis of Intermediate s4

[0405]

[0406] Step 1: Synthesis of s4-1

[0407] At 0 °C, a solution of MsCl (14.7 g, 0.13 mmol) in DCM (80 mL) was added dropwise to a stirred solution of compound s1 (29.1 g, 0.086 mol) and triethylamine (26 g, 0.25 mmol) in DCM (300 mL). The mixture was stirred at 25 °C for 3 hours. Then the reaction mixture was quenched with H 2 O. The two phases were separated, and the aqueous layer was extracted with DCM (100 mL × 3). The combined organic layers were dried and evaporated, and the residue was purified by chromatography to give compound s4-1 (33.9 g, 95%) as a white solid.

[0408] 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 - 7.24 (m, 5H), 5.45 - 5.35 (m, 1H), 5.13 - 5.07 (m, 2H), 4.27 (d, J = 8.0 Hz, 1H), 3.96 (q, J = 8.0 Hz, 2H), 2.97 (s, 3H), 1.46 (s, 9H), 1.05 (s, 3H), 1.00 (s, 3H).

[0409] Step 2: Synthesis of s4-2

[0410] At 0 °C, NaN 3 (53 g, 0.82 mol) was added to a stirred solution of compound s4-1 (33.9 g, 0.082 mol) in anhydrous HMPA (250 mL). The mixture was stirred at 95 °C for 24 hours. The reaction mixture was cooled to ambient temperature. The mixture was filtered, and the filtrate was extracted three times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 4, filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography using EtOAc / hexane (7%) as the eluent to give compound s4-2 (14.0 g) as a colorless oil.

[0411] MS (ESI+) [(M + H) + 363.2

[0412] 11H NMR (400 MHz, CDCl3) δ 7.38 - 7.30 (m, 5H), 5.45 (d, J = 9.2 Hz, 1H), 5.15 - 5.08 (m, 2H), 4.23 (d, J = 9.2 Hz, 1H), 3.29 (d, J = 12.0 Hz, 1H), 3.23 (d, J = 12.0 Hz, 1H), 1.48 (s, 9H), 1.00 (s, 3H), 0.98 (s, 3H).

[0413] Step 3: Synthesis of s4

[0414] Add triphenylphosphine (14.2 g, 0.054 mol) to a solution of compound s4-2 (14 g, 0.039 mol) in anhydrous THF (150 mL), and heat the reactants to 65 °C and stir for 22 h. Then add H 2 O (13 mL), and stir the reactants for another 2 h. Concentrate the reactants under reduced pressure, and purify the residue by chromatography to obtain compound s4 (8.3 g) as a colorless oil.

[0415] MS (ESI+) [(M + H) + 337.2

[0416] 1 1H NMR (400 MHz, CDCl 3 ) δ 7.35 - 7.31 (m, 5H), 6.29 (d, J = 8.0 Hz, 1H). 5.11 - 5.08 (m, 2H), 4.15 (d, J = 8.0 Hz, 1H), 2.67 (d, J = 16 Hz, 1H), 2.46 (d, J = 16 Hz, 1H), 1.46 (s, 9H), 0.98 (s, 3H), 0.88 (s, 3H).

[0417] Example 1.4 Synthesis of Intermediate s5

[0418]

[0419] Add CH 3 NH 2 .HCl (2.5 g, 37.5 mmol), CH 3 COOH (1.5 g, 25.0 mmol) and NaBH 3 CN (3.1 g, 50.0 mmol) to a solution of compound s2 (8.4 g, 25.0 mmol) in methanol (85 mL), and then stir the mixture at 20 °C for 16 h. Filter the suspension with saturated NaHCO 3(50 mL) was quenched and then extracted with DCM (50 mL × 2). The combined organic layers were concentrated and purified by silica gel chromatography (PE:EA = 1:2) to give compound s5 as a pale yellow oil (2.93 g, 33%).

[0420] LC-MS [M+H] + = 351.2

[0421] 1 1H NMR (400 MHz, CDCl3) δ 7.38 - 7.30 (m, 5H), 7.07 (d, J = 6.4 Hz, 1H), 5.14 - 5.06 (m, 2H), 4.04 (d, J = 6.8 Hz, 1H), 2.60 (d, J = 12.4 Hz, 1H), 2.40 - 2.37 (m, 4H), 1.96 (br s, 1H), 1.47 (s, 9H), 1.08 (s, 3H), 0.95 (s, 3H).

[0422] Example 1.5 Synthesis of Intermediate s6

[0423]

[0424] Step 1: Synthesis of s6-2

[0425] To a solution of compound s6-1 (30 g, 123 mmol) in THF (1000 mL) at -78 °C was added dropwise LiHMDS (184 mL, 184 mmol, 1 N THF solution). After stirring at -78 °C for 1 h, allyl iodide (21 g, 123 mmol) was added dropwise and the resulting mixture was stirred at -78 °C for a further 1 h. The reaction was quenched with saturated NH 4 Cl (300 mL). The two phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 4, filtered and concentrated under reduced pressure to give a crude product which was purified by flash silica gel chromatography, eluting with 10% EtOAc / petroleum ether to give compound s6-2 as a colorless oil (13.5 g, 38.6%) and s6a-1 as a colorless oil (5.8 g, 16.6%).

[0426] s6-2:

[0427] MS (ESI+) [(2M+H) + 589.3.

[0428] 11H NMR (400 MHz, methanol-d4) δ 5.82–5.71 (m, 1H), 5.14–5.04 (m, 2H), 4.65 - 4.62 (m, 1H), 3.78 (s, 3H), 2.77 - 2.69 (m, 1H), 2.59–2.50 (m, 1H), 2.25–2.03 (m, 3H), 1.47 (s, 9H).

[0429] s6a-1:

[0430] MS (ESI+) [(2M + H) + 589.3.

[0431] 1 1H NMR (400 MHz, CDCl3) δ 5.68 - 5.61 (m, 1H), 4.99 - 4.95 (m, 2H), 4.42 (d, J = 8.0 Hz, 1H), 3.68 (s, 3H), 2.58 - 2.52 (m, 2H), 2.40 - 2.37 (m, 1H), 2.14 - 2.12 (m, 1H), 1.64 - 1.59 (m, 1H), 1.39 (s, 9H).

[0432] Step 2: Synthesis of s6-3

[0433] Bubble O 3 through a mixture of compound s6-2 (60.0 g, 0.2 mol) in DCM (600 mL) for 4 h at -78 °C. Then add dropwise Me 2 S (131.3 g, 2.1 mol). Stir the mixture at 25 °C for 16 h. Then concentrate the reaction mixture to obtain a yellow oil. Dissolve the residue in EtOAc (1 L) and wash with brine. Dry the organic layer over anhydrous Na 2 SO 4 dry, filter and concentrate. Purify the residue by flash silica gel chromatography, eluting with petroleum ether and ethyl acetate (1:1 v / v) to obtain compound s6-3 as a white solid (7.00 mg, 58.5%).

[0434] MS observed (ESI+) [(M + H) + 285.

[0435] Step 3: Synthesis of s6-5

[0436] Mix compound s6-3 (23 g, 80.62 mmol) and (2R)-2-amino-2-phenylethanol (13.27 g, 96.74 mmol) in CHCl 3(900 mL) The mixture was stirred at 0 °C for 1 hour. Then TMSCN (20.81 g, 210.16 mmol) was added, and the resulting mixture was stirred at 0 °C for 1 hour. Finally, triethylamine trihydrofluoride (20.33 g, 126.10 mmol) was added at 0 °C and the mixture was stirred at 0 °C for 1 hour. The mixture was concentrated, then dissolved in EtOAc (500 mL), the organic layer was washed with brine, and dried over anhydrous Na 2 SO 4 After concentration, the residue was crystallized from petroleum ether and EtOAc (1:10 by volume) to give compound s6-5 as a white solid (12.00 g, crude product).

[0437] LCMS: m / z = 432.2 [M+1] + ;

[0438] 1 1H NMR (400 MHz, CDCl3) δ 7.384 - 7.26 (m, 5H), 5.07 (t, J = 5.6 Hz, 1H), 4.5 (d, J = 8.8, 1H), 3.84 - 3.82 (m, 1H), 3.78 (s, 3H), 3.43 - 3.38 (m, 2H), 3.24 - 3.18 (m.1H), 3.09 (d, J = 12.0 Hz, 1H), 2.89 - 2.80 (m, 1H), 2.24 - 2.18 (m, 1H), 1.96 - 1.89 (m, 1H), 1.78 - 1.62 (m, 2H), 1.39 (s, 9H).

[0439] Step 4: Synthesis of s6-6

[0440] To a mixture of compound s6-5 (10 g, 23.18 mmol) in DCM (50 mL) and methanol (50 mL) at 0 °C was added Pb(AcO) 4 (18.48 g, 41.72 mmol). After addition, the mixture was stirred at 0 °C for 10 minutes, then a buffer solution (Na 2 HPO 4 / NaH 2 PO 4 aqueous solution, 300 mL) was added, and the reaction mixture was stirred at 25 °C for 1 hour. The mixture was filtered, and the filtrate was extracted with DCM (50 mL × 2). The combined organic layers were concentrated, and the residue was dissolved in MTBE (200 mL). 3N HCl (200 mL) was added to the above mixture, and the mixture was partitioned. The aqueous layer was collected and adjusted to pH = 8 with solid NaHCO 3 The resulting mixture was extracted with ethyl acetate (50 mL × 2), the organic layer was washed with brine, and dried over Na2 SO 4 It was dried and concentrated to obtain crude compound s6-6 (5.00 g, crude product) as a colorless oil, which was used in the next step without further purification.

[0441] MS (ESI+) [(M + H) + 312.1.

[0442] Step 5: Synthesis of s6-8

[0443] To a solution of compound s6-7 (820.0 mg, 3.21 mmol) in DMF (10 mL) was added HATU (1.47 g, 3.85 mmol). After addition, the mixture was stirred at 25 °C for 30 minutes, then compound s6-6 (1.0 g, 3.21 mmol) and DIEA (830.25 mg, 6.42 mmol) were added. The resulting mixture was stirred at 25 °C for 2 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 2). The organic layer was washed with water (20 mL) and brine, and dried over Na 2 SO 4 It was dried, concentrated and purified by flash silica gel chromatography, eluting with 16% to 33% EtOAc / petroleum ether to obtain compound s6-8 (1.10 g, 53.2% yield) as a white solid.

[0444] MS (ESI+) [(M + Na) + 571.3

[0445] 1 1H NMR (400 MHz, CDCl3) δ 5.01 - 4.94 (m, 1H), 4.63 – 4.54 (m, 1H), 4.10 - 4.04 (m, 1H), 3.76 (s, 3H), 3.52 - 3.42 (m, 2H), 2.69 - 2.61 (m, 1H), 2.41 - 2.31 (m, 2H), 2.03 – 1.67 (m, 4H), 1.48 (s, 9H), 1.42 (s, 9H), 1.03 (s, 3H), 0.89 - 0.87 (m, 3H).

[0446] Step 6: Synthesis of s6

[0447] To a solution of compound s6-8 (1.1 g, 2.01 mmol) in toluene (2 mL) was added trimethyltin hydroxide (2.39 g, 4.01 mmol). After addition, the mixture was stirred at 100 °C for 12 h. When the reaction was complete, the reaction mixture was concentrated and the residue was dissolved in EtOAc (20 mL). Then triethylamine trihydrofluoride (3.2 g, 8.02 mmol) was added and the mixture was stirred at 25 °C for 2 h. Water (20 mL) was added and the resulting slurry was filtered. The filtrate was concentrated to give compound s6 (1.21 g, crude) as a white solid. This compound was used in the next step without further purification.

[0448] MS(ESI+)[(M+Na) + 557.3

[0449] Example 1.6 Synthesis of Intermediate s6a

[0450] Intermediate s6a was prepared from s6a-1 according to a similar chemical reaction and procedure as described above.

[0451]

[0452] LCMS: m / z = 535.30 [M+1] +

[0453] Example 1.7 Synthesis of Intermediates s7-s11 and Compound 76

[0454]

[0455] Step 1: Synthesis of s7-1

[0456] At 25 °C, to a solution of compound s1 (2.52 g, 7.48 mmol) and compound s6 (4.0 g, 7.48 mmol) in DCM (30 mL) was added DCC (2.32 g, 11.22 mmol) and DMAP (0.228 g, 1.87 mmol), and then the mixture was stirred at 25 °C for 16 h. Then the reaction mixture was washed with water twice (30 mL * 2). The organic layer was dried over Na 2 SO 4 dried, filtered and concentrated to give a residue, which was purified by silica gel chromatography (PE:EA = 1:1) to give s7-1 (2.1 g, 33%) as a white solid.

[0457] LC-MS [M-199] + = 654.4

[0458] 1HNMR (400 MHz, CDCl3) δ 7.32 - 7.23 (m, 5H), 5.41 - 5.33 (m, 1H), 5.12 - 4.82 (m, 3H), 4.62 - 4.53 (m, 1H), 4.04 - 3.93 (m, 2H), 3.87 - 3.81 (m, 1H), 3.72 - 3.63 (m, 1H), 3.46 - 3.33 (m, 1H), 2.88 - 2.73 (m, 1H), 2.62 - 2.39 (m, 1H), 2.31 - 2.23 (m, 1H), 2.01 - 1.84 (m, 2H), 1.61 - 1.51 (m, 2H), 1.43 - 1.34 (m, 27H), 9.94 - 0.91 (m, 9H), 0.87 - 0.79 (m, 3H).

[0459] Step 2: Synthesis of s7 - 2

[0460] To a solution of s7 - 1 (2.1 g, 2.46 mmol) in TFA (10 mL) and ACN (10 mL) was added anisole (0.40 g, 3.69 mmol). The mixture was stirred at 25 °C for 16 h. The suspension was concentrated and the residue was purified by a reverse - phase column (ACN:H 2 O = 55:45) to give compound s7 - 2 (730 mg, 50%) as a white solid, which was used directly in the next step.

[0461] LC - MS [M + H] + = 598.3

[0462] Step 3: Synthesis of compound 76

[0463] To a solution of s7 - 2 (630 mg, 1.05 mmol) in DMF (12 mL) was added HATU (1.0 g, 2.64 mmol) and DIEA (681.17 mg, 5.27 mmol). The reaction mixture was stirred at 30 °C for 2 h. The suspension was concentrated and the residue was purified by a reverse - phase column to give compound 76 (300 mg, 49%).

[0464] LC - MS [M + H] + = 580.3

[0465] 1HNMR (400 MHz, methanol-d4) δ 7.38 - 7.26 (m, 5H), 5.13 - 5.01 (m, 3H), 4.90 - 4.86 (m, 2H), 4.33 (s, 1H), 4.08 - 4.06 (m, 2H), 4.02 - 3.97 (m, 1H), 3.88 - 3.85 (m, 1H), 2.96 - 2.92 (m, 1H), 2.47 - 2.33 (m, 2H), 1.98 - 1.90 (m, 1H), 1.81 - 1.74 (m, 1H), 1.65 - 1.58 (m, 1H), 1.38 - 1.33 (m, 1H), 1.21 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.85 (s, 3H).

[0466] Step 4: Synthesis of s7

[0467] In H 2 To a solution of compound 76 (60 mg, 103 μmol) in THF (4 mL) was added Pd / C (120 mg), and H 2 was added three times to the reaction mixture, and the mixture was stirred at 25 °C for 2 h. The reaction solution was filtered and the filtrate was concentrated to give s7 (23.0 mg, 48%) as a colorless oil, which was used directly in the next step.

[0468] LC-MS [M + H] + = 446.2

[0469] Intermediates s8, s9 and s10 were prepared according to similar chemical reactions and procedures as described above.

[0470] Intermediate s8 was prepared from s3 and s6.

[0471]

[0472] LC-MS [M + 1] + = 460.20

[0473] Intermediate s9 was prepared from s4 and s6.

[0474]

[0475] LCMS: [M + 1] + m / z = 541.20; [M - 1] + m / z = 539.20;

[0476] Intermediate s10 was prepared from s5 and s6.

[0477]

[0478] LC-MS [M+H] + = 459.4

[0479] Intermediate s11 was prepared from s4 and s6a.

[0480]

[0481] LC-MS [M+1] + = 445.20

[0482] Compound 146 was prepared according to a similar chemical reaction and procedure as described above.

[0483] LCMS: m / z = 579.30 [M+1]+,

[0484] 1 H NMR (400 MHz, methanol-d4) δ 7.60 - 7.55 (m, 1H), 7.30 - 7.25 (m, 5H), 5.14–5.07 (m, 2H), 5.01 (d, J = 12.9 Hz, 1H), 4.34 (s, 1H), 4.12 (s, 1H), 3.97 - 3.88 (m, 3H), 3.36 - 3.30 (m, 1H), 3.07 - 3.03 (m, 2H), 2.40–2.29 (m, 2H), 2.22–2.11 (m, 1H), 1.80 - 1.75 (m, 1H), 1.65 - 1.60 (m, 1H), 1.40 (d, J = 7.4 Hz, 1H), 1.05 (s, 3H), 1.01 (s, 3H), 0.98 (s, 3H), 0.85 (s, 3H).

[0485] Example 1.8 Synthesis of Compound 1

[0486] At 0 °C and N 2 under, to a solution of s9 (11.6 mg, 0.026 mmol) in MeOH (1 mL) was added TEA (78 mg, 0.78 mmol, 30 equiv) and methyl 2,2,2-trifluoroacetate (99.7 mg, 0.78 mmol, 30 equiv). The mixture was stirred at 80 °C for 16 h. The reaction mixture was cooled and concentrated to give a crude product, which was purified by preparative HPLC (MeCN / H 2 O, additive: 0.1% FA) to afford Compound 1 (4.1 mg).

[0487] LCMS: m / z = 541.20 [M+1] + ; m / z = 539.20 [M-1] + ;

[0488] 11H NMR (400 MHz, CD3OD) δ: 5.38 - 5.30 (m, 1H), 4.90 - 4.86 (m, 1H), 4.59 (s, 1H), 4.05 - 3.95 (m, 2H), 3.86 (d, J = 8.0 Hz, 1H), 3.41 - 3.37 (m, 1H), 3.13 - 3.10 (m, 2H), 2.40 - 2.30 (m, 2H), 2.20 - 2.17 (m, 2H), 1.29 - 1.25 (m, 2H), 1.08 (s, 3H), 1.07 (s, 3H), 0.98 (s, 3H), 0.91 (s, 3H).

[0489] Compound 77 was prepared according to a similar chemical reaction and procedure as described above.

[0490] LC-MS [M+1]+ = 541.25

[0491] 1 1H NMR (400 MHz, CD3OD) δ: 9.12 (d, J = 8.0 Hz, 1H), 7.63 - 7.60 (m, 1H), 5.12 - 5.08 (m, 1H), 4.72 (s, 1H), 4.14 (s, 1H), 4.05 - 3.95 (m, 2H), 3.83 (d, J = 8.0 Hz, 1H), 3.41 - 3.37 (m, 1H), 3.13 - 3.10 (m, 2H), 2.38 - 2.33 (m, 2H), 2.20 - 2.17 (m, 1H), 1.83 - 1.80 (m, 1H), 1.68 - 1.62 (m, 1H), 1.44 - 1.42 (m, 1H), 1.29 - 1.25 (m, 1H), 1.08 (s, 3H), 1.07 (s, 3H), 0.97 (s, 3H), 0.89 (s, 3H).

[0492] Example 1.9 Synthesis of Compound 140

[0493] At 0 °C and N 2 under, to a solution of s9 (12.0 mg, 0.027 mmol, 1 equiv) in MeOH (1 mL) was added HOBt (3.65 mg, 0.027 mmol, 1 equiv), EDCI (5.2 mg, 0.027 mmol, 1 equiv) and DIEA (8.7 mg, 0.068 mmol, 3 equiv). After stirring for 5 minutes, cyclopropanecarboxylic acid (2.3 mg, 0.027 mmol, 1 equiv) was slowly added at -5 °C, and the mixture was stirred from -5 °C to RT for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (MeCN / H 2O, additive: 0.1% FA) was purified to obtain compound 140 (3.7 mg).

[0494] LCMS: m / z = 513.45 [M+1] + ; m / z = 511.45 [M-1] + ;

[0495] The following compounds were prepared according to similar chemical reactions and procedures as described above.

[0496] Compound 122 was prepared from intermediate s7.

[0497] LCMS: m / z = 542.4 [M+1]+, m / z = 540.2 [M-1]-;

[0498] 1 H NMR (400 MHz, methanol-d4) δ 5.16–5.07 (m, 1H), 4.95 - 4.90 (m, 1H), 4.68 (s, 1H), 4.17–3.98 (m, 3H), 3.84 - 3.81 (m, 1H), 3.43 - 3.40 (m, 1H), 2.98 - 2.94 (m, 1H), 2.48 - 2.36 (m, 2H), 2.03–1.93 (m, 1H), 1.84–1.75 (m, 1H), 1.71–1.64 (m, 1H), 1.41 (d, J = 7.6 Hz, 1H), 1.32 - 1.28 (m, 1H), 1.26 (s, 3H), 1.07 (s, 3H), 0.98 (s, 3H), 0.90 (s, 3H).

[0499] Compound 132 was prepared from intermediate s9.

[0500] 11H NMR (400 MHz, CD3OD) δ 9.13 (d, J = 8.0 Hz, 1H), 8.42 (d, J = 9.6 Hz, 1H), 7.57 (d, J = 6.4 Hz, 1H), 7.03 - 7.00 (m, 2H), 6.84 (t, J = 8.8 Hz, 1H), 5.15–5.06 (m, 1H), 4.69 (d, J = 8.0 Hz, 1H), 4.62 (s, 1H), 4.13 (s, 1H), 4.03–3.98 (m, 2H), 3.92 - 3.88 (m, 1H), 3.42 - 3.37 (m, 1H), 3.10 - 3.05 (m, 2H), 2.36 - 2.30 (m, 2H), 2.23 - 2.18 (m, 1H), 1.81 - 1.75 (m, 1H), 1.66–1.61 (m, 1H), 1.42 - 1.29 (m, 2H), 1.07 (s, 3H), 1.06 (s, 3H), 0.96 (s, 3H), 0.84 (s, 3H).

[0501] Compound 137 was prepared from intermediate s9.

[0502] LCMS: m / z = 607.50 [M+1] + , m / z = 605.45 [M-1] - ;

[0503] 1 1H NMR (400 MHz, CD3OD) δ: 6.99 - 6.95 (m, 2H), 6.93 - 6.87 (m, 1H), 5.12 - 5.06 (m, 1H), 4.80 - 4.77 (m, 1H), 4.37 - 4.26 (m, 2H), 4.17 (s, 1H), 4.09 - 4.02 (m, 1H), 3.99 - 3.89 (m, 2H), 3.41 - 3.36 (m, 1H), 3.14 - 3.01 (m, 1H), 2.39 - 2.30 (m, 2H), 2.21 (s, 6H), 2.18 - 2.13 (m, 1H), 1.84 - 1.74 (m, 1H), 1.68 - 1.64 (m, 1H), 1.44 - 1.42 (m, 1H), 1.30 - 1.22 (m, 1H), 1.09 (s, 3H), 1.07 (s, 3H), 0.93 (s, 3H), 0.88 (s, 3H).

[0504] Compound 138 was prepared from intermediate s9.

[0505] LCMS: m / z = 529.50 [M+1] + ; m / z = 527.50 [M-1] + ;

[0506] 1 1H NMR (400 MHz, CD3OD) δ 7.73 - 7.70 (m, 1H), 7.44 (d, J = 9.6 Hz, 1H), 5.35 - 5.33 (m, 1H), 4.77 (d, J = 9.6 Hz, 1H), 4.12 (s, 1H), 4.08 - 4.01 (m, 2H), 3.92 - 3.88 (m, 1H), 3.31 - 3.10 (m, 3H), 2.37 - 2.30 (m, 2H), 2.18 - 2.10 (m, 1H), 1.87 - 1.75 (m, 1H), 1.64 - 1.60 (m, 1H), 1.43 - 1.40 (m, 1H), 1.18 (s, 9H), 1.07 (s, 6H), 0.93 (s, 3H), 0.88 (s, 3H).

[0507] Compound 152 was prepared from intermediate s7.

[0508] LC-MS [M+H] + = 564.1

[0509] 1 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 9.7 Hz, 1H), 8.20 - 8.14 (m, 2H), 5.05 - 4.98 (m, 1H), 4.90 (d, J = 12.3 Hz, 1H), 4.52 (d, J = 9.2 Hz, 1H), 4.04 - 4.00 (m, 2H), 3.95 - 3.91 (m, 1H), 3.77 (d, J = 10.5 Hz, 1H), 3.55 - 3.50 (m, 1H), 2.80–2.64 (m, 1H), 2.25–2.17 (m, 1H), 1.90–1.81 (m, 1H), 1.73–1.57 (m, 3H), 1.37 (d, J = 7.7 Hz, 1H), 1.23 (s, 1H), 1.15 (s, 3H), 1.02 (s, 3H), 0.91 (s, 3H), 0.81 (s, 3H), 0.64 - 0.59 (m, 4H).

[0510] Compound 153 was prepared from intermediate s7.

[0511] LCMS: m / z = 528.3 [M+1] + ;

[0512] 1 1H NMR (400 MHz, DMSO-d 6)δ9.04(d, J = 9.6 Hz, 1H), 8.20(s, 1H), 7.92(d, J = 9.2 Hz, 1H), 5.05 - 4.99(m, 1H), 4.78(d, J = 12.4 Hz, 1H), 4.48(d, J = 8.8 Hz, 1H), 4.04 - 4.00(m, 2H), 3.92 - 3.85(m, 2H), 3.36(d, J = 12.0 Hz, 1H), 2.68 - 2.62(m, 1H), 2.29–2.17(m, 2H), 2.12–1.99(m, 2H), 1.87–1.79(m, 1H), 1.69–1.59(m, 1H), 1.58 - 1.55(m, 1H), 1.33(d, J = 7.6 Hz, 1H), 1.09(s, 3H), 1.02(s, 3H), 0.90 - 0.85(m, 4H), 0.84(s, 3H), 0.41 - 0.33(m, 2H), 0.16 - 0.05(m, 2H).

[0513] Compound 157 was prepared from intermediate s7.

[0514] LCMS: m / z = 514.3 [M + 1] +

[0515] Compound 177 was prepared from intermediate s10.

[0516] 1 HNMR(400 MHz, chloroform - d) δ8.81(br s, 1H), 6.75(br s, 1H), 5.08 - 5.06(m, 1H), 4.61(d, J = 7.6 Hz, 1H), 4.59 - 4.40(m, 2H), 4.01 - 3.90(m, 2H), 3.64–3.51(m, 2H), 3.11(s, 3H), 2.60 - 2.20(m, 3H), 1.90 - 1.70(m, 2H), 1.50–1.40(m, 2H), 1.09(s, 6H), 1.05(s, 3H), 0.92(s, 3H).

[0517] LC - MS [M + H] + = 555.4

[0518] Example 1.10 Synthesis of Compound 125

[0519] To a solution of intermediate s7 (20.0 mg, 44.89 μmol) and 2,2-difluoro-3-phenylpropanoic acid in DMF (1 mL) were added HATU (34.14 mg, 89.78 μmol) and DIEA (17.41 mg, 134.68 μmol). The mixture was stirred at 25 °C for 2 h. The suspension was concentrated and purified by preparative HPLC (0.04% TFA, acetonitrile / water = 40% - 65%) to give compound 125 (8.15 mg, 55%).

[0520] 1 HNMR (400 MHz, CDCl3) δ 8.28 (d, J = 7.2 Hz, 2H), 7.28 - 7.26 (m, 5H), 6.77 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.14 (s, 1H), 4.75 (m, 1H), 4.52 - 3.74 (m, 4H), 3.52 - 3.16 (m, 4H), 2.68 (m, 1H), 2.43 - 2.17 (m, 3H), 1.68 - 1.35 (m, 2H), 1.12 (s, 3H), 0.98 (s, 3H), 0.89 (s, 3H), 0.72 (s, 3H).

[0521] LC-MS [M+H] + = 614.4

[0522] Example 1.11 Synthesis of Compound 160

[0523] To a solution of s7 (10 mg, 22.45 μmol) and 2,2-difluoro-2-(4-fluorophenyl)acetic acid (6 mg, 31.56 μmol) in DMF (1.0 mL) were added DIEA (10 mg, 77.38 μmol) and HATU (16 mg, 42.08 μmol). The mixture was stirred at 20 °C for 2 h. The mixture was diluted with ethyl acetate (10 mL) and washed with saturated NH 4 Cl (5 mL). The organic layer was separated and concentrated. The residue was purified by preparative HPLC (additive: 0.04% TFA, acetonitrile / water = 45% - 65%) to give compound 160 (1.50 mg, 10.67%).

[0524] LC-MS [M+H]+ = 618.20.

[0525] 11H NMR (400 MHz, CD3OD) δ 7.67 - 7.63 (m, 2H), 7.23 - 7.18 (m, 2H), 5.15 - 5.08 (m, 1H), 4.91 (d, J = 12.4 Hz, 1H), 4.68 - 4.64 (m, 1H), 4.12 (d, J = 9.6 Hz, 1H), 4.05 - 3.95 (m, 2H), 3.76 - 3.70 (m, 1H), 3.36 (d, J = 12.0 Hz, 1H), 3.09 - 3.00 (m, 1H), 2.46 - 2.38 (m, 2H), 2.03 - 1.93 (m, 1H), 1.83 - 1.76 (m, 1H), 1.66 - 1.59 (m, 1H), 1.38 (d, J = 8.0 Hz, 1H), 1.25 (s, 3H), 1.04 (s, 3H), 0.90 (s, 3H), 0.68 (s, 3H).

[0526] The following compounds were prepared according to similar chemical reactions and procedures as described above.

[0527] Compound 97 was prepared from intermediate s8.

[0528] LC-MS [M+1] + = 556.20

[0529] 1 1H NMR (400 MHz, DMSO-d6) δ 9.62 (d, J = 8.8 Hz, 1H), 9.15 (d, J = 9.3 Hz, 1H), 8.13 (s, 1H), 5.00 - 4.94 (m, 1H), 4.47–4.35 (m, 2H), 4.15 (s, 1H), 4.06 (d, J = 8.8 Hz, 1H), 4.01–3.90 (m, 2H), 3.68 - 3.65 (m, 1H), 2.48–2.42 (m, 1H), 2.30–2.19 (m, 2H), 2.13–2.03 (m, 2H), 1.69 - 1.61 (m, 1H), 1.60–1.51 (m, 2H), 1.35 - 1.30 (m, 1H), 1.01 (s, 3H), 0.92 (s, 3H), 0.88 (s, 3H), 0.81 (s, 3H).

[0530] Synthesis of Compound 159 in Example 1.12

[0531] To a solution of s7 (128.0 mg, 287.31 μmol) and DIEA (74.26 mg, 574.63 μmol) in DCM (1 mL) was added methyl chloroformate (36.78 mg, 389.21 μmol), and the mixture was stirred at 20 °C for 10 minutes. The reaction solution was concentrated, and the residue was purified by preparative HPLC (0.1% FA, acetonitrile / water = 30% - 50%) to give compound 159 (32.26 mg, 22%).

[0532] LC-MS[M+H] + = 504.3

[0533] 1 HNMR(400MHz,DMSO-d6)δ9.03(d,J = 8Hz,1H),8.18(s,1H),7.18(s,1H),5.01(m,1H),4.80 - 4.77(m,1H),4.10 - 3.82(m,5H),3.51(s,3H),3.35 - 3.31(m,1H),2.70 - 2.67(m,1H),2.28 - 2.25(m,2H),1.66 - 1.55(m,3H),1.34 - 1.32(m,1H),1.25(s,3H),1.10(s,3H),1.00(s,3H),0.81(s,3H).

[0534] Compound 156 was prepared from intermediate s7.

[0535] LC-MS[M+H] + = 530.30.

[0536] Example 1.13 Synthesis of Compound 98

[0537] To a solution of s8 (70 mg, 152.33 μmol) in DCM (2 mL) was added DIEA (59.06 mg, 456.98 μmol) and methyl chloroformate (21.59 mg, 228.49 μmol), and the mixture was stirred at 15 °C for 1 hour. The residue was purified by preparative HPLC (0.1% TFA, 45% - 60% ACN) to give compound 98 (26 mg, 33%).

[0538] LC-MS[M+1] + = 518.30

[0539] 11H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J = 9.2 Hz, 1H), 8.13 (s, 1H), 7.27 (d, J = 9.2 Hz, 1H), 4.99 - 4.93 (m, 1H), 4.36 - 4.31 (m, 1H), 4.14 (s, 1H), 4.09–4.02 (m, 2H), 3.99–3.92 (m, 1H), 3.88 - 3.82 (m, 2H), 3.51 (s, 3H), 2.44–2.30 (m, 1H), 2.30–2.18 (m, 2H), 2.12–1.98 (m, 2H), 1.67 - 1.59 (m, 1H), 1.57–1.43 (m, 2H), 1.26 (d, J = 7.6 Hz, 1H), 1.01 (s, 3H), 0.88 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H).

[0540] Example 2

[0541] Biochemical assay

[0542] Assay 1: Inhibition of 3CLpro

[0543] The test compound was serially diluted 3-fold to obtain 10 doses and added to the assay plate (384w format) in duplicate wells using ECHO. Then, 25 μL of 3CLpro protein was added to the assay plate containing the compound using Multidrop. The mixture of the compound and 3CLpro protein was pre-incubated at room temperature for 30 minutes. Then, 5 μL of substrate was added using Multidrop. The final concentrations of 3CLpro and the substrate were 25 nM and 25 μM, respectively. For the 100% inhibition control (HPE, hundred percent effect), 1 μM GC376 was added. For the no-inhibition control (ZPE, zero percent effect), no compound was added. The final DMSO concentration was 1%. Each active test point had a related background control to normalize the fluorescence interference of the compound. After incubation at 30 °C for 60 minutes, the fluorescence signal (RFU) was detected using a microplate reader M2e (SpectraMax) at Ex / Em = 340 nm / 490 nm. The inhibition activity was calculated using the following formula: Inhibition % = [(Sample - Average ZPE) / (Average HPE - Average ZPE)] * 100%,

[0544] HEP: Hundred percent effect control. Contains substrate + assay buffer + 1 μM GC376.

[0545] ZPE: Zero percent effect control. Contains enzyme + substrate, without compound.

[0546] Sample: Compound active test well. Contains compound + enzyme + substrate.

[0547] BG: Compound background control well. Contains compound + substrate, without enzyme.

[0548] IC 50 Determined from the inhibition curve, and the results are shown in Table 1.

[0549] Assay 2: Human liver microsome (HLM) stability

[0550] The test article was prepared at 10 mM in DMSO and diluted to 100 μM with ACN:H 2 O = 1:1 (v / v) to obtain a working solution. The working solution was diluted to 1 μM in potassium phosphate buffer (100 mM, pH 7.4) with a final volume of 200 μL and incubated in a shaking incubator at 37 °C. The potassium phosphate buffer contained MgCl 2 (3 mM), NADPH (1 mM), and HLM (1 mg / mL). Incubation was carried out in the absence and presence of the selective CYP3A inhibitor ketoconazole (1 μM). Incubation was terminated by adding 200 μL of acetonitrile (300 ng / mL tolbutamide) to 100 μL of the sample at selected time points (0 min, 5 min, 15 min, 30 min, 45 min, 60 min, 80 min). The quenched samples at each time point were mixed for 5 min and centrifuged at 3700 rmp for 15 min. The supernatant was transferred to a 96-well plate, mobile phase A was added to the samples, and analysis was performed by LC-MS / MS. The half-life (t 1 / 2 ) was estimated as t 1 / 2 = -0.693 / k and is shown in Table 1, where k is the slope of the linear regression fit of the peak area ratio versus the natural logarithm of time.

[0551] Assay 3: In vitro antiviral activity against OC43

[0552] The in vitro anti-OC43 activity and cytotoxicity were evaluated using Huh7 cells as described below.

[0553] Antiviral activity assay: Huh7 cells were seeded in a 96-well plate at a density of 8000 cells / well, 100 μL of assay medium per well, and incubated at 37 °C and 5% CO 2Cultivate below. After incubating for 24 hours, dilute the test compound and positive control (PF-07321332) with the assay medium and then add them to the cells, 50 μL per well. Then add 50 μL of the virus diluted with the assay medium to each well. Incubate the resulting cell culture for another 7 days until significant CPE (cytopathic effect) is shown in the virus control (cells infected with the virus, without compound treatment). CPE is measured by CellTiter Glo according to the manufacturer's manual. Calculate the antiviral activity of the compound based on the protection against virus-induced CPE at each concentration normalized to the virus control.

[0554] Calculate the inhibition percentage by the following equation: Inhibition (%) = (Raw data CPD – Average VC) / (Average CC – Average VC) * 100.

[0555] Cytotoxicity assay: The cytotoxicity of the compound is evaluated by the same method as the antiviral activity assay, but without the step of virus infection. The viability of Huh7 cells is measured by Cell-Titer Glo according to the manufacturer's manual. Calculate the viability percentage by the following equation: Viability (%) = (Raw data CPD – Average MC) / (Average CC – Average MC) * 100.

[0556] Raw data CPD: The value of the sample-treated well.

[0557] Average VC: The average value of the virus control

[0558] Average CC: The average value of the cell control (cells without virus infection or compound treatment)

[0559] Average MC: The average value of the medium control (medium only) wells.

[0560] Assay 4: In vitro antiviral activity against 229E

[0561] Evaluate the in vitro anti-229E activity and cytotoxicity using MRC5 cells as described below.

[0562] Antiviral activity assay: MRC5 cells are seeded in 96-well plates at a density of 20,000 cells / well, 100 μL of assay medium per well, and incubated at 37 °C and 5% CO 2Incubate below. After 24 hours of incubation, dilute the test compound and the positive control (PF-07321332) with the assay medium, and then add them to the cells, 50 μL per well. Then add 50 μL of the virus diluted with the assay medium to each well. Incubate the resulting cell culture for another 3 days until significant CPE is shown in the virus control (cells infected with the virus, without compound treatment). CPE is measured by CellTiter Glo according to the manufacturer's manual. Calculate the antiviral activity of the compound based on the protection of virus-induced CPE at each concentration normalized to the virus control.

[0563] Calculate the inhibition percentage by the following equation: Inhibition (%) = (Raw data CPD – Average VC) / (Average CC – Average VC) * 100.

[0564] Cytotoxicity assay: The cytotoxicity of the compound was evaluated by the same method as the antiviral activity assay, but without the virus infection step. Cell viability was measured by Cell-Titer Glo according to the manufacturer's manual. Calculate the viability percentage by the following equation: Viability (%) = (Raw data CPD – Average MC) / (Average CC – Average MC) * 100.

[0565] Raw data CPD: The value of the sample-treated well

[0566] Average VC: The average value of the virus control

[0567] Average CC: The average value of the cell control (cells without virus infection or compound treatment)

[0568] Average MC: The average value of the medium control (medium only) wells.

[0569] Assay 5: In vitro antiviral activity against SARS-CoV-2 replicon

[0570] Serial dilute the compound in DMSO and add 0.3 μL per well (8 doses, 3-fold, duplicate wells) to a 384-well plate. The replicon RNA is generated in an in vitro transcript. Seed Huh7 cells transfected with purified SARS-CoV-2 replicon RNA at 4000 cells / well into a 384-well microplate containing the serial diluted compound, and then incubate at 37 °C and 5% CO 2 for 1 day. The final volume of the cell culture is 60 μL / well, and the final concentration of DMSO in the test plate is 0.5%.

[0571] Measure the fluorescence intensity using Acumen Cellista (TTP LabTech), and calculate the antiviral activity of the compound based on the inhibition of GFP expression. Cell viability was measured by CellTiter Glo according to the manufacturer's manual.

[0572] The antiviral activity and viability of the compound are expressed as % inhibition and % viability, respectively, and are calculated using the following equations:

[0573] Inhibition (%) = (Raw data CPD – Average ZPE) / (Average HPE – Average ZPE) * 100

[0574] Viability (%) = (Raw data CPD – Average HPE) / (Average ZPE – Average HPE) * 100

[0575] Raw data CPD: The value of the sample-treated well

[0576] Average ZPE: The average value of the virus control

[0577] Average HPE: The average value of the medium control (medium only) well.

[0578] The EC50 value and CC50 value were calculated using GraphPad Prism software with a non-linear regression model of log(inhibitor) vs. response – variable slope (four parameters), and the results are shown in Table 1.

[0579] Assay 6: In vitro antiviral activity against SARS-CoV-2

[0580] The in vitro anti-SARS-COV-2 activity and cytotoxicity were evaluated using Vero cells as described below.

[0581] Antiviral activity assay: Vero cells were seeded in 96-well plates at a density of Vero cells / well, 100 μL of assay medium per well, and cultured at 37 °C and 5% CO2. After incubation for 24 hours, the test compound and positive control (PF-07321332) were diluted with assay medium and then added to the cells, 50 μL per well. Then 50 μL of virus diluted with assay medium was added to each well. The resulting cell culture was incubated for another 3 days until the virus infection in the virus control (virus-infected cells without compound treatment) showed significant CPE. CPE was measured by CellTiter Glo according to the manufacturer's manual. The antiviral activity of the compound was calculated based on the protection of virus-induced CPE at each concentration normalized to the virus control.

[0582] The % inhibition was calculated using the following equation: Inhibition (%) = (Raw data CPD – Average VC) / (Average CC – Average VC) * 100.

[0583] Cytotoxicity assay: The cytotoxicity of the compound was evaluated in the same manner as the antiviral activity assay, but without the virus infection step. Cell viability was measured using Cell-Titer Glo according to the manufacturer's manual. The viability % was calculated by the following equation: Viability (%) = (Raw data CPD – Mean MC) / (Mean CC – Mean MC) * 100.

[0584] Raw data CPD: The value of the sample-treated well

[0585] Mean VC: The mean of the virus control

[0586] Mean CC: The mean of the cell control (cells without virus infection or compound treatment)

[0587] Mean MC: The mean of the medium control (medium only) wells.

[0588] Table 1

[0589]

[0590]

[0591] *IC 50 (nM): A < 100, B 100 - 1000, C > 1000

[0592] **EC 50 (nM): A < 100, B 100 - 1000, C > 1000

[0593] ***Liver microsome T 1 / 2 (min): A > 100, B ≤ 100

[0594] The foregoing description is to be considered as merely illustrative of the principles of the present disclosure. Furthermore, since many modifications and variations will be apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process as described above. Accordingly, all suitable modifications and equivalents are considered to fall within the scope of the invention as defined by the appended claims.

Claims

1. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating coronavirus infection, wherein, the compound is selected from the following group:

2. The use according to claim 1, wherein, the virus is SARS-COV-2.

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