WO2024102455A1 - Non-covalent inhibitors of coronavirus main protease - Google Patents

Abstract

Non-covalent inhibitors of coronavirus main protease and pharmaceutical formulations thereof are disclosed. The compounds and pharmaceutical formulations disclosed herein can be used to treat or prevent coronavirus infection, especially SARS-CoV-2 infection.

Description

NON-COVALENT INHIBITORS OF CORONAVIRUS MAIN PROTEASE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/450,840 filed March 8, 2023 and U.S. Provisional Application No. 63/423,974 filed November 9, 2022. The entirety of each of these applications is hereby incorporated by reference for all purposes. TECHNICAL FIELD The present disclosure relates to non-covalent inhibitors of coronavirus main protease. It also relates to pharmaceutical formulations of the compounds and methods for treating conditions, disorders, or diseases using the compounds. BACKGROUND Severe acute respiratory coronavirus-2 (SARS-CoV-2), the causative agent of the COVID- 19 pandemic, continues to flourish despite the current availability of several vaccines, resulting in not only a severe economic burden felt in countries the world over, but also the tragedy of loss of life. SARS-CoV-2 is one of seven coronaviruses able to infect humans and shares an a80% similarity in genome sequence with that of SARS-CoV. However, unlike SARS-CoV (hereinafter referred to as SARS-CoV-1), which appeared in 2002-2003 and resulted in around 8000 reported cases and 774 deaths (10% fatality rate), SARS-CoV-2 has been significantly more devastating, with over 440 million confirmed COVID-19 cases and over 6 million related deaths worldwide as of March 2022. The continued problematic spread of the virus is largely due to a high proportion of people who are not vaccinated, but of even greater concern is while the virus is thus allowed to flourish, it is constantly mutating, leading to variants that may escape the efficacy of the currently available vaccines. Given that a large proportion of the population will continue to remain unvaccinated, and the potential that our current vaccines may prove to be less and less effective as the virus mutates, there remains a pressing need to develop effective antiviral agents that can be administered quickly and conveniently to afflicted individuals. The SARS-CoV-2 genome encodes for multiple enzymes that are essential for viral replication and are thus potential targets for intervention. Two of the most promising targets include the SARS-CoV-2 nsp12 polymerase and the main protease (M^pro). In the case of the former target, significant progress has already been made, with Remdesivir approved as an intravenous medication and molnupiravir approved as an oral medication. However, a very valuable lesson learned from developing highly effective HIV therapies is the benefit of employing combination therapies in drug regimens to overcome problems associated with the onset of resistance. Therefore, targeting a second enzyme becomes very important. Two viral cysteine proteases, namely the chymotrypsin-like cysteine protease (also known as the main protease or M^pro) and a papain-like cysteine protease (PL^pro), catalyze the proteolysis of the produced polypeptides into functional viral proteins and are therefore essential for viral efficacy. In particular, the M^pro has garnered significant attention as an attractive drug target, given that it is very similar to the main protease of SARS-CoV-1 (a96% sequence identity), and therefore, many of the inhibitors designed for the SARS-CoV-1 M^pro serve as good candidates for designing SARS-CoV-2 M^pro inhibitors. Furthermore, the SARS-CoV-2 M^pro hydrolyses the Gln-Ser peptide bond in the Leu-Gln-Ser recognition sequence, which is distinct from other human cysteine proteases, thereby neatly circumventing toxicity issues associated with inadvertent inhibition of human cysteine proteases upon administering SARS-CoV-2 M^pro inhibitors. Nevertheless, a big problem with protease inhibitors in general is that these compounds tend to be peptidomimetic compounds, which are highly polar, leading to poor membrane permeation, and are prone to metabolic degradation, all in all leading to poor bioavailability. For example, the Pfizer SARS- CoV-2 M^pro inhibitor, PF-07321332 or nirmatrelvir, which received Emergency Use Authorization from the FDA, must be co-administered with ritonavir, an inhibitor of cytochrome P450 enzymes, to slow down its degradation, thereby creating a risk for drug-drug interactions. Furthermore, in the specific case of the mainstream SARS-CoV-2 M^pro inhibitors currently under investigation, these are covalent modifiers, incorporating a covalent warhead to react with the catalytic cysteine residue in the active site pocket. Though many of these compounds are highly potent, the peptidomimetic nature of these compounds, as well as off-target irreversible reactions caused by the covalent warhead, often results in these compounds being poor candidates for clinical use. A number of research groups designed non-covalent inhibitors of SARS-CoV-2 M^pro (Kitamura, et al., J. Med. Chem., 2022, 65, 4, 2848–2865; Han, et al., J. Med. Chem., 2022, 65, 4, 2880–2904; Ghahremanpour, et al., ACS Medicinal Chemistry Letters, 2020, 11(12), 2526; Zhang, et al., ACS Medicinal Chemistry Letters, 2021, 12(8), 1325; Zhang, et al., ACS Central Science, 2021, 7(3), 467). However, these non-covalent inhibitors suffer from various issues, including (1) reminiscence of peptide-like character, (2) mediocre target potency, (3) mediocre antiviral activity, (4) poor membrane permeability, and/or (5) poor metabolic stability. Accordingly, there is an urgent need for newer and safer inhibitors of coronavirus main protease, especially those having improved pharmacokinetic and therapeutic profiles. In particular, there is an urgent need for newer and safer non-covalent inhibitors of coronavirus main protease, especially those having improved pharmacokinetic and therapeutic profiles. SUMMARY The present disclosure describes non-covalent inhibitors of coronavirus main protease (M^pro). In some embodiments, the compounds have a structure of Formula I or II or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof,

Formula II wherein R¹ is halogen, –O–(C(R^a)(R^b))m–R^X, or –S–(C(R^a)(R^b))m–R^X, wherein: m is 1 or 2, R^a and R^b, at each occurrence, are independently and individually hydrogen, halogen, C₁– C3 alkyl, or C1–C3 haloalkyl, and R^X is optionally substituted C₁–C₃ alkyl, optionally substituted C₁–C₃ haloalkyl, optionally substituted carbocyclyl, optionally substituted halocarbocyclyl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, optionally substituted aryl, optionally substituted haloaryl, optionally substituted heteroaryl, or optionally substituted haloheteroaryl; wherein R², R³, R⁵, R⁶, and R⁷ are independently and individually hydrogen, halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, alkylaryl, alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkyloxycarbonyl, aryloxycarbonyl, primary amino, alkylamino, alkylammonium, alkylcarbonylamino, arylcarbonylamino, carbamoyl, N-alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or N- alkylsulfamoyl; and

Y¹, Y², Y³, and Y⁴ are independently and individually CH or N, X is N or O, Z¹, Z², and Z³ are independently and individually CH, N, NH, O, or S, R^c, at each occurrence, is independently and individually halogen, C1–C3 alkyl, or C1–C3 haloalkyl, l is 0, 1, 2, or 3, k is 0, 1, or 2, n is 0, 1, 2, 3, 4, or 5, o is 0, 1, 2, 3, or 4, when n is not 0, the corresponding R^c substituent(s) can be on either or both rings, when o is not 0, the corresponding R^c substituent(s) can be on either or both rings, and when an R^c group is present, it replaces the hydrogen atom at the ring atom that the R^c group connects to. In some embodiments, the compounds have a structure of Formula I or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. In some embodiments, R², R³, R⁵, R⁶, and R⁷ are independently and individually hydrogen, halogen, C1–C3 alkyl such as methyl, or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R², R⁵, R⁶, and R⁷ are hydrogen, and R³ is halogen. In some embodiments, R², R⁶, and R⁷ are hydrogen, R⁵ is methyl, –CH₂F, –CHF₂, or –CF₃, and R³ is halogen. In some embodiments, R², R⁵, and R⁷ are hydrogen, R⁶ is methyl, –CH₂F, –CHF₂, or –CF₃, and R³ is halogen. In some embodiments, R² and R⁷ are hydrogen, R⁵ and R⁶ are independently methyl, – CH2F, –CHF2, or –CF3, and R³ is halogen. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R¹ is halogen, such as chloro or fluoro. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X. R^a and R^b, at each occurrence, are independently and individually hydrogen, halogen, C1– C₃ alkyl such as methyl, or C₁–C₃ haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiments, R^a and R^a, at each occurrence, are hydrogen. In some embodiments, R^X is optionally substituted C1–C3 alkyl or optionally substituted C₁–C₃ haloalkyl. In some embodiments, R^X is –CH₂F, –CHF₂, –CF₃, isopropyl, or tert-butyl. In some embodiments, R^X is optionally substituted carbocyclyl, optionally substituted halocarbocyclyl, optionally substituted heterocyclyl, or optionally substituted haloheterocyclyl. In some embodiments, R^X is selected from optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted azetidinyl, and optionally substituted oxetanyl. In some O e

. In some embodiments, R^X is optionally substituted aryl, optionally substituted haloaryl, optionally substituted heteroaryl, or optionally substituted haloheteroaryl. In some embodiments, R^X is optionally substituted phenyl, optionally substituted halophenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered haloheteroaryl.

wherein V¹, V², V³, V⁴, and V⁵ are independently and individually CH or N, wherein W¹, W², W³, and W⁴ are independently and individually CH, N, NH, O, or S, wherein R^e, at each occurrence, is independently and individually halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, alkylaryl, alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkyloxycarbonyl, aryloxycarbonyl, primary amino, alkylamino, alkylammonium, alkylcarbonylamino, arylcarbonylamino, carbamoyl, N- alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or N-alkylsulfamoyl, wherein p is 0, 1, 2, or 3, wherein q is 0, 1, or 2, wherein r is 0, 1, 2, 3, 4, or 5, wherein s is 0, 1, 2, 3, or 4, wherein when r is not 0, the corresponding R^e substituent(s) can be on either or both rings, wherein when s is not 0, the corresponding R^e substituent(s) can be on either or both rings, and wherein when an R^e group is present, it replaces the hydrogen atom at the ring atom that the R^e group connects to. . e

I I

n some embodiments, s is 0 or 1.In some embodiments, R^e, at each occurrence, is independently and individually chloro, fluoro, nitro, cyano, hydroxyl, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, R^e, at each occurrence, is independently and individually chloro, fluoro, nitro, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. ,

_{, , ,} , , .

In some embodiments, n is 0 or 1.

This disclosure also provides deuterated analogs of the non-covalent inhibitors of coronavirus M^pro. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein one or more of the non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, the –(C(R^a)(R^b))_m– moiety of R¹ is deuterated. For example, the –(C(R^a)(R^b))_m– moiety may be –(CD₂)_m–. In some embodiments, the R^X moiety of R¹ is deuterated. In some embodiments, both the –(C(R^a)(R^b))m– moiety and the R^X moiety are deuterated. Also disclosed are compositions containing a compound described herein, wherein the compound is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess. In some embodiments, the compound in the compositions is in greater than 95% enantiomeric or diastereomeric excess. Also disclosed are pharmaceutical formulations of the disclosed compounds or compositions. In general, the pharmaceutical formulations contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical formulations are in a form chosen from tablets, capsules, caplets, pills, beads, granules, particles, powders, gels, creams, solutions, suspensions, emulsions, and nanoparticulate formulations. In some embodiments, the pharmaceutical formulations are oral formulations. In some embodiments, the pharmaceutical formulations are intravenous formulations. In some embodiments, the pharmaceutical formulations are intramuscular formulations. In some embodiments, the pharmaceutical 1 formulations are intranasal formulations. In some embodiments, the pharmaceutical formulations are subcutaneous formulations. This disclosure also relates to (1) the compounds, compositions, and pharmaceutical formulations disclosed herein for treatment or prevention of coronavirus infection or use as a medicament, (2) the compounds, compositions, and pharmaceutical formulations disclosed herein for use in the treatment or prevention of coronavirus infection, or (3) the compounds, compositions, and pharmaceutical formulations disclosed herein for the manufacture of a medicament for treatment or prevention of coronavirus infection. In some embodiments, the coronavirus infection is SARS-CoV-2 infection. This disclosure also provides methods of treating or preventing coronavirus infection in a subject in need thereof. The method includes administering an effective amount of a compound, composition, or pharmaceutical formulation disclosed herein to the subject. In some embodiments, the compound, composition, or pharmaceutical formulation is administered orally, intravenously, intranasally, subcutaneously, or intramuscularly. In some embodiments, the coronavirus infection is SARS-CoV-2 infection. DETAILED DESCRIPTION The present disclosure describes non-covalent inhibitors of coronavirus main protease and pharmaceutical formulations thereof. It also describes methods for treating or preventing coronavirus infection using the disclosed compounds and pharmaceutical formulations thereof. Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to the particular embodiments described herein and, as such, may vary in accordance with the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All publications and patents cited in this specification are herein incorporated by reference as if each individual publication and patent were specifically and individually indicated to be incorporated by reference. They are incorporated by reference to disclose and describe the methods and/or materials in connection with which the publications and patents are cited. As will be apparent to those of ordinary skill in the art upon reading this disclosure, each of the particular embodiments described and illustrated herein has discrete components and/or features that may be readily separated from or combined with one or more components and/or features of any of the other embodiments described herein, without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited herein or in any other order that is logically possible. Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, organic chemistry, medicinal chemistry, biochemistry, molecular biology, pharmacology, neurology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature, such as the publications and patents cited herein. I. DEFINITIONS As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. The terms “may,” “may be,” “can,” and “can be,” and related terms are intended to convey that the subject matter involved is optional (that is, the subject matter is present in some examples and is not present in other examples), not a reference to a capability of the subject matter or to a probability, unless the context clearly indicates otherwise. The terms “optional” and “optionally” mean that the subsequently described event, circumstance, or material may or may not occur or be present, and that the description includes instances where the event, circumstance, or material occurs or is present, as well as instances where it does not occur or is not present. Use of the term “about” is intended to describe values either above or below the stated value in a range of approx. ^/^ 10%; in other examples, the values may range in value either above or below the stated value in a range of approx. ^/^ 5%; in other examples, the values may range in value either above or below the stated value in a range of approx. ^/^ 2%; in other examples, the values may range in value either above or below the stated value in a range of approx. ^/^ 1%. A carbon range (e.g., C1^C10) is intended to disclose individually every possible carbon value and/or sub-range encompassed within. For example, a carbon range of C1^C10 discloses C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10, as well as sub-ranges encompassed therein, such as C2-C9, C3-C8, C1-C5, etc. As used herein, the term “subject” refers to an animal, including human and non-human animals. Human subjects may include pediatric patients and adult patients. Non-human animals may include domestic pets, livestock and farm animals, and zoo animals. In some cases, the non- human animals may be non-human primates. As used herein, the terms “prevent” and “preventing” include the prevention of the occurrence, onset, spread, and/or recurrence. It is not intended that the present disclosure is limited to complete prevention. For example, prevention is considered as achieved when the occurrence is delayed, the severity of the onset is reduced, or both. As used herein, the terms “treat” and “treating” include medical management of a condition, disorder, or disease of a subject as would be understood by a person of ordinary skill in the art (see, for example, Stedman’s Medical Dictionary). In general, treatment is not limited to cases where the subject is cured and the condition, disorder, or disease is eradicated. Rather, treatment also contemplates cases where a treatment regimen containing one of the compounds, compositions, or pharmaceutical formulations of the present disclosure provides an improved clinical outcome. The improved clinical outcome may include one or more of the following: abatement, lessening, and/or alleviation of one or more symptoms that result from or are associated with the condition, disorder, or disease to be treated; decreased occurrence of one or more symptoms; improved quality of life; diminishment of the extent of the condition, disorder, or disease; reaching or establishing a stabilized state (i.e., not worsening) of the condition, disorder, or disease; delay or slowing of the progression of the condition, disorder, or disease; amelioration or palliation of the state of the condition, disorder, or disease; partial or total remission; and improvement in survival (whether increase in the overall survival rate or prolonging of survival when compared to expected survival if the subject were not receiving the treatment). In the context of COVID-19, examples of improved clinical outcomes include reduction or alleviation in COVID-19 symptoms, reduced lung pathology, reduction in the amount of SARS-CoV-2 viral load, and decreased mortality. The terms “deuterated” and “deuteration” refer to replacement of one or more non- ionizable hydrogen atoms in a chemical compound/moiety with deuterium. A deuterated chemical compound/group/moiety may be fully deuterated (i.e., all the non-ionizable hydrogen atoms in the chemical compound/moiety are replaced with deuterium) or partially deuterated (i.e., one or more non-ionizable hydrogen atoms, but not all the non-ionizable hydrogen atoms, in the chemical compound/group/moiety are replaced with deuterium). The terms “derivative” and “derivatives” refer to chemical compounds/groups/moieties with a structure similar to that of a parent compound/group/moiety but different from it in respect to one or more components, functional groups, atoms, etc. Optionally, the derivatives retain certain functional attributes of the parent compound/group/moiety. Optionally, the derivatives can be formed from the parent compound/group/moiety by chemical reaction(s). The differences between the derivatives and the parent compound/group/moiety can include, but are not limited to, replacement of one or more functional groups with one or more different functional groups or introducing or removing one or more substituents of hydrogen atoms. The term “alkyl” refers to univalent groups derived from alkanes (i.e., acyclic saturated hydrocarbons) by removal of a hydrogen atom from any carbon atom. Alkyl groups can be linear or branched. Suitable alkyl groups can have one to 30 carbon atoms, i.e., C1-C30 alkyl. If the alkyl is branched, it is understood that at least three carbon atoms are present. The term “alkenyl” refers to univalent groups derived from alkenes by removal of a hydrogen atom from any carbon atom. Alkenes are unsaturated hydrocarbons that contain at least one carbon-carbon double bond. Alkenyl groups can be linear or branched. Suitable alkenyl groups can have two to 30 carbon atoms, i.e., C2-C30 alkenyl. If the alkenyl is branched, it is understood that at least three carbon atoms are present. The term “alkynyl” refers to univalent groups derived from alkynes by removal of a hydrogen atom from any carbon atom. Alkynes are unsaturated hydrocarbons that contain at least one carbon-carbon triple bond. Alkynyl groups can be linear or branched. Suitable alkynyl groups can have two to 30 carbon atoms, i.e., C₂-C₃₀ alkynyl. If the alkynyl is branched, it is understood that at least four carbon atoms are present. The term “aryl” refers to univalent groups derived from arenes by removal of a hydrogen atom from a ring atom. Arenes are monocyclic or polycyclic aromatic hydrocarbons. In polycyclic arenes, the rings can be attached together in a pendent manner, a fused manner, or a combination thereof. Accordingly, in polycyclic aryl groups, the rings can be attached together in a pendent manner, a fused manner, or a combination thereof. Suitable aryl groups can have six to 30 carbon atoms, i.e., C6-C30 aryl. The number of “members” of an aryl group refers to the total number of carbon atoms in the ring(s) of the aryl group. The term “heteroaryl” refers to univalent groups derived from heteroarenes by removal of a hydrogen atom from a ring atom. Heteroarenes are heterocyclic compounds derived from arenes by replacement of one or more methine (-C ) and/or vinylene (-CH CH-) groups by trivalent or divalent heteroatoms, respectively, in such a way as to maintain the continuous S-electron system characteristic of aromatic systems and a number of out-of-plane S-electrons corresponding to the Hückel rule (4n - 2). Heteroarenes can be monocyclic or polycyclic. In polycyclic heteroarenes, the rings can be attached together in a pendent manner, a fused manner, or a combination thereof. Accordingly, in polycyclic heteroaryl groups, the rings can be attached together in a pendent manner, a fused manner, or a combination thereof. Suitable heteroaryl groups can have one to 30 carbon atoms, i.e., C1-C30 heteroaryl. The number of “members” of a heteroaryl group refers to the total number of carbon atom(s) and heteroatom(s) in the ring(s) of the heteroaryl group. “Carbocycle” or “carbocyclyl” refers to mono- and polycyclic ring systems containing only carbon atoms as ring atoms. The mono- and polycyclic ring systems may be aromatic, non- aromatic (saturated or unsaturated), or a mixture of aromatic and non-aromatic rings. Carbocyclyls are univalent, derived from carbocycles by removal of a hydrogen atom from a ring atom. Carbocycles include arenes; carbocyclyls include aryls. In polycyclic carbocycles or carbocyclyls, the rings can be attached together in a pendent manner (i.e., two rings are connected by a single bond), a spiro manner (i.e., two rings are connected through a defining single common atom), a fused manner (i.e., two rings share two adjacent atoms; in other words, two rings share one covalent bond), a bridged manner (i.e., two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom), or a combination thereof. Suitable carbocycle or carbocyclyl groups can have three to 30 carbon atoms, i.e., C3-C30 carbocycle or carbocyclyl. The number of “members” of a carbocycle or carbocyclyl group refers to the total number of carbon atoms in the ring(s) of the carbocycle or carbocyclyl group. “Heterocycle” or “heterocyclyl” refers to mono- and polycyclic ring systems containing at least one carbon atom and one or more heteroatoms independently selected from elements like nitrogen, oxygen, and sulfur, as ring atoms. Optionally, the nitrogen and/or sulfur heteroatom(s) may be oxidized, and the nitrogen heteroatom(s) may be quaternized. The mono- and polycyclic ring systems may be aromatic, non-aromatic, or a mixture of aromatic and non-aromatic rings. Heterocyclyls are univalent, derived from heterocycles by removal of a hydrogen atom from a ring atom. Heterocycles include heteroarenes; heterocyclyls include heteroaryls. In polycyclic heterocycle or heterocyclyl groups, the rings can be attached together in a pendant manner (i.e., two rings are connected by a single bond), a spiro manner (i.e., two rings are connected through a defining single common atom), a fused manner (i.e., two rings share two adjacent atoms; in other words, two rings share one covalent bond), a bridged manner (i.e., two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom), or a combination thereof. Suitable heterocycle or heterocyclyl groups can have one to 30 carbon atoms, i.e., C₁-C₃₀ heterocycle or heterocyclyl. The number of “members” of a heterocycle or heterocyclyl group refers to the total number of carbon atom(s) and heteroatom(s) in the ring(s) of the heterocycle or heterocyclyl group. As used herein, the terms “halogen” and “halo” refer to fluorine, chlorine, bromine, and iodine. As used herein, “haloalkyl” refers to halogen-substituted alkyl groups. Optionally, the haloalkyl groups contain one halogen substituent. Optionally, the haloalkyl groups contain multiple halogen substituents, i.e., polyhaloalkyl. In some examples, the haloalkyl groups contain one or more fluorine substituents. As used herein, “haloalkenyl” refers to halogen-substituted alkenyl groups. Optionally, the haloalkenyl groups contain one halogen substituent. Optionally, the haloalkenyl groups contain multiple halogen substituents. In some examples, the haloalkenyl groups contain one or more fluorine substituents. As used herein, “haloalkynyl” refers to halogen-substituted alkynyl groups. Optionally, the haloalkynyl groups contain one halogen substituent. Optionally, the haloalkynyl groups contain multiple halogen substituents. In some examples, the haloalkynyl groups contain one or more fluorine substituents. As used herein, “halocarbocyclyl” refers to halogen-substituted carbocyclyl groups. Optionally, the halocarbocyclyl groups contain one halogen substituent. Optionally, the halocarbocyclyl groups contain multiple halogen substituents. In some examples, the halocarbocyclyl groups contain one or more fluorine substituents. As used herein, “haloheterocyclyl” refers to halogen-substituted heterocyclyl groups. Optionally, the haloheterocyclyl groups contain one halogen substituent. Optionally, the haloheterocyclyl groups contain multiple halogen substituents. In some examples, the haloheterocyclyl groups contain one or more fluorine substituents. As used herein, “haloaryl” refers to halogen-substituted aryl groups. Optionally, the haloaryl groups contain one halogen substituent. Optionally, the haloaryl groups contain multiple halogen substituents. In some examples, the haloaryl groups contain one or more fluorine substituents. As used herein, “haloheteroaryl” refers to halogen-substituted heteroaryl groups. Optionally, the haloheteroaryl groups contain one halogen substituent. Optionally, the haloheteroaryl groups contain multiple halogen substituents. In some examples, the haloheteroaryl groups contain one or more fluorine substituents. The term “substituted,” as used herein, means that the chemical group or moiety contains one or more substituents replacing the hydrogen atom(s) in the original chemical group or moiety. It is understood that any substitution is in accordance with a permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc., under room temperature. Unless otherwise specified, the substituents are R groups. The R groups, on each occurrence, can be independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, alkylcarbocyclyl, haloalkylcarbocyclyl, halocarbocyclyl, heterocyclyl, alkylheterocyclyl, haloalkylheterocyclyl, haloheterocyclyl, aryl, alkylaryl, haloalkylaryl, haloaryl, heteroaryl, alkylheteroaryl, haloalkylheteroaryl, haloheteroaryl, -OH, -SH, -NH2, -N3, -OCN, -NCO, -ONO2, -CN, -NC, -ONO, -CONH2, -NO, -NO2, -ONH2, -SCN, -SNCS, -CF3, -CH2CF3, -CH2Cl, -CHCl2, -CH2NH2, -NHCOH, -CHO, -COOH, -SO3H, -CH2SO2CH3, -PO3H2, -OPO3H2, -P( O)(OR^G1)(OR^G2), -OP( O)(OR^G1)(OR^G2), -BR^G1(OR^G2), -B(OR^G1)(OR^G2), –Si(R^G1)(R^G2)(R^G3), –C(R^G1)(R^G2)(R^G3), –N[(R^G1)(R^G2)(R^G3)]⁺, and -GR^G1, in which -G is -O-,-S-, -NR^G2-, -C( O)-, -S( O)-, -SO₂-, -C( O)O-, -C( O)NR^G2-, -OC( O)-, -NR^G2C( O)-, -OC( O)O-, -OC( O)NR^G2-, -NR^G2C( O)O-, -NR^G2C( O)NR^G3-, -C( S)-, -C( S)S-, -SC( S)-, -SC( S)S-, -C( NR^G2)-, -C( NR^G2)O-, -C( NR^G2)NR^G3-, -OC( NR^G2)-, -NR^G2C( NR^G3)-, -NR^G2SO₂-, -C( NR^G2)NR^G3-, -OC( NR^G2)-, -NR^G2C( NR^G3)-, -NR^G2SO₂-, -NR^G2SO₂NR^G3-, -NR^G2C( S)-, -SC( S)NR^G2-, -NR^G2C( S)S-, -NR^G2C( S)NR^G3-, -SC( NR^G2)-, -C( S)NR^G2-, -OC( S)NR^G2-, -NR^G2C( S)O-, -SC( O)NR^G2-, -NR^G2C( O)S-, -C( O)S-, -SC( O)-, -SC( O)S-, -C( S)O-, -OC( S)-, -OC( S)O-, -SO₂NR^G2-, -BR^G2-, or -PR^G2-, wherein each occurrence of R^G1, R^G2, and R^G3 is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, alkylcarbocyclyl, haloalkylcarbocyclyl, halocarbocyclyl, heterocyclyl, alkylheterocyclyl, haloalkylheterocyclyl, haloheterocyclyl, aryl, alkylaryl, haloalkylaryl, haloaryl, heteroaryl, alkylheteroaryl, haloalkylheteroaryl, and haloheteroaryl. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. Alternatively, two R groups on the same atom can merge into one oxygen (=O) or sulfur (=S) atom. The term “optionally substituted,” as used herein, means that substitution is optional, and therefore it is possible for the designated atom/chemical group/compound to be unsubstituted. As used herein, the term “stereoisomer” refers to compounds made up of the same atoms having the same bond order but having different three-dimensional arrangements of atoms that are not interchangeable. As used herein, the term “enantiomer” refers to a pair of stereoisomers that are non-superimposable mirror images of one another. As used herein, the term “diastereomer” refers to two stereoisomers that are not mirror images but also not superimposable. The terms “racemate” and “racemic mixture” refer to a mixture of enantiomers. The term “chiral center” refers to a carbon atom to which four different groups are attached. Choice of the appropriate chiral column, eluent, and conditions necessary for effective separation of stereoisomers, such as a pair of enantiomers, is well known to one of ordinary skill in the art (e.g., Jacques et al., Enantiomers, Racemates, and Resolutions, John Wiley and Sons, Inc., 1981). As used herein, the term “pharmaceutically acceptable” refers to compounds, materials, compositions, or formulations that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and non-human animals without excessive toxicity, irritation, allergic response, or other problems or complications that commensurate with a reasonable benefit/risk ratio, in accordance with the guidelines of regulatory agencies of a certain country, such as the Food and Drug Administration (FDA) in the United States or its corresponding agencies in countries other than the United States (e.g., the European Medicines Agency (EMA) in Europe, the National Medical Products Administration (NMPA) in China). As used herein, the term “salt” refers to acid or base salts of the original compound. In some cases, the salt is formed in situ during preparation of the original compound, i.e., the designated synthetic chemistry procedures produce the salt instead of the original compound. In some cases, the salt is obtained via modification of the original compound. In some cases, the salt is obtained via ion exchange with an existing salt of the original compound. Examples of salts 19 include, but are not limited to, mineral or organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids and phosphonic acids. For original compounds containing a basic residue, the salts can be prepared by treating the compounds with an appropriate amount of a non-toxic inorganic or organic acid; alternatively, the salts can be formed in situ during preparation of the original compounds. Exemplary salts of the basic residue include salts with an inorganic acid selected from hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids or with an organic acid selected from acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, naphthalenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic acids. For original compounds containing an acidic residue, the salts can be prepared by treating the compounds with an appropriate amount of a non-toxic base; alternatively, the salts can be formed in situ during preparation of the original compounds. Exemplary salts of the acidic residue include salts with a base selected from ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, and histidine. Optionally, the salts can be prepared by reacting the free acid or base form of the original compounds with a stoichiometric amount or more of an appropriate base or acid, respectively, in water or an aqueous solution, an organic solvent or an organic solution, or a mixture thereof. Lists of exemplary pharmaceutically acceptable salts can be found in Remington’s Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, as well as Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH, Weinheim, 2002. As used herein, the term “excipient” refers to any components present in the pharmaceutical formulations disclosed herein, other than the active ingredient (i.e., a compound or composition of the present disclosure). As used herein, the term “effective amount” of a material refers to a nontoxic but sufficient amount of the material to provide the desired result. The exact amount required may vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, disorder, or disease that is being treated, the active ingredient or therapy used, and the like. II. COMPOUNDS The present disclosure describes non-covalent inhibitors of coronavirus main protease, such as SARS-CoV-2 M^pro. To the extent that chemical formulas described herein contain one or more unspecified chiral centers, the formulas are intended to encompass all stable stereoisomers, enantiomers, and diastereomers. Such compounds can exist as a single enantiomer, a racemic mixture, a mixture of diastereomers, or combinations thereof. It is also understood that the chemical formulas encompass all tautomeric forms if tautomerization occurs. Methods of making exemplary compounds are disclosed in subsequent sections and exemplified by the Examples. The synthetic methods disclosed herein are compatible with a wide variety of functional groups and starting materials. Thus, a wide variety of compounds can be obtained from the disclosed methods. Optionally, the alkyl groups described herein have 1–30 carbon atoms, i.e., C₁–C₃₀ alkyl. In some forms, the C₁–C₃₀ alkyl can be a linear C₁–C₃₀ alkyl or a branched C₃–C₃₀ alkyl. Optionally, the alkyl groups have 1–20 carbon atoms, i.e., C1–C20 alkyl. In some forms, the C1–C20 alkyl can be a linear C₁–C₂₀ alkyl or a branched C₃–C₂₀ alkyl. Optionally, the alkyl groups have 1–10 carbon atoms, i.e., C₁–C₁₀ alkyl. In some forms, the C₁–C₁₀ alkyl can be a linear C₁–C₁₀ alkyl or a branched C3–C10 alkyl. Optionally, the alkyl groups have 1–6 carbon atoms, i.e., C1–C6 alkyl. In some forms, the C₁–C₆ alkyl can be a linear C₁–C₆ alkyl or a branched C₃–C₆ alkyl. Representative straight- chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, and the like. Representative branched alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Optionally, the alkenyl groups described herein have 2–30 carbon atoms, i.e., C₂–C₃₀ alkenyl. In some forms, the C2–C30 alkenyl can be a linear C2–C30 alkenyl or a branched C3–C30 alkenyl. Optionally, the alkenyl groups have 2–20 carbon atoms, i.e., C2–C20 alkenyl. In some forms, the C₂–C₂₀ alkenyl can be a linear C₂–C₂₀ alkenyl or a branched C₃–C₂₀ alkenyl. Optionally, the alkenyl groups have 2–10 carbon atoms, i.e., C₂–C₁₀ alkenyl. In some forms, the C₂–C₁₀ alkenyl can be a linear C2–C10 alkenyl or a branched C3–C10 alkenyl. Optionally, the alkenyl groups have 2–6 carbon atoms, i.e., C2–C6 alkenyl. In some forms, the C2–C6 alkenyl can be a linear C2– C6 alkenyl or a branched C3–C6 alkenyl. Representative alkenyl groups include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2- methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like. Optionally, the alkynyl groups described herein have 2–30 carbon atoms, i.e., C2–C30 alkynyl. In some forms, the C₂–C₃₀ alkynyl can be a linear C₂–C₃₀ alkynyl or a branched C₄–C₃₀ alkynyl. Optionally, the alkynyl groups have 2–20 carbon atoms, i.e., C₂–C₂₀ alkynyl. In some forms, the C2–C20 alkynyl can be a linear C2–C20 alkynyl or a branched C4–C20 alkynyl. Optionally, the alkynyl groups have 2–10 carbon atoms, i.e., C₂–C₁₀ alkynyl. In some forms, the C₂–C₁₀ alkynyl can be a linear C₂–C₁₀ alkynyl or a branched C₄–C₁₀ alkynyl. Optionally, the alkynyl groups have 2–6 carbon atoms, i.e., C2–C6 alkynyl. In some forms, the C2–C6 alkynyl can be a linear C2–C6 alkynyl or a branched C4–C6 alkynyl. Representative alkynyl groups include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like. Optionally, the aryl groups described herein have 6–30 carbon atoms, i.e., C6–C30 aryl. Optionally, the aryl groups have 6–20 carbon atoms, i.e., C6–C20 aryl. Optionally, the aryl groups have 6–12 carbon atoms, i.e., C₆–C₁₂ aryl. Representative aryl groups include phenyl, naphthyl, and biphenyl. Optionally, the heteroaryl groups described herein have 1–30 carbon atoms, i.e., C1–C30 heteroaryl. Optionally, the heteroaryl groups have 1–20 carbon atoms, i.e., C₁–C₂₀ heteroaryl. Optionally, the heteroaryl groups have 1–11 carbon atoms, i.e., C₁–C₁₁ heteroaryl. Optionally, the heteroaryl groups have 1–5 carbon atoms, i.e., C1–C5 heteroaryl. Optionally, the heteroaryl groups are 5–20 membered heteroaryl groups. Optionally, the heteroaryl groups are 5–12 membered heteroaryl groups. Optionally, the heteroaryl groups are 5 or 6 membered heteroaryl groups. Representative heteroaryl groups include furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. Optionally, the carbocyclyl groups described herein have 3–30 carbon atoms, i.e., C3–C30 carbocyclyl. Optionally, the carbocyclyl groups described herein have 3–20 carbon atoms, i.e., C₃– C₂₀ carbocyclyl. Optionally, the carbocyclyl groups described herein have 3–12 carbon atoms, i.e., C3–C12 carbocyclyl. Representative saturated carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Representative unsaturated carbocyclyl groups include cyclopentenyl, cyclohexenyl, and the like. Optionally, the heterocyclyl groups described herein have 1–30 carbon atoms, i.e., C₁–C₃₀ heterocyclyl. Optionally, the heterocyclyl groups described herein have 1–20 carbon atoms, i.e., C1–C20 heterocyclyl. Optionally, the heterocyclyl groups described herein have 1–11 carbon atoms, i.e., C₁–C₁₁ heterocyclyl. Optionally, the heterocyclyl groups described herein have 1–6 carbon atoms, i.e., C₁–C₆ heterocyclyl. Optionally, the heterocyclyl groups are 3–20 membered heterocyclyl groups. Optionally, the heterocyclyl groups are 3–12 membered heterocyclyl groups. Optionally, the heteroaryl groups are 4–7 membered heterocyclyl groups. The optionally substituted groups described in the chemical formulas described herein (e.g., Formulas I and II), on each occurrence when not specified, may have one or more substituents in the form of the R groups described above. The R groups, on each occurrence, can be independently selected from halogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, alkylcarbocyclyl, haloalkylcarbocyclyl, halocarbocyclyl, heterocyclyl, alkylheterocyclyl, haloalkylheterocyclyl, haloheterocyclyl, aryl, alkylaryl, haloalkylaryl, haloaryl, heteroaryl, alkylheteroaryl, haloalkylheteroaryl, haloheteroaryl, -OH, -SH, -NH2, -N3, -OCN, -NCO, -ONO2, -CN, -NC, -ONO, -CONH2, -NO, -NO2, -ONH2, -SCN, -SNCS, -CF3, -CH2CF3, -CH2Cl, -CHCl2, -CH2NH2, -NHCOH, -CHO, -COOH, -SO3H, -CH2SO2CH3, -PO3H2, -OPO3H2, -P( O)(OR^G1)(OR^G2), -OP( O)(OR^G1)(OR^G2), -BR^G1(OR^G2), -B(OR^G1)(OR^G2), –Si(R^G1)(R^G2)(R^G3), –C(R^G1)(R^G2)(R^G3), –N[(R^G1)(R^G2)(R^G3)]⁺, and -GR^G1, in which -G is -O-, - , , , , , , , e ,

haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, alkylcarbocyclyl, haloalkylcarbocyclyl, halocarbocyclyl, heterocyclyl, alkylheterocyclyl, haloalkylheterocyclyl, haloheterocyclyl, aryl, alkylaryl, haloalkylaryl, haloaryl, heteroaryl, alkylheteroaryl, haloalkylheteroaryl, and haloheteroaryl. Optionally, two R groups on the same atom can join together with that atom to form a cyclic moiety, such as a carbocycle or a heterocycle. Alternatively, two R groups on the same atom can merge into one oxygen (=O) or sulfur (=S) atom. In some examples, the R groups are independently selected from halogen, nitro, cyano, hydroxyl, formyl, carboxyl, thiol, =O (counting as two R groups), =S (counting as two R groups), sulfamoyl, alkyl (such as methyl, ethyl, isopropyl, tert-butyl), haloalkyl (such as trifluoromethyl), alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl (such as benzyl), alkylaryl, alkyloxy (such as methoxy, ethoxy), haloalkyloxy (such as trifluoromethoxy), aryloxy, alkylcarbonyl (such as acetyl), arylcarbonyl (such as benzoyl), alkylcarbonyloxy (such as acetoxy), arylcarbonyloxy (such as benzoyloxy), alkyloxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl), aryloxycarbonyl, primary amino, alkylamino (such as methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino), alkylammonium (such as trimethylammonium), alkylcarbonylamino (such as acetylamino), arylcarbonylamino (such as benzoylamino), carbamoyl, N-alkylcarbamoyl (such as N- methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl- N-ethylcarbamoyl), alkylthio (such as methylthio, ethylthio), alkylsulfinyl (such as methylsulfinyl, ethylsulfinyl), alkylsulfonyl (such as mesyl, ethylsulfonyl), and N-alkylsulfamoyl (such as N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl). In some examples, the R groups are independently selected from halogen, nitro, cyano, hydroxyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, primary amino, formyl, carboxyl, carbamoyl, thiol, =O, =S, sulfamoyl, acetyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, trimethylammonium, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N- dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzyl, benzoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, and haloheteroaryl. In some examples, the R groups are independently selected from halogen, =O, =S, alkyl, haloalkyl, carbocyclyl, halocarbocyclyl, aryl, haloaryl, heterocyclyl, and haloheterocyclyl. In some examples, the R groups are independently selected from halogen, alkyl, haloalkyl, carbocyclyl, halocarbocyclyl, aryl, haloaryl, heterocyclyl, and haloheterocyclyl. As used herein, “alkyloxy” refers to a hydroxyl group substituted by an alkyl group at the oxygen atom. Exemplary alkyloxy groups include, but are not limited to, methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. As used herein, “haloalkyloxy” refers to a hydroxyl group substituted by a haloalkyl group at the oxygen atom. An example of haloalkyloxy is trifluoromethoxy. As used herein, “aryloxy” refers to a hydroxyl group substituted by an aryl group at the oxygen atom. As used herein, “haloaryloxy” refers to a hydroxyl group substituted by a haloaryl group at the oxygen atom. As used herein, “alkylcarbonyl” refers to an alkyl group attached through a carbonyl bridge (–C(=O)–). As used herein, “arylcarbonyl” refers to an aryl group attached through a carbonyl bridge. As used herein, “alkylcarbonyloxy” refers to a hydroxyl group substituted by an alkylcarbonyl group at the oxygen atom of the hydroxyl group. As used herein, “arylcarbonyloxy” refers to a hydroxyl group substituted by an arylcarbonyl group at the oxygen atom of the hydroxyl group. As used herein, “alkyloxycarbonyl” refers to an alkyloxy group attached through a carbonyl bridge. As used herein, “aryloxycarbonyl” refers to an aryloxy group attached through a carbonyl bridge. As used herein, “alkylamino” refers to a primary amino group substituted by one or two alkyl groups. When the primary amino group is substituted by two alkyl groups, the two alkyl groups can be the same or different. An example of alkylamino is methylamino (i.e., –NH–CH₃). As used herein, “alkylammonium” refers to a primary ammonium group substituted by one, two, or three alkyl groups. When the primary ammonium group is substituted by two or three alkyl 2 groups, the two or three alkyl groups can be the same or different. An example of alkylammonium is trimethylammonium (i.e., –N(CH3)3⁺). As used herein, “alkylcarbonylamino” refers to a primary amino group substituted by one alkylcarbonyl group. As used herein, “arylcarbonylamino” refers to a primary amino group substituted by one arylcarbonyl group. As used herein, “N-alkylcarbamoyl” refers to a carbamoyl group (–C(=O)–NH₂) substituted by one or two alkyl groups at the nitrogen atom. When the carbamoyl group is substituted by two alkyl groups, the two alkyl groups can be the same or different. As used herein, “alkylthio” refers to a thiol group substituted by an alkyl group at the sulfur atom. An example of alkylthio is methylthio (i.e., –S–CH3). As used herein, “alkylsulfinyl” refers to an alkyl group attached through a sulfinyl bridge (–S(=O)–). As used herein, “alkylsulfonyl” refers to an alkyl group attached through a sulfonyl bridge (–S(=O)2–). As used herein, “N-alkylsulfamoyl” refers to a sulfamoyl group (–S(=O)₂–NH₂) substituted by one or two alkyl groups at the nitrogen atom. When the sulfamoyl group is substituted by two alkyl groups, the two alkyl groups can be the same or different. As used herein, “thiol” refers to the univalent radical –SH. As used herein, “sulfonate” refers to –SO₃-. A. General structure In some embodiments, the compounds have a structure of Formula I or II or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof,

Formula II wherein R¹ is halogen, –O–(C(R^a)(R^b))m–R^X, or –S–(C(R^a)(R^b))m–R^X, wherein: m is 1 or 2, R^a and R^b, at each occurrence, are independently and individually hydrogen, halogen, C₁– C3 alkyl, or C1–C3 haloalkyl, and R^X is optionally substituted C₁–C₃ alkyl, optionally substituted C₁–C₃ haloalkyl, optionally substituted carbocyclyl, optionally substituted halocarbocyclyl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, optionally substituted aryl, optionally substituted haloaryl, optionally substituted heteroaryl, or optionally substituted haloheteroaryl; wherein R², R³, R⁵, R⁶, and R⁷ are independently and individually hydrogen, halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, alkylaryl, alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkyloxycarbonyl, aryloxycarbonyl, primary amino, alkylamino, alkylammonium, alkylcarbonylamino, arylcarbonylamino, carbamoyl, N-alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or N- alkylsulfamoyl; and r

Y¹, Y², Y³, and Y⁴ are independently and individually CH or N, X is N or O, Z¹, Z², and Z³ are independently and individually CH, N, NH, O, or S, R^c, at each occurrence, is independently and individually halogen, C₁–C₃ alkyl, or C₁–C₃ haloalkyl, l is 0, 1, 2, or 3, k is 0, 1, or 2, n is 0, 1, 2, 3, 4, or 5, o is 0, 1, 2, 3, or 4, when n is not 0, the corresponding R^c substituent(s) can be on either or both rings, when o is not 0, the corresponding R^c substituent(s) can be on either or both rings, and when an R^c group is present, it replaces the hydrogen atom at the ring atom that the R^c group connects to. It is understood by those skilled in the art that when an R^c group is present, it replaces the hydrogen atoms in CH or NH on the ring(s) of the T moiety. In some embodiments, when the compounds bind to SARS-CoV-2 M^pro, the N or X atom labeled by the “*” symbol in the T moiety can form an H-bonding interaction with His163 of SARS-CoV-2 M^pro. In some embodiments, the compounds have a structure of Formula I or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. In some embodiments, the compounds have a structure of Formula II or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. R², R³, R⁵, R⁶, and R⁷ are independently and individually hydrogen, halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, alkylaryl, alkyloxy, haloalkyloxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkyloxycarbonyl, aryloxycarbonyl, primary amino, alkylamino, alkylammonium, alkylcarbonylamino, arylcarbonylamino, carbamoyl, N- alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or N-alkylsulfamoyl. In some embodiments, R² is hydrogen, halogen, C1–C3 alkyl such as methyl, or C1–C3 haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiments, R² is hydrogen or halogen. In some embodiments, R² is hydrogen. In some embodiments, R² is halogen. In some embodiments, R² is chloro or fluoro. In some embodiments, R² is chloro. In some embodiments, R² is fluoro. In some embodiments, R² is methyl. In some embodiments, R² is –CH₂F. In some embodiments, R² is –CHF₂. In some embodiments, R² is –CF₃. In some embodiments, R³ is hydrogen, halogen, C1–C3 alkyl such as methyl, or C1–C3 haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiments, R³ is hydrogen or halogen. In some embodiments, R³ is hydrogen. In some embodiments, R³ is halogen. In some embodiments, R³ is chloro or fluoro. In some embodiments, R³ is chloro. In some embodiments, R³ is fluoro. In some embodiments, R³ is methyl. In some embodiments, R³ is –CH2F. In some embodiments, R³ is –CHF₂. In some embodiments, R³ is –CF₃. In some embodiments, R⁵ is hydrogen, halogen, C1–C3 alkyl such as methyl, or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁵ is hydrogen or halogen. In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is halogen. In some embodiments, R⁵ is chloro or fluoro. In some embodiments, R⁵ is chloro. In some embodiments, R⁵ is fluoro. In some embodiments, R⁵ is C1–C3 alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁵ is methyl, –CH2F, –CHF2, or –CF3. In some embodiments, R⁵ is methyl or –CF3. In some embodiments, R⁵ is methyl. In some embodiments, R⁵ is –CH2F. In some embodiments, R⁵ is –CHF₂. In some embodiments, R⁵ is –CF₃. In some embodiments, R⁶ is hydrogen, halogen, C1–C3 alkyl such as methyl, or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁶ is hydrogen or halogen. In some embodiments, R⁶ is hydrogen. In some embodiments, R⁶ is halogen. In some embodiments, R⁶ is chloro or fluoro. In some embodiments, R⁶ is chloro. In some embodiments, R⁶ is fluoro. In some embodiments, R⁶ is C1–C3 alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF₃. In some embodiments, R⁶ is methyl, –CH₂F, –CHF₂, or –CF₃. In some embodiments, R⁶ is methyl or –CF₃. In some embodiments, R⁶ is methyl. In some embodiments, R⁶ is –CH₂F. In some embodiments, R⁶ is –CHF2. In some embodiments, R⁶ is –CF3. In some embodiments, R⁵ and R⁶ are independently hydrogen, halogen, C1–C3 alkyl such as methyl, or C₁–C₃ haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiments, R⁵ and R⁶ are independently hydrogen, halogen, methyl,–CH2F, –CHF2, or –CF3. In some embodiments, R⁵ and R⁶ are independently hydrogen, methyl, or –CF3. In some embodiments, R⁵ is hydrogen or halogen, and R⁶ is C₁–C₃ alkyl such as methyl or C₁–C₃ haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiments, R⁵ is hydrogen or halogen, and R⁶ is methyl,–CH2F, –CHF2, or –CF3. In some embodiments, R⁵ is hydrogen, and R⁶ is methyl or –CF₃. In some embodiments, R⁶ is hydrogen or halogen, and R⁵ is C₁–C₃ alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁶ is hydrogen or halogen, and R⁵ is methyl,–CH₂F, –CHF₂, or –CF₃. In some embodiments, R⁶ is hydrogen, and R⁵ is methyl or –CF₃. In some embodiments, R⁵ and R⁶ are independently C1–C3 alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁵ and R⁶ are independently methyl,–CH₂F, –CHF₂, or –CF₃. In some embodiments, R⁵ and R⁶ are independently methyl or –CF3. In some embodiments, at least one of R⁵ and R⁶ is selected from C1–C3 alkyl (such as methyl) and C₁–C₃ haloalkyl (such as –CH₂F, –CHF₂, and –CF₃). In some embodiments, at least one of R⁵ and R⁶ is selected from methyl,–CH₂F, –CHF₂, and –CF₃. In some embodiments, at least one of R⁵ and R⁶ is selected from methyl and –CF3. When R⁵ or R⁶ is bulkier than hydrogen and halogen, e.g., selected from methyl, –CH2F, –CHF2, and –CF3, they can act as conformational blockers, keeping the two aromatic rings in the corresponding structures from becoming coplanar with one another, thereby disrupting intermolecular Pi-Pi stacking. This diminished intermolecular Pi-Pi stacking can help to increase aqueous solubility, improve oral bioavailability, and/or facilitate binding to M^pro (the two aromatic rings from which R⁵ and R⁶ reside need to be orthogonal to each other to fit in the binding pocket of M^pro. Therefore, it can be beneficial to have one or both of R⁵ and R⁶ bulkier than hydrogen and halogen, e.g., selected from methyl, –CH2F, –CHF2, and –CF3. In some embodiments, R⁷ is hydrogen, halogen, C₁–C₃ alkyl such as methyl, or C₁–C₃ haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiments, R⁷ is hydrogen or halogen. In some embodiments, R⁷ is hydrogen. In some embodiments, R⁷ is halogen. In some embodiments, R⁷ is chloro or fluoro. In some embodiments, R⁷ is chloro. In some embodiments, R⁷ is fluoro. In some embodiments, R⁶ is methyl. In some embodiments, R⁶ is –CH₂F. In some embodiments, R⁶ is –CHF2. In some embodiments, R⁶ is –CF3. In some embodiments, R², R³, R⁵, R⁶, and R⁷ are independently and individually hydrogen, halogen, C₁–C₃ alkyl such as methyl, or C₁–C₃ haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiments, R², R⁵, R⁶, and R⁷ are hydrogen, and R³ is halogen. In some embodiments, R², R⁵, R⁶, and R⁷ are hydrogen, and R³ is chloro or fluoro. In some embodiments, R², R⁵, R⁶, and R⁷ are hydrogen, and R³ is chloro. In some embodiments, R², R⁵, R⁶, and R⁷ are hydrogen, and R³ is fluoro. In some embodiments, R², R⁶, and R⁷ are hydrogen, R⁵ is C1–C3 alkyl or C1–C3 haloalkyl, and R³ is halogen. In some embodiments, R², R⁶, and R⁷ are hydrogen, R⁵ is methyl, –CH₂F, –CHF₂, or –CF₃, and R³ is chloro or fluoro. In some embodiments, R², R⁶, and R⁷ are hydrogen, R⁵ is methyl or –CF3, and R³ is chloro. In some embodiments, R², R⁶, and R⁷ are hydrogen, R⁵ is methyl or –CF3, and R³ is fluoro. In some embodiments, R², R⁵, and R⁷ are hydrogen, R⁶ is C₁–C₃ alkyl or C₁–C₃ haloalkyl, and R³ is halogen. In some embodiments, R², R⁵, and R⁷ are hydrogen, R⁶ is methyl, –CH2F, –CHF2, or –CF3, and R³ is chloro or fluoro. In some embodiments, R², R⁵, and R⁷ are hydrogen, R⁶ is methyl or –CF₃, and R³ is chloro. In some embodiments, R², R⁵, and R⁷ are hydrogen, R⁶ is methyl or –CF₃, and R³ is fluoro. In some embodiments, R² and R⁷ are hydrogen, R⁵ and R⁶ are independently C1–C3 alkyl or C1–C3 haloalkyl, and R³ is halogen. In some embodiments, R² and R⁷ are hydrogen, R⁵ and R⁶ are independently methyl, –CH₂F, –CHF₂, or –CF₃, and R³ is chloro or fluoro. In some embodiments, R² and R⁷ are hydrogen, R⁵ and R⁶ are independently methyl or –CF3, and R³ is chloro. In some embodiments, R² and R⁷ are hydrogen, R⁵ and R⁶ are independently methyl or –CF₃, and R³ is fluoro. In some embodiments, the compounds are in a non-salt form as shown in Formula I or II. In some embodiments, the compounds are in a salt form. In some embodiments, the compounds are in a HCl, sulfate, or oxalate salt form. In some embodiments, the compounds are in a HCl salt form. In some embodiments, the compounds are in a sulfate salt form. In some embodiments, the compounds are in an oxalate salt form. 1. The R¹ moiety R¹ is halogen, –O–(C(R^a)(R^b))_m–R^X, or –S–(C(R^a)(R^b))_m–R^X. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R¹ is halogen, such as chloro or fluoro. In some embodiments, R¹ is chloro. In some embodiments, R¹ is fluoro. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X. In some embodiments, R¹ is –S–(C(R^a)(R^b))m–R^X. R^a and R^b, at each occurrence, are independently and individually hydrogen, halogen, C₁– C₃ alkyl such as methyl, or C₁–C₃ haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiment, R^a, at each occurrence, is hydrogen. In some embodiments, R^b, at each occurrence, is hydrogen. In some embodiments, R^a and R^a, at each occurrence, are hydrogen. In some embodiments, R¹ is –O–(CH₂)_m–R^X or –S–(CH₂)_m–R^X. In some embodiments, R¹ is –O–CH2–R^X or –S–CH2–R^X. In some embodiments, ^X

. R^X is optionally substituted C1–C3 alkyl, optionally substituted C1–C3 haloalkyl, optionally substituted carbocyclyl, optionally substituted halocarbocyclyl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, optionally substituted aryl, optionally substituted haloaryl, optionally substituted heteroaryl, or optionally substituted haloheteroaryl. In some embodiments, R^X is optionally substituted C₁–C₃ alkyl or optionally substituted C₁–C₃ haloalkyl. In some embodiments, R^X is –CH₂F, –CHF₂, –CF₃, isopropyl, or tert-butyl. In some embodiments, R^X is –CH2F. In some embodiments, R^X is –CHF2. In some embodiments, R^X is –CF3. In some embodiments, R^X is isopropyl. In some embodiments, R^X is tert-butyl. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R^a and R^b, at each occurrence, are hydrogen. Examples of R¹ include: , ,

In some embodiments, R^X is optionally substituted carbocyclyl, optionally substituted halocarbocyclyl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, optionally substituted aryl, optionally substituted haloaryl, optionally substituted heteroaryl, or optionally substituted haloheteroaryl. In some embodiments, R^X is optionally substituted carbocyclyl, optionally substituted halocarbocyclyl, optionally substituted heterocyclyl, or optionally substituted haloheterocyclyl. In some embodiments, R^X is selected from optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted azetidinyl, and optionally substituted oxetanyl. In some embodiments, R^X is selected from optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted 1-azetidinyl, and optionally substituted 3-oxetanyl. In some e e

O

. In some embodiments, R^X is . In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R^a and R^b, at each occurrence, are hydrogen. Examples of R¹ include:

In some embodiments, R^X is optionally substituted aryl, optionally substituted haloaryl, optionally substituted heteroaryl, or optionally substituted haloheteroaryl. In some embodiments, R^X is optionally substituted phenyl, optionally substituted halophenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered haloheteroaryl. In some embodiments, R^X is optionally substituted phenyl or optionally substituted halophenyl. In some embodiments, R^X is optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6-membered haloheteroaryl. In some embodiments, R^X is optionally substituted 5-membered heteroaryl or optionally substituted 5-membered haloheteroaryl. In some embodiments, R^X is optionally substituted 6-membered heteroaryl or optionally substituted 6-membered haloheteroaryl. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R^a and R^b, at each occurrence, are hydrogen. r ,

wherein V¹, V², V³, V⁴, and V⁵ are independently and individually CH or N, wherein W¹, W², W³, and W⁴ are independently and individually CH, N, NH, O, or S, wherein R^e, at each occurrence, is independently and individually halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, alkylaryl, alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkyloxycarbonyl, aryloxycarbonyl, primary amino, alkylamino, alkylammonium, alkylcarbonylamino, arylcarbonylamino, carbamoyl, N- alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or N-alkylsulfamoyl, wherein p is 0, 1, 2, or 3, wherein q is 0, 1, or 2, wherein r is 0, 1, 2, 3, 4, or 5, wherein s is 0, 1, 2, 3, or 4, wherein when r is not 0, the corresponding R^e substituent(s) can be on either or both rings, wherein when s is not 0, the corresponding R^e substituent(s) can be on either or both rings, and wherein when an R^e group is present, it replaces the hydrogen atom at the ring atom that the R^e group connects to. It is understood by those skilled in the art that when an R^e group is present, it replaces the hydrogen atoms in CH or NH on the ring(s) of the R^X moiety. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R^a and R^b, at each occurrence, are hydrogen. p In some embodiments,

. In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R^a and R^b, at each occurrence, are hydrogen. In some embodiments,

. For example, R^X is selected from e

e embodiments,

. In some embodiments,

e embodiments, q is 0 or 1. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R^a and R^b, at each occurrence, are hydrogen. In some embodiments,

some embodiments, r is 0 or 1. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R^a and R^b, at each occurrence, are hydrogen.

n some embodiments, s is 0 or 1. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, R^a and R^b, at each occurrence, are hydrogen. In some embodiments, R^e, at each occurrence, is independently and individually halogen, nitro, cyano, hydroxyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, primary amino, formyl, carboxyl, carbamoyl, sulfamoyl, acetyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, trimethylammonium, acetylamino, N- methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl- N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N- ethylsulfamoyl, benzyl, benzoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl. In some embodiments, R^e, at each occurrence, is independently and individually chloro, fluoro, nitro, cyano, hydroxyl, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, R^e, at each occurrence, is independently and individually chloro, fluoro, nitro, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. , , ,

, , , _{, ,} , ,

:

_,

_{, , ,} , , , ,

_, , , , , _{, ,}

_{, , ,} , , _{, , ,}

, ,

_{, , d} r

Y¹, Y², Y³, and Y⁴ are independently and individually CH or N, X is N or O, Z¹, Z², and Z³ are independently and individually CH, N, NH, O, or S, R^c, at each occurrence, is independently and individually halogen, C₁–C₃ alkyl such as methyl, or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3, l is 0, 1, 2, or 3, k is 0, 1, or 2, n is 0, 1, 2, 3, 4, or 5, o is 0, 1, 2, 3, or 4, when n is not 0, the corresponding R^c substituent(s) can be on either or both rings, when o is not 0, the corresponding R^c substituent(s) can be on either or both rings, and when an R^c group is present, it replaces the hydrogen atom at the ring atom that the R^c group connects to. It is understood by those skilled in the art that when an R^c group is present, it replaces the hydrogen atoms in CH or NH on the ring(s) of the T moiety. In some embodiments, when the compounds bind to SARS-CoV-2 M^pro, the N or X atom labeled by the “*” symbol in the T moiety can form an H-bonding interaction with His163 of SARS-CoV-2 M^pro.

. l For example, T is

. In some embodiments, l is 0 or 1. In some embodiments, l is 0. In some embodiments, l is 1. Z³ Z² c k(R ) X In some embodiments, T is Z¹ . In some embodiments, X is N. In some O S c c k(R ) _k(R ) N N embodiments, X is O. In some embodiments, T is , ,

s i

, k is 0 or 1. In some embodiments, k is 0. In some embodiments, k is 1.

.

some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments,

some embodiments, o is 0 or 1. In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, R^c, at each occurrence, is independently and individually halogen, methyl,–CH₂F, –CHF₂, or –CF₃. In some embodiments, R^c, at each occurrence, is independently and individually methyl or –CF3. , , n s e

_,

s s s

s . I

embodiments,

some embodiments, T is

. In some e

3. Exemplary structures Formulas I’ and II’ In some embodiments, the compounds have a structure of Formula I’ or II’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof, wherein R¹, R³, and T are the same as those described above for Formula I or II, respectively.

Formula II’ In some embodiments, R³ is chloro or fluoro. In some embodiments, R³ is chloro. In some embodiments, R³ is fluoro.

In some embodiments, R¹ is selected from chloro, fluoro, ,

, CHF CF₃ CHF₂ O O O ₂ O O O S , , , , , , , CF S ₃ S S CHF C S ₂ F S ₃ S S , , , , , , , O S , ^O _{, ,} ^S _, O S , ^O _{, ,} ^S _, O O O O O S , ^O , _, ^S , _, , , _{, , ,} , ,

_{, ,} , , _{, ,} ,

_, , , , , _, ,

, , , _{, ,} ,

, , , , , , , ,

, , _, ,

, n s

e embodiments,

_{some embodiments,} some embodiments,

s

embodiments,

. In some embodiments, T is s s .

e e e

Exemplary compounds of Formula I’ include, but are not limited to, the following:

,

l , ,

,

, ,

,

, ,

,

ON NO N N N

, ,

,

N , N , N ,

salts, hydrates, and hydrated salts thereof. Exemplary compounds of Formula I’ also include the following:

l , ,

,

, ,

,

, ,

,

N , N , N

,

, ,

,

, , ,

,

e salts, hydrates, and hydrated salts thereof. Exemplary compounds of Formula II’ include, but are not limited to, the following: ,

l , , ,

, 3 , ,

N N N

, , 3 ,

N N N

, , ,

,

e salts, hydrates, and hydrated salts thereof. Exemplary compounds of Formula II’ also include the following: ,

l , , ,

, 3 , N ,

N N N

, , 3 ,

_{, 3} , ,

₃ , , ,

salts, hydrates, and hydrated salts thereof. In some embodiments, the compounds are in a non-salt form as shown in Formula I’ or II’. In some embodiments, the compounds are in a salt form. In some embodiments, the compounds are in a HCl, sulfate, or oxalate salt form. Formulas I’’ and II’’ In some embodiments, the compounds have a structure of Formula I’’ or II’’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof, wherein R¹, R³, R⁵, R⁶, and T are the same as those described above for Formula I or II, respectively.

Formula II’’ In some embodiments, R³ is chloro or fluoro. In some embodiments, R³ is chloro. In some embodiments, R³ is fluoro. In some embodiments, R⁵ is hydrogen, halogen, C1–C3 alkyl such as methyl, or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁵ is hydrogen or halogen. In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is halogen. In some embodiments, R⁵ is chloro or fluoro. In some embodiments, R⁵ is chloro. In some embodiments, R⁵ is fluoro. In some embodiments, R⁵ is C1–C3 alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF₃. In some embodiments, R⁵ is methyl, –CH₂F, –CHF₂, or –CF₃. In some embodiments, R⁵ is methyl or –CF₃. In some embodiments, R⁵ is methyl. In some embodiments, R⁵ is –CH₂F. In some embodiments, R⁵ is –CHF2. In some embodiments, R⁵ is –CF3. In some embodiments, R⁶ is hydrogen, halogen, C1–C3 alkyl such as methyl, or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁶ is hydrogen or halogen. In some embodiments, R⁶ is hydrogen. In some embodiments, R⁶ is halogen. In some embodiments, R⁶ is chloro or fluoro. In some embodiments, R⁶ is chloro. In some embodiments, R⁶ is fluoro. In some embodiments, R⁶ is C1–C3 alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF₃. In some embodiments, R⁶ is methyl, –CH₂F, –CHF₂, or –CF₃. In some embodiments, R⁶ is methyl or –CF₃. In some embodiments, R⁶ is methyl. In some embodiments, R⁶ is –CH₂F. In some embodiments, R⁶ is –CHF2. In some embodiments, R⁶ is –CF3. In some embodiments, R⁵ and R⁶ are independently hydrogen, halogen, C₁–C₃ alkyl such as methyl, or C₁–C₃ haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiments, R⁵ and R⁶ are independently hydrogen, halogen, methyl,–CH2F, –CHF2, or –CF3. In some embodiments, R⁵ and R⁶ are independently hydrogen, methyl, or –CF3. In some embodiments, R⁵ is hydrogen or halogen, and R⁶ is C₁–C₃ alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁵ is hydrogen or halogen, and R⁶ is methyl,–CH2F, –CHF2, or –CF3. In some embodiments, R⁵ is hydrogen, and R⁶ is methyl or –CF₃. In some embodiments, R⁶ is hydrogen or halogen, and R⁵ is C₁–C₃ alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁶ is hydrogen or halogen, and R⁵ is methyl,–CH₂F, –CHF₂, or –CF₃. In some embodiments, R⁶ is hydrogen, and R⁵ is methyl or –CF₃. In some embodiments, R⁵ and R⁶ are independently C1–C3 alkyl such as methyl or C1–C3 haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiments, R⁵ and R⁶ are independently methyl,–CH₂F, –CHF₂, or –CF₃. In some embodiments, R⁵ and R⁶ are independently methyl or –CF3. In some embodiments, at least one of R⁵ and R⁶ is selected from C1–C3 alkyl (such as methyl) and C₁–C₃ haloalkyl (such as –CH₂F, –CHF₂, and –CF₃). In some embodiments, at least one of R⁵ and R⁶ is selected from methyl,–CH2F, –CHF2, and –CF3. In some embodiments, at least one of R⁵ and R⁶ is selected from methyl and –CF3. In some embodiments, R³ is chloro or fluoro, R⁵ is hydrogen, halogen, methyl,–CH₂F, –CHF₂, or –CF₃, and R⁶ is hydrogen, halogen, methyl,–CH₂F, –CHF₂, or –CF₃. In some embodiments, R³ is chloro, R⁵ is hydrogen, methyl, or –CF3, and R⁶ is hydrogen, methyl, or –CF3. In some embodiments, R³ is chloro or fluoro, R⁵ is hydrogen or halogen, and R⁶ is methyl, –CH2F, –CHF2, or –CF3. In some embodiments, R³ is chloro, R⁵ is hydrogen, and R⁶ is methyl or –CF₃. In some embodiments, R³ is chloro or fluoro, R⁶ is hydrogen or halogen, and R⁵ is methyl, –CH2F, –CHF2, or –CF3. In some embodiments, R³ is chloro, R⁶ is hydrogen, and R⁵ is methyl or –CF₃. In some embodiments, R³ is chloro or fluoro, R⁵ is methyl,–CH₂F, –CHF₂, or –CF₃, and R⁶ is methyl,–CH2F, –CHF2, or –CF3. In some embodiments, R³ is chloro, R⁵ is methyl or –CF3, and R⁶ is methyl or –CF₃.

_{, , ,} , , , _,

_{, ,} , , _{, ,} ,

_{, , ,} , , , _,

_, , , , , , ,

101

Exemplary compounds of Formula I’’ include those specified above for Formula I’, with the exception that R⁵ is methyl or CF₃ rather than hydrogen. Exemplary compounds of Formula I’’ also include those specified above for Formula I’, with the exception that R⁶ is methyl or CF3 rather than hydrogen. Exemplary compounds of Formula I’’ also include those specified above for Formula I’, with the exception that both R⁵ and R⁶ are independently methyl or CF₃, rather than hydrogen. Exemplary compounds of Formula II’’ include those specified above for Formula II’, with the exception that R⁵ is methyl or CF₃ rather than hydrogen. Exemplary compounds of Formula II’’ also include those specified above for Formula II’, with the exception that R⁶ is methyl or CF3 rather than hydrogen. Exemplary compounds of Formula II’’ also include those specified above for Formula II’, with the exception that both R⁵ and R⁶ are independently methyl or CF₃, rather than hydrogen. In some embodiments, the compounds are in a non-salt form as shown in Formula I’’ or II’’. In some embodiments, the compounds are in a salt form. In some embodiments, the compounds are in a HCl, sulfate, or oxalate salt form. B. Deuterated analogs This disclosure also provides deuterated analogs of the non-covalent inhibitors of coronavirus M^pro described above in Section II(A) of the Detailed Description. In this context, the deuterated analogs have a structure of Formula I or II or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof,

Formula II wherein R¹, R², R³, R⁵, R⁶, R⁷, and T are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in the formula are replaced by deuterium. In some embodiments, the deuterated analogs are fully deuterated, i.e., all the non-ionizable hydrogen atoms in the chemical formula are replaced with deuterium. In some embodiments, the deuterated analogs are partially deuterated, i.e., one or more non-ionizable hydrogen atoms, but not all the non-ionizable hydrogen atoms, in the chemical formula are replaced with deuterium. In some embodiments, the deuterated analogs contain deuteration in R¹. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the deuterated analogs have enhanced metabolic stability. The enhanced metabolic stability may origin from the kinetic isotope effect (KIE), e.g., an elevated energy barrier associated with cytochrome P450-mediated deuterium abstraction, compared to hydrogen abstraction. In some embodiments, the enhanced metabolic stability corresponds to a larger HLM t_1/2, RLM t1/2, or MLM t1/2. An exemplary method of measuring HLM t1/2, RLM t1/2, and MLM t1/2 is described in Example 7. In some embodiments, the enhanced metabolic stability corresponds to a higher oral bioavailability in an animal model (such as mouse, rat, dog, or non-human primate) or human. In some embodiments, the deuterated analogs are in a non-salt form. In some embodiments, the deuterated analogs are in a salt form. In some embodiments, the deuterated analogs are in a HCl, sulfate, or oxalate salt form. In some embodiments, the deuterated analogs are in a HCl salt form. In some embodiments, the deuterated analogs are in a sulfate salt form. In some embodiments, the deuterated analogs are in an oxalate salt form. Methods of making exemplary deuterated analogs are disclosed in subsequent sections and exemplified by the Examples. The synthetic methods disclosed herein are compatible with a wide variety of functional groups and starting materials. Thus, a wide variety of deuterated analogs can be obtained from the disclosed methods. 1. Deuteration in R¹ In some embodiments, R¹ in the non-covalent inhibitors of coronavirus M^pro described in Section II(A) of the Detailed Description is deuterated. In this context, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein R^a, R^b, m, and R^X are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))_m– moiety may be –(CD₂)_m–, such as –CD₂– and –(CD₂)₂–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –O–CD₂–R^X or –S–CD₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–(CD2)2–R^X or –S–(CD2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–CH₂–R^X or –S–CH₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(CH₂)₂–R^X or –S–(CH₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X, wherein R^a, R^b, m, and R^X are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))_m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))m– moiety may be –(CD2)m–, such as –CD2– and –(CD2)2–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))_m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –O–CD₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O– (CD2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–CH₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(CH2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –S–(C(R^a)(R^b))m–R^X, wherein R^a, R^b, m, and R^X are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))_m– moiety may be –(CD₂)_m–, such as –CD₂– and –(CD₂)₂–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ wherein the ^X

R moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –S– (

wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –S–CH2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –S–(CH₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CD₂– or –(CD₂)₂–, wherein the R^X moiety is –CH₂F, –CHF₂, –CF₃, isopropyl, or tert-butyl. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m– R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CD₂– or –(CD₂)₂–, wherein the R^X moiety is deuterated –CH₂F, –CDF₂, –CF₃, deuterated isopropyl, or deuterated tert-butyl. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CD2– or –(CD2)2–, wherein the R^X moiety is –CD2F, –CDF2, –CF3, d7-isopropyl, or d9-tert-butyl. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CH2– or –(CH2)2–, wherein the R^X moiety is deuterated –CH2F, –CDF2, deuterated isopropyl, or deuterated tert-butyl. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CH₂– or –(CH₂)₂–, wherein the R^X moiety is –CD₂F, –CDF₂, d7-isopropyl, or d9-tert-butyl. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CD2– or –(CD2)2–, wherein the R^X moiety is selected from cyclopropyl, cyclobutyl, 1-azetidinyl, and 3-oxetanyl. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CD2– or –(CD2)2–, wherein the R^X moiety is selected from deuterated cyclopropyl, deuterated cyclobutyl, deuterated 1-azetidinyl, and deuterated 3-oxetanyl. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CD₂– or –(CD₂)₂–, wherein the R^X moiety is selected from d5-cyclopropyl, d7-cyclobutyl, d6-1-azetidinyl, and d5-3-oxetanyl. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CH₂– or –(CH₂)₂–, wherein the R^X moiety is selected from deuterated cyclopropyl, deuterated cyclobutyl, deuterated 1-azetidinyl, and deuterated 3-oxetanyl. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CH₂– or –(CH₂)₂–, wherein the R^X moiety is selected from d5-cyclopropyl, d7- cyclobutyl, d6-1-azetidinyl, and d5-3-oxetanyl. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CD₂– or –(CD₂)₂–, wherein the R^X moiety is selected from:

112

_{. In some embodiments, R} ¹ _{is –O–} (C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CD₂– or –(CD₂)₂–, wherein the R^X moiety is selected from: fully deuterated

, fully deuterated

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CH2– or –(CH2)2–, wherein the R^X moiety is selected from: deuterated N N

d

d

_{. In some embodiments, R} ¹ _{is –O–} (C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CH₂– or –(CH₂)₂–, wherein the R^X moiety is selected from: fully deuterated

, fully deuterated

_{y y d ,} f d , f _d

2. Exemplary deuterated analogs In some embodiments, the deuterated analogs have a structure of Formula I or II or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof,

Formula II wherein R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein R^a, R^b, m, R^X, R², R³, R⁵, R⁶, R⁷, and T are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, the deuterated analogs have a structure of Formula I or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. In some embodiments, the deuterated analogs have a structure of Formula II or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))m– moiety may be –(CD2)m–, such as –CD2– and –(CD2)2–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))_m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –O–CD₂–R^X or –S–CD₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–(CD2)2–R^X or –S–(CD2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–CH₂–R^X or –S–CH₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, ^X

or –S–(CH₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X, wherein R^a, R^b, m, and R^X are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))_m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))m– moiety may be –(CD2)m–, such as –CD2– and –(CD2)2–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))_m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –O–CD2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O– (CD₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–CH2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(CH₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –S–(C(R^a)(R^b))_m–R^X, wherein R^a, R^b, m, and R^X are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))_m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))m– moiety may be –(CD2)m–, such as –CD2– and –(CD2)2–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))_m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –S–CD2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –S– (CD₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –S–CH₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –S–(CH2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X

, wherein the –(C(R^a)(R^b))m– moiety is –CD2– or –(CD2)2–, wherein the R^X moiety is selected from –CH2F, deuterated –CH₂F, –CHF₂, –CDF₂, –CF₃, isopropyl, deuterated isopropyl, tert-butyl, deuterated tert-butyl, cyclopropyl, deuterated cyclopropyl, cyclobutyl, deuterated cyclobutyl, 1-azetidinyl, deuterated 1-azetidinyl, 3-oxetanyl, deuterated 3-oxetanyl,

, ,

, , ,

In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CH₂– or –(CH₂)₂–, wherein the R^X moiety is selected from deuterated –CH2F, –CDF2, deuterated isopropyl, deuterated tert-butyl, deuterated cyclopropyl, deuterated

_. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CD2– or –(CD2)2–, wherein the R^X moiety is selected from –CH2F, –CD₂F, –CHF₂, –CDF₂, –CF₃, isopropyl, d7-isopropyl, tert-butyl, d9-tert-butyl, cyclopropyl, d5- cyclopropyl, cyclobutyl, d7-cyclobutyl, 1-azetidinyl, d6-1-azetidinyl, 3-oxetanyl, d5-3-oxetanyl,

132

_d d y y y y _y

_{y d , f} d y d d f

In some embodiments, R¹ is ^{a b X}

or –S–(C(R)(R))_m–R, wherein the –(C(R^a)(R^b))m– moiety is –CH2– or –(CH2)2–, wherein the R^X moiety is selected from –CD2F, –CDF2, d7-isopropyl, d9-tert-butyl, d5-cyclopropyl, d7-cyclobutyl, d6-1-azetidinyl, d5-3-

d d d _{d d y}

_d , f , f

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the

moiety is –CD2–, wherein the R^X moiety is selected from

, ,

d d

_. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CH₂–, wherein the R^X moiety is selected from deuterated

, d _{, d}

_, d d , d _{, d}

_y

_{d ,} f , f

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CH2–, wherein the R^X moiety is selected from fully deuterated N

d f

In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the

d d

In some embodiments, R¹ is –O–(C ^X

))_m–R , wherein the –(C(R^a)(R^b))m– moiety is –CD2–, wherein the R^X moiety is selected from fully deuterated

15

In some embodiments, the deuterated analogs are in a non-salt form. In some embodiments, the deuterated analogs are in a salt form. In some embodiments, the deuterated analogs are in a HCl, sulfate, or oxalate salt form. Formulas I’ and II’ In some embodiments, the deuterated analogs have a structure of Formula I’ or II’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof,

Formula II’ wherein R¹, R³, and T are the same as those described above in Section II(A) of the Detailed Description for Formula I or II, respectively, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, the deuterated analogs have a structure of Formula I’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. In some embodiments, the deuterated analogs have a structure of Formula II’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))_m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))_m– moiety may be –(CD₂)_m–, such as –CD₂– and –(CD₂)₂–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))_m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –O–CD2–R^X or –S–CD2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–(CD₂)₂–R^X or –S–(CD₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–CH2–R^X or –S–CH2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(CH₂)₂–R^X or –S–(CH2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X, wherein R^a, R^b, m, and R^X are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))_m– moiety may be –(CD₂)_m–, such as –CD₂– and –(CD₂)₂–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –O–CD₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O– (CD2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–CH₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(CH2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –S–(C(R^a)(R^b))m–R^X, wherein R^a, R^b, m, and R^X are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))_m– moiety may be –(CD₂)_m–, such as –CD₂– and –(CD₂)₂–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –S–CD₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –S– (CD₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –S–CH2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –S–(CH₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CD2– or –(CD2)2–, wherein the R^X moiety is selected from –CH2F, deuterated –CH2F, –CHF2, –CDF2, –CF3, isopropyl, deuterated isopropyl, tert-butyl, deuterated tert-butyl, cyclopropyl, deuterated cyclopropyl, cyclobutyl, deuterated cyclobutyl, 1-azetidinyl,

In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –

or –(CH₂)₂–, wherein the R^X moiety is selected from deuterated –CH2F, –CDF2, deuterated isopropyl, deuterated tert-butyl, deuterated cyclopropyl, deuterated

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CD2– or –(CD2)2–, wherein the R^X moiety is selected from –CH2F, –CD₂F, –CHF₂, –CDF₂, –CF₃, isopropyl, d7-isopropyl, tert-butyl, d9-tert-butyl, cyclopropyl, d5- cyclopropyl, cyclobutyl, d7-cyclobutyl, 1-azetidinyl, d6-1-azetidinyl, 3-oxetanyl, d5-3-oxetanyl,

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CH2– or –(CH2)2–, wherein the R^X moiety is selected from –CD2F, –CDF₂, d7-isopropyl, d9-tert-butyl, d5-cyclopropyl, d7-cyclobutyl, d6-1-azetidinyl, d5-3- oxetanyl, fully deuterated

, fully deuterated

deuterated

f f

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the moiety is –CD–, wh ^X

2 erein the R moiety is selected

,

_, d , d _{, d ,}

, ,

d d

_. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CH₂–, wherein the R^X moiety is selected from deuterated

, deuterated

, deuterated

_d

_{, , , ,}

, ,

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CH2–, wherein the R^X moiety is selected from fully deuterated

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the

189

In some embodiments, R¹ is –O–(C ) ^X

)_m–R, wherein the –(C(R^a)(R^b))m– moiety is –CD2–, wherein the R^X moiety is selected from fully deuterated

_{y d , f} d y d d f

In some embodiments, R³ is chloro or fluoro. In some embodiments, R³ is chloro. In some embodiments, R³ is fluoro. In some embodiments, T is selected from

s

s s . I

e embodiments,

. In some embodiments, T is

. In some 3 embodiments,

some embodiments,

. In some e

. Exemplary deuterated analogs of Formula I’ include, but are not limited to, the following: 194

, , ,

salts, hydrates, and hydrated salts thereof. Exemplary deuterated analogs of Formula I’ also include the following:

salts, hydrates, and hydrated salts thereof. In some embodiments, the deuterated analogs are in a non-salt form. In some embodiments, the deuterated analogs are in a salt form. In some embodiments, the deuterated analogs are in a HCl, sulfate, or oxalate salt form. Formulas I’’ and II’’ In some embodiments, the deuterated analogs have a structure of Formula I’’ or II’’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof,

Formula II’’ wherein R¹, R³, R⁵, R⁶, and T are the same as those described above in Section II(A) of the Detailed Description for Formula I or II, respectively, with the exception that one or more non- ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, the deuterated analogs have a structure of Formula I’’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. In some embodiments, the deuterated analogs have a structure of Formula II’’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))_m– moiety may be –(CD₂)_m–, such as –CD₂– and –(CD₂)₂–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –O–CD₂–R^X or –S–CD₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–(CD2)2–R^X or –S–(CD2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–CH2–R^X or –S–CH2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(CH₂)₂–R^X or –S–(CH2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X, wherein R^a, R^b, m, and R^X are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))_m– moiety may be –(CD₂)_m–, such as –CD₂– and –(CD₂)₂–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –O–CD₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O– (CD2)2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –O–CH₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(CH₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –S–(C(R^a)(R^b))_m–R^X, wherein R^a, R^b, m, and R^X are the same as those described above in Section II(A) of the Detailed Description, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. In some embodiments, R¹ is fully deuterated. In some embodiments, R¹ is partially deuterated. In some embodiments, the –(C(R^a)(R^b))_m– moiety of R¹ is deuterated, either fully or partially. For example, the –(C(R^a)(R^b))m– moiety may be –(CD2)m–, such as –CD2– and –(CD2)2–. In some embodiments, the R^X moiety of R¹ is deuterated, either fully or partially. In some embodiments, both the –(C(R^a)(R^b))_m– moiety and the R^X moiety are deuterated, each of which may be either fully or partially deuterated. In some embodiments, R¹ is –S–CD2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –S– (CD₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description. In some embodiments, R¹ is –S–CH2–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –S–(CH₂)₂–R^X, wherein the R^X moiety is the same as those described above in Section II(A) of the Detailed Description, with the exception that the R^X moiety is deuterated, either fully or partially. In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CD2– or –(CD2)2–, wherein the R^X moiety is selected from –CH2F, deuterated –CH2F, –CHF2, –CDF2, –CF3, isopropyl, deuterated isopropyl, tert-butyl, deuterated tert-butyl, cyclopropyl, deuterated cyclopropyl, cyclobutyl, deuterated cyclobutyl, 1-azetidinyl,

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CH2– or –(CH2)2–, wherein the R^X moiety is selected from deuterated –CH₂F, –CDF₂, deuterated isopropyl, deuterated tert-butyl, deuterated cyclopropyl, deuterated cyclobutyl, deuterated 1-azetidinyl, deuterated 3-oxetanyl, deuterated deuterated

218

In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CD2– or –(CD2)2–, wherein the R^X moiety is selected from –CH2F, –CD2F, –CHF2, –CDF2, –CF3, isopropyl, d7-isopropyl, tert-butyl, d9-tert-butyl, cyclopropyl, d5- cyclopropyl, cyclobutyl, d7-cyclobutyl, 1-azetidinyl, d6-1-azetidinyl, 3-oxetanyl, d5-3-oxetanyl,

d d f

In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CH2– or –(CH2)2–, wherein the R^X moiety is selected from –CD2F, –CDF2, d7-isopropyl, d9-tert-butyl, d5-cyclopropyl, d7-cyclobutyl, d6-1-azetidinyl, d5-3-

_{, fully deuterated}

224

_{, , fully deuterated}

_{, fully deuterated d} , f

,

f , , , ,

, , _{, ,} , , d

, d _{, d ,} d ,

d _d

_d

_. In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the moiety is –CH–, wherein the R^X moi

₂ ety is selected from deuterated , d _{, d ,}

d d , d _{, d d}

_d d d d

In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X

, wherein the –(C(R^a)(R^b))m– moiety is –CD2–, wherein the R^X moiety is selected from

,

, , , , _{, ,} ,

_, y y _y y y y

d d f d d _{d d}

_{d ,} f d , f _d

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CH2–, wherein the R^X moiety is selected from fully deuterated d

d

y y _{y y d , f} d y

d f

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the –(C(R^a)(R^b))_m– moiety is –CD₂–, wherein the R^X moiety is selected from

, , , ,

, , _{, ,} , ,

In some embodiments, R¹ is –O–(C(R^a)(R^b))m–R^X or –S–(C(R^a)(R^b))m–R^X, wherein the , d _{, d ,} d d

, d _{, d d d} d

d d

In some embodiments, R¹ is –O–(C(R^a)(R^b))_m–R^X or –S–(C(R^a)(R^b))_m–R^X, wherein the –(C(R^a)(R^b))m– moiety is –CD2–, wherein the R^X moiety is selected from fully deuterated d d d d

_{y d , f} d y d d f

In some embodiments, R³ is chloro or fluoro. In some embodiments, R³ is chloro. In some embodiments, R³ is fluoro. In some embodiments, R⁵ is hydrogen, halogen, C₁–C₃ alkyl such as methyl, or C₁–C₃ haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁵ is hydrogen or halogen. In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is halogen. In some embodiments, R⁵ is chloro or fluoro. In some embodiments, R⁵ is chloro. In some embodiments, R⁵ is fluoro. In some embodiments, R⁵ is C₁–C₃ alkyl such as methyl or C₁–C₃ haloalkyl such as –CH₂F, –CHF₂, and –CF3. In some embodiments, R⁵ is methyl, –CH2F, –CHF2, or –CF3. In some embodiments, R⁵ is methyl or –CF₃. In some embodiments, R⁵ is methyl. In some embodiments, R⁵ is –CH₂F. In some embodiments, R⁵ is –CHF₂. In some embodiments, R⁵ is –CF₃. In some embodiments, R⁶ is hydrogen, halogen, C1–C3 alkyl such as methyl, or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁶ is hydrogen or halogen. In some embodiments, R⁶ is hydrogen. In some embodiments, R⁶ is halogen. In some embodiments, R⁶ is chloro or fluoro. In some embodiments, R⁶ is chloro. In some embodiments, R⁶ is fluoro. In some embodiments, R⁶ is C1–C3 alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF₃. In some embodiments, R⁶ is methyl, –CH₂F, –CHF₂, or –CF₃. In some embodiments, R⁶ is methyl or –CF₃. In some embodiments, R⁶ is methyl. In some embodiments, R⁶ is –CH₂F. In some embodiments, R⁶ is –CHF2. In some embodiments, R⁶ is –CF3. In some embodiments, R⁵ and R⁶ are independently hydrogen, halogen, C₁–C₃ alkyl such as methyl, or C₁–C₃ haloalkyl such as –CH₂F, –CHF₂, and –CF₃. In some embodiments, R⁵ and R⁶ are independently hydrogen, halogen, methyl,–CH2F, –CHF2, or –CF3. In some embodiments, R⁵ and R⁶ are independently hydrogen, methyl, or –CF₃. In some embodiments, R⁵ is hydrogen or halogen, and R⁶ is C₁–C₃ alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁵ is hydrogen or halogen, and R⁶ is methyl,–CH2F, –CHF2, or –CF3. In some embodiments, R⁵ is hydrogen, and R⁶ is methyl or –CF₃. In some embodiments, R⁶ is hydrogen or halogen, and R⁵ is C1–C3 alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁶ is hydrogen or halogen, and R⁵ is methyl,–CH₂F, –CHF₂, or –CF₃. In some embodiments, R⁶ is hydrogen, and R⁵ is methyl or –CF₃. In some embodiments, R⁵ and R⁶ are independently C1–C3 alkyl such as methyl or C1–C3 haloalkyl such as –CH2F, –CHF2, and –CF3. In some embodiments, R⁵ and R⁶ are independently methyl,–CH₂F, –CHF₂, or –CF₃. In some embodiments, R⁵ and R⁶ are independently methyl or – CF3. In some embodiments, at least one of R⁵ and R⁶ is selected from C1–C3 alkyl (such as methyl) and C₁–C₃ haloalkyl (such

–CHF₂, and –CF₃). In some embodiments, at least one of R⁵ and R⁶ is selected from methyl,–CH₂F, –CHF₂, and –CF₃. In some embodiments, at least one of R⁵ and R⁶ is selected from methyl and –CF3. In some embodiments, R³ is chloro or fluoro, R⁵ is hydrogen, halogen, methyl,–CH₂F, –CHF₂, or –CF₃, and R⁶ is hydrogen, halogen, methyl,–CH₂F, –CHF₂, or –CF₃. In some embodiments, R³ is chloro, R⁵ is hydrogen, methyl, or –CF3, and R⁶ is hydrogen, methyl, or –CF3. In some embodiments, R³ is chloro or fluoro, R⁵ is hydrogen or halogen, and R⁶ is methyl, –CH₂F, –CHF₂, or –CF₃. In some embodiments, R³ is chloro, R⁵ is hydrogen, and R⁶ is methyl or –CF3. In some embodiments, R³ is chloro or fluoro, R⁶ is hydrogen or halogen, and R⁵ is methyl, –CH₂F, –CHF₂, or –CF₃. In some embodiments, R³ is chloro, R⁶ is hydrogen, and R⁵ is methyl or –CF₃. In some embodiments, R³ is chloro or fluoro, R⁵ is methyl,–CH2F, –CHF2, or –CF3, and R⁶ is methyl,–CH₂F, –CHF₂, or –CF₃. In some embodiments, R³ is chloro, R⁵ is methyl or –CF₃, and R⁶ is methyl or –CF₃. In some embodiments, T is selected from

, CF

, n s

e ,

s s s s

.

e embodiments, T is

. In some embodiments, T is

e 3 embodiments,

. In some embodiments,

. In some e

. Exemplary deuterated analogs of Formula I’’ include those specified above for the deuterated analogs of Formula I’, with the exception that R⁵ is methyl or CF₃ rather than hydrogen. Exemplary deuterated analogs of Formula I’’ also include those specified above for the deuterated analogs of Formula I’, with the exception that R⁶ is methyl or CF₃ rather than hydrogen. Exemplary deuterated analogs of Formula I’’ also include those specified above for the deuterated analogs of Formula I’, with the exception that both R⁵ and R⁶ are independently methyl or CF3, rather than hydrogen. In some embodiments, the deuterated analogs are in a non-salt form. In some embodiments, the deuterated analogs are in a salt form. In some embodiments, the deuterated analogs are in a HCl, sulfate, or oxalate salt form. III. COMPOSITIONS Disclosed are compositions containing a compound disclosed herein. In this context, the compound may be a non-covalent inhibitor of coronavirus M^pro described in Section II(A) of the Detailed Description or a deuterated analog described in Section II(B) of the Detailed Description. In some embodiments, the compound in the composition is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess. In some embodiments, the compound in the composition is in greater than 95% enantiomeric or diastereomeric excess. In some embodiments, the compositions contain a compound having a structure of Formula I or a pharmaceutically acceptable salt, hydrate, or hydrated salt of Formula I, wherein the compound is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess. In some embodiments, the compound is in greater than 95% enantiomeric or diastereomeric excess. In some embodiments, the compositions contain a compound having a structure of Formula II or a pharmaceutically acceptable salt, hydrate, or hydrated salt of Formula II, wherein the compound is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess. In some embodiments, the compound is in greater than 95% enantiomeric or diastereomeric excess. In some embodiments, the compositions contain a compound having a structure of Formula I’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt of Formula I’, wherein the compound is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess. In some embodiments, the compound is in greater than 95% enantiomeric or diastereomeric excess. In some embodiments, the compositions contain a compound having a structure of Formula I’’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt of Formula I’, wherein the compound is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess. In some embodiments, the compound is in greater than 95% enantiomeric or diastereomeric excess. In some embodiments, the compositions contain a compound having a structure of Formula II’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt of Formula II’, wherein the compound is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess. In some embodiments, the compound is in greater than 95% enantiomeric or diastereomeric excess. In some embodiments, the compositions contain a compound having a structure of Formula II’’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt of Formula II’, wherein the compound is in greater than 80%, 85%, 90%, or 95% enantiomeric or diastereomeric excess. In some embodiments, the compound is in greater than 95% enantiomeric or diastereomeric excess. The disclosed compounds may be present in a mixture of a salt form and a non-salt form. In some embodiments, more than 50%, 60%, 70%, 80%, 90%, 95%, or 98% of the compound in the mixture may be in the non-salt form, calculated as the ratio of the weight of the non-salt form to the total weight of the mixture. In some embodiments, more than 90% of the compound in the mixture may be in the non-salt form. In some embodiments, more than 50%, 60%, 70%, 80%, 90%, 95%, or 98% of the compound in the mixture may be in the salt form, calculated as the ratio of the weight of the salt form to the total weight of the mixture. In some embodiments, more than 90% of the compound in the mixture may be in the salt form. In some embodiments, the salt form is a HCl, sulfate, or oxalate salt form. IV. FORMULATIONS Disclosed are pharmaceutical formulations containing a compound or composition described herein. In this context, the compound may be a non-covalent inhibitor of coronavirus M^pro described in Section II(A) of the Detailed Description or a deuterated analog described in Section II(B) of the Detailed Description. Also in this context, the composition may contain a non- covalent inhibitor of coronavirus M^pro described in Section II(A) of the Detailed Description or a deuterated analog described in Section II(B) of the Detailed Description. Generally, the pharmaceutical formulations also contain one or more pharmaceutically acceptable excipients. The pharmaceutical formulations can be in a form chosen from tablets, capsules, caplets, pills, powders, beads, granules, particles, creams, gels, solutions (such as aqueous solutions, e.g., buffer, saline, and buffered saline), emulsions, suspensions (including nano- and micro- suspensions), nanoparticulate formulations, etc. In some embodiments, the pharmaceutical formulations are formulated for oral administration. In some embodiments, the pharmaceutical formulations are formulated for intravenous administration. In some embodiments, the pharmaceutical formulations are formulated for intramuscular administration. In some embodiments, the pharmaceutical formulations are formulated for intranasal administration. In some embodiments, the pharmaceutical formulations are formulated for subcutaneous administration. As used herein, “emulsion” refers to a mixture of non-miscible components homogenously blended together. In some forms, the non-miscible components include a lipophilic component and an aqueous component. For example, an emulsion may be a preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil or an oleaginous substance is the dispersed liquid and water or an aqueous solution is the continuous phase, it is known as an oil-in-water emulsion, whereas when water or an aqueous solution is the dispersed phase and oil or an oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. As used herein, “biocompatible” refers to materials that are neither themselves toxic to the host (e.g., a non-human animal or human), nor degrade (if the material degrades) at a rate that produces monomeric or oligomeric subunits or other byproducts at toxic concentrations in the host. As used herein, “biodegradable” refers to degradation or breakdown of a polymeric material into smaller (e.g., non-polymeric) subunits or digestion of the material into smaller subunits. As used herein, “enteric polymers” refers to polymers that become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as they pass through the gastrointestinal tract. As used herein, “nanoparticulate formulations” generally refers to formulations containing nanoparticles, which are particles having a diameter from about 1 nm to about 1000 nm, from about 10 nm to about 1000 nm, from about 100 nm to about 1000 nm, or from about 250 nm to about 1000 nm. In some embodiments, “nanoparticulate formulations” can also refer to formulations containing microparticles, which are particles having a diameter from about 1 micron to about 100 microns, from about 1 to about 50 microns, from about 1 to about 30 microns, from about 1 micron to about 10 microns. In some embodiments, the nanoparticulate formulation may contain a mixture of nanoparticles, as defined above, and microparticles, as defined above. As used herein, “surfactant” refers to any agent that preferentially absorbs to an interface between two immiscible phases, such as the interface between water (or aqueous solution) and an organic solvent (or organic solution), between water (or aqueous solution) and air, or between organic solvent (or organic solution) and air. Surfactants generally possess a hydrophilic moiety and a lipophilic moiety. As used herein, “gel” is a semisolid system containing a dispersion of the active ingredient, i.e., a compound or composition according to the present disclosure, in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle. The liquid vehicle may include a lipophilic component, an aqueous component, or both. As used herein, “hydrogel” refers to a swollen, water-containing network of finely dispersed polymer chains that are water-insoluble, where the polymer molecules are in the external or dispersion phase and water (or an aqueous solution) forms the internal or dispersed phase. The polymer chains can be chemically cross-linked (chemical gels) or physically cross-linked (physical gels). Chemical gels possess polymer chains connected through covalent bonds, whereas physical gels have polymer chains linked by non-covalent interactions, such as van der Waals interactions, ionic interactions, hydrogen bonding interactions, and hydrophobic interactions. As used herein, “beads” refers to beads made with the active ingredient (i.e., a compound or composition according to the present disclosure) and one or more pharmaceutically acceptable excipients. The beads can be produced by applying the active ingredient to an inert support, e.g., inert sugar core coated with the active ingredient. Alternatively, the beads can be produced by creating a “core” comprising both the active ingredient and at least one of the one or more pharmaceutically acceptable excipients. As used herein, “granules” refers to a product made by processing particles of the active ingredient (i.e., a compound or composition according to the present disclosure) that may or may not include one or more pharmaceutical acceptable excipients. Typically, granules do not contain an inert support and are bigger in size compared to the particles used to produce them. Although beads, granules, and particles may be formulated to provide immediate release, beads and granules are usually employed to provide delayed release. As used herein, “enzymatically degradable polymers” refers to polymers that are degraded by bacterial enzymes present in the intestines and/or lower gastrointestinal tract. A. Physical forms and unit dosages Depending upon the administration route, the compounds or compositions described herein may be formulated in a variety of ways. The pharmaceutical formulations can be prepared in various forms, such as tablets, capsules, caplets, pills, granules, powders, nanoparticle formulations, solutions (such as aqueous solutions, e.g., buffer, saline, and buffered saline), suspensions (including nano- and micro-suspensions), emulsions, creams, gels, and the like. In some embodiments, the pharmaceutical formulations are in a solid dosage form suitable for simple administration of precise dosages. For example, the solid dosage form may be selected from tablets, soft or hard gelatin or non-gelatin capsules, and caplets for oral administration. Optionally, the solid dosage form is a lyophilized powder that can be readily dissolved and converted to a liquid dosage form for intravenous or intramuscular administration. In some embodiments, the lyophilized powder is manufactured by dissolving the active ingredient (i.e., a compound or composition disclosed herein) in an aqueous medium followed by lyophilization. In some embodiments, the aqueous medium is water, normal saline, PBS, or an acidic aqueous medium such as an acetate buffer. In some embodiments, the pharmaceutical formulations are in a liquid dosage form suitable for intravenous or intramuscular administration. Exemplary liquid dosage forms include, but are not limited to, solutions, suspensions, and emulsions. In some embodiments, the pharmaceutical formulations are in the form of a sterile aqueous solution. In some embodiments, the sterile aqueous solution is a sterile normal saline solution. In some embodiments, the sterile aqueous solution is a sterile PBS solution. In some embodiments, the sterile aqueous solution is an acidic, sterile aqueous solution such as a sterile acetate buffer. In some embodiments, the sterile aqueous solution is manufactured by dissolving a lyophilized powder containing the active ingredient (i.e., a compound or composition disclosed herein) in an aqueous medium. For example, the sterile aqueous solution can be prepared by dissolving the lyophilized powder containing the active ingredient in a dose-appropriate volume of sterile water, sterile normal saline, sterile PBS, or acidic, sterile aqueous medium such as a sterile acetate buffer. In some embodiments, the lyophilized powder containing the active ingredient is the same as those described in the paragraph above. In some embodiments, the pharmaceutical formulations are in a unit dosage form, and may be suitably packaged, for example, in a box, blister, vial, bottle, syringe, sachet, ampoule, or in any other suitable single-dose or multi-dose holder or container, optionally with one or more leaflets containing product information and/or instructions for use. B. Pharmaceutically acceptable excipients Exemplary pharmaceutically acceptable excipients include, but are not limited to, diluents, binders, lubricants, disintegrants, pH-modifying or buffering agents, salts (such as NaCl), preservatives, antioxidants, solubility enhancers, wetting or emulsifying agents, plasticizers, colorants (such as pigments and dyes), flavoring or sweetening agents, thickening agents, emollients, humectants, stabilizers, glidants, solvents or dispersion mediums, surfactants, pore formers, and coating or matrix materials. In some embodiments, the powders described herein, including the lyophilized powders, contain one or more of the following pharmaceutically acceptable excipients: pH-modifying or buffering agents, salts (such as NaCl), and preservatives. In some embodiments, the tablets, beads, granules, and particles described herein contain one or more of the following pharmaceutically acceptable excipients: coating or matrix materials, diluents, binders, lubricants, disintegrants, pigments, stabilizers, and surfactants. If desired, the tablets, beads, granules, and particles may also contain a minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH-buffering agents, and preservatives. Examples of the coating or matrix materials include, but are not limited to, cellulose polymers (such as methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, and carboxymethylcellulose sodium), vinyl polymers and copolymers (such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate-crotonic acid copolymer, and ethylene-vinyl acetate copolymer), acrylic acid polymers and copolymers (such as those formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, or ethyl methacrylate, as well as methacrylic resins that are commercially available under the tradename EUDRAGIT®), enzymatically degradable polymers (such as azo polymers, pectin, chitosan, amylose, and guar gum), zein, shellac, and polysaccharides. In some embodiments, the coating or matrix materials may contain one or more excipients such as plasticizers, colorants, glidants, stabilizers, pore formers, and surfactants. In some embodiments, the coating or matrix materials are pH-sensitive or pH-responsive polymers, such as the enteric polymers commercially available under the tradename EUDRAGIT®. For example, EUDRAGIT® L30D-55 and L100-55 are soluble at pH 5.5 and above; EUDRAGIT® L100 is soluble at pH 6.0 and above; EUDRAGIT® S is soluble at pH 7.0 and above. In some embodiments, the coating or matrix materials are water-insoluble polymers having different degrees of permeability and expandability, such as EUDRAGIT® NE, RL, and RS. Depending on the coating or matrix materials, the decomposition/degradation or structural change of the pharmaceutical formulations may occur at different locations of the gastrointestinal tract. In some embodiments, the coating or matrix materials are selected such that the pharmaceutical formulations can survive exposure to gastric acid and release the active ingredient in the intestines after oral administration. Diluents can increase the bulk of a solid dosage formulation so that a practical size is provided for compression of tablets or formation of beads, granules, or particles. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate, powdered sugar, and combinations thereof. Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet, bead, granule, or particle remains intact after the formation of the solid dosage formulation. Suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (such as acacia, tragacanth, and sodium alginate), cellulose (such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and ethylcellulose), veegum, and synthetic polymers (such as acrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid, polymethacrylic acid, and polyvinylpyrrolidone), and combinations thereof. Lubricants are used to facilitate tablet manufacture. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil. Disintegrants are used to facilitate disintegration or “breakup” of a solid dosage formulation after administration. Suitable disintegrants include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, gums, and cross-linked polymers, such as cross-linked polyvinylpyrrolidone (e.g., POLYPLASDONE® XL). Plasticizers are normally present to produce or promote plasticity and flexibility and to reduce brittleness. Examples of plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil, and acetylated monoglycerides. Stabilizers are used to inhibit or retard decomposition reactions of the active ingredient in the pharmaceutical formulations or stabilize particles in a dispersion. For example, when the decomposition reactions involve an oxidation reaction of the active ingredient in the pharmaceutical formulations, the stabilizer can be an antioxidant or a reducing agent. Stabilizers also include nonionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Glidants are used to reduce sticking effects during film formation and drying. Exemplary glidants include, but are not limited to, talc, magnesium stearate, and glycerol monostearates. Preservatives can inhibit the deterioration and/or decomposition of a pharmaceutical formulation. Deterioration or decomposition can be brought about by one or more of microbial growth, fungal growth, and undesirable chemical or physical changes. Suitable preservatives include benzoate salts (e.g., sodium benzoate), ascorbic acid, methyl hydroxybenzoate, ethyl p- hydroxybenzoate, n-propyl p-hydroxybenzoate, n-butyl p-hydroxybenzoate, potassium sorbate, sorbic acid, propionate salts (e.g., sodium propionate), chlorobutanol, benzyl alcohol, and combinations thereof. Surfactants may be anionic, cationic, amphoteric, or nonionic surface-active agents. Exemplary anionic surfactants include, but are not limited to, those containing a carboxylate, sulfonate, or sulfate ion. Examples of anionic surfactants include sodium, potassium, and ammonium salts of long-chain (e.g., 13-21) alkyl sulfonates (such as sodium lauryl sulfate), alkylaryl sulfonates (such as sodium dodecylbenzene sulfonate), and dialkyl sulfosuccinates (such as sodium bis-(2-ethylthioxyl)-sulfosuccinate). Examples of cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene, and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, poloxamers (such as poloxamer 401), stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include, but are not limited to, sodium N-dodecyl-ȕ-alanine, sodium N-lauryl-ȕ-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine. Pharmaceutical formulations in the liquid dosage forms typically contain a solvent or dispersion medium such as water, aqueous solution (e.g., buffer, saline, buffered saline), ethanol, polyol (such as glycerol, propylene glycol, and polyethylene glycol), oil (such as vegetable oil, e.g., peanut oil, corn oil, sesame oil), and combinations thereof. In some embodiments, the pharmaceutical formulations in the liquid dosage forms are aqueous formulations. Suitable solvents or dispersion mediums for aqueous formulations include, but are not limited to, water, buffers (such as acidic buffers), salines (such as normal saline), buffered salines (such as PBS), and Ringer’s solution. C. Pharmaceutical acceptable carriers In some embodiments, the pharmaceutical formulations are prepared using a pharmaceutically acceptable carrier, which encapsulates, embeds, entraps, dissolves, disperses, absorbs, and/or binds to a compound or composition disclosed herein. The pharmaceutical acceptable carrier is composed of materials that are considered safe and can be administered to a subject without causing undesirable biological side effects or unwanted interactions. Preferably, the pharmaceutically acceptable carrier does not interfere with the effectiveness of the compound or composition in performing its function. The pharmaceutically acceptable carrier can be formed of biodegradable materials, non-biodegradable materials, or combinations thereof. One or more of the pharmaceutical acceptable excipients described above may be present in the pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical acceptable carrier is a controlled-release carrier, such as delayed-release carriers, sustained-release (extended-release) carriers, and pulsatile- release carriers. In some embodiments, the pharmaceutical acceptable carrier is pH-sensitive or pH- responsive. In some forms, the pharmaceutical acceptable carrier can decompose or degrade in a certain pH range. In some forms, the pharmaceutical acceptable carrier can experience a structural change when experiencing a change in the pH. Exemplary pharmaceutical acceptable carriers include, but are not limited to nanoparticles, microparticles, and combinations thereof; liposomes; hydrogels; polymer matrices; and solvent systems. In some embodiments, the pharmaceutical acceptable carrier is nanoparticles, microparticles, or a combination thereof. In some embodiments, the compound or composition is embedded in the matrix formed by the materials of the nanoparticles, microparticles, or combination thereof. The nanoparticles, microparticles, or combination thereof can be biodegradable, and optionally are capable of biodegrading at a controlled rate for delivery of the compound or composition. The nanoparticles, microparticles, or combination thereof can be made of a variety of materials. Both inorganic and organic materials can be used. Both polymeric and non-polymeric materials can be used. For example, the nanoparticles, microparticles, or combination thereof are formed of one or more biocompatible polymers. In some forms, the biocompatible polymers are biodegradable. In some forms, the biocompatible polymers are non-biodegradable. In some forms, the nanoparticles, microparticles, or combination thereof are formed of a mixture of biodegradable and non-biodegradable polymers. The polymers used to form the nanoparticles, microparticles, or combination thereof may be tailored to optimize different characteristics of the nanoparticles, microparticles, or combination thereof, including: (i) interactions between the active ingredient and the polymer to provide stabilization of the active ingredient and retention of activity upon delivery; (ii) rate of polymer degradation and, thereby, rate of release; (iii) surface characteristics and targeting capabilities; and (iv) particle porosity. Exemplary polymers include, but are not limited to, polymers prepared from lactones (such as poly(caprolactone) (PCL)), polyhydroxy acids and copolymers thereof (such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(lactic acid-co-glycolic acid) (PLGA)), polyalkyl cyanoacralate, polyurethanes, polyamino acids (such as poly-L-lysine (PLL), poly(valeric acid), and poly-L-glutamic acid), hydroxypropyl methacrylate (HPMA), polyanhydrides, polyorthoesters, poly(ester amides), polyamides, poly(ester ethers), polycarbonates, ethylene vinyl acetate polymer (EVA), polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters (such as poly(vinyl acetate)), polyvinyl halides (such as poly(vinyl chloride) (PVC)), polyvinylpyrrolidone, polysiloxanes, polystyrene (PS), celluloses and derivatized celluloses (such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, hydroxypropylcellulose, and carboxymethylcellulose), polymers of acrylic acids (such as poly(methyl(meth)acrylate) (PMMA), poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate), poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate)), polydioxanone, polyhydroxyalkanoates, polypropylene fumarate, polyoxymethylene, poloxamers, poly(butyric acid), polyphosphazenes, polysaccharides, polypeptides, and blends thereof. In some embodiments, the one or more biocompatible polymers forming the nanoparticles, microparticles, or combination thereof include an FDA-approved biodegradable polymer such as polyhydroxy acids (e.g., PLA, PGA, and PLGA), polyanhydrides, and polyhydroxyalkanoate (e.g., poly(3-butyrate) and poly(4-butyrate)). Materials other than polymers may be used to form the nanoparticles, microparticles, or combination thereof. Suitable materials include surfactants. The use of surfactants in the nanoparticles, microparticles, or combination thereof may improve surface properties by, for example, reducing particle-particle interactions, and render the surface of the particles less adhesive. Both naturally occurring surfactants and synthetic surfactants can be incorporated into the nanoparticles, microparticles, or combination thereof. Exemplary surfactants include, but are not limited to, phosphoglycerides such as phosphatidylcholines (e.g., L-D-phosphatidylcholine dipalmitoyl), diphosphatidyl glycerol, hexadecanol, fatty alcohols, polyoxyethylene-9-lauryl ether, fatty acids such as palmitic acid and oleic acid, sorbitan trioleate, glycocholate, surfactin, poloxomers, sorbitan fatty acid esters such as sorbitan trioleate, tyloxapol, and phospholipids. The nanoparticles, microparticles, or combination thereof may contain a plurality of layers. The layers can have similar or different release kinetic profiles for the active ingredient. For example, the nanoparticles, microparticles, or combination thereof can have a controlled-release core surrounded by one or more additional layers. The one or more additional layers can include an instant-release layer, preferably on the surface of the nanoparticles, microparticles, or combination thereof. The instant-release layer can provide a bolus of the active ingredient shortly after administration. The composition and structure of the nanoparticles, microparticles, or combination thereof can be selected such that the nanoparticles, microparticles, or combination thereof are pH-sensitive or pH-responsive. In some embodiments, the nanoparticles, microparticles, or combination thereof are formed of one or more pH-sensitive or pH-responsive polymers such as the enteric polymers commercially available under the tradename EUDRAGIT®, as described above. Depending on the particle materials, the decomposition/degradation or structural change of the nanoparticles, microparticles, or combination thereof may occur at different locations of the gastrointestinal tract. In some embodiments, the particle materials are selected such that the nanoparticles, microparticles, or combination thereof can survive exposure to gastric acid and release the active ingredient in the intestines after oral administration. D. Controlled release In some embodiments, the pharmaceutical formulations can be controlled-release formulations. Examples of controlled-release formulations include extended-release formulations, delayed-release formulations, and pulsatile-release formulations. 1. Extended release In some embodiments, the extended-release formulations are prepared as diffusion or osmotic systems, for example, as described in “Remington – The science and practice of pharmacy” (20th Ed., Lippincott Williams & Wilkins, 2000). A diffusion system is typically in the form of a matrix, generally prepared by combining the active ingredient with a slowly dissolving, pharmaceutically acceptable carrier, optionally in a tablet form. Suitable materials used in the preparation of the matrix include plastics, hydrophilic polymers, and fatty compounds. Suitable plastics include, but are not limited to, acrylic polymer, methyl acrylate-methyl methacrylate copolymer, polyvinyl chloride, and polyethylene. Suitable hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl ethyl cellulose, hydroxyalkylcelluloses (such as hydroxypropylcellulose and hydroxypropylmethylcellulose), sodium carboxymethylcellulose, CARBOPOL® 934, polyethylene oxides, and combinations thereof. Suitable fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate, wax-type substances such as hydrogenated castor oil and hydrogenated vegetable oil, and combinations thereof. In some embodiments, the plastic is a pharmaceutically acceptable acrylic polymer. In some embodiments, the pharmaceutically acceptable acrylic polymer is chosen from acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate copolymers, cyanoethyl methacrylate copolymers, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymers, poly(methyl methacrylate), poly(methacrylic acid), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. In some embodiments, the pharmaceutically acceptable acrylic polymer can be an ammonio methacrylate copolymer. Ammonio methacrylate copolymers are well known in the art and are described as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In some embodiments, the pharmaceutically acceptable acrylic polymer is an acrylic resin lacquer such as those commercially available under the tradename EUDRAGIT®. In some embodiments, the pharmaceutically acceptable acrylic polymer contains a mixture of two acrylic resin lacquers, EUDRAGIT® RL (such as EUDRAGIT® RL30D) and EUDRAGIT® RS (such as EUDRAGIT® RS30D). EUDRAGIT® RL30D and EUDRAGIT® RS30D are copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral methacrylic esters being 1:20 in EUDRAGIT® RL30D and 1:40 in EUDRAGIT® RS30D. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these polymers. EUDRAGIT® RL/RS mixtures are insoluble in water and in digestive fluids. However, multi-particulate systems formed to include the same are swellable and permeable in aqueous solutions and digestive fluids. The EUDRAGIT® RL/RS mixtures may be prepared in any desired ratio in order to ultimately obtain a sustained-release formulation having a desirable release profile. Suitable sustained-release, multi-particulate systems may be obtained, for instance, from 90% EUDRAGIT® RL + 10% EUDRAGIT® RS, to 50% EUDRAGIT® RL + 50% EUDRAGIT® RS, and to 10% EUDRAGIT® RL + 90% EUDRAGIT® RS. In some embodiments, the pharmaceutically acceptable acrylic polymer can also be or include other acrylic resin lacquers, such as EUDRAGIT® S-100, EUDRAGIT® L-100, and mixtures thereof. Matrices with different release mechanisms or profiles can be combined in a final dosage form containing single or multiple units. Examples of multiple units include, but are not limited to, multilayer tablets and capsules containing beads, granules, and/or particles of the active ingredient. An immediate release portion can be added to the extended-release system by means of either applying an immediate release layer on top of the extended-release core using a coating or compression process or in a multiple unit system such as a capsule containing both extended- and immediate-release beads. Extended-release tablets containing one or more of the hydrophilic polymers can be prepared by techniques commonly known in the art such as direct compression, wet granulation, and dry granulation. Extended-release tablets containing one or more of the fatty compounds can be prepared using methods known in the art such as direct blend methods, congealing methods, and aqueous dispersion methods. In the congealing methods, the active ingredient is mixed with the fatty compound(s) and congealed. Alternatively, the extended-release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to a solid dosage form. In the latter case, the desired release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportions. 2. Delayed release Delayed-release formulations can be prepared by coating a solid dosage form with a coating. In some embodiments, the coating is insoluble and impermeable in the acidic environment of the stomach, and becomes soluble or permeable in the less acidic environment of the intestines and/or the lower GI tract. In some embodiments, the solid dosage form is a tablet for incorporation into a capsule, a tablet for use as an inner core in a “coated-core” dosage form, or a plurality of beads, granules, and/or particles containing the active ingredient, for incorporation into either a tablet or capsule. Suitable coating materials may be bioerodible polymers, gradually hydrolysable polymers, gradually water-dissolvable polymers, and enzymatically degradable polymers. In some embodiments, the coating material is or contains enteric polymers. Combinations of different coating materials may also be used. Multilayer coatings using different coating materials may also be applied. The coating may also contain one or more additives, such as plasticizers as described above (optionally representing about 10 wt % to 50 wt % relative to the dry weight of the coating), colorants as described above, stabilizers as described above, glidants as described above, etc. 3. Pulsatile release Pulsatile-release formulations release a plurality of doses of the active ingredient at spaced- apart time intervals. Generally, upon administration, such as oral administration, of the pulsatile- release formulations, release of the initial dose is substantially immediate, e.g., the first release “pulse” occurs within about three hours, two hours, or one hour of administration. This initial pulse may be followed by a first time-interval (lag time) during which very little or no active ingredient is released from the formulations, after which a second dose may be released. Similarly, a second lag time (nearly release-free interval) between the second and third release pulses may be designed. The duration of the lag times will vary depending on the formulation design, especially on the length of the dosing interval, e.g., a twice daily dosing profile, a three-time daily dosing profile, etc. For pulsatile-release formulations providing a twice daily dosage profile, they deliver two release pulses of the active ingredient. In some embodiments, the one nearly release-free interval between the first and second release pulses may have a duration of between 3 hours and 14 hours. For pulsatile-release formulations providing a three daily dosage profile, they deliver three release pulses of the active ingredient. In some embodiments, the two nearly release-free interval between two adjacent pulses may have a duration of between 2 hours and 8 hours. In some embodiments, the pulsatile-release formulations contain a plurality of pharmaceutically acceptable carriers with different release kinetics. In some embodiments, the pulsatile-release formulations contain a pharmaceutically acceptable carrier with a plurality of layers loaded with the active ingredient. In some embodiments, the layers may have different release kinetics. In some embodiments, the layers may be separated by a delayed-release coating. For example, the pulsatile-release formulations may have a first layer loaded with the active ingredient on the surface for the first release pulse and a second layer, e.g., a core loaded with the active ingredient, for the second release pulse; the second layer may be surrounded by a delayed-release coating, which creates a lag time between the two release pulses. In some embodiments, the pulsatile-release profile is achieved with formulations that are closed and optionally sealed capsules housing at least two “dosage units” wherein each dosage unit within the capsules provides a different release profile. In some embodiments, at least one of the dosage units is a delayed-release dosage unit. Control of the delayed-release dosage unit(s) may be accomplished by a controlled-release polymer coating on the dosage unit(s) or by incorporation of the active ingredient in a controlled-release polymer matrix. In some embodiments, each dosage unit may comprise a compressed or molded tablet, wherein each tablet within the capsule provides a different release profile. E. Exemplary formulations for different routes of administration A subject suffering from a condition, disorder, or disease as described herein can be treated by either targeted or systemic administration, via oral, inhalation, topical, trans- or sub-mucosal, subcutaneous, intramuscular, intravenous, or transdermal administration of a pharmaceutical formulation containing a compound or composition described herein. In some embodiments, the pharmaceutical formulation is suitable for oral administration. In some embodiments, the pharmaceutical formulation is suitable for subcutaneous, intravenous, or intramuscular administration. In some embodiments, the pharmaceutical formulation is suitable for inhalation or intranasal administration. In some embodiments, the pharmaceutical formulation is suitable for transdermal or topical administration. In some embodiments, the pharmaceutical formulation is an oral pharmaceutical formulation. In some embodiments, the active ingredient may be incorporated with one or more pharmaceutically acceptable excipients as described above and used in the form of tablets, pills, caplets, or capsules. For example, the corresponding oral pharmaceutical formulation may contain one or more of the following pharmaceutically acceptable excipients or those of a similar nature: a binder as described above, a disintegrant as described above, a lubricant as described above, a glidant as described above, a sweetening agent (such as sucrose and saccharin), and a flavoring agent (such as methyl salicylate and fruit flavorings). In some embodiments, when the oral pharmaceutical formulation is in the form of capsules, it may contain, in addition to the material(s) listed above, a liquid carrier (such as a fatty oil). In some embodiments, when the oral pharmaceutical formulation is in the form of capsules, each capsule may contain a plurality of beads, granules, and/or particles of the active ingredient. In some embodiments, the oral pharmaceutical formulation may contain one or more other materials that modify the physical form or one or more pharmaceutical properties of the dosage unit, for example, coatings of polysaccharides, shellac, or enteric polymers as described in previous sections. In some embodiments, the oral pharmaceutical formulation can be in the form of an elixir, suspension, syrup, wafer, chewing gum, or the like. A syrup may contain, in addition to the active ingredient, one or more sweetening agents (such as sucrose and saccharine), one or more flavoring agents, one or more preservatives, and/or one or more dyes or colorings. In some embodiments, the pharmaceutical formulation is a subcutaneous, intramuscular, or intravenous pharmaceutical formulation. In some embodiments, the subcutaneous, intramuscular, or intravenous pharmaceutical formulation can be enclosed in an ampoule, syringe, or a single or multiple dose vial made of glass or plastic. In some embodiments, the subcutaneous, intramuscular, or intravenous pharmaceutical formulation contains a liquid pharmaceutically acceptable carrier for the active ingredient. Suitable liquid pharmaceutically acceptable carriers include, but are not limited to, water, buffer, saline, buffered saline (such as PBS), and combinations thereof. In some embodiments, the pharmaceutical formulation is a topical pharmaceutical formulation. Suitable forms of the topical pharmaceutical formulation include lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, and suppositories for application to rectal, vaginal, nasal, or oral mucosa. In some embodiments, thickening agents, emollients (such as mineral oil, lanolin and its derivatives, and squalene), humectants (such as sorbitol), and/or stabilizers can be used to prepare the topical pharmaceutical formulations. Examples of thickening agents include petrolatum, beeswax, xanthan gum, and polyethylene. In some embodiments, the pharmaceutical formulation is an intranasal pharmaceutical formulation. In some embodiments, the intranasal pharmaceutical formulation is in the form of an aqueous suspension, which can be optionally placed in a pump spray bottle. Other than water, the aqueous suspension may contain one or more pharmaceutically acceptable excipients, such as suspending agents (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl-methyl cellulose), humectants (e.g., glycerol, propylene glycol), acids, bases, and/or pH-buffering agents for adjusting the pH (e.g., citric acid, sodium citrate, phosphoric acid, sodium phosphate, and combinations thereof), surfactants (e.g., polysorbate 80), and preservatives (e.g., benzalkonium chloride, phenylethyl alcohol, potassium sorbate). In some embodiments, the pharmaceutical formulation is an inhalation pharmaceutical formulation. In some embodiments, the inhalation pharmaceutical formulation may be in the form of an aerosol suspension, a dry powder, or a liquid suspension. The inhalation pharmaceutical formulation may be prepared for delivery as a nasal spray or an inhaler, such as a metered dose inhaler (MDI). In some embodiments, MDIs can deliver aerosolized particles suspended in chlorofluorocarbon propellants such as CFC-11 and CFC-12, or non-chlorofluorocarbons or alternate propellants such as fluorocarbons (e.g., HFC-134A, HFC-227), with or without surfactants or suitable bridging agents. Dry-powder inhalers can also be used, either breath activated or delivered by pressure. In some embodiments, the active ingredient is prepared with a pharmaceutically acceptable carrier that will protect it against rapid degradation or elimination from the body of the subject after administration, such as the controlled-release formulations described in previous sections. V. METHODS OF USE Disclosed are methods of inhibiting or preventing coronavirus replication in a subject in need thereof. The methods include administering an effective amount of a compound, composition, or pharmaceutical formulation disclosed herein to the subject. In this context, the compound may be a non-covalent inhibitor of coronavirus M^pro described in Section II(A) of the Detailed Description or a deuterated analog described in Section II(B) of the Detailed Description. Also in this context, the composition may contain a non-covalent inhibitor of coronavirus M^pro described in Section II(A) of the Detailed Description or a deuterated analog described in Section II(B) of the Detailed Description. Further in this context, the pharmaceutical formulation may contain a non-covalent inhibitor of coronavirus M^pro described in Section II(A) of the Detailed Description or a deuterated analog described in Section II(B) of the Detailed Description. In some embodiments, the coronavirus is SARS-CoV-2. In some embodiments, the subject is diagnosed with COVID-19, e.g., a COVID-19 patient. In some embodiments, the subject has a risk of contracting COVID-19. Disclosed are methods of treating or prevent coronavirus infection in a subject in need thereof. The methods include administering an effective amount of a compound, composition, or pharmaceutical formulation disclosed herein to the subject. In some embodiments, the coronavirus infection is SARS-CoV-2 infection. In some embodiments, the subject is diagnosed with COVID- 19, i.e., a COVID-19 patient. In some embodiments, the subject has a risk of contracting COVID- 19. Disclosed are methods of treating or preventing COVID-19 in a subject in need thereof. The methods include administering an effective amount of a compound, composition, or pharmaceutical formulation disclosed herein to the subject. In some embodiments, the subject is a COVID-19 patient. In some embodiments, the subject has mild illness per the clinical spectrum of SARS-CoV-2 infection under the NIH COVID-19 Treatment Guidelines (individuals who have any of the various signs and symptoms of COVID-19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but who do not have shortness of breath, dyspnea, or abnormal chest imaging). In some embodiments, the subject has moderate illness per the clinical spectrum of SARS-CoV-2 infection under the NIH COVID-19 Treatment Guidelines (individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have an oxygen saturation measured by pulse oximetry (SpO₂) Ŏ 94% on room air at sea level). In some embodiments, the subject has severe illness per the clinical spectrum of SARS-CoV-2 infection under the NIH COVID-19 Treatment Guidelines (individuals who have SpO₂ < 94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) < 300 mm Hg, a respiratory rate > 30 breaths/min, or lung infiltrates > 50%). In some embodiments, the subject has critical illness per the clinical spectrum of SARS-CoV-2 infection under the NIH COVID-19 Treatment Guidelines (individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction). In some embodiments, the compound, composition, or pharmaceutical formulation is used as a therapeutic, such as an antiviral. In some embodiments, the compound, composition, or pharmaceutical formulation is used as a prophylactic, such as pre-exposure prophylaxis (PrEP). The compound, composition, or pharmaceutical formulation can be administered in a variety of manners, depending on whether local or systemic administration is desired. In some embodiments, the compound, composition, or pharmaceutical formulation is directly administered to a specific bodily location of the subject, e.g., topical administration and intranasal administration. In some embodiments, the compound, composition, or pharmaceutical formulation is administered in a systemic manner, such as enteral administration (e.g., oral administration) and parenteral administration (e.g., injection, infusion, and implantation). Exemplary administration routes include oral administration, intravenous administration such as intravenous injection or infusion, intramuscular administration such as intramuscular injection, intranasal administration, and topical administration. In some embodiments, the compound, composition, or pharmaceutical formulation is administered orally. In some embodiments, the compound, composition, or pharmaceutical formulation is administered intravenously. In some embodiments, the compound, composition, or pharmaceutical formulation is administered intramuscularly. In some embodiments, the compound, composition, or pharmaceutical formulation is administered intranasally. In some embodiments, the compound, composition, or pharmaceutical formulation is administered subcutaneously. In some embodiments, the subject is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a non-adult human. In some embodiments, the subject is a non-human animal, such as domestic pets, livestock and farm animals, and zoo animals. In some embodiments, the non-human animal may be a non-human primate. Combination therapies In certain embodiments, the disclosure relates combination therapies for treating or preventing coronavirus infection, wherein the combination therapies include a compound, composition, or pharmaceutical formulation disclosed herein and at least another therapeutic agent. In some embodiments, the another therapeutic agent is a coronavirus antiviral. In some embodiments, the coronavirus antiviral is an inhibitor of coronavirus RNA-dependent RNA polymerase. In some embodiments, the coronavirus antiviral is an inhibitor of SARS-CoV-2 RNA- dependent RNA polymerase, such as molnupiravir, remdesivir, GS-441524, GS-621763, AT-527, EIDD-2749, and JT001 (VV116). In some embodiments, the coronavirus antiviral is molnupiravir. In some embodiments, the coronavirus antiviral is an inhibitor of a coronavirus protease. In some embodiments, the coronavirus antiviral is an inhibitor of SARS-CoV-2 M^pro or SARS-CoV-2 PL^pro, such as nirmatrelvir and ensitrelvir. Additional therapeutic agents that can be used in the combination therapies include the following: P-glycoprotein inhibitors, interferon (such as interferon alpha), pegylated interferon (such as PEG-Intron or Pegasus), dexamethasone, azithromycin; PLpro inhibitors, Apilomod, Ribavirin, Valganciclovir, ȕ-Thymidine, Aspartame, 2[SUHQRORO^^'R[\F\FOLQH^^$FHWRSKHQD]LQH^^,RSURPLGH^^5LERIODYLQ^^5HSURWHURO^^-^-ƍ-Cyclocytidine, Chloramphenicol, Chlorphenesin carbamate, Levodropropizine, Cefamandole, Floxuridine, Tigecycline, Pemetrexed, L(+)-Ascorbic acid, Glutathione, Hesperetin, Ademetionine, Masoprocol, Isotretinoin, Dantrolene, Sulfasalazine Anti-bacterial, Silybin, Nicardipine, Sildenafil, Platycodin, Chrysin, Neohesperidin, Baicalin, Sugetriol-3,9-GLDFHWDWH^^ ^í^-Epigallocatechin gallate, Phaitanthrin D, 2-(3,4-Dihydroxyphenyl)-2-[[2-(3,4-dihydroxyphenyl)-3,4-dihydro-5,7- dihydroxy-2H-1-benzopyran-3-yl]oxy]-3,4-dihydro-2H-1-benzopyran-3,4,5,7-tetrol, 2,2-di(3- indolyl)-3-indolone, (S)-(1 S,2R,4aS,5R,8aS)-1-Formamido-1,4a-dimethyl-6-methylene-5-((E)- 2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl-2-amino-3-phenylpropanoate, Piceatannol, Rosmarinic acid, Magnolol; Lymecycline, Chlorhexidine, Alfuzosin, Cilastatin, Famotidine, Almitrine, Progabide, Nepafenac, Carvedilol, Amprenavir, Tigecycline, Montelukast, Carminic acid, Mimosine, Flavin, Lutein, Cefpiramide, Phenethicillin, Candoxatril, Nicardipine, Estradiol valerate, Pioglitazone, Conivaptan, Telmisartan, Doxycycline, Oxytetracycline, (1 S,2R,4aS,5R,8aS)-1-Formamido-1,4a- dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2- yl5-((R)-1,2-dithiolan-3-yl) pentanoate, Betulonal, Chrysin-7-O-ȕ-glucuronide, Andrographiside, (1 S,2R,4aS,5R,8aS)-1-Formamido-1,4a-dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5- dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl 2-nitrobenzoate, 2ȕ-Hydroxy-3,4-seco- friedelolactone-27-oic acid (S)-(1 S,2R,4aS,5R,8aS)-1-Formamido-1,4a-dimethyl-6-methylene-5- ((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl) decahydronaphthalen-2-yl-2-amino-3- phenylpropanoate, Isodecortinol, Cerevisterol, Hesperidin, Neohesperidin, Andrograpanin, 2- ((1R,5R,6R,8aS)-6-Hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2- methylenedecahydronaphthalen-1-yl)ethyl benzoate, Cosmosiin, Cleistocaltone A, 2,2-Di(3- indolyl)-3-LQGRORQH^^%LRURELQ^^*QLGLFLQ^^3K\OODHPEOLQRO^^7KHDIODYLQ^-^-ƍ-di-O-gallate, Rosmarinic acid, Kouitchenside I, Oleanolic acid, Stigmast-5-en-3-ol, Deacetylcentapicrin, Berchemol; Valganciclovir, Chlorhexidine, Ceftibuten, Fenoterol, Fludarabine, Itraconazole, Cefuroxime, Atovaquone, Chenodeoxycholic acid, Cromolyn, Pancuronium bromide, Cortisone, Tibolone, Novobiocin, Silybin, Idarubicin Bromocriptine, Diphenoxylate, Benzylpenicilloyl G, Dabigatran etexilate, Betulonal, Gnidicin, 2,6,30,6-Dihydroxy-3,4-seco-friedelolactone-27- Iactone, 14-Deoxy-11,12-GLGHK\GURDQGURJUDSKROLGH^^*QLGLWULQ^^7KHDIODYLQ^-^-ƍ-di-O-gallate, (R)- ((1R,5aS,6R,9aS)-1,5a-Dimethyl-7-methylene-3-oxo-6-((E)-2-(2-oxo-2,5-dihydrofuran-3- yl)ethenyl)decahydro-1H-benzo[c]azepin-1-yl)methyl2-amino-3-phenylpropanoate, 2ȕ-Hydroxy- 3,4-seco-friedelolactone-27-oic acid, 2-(3,4-Dihydroxyphenyl)-2-[[2-(3,4-dihydroxyphenyl)-3,4- dihydro-5,7-dihydroxy-2H-1-benzopyran-3-yl]oxy]-3,4-dihydro-2H-1-benzopyran-3,4,5,7-tetrol, Phyllaemblicin B, 14-hydroxycyperotundone, Andrographiside, 2-((1R,5R,6R,8aS)-6-Hydroxy-5- (hydroxymethyl)-5,8a-dimethyl-2-methylenedecahydro naphthalen-1-yl)ethyl benzoate, Andrographolide, Sugetriol-3,9-diacetate, Baicalin, (1 S,2R,4aS,5R,8aS)-1-Formamido-1,4a- dimethyl-6-methylene-5-((E)-2-(2-oxo-2,5-dihydrofuran-3-yl)ethenyl)decahydronaphthalen-2-yl 5-((R)-1,2-dithiolan-3-yl)pentanoate, 1,7-Dihydroxy-3-methoxyxanthone, 1,2,6-Trimethoxy-8- [(6-O-ȕ-D-xylopyranosyl-ȕ-D-glucopyranosyl)oxy]-9H-xanthen-9-one, and 1,8-Dihydroxy-6- methoxy-2-[(6-O-ȕ-D-xylopyranosyl-ȕ-D-glucopyranosyl)oxy]-9H-xanthen-9-one, 8-(ȕ-D- Glucopyranosyloxy)-1,3,5-trihydroxy-9H-xanthen-9-one; and Diosmin, Hesperidin, MK-3207, Venetoclax, Dihydroergocristine, Bolazine, R428, Ditercalinium, Etoposide, Teniposide, UK-432097, Irinotecan, Lumacaftor, Velpatasvir, Eluxadoline, Ledipasvir, Lopinavir/Ritonavir+Ribavirin, Alferon, and prednisone. In some embodiments, a compound, composition, or pharmaceutical formulation disclosed herein is used in combination with another therapeutical agent selected from: antivirals such as remdesivir, galidesivir, favilavir/avifavir, molnupiravir (MK-4482/EIDD 2801), AT-527, AT-301, BLD-2660, favipiravir, camostat, SLV213 emtrictabine/tenofivir, clevudine, dalcetrapib, boceprevir and ABX464, glucocorticoids such as dexamethasone and hydrocortisone, convalescent plasma, a recombinant human plasma such as gelsolin (Rhu-p65N), monoclonal antibodies such as regdanvimab (Regkirova), ravulizumab (Ultomiris), VIR-7831/VIR-7832, BRII-196/BRII-198, COVI-AMG/COVI DROPS (STI-2020), bamlanivimab (LY-CoV555), mavrilimab, leronlimab (PRO140), AZD7442, lenzilumab, infliximab, adalimumab, JS 016, STI- 1499 (COVIGUARD), lanadelumab (Takhzyro), canakinumab (Ilaris), gimsilumab and otilimab, antibody cocktails such as casirivimab/imdevimab (REGN-Cov2), recombinant fusion protein such as MK-7110 (CD24Fc/SACCOVID), anticoagulants such as heparin and apixaban, IL-6 receptor agonists such as tocilizumab (Actemra) and sarilumab (Kevzara), PIKfyve inhibitors such as apilimod dimesylate, RIPK1 inhibitors such as DNL758, DC402234, VIP receptor agonists such as PB1046, SGLT2 inhibitors such as dapaglifozin, TYK inhibitors such as abivertinib, kinase inhibitors such as ATR-002, bemcentinib, acalabrutinib, losmapimod, baricitinib and tofacitinib, H2 blockers such as famotidine, anthelmintics such as niclosamide, furin inhibitors such as diminazene. EXAMPLES The examples below describe the synthesis and evaluation of exemplary non-covalent inhibitors of coronavirus main protease. General information for synthetic chemistry: All solvents and reagents were purchased from commercial suppliers and used without further purification. Analytical thin layer chromatography was carried out on silica pre-coated glass plates from Merck KGaA (silica gel 60 F254, 0.25 mm thickness) and visualized with UV light at 254 nm and/or with phosphomolybdic acid or iodine. Automated flash chromatography was performed on Teledyne ISCO CombiFlash Rf 200 system with RediSep Rf prepacked silica cartridges (60 Å, 40–63 -m particle size). Concentration refers to rotary evaporation under reduced pressure. 1H and ¹³C NMR spectra were recorded on Varian INOVA or VNMR spectrometer operating at 400 or 500 MHz at ambient temperature with CDCl3 or methanol-d4 as solvents. Data for ¹H NMR were recorded as follows: į chemical shift (ppm), multiplicity (s, singlet; d, doublet; dd = doublet of doublet; t, triplet; q, quartet; m, multiplet; br, broad), coupling constant (Hz), integration. Chemical shifts are reported in parts per million relative to internal reference CDCl₃ (¹H NMR: į 7.26; ¹³C NMR: į 77.16), methanol-d4 (¹H NMR, į 4.87, 3.31; ¹³C NMR, į^49.00), and TMS (¹H NMR: į 0.00). Liquid chromatography/mass spectrometry (LC-MS) data was obtained to verify molecular mass and analyze the purity of products. Typical specifications of the LC-MS instrument are the following: Agilent 1200 HPLC coupled to a 6120 quadrupole mass spectrometer (ESI-API), UV detection at 254 and 210 nm, Agilent Zorbax XDB-18 C18 column (50 mm × 4.6 mm, 3.5 μm), gradient mobile phase consisting of MeOH/water with 0.1 % formic acid, and a flow rate of 1.00 mL/min. The chemical purity of all final compounds was determined by LC-MS and confirmed to EH^-^--^^ High-resolution mass spectra (HRMS) were acquired on a VG 70-S Nier Johnson or JEOL mass spectrometer. Exemplary general procedures are described below. The experimental conditions for these general procedures may be optimized or adjusted for each compound. General Procedure A Into a 100 mL two-neck round-bottom flask containing argon was placed the respective phenol (1 eq) followed by DMF (15 mL per 500 mg), thus forming a clear to pale yellow solution. To this was added potassium carbonate (3 eq) and then the respective electrophile (R-CH₂-X, where X = Cl, Br or I) (1.3 eq). The reaction was heated to 60 qC for 18 hours, after which time analysis by LCMS typically indicated complete conversion of the starting material. The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL), and the phases were mixed and separated. The aqueous phase was extracted twice with EtOAc (2 × 100 mL), and then the combined organic fractions were washed with brine (100 mL), separated, and dried over anhydrous magnesium sulfate. After concentrating in vacuo, the crude material was purified by column chromatography (EtOAc/Hex) to afford the desired products as white to off-white solids. General Procedure B Into a two-neck 100 mL round-bottom flask filled with argon was placed respective phenol (1 eq) followed by CH₃CN (50 mL for 500 mg), the respective alcohol (1.4 eq), and finally triphenylphosphine (1.4 eq), typically forming a heterogenous mixture. This mixture was cooled to 0 qC, and then diisopropyl azodicarboxylate (1.4 eq) was added, often resulting in a homogeneous solution. The reaction was then heated to 55 qC and left to proceed under argon for 18 h. The reaction mixture was diluted with EtOAc (150 mL) and water (150 mL), and the phases were mixed and separated. The aqueous phase was extracted twice with EtOAc (2 × 150 mL), and then the combined organic fractions were washed with brine (150 mL), separated, and dried over anhydrous magnesium sulfate. After concentrating in vacuo, the crude material was purified by column chromatography (EtOAc/Hex) to afford the desired products as white to off-white solids. General Procedure C Into a 100 mL two-neck round-bottom flask containing argon was placed the methoxy pyridine derivative (1 eq) followed by dry MeCN (30 mL for 500 mg), thus forming a clear solution. To this mixture was added sodium iodide (3 eq) followed immediately by chlorotrimethylsilane (3 eq), thus forming a pale-yellow solution. The reaction mixture was heated to 60 qC for 30 min, after which time analysis by TLC revealed that all of the starting material had been consumed. After cooling, the reaction mixture was diluted with EtOAc (150 mL) and 5% sodium thiosulfate solution (150 mL). After thoroughly mixing, the phases were separated, and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organic fractions were then washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The crude material was purified by column chromatography (initially EtOAc/Hex, then 3% MeOH/EtOAc) to afford the desired pyridone products as white to off-white solids.

Example 1. Synthesis of 1-(3,5-dichlorophenyl)-5-(2-oxo-1,2-dihydropyridin-3-yl)-3- (pyridin

Scheme 1 Synthesis of 2,4-bis(benzyloxy)-5-(2-methoxypyridin-3-yl)pyrimidine [3] Into a 500 mL three-neck round-bottom flask fitted with a condenser, and filled with argon, was placed 3-bromo-2-methoxy-pyridine 1 (2.8 mL, 23 mmol) followed by DME (200 mL), thus forming a clear solution. To this was added (2,4-dibenzyloxypyrimidin-5-yl)boronic acid 2 (9.65 g, 28.7 mmol), which quickly dissolved, and then saturated sodium bicarbonate solution was added (150 mL), resulting in an immediate white precipitate forming. The solution was then degassed for 10 minutes by bubbling argon into the mixture, and then tetrakis(triphenylphosphine)palladium(0) (5.53 g, 4.79 mmol) was added in one portion. The reaction mixture was heated to reflux under argon, resulting in most of the white precipitate solubilizing and thus forming a yellow solution. The reaction was left to proceed for 6 hours at reflux, and the color changed to a darker orange color. After this time, it was cooled, poured into a separating funnel, and diluted with EtOAc (400 mL) and water (300 mL). After vigorously shaking, the layers were allowed to separate, and the organic layer was collected. The aqueous layer was extracted twice more with EtOAc (2 × 200 mL). The organic fractions were combined and dried over anhydrous magnesium sulfate and then filtered. After concentrating to ca 300 mL, this organic phase was pulled through a filter bed of silica gel. The silica bed was washed with ethyl acetate. The organic solution was then concentrated in vacuo, and the crude material was purified by column chromatography (EtOAc/Hex) to afford 2,4-dibenzyloxy-5-(2-methoxy-3-pyridyl)pyrimidine 3 (8.86 g, 22.2 mmol, 93% yield) as a white solid. Synthesis of 5-(2-methoxypyridin-3-yl)pyrimidine-2,4(1H,3H)-dione [4] Into a two-neck 500 mL round-bottom flask containing methanol (150 mL) and THF (150 mL) was placed 2,4-dibenzyloxy-5-(2-methoxy-3-pyridyl)pyrimidine 3 (8.10 g, 20.3 mmol) thus forming a clear solution, which was blanketed with argon. To this was then added 10% palladium on carbon (2.16 g, 20.3 mmol) in one portion. A balloon containing hydrogen was fitted to the flask and the flask was purged somewhat with hydrogen. The reaction was heated to 45 qC and was left to proceed for 10 h, after which time analysis by LCMS indicated that all of the starting material had been converted to the desired product. The reaction mixture was filtered through celite and concentrated in vacuo to afford 5-(2-methoxy-3-pyridyl)-1H-pyrimidine-2,4-dione 4 (4.10 g, 18.7 mmol, 92% yield) as a white solid. (Note that earlier attempts to purify this material by column chromatography proved very problematic due to precipitation on the material within the column). Synthesis of 1-(3,5-dichlorophenyl)-5-(2-methoxypyridin-3-yl)pyrimidine-2,4(1H,3H)- dione [7] A Schlenk tube was charged with 5-(2-methoxypyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 4 (483 mg, 2.20 mmol), followed by 1,3-dichloro-5-iodobenzene (500 mg, 1.83 mmol), K₃PO₄ (817 mg, 3.85 mmol), CuI (35 mg, 0.18 mmol) and N-(2-cyanophenyl)picolinamide 6 (50 mg, 0.22 mmol). The vessel was evacuated and back filled with argon. DMSO (13 mL) was added, and the reaction mixture was degassed for 15 min by bubbling argon into the solution. The reaction was stirred overnight at 60 qC. Once cooled, the reaction solution was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc (×3). The combined organic layers were then washed with Cu(OAc)2.H2O (x2), 15% NH4Cl (×2), brine and dried over MgSO4. After filtration and removal of solvent in vacuo, the crude material was purified using column chromatography (1-5% MeOH/DCM) to afford 1-(3,5-dichlorophenyl)-5-(2-methoxypyridin-3- yl)pyrimidine-2,4(1H,3H)-dione 7 (268 mg, 0.736 mmol, 40%) as a white solid. Synthesis of 1-(3,5-dichlorophenyl)-5-(2-methoxypyridin-3-yl)-3-(pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione [9] To a round-bottom flask was added 1-(3,5-dichlorophenyl)-5-(2-methoxypyridin-3- yl)pyrimidine-2,4(1H,3H)-dione 7 (250 mg, 0.687 mmol), followed by 3-pyridinyl boronic acid 8 (253 mg, 2.06 mmol) and DMSO (3 mL). Copper(II) acetate (125 mg, 0.687 mmol) was then added to the reaction solution, followed by TMEDA (0.23 mL, 1.5 mmol). The reaction mixture was stirred at 60 qC open to the atmosphere and monitored using LCMS. Once completed, EtOAc was added, and the solution was washed with H₂O (×2) and brine and dried over MgSO₄. Filtration was then followed by in vacuo removal of solvent and purification by column chromatography (EtOAc/Hex) to afford 1-(3,5-dichlorophenyl)-5-(2-methoxypyridin-3-yl)-3-(pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione 9 as a white solid (286 mg, 0.648 mmol, 95%). Synthesis of 1-(3,5-dichlorophenyl)-5-(2-oxo-1,2-dihydropyridin-3-yl)-3-(pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione [10] Reaction carried out according to General Procedure C using 1-(3,5-dichlorophenyl)-5-(2- methoxypyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 9 (270 mg, 0.614 mmol), NaI (230 mg, 1.53 mmol), TMSCl (166 mg, 1.53 mmol), acetonitrile (24 mL). Afforded 1-(3,5- dichlorophenyl)-5-(2-oxo-1,2-dihydropyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 10 as an off-white solid (162 mg, 0.379 mmol, 62%). Rf = 0.60 (15% MeOH/DCM); ¹H NMR (400 MHz, DMSO) į 11.92 (s, 1H), 8.69 (s, 1H), 8.62 (dd, J = 4.8, 1.6 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 7.1, 2.1 Hz, 1H), 7.84 (ddd, J = 8.1, 2.5, 1.5 Hz, 1H), 7.79 – 7.77 (m (app.t), 1H), 7.75 (d, J = 1.9 Hz, 2H), 7.57 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 7.38 (dd, J = 6.4, 2.1 Hz, 1H), 6.30 (dd, J = 7.1, 6.4 Hz, 1H).¹³C NMR (101 MHz, DMSO) į 161.6, 160.9, 149.6, 149.2, 143.0, 141.1, 140.2, 136.8, 134.5, 134.2 (2C), 132.7, 128.4, 126.2 (2C), 124.0, 121.4, 108.4, 105.1. HRMS: (APCI+) [M+H]⁺ calc. for C₂₀H₁₃Cl₂2^1₄, 427.0365, observed, 427.03592.

Example 2. Synthesis of 1-(3,5-dichlorophenyl)-5-(6-oxo-1,6-dihydropyridin-3-yl)-3- (pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione [16]

Scheme 2 Synthesis of 2,4-bis(benzyloxy)-5-(6-methoxypyridin-3-yl)pyrimidine [12] Into a 500 mL three-neck round-bottom flask fitted with a condenser, and filled with argon, was placed 5-bromo-2-methoxypyridine 11 (4.50 g, 23.9 mmol) followed by DME (200 mL), thus forming a clear solution. To this was added (2,4-dibenzyloxypyrimidin-5-yl)boronic acid 2 (9.70 g, 28.9 mmol), which quickly dissolved, and then saturated sodium bicarbonate solution was added (150 mL), resulting in an immediate white precipitate forming. The solution was then degassed for 10 minutes by bubbling argon into the mixture, and then tetrakis(triphenylphosphine)palladium(0) (5.50 g, 4.78 mmol) was added in one portion. The reaction mixture was heated to reflux under argon, resulting in most of the white precipitate solubilizing and thus forming a yellow solution. The reaction was left to proceed for 6 hours at reflux, and the color changed to a darker orange color. After this time, it was cooled, poured into a separating funnel, and diluted with EtOAc (400 mL) and water (300 mL). After vigorously shaking, the layers were allowed to separate, and the organic layer was collected. The aqueous layer was extracted twice more with EtOAc (2 × 200 mL). The organic fractions were combined and dried over anhydrous magnesium sulfate and then filtered. After concentrating to ca 300 mL, this organic phase was pulled through a filter bed of silica gel. The silica bed was washed with ethyl acetate. The organic solution was then concentrated in vacuo, and the crude material was purified by column chromatography (EtOAc/Hex) to afford 2,4-bis(benzyloxy)-5-(6-methoxypyridin-3-yl)pyrimidine (8.24 g, 20.6 mmol, 86%) as a white solid. Synthesis of 5-(6-methoxypyridin-3-yl)pyrimidine-2,4(1H,3H)-dione [13] Into a two-neck 500 mL round-bottom flask containing ethanol (150 mL) and THF (150 mL) was placed 2,4-bis(benzyloxy)-5-(6-methoxypyridin-3-yl)pyrimidine 12 (8.20 g, 20.5 mmol) thus forming a clear solution, which was blanketed with argon. To this was then added 10% palladium on carbon (0.218 g, 2.05 mmol) in one portion. A balloon containing hydrogen was fitted to the flask, and the flask was purged somewhat with hydrogen. The reaction was left to proceed for 18 h at room temperature, resulting in a white precipitate forming. The solids (precipitate and catalyst) were removed by filtration, and the filter cake was washed with DMSO in an attempt to recover the product. The DMSO washings were combined and cooled overnight, resulting in the precipitation of the product. This was filtered once again, and the filter cake was washed with MeOH/DCM to remove residual DMSO. Finally, the original filtrate was concentrated in vacuo, and all product solids combined to afford 5-(6-methoxypyridin-3- yl)pyrimidine-2,4(1H,3H)-dione 13 (1.25 g, 5.7 mmol, 27%) as a white solid. Synthesis of 1-(3-(benzyloxy)-5-chlorophenyl)-5-(6-methoxypyridin-3-yl)pyrimidine- 2,4(1H,3H)-dione [14] A Schlenk tube was charged with 5-(6-methoxypyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 13 (400 mg, 1.83 mmol), followed by 1,3-dichloro-5-iodobenzene (500 mg, 1.83 mmol), K₃PO₄ (818 mg, 3.85 mmol), CuI (35 mg, 0.18 mmol) and N-(2-cyanophenyl)picolinamide 6 (50 mg, 0.22 mmol). The vessel was evacuated and back filled with argon. DMSO (13 mL) was added, and the reaction mixture was degassed for 15 min by bubbling argon into the solution. The reaction was stirred overnight at 60 qC. Once cooled, the reaction solution was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc (×3). The combined organic layers were then washed with Cu(OAc)2.H2O (x2), 15% NH4Cl (×2), brine and dried over MgSO4. After filtration and removal of solvent in vacuo, the crude material was purified using column chromatography (1-5% MeOH/DCM) to afford 1-(3,5-dichlorophenyl)-5-(6-methoxypyridin-3- yl)pyrimidine-2,4(1H,3H)-dione 14 (230 mg, 0.632 mmol, 35%) as a white solid. Synthesis of 1-(3,5-dichlorophenyl)-5-(6-methoxypyridin-3-yl)-3-(pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione [15] To a round-bottom flask was added 1-(3,5-dichlorophenyl)-5-(6-methoxypyridin-3- yl)pyrimidine-2,4(1H,3H)-dione 14 (230 mg, 0.632 mmol), followed by 3-pyridinyl boronic acid 8 (777 mg, 6.32 mmol) and DMSO (5 mL). Copper(II) acetate (230 mg, 1.27 mmol) was then added to the reaction solution, followed by TMEDA (0.95 mL, 6.3 mmol). The reaction mixture was stirred at 60 qC open to the atmosphere, and monitored using LCMS. Once completed, EtOAc was added, and the solution was washed with H2O (×2) and brine and dried over MgSO4. Filtration was then followed by in vacuo removal of solvent and purification by column chromatography (EtOAc/Hex) to afford 1-(3,5-dichlorophenyl)-5-(6-methoxypyridin-3-yl)-3-(pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione 15 as a white solid (225 mg, 0.551 mmol, 81%). Synthesis of 1-(3,5-dichlorophenyl)-5-(6-oxo-1,6-dihydropyridin-3-yl)-3-(pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione [16] Reaction carried out according to General Procedure C using 1-(3,5-dichlorophenyl)-5-(6- methoxypyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 15 (200 mg, 0.455 mmol), NaI (170 mg, 1.14 mmol), TMSCl (123 mg, 1.14 mmol), acetonitrile (10 mL). Afforded 1-(3,5- dichlorophenyl)-5-(6-oxo-1,6-dihydropyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 16 as an off-white solid (181 mg, 0.425 mmol, 94%). Rf = 0.50 (10% MeOH/DCM). ¹H NMR (400 MHz, DMSO) į 11.80 (s, 1H), 8.62 (dd, J = 4.8, 1.5 Hz, 1H), 8.56 (dd, J = 2.5, 0.8 Hz, 1H), 8.19 (s, 1H), 7.84 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.79 (dd, J = 2.7, 0.8 Hz, 1H), 7.78 – 7.74 (m, 3H), 7.73 (d, J = 2.7 Hz, 1H), 7.57 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 6.37 (dd, J = 9.6, 0.7 Hz, 1H). ¹³C NMR (101 MHz, DMSO) į 161.7, 161.7, 149.7, 149.6, 149.3, 141.1, 140.8, 140.1, 136.8, 134.4, 134.1 (2C), 132.5, 128.3, 126.5 (2C), 124.1, 119.3, 110.3, 109.7. HRMS: (APCI+) [M+H]⁺ calc. for C20H13Cl2O3N4, 427.0365, observed, 427.03580.

Example 3. Synthesis of 1-(3-chloro-5-((5-methylthiazol-4-yl)methoxy)phenyl)-5-(6-oxo-1,6- dihydropyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione [23]

O Scheme 3 Synthesis of 1-(3-(benzyloxy)-5-chlorophenyl)-5-(6-methoxypyridin-3-yl)pyrimidine- 2,4(1H,3H)-dione [18] A Schlenk tube was charged with 5-(6-methoxypyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 13 (950 mg, 4.33 mmol), followed by 1-(benzyloxy)-3-chloro-5-iodobenzene 17 (1.24 g, 3.60 mmol), K₃PO₄ (1.60 mg, 7.54 mmol), CuI (70 mg, 0.37 mmol) and N-(2- cyanophenyl)picolinamide 6 (96 mg, 0.43 mmol). The vessel was evacuated and back filled with argon. DMSO (25 mL) was added, and the reaction mixture was degassed for 15 min by bubbling argon into the solution. The reaction was stirred overnight at 60 qC. Once cooled, the reaction solution was diluted with EtOAc and washed with water. The aqueous layer was then extracted with EtOAc (×3). The combined organic layers were then washed with Cu(OAc)₂.H2O (×2), 15% NH4Cl (×2), brine and dried over MgSO4. After filtration, the solution was concentrated in vacuo, and then DCM was added, resulting in the formation of a precipitate. This was collected and used without further purification to afford 1-(3-(benzyloxy)-5-chlorophenyl)-5-(6-methoxypyridin-3- yl)pyrimidine-2,4(1H,3H)-dione 18 (285 mg, 0.654 mmol, 18%) as an off-white solid. Synthesis of 1-(3-(benzyloxy)-5-chlorophenyl)-5-(6-methoxypyridin-3-yl)-3-(pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione [19] To a round-bottom flask was added 1-(3-(benzyloxy)-5-chlorophenyl)-5-(6- methoxypyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 18 (265 mg, 0.609 mmol), followed by 3- pyridinyl boronic acid 8 (749 mg, 6.09 mmol) and DMSO (6 mL). Copper(II) acetate (221 mg, 1.22 mmol) was then added to the reaction solution, followed by TMEDA (0.91 mL, 6.1 mmol). The reaction mixture was stirred at 60 qC open to the atmosphere, and monitored using LCMS. Once completed, EtOAc was added, and the solution was washed with H2O (×2) and brine and dried over MgSO4. Filtration was then followed by in vacuo removal of solvent and purification by column chromatography (EtOAc/Hex) to afford 1-(3-(benzyloxy)-5-chlorophenyl)-5-(6- methoxypyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 19 (270 mg, 0.526 mmol, 86%) as an off-white solid. Synthesis of 1-(3-chloro-5-hydroxyphenyl)-5-(6-methoxypyridin-3-yl)-3-(pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione [20] Into two-neck round-bottom flask containing argon was placed 11-(3-(benzyloxy)-5- chlorophenyl)-5-(6-methoxypyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (254 mg, 0.495 mmol) followed by methanol (3 mL) and THF (3 mL). With heating, the starting material was solubilized and remained in solution after cooling. To this was added Pd/C (11 mg, 0.099 mmol), and a balloon filled with hydrogen was fitted to the flask. The atmosphere in the flask was purged with hydrogen gas, and the reaction was left to proceed at 40 qC. After three hours, analysis by LCMS revealed that all of the starting material had been converted to the desired product, and the reaction mixture was filtered through celite and concentrated in vacuo to afford 1-(3-chloro-5- hydroxyphenyl)-5-(6-methoxypyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (177 mg, 0.419 mmol, 85%) as a white solid which was used without further purification or characterization other than LCMS. Synthesis of 1-(3-chloro-5-((5-methylthiazol-4-yl)methoxy)phenyl)-5-(6-methoxypyridin- 3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione [22] Carried out according to General Procedure A using 1-(3-chloro-5-hydroxyphenyl)-5-(6- methoxypyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 20 (177 mg, 0.419 mmol), 4- (chloromethyl)-5-methyl-1,3-thiazole hydrochloride 21 (154 mg, 0.839 mmol), K₂CO₃ (232 mg, 1.68 mmol), DMF (10 mL). Afforded 1-(3-chloro-5-((5-methylthiazol-4-yl)methoxy)phenyl)-5- (6-methoxypyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 22 (187 mg, 0.350 mmol, 71%) as a pale yellow solid. Rf = 0.25 (5% MeOH/DCM).¹H NMR (600 MHz, DMSO) į 8.90 (s, 1H), 8.62 (dt, J = 4.9, 1.5 Hz, 1H), 8.59 (dd, J = 1.5, 0.8 Hz, 1H), 8.43 (dd, J = 1.6, 0.9 Hz, 1H), 8.21 (s, 1H), 7.96 (dd, J = 8.8, 2.7 Hz, 1H), 7.89 – 7.84 (m, 1H), 7.57 (dd, J = 7.3, 4.8 Hz, 1H), 7.34 – 7.33 (m, 1H), 7.30 (s, 2H), 6.86 (d, J = 8.6, 0.8 Hz, 1H), 5.22 (s, 2H), 3.86 (s, 3H). ¹³C NMR (151 MHz, DMSO) į 162.9, 161.8, 159.4, 151.1, 149.8, 149.6, 149.2, 147.1, 146.1, 141.5, 140.7, 139.3, 136.8, 133.6, 133.3, 132.6, 124.0, 122.1, 119.8, 114.8, 113.3, 110.4, 109.8, 63.9, 53.3, 10.7. HRMS: (APCI+) [M+H]⁺ calc. for C26H21ClO4N5S, 534.1003, observed, 534.09955. Synthesis of 1-(3-chloro-5-((5-methylthiazol-4-yl)methoxy)phenyl)-5-(6-oxo-1,6- dihydropyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione [23] Carried out according to General Procedure C using 1-(3-chloro-5-((5-methylthiazol-4- yl)methoxy)phenyl)-5-(6-methoxypyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 22 (170 mg, 0.319 mmol), NaI (120 mg, 0.797 mmol), TMSCl (87 mg, 0.80 mmol), CH₃CN (8 mL). Afforded 1-(3-chloro-5-((5-methylthiazol-4-yl)methoxy)phenyl)-5-(6-oxo-1,6-dihydropyridin-3- yl)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 23 as an off-white solid ( 75 mg, 0.15 mmol).

Example 4. Synthesis of additional non-covalent inhibitors of coronavirus main protease

Scheme 4 Synthesis of ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate [48] Ethyl 2-chloro-4,4,4-trifluoro-3-oxo-butanoate 47 (2.00 g, 9.15 mmol, 1.44 mL) and thiourea (2.09 g, 27.5 mmol) were dissolved in DMF (12 mL) and heated to 120 °C for 5 hours. The reaction was allowed to cool to room temperature and diluted with EtOAc (100 mL). The organic phase was washed with deionized water (3 × 100 mL), followed by a wash with brine and dried over MgSO4. The solvent was reduced in vacuo, and the crude was purified over silica gel using EtOAc/hexanes as eluent to produce ethyl 2-amino-4-(trifluoromethyl)thiazole-5- carboxylate 48 (1.93 g, 88% yield) as a yellow solid. Synthesis of ethyl 4-(trifluoromethyl)thiazole-5-carboxylate [49] A solution of ethyl 2-amino-4-(trifluoromethyl)thiazole-5-carboxylate 48 (1.93 g, 8.02 mmol) in dioxane (23 mL) was heated to 90 °C. To this was added tert-butyl nitrite (2.4 mL, 18 mmol) dropwise, taking precautions due to the rapid evolution of nitrogen gas. After gas evolution had subsided, the reaction was allowed to stir for an additional 40 minutes and then cooled. The solvent was removed in vacuo, and the crude material was purified by column chromatography (EtOAc/Hex) to afford ethyl 4-(trifluoromethyl)thiazole-5-carboxylate 49 as a yellow liquid (1.11 g, 61% yield). Synthesis of [4-(trifluoromethyl)thiazol-5-yl]methanol [50] To a solution of ethyl 4-(trifluoromethyl)thiazole-5-carboxylate 49 (1.11 g, 4.92 mmol) in methanol (22 mL) and water (8 mL) was added CaCl₂ (0.710 g, 6.40 mmol). The solution was cooled to 0 °C after the complete dissolution of the solids, NaBH4 (0.483 g, 12.8 mmol) was added in portions. The reaction was allowed to stir at room temperature overnight, after which the reaction was naturalized by the addition of an aqueous saturated sodium bicarbonate solution. The product was extracted with DCM (2 × 100 mL), and the organic phase was washed with brine and dried over MgSO4. After filtration, the solvent was removed, and the crude [4- (trifluoromethyl)thiazol-5-yl]methanol 50 (0.900 g, 99% yield) was used in the next reaction without purification. Synthesis of (1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol [52] To a solution of ethyl 1-methyl-3-(trifluoromethyl)pyrazole-4-carboxylate 51 (0.500 mg, 2.25 mmol) in THF (11 mL) at 0 qC, was added LiAlH₄ (188 mg, 4.95 mmol) and the reaction was allowed to stir at that temperature for 3 h. The reaction was quenched with saturated sodium bicarbonate solution and washed with EtOAc (2 × 50 mL). The organic phase was washed with brine, dried over MgSO4, and the solvent reduced in vacuo to afford (1-methyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl)methanol 52 (367 mg, 91% yield) which was used without further purification in the next step. Synthesis of 1-(3-benzyloxy-5-chloro-phenyl)-5-(2-methoxy-3-pyridyl)pyrimidine-2,4- dione [24] Into a two-neck round-bottom flask containing argon was placed DMSO (40 mL) followed by 5-(2-methoxy-3-pyridyl)-1H-pyrimidine-2,4-dione 4 (2.00 g, 9.12 mmol), 1-benzyloxy-3- chloro-5-iodo-benzene (3.77 g, 11.0 mmol), N-(2-cyanophenyl)picolinamide 5 (0.24 g, 1.1 mmol) and potassium phosphate (4.07 g, 19.2 mmol), thus forming a brown suspension. This mixture was degassed by bubbling argon into the solvent for 10 min, and then copper(i) iodide (0.17 g, 0.91 mmol) was added against a flow of argon. The reaction mixture was heated to 60 qC, and the color of the mixture turned to very dark green. The reaction was left to proceed under argon at this temperature for three days. The reaction mixture was then diluted with EtOAc (200 mL) and water (500 mL). Upon mixing, a suspension was formed, which was broken by pulling the entire mixture through a pad of celite. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc (2 × 200 mL). The combined organic fractions were then dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo, and the crude material was purified by column chromatography (EtOAc/Hex) to afford 1-(3-benzyloxy-5-chloro-phenyl)-5- (2-methoxy-3-pyridyl)pyrimidine-2,4-dione 24 (1.84 g, 4.22 mmol, 46% yield) as a white solid. Synthesis of 1-(3-benzyloxy-5-chloro-phenyl)-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione [25] Into a 500 mL one-neck round-bottom flask containing 1-(3-benzyloxy-5-chloro-phenyl)- 5-(2-methoxy-3-pyridyl)pyrimidine-2,4-dione 24 (1.84 g, 4.22 mmol) was added 3- pyridylboronicacid 8 (1.56 g, 12.7 mmol), copper(II) acetate (1.15 g, 6.33 mmol), DMSO (20 mL) and finally TMEDA (1.27 mL, 8.44 mmol), forming a deep blue solution. This was stirred open to the atmosphere at 60 qC for 18 h after which analysis by LCMS indicated complete conversion of the starting material to the desired product. The reaction mixture was diluted with ethyl acetate (200 mL) and water (300 mL) and mixed vigorously. After separating the phases, the aqueous phase was extracted twice with EtOAc (2 × 200 mL), and the combined organic fractions were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/Hex) affording 1-(3-benzyloxy-5-chloro- phenyl)-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 25 (1.94 g, 3.78 mmol, 90% yield) as a white solid. Synthesis of 1-(3-chloro-5-hydroxy-phenyl)-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione [26] Into two-neck round-bottom flask containing argon was placed 1-(3-benzyloxy-5-chloro- phenyl)-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 25 (1.94 g, 3.78 mmol) followed by methanol (100 mL) and THF (100 mL). With heating, the starting material was solubilized and remained in solution after cooling. To this was added Pd/C (0.40 g, 0.38 mmol) and a balloon filled with hydrogen was fitted to the flask. The atmosphere in the flask was purged with hydrogen gas, and the reaction was left to proceed at 40 qC. After three hours, analysis by LCMS revealed that all of the starting material had been converted to the desired product so the reaction mixture was filtered through celite and concentrated in vacuo to afford 1-(3-chloro-5- hydroxy-phenyl)-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (1.38 g, 3.26 mmol, 86 % yield) as a white solid which was used without further purification. Synthesis of 1-[3-chloro-5-[(5-methylthiazol-4-yl)methoxy]phenyl]-5-(2-methoxy-3- pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione [27] Carried out according to General Procedure A using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (400 mg, 0.946 mmol) and 4- (chloromethyl)-5-methyl-thiazole hydrochloride (226 mg, 1.23 mmol) afforded 1-[3-chloro-5-[(5- methylthiazol-4-yl)methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 27 (372 mg, 0.697 mmol, 74 % yield) as an off-white solid. Synthesis of 1-[3-chloro-5-[(2-chlorophenyl)methoxy]phenyl]-5-(2-methoxy-3-pyridyl)- 3-(3-pyridyl)pyrimidine-2,4-dione [28] Carried out according to General Procedure A using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (400 mg, 0.946 mmol) and 1-chloro-2- (chloromethyl)benzene (0.14 mL, 1.1 mmol) afforded 1-[3-chloro-5-[(2- chlorophenyl)methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 28 (390 mg, 0.713 mmol, 75 % yield) as an off-white solid. Synthesis of 1-[3-chloro-5-[(2,4-dimethylthiazol-5-yl)methoxy]phenyl]-5-(2-methoxy-3- pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione [29] Carried out according to General Procedure A using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (300 mg, 0.710 mmol) and 5- (chloromethyl)-2,4-dimethyl-thiazole hydrochloride (169 mg, 0.851 mmol) afforded 1-[3-chloro- 5-[(2,4-dimethylthiazol-5-yl)methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione (328 mg, 0.599 mmol, 84% yield) as a white solid. Synthesis of 1-[3-chloro-5-(cyclopropylmethoxy)phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione [30] Carried out according to General Procedure A using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (400 mg, 0.946 mmol) and bromomethylcyclopropane (0.11 mL, 1.1 mmol) afforded 1-[3-chloro-5- (cyclopropylmethoxy)phenyl]-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 30 (352 mg, 0.738 mmol, 78% yield). Synthesis of 1-[3-chloro-5-[[1-(difluoromethyl)benzimidazol-2-yl]methoxy]phenyl]-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione [31] Carried out according to General Procedure A using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (300 mg, 0.710 mmol) and 2- (chloromethyl)-1-(difluoromethyl)benzimidazole hydrochloride (233 mg, 0.922 mmol) afforded 1-[3-chloro-5-[[1-(difluoromethyl)benzimidazol-2-yl]methoxy]phenyl]-5-(2-methoxy-3-pyridyl)- 3-(3-pyridyl)pyrimidine-2,4-dione 31 (411 mg, 0.682 mmol, 96% yield). Synthesis of 1-[3-chloro-5-[[1-(difluoromethyl)imidazol-2-yl]methoxy]phenyl]-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione [32] Carried out according to General Procedure A using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (172 mg, 0.407 mmol) and 2- (chloromethyl)-1-(difluoromethyl)imidazole hydrochloride (246 mg, 1.21 mmol) afforded 1-[3- chloro-5-[[1-(difluoromethyl)imidazol-2-yl]methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione 32 (149 mg, 0.270 mmol, 66% yield) as a yellow solid. Synthesis of 1-[3-chloro-5-[[4-(trifluoromethyl)thiazol-5-yl]methoxy]phenyl]-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione [33] Carried out according to General Procedure B using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (172 mg, 0.407 mmol) and [4- (trifluoromethyl)thiazol-5-yl]methanol (78.8 mg, 0.430 mmol) 50 afforded 1-[3-chloro-5-[[4- (trifluoromethyl)thiazol-5-yl]methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione 33 (152 mg, 0.259 mmol, 78% yield) as a white solid. Synthesis of 1-[3-chloro-5-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methoxy]phenyl]- 5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione [34] Carried out according to General Procedure B using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (100 mg, 0.237 mmol) and [1-methyl- 3-(trifluoromethyl)pyrazol-4-yl]methanol 52 (59.6 mg, 0.331 mmol) afforded 1-[3-chloro-5-[[1- methyl-3-(trifluoromethyl)pyrazol-4-yl]methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione 34 (54 mg, 0.10 mmol, 44% yield) as a white solid. Synthesis of 1-[3-chloro-5-(3,3,3-trifluoropropoxy)phenyl]-5-(2-methoxy-3-pyridyl)-3- (3-pyridyl)pyrimidine-2,4-dione [35] Carried out according to General Procedure B using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (100 mg, 0.237 mmol) and 3,3,3- trifluoropropan-1-ol (37 mg, 0.331 mmol) afforded 1-[3-chloro-5-(3,3,3- trifluoropropoxy)phenyl]-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 35 (107 mg, 0.206 mmol, 87% yield) as a white solid. Synthesis of 1-(3-chloro-5-((1-methyl-5-nitro-1H-imidazol-2-yl)methoxy)phenyl)-5-(2- methoxypyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4-dione [36] Carried out according to General Procedure A using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (250 mg, 0.591 mmol) and 2- (chloromethyl)-1-methyl-5-nitro-1H-imidazole hydrochloride (188 mg, 0.887 mmol) afforded 1- (3-chloro-5-((1-methyl-5-nitro-1H-imidazol-2-yl)methoxy)phenyl)-5-(2-methoxypyridin-3-yl)-3- (pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 36 (308 mg, 0.450 mmol, 93% yield) as a light brown solid. Synthesis of 1-[3-chloro-5-[(5-methylthiazol-4-yl)methoxy]phenyl]-5-(2-oxo-1H-pyridin- 3-yl)-3-(3-pyridyl)pyrimidine-2,4-dione [37] Carried out according to General Procedure C using 1-[3-chloro-5-[(5-methylthiazol-4- yl)methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 27 (372 mg, 0.697 mmol) afforded 1-[3-chloro-5-[(5-methylthiazol-4-yl)methoxy]phenyl]-5-(2-oxo-1H- pyridin-3-yl)-3-(3-pyridyl)pyrimidine-2,4-dione 37 (137 mg, 0.264 mmol, 38 % yield) as an off white solid.¹H NMR (400 MHz, DMSO) į 11.92 (s, 1H), 8.90 (s, 1H), 8.71 (s, 1H), 8.61 (dd, J = 4.8, 1.6 Hz, 1H), 8.57 (dd, J = 2.5, 0.8 Hz, 1H), 8.03 (dd, J = 7.1, 2.1 Hz, 1H), 7.85 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.57 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 7.38 (dd, J = 6.4, 2.1 Hz, 1H), 7.32 (d, J = 2.0 Hz, 2H), 7.25 (t, J = 2.1 Hz, 1H), 6.37 – 6.25 (m, 1H), 5.22 (s, 2H), 2.50 (s, 3H).¹³C NMR (101 MHz, DMSO) į 161.7, 160.9, 159.5, 151.1, 149.6, 149.5, 149.1, 147.0, 143.4, 141.1, 140.0, 136.8, 134.3, 133.8, 133.3, 132.8, 124.0, 121.4, 119.5, 114.9, 113.1, 108.0, 105.1, 63.9, 10.7. HRMS: (APCI+) [M+H]⁺ calc. for C25H19ClN5O4S, 520.08408, observed, 520.08437. Synthesis of 1-[3-chloro-5-[(2-chlorophenyl)methoxy]phenyl]-5-(2-oxo-1H-pyridin-3-yl)- 3-(3-pyridyl)pyrimidine-2,4-dione [38] Carried out according to General Procedure C using 1-[3-chloro-5-[(2- chlorophenyl)methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione (380 mg, 0.694 mmol) 28 afforded 1-[3-chloro-5-[(2-chlorophenyl)methoxy]phenyl]-5-(2-oxo-1H- pyridin-3-yl)-3-(3-pyridyl)pyrimidine-2,4-dione 38 (194 mg, 0.364 mmol, 52% yield).¹H NMR (400 MHz, DMSO) į 11.91 (s, 1H), 8.72 (s, 1H), 8.65 – 8.56 (m, 2H), 8.04 (dd, J = 7.1, 2.1 Hz, 1H), 7.85 (ddd, J = 8.1, 2.5, 1.5 Hz, 1H), 7.68 – 7.61 (m, 1H), 7.60 – 7.51 (m, 2H), 7.47 – 7.29 (m, 6H), 6.34 – 6.26 (m, 1H), 5.23 (s, 2H).¹³C NMR (101 MHz, DMSO) į 161.7, 160.9, 159.3, 149.6, 149.5, 149.1, 143.4, 141.2, 140.0, 136.8, 134.3, 133.9, 133.5, 132.9, 132.8, 130.6, 130.3, 129.5, 127.5, 124.0, 121.3, 119.8, 115.1, 112.9, 107.9, 105.1, 67.8. HRMS: (APCI+) [M+H]⁺ calc. for C27H19Cl2N4O4, 533.07779, observed, 533.07802. Synthesis of 1-[3-chloro-5-[(2,4-dimethylthiazol-5-yl)methoxy]phenyl]-5-(2-oxo-1H- pyridin-3-yl)-3-(3-pyridyl)pyrimidine-2,4-dione [39] Carried out according to General Procedure C using 1-[3-chloro-5-[(2,4-dimethylthiazol- 5-yl)methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 29 (328 mg, 0.599 mmol) afforded 1-[3-chloro-5-[(2,4-dimethylthiazol-5-yl)methoxy]phenyl]-5-(2-oxo-1H- pyridin-3-yl)-3-(3-pyridyl)pyrimidine-2,4-dione 39 (150 mg, 0.281 mmol, 47% yield) as a white solid.¹H NMR (400 MHz, DMSO) į 11.92 (s, 1H), 8.71 (s, 1H), 8.62 (dd, J = 4.8, 1.5 Hz, 1H), 8.57 (dd, J = 2.5, 0.8 Hz, 1H), 8.03 (dd, J = 7.2, 2.1 Hz, 1H), 7.85 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.57 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 7.38 (dd, J = 6.4, 2.1 Hz, 1H), 7.33 (t, J = 1.8 Hz, 1H), 7.28 (t, J = 2.1 Hz, 1H), 7.23 (t, J = 2.1 Hz, 1H), 6.30 (dd, J = 7.2, 6.4 Hz, 1H), 5.30 (s, 2H), 2.58 (s, 3H), 2.33 (s, 3H).¹³C NMR (101 MHz, DMSO) į 164.6, 161.7, 160.9, 158.9, 150.6, 149.6, 149.5, 149.2, 143.4, 141.1, 140.0, 136.8, 134.3, 133.9, 132.8, 124.9, 124.0, 121.3, 119.8, 115.1, 113.3, 108.0, 105.1, 62.2, 18.8, 14.8. HRMS: (APCI+) [M+H]⁺ calc. for C26H21ClN5O4S, 534.09973, observed, 534.10008. HRMS: (APCI+) [M+H]⁺ calc. for C26H21ClN5O4S, 534.09973, observed, 534.10008. Synthesis of 1-[3-chloro-5-(cyclopropylmethoxy)phenyl]-5-(2-oxo-1H-pyridin-3-yl)-3-(3- pyridyl)pyrimidine-2,4-dione [40] Carried out according to General Procedure C using 1-[3-chloro-5- (cyclopropylmethoxy)phenyl]-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 30 (352 mg, 0.738 mmol) afforded 1-[3-chloro-5-(cyclopropylmethoxy)phenyl]-5-(2-oxo-1H- pyridin-3-yl)-3-(3-pyridyl)pyrimidine-2,4-dione 40 (88 mg, 0.19 mmol, 26% yield) as a white solid.¹H NMR (400 MHz, DMSO) į 11.90 (s, 1H), 8.71 (s, 1H), 8.62 (dd, J = 4.8, 1.6 Hz, 1H), 8.59 – 8.52 (m, 1H), 8.04 (dd, J = 7.2, 2.1 Hz, 1H), 7.85 (ddd, J = 8.1, 2.5, 1.5 Hz, 1H), 7.57 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 7.37 (dd, J = 6.4, 2.1 Hz, 1H), 7.26 (t, J = 1.8 Hz, 1H), 7.15 (p, J = 2.3 Hz, 2H), 6.30 (dd, J = 7.1, 6.4 Hz, 1H), 3.89 (d, J = 7.1 Hz, 2H), 1.30 – 1.13 (m, 1H), 0.64 – 0.51 (m, 2H), 0.37 – 0.29 (m, 2H).¹³C NMR (101 MHz, DMSO) į 162.1, 161.4, 160.2, 150.0, 150.0, 149.5, 143.9, 141.6, 140.4, 137.4, 134.7, 134.3, 133.2, 124.5, 121.8, 119.5, 115.3, 113.1, 108.3, 105.6, 73.5, 10.3, 3.6. HRMS: (APCI+) [M+H]⁺ calc. for C24H20ClN4O4, 463.11676, observed, 463.11671. Synthesis of 1-[3-chloro-5-[[1-(difluoromethyl)benzimidazol-2-yl]methoxy]phenyl]-5-(2- oxo-1H-pyridin-3-yl)-3-(3-pyridyl)pyrimidine-2,4-dione [41] Carried out according to General Procedure C using 1-[3-chloro-5-[[1- (difluoromethyl)benzimidazol-2-yl]methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione 31 (400 mg, 0.663 mmol) afforded 1-[3-chloro-5-[[1- (difluoromethyl)benzimidazol-2-yl]methoxy]phenyl]-5-(2-oxo-1H-pyridin-3-yl)-3-(3- pyridyl)pyrimidine-2,4-dione 41 (182 mg, 0.309 mmol, 47% yield) as a white solid.¹H NMR (400 MHz, DMSO) į 11.93 (s, 1H), 8.69 (s, 1H), 8.65 – 8.55 (m, 2H), 8.36 – 7.99 (m, 2H), 7.85 (dt, J = 8.2, 1.8 Hz, 1H), 7.77 (dd, J = 14.2, 7.9 Hz, 2H), 7.57 (dd, J = 8.1, 4.8 Hz, 1H), 7.50 – 7.30 (m, 6H), 6.30 (t, J = 6.8 Hz, 1H), 5.62 (s, 2H).¹³C NMR (101 MHz, DMSO) į 161.7, 161.0, 158.5, 149.6, 149.5, 149.2, 147.5, 143.4, 141.9, 141.1, 140.1, 136.8, 134.4, 133.9, 132.8, 131.4, 125.1, 124.1, 124.0, 121.3, 120.4, 115.1, 113.4, 112.2, 109.6, 108.0, 105.1, 63.2, 18.6. HRMS: (APCI+) [M+H]⁺ calc. for C29H20ClF2N6O4, 589.11971, observed, 589.12008. Synthesis of 1-[3-chloro-5-[[1-(difluoromethyl)imidazol-2-yl]methoxy]phenyl]-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione [42] Carried out according to General Procedure C using 1-[3-chloro-5-[[1- (difluoromethyl)imidazol-2-yl]methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione 32 (128 mg, 0.232 mmol) afforded 1-[3-chloro-5-[[1- (difluoromethyl)imidazol-2-yl]methoxy]phenyl]-5-(2-oxo-1H-pyridin-3-yl)-3-(3- pyridy1)pyrimidine-2, 4-dione 42 ( 120 mg, 0.223 mmol, 96% yield) as an off white solid. ¹H NMR (400 MHz, d6-DMSO) 0 11.93 (s, 1H), 8.70 (s, 1H), 8.61 (dd, J = 4.8, 1.6 Hz, 1H), 8.57 (dd, J = 2.5, 0.7 Hz, 1H), 8.03 (dd, J T 2.1 Hz, 1H), 7.93 (t, J ------ 58.8 Hz, 1H), 7.85 (ddd, ./== 8. 1, 2 5, 1.6 Hz, IH), 7.69 (d, .7= 1.6 Hz, 1H), 7.57 (ddd, .7 = 8.1, 4.8, 0.8 Hz, 1H), 7.38 (dd, J= 6.4, 2.1 Hz, H I). 7.36 (t, J ----- 1.9 Hz, IH), 7.3.3 (t . ./ 2.1 Hz, IH), 7.26 2.1 Hz, H I). 7.13 (d, J ------ 1.6

Hz, IH), 6.30 (dd, ,7 = 7.1, 6.4 Hz, 1H), 5.37 (s, 2H) ppm; ¹⁹F NMR (376 MHz, d6-DMSO) 5 - 92.49 (d, J --"- 58.6 Hz, 2F) ppm; ⁱ³C NMR (.101 MHz, d6-DMSO) 8 161.7, 161.0, 158.6, 149.6, 149.5. 149.1, 14.3.3, 142.0, 141.1, 140.0, 136.8, 134.4, 133.8, 132.7, 129.4, 124.0, 121.3, 120.2, 117.7, 115.0, 113.3, 108.4 (t, .7 = 248.4 Hz), 108.0, 105.1, 62.4 ppm; HRMS (APCI) m/z: [M + H]⁺ Calcd for C25H18O4CIF2N6 539.1041; Found 539.1044.

Synthesis of l-(3-chloro-5-((4-(trifluoromethyl)thiazol-5-yl)methoxy)phenyl)-5-(2-oxo- l,2-dihydropyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2, 4-dione [4.3]

Carried out according ttoo General Procedure C using l-[3-chloro-5-[[4-

(trifluoromethyl)thiazol-5-yl]methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2, 4-dione 33 (152 mg, 0.259 mmol) afforded l-(3-chloro-5-((4-

(trifluoromethyl)thiazol-5-yl)methoxy)phenyl)-5-(2-oxo-l,2-dihydropyridin-3-yl)-3-(pyri din-3- yj)pyrimidine-2, 4-dione 43 ( 100 mg, 0.174 mmol, 67% yield) as a. white solid, NMR (500 MHz, dmso) 8 11.91 (s, 1H), 9.27 (s, 1H), 8.70 (s, IH), 8.62 (dd, ,7 = 4.8, 1.6 Hz, IH), 8.57 (dd, J --- 2.4, 0.8 Hz, IH), 8.03 (dd, J 7.1, 2.1 Hz, I H), 7.84 (ddd. J ------ 8.1, 2.5, 1.6 Hz, H I). 7.57 (ddd, .7 = 8.1, 4.8, 0.8 Hz, 1H), 7.40 - 7.33 (m, 3H), 7.31 (t, .7 = 2.1 Hz, IH), 6.30 (dd, .7 = 7.2, 6.4 Hz, HI), 5.62 - 5.57 (m, 2H). ^!3C NMR (15 I MHz, DMSO) 6 161.7, 160.9, 158.4, 156.4, 149.6, 149.5, 149.1, 143.3, 141.2, 134.0, 139.7, 139.5, 139.3, 139.0, 137.6, 137.6, 136.8, 134.3, 134.0, 132.7, 124.0, 123.8, 122.0, 121.3, 120.4, .120.2, 118.4, 115.1 , 113.3, 108.0, 105.1, 61.7. ¹⁹F NMR (565 MHz, DMSO) 5 -59.62. HRMS (APCI) m/z calculated for C₂₃H₁₆O₄N₅ ³⁵ClF₃ ³²S [M+H]⁺" 574.0558 found 574.0556.

Synthesis ooff l-(3-chloro-5-((l-methyl-3-(trifluoromethy1)-lH-pyrazol-4- yl)methoxy)phenyl)-5-(2-oxo-l,2-dihydropyridin-3-yI)-3-(pyridin-3-yl)pyrimidine-2, 4-dione [44]

Carried out according to General Procedure C using l-[3-chtoro-5-[[l -methyl-3- (trifluoromethyl)pyrazol-4-yl]methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2, 4-dione 34 (134 mg, 0.229 mmol) afforded l-(3-chloro-5-((l-methyl-3- (trifluoromethyl)-lH-pyrazol-4-yl)m ethoxy )phenyl)-5-(2-oxo- 1,2-dihydropyridin-3-yl)-3- (pyridin-3-yl)pyrimidine-2,4-dione 44 (75 mg, 0.13 mmol, 57%) as a white solid.¹H NMR (600 MHz, DMSO) į^--^--^^s, 1H), 8.73 (d, J = 1.8 Hz, 1H), 8.61 (dd, J = 4.3, 2.2 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H), 8.13 – 8.09 (m, 1H), 8.04 (dt, J = 7.2, 2.0 Hz, 1H), 7.85 (dq, J = 8.2, 1.9 Hz, 1H), 7.57 (ddd, J = 7.0, 5.0, 1.6 Hz, 1H), 7.38 (dt, J = 6.5, 2.0 Hz, 1H), 7.31 (q, J = 1.9 Hz, 1H), 7.24 (dq, J = 8.4, 2.1 Hz, 2H), 6.30 (td, J = 6.8, 1.7 Hz, 1H), 5.10 (s, 2H), 3.92 (d, J = 1.7 Hz, 3H).¹³C NMR (151 MHz, DMSO) į^---^-^^---^-^^---^-^^---^-^^---^-^^---^-^^---^-^^---^-^^---^-^^---^-^^ 138.3, 136.8, 134.4, 134.2, 133.9, 132.7, 124.0, 122.5, 121.2, 120.7, 119.6, 115.1, 114.5, 112.8, 107.9, 105.1, 60.0. HRMS ^$3&,^^P^]^FDOFXODWHG^IRU^&^^+^^2^1^ñ^&O)^^>0-+@⁺ 571.1103 found 571.1105.¹⁹F NMR (565 MHz, DMSO) į^-59.47. Synthesis of 1-[3-chloro-5-(3,3,3-trifluoropropoxy)phenyl]-5-(2-oxo-1H-pyridin-3-yl)-3- (3-pyridyl)pyrimidine-2,4-dione [45] Carried out according to General Procedure C using 1-[3-chloro-5-(3,3,3- trifluoropropoxy)phenyl]-5-(2-methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 35 (500 mg, 0.964 mmol) afforded 1-[3-chloro-5-(3,3,3-trifluoropropoxy)phenyl]-5-(2-oxo-1H-pyridin-3- yl)-3-(3-pyridyl)pyrimidine-2,4-dione 45 (318 mg, 0.630 mmol, 65% yield) as a white solid.¹H NMR (400 MHz, DMSO) į 11.90 (s, 1H), 8.70 (s, 1H), 8.61 (dd, J = 4.8, 1.5 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.03 (dd, J = 7.1, 2.1 Hz, 1H), 7.84 (ddd, J = 8.1, 2.5, 1.5 Hz, 1H), 7.61 – 7.53 (m, 1H), 7.40 – 7.34 (m, 1H), 7.32 (t, J = 1.8 Hz, 1H), 7.25 – 7.18 (m, 2H), 6.29 (t, J = 6.8 Hz, 1H), 4.29 (t, J = 5.9 Hz, 2H), 2.82 (qt, J = 11.4, 5.8 Hz, 2H).¹³C NMR (151 MHz, DMSO) į 161.66, 160.91, 158.94, 149.60, 149.49, 149.10, 143.39, 141.14, 139.97, 136.77, 134.28, 133.94, 132.72, 126.62 (q, JC-F = 277.0 Hz), 123.97, 121.35, 119.74, 114.78, 112.83, 107.91, 105.06, 61.85 (d, JC- _F = 4.0 Hz), 32.61 (q, J_C-F = 28.0 Hz). HRMS: (APCI+) [M+H]⁺ calc. for C₂₃H₁₇ClF₃N₄O₄, 505.08849, observed, 505.08853. Synthesis of 1-(3-chloro-5-((1-methyl-5-nitro-1H-imidazol-2-yl)methoxy)phenyl)-5-(2- oxo-1,2-dihydropyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4-dione [46] Carried out according to General Procedure C using 1-(3-chloro-5-((1-methyl-5-nitro-1H- imidazol-2-yl)methoxy)phenyl)-5-(2-methoxypyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4-dione 36 (160 mg, 0.285 mmol) afforded 1-(3-chloro-5-((1-methyl-5-nitro-1H-imidazol-2- yl)methoxy)phenyl)-5-(2-oxo-1,2-dihydropyridin-3-yl)-3-(pyridin-3-yl)pyrimidine-2,4-dione 46 (57 mg, 0.10 mmol, 37% yield) as an off white solid. Rf = 0.50 (10% MeOH/DCM).¹H NMR (400 MHz, DMSO) į 11.92 (br s, 1H), 8.69 (s, 1H), 8.61 (dd, J = 4.8, 1.6 Hz, 1H), 8.57 (dd, J = 2.4, 0.8 Hz, 1H), 8.10 (s, 1H), 8.02 (dd, J = 7.2, 2.1 Hz, 1H), 7.85 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.57 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 7.41 – 7.34 (m, 3H), 7.32 – 7.27 (m (app. t), 1H), 6.30 (dd, J = ¹ , , r - ( l

Scheme 5 Synthesis of ethyl 5-iodothiazole-4-carboxylate [54] Into a 100mL two-neck, flame-dried, round-bottom flask containing a solution of tert- butylnitrite (1.8 mL, 15 mmol) and DMSO (0.07 mL, 1.01 mmol) in THF (15 mL) at 30 °C under argon, was added ethyl 2-amino-5-iodo-thiazole-4-carboxylate 53 (3.0 g, 10 mmol) portionwise. The mixture was stirred at 30 °C for approximately 2 hours, at which point TLC confirmed complete consumption of the starting material. The solvent was then evaporated in vacuo, and the resultant crude material was purified by column chromatography (EtOAc/Hex) to afford ethyl 5- iodothiazole-4-carboxylate 54 (1.88 g, 6.64 mmol, 66% yield) as an orange solid. Synthesis of ethyl 5-(trifluoromethyl)thiazole-4-carboxylate [55] To a 75mL round-bottom pressure vessel charged with ethyl 5-iodothiazole-4-carboxylate 54 (1.88 g, 6.64 mmol) and DMF (25 mL) was added methyl 2,2-difluoro-2-fluorosulfonyl-acetate (1.7 mL, 13 mmol), followed by copper (I) iodide (2.53 g, 13.3 mmol). The pressure vessel was sealed, and the reaction mixture was stirred at 85 °C for 18 h. The reaction mixture was cooled to room temperature, taken up in ether, and filtered through a pad of celite. The filtrate was then washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue obtained was purified by column chromatography (EtOAc/Hex) to give the ethyl 5- (trifluoromethyl)thiazole-4-carboxylate 55 (919 mg, 4.08 mmol, 62% yield) as a yellow solid. Synthesis of [5-(trifluoromethyl)thiazol-4-yl]methanol [56] To a solution of ethyl 5-(trifluoromethyl)thiazole-4-carboxylate 55 (0.81 g, 3.59 mmol) in ethanol (12 mL) and water (3 mL) was added calcium chloride (518 mg, 4.66 mmol). Once all solid particles had dissolved, the solution was cooled to 0 °C, and sodium borohydride (353 mg, 9.33 mmol) was added portionwise. The reaction was then left to stir at room temperature for 18h, after which the reaction was quenched with a saturated NaHCO3 solution. The product was extracted three times into DCM, and the organic phases were combined, washed with brine, and dried over MgSO₄. After filtration, the solvent was removed in vacuo, and the crude product [5- (trifluoromethyl)thiazol-4-yl]methanol 56 (524 mg, 2.86 mmol) was used in the next reaction without further purification. Synthesis of 1-[3-chloro-5-[[5-(trifluoromethyl)thiazol-4-yl]methoxy]phenyl]-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione [57] Carried out according to General Procedure B using 1-(3-chloro-5-hydroxy-phenyl)-5-(2- methoxy-3-pyridyl)-3-(3-pyridyl)pyrimidine-2,4-dione 26 (900 mg, 2.13 mmol) and [5- (trifluoromethyl)thiazol-4-yl]methanol (507 mg, 2.77 mmol) 56 afforded 1-[3-chloro-5-[[5- (trifluoromethyl)thiazol-4-yl]methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione 57 (1.17 g, 1.99 mmol) as a crude white solid which was carried forward without further purification. Synthesis of 1-[3-chloro-5-[[5-(trifluoromethyl)thiazol-4-yl]methoxy]phenyl]-5-(2-oxo- 1H-pyridin-3-yl)-3-(3-pyridyl)pyrimidine-2,4-dione [58] Carried out according to General Procedure C using 1-[3-chloro-5-[[5- (trifluoromethyl)thiazol-4-yl]methoxy]phenyl]-5-(2-methoxy-3-pyridyl)-3-(3- pyridyl)pyrimidine-2,4-dione 57 (500 mg, 0.85 mmol) afforded 1-[3-chloro-5-[[5- (trifluoromethyl)thiazol-4-yl]methoxy]phenyl]-5-(2-oxo-1H-pyridin-3-yl)-3-(3- pyridyl)pyrimidine-2,4-dione 58 (293 mg, 0.511 mmol, 60% yield) as a white solid.¹H NMR (400 MHz, DMSO-d6) į^--^--^^s, 1H), 9.43 (s, 1H), 8.71 (s, 1H), 8.64 – 8.54 (m, 2H), 8.02 (dd, J = 7.1, 2.1 Hz, 1H), 7.84 (ddd, J = 8.1, 2.5, 1.6 Hz, 1H), 7.57 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 7.35 (m, 3H), 7.27 (t, J = 2.1 Hz, 1H), 6.29 (dd, J = 7.1, 6.4 Hz, 1H), 5.39 (d, J = 1.4 Hz, 2H).¹³C NMR (151 MHz, DMSO-d6) į^---^-^^---^9, 159.0, 157.7, 152.6 (q, JCF = 2.4 Hz), 149.6, 149.5, 149.1, 143.3, 141.1, 140.0, 136.8, 134.3, 133.9, 132.7, 124.0 (q, JCF = 37.5 Hz), 124.0, 122.3 (q, JCF = 269.8 Hz), 121.4, 120.0, 114.8, 113.1, 108.0, 105.1, 64.0. ¹⁹F NMR (376 MHz, DMSO-d6) į^-51.60. HRMS: (APCI+) [M+H]⁺ calc. for C₂₄H₂₀ClN₄O₄, 574.05581, observed, 574.05631. Example 6. Enzymatic assay and computational modeling A. Materials and methods SARS-CoV-2 M^pro inhibition assay The SARS-CoV-2 M^pro inhibition assay was performed by Reaction Biology using the protocol described below. Reaction Buffer: 50 mM Tris-HCl pH 7.3, 1 mM EDTA, 0.005% Triton X-100, 1% DMSO, and 1 mM DTT. SARS-CoV-2 M^pro (3CL^pro): RBC product, MSC-11-519, recombinant protease (GenBank accession: QHD43415, aa3264-3569) expressed in E. coli with no tag, MW = 33.8 kDa. Substrate: Covidyte ED450, AAT Bioquest Cat# 13538, [NH₂- C(EDANS)VNSTQSGLRK(DABCYL)M-COOH] FRET peptide substrate, MW = 2,034 Da, 5 PM in the reaction. Control: GC376. Measurement: EnVision (PE), E_x/E_m 340/492 nm. Reaction Procedure: (1) prepare indicated enzyme and substrate in freshly prepared Reaction Buffer; (2) deliver enzyme solution into the reaction well; (3) deliver compounds in DMSO into the reaction mixture by using Acoustic Technology (Echo 550, LabCyte Inc. Sunnyvale, CA) in nanoliter range; (4) after 20 min pre-incubation, deliver substrate solution into the reaction well to initiate the reaction; (5) the enzyme activities were monitored every 5 min as a time-course measurement of the increase in fluorescence signal from fluorescently-labeled peptide substrate for 120 min at room temperature; (6) analyze data by taking slope (signal/time) of linear portion of measurement; and (7) slope is calculated using Excel, and curve fits are performed using Prism software. The IC₅₀ curve fittings were performed using GraphPad Prism 4 software with four parameters fit using the following formula. Prism setting: four parameters sigmoidal dose-response (variable slope), constraint; Bottom = 0, Top less than 120. Curve fittings were performed when the % enzyme activities at the highest concentration of compounds were less than 65%. Y = Bottom + (Top - Bottom)/(1 + 10-((LogIC₅₀-X)*HillSlope)) Computational modeling Free Energy Perturbation (FEP) modeling was performed with the Schrödinger molecular modeling software using methods described in Zhang, et al., ACS Central Science, 2021, 7(3), 467. Relative free energies of binding, ǻǻG, were obtained by mutating a control ligand from Zhang, et al., ACS Central Science, 2021, 7(3), 467 (structure shown below) to each of the test compounds.

Control ligand from Zhang et al. (denoted as LJ-Mpro-019) B. Results Table 1 shows (1) the IC50 values of the test compounds against SARS-CoV-2 M^pro and (2) the calculated relative free energies of binding, ǻǻG, of the test compounds. There is an excellent correlation between the experimental (IC₅₀ values) and calculated (ǻǻG) results, demonstrating the utility of FEP modeling in the SARS-CoV-2 M^pro system. Notably, the FEP calculations showed that replacing the pyridine moiety (

pyridazine ( ^N ) resulted in a lower ǻǻG, which represents a tighter binding. See, for example, the comparison between SCP-Mpro-051 and SCP-Mpro-051-pyridazine shown in Table 1. Table 1. IC₅₀ for SARS-CoV-2 M^pro inhibition and relative free energies of binding

The binding posts of various compounds in the active site of SARS-CoV-2 M^pro were calculated and compared. Some compounds had an R₂ pyridone group instead of an R₂ uracil group. FEP calculations showed that certain compounds with the R2 pyridone group had more energetically favorable binding to SARS-CoV-2 M^pro than with the R₂ uracil group. Notably, a compound with 3-pyridone is an isomer of a compound with 5-pyridone (isomerization). The compound with 3-pyridone was calculated to be superior in SARS-CoV-2 M^pro binding due to a more stable H-bonding network with the active site of SARS-CoV-2 M^pro. Example 7. Bioanalytical studies A. Materials and methods Nephelometry Nephelometry experiments were performed using untreated CORNING® COSTAR® 96-well black polystyrene plates with clear flat bottoms. Sample stock solutions and serial dilutions were prepared with DRISOLV® DMSO purchased from MilliporeSigma. All 100-fold dilutions and replicate experiments were prepared using GIBCO® Dulbecco’s phosphate-buffered saline (DPBS) with a pH range of 7.0–7.3 as aqueous medium. Incubation of the 96-well plates was achieved with a Benchmark Incu-Shaker Mini Shaking Incubator. Nephelometry data was obtained using a NEPHELOSTAR® microplate reader and processed with the MARS data analysis s

. Tested compounds were dissolved in 100% DMSO to make stock solutions of specified concentrations, ranging from 10 mM minimum up to 75 mM maximum. The sample then underwent serial dilution in a 96-well plate. Well A1 of the plate contained 100% DMSO. Wells A2-A12 possessed the test compound in DMSO with concentration factors as follows (prepared via serial dilution with DMSO): X mM for A2, (0.8)X mM for A3, (0.6)X mM for A4, (0.4)X mM for A5, (0.2)X mM for A6, (0.1)X mM for A7, (0.05)X mM for A8, (0.025)X mM for A9, (0.0125)X mM for A10, (0.00625)X mM for A11, and (0.003125)X mM for A12. Using a 12- channel multichannel pipette, 2.5 -L of sample from row A was transferred to each well in row B through row H of the plate. Next, 30 -L of DPBS was added to row B through row H, providing each well with 32.5 -L. The plate was then incubated for 30 sec with shaking. Finally, 217.5 PL of DPBS buffer was added to row B through row H, and the entire plate was incubated with shaking at 25 °C for 90 min. The final volume of DMSO in actual experiments with the DPBS buffer is 1% throughout the plate. After 90 min, the 96-well plate was analyzed with the NEPHELOSTAR® instrument and the data was processed with the MARS data analysis software. Plasma stability assay Procaine and procainamide were purchased from Sigma Aldrich. HPLC-grade acetonitrile, water, methanol, and formic acid were purchased from Fisher Scientific. Human plasma (Cat. No. HUMANPLLHP2N) was obtained from BIOIVT, and PBS (1× Dulbecco’s, pH 7.4) from Thermo Fisher Scientific. Test compounds were dissolved in DMSO to make a stock solution of 10 mM and then diluted to 500 -M in buffer or 70% methanol. Human plasma was thawed at ambient temperature and aliquoted (994.0 -L) to a 1.5 mL Eppendorf tube in duplicates (vials A and B) for each compound. The plasma was incubated at 37 °C for 10 min in an incubator shaker at 150 RPM; the reaction was initiated by addition of the test compound (6.0^PL), followed by vortex mixing. The total reaction volume was 1000 ^PL, the final organic solvent concentrations were 0.6% methanol (when 70% methanol was used for dilution) and 0.03% DMSO, and the final concentration of the test compound was 3 -M. The spiked plasma samples were incubated at 37 °C for 4 h. The reactions were terminated at time point 0, 15, 30, 60, 120, 180, and 240 min by taking a 100 PL aliquot from the test incubation mixture and immediately quenching it by adding it into ice-cold acetonitrile or methanol (150 PL) containing 2 PM internal standard (ISTD), followed by vortex mixing. The ISTD was d₅-7-ethoxy coumarin. The samples were then centrifuged at 15000 RPM for 25 min at 4 °C, and the supernatant was transferred to an LC-MS vial for analysis by LC- MS/MS. Each time point was tested in duplicates followed by in-between blank washes to avoid carryover and to equilibrate the column. Procaine (poor plasma stability) and procainamide (good plasma stability) were used as controls at the same concentration as that of the test compound. These controls were run in parallel to test the assay’s competency. Matrix blank was prepared by adding acetonitrile or methanol containing ISTD to plasma samples without any of the test or control compounds. Also, an additional control sample was made to simply monitor compound degradation in PBS buffer. Below is a summary of samples prepared for a given test compound in a typical plasma stability assay: Test compound (TC): 994 PL human plasma + 6.0 PL TC (Vial A) 994 PL human plasma + 6.0 PL TC (Vial B) Control: 596 PL human plasma + 3.6 PL (procaine + procainamide) Blank matrix: 500 PL PBS buffer + 100 PL human plasma Additional control: 142 PL PBS buffer + 0.9 PL TC Quenching mixture: 150 PL acetonitrile or methanol with ISTD (2 PM) Final volume: 250 PL (100 PL from the incubation mixture + 150 PL quenching mixture; final ISTD conc.: 1.2 PM) LC-MS/MS analysis was performed using Agilent 1260 Infinity II HPLC, coupled with an Agilent G6460 triple quadrupole mass spectrometer (Agilent Technologies, USA). The data were acquired and processed using the Agilent 6460 Quantitative Analysis data processing software. Reverse-phase HPLC separation for each compound was achieved on an Agilent InfinityLab Poroshell 120 C18 column (2.1 × 50 mm, 2.7 Pm) with a mobile phase composed of methanol/water with 0.1% formic acid or acetonitrile/water with 0.1% formic acid at a flow rate of 0.5 mL/min. Each method was developed in the presence of the ISTD. The column temperature was maintained at 40 qC. The detection was operated using the Agilent Jet-Stream electrospray positive ionization under the multiple reaction monitoring mode. The mass spec conditions were as follows: dwell time 100 ms; gas flow 10 L/min; nebulizer pressure 45 psi; delta EMV 200 V. Plots of time (x-axis) vs. the natural logarithm of percent parent remaining (y-axis) were subsequently constructed to determine the slope. Finally, the plasma stability was evaluated using the following equation: t1/2 = ln(2)/-slope The rat plasma and mouse plasma assays were performed using the same procedures as those described above for the human plasma assay. Liver microsome stability assay The LC-MS/MS analysis was performed using Agilent 1260 Infinity II HPLC, coupled with an Agilent G6460 triple quadrupole mass spectrometer (Agilent Technologies, USA). All the data were acquired employing Agilent 6460 Quantitative Analysis data processing software. Reverse-phase HPLC separation for each compound was achieved either on an Agilent Porshell 120 EC-C8 column (2.1 × 50 mm, 2.7 Pm), or on an Agilent Zorbax XDB C18 column (2.1 × 50 mm, 3.5 Pm) with a mobile phase composed of methanol-water-formic acid or acetonitrile-water-formic acid (0.1%) at a flow rate of 0.5 mL/min (changes for some compounds). Each method was developed in the presence of an internal standard (ISTD) d₅-7-ethoxy coumarin. The column temperature was maintained at 40 qC for most of the samples otherwise noted. The detection was operated in the Agilent JetStream electrospray positive ionization using multiple reaction monitoring mode (MRM). Other MS conditions were as follows: dwell time 100 ms; gas flow 10 L/min; nebulizer pressure 45 psi; delta EMV 200 V; fragmentor voltage and collision energy for individual compounds vary. Test compounds were dissolved in 100% DMSO or 100 % MeOH to make 10 mM stock solutions. Verapamil (Sigma Aldrich) aided as a positive control and was dissolved in 100% DMSO to make 10 mM stock solutions. The 10 mM stock solution of test and control compounds were further diluted in potassium phosphate buffer (100 mM, pH 7.4) to 500 -M to ensure the organic solvent content was < 0.2%. Human liver microsomes (HLMs), rat liver microsomes (RLMs), and mouse liver microsomes (MLMs) were purchased from Xenotech at 20 mg/mL. NADPH (Sigma Aldrich) 10 mM stocks were prepared in deionized water. The HLM assay was prepared in a 1.5 mL Eppendorf tube with a final volume of 1100 -L for duplicate runs. Each reaction contained phosphate buffer (928.4 -L), liver microsomes (55 -L), and test compound resulting in a final concentration of 3 -M (6.6 -L of 500 -M). The reaction was initiated with 110 -L of 10 mM NADPH. Aliquots (100 -L) were removed in duplicate at 0, 15, 30, 60, 120 min (for prodrug compounds) and 0, 5, 10, 15, 30 min (verapamil, positive control compound) time intervals and quenched in cold 100 mL of 100 % methanol which contained internal standard (ISTD: d5-7-ethoxy coumarin 4 PM). Before centrifugation each of the aliquoted tubes were vortexed to make sure compounds were in the solution. The aliquots were centrifuged at 12,000 g for 5 min and the supernatant removed and placed in an LC-MS vial. Each time point was assessed using LC-MS and the area, based on the extracted ion, was integrated with respect to the ISTD. Positive controls were conducted at a final volume of 550 -L to give each time point in a single run. A no-NADPH negative control with test or control compound was performed in a single run (150 -L) at the longest time point. Controls were processed and analyzed like the test compounds. Each time point was run in duplicates followed by in-between blank washes to avoid the carryover and to equilibrate the column. The rat liver microsome (RLM) and mouse liver microsomes (MLM) assays were performed using the same procedures as those described above for the HLM assay. B. Results Table 2. Aqueous solubility and metabolic stability profiles of selected compounds

Example 8. Metabolite identification studies A. Materials and methods Test compounds and positive controls were dissolved in 100% DMSO to make 10 mM stock solutions. The 10 mM stock solutions of test and control compounds were further diluted in potassium phosphate buffer (100 mM, pH 7.4) to 500 -M to ensure that the organic solvent content was < 0.2%. The liver microsome (HLM or RLM) MetID assay was prepared in a 1.5 mL Eppendorf tube with a final volume of 1100 -L for duplicate runs. Each reaction contained phosphate buffer (374 -L), liver microsomes (550 -L), and test compound (66 -L of 500 -M), resulting in a final concentration of 30 -M for the test compound. The reaction was initiated with ---^-L of 10 mM NADPH. Aliquots (100 -L) were removed in duplicate at 0, 5, 10, 15, and 30 min and quenched in 200 -L of 100 % cold acetonitrile which contained internal standard (ISTD: d5-7-ethoxy coumarin 2 -M). The aliquots were centrifuged at 13,000 g for 5 min, and the supernatant was transferred into autosampler vials for LC-HRMS analysis (Thermo Scientific ID- X Orbitrap MS). MS analysis was performed using full scan from a mass range of 100-700 m/z at 60k resolution with data dependent MS/MS and MSn programs enabled for the top 5 ions detected for each scan. Compounds were detected based on their MS1 precursor ion accurate mass m/z and identified with matching theoretical and observed accurate mass MS1 ions with interpretation of accurate mass MS/MS spectra from expected metabolites. B. Results MetID studies were performed on SCP-Mpro-022, LJ-Mpro-058, and the control compound LJ-Mpro-019 in liver microsomes (HLMs or RLMs) using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). The data showed that all three test compounds were susceptible to cleavage at the phenylic ether position when incubated with liver microsomes. This cleavage was attributed to, at least in part, cytochrome P450-mediated oxidative reactions. An exemplary MetID result, i.e., SCP-Mpro-022 in HLMs, is shown in Scheme 6, demonstrating cleavage at the phenylic ether position.

Example 9. Synthesis of deuterated analogs (exemplary prophetic compounds) Synthesis of the following exemplary deuterated analogs will be performed by following Schemes 7 and 8, in view of the methods described in Examples 1–5. N

First, installation of the geminal deuterium atoms will be carried out by reduction of an ester group (for example, methyl or ethyl ester) on the respective aryl or heteroaryl building block (Scheme 7). To this end, the ester-containing aryl or heteroaryl building block will be treated with lithium aluminum deuteride in THF at 0 qC. Upon completion of the reaction, the reaction mixture will be diluted with saturated ammonium chloride solution and ethyl acetate. The organic phase will be separated and extracted three times with ethyl acetate. The combined organic fractions will then be washed with brine, dried over anhydrous magnesium sulfate, and then filtered. After concentration in vacuo, the crude R-CD₂-OH product will be purified by column chromatography.

Scheme 7 Second, the purified R-CD₂-OH intermediate will be coupled to intermediate 20-1, 26-1, 20-2, or 26-2 using the coupling methods described in Examples 3 and 4 to produce the deuterated analogs. For example, Scheme 8 shows synthetic pathways of coupling the purified R-CD2-OH intermediate with intermediate 20-1, 26-1, 20-2, or 26-2 using the Mitsunobu reaction.

l l

Scheme 8

Claims

CLAIMS We claim: 1. A compound of Formula I or II or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof,

Formula II wherein R¹ is halogen, –O–(C(R^a)(R^b))_m–R^X, or –S–(C(R^a)(R^b))_m–R^X, wherein: m is 1 or 2, R^a and R^b, at each occurrence, are independently and individually hydrogen, halogen, C1– C₃ alkyl, or C₁–C₃ haloalkyl, and R^X is optionally substituted C1–C3 alkyl, optionally substituted C1–C3 haloalkyl, optionally substituted carbocyclyl, optionally substituted halocarbocyclyl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, optionally substituted aryl, optionally substituted haloaryl, optionally substituted heteroaryl, or optionally substituted haloheteroaryl; wherein R

², R³, R⁵, R⁶, and R⁷ are independently and individually hydrogen, halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, alkylaryl, alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkyloxycarbonyl, aryloxycarbonyl, primary amino, alkylamino, alkylammonium, alkylcarbonylamino, arylcarbonylamino, carbamoyl, N-alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or N- alkylsulfamoyl; and r

, Y¹, Y², Y³, and Y⁴ are independently and individually CH or N, X is N or O, Z¹, Z², and Z³ are independently and individually CH, N, NH, O, or S, R^c, at each occurrence, is independently and individually halogen, C₁–C₃ alkyl, or C₁–C₃ haloalkyl, l is 0, 1, 2, or 3, k is 0, 1, or 2, n is 0, 1, 2, 3, 4, or 5, o is 0, 1, 2, 3, or 4, when n is not 0, the corresponding R^c substituent(s) can be on either or both rings, when o is not 0, the corresponding R^c substituent(s) can be on either or both rings, and when an R^c group is present, it replaces the hydrogen atom at the ring atom that the R^c group connects to. 2. The compound of claim 1, wherein the compound is Formula I or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. 3. The compound of claim 1, wherein the compound is Formula II or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof. 4. The compound of any one of claims 1–3, wherein R¹ is halogen. 5. The compound of claim 4, wherein R¹ is chloro or fluoro. 6. The compound of any one of claims 1–3, wherein R¹ is –O–(C(R^a)(R^b))_m–R^X or –S– (C(R^a)(R^b))_m–R^X. 7. The compound of claim 6, wherein R^a, at each occurrence, is hydrogen. 8. The compound of claim 6 or 7, wherein R^b, at each occurrence, is hydrogen. 9. The compound of claim 6, wherein R¹ is –O–(CH₂)_m–R^X or –S–(CH₂))_m–R^X. 10. The compound of any one of claims 6–9, wherein m is 1. 11. The compound of any one of claims 6–9, wherein m is 2. 12. The compound of any one of claims 6–11, wherein R^X is optionally substituted C₁–C₃ alkyl or optionally substituted C₁–C₃ haloalkyl.

13. The compound of claim 12, wherein R^X is –CH2F, –CHF2, –CF3, isopropyl, or tert-butyl. 14. The compound of claim 12 or 13, wherein R^a and R^b, at each occurrence, are hydrogen. 15. The compound of claim 12, wherein R¹ is selected from: , ,

16. The compound of any one of claims 6–11, wherein R^X is optionally substituted carbocyclyl, optionally substituted halocarbocyclyl, optionally substituted heterocyclyl, optionally substituted haloheterocyclyl, optionally substituted aryl, optionally substituted haloaryl, optionally substituted heteroaryl, or optionally substituted haloheteroaryl. 17. The compound of claim 16, wherein R^X is optionally substituted carbocyclyl, optionally substituted halocarbocyclyl, optionally substituted heterocyclyl, or optionally substituted haloheterocyclyl. 18. The compound of claim 17, wherein R^X is selected from optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted azetidinyl, and optionally substituted oxetanyl. , a

20. The compound of any one of claims 17–19, wherein R^a and R^b, at each occurrence, are hydrogen. 2 , _, ,

22. The compound of claim 16, wherein R^X is optionally substituted aryl, optionally substituted haloaryl, optionally substituted heteroaryl, or optionally substituted haloheteroaryl. 23. The compound of claim 22, wherein R^X is optionally substituted phenyl, optionally substituted halophenyl, optionally substituted 5- or 6-membered heteroaryl, or optionally substituted 5- or 6-membered haloheteroaryl. 24. The compound of claim 23, wherein R^X is optionally substituted phenyl or optionally substituted halophenyl. 25. The compound of claim 23, wherein R^X is optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6-membered haloheteroaryl.

e 26. The compound of claim 22, wherein

,

wherein V¹, V², V³, V⁴, and V⁵ are independently and individually CH or N, wherein W¹, W², W³, and W⁴ are independently and individually CH, N, NH, O, or S, wherein R^e, at each occurrence, is independently and individually halogen, nitro, cyano, hydroxyl, formyl, carboxyl, sulfamoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, haloheteroaryl, arylalkyl, alkylaryl, alkyloxy, haloalkyloxy, aryloxy, haloaryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkyloxycarbonyl, aryloxycarbonyl, primary amino, alkylamino, alkylammonium, alkylcarbonylamino, arylcarbonylamino, carbamoyl, N- alkylcarbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, or N-alkylsulfamoyl, wherein p is 0, 1, 2, or 3, wherein q is 0, 1, or 2, wherein r is 0, 1, 2, 3, 4, or 5, wherein s is 0, 1, 2, 3, or 4, wherein when r is not 0, the corresponding R^e substituent(s) can be on either or both rings, wherein when s is not 0, the corresponding R^e substituent(s) can be on either or both rings, and wherein when an R^e group is present, it replaces the hydrogen atom at the ring atom that the R^e group connects to. 27. The compound of claim 26, wherein

.

28. The compound of claim 27, wherein

. 29. The compound of claim 27 or 28, wherein p is 0 or 1. q 30. The compound of claim 26, wherein

. e q 31. The compound of claim 30, wherein R^X is selected from

,

. 32. The compound of claim 30 or 31, wherein q is 0 or 1. 33. The compound of claim 26, wherein

. 34. The compound of claim 33, wherein

. 35. The compound of claim 33 or 34, wherein s is 0 or 1.

36. The compound of any one of claims 26–35, wherein R^e, at each occurrence, is independently and individually halogen, nitro, cyano, hydroxyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, primary amino, formyl, carboxyl, carbamoyl, sulfamoyl, acetyl, acetoxy, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, trimethylammonium, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N- dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzyl, benzoyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, halocarbocyclyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl. 37. The compound of claim 36, wherein R^e, at each occurrence, is independently and individually chloro, fluoro, nitro, cyano, hydroxyl, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl. S 38. The compound of claim 26, wherein R^X is selected from

, , _,

, , , _{, ,}

,

,

39. The compound of any one of claims 22–38, wherein R^a and R^b, at each occurrence, are hydrogen. 40. The compound of claim 38, wherein R¹ is selected from: , , , _,

, , , ,

_, ,

_, , , _{, ,} , ,

_, ,

_, , , , , , , , ,

_, , , ,

41. The compound of any one of claims 1–40, wherein R², R³, R⁵, R⁶, and R⁷ are independently and individually hydrogen, halogen, C1–C3 alkyl, or C1–C3 haloalkyl.

42. The compound of any one of claims 1–41, wherein R² is hydrogen or halogen. 43. The compound of any one of claims 1–42, wherein R³ is hydrogen or halogen. 44. The compound of any one of claims 1–43, wherein R⁵ is hydrogen or halogen. 45. The compound of any one of claims 1–43, wherein R⁵ is selected from methyl, –CH2F, –CHF₂, and –CF₃. 46. The compound of any one of claims 1–45, wherein R⁶ is hydrogen or halogen. 47. The compound of any one of claims 1–45, wherein R⁶ is selected from methyl, –CH₂F, –CHF2, and –CF3. 48. The compound of any one of claims 1–47, wherein R⁷ is hydrogen or halogen. 49. The compound of claim 41, wherein R², R⁵, R⁶, and R⁷ are hydrogen and R³ is halogen. 50. The compound of claim 49, wherein R², R⁵, R⁶, and R⁷ are hydrogen and R³ is chloro or fluoro. 51. The compound of claim 41, wherein R² and R⁷ are hydrogen, R⁵ and R⁶ are independently selected from hydrogen, methyl, –CH2F, –CHF2, and –CF3, and R³ is halogen. 52. The compound of claim 51, wherein at least one of R⁵ and R⁶ is selected from methyl, –CH2F, –CHF2, and –CF3. 53. The compound of any one of claims 1–52, wherein

.

54.

. 55. The compound of claim 53, wherein

. 56. The compound of any one of claims 53–55, wherein l is 0 or 1. 57. The compound of any one of claims 1–52, wherein T

. 58. The compound of claim 57, wherein X is N. 59. The compound of claim 58, wherein

, k(R , k(R

60. The compound of any one of claims 57–59, wherein k is 0 or 1.

61. The compound of any one of claims 1–52, wherein T

.

. 63. The compound of claim 61 or 62, wherein n is 0 or 1. 6 . The compound of any one of claims 1–52, wherein T is selected from

, ,

,

,

65. The compound of any one of claims 1, 4–40, and 53–64, having a structure of Formula I’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof, wherein R¹, R³, and T are the same as those described in the foregoing claims.

66. The compound of claim 65, wherein: R³ is chloro or fluoro, R¹ is selected from chloro, fluoro,

, , , CHF CF 2 ₃ CHF O O ₂ O O O S , , , , , , , , _, , , , , _{, ,}

, , , _{, , ,} ,

_{, , ,} , , _{, ,}

, , , _{, ,} , ,

,

_{, ,} ,

_,

_, ,

, , , _{, d}

_, , ,

67. The compound of claim 66, wherein

. 68. The compound of claim 66, wherein T is

_. 69. The compound of any one of claims 1, 4–40, and 53–64, having a structure of Formula II’ or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof, wherein R¹, R³, and T are the same as those described in the foregoing claims. R¹ 70.

_, , , _{, ,} , , ,

_{, , ,} , , _{, ,}

, , _{, ,} , , ,

_{, ,} , , , _, ,

_, , , , , , , ,

_{, ,} ,

,

71. The compound of claim 70, wherein T is

. 7 The compound of claim 70, wherein T is

_. 73. The compound of claim 1, selected from:

, l , ,

,

, ,

,

, ,

,

ON NO N N N

, ,

,

N , N , N ,

,

e salts, hydrates, and hydrated salts thereof. 74. The compound of claim 1, selected from: ,

l , N , N

,

, ,

,

, ,

,

N , N , N

,

, ,

,

, , ,

NO₂ N NH N N O O O O O O N N N N N N Cl N N N Cl N N N Cl O O O O O O HN HN HN , , , N ^N _CHF2 ^{N N} _CF3 O O O O N N N N N Cl N N N Cl O O O O HN HN , , and pharmaceutically acceptable salts, hydrates, and hydrated salts thereof. 75. The compound of any one of claims 1–74, wherein the compound is in the form of a pharmaceutically acceptable salt. 76. The compound of claim 75, wherein the compound is in the form of a HCl, sulfate, or oxalate salt. 77. A pharmaceutical formulation, comprising a compound of any one of claims 1–76 and a pharmaceutically acceptable carrier.

78. The pharmaceutical formulation of claim 77, wherein the pharmaceutical formulation is in the form of tablet, capsule, pill, gel, cream, granule, solution, suspension, emulsion, or nanoparticulate formulation. 79. The pharmaceutical formulation of claim 78, wherein the pharmaceutical formulation is in the form of tablet, capsule, or pill. 80. The pharmaceutical formulation of any one of claims 77–79, wherein the pharmaceutical formulation is an oral formulation. 81. A method of treating or preventing coronavirus infection, comprising administering an effective amount of a compound of any one of claims 1–76 to a subject in need thereof. 82. The method of claim 81, wherein the compound is administered orally. 83. The method of claim 81 or 82, wherein the coronavirus infection is SARS-CoV-2 infection. 84. The method of any one of claims 81–83, wherein the subject is diagnosed with COVID- 19. 85. The method of any one of claims 81–83, wherein the subject has a risk of contracting COVID-19. 86. The method of any one of claims 81–85, wherein the compound is administered together with a second active agent. 87. The method of claim 86, wherein the second active agent is a coronavirus antiviral. 88. The method of claim 87, wherein the coronavirus antiviral is an inhibitor of coronavirus RNA-dependent RNA polymerase.

89. The method of claim 88, wherein the inhibitor of coronavirus RNA-dependent RNA polymerase is molnupiravir. 90. A deuterated analog of the compound as claimed in any one of claims 1–76, wherein one or more non-ionizable hydrogen atoms in the corresponding formula are replaced with deuterium. 91. The deuterated analog of claim 90, wherein R¹ is –O–(C(R^a)(R^b))_m–R^X or –S– (C(R^a)(R^b))m–R^X, wherein R^a, R^b, m, and R^X, when appropriate, are the same as those described in claims 1–3 and 6–76, with the exception that one or more non-ionizable hydrogen atoms in R¹ are replaced with deuterium. 92. The deuterated analog of claim 91, wherein the –(C(R^a)(R^b))m– moiety of R¹ is deuterated. 93. The deuterated analog of claim 92, wherein the –(C(R^a)(R^b))m– moiety of R¹ is fully deuterated. 94. The deuterated analog of claim 93, wherein the –(C(R^a)(R^b))_m– moiety of R¹, when appropriate, is –CD2– or –(CD2)2–. 95. The deuterated analog of any one of claims 91–94, wherein the R^X moiety of R¹ is deuterated. 96. The deuterated analog of claim 95, wherein the R^X moiety of R¹ is fully deuterated. 97. The deuterated analog of any one of claims 91–94, wherein the R^X moiety of R¹, when appropriate, is selected from –CH₂F, deuterated –CH₂F, –CHF₂, –CDF₂, –CF₃, isopropyl, deuterated isopropyl, tert-butyl, deuterated tert-butyl, cyclopropyl, deuterated cyclopropyl, cyclobutyl, deuterated cyclobutyl, 1-azetidinyl, deuterated 1-azetidinyl, 3-oxetanyl, deuterated 3- o , , , , , _{, ,}

, , d _{, d ,} d

, , ,

98. The deuterated analog of claim 97, wherein the R^X moiety of R¹, when appropriate, is selected from –CH2F, –CD2F, –CHF2, –CDF2, –CF3, isopropyl, d7-isopropyl, tert-butyl, d9-tert- butyl, cyclopropyl, d5-cyclopropyl, cyclobutyl, d7-cyclobutyl, 1-azetidinyl, d6-1-azetidinyl, 3-

_, , , _{, ,} , ,

_{d d} d d d _d d

d d d _{d d d}

99. The deuterated analog of claim 91, wherein the –(C(R^a)(R^b))_m– moiety, when appropriate, is –CD₂–, wherein the R^X moiety, when appropriate, is selected from

_, , , , , _{, ,}

, , , d , d _,

_d , d , _{d , ,}

_d , d , d _, d

100. The deuterated analog of claim 99, wherein the R^X moiety, when appropriate, is selected

, , _{, ,} , , d

_d d d d _d d y

f

101. The deuterated analog of claim 99, wherein the R^X moiety, when appropriate, is selected

, , , _{, ,}

,

₂ ,

102. The deuterated analog of claim 91, wherein the deuterated analog is selected from: l , ,

, ,

,

, ,

, N N N N

N N N

, ,

,

, ,

,

, ,

e salts, hydrates, and hydrated salts thereof. 103. The deuterated analog of any one of claims 90–102, wherein the deuterated analog is in the form of a pharmaceutically acceptable salt.

104. The deuterated analog of claim 103, wherein the deuterated analog is in the form of a HCl, sulfate, or oxalate salt. 105. A pharmaceutical formulation, comprising a deuterated analog of any one of claims 90– 104 and a pharmaceutically acceptable carrier. 106. The pharmaceutical formulation of claim 105, wherein the pharmaceutical formulation is in the form of tablet, capsule, pill, gel, cream, granule, solution, suspension, emulsion, or nanoparticulate formulation. 107. The pharmaceutical formulation of claim 106, wherein the pharmaceutical formulation is in the form of tablet, capsule, or pill. 108. The pharmaceutical formulation of any one of claims 105–107, wherein the pharmaceutical formulation is an oral formulation. 109. A method of treating or prevent coronavirus infection, comprising administering an effective amount of a deuterated analog of any one of claims 90–104 to a subject in need thereof. 110. The method of claim 109, wherein the deuterated analog is administered orally. 111. The method of claim 109 or 110, wherein the coronavirus infection is SARS-CoV-2 infection. 112. The method of any one of claims 109–111, wherein the subject is diagnosed with COVID- 19. 113. The method of any one of claims 109–111, wherein the subject has a risk of contracting COVID-19.

114. The method of any one of claims 109–113, wherein the deuterated analog is administered together with a second active agent. 115. The method of claim 114, wherein the second active agent is a coronavirus antiviral. 116. The method of claim 115, wherein the coronavirus antiviral is an inhibitor of coronavirus RNA-dependent RNA polymerase. 117. The method of claim 116, wherein the inhibitor of coronavirus RNA-dependent RNA polymerase is molnupiravir.