COMPOUNDS FOR THE TREATMENT OF SARS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional patent application No. 63/194,647, which was filed on May 28, 2021, and which is hereby incorporated by reference in its entirety. STATEMENT OF GOVERNMENT SUPPORT [0002] This invention was made with government support under AI150466 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD [0003] This disclosure relates to novel bis-amide inhibitors of SARS-CoV-2 (COVID) and methods of treating severe acute respiratory syndrome. BACKGROUND [0004] Coronaviruses (CoVs) are enveloped viruses with a positive-sense, single- stranded RNA and are associated with various natural hosts. CoVs are divided into alpha, beta, gamma, and delta groups, and the beta group is further composed of A, B, C, and D subgroups. Among them, six CoVs can infect humans (HCoVs), including HCoV-229E (229E) and HCoV-NL63 (NL63) in the alpha group, HCoV-OC43 (OC43) and HCoV-HKU1 (HKU1) in beta subgroup A, severe acute respiratory syndrome CoV (SARS-CoV) in beta subgroup B, and Middle East respiratory syndrome CoV (MERS-CoV) in beta subgroup C. [0005] In this century, SARS-CoV and MERS-CoV have emerged in the human population and caused severe pulmonary disease with alarmingly high case-fatality rates. In 2002, SARS-CoV infections first appeared in China and then quickly spread as a global epidemic in more than 30 countries with 8,273 infections and 775 deaths (nearly 10% mortality). In 2012, MERS-CoV emerged in Saudi Arabia and spread throughout the Middle East. In 2015, the second pandemic of MERS-CoV occurred in South Korea, causing super- spreading events with third- and fourth-generation cases of infection. The World Health Organization has reported 2,229 laboratory-confirmed cases of MERS-CoV infection, including 791 deaths (about 35% case fatality) in 27 countries as of August 2018. Meanwhile, the remaining common HCoVs, such as 229E, OC43, and NL63, usually infect the human upper respiratory tract and cause the common cold, but they also are responsible for severe and even fatal diseases in children, elderly, and immunocompromised patients. These scenarios suggest that those common HCoVs might also pose a lethal threat to humans. Note that HCoVs are rapidly evolving. OC43 isolates with novel genomes are being continuously identified. [0006] The ongoing outbreak of coronavirus disease 2019 (COVID-19) originated in China in December 2019 and became a global pandemic by March 2020. COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome–coronavirus 2 (SARS- CoV-2). Two other coronaviruses have caused worldwide outbreaks in the past two decades, namely SARS-CoV (2002–2003) and Middle East respiratory syndrome coronavirus (MERS-CoV) (2012–present). There is currently no treatment for COVID-19. Therefore, the development of a drug that would inhibit SARS-CoV-2 would address an urgent unmet medical need. SUMMARY [0007] The disclosure relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R ¹ is alkyl, -O-alkyl, - heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -alkylene-heterocyclyl, -N(R ^a )alkyl, -N(R ^a )heterocyclyl, alkylene-O-heterocyclyl, or alkylene-O-aryl; each of which can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R ² is alkyl, aryl, substituted aryl; R ³ is a cycloalkyl or heterocyclyl (e.g., 3-pyrrolidin-2-one and 3-piperidin-2- one); each R ⁴ is independently any suitable substituent, such as alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, halo, hydroxy, amino or amido (e.g., C(O)NR ₂ ); or two instances of R ⁴ can be taken together to form a substituted or unsubstituted cycloalkyl or heterocyclyl; m is 0, 1, 2, 3, 4, or 5; and n is 1 or 2. [0008] The disclosure relates to a compound of formula (II), wherein: or a pharmaceutically acceptable salt thereof, wherein: R ¹ is alkyl, -O-alkyl, - heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene-aryl, -alkylene-heterocyclyl, -N(R ^a )alkyl, -N(R ^a )heterocyclyl, alkylene-O- heterocyclyl, alkylene-O-aryl, aryl, CF ₃ , or CCl ₃ ; each of which can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R ² is alkyl, aryl, substituted aryl; each R ^2a is independently H or Me; R ³ is a cycloalkyl or heterocyclyl (e.g., 3-pyrrolidin-2-one and 3-piperidin-2- one); each R ⁴ is independently any suitable substituent, such as alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, halo, hydroxy, amino or amido (e.g., C(O)NR ₂ ) O-alkyl; or two instances of R ⁴ can be taken together to form a substituted or unsubstituted cycloalkyl or heterocyclyl or aryl; m is 0, 1, 2, 3, 4, or 5; and n is 1 or 2. [0009] The disclosure relates to a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein: R ¹⁰ is alkyl, -O-alkyl, -heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene-aryl, -alkylene-heterocyclyl, -N(R ^a )alkyl, -N(R ^a )heterocyclyl, alkylene-O- heterocyclyl, alkylene-O-aryl, aryl, CF _3, or CCl ₃ ; each of which can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R ³⁰ is a cycloalkyl or heterocyclyl (e.g., 3-pyrrolidin-2-one and 3-piperidin-2- one); R ⁴⁰ is alkylene-aryl, or -C(O)O-tButyl. [0010] The disclosure relates to a compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein: R ¹ is alkyl, -O-alkyl, - heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene-aryl, -alkylene-heterocyclyl, -N(R ^a )alkyl, -N(R ^a )heterocyclyl, alkylene-O- heterocyclyl, alkylene-O-aryl, aryl, CF ₃ , or CCl ₃ ; each of which can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; each R ^2a is independently H or Me; R ³ is a cycloalkyl or heterocyclyl (e.g., 3-pyrrolidin-2-one and 3-piperidin-2- one); each R ⁴ is independently any suitable substituent, such as alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, halo, hydroxy, amino or amido (e.g., C(O)NR ₂ ) O-alkyl; or two instances of R ⁴ can be taken together to form a substituted or unsubstituted cycloalkyl or heterocyclyl or aryl; m is 0, 1, 2, 3, 4, or 5; and n is 1 or 2. [0011] The disclosure relates to a compound of formula (V): or a pharmaceutically acceptable salt thereof, wherein: R ¹ is alkyl, -O-alkyl, - heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene-aryl, -alkylene-heterocyclyl, -N(R ^a )alkyl, -N(R ^a )heterocyclyl, alkylene-O- heterocyclyl, alkylene-O-aryl, aryl, CF ₃ , or CCl ₃ ; each of which can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; each R ^2a is independently H or Me; R ³ is a cycloalkyl or heterocyclyl (e.g., 3-pyrrolidin-2-one and 3-piperidin-2- one); each R ⁴ is independently any suitable substituent, such as alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, halo, hydroxy, amino or amido (e.g., C(O)NR ₂ ) O-alkyl; or two instances of R ⁴ can be taken together to form a substituted or unsubstituted cycloalkyl or heterocyclyl or aryl; m is 0, 1, 2, 3, 4, or 5; and n is 1 or 2. [0012] The disclosure relates to a compound listed in Table 1. [0013] The disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds and a pharmaceutically acceptable excipient. [0014] The disclosure relates to a method for treating a severe acute respiratory syndrome, the method comprising administering a therapeutically effective amount of one or more compounds to a patient in need thereof. DETAILED DESCRIPTION [0015] While the concepts of the present disclosure are illustrated and described in detail in the figures and descriptions herein, results in the figures and their description are to be considered as examples and not restrictive in character; it being understood that only the illustrative embodiments are shown and described and that all changes and modifications that come within the spirit of the disclosure are desired to be protected. [0016] The disclosure relates to compounds that inhibit SARS-CoV-2. The compounds are useful for the treatment of severe acute respiratory system. Compounds [0017] The disclosure relates to a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R ¹ is alkyl, -O-alkyl, - heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -alkylene-heterocyclyl, -N(R ^a )alkyl, -N(R ^a )heterocyclyl, alkylene-O-heterocyclyl, or alkylene-O-aryl; each of which can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R ² is alkyl, haloalkyl, aryl; R ³ is cycloalkyl or heterocyclyl (e.g., 3-pyrrolidin-2-one and 3-piperidin-2-one); each R ⁴ is independently any suitable substituent, such as alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, halo, hydroxy, amino or amido (e.g., C(O)NR ₂ ); or two instances of R ⁴ can be taken together to form a substituted or unsubstituted cycloalkyl; R ^a is H or alkyl; m is 0, 1, 2, 3, 4, or 5; and n is 1 or 2. [0018] For example, the compounds of the formula (I) can be compounds of the formula: or or a pharmaceutically acceptable salt thereof. [0019] For example, the compounds of the formula (I), can be compounds of the formula: or a pharmaceutically acceptable salt thereof. [0020] For example, the compounds of the formula (I) can be compounds of the formula: or a pharmaceutically acceptable salt thereof. [0021] The disclosure relates to a compound of formula (I), wherein the compound of formula (I) is a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: R ¹ is alkyl, -O-alkyl, - heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene-aryl, -alkylene-heterocyclyl, -N(R ^a )alkyl, -N(R ^a )heterocyclyl, alkylene-O- heterocyclyl, alkylene-O-aryl, aryl, CF _{3, or} CCl ₃ ; each of which can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R ² is alkyl, aryl, substituted aryl; each R ^2a is independently H or Me; R ³ is a cycloalkyl or heterocyclyl (e.g., 3-pyrrolidin-2-one and 3-piperidin-2- one); each R ⁴ is independently any suitable substituent, such as alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, halo, hydroxy, amino or amido (e.g., C(O)NR ₂ ) O-alkyl; or two instances of R ⁴ can be taken together to form a substituted or unsubstituted cycloalkyl or heterocyclyl or aryl; m is 0, 1, 2, 3, 4, or 5; and n is 1 or 2. [0022] The disclosure relates to a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein: R ¹⁰ is alkyl, -O-alkyl, - heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene-aryl, -alkylene-heterocyclyl, -N(R ^a )alkyl, -N(R ^a )heterocyclyl, alkylene-O- heterocyclyl, alkylene-O-aryl, aryl, CF ₃ , or CCl ₃ ; each of which can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; R ³⁰ is a cycloalkyl or heterocyclyl (e.g., 3-pyrrolidin-2-one and 3-piperidin-2- one); R ⁴⁰ is alkylene-aryl, or -C(O)O-tButyl. [0023] The compound of Formula (III) can be a compound of formula: . , wherein R ¹⁰ and R ⁴⁰ are as described in Formula (III). [0024] The compound of Formula (III) can be a compound selected from: , , and . [0025] The disclosure relates to a compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein: R ¹ is alkyl, -O-alkyl, - heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene-aryl, -alkylene-heterocyclyl, -N(R ^a )alkyl, -N(R ^a )heterocyclyl, alkylene-O- heterocyclyl, alkylene-O-aryl, aryl, CF ₃ , or CCl ₃ ; each of which can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; each R ^2a is independently H or Me; R ³ is a cycloalkyl or heterocyclyl (e.g., 3-pyrrolidin-2-one and 3-piperidin-2- one); each R ⁴ is independently any suitable substituent, such as alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, halo, hydroxy, amino or amido (e.g., C(O)NR ₂ ) O-alkyl ; or two instances of R ⁴ can be taken together to form a substituted or unsubstituted cycloalkyl or heterocyclyl or aryl; m is 0, 1, 2, 3, 4, or 5; and n is 1 or 2. [0026] The disclosure relates to a compound of formula (V): or a pharmaceutically acceptable salt thereof, wherein: R ¹ is alkyl, -O-alkyl, - heterocyclyl, -O-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene-aryl, -alkylene-heterocyclyl, -N(R ^a )alkyl, -N(R ^a )heterocyclyl, alkylene-O- heterocyclyl, alkylene-O-aryl, aryl, CF ₃ , or CCl ₃ ; each of which can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; each R ^2a is independently H or Me; R ³ is a cycloalkyl or heterocyclyl (e.g., 3-pyrrolidin-2-one and 3-piperidin-2- one); each R ⁴ is independently any suitable substituent, such as alkyl, alkoxy, alkoxyalkyl, aminoalkyl, aryl, heterocyclyl, halo, hydroxy, amino or amido (e.g., C(O)NR ₂ ) O-alkyl ; or two instances of R ⁴ can be taken together to form a substituted or unsubstituted cycloalkyl or heterocyclyl or aryl; m is 0, 1, 2, 3, 4, or 5; and n is 1 or 2. [0027] In the compounds described herein (e.g., the compounds of the formulae (I)- (V)), R ¹ can be alkyl. R ¹ can be -O-alkyl. R ¹ can be -O-t-butyl. R ¹ can be – heterocyclyl. R ¹ can be -O-heterocyclyl. R ¹ can be -O-alkylene-heterocyclyl. R ¹ can be -alkylene- heterocyclyl. R ¹ can be -N(R ^a )alkyl. R ¹ can be -N(H)-t-butyl. R ¹ can be or - N(R ^a )heterocyclyl. R ¹ can be alkylene-O-heterocyclyl. R ¹ can be alkylene-O-aryl. R ¹ can be - O-alkylene-heterocyclyl. R ¹ can be -O-alkylene-aryl. R ¹ can be -O-CH ₂ Ph. R ¹ can be -O- CH ₂ -pyridinyl. R ¹ can be-O-alkylene-aryl. R ¹ can be phenyl. [0028] R ¹ can be : -CF ₃ , -CH ₂ CF ₃ , -N(H)CH ₂ CF ₃ , CCl ₃ , , or wherein X ⁵ is N or CH; R ^b is heterocyclyl (e.g., tetrahydrofuranyl or pyrrolidinyl) or alkyl; X ⁴ is S, O or NR ⁷ ; R ⁷ is H, alkyl, cylcoalkyl or alkylaryl; and each R ^c is independently H or alkyl; each of which can be optionally substituted as previously described. [0029] Alternatively, or in addition in the compounds described herein (e.g., the compounds of the formulae (I)-(V)), R ² can be alkyl. R ² can haloalkyl. R ² can be aryl. [0030] Alternatively, or in addition in the compounds described herein (e.g., the compounds of the formulae (I)-(V)), R ³ can be cycloalkyl. R ³ can be heterocyclyl. R ³ can be 3-pyrrolidin-2-one. R ³ can be 3-piperidin-2-one. [0031] R ³ can be or , wherei ^{a 1} n Y is O or NR ; T and T are each, independently, NR ^a or C(O); each R ⁵ is independently H, alkyl, amino or two adjacent R ⁵ groups, together with the carbon atoms to which they are attached, form a five- or six- membered aryl or heteroaryl group; each R ⁶ is independently H, alkyl, alkylene-OH, OH, OTs, or Ts, and R ^a is H or alkyl. [0032] Alternatively, or in addition in the compounds described herein (e.g., the compounds of the formulae (I)-(V)), R ⁴ can be alkyl. R ⁴ can be alkoxy. R ⁴ can be alkoxyalkylene. R ⁴ can be aminoalkylene. R ⁴ can be aryl. R ⁴ can be heterocyclyl. R ⁴ can be halo. R ⁴ can be fluoro. R ⁴ can be hydroxy. R ⁴ can be amino. R ⁴ can be amido (e.g., C(O)NR ₂ ). R ⁴ can be -N(Et) ₂ . R ⁴ can be -N((CH ₂ ) ₂ CH ₃ ) ₂ . R ⁴ can be -O(CH ₂ ) ₂ CH ₃ . R ⁴ can be - OC(H)(CH ₃ ) ₂ . R ⁴ can be . [0033] Two instances of R ⁴ can be taken together to form a substituted or unsubstituted cycloalkyl or heterocyclalkyl. Two instances of R ⁴ can be taken together to form a substituted cyclohexyl. Two instances of R ⁴ can be taken together to form a phenyl. [0034] Alternatively, or in addition in the compounds described herein (e.g., the compounds of the formulae (I)-(V)), R ^a can be H. R ^a can be alkyl. [0035] Alternatively, or in addition in the compounds described herein (e.g., the compounds of the formulae (I)-(V)), m can be 0. m can be 1. m can be 2. m can be 3. m can be 4. m can be 5. [0036] Alternatively, or in addition in the compounds described herein (e.g., the compounds of the formulae (I)-(V)), n can be 1. n can be 2. [0037] Alternatively, or in addition in the compounds described herein (e.g., the compounds of the formulae (I)-(V)), R ¹⁰ can be alkyl. R ¹⁰ can be -O-alkyl. R ¹⁰ can be – heterocyclyl. R ¹⁰ can be -O-heterocyclyl. R ¹⁰ can be -O-alkylene-heterocyclyl. R ¹⁰ can be -O- alkylene-aryl. R ¹⁰ can be -alkylene-heterocyclyl. R ¹⁰ can be -N(R ^a )alkyl. R ¹⁰ can be - N(R ^a )heterocyclyl. R ¹⁰ can be alkylene-O-heterocyclyl. R ¹⁰ can be alkylene-O-aryl. R ¹⁰ can be aryl. R ¹⁰ can be CF _3. R ¹⁰ can be CCl ₃ . Each R ¹⁰ can be substituted with any suitable substituent, including hydroxy, halo, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; [0038] Alternatively, or in addition in the compounds described herein (e.g., the compounds of the formulae (I)-(V)), R ³⁰ can be cycloalkyl. R ³⁰ can be heterocyclyl. R ³⁰ can be 3-pyrrolidin-2-one. R ³⁰ can be 3-piperidin-2-one. [0039] Alternatively, or in addition in the compounds described herein (e.g., the compounds of the formulae (I)-(V)), R ⁴⁰ can be alkyl. R ⁴⁰ can be alkoxy. R ⁴⁰ can be alkoxyalkyl. R ⁴⁰ can be aminoalkyl. R ⁴⁰ can be aryl. R ⁴⁰ can be heterocyclyl. R ⁴⁰ can be halo. R ⁴⁰ can be hydroxy. R ⁴⁰ can be amino. R ⁴⁰ can be amido (e.g., C(O)NR ₂ ). R ⁴⁰ can be O-alkyl. Two instances of R ⁴⁰ can be taken together to form a substituted or unsubstituted cycloalkyl or heterocyclyl or aryl. [0040] Compounds of formula (I) can be , , or . [0041] The compound of formula (I) can be , , , ,

, and . [0042] The compound can be:

, , , or . [0043] The compound can be: [0044] The compound can be: , or [0045] The compound can be: . [0046] The compound can be: or . [0047] The compound can be:

, or . [0048] The compound can be:

, , , or . [0049] The compound can be: . or . [0050] The compound can be: [0051] The compound can be: , , or . [0052] The compound can be: , or . [0053] The compound can be: . [0054] The compound can be:

or . [0055] The compound of formula (I), (II), (III), (IV) or (V) can be a compound in Table 1. [0056] All diastereomers of the compounds of the formula (I), (II), (III), (IV) and (V) are contemplated herein. [0057] Compounds of the disclosure can be synthesized by any method well known in the art. Methods of Treatment [0058] The disclosure relates to a method of treating a severe acute respiratory syndrome comprising the step of administering to a subject in need thereof a therapeutically effective amount of any one of the aforementioned compounds. [0059] The severe acute respiratory syndrome can be a caused by a coronavirus. The coronavirus can be COVID-19. Pharmaceutical Compositions, Routes of Administration, and Dosing [0060] In certain embodiments, the disclosure is directed to a pharmaceutical composition, comprising a compound and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds and a pharmaceutically acceptable carrier. The pharmaceutical composition can comprise a pharmaceutically acceptable salt, polymorph, prodrug, clathrate or solvate or of a compound. [0061] In certain embodiments, a pharmaceutical composition further comprises at least one additional pharmaceutically active agent. The at least one additional pharmaceutically active agent can be an agent useful in the treatment of ischemia-reperfusion injury. [0062] Pharmaceutical compositions can be prepared by combining one or more compounds with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents. [0063] As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound and/or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein. “Dosage unit form,” as used herein, refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals. In therapeutic use for treatment of conditions in mammals (e.g., humans) for which the compounds of the various embodiments described herein or an appropriate pharmaceutical composition thereof are effective, the compounds of the various embodiments described herein may be administered in an effective amount. The dosages as suitable for this invention may be a composition, a pharmaceutical composition or any other compositions described herein. [0064] Generally, daily oral doses of a compound are, for human subjects, from about 0.01 milligrams/kg per day to 1,000 milligrams/kg per day. Oral doses in the range of 0.5 to 50 milligrams/kg, in one or more administrations per day, can yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, intravenous administration may vary from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound. [0065] For any compound the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan. [0066] For clinical use, any compound can be administered in an amount equal or equivalent to 0.2-2,000 milligram (mg) of compound per kilogram (kg) of body weight of the subject per day. The compounds can be administered in a dose equal or equivalent to 2-2,000 mg of compound per kg body weight of the subject per day. The compounds can be administered in a dose equal or equivalent to 20-2,000 mg of compound per kg body weight of the subject per day. The compounds can be administered in a dose equal or equivalent to 50-2,000 mg of compound per kg body weight of the subject per day. The compounds can be administered in a dose equal or equivalent to 100-2,000 mg of compound per kg body weight of the subject per day. The compounds can be administered in a dose equal or equivalent to 200-2,000 mg of compound per kg body weight of the subject per day. Where a precursor or prodrug of a compound is to be administered, it is administered in an amount that is equivalent to, i.e., sufficient to deliver, the above-stated amounts of the compound. [0067] The formulations of the compounds can be administered to human subjects in therapeutically effective amounts. Typical dose ranges are from about 0.01 microgram/kg to about 2 mg/kg of body weight per day. The dosage of drug to be administered is likely to depend on such variables as the type and extent of the disorder, the overall health status of the particular subject, the specific compound being administered, the excipients used to formulate the compound, and its route of administration. Routine experiments may be used to optimize the dose and dosing frequency for any particular compound. [0068] The compounds can be administered at a concentration in the range from about 0.001 microgram/kg to greater than about 500 mg/kg. For example, the concentration may be 0.001 microgram/kg, 0.01 microgram/kg, 0.05 microgram/kg, 0.1 microgram/kg, 0.5 microgram/kg, 1.0 microgram/kg, 10.0 microgram/kg, 50.0 microgram/kg, 100.0 microgram/kg, 500 microgram/kg, 1.0 mg/kg, 5.0 mg/kg, 10.0 mg/kg, 15.0 mg/kg, 20.0 mg/kg, 25.0 mg/kg, 30.0 mg/kg, 35.0 mg/kg, 40.0 mg/kg, 45.0 mg/kg, 50.0 mg/kg, 60.0 mg/kg, 70.0 mg/kg, 80.0 mg/kg, 90.0 mg/kg, 100.0 mg/kg, 150.0 mg/kg, 200.0 mg/kg, 250.0 mg/kg, 300.0 mg/kg, 350.0 mg/kg, 400.0 mg/kg, 450.0 mg/kg, to greater than about 500.0 mg/kg or any incremental value thereof. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed. [0069] The compounds can be administered at a dosage in the range from about 0.2 milligram/kg/day to greater than about 100 mg/kg/day. For example, the dosage may be 0.2 mg/kg/day to 100 mg/kg/day, 0.2 mg/kg/day to 50 mg/kg/day, 0.2 mg/kg/day to 25 mg/kg/day, 0.2 mg/kg/day to 10 mg/kg/day, 0.2 mg/kg/day to 7.5 mg/kg/day, 0.2 mg/kg/day to 5 mg/kg/day, 0.25 mg/kg/day to 100 mg/kg/day, 0.25 mg/kg/day to 50 mg/kg/day, 0.25 mg/kg/day to 25 mg/kg/day, 0.25 mg/kg/day to 10 mg/kg/day, 0.25 mg/kg/day to 7.5 mg/kg/day, 0.25 mg/kg/day to 5 mg/kg/day, 0.5 mg/kg/day to 50 mg/kg/day, 0.5 mg/kg/day to 25 mg/kg/day, 0.5 mg/kg/day to 20 mg/kg/day, 0.5 mg/kg/day to 15 mg/kg/day, 0.5 mg/kg/day to 10 mg/kg/day, 0.5 mg/kg/day to 7.5 mg/kg/day, 0.5 mg/kg/day to 5 mg/kg/day, 0.75 mg/kg/day to 50 mg/kg/day, 0.75 mg/kg/day to 25 mg/kg/day, 0.75 mg/kg/day to 20 mg/kg/day, 0.75 mg/kg/day to 15 mg/kg/day, 0.75 mg/kg/day to 10 mg/kg/day, 0.75 mg/kg/day to 7.5 mg/kg/day, 0.75 mg/kg/day to 5 mg/kg/day, 1.0 mg/kg/day to 50 mg/kg/day, 1.0 mg/kg/day to 25 mg/kg/day, 1.0 mg/kg/day to 20 mg/kg/day, 1.0 mg/kg/day to 15 mg/kg/day, 1.0 mg/kg/day to 10 mg/kg/day, 1.0 mg/kg/day to 7.5 mg/kg/day, 1.0 mg/kg/day to 5 mg/kg/day, 2 mg/kg/day to 50 mg/kg/day, 2 mg/kg/day to 25 mg/kg/day, 2 mg/kg/day to 20 mg/kg/day, 2 mg/kg/day to 15 mg/kg/day, 2 mg/kg/day to 10 mg/kg/day, 2 mg/kg/day to 7.5 mg/kg/day, or 2 mg/kg/day to 5 mg/kg/day. [0070] The compounds can be administered at a dosage in the range from about 0.25 milligram/kg/day to about 25 mg/kg/day. For example, the dosage may be 0.25 mg/kg/day, 0.5 mg/kg/day, 0.75 mg/kg/day, 1.0 mg/kg/day, 1.25 mg/kg/day, 1.5 mg/kg/day, 1.75 mg/kg/day, 2.0 mg/kg/day, 2.25 mg/kg/day, 2.5 mg/kg/day, 2.75 mg/kg/day, 3.0 mg/kg/day, 3.25 mg/kg/day, 3.5 mg/kg/day, 3.75 mg/kg/day, 4.0 mg/kg/day, 4.25 mg/kg/day, 4.5 mg/kg/day, 4.75 mg/kg/day, 5 mg/kg/day, 5.5 mg/kg/day, 6.0 mg/kg/day, 6.5 mg/kg/day, 7.0 mg/kg/day, 7.5 mg/kg/day, 8.0 mg/kg/day, 8.5 mg/kg/day, 9.0 mg/kg/day, 9.5 mg/kg/day, 10 mg/kg/day, 11 mg/kg/day, 12 mg/kg/day, 13 mg/kg/day, 14 mg/kg/day, 15 mg/kg/day, 16 mg/kg/day, 17 mg/kg/day, 18 mg/kg/day, 19 mg/kg/day, 20 mg/kg/day, 21 mg/kg/day, 22 mg/kg/day, 23 mg/kg/day, 24 mg/kg/day, 25 mg/kg/day, 26 mg/kg/day, 27 mg/kg/day, 28 mg/kg/day, 29 mg/kg/day, 30 mg/kg/day, 31 mg/kg/day, 32 mg/kg/day, 33 mg/kg/day, 34 mg/kg/day, 35 mg/kg/day, 36 mg/kg/day, 37 mg/kg/day, 38 mg/kg/day, 39 mg/kg/day, 40 mg/kg/day, 41 mg/kg/day, 42 mg/kg/day, 43 mg/kg/day, 44 mg/kg/day, 45 mg/kg/day, 46 mg/kg/day, 47 mg/kg/day, 48 mg/kg/day, 49 mg/kg/day, or 50 mg/kg/day. [0071] The compound or precursor thereof can be administered in concentrations that range from 0.01 micromolar to greater than or equal to 500 micromolar. For example, the dose may be 0.01 micromolar, 0.02 micromolar, 0.05 micromolar, 0.1 micromolar, 0.15 micromolar, 0.2 micromolar, 0.5 micromolar, 0.7 micromolar, 1.0 micromolar, 3.0 micromolar, 5.0 micromolar, 7.0 micromolar, 10.0 micromolar, 15.0 micromolar, 20.0 micromolar, 25.0 micromolar, 30.0 micromolar, 35.0 micromolar, 40.0 micromolar, 45.0 micromolar, 50.0 micromolar, 60.0 micromolar, 70.0 micromolar, 80.0 micromolar, 90.0 micromolar, 100.0 micromolar, 150.0 micromolar, 200.0 micromolar, 250.0 micromolar, 300.0 micromolar, 350.0 micromolar, 400.0 micromolar, 450.0 micromolar, to greater than about 500.0 micromolar or any incremental value thereof. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed. [0072] The compound or precursor thereof can be administered at concentrations that range from 0.10 microgram/mL to 500.0 microgram/mL. For example, the concentration may be 0.10 microgram/mL, 0.50 microgram/mL, 1 microgram/mL, 2.0 microgram/mL, 5.0 microgram/mL, 10.0 microgram/mL, 20 microgram/mL, 25 microgram/mL.30 microgram/mL, 35 microgram/mL, 40 microgram/mL, 45 microgram/mL, 50 microgram/mL, 60.0 microgram/mL, 70.0 microgram/mL, 80.0 microgram/mL, 90.0 microgram/mL, 100.0 microgram/mL, 150.0 microgram/mL, 200.0 microgram/mL, 250.0 g/mL, 250.0 micro gram/mL, 300.0 microgram/mL, 350.0 microgram/mL, 400.0 microgram/mL, 450.0 microgram/mL, to greater than about 500.0 microgram/mL or any incremental value thereof. It is to be understood that all values and ranges between these values and ranges are meant to be encompassed. [0073] The formulations can be administered in pharmaceutically acceptable solutions, which can routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition can be accomplished by any means known to the skilled artisan. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical. [0074] For intravenous and other parenteral routes of administration, a compound can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome- intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration. [0075] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well-known in the art. Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations can also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions, or can be administered without any carriers. [0076] Also contemplated are oral dosage forms of the compounds. The compounds can be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the compound itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the compounds and increase in circulation time in the body. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts,” In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-189 (1982). Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable. [0077] The location of release of a compound may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations, which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. The release can avoid the deleterious effects of the stomach environment, either by protection of the compound or by release of the compound beyond the stomach environment, such as in the intestine. [0078] To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films. [0079] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules can consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell can be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used. [0080] The therapeutic agent can be included in the formulation as fine multi- particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic agent could be prepared by compression. [0081] Colorants and flavoring agents may all be included. For example, the compound may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents. [0082] One may dilute or increase the volume of the therapeutic agent with an inert material. These diluents can include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts also may be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell. [0083] Disintegrants can be included in the formulation of the therapeutic agent into a solid dosage form. Materials used as disintegrates include, but are not limited to, starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrant is the insoluble cationic exchange resin. Powdered gums can be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants. [0084] Binders can be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) can both be used in alcoholic solutions to granulate the therapeutic agent. [0085] An anti-frictional agent can be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants can be used as a layer between the therapeutic agent and the die wall, and these can include, but are not limited to, stearic acid, including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants can also be used, such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000. [0086] Glidants, which can improve the flow properties of the drug during formulation and aid rearrangement during compression, can be added. The glidants can include starch, talc, pyrogenic silica and hydrated silicoaluminate. [0087] To aid dissolution of the therapeutic agent into the aqueous environment a surfactant can be added as a wetting agent. Surfactants can include anionic detergents, such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that can be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound or derivative thereof either alone or as a mixture in different ratios. [0088] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. Microspheres formulated for oral administration can also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration. [0089] For buccal administration, the compositions can take the form of tablets or lozenges formulated in conventional manner. [0090] For topical administration, the compound can be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration. [0091] For administration by inhalation, compounds can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. [0092] Also contemplated is pulmonary delivery of the compounds (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl.5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (a1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins," Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Pat. No.5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569 (specifically incorporated by reference for its disclosure regarding same), issued Sep.19, 1995, to Wong et al. [0093] Contemplated for use are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art. [0094] Nasal delivery of a pharmaceutical composition is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran. [0095] The compounds, when it is desirable to deliver them systemically, can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. [0096] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [0097] Alternatively, the active compounds can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [0098] The compounds can also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. [0099] In addition to the formulations described above, a compound can also be formulated as a depot preparation. Such long-acting formulations can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [00100] The pharmaceutical compositions also can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. [00101] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-1533 (1990). [00102] The compound and optionally one or more other therapeutic agents can be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicine the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2- sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group. [00103] Suitable buffering agents include acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% w/v). [00104] Pharmaceutical compositions contain an effective amount of a compound as described herein and optionally one or more other therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also can be commingled with the compounds, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency. [00105] The therapeutic agent(s), including specifically, but not limited to, a compound, may be provided in particles. “Particles” as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound or the other therapeutic agent(s) as described herein. The particles can contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also can be dispersed throughout the particles. The therapeutic agent(s) also can be adsorbed into the particles. The particles can be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle can include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles can be microcapsules which contain the compound in a solution or in a semi-solid state. The particles can be of virtually any shape. [00106] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers can be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney et al., Macromolecules 26:581-587 (1993), the teachings of which are specifically incorporated by reference herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate). [00107] The therapeutic agent(s) can be contained in controlled-release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including, but not limited to, sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that can result in substantially constant blood levels of a drug over an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.” [00108] Use of a long-term sustained release implant can be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and up to 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above. Definitions [00109] For convenience, before further description of the present disclosure, some terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. [00110] In order for the present disclosure to be more readily understood, some terms and phrases are defined below and throughout the specification. [00111] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. [00112] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, to A only (optionally including elements other than B); or to B only (optionally including elements other than A); or yet, to both A and B (optionally including other elements); etc. [00113] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [00114] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); or to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); or yet, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. [00115] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. [00116] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. [00117] Various compounds contained in compositions of the present disclosure may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present disclosure may also be optically active. The present disclosure contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)- isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the disclosure. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this disclosure. [00118] If, for instance, a particular enantiomer of compound of the present disclosure is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. [00119] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13C- or 14C-enriched carbon are within the scope of this disclosure. [00120] The term “solvate” means a compound, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. [00121] The term “clathrate” means chemical substance consisting of a lattice that traps or contains molecules. Clathrate can be polymeric, or can be host–guest complexes and inclusion compounds. Clathrates can be inclusion compounds in which the guest molecule is in a cage formed by the host molecule or by a lattice of host molecules. [00122] The term “polymorph” refers to a specific form of a compound, for example, polymorphs may represent crystalline forms that can vary in pharmaceutically relevant physical properties between one form and another, for example under different crystallization conditions, environmental conditions, hygroscopic activity of the compounds, etc. [00123] The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. The prodrug can be converted by an enzymatic activity of the host animal. [00124] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. Pharmaceutical compositions of the present disclosure are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. [00125] The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.) [00126] In other cases, the compounds useful in the methods of the present disclosure may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra). [00127] A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, such as a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment. [00128] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the patient of one or more compound of the disclosure. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). [00129] The term “patient” or “subject” refers to a mammal suffering of a disease, disorder, or condition. A patient or subject can be a primate, canine, feline, or equine. A patient can ne subject is a bird. The bird can be a domesticated bird, such as chicken. The bird can be a fowl. A patient or subject can be a human. [00130] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. [00131] “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. A straight chain or branched chain alkyl can have 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), or 20 or fewer. Alkyl groups may be substituted or unsubstituted. [00132] As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents. [00133] "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. In various aspects, cycloalkyls have from 3-10 carbon atoms in their ring structure, or 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. [00134] Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, or from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. A substituent designated herein as alkyl can be a lower alkyl. [00135] “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). [00136] “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl but having one or more triple bonds in the moiety. [00137] The term “alkylthio” refers to an alkyl group, as defined above, having a sulfur moiety attached thereto. The “alkylthio” moiety can be represented by one of -(S)-alkyl, -(S)- alkenyl, -(S)-alkynyl, and -(S)-(CH2)m-R1, wherein m and R1 are defined below. Representative alkylthio groups include methylthio, ethylthio, and the like. The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group, as defined below, having an oxygen moiety attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O-alkenyl, -O- alkynyl, -O-(CH2)m-R10, where m and R10 are described below. [00138] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the formulae: [00139] wherein R11 and R12 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R10, or R11 and R12 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R10 represents an alkenyl, aryl, cycloalkyl, a cycloalkenyl, a heterocyclyl, or a polycyclyl; and m is zero or an integer in the range of 1 to 8. In some instances, only one of R11 or R12 can be a carbonyl, e.g., R11, R12, and the nitrogen together do not form an imide. R11 and R12 each independently can represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m- R10. Thus, the term “alkylamine” as used herein means an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R11 and R12 is an alkyl group. An amino group or an alkylamine is basic, meaning it has a conjugate acid with a pKa > 7.00, i.e., the protonated forms of these functional groups have pKas relative to water above about 7.00. [00140] The term “amide”, as used herein, refers to a group [00141] wherein each R13 independently represent a hydrogen or hydrocarbyl group, or two R13 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. [00142] The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). In various aspects, aryl groups include 5- to 12-membered rings, or 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, 5- to 12-membered rings, or 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic. Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 4 substituents, 1 to 3 substituents, 1 to 2 substituents or just 1 substituent. The aromatic ring may be substituted at one or more ring positions with one or more substituents, such as halogen, azide, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. For example, the aryl group can be an unsubstituted C5-C12 aryl or the aryl group can be a substituted C5-C10 aryl. [00143] The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. Halo can be selected from the group consisting of fluoro, chloro and bromo. [00144] The terms “heterocyclyl” or “heterocyclic group” refer to 3- to 12-membered ring structures, 5- to 12-membered rings, or 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocycles can be saturated or unsaturated. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like. [00145] The term “carbonyl” is art-recognized and includes such moieties as can be represented by the formula: [00146] or [00147] wherein X’ is a bond or represents an oxygen, a nitrogen, or a sulfur, and R14 represents a hydrogen, an alkyl, an alkenyl, -(CH2)m-R10 or a pharmaceutically acceptable salt, R15 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R10, where m and R10 are as defined above. Where X’ is an oxygen and R14 or R15 is not hydrogen, the formula represents an “ester.” Where X’ is an oxygen, and R14 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R14 is a hydrogen, the formula represents a “carboxylic acid”. Where X’ is an oxygen, and R15 is a hydrogen, the formula represents a “formate.” In general, where the oxygen atom of the above formula is replaced by a sulfur, the formula represents a “thiocarbonyl” group. Where X’ is a sulfur and R14 or R15 is not hydrogen, the formula represents a “thioester” group. Where X’ is a sulfur and R14 is a hydrogen, the formula represents a “thiocarboxylic acid” group. Where X’ is a sulfur and R15 is a hydrogen, the formula represents a “thioformate” group. On the other hand, where X’ is a bond, and R14 is not hydrogen, the above formula represents a “ketone” group. Where X’ is a bond, and R14 is a hydrogen, the above formula represents an “aldehyde” group. [00148] As used herein, the term “nitro” means -NO2; the term “halogen” designates - F, -Cl, -Br, or -I; the term “sulfhydryl” means -SH; the term “hydroxyl” means -OH; the term “sulfonyl” means -SO2-; the term “azido” means –N3; the term “cyano” means –CN; the term “isocyanato” means –NCO; the term “thiocyanato” means –SCN; the term “isothiocyanato” means –NCS; and the term “cyanato” means –OCN. [00149] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. [00150] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aryl, or an aromatic or heteroaromatic moiety. The substituents on substituted alkyls can be selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. The substituents on substituted alkyls can be selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. [00151] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. [00152] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in the specification are indicative of the level of skill of those in the art to which the disclosure pertains. All such publications are incorporated herein by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference. [00153] The invention illustratively described herein may be suitably practiced in the absence of any element(s) or limitation(s), which is/are not specifically disclosed herein. Thus, for example, each instance herein of any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms. Likewise, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, references to "the method" includes one or more methods and/or steps of the type, which are described herein and/or which will become apparent to those ordinarily skilled in the art upon reading the disclosure. [00154] The terms and expressions, which have been employed, are used as terms of description and not of limitation. In this regard, where certain terms are defined under "Definitions" and are otherwise defined, described, or discussed elsewhere in the "Detailed Description," all such definitions, descriptions, and discussions are intended to be attributed to such terms. There also is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof. Furthermore, while subheadings, e.g., "Definitions," are used in the "Detailed Description," such use is solely for ease of reference and is not intended to limit any disclosure made in one section to that section only; rather, any disclosure made under one subheading is intended to constitute a disclosure under each and every other subheading. [00155] It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the disclosure contained herein in view of information known to the ordinarily skilled artisan and may be made without departing from the scope of the disclosure. Having now described the present disclosure in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the disclosure. EXAMPLES [00156] The present invention can be better understood by reference to the following examples which are offered by way of illustration. The present invention is not limited to the examples given herein. [00157] Scheme 1, herein, shows a general approach for the synthesis of the compounds described herein: Scheme 1 wherein X can represent the group: . [00158] Synthesis of Inhibitors 19 and 20: [00159] Preparation of Compound B: [00160] 1,1'-Carbonyldiimidazole (1.11 g, 6.87 mmol) was dissolved in 10 mL dry acetonitrile at 23 °C and 4-pyridinemethanol (500 mg, 4.58 mmol) was added to the vigorously stirred solution. After 1h, the solvent was evaporated under reduced pressure. The resulting crude oil was diluted in 30 mL ethyl acetate and 30 mL water and partitioned. The combined organic layers were washed with saturated sodium bicarbonate solution and brine. The volatiles were removed under reduced pressure, furnishing the carbamate (890 mg) as a white solid. The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the crude product was used for the subsequent reaction without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.70 – 8.66 (m, 2H), 8.18 (t, J = 1.1 Hz, 1H), 7.46 (t, J = 1.5 Hz, 1H), 7.34 – 7.30 (m, 2H), 7.10 (dd, J = 1.7, 0.9 Hz, 1H), 5.43 (d, J = 0.7 Hz, 2H). [00161] To a solution of L-tert-leucine methyl ester hydrochloride (300 mg, 2.07 mmol) in 20 mL CH ₂ Cl ₂ at 0 °C were added DMAP (51 mg, 0.41 mmol) and N,N- diisopropylethylamine (720 µL, 4.14 mmol). To this reaction mixture was added the above carbamate (420 mg, 2.07 mmol) solution in 2.0 mL CH ₂ Cl ₂ dropwise at 0 °C. The resulting solution was warmed to 23°C and stirred for 12h. The reaction was quenched by saturated sodium bicarbonate solution and extracted with CH ₂ Cl ₂ (3x). The combined organic layers were washed with saturated sodium bicarbonate solution, and brine. The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the residue was purified by column chromatography (0-1% MeOH/CH ₂ Cl ₂ ) to give the coupling product (394 mg, 68%) as fluffy white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (d, J = 5.0 Hz, 2H), 7.22 – 7.16 (m, 2H), 5.63 (d, J = 9.7 Hz, 1H), 5.08 (s, 2H), 4.15 (d, J = 9.7 Hz, 1H), 3.70 (s, 3H), 0.96 (s, 9H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 171.9, 155.6, 149.8, 145.3, 121.6, 64.8, 62.1, 51.7, 34.6, 26.3. ESI-MS (m/z): [M + H] ⁺ 281.1 [00162] To a vigorously stirring solution of above methyl ester (280 mg, 1.0 mmol) in a mixture of 1.7 mL THF and 5.0 mL H ₂ O at 0 °C was added LiOH·H ₂ O (126 mg, 3.0 mmol). After 1 h, the solvent was evaporated under reduced pressure. The reaction mixture was diluted with ethyl acetate and neutralized with 1 N HCl. The solution was extracted with EtOAc (3x), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the corresponding acid B (222 mg, 83%) as a white solid. The crude residue was used for the subsequent reaction without further purification. [00163] Preparation of cyanide derivative (D): Compound 4: [00164] Boc-protected amino ester C (286 mg, 1.0 mmol) was dissolved in a 1:1 mixture of MeOH (5.0 mL) and NH4OH (28-30% NH ₃ , 5.0 mL) at 23°C. The reaction mixture was stirred for 24 h. Upon completion, the solvents were evaporated under reduced pressure and the crude primary amide was used for the subsequent reaction without further purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.20 (s, 1H), 7.03 – 6.73 (m, 1H), 6.23 (s, 1H), 6.08 (d, J = 7.2 Hz, 1H), 4.33 (d, J = 8.3 Hz, 1H), 3.38 – 3.25 (m, 2H), 2.58 – 2.42 (m, 1H), 2.35 (d, J = 8.3 Hz, 1H), 2.05 (d, J = 6.9 Hz, 1H), 1.89 – 1.76 (m, 2H), 1.41 (s, 9H). [00165] To a solution of the above primary amide (271 mg, 1.0 mmol) in 2.5 mL CH ₂ Cl ₂ at 0 °C were added p-toluene sulfonyl chloride (381 mg, 2.0 mmol) and pyridine (402 µL, 5.0 mmol). The resulting solution was warmed to 23°C and stirred for 18h. The reaction was quenched by saturated sodium bicarbonate solution and extracted with CH ₂ Cl ₂ (3x). The combined organic layers were washed with 1N HCl, saturated sodium bicarbonate solution and brine. The organic phase was dried over Na ₂ SO ₄ , concentrated under reduced pressure and the residue was purified by column chromatography (0-2% MeOH/CH ₂ Cl ₂ ) to give the nitrile D (131 mg, 52%) as fluffy white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.46 (s, 1H), 6.06 – 5.77 (m, 1H), 4.67 (d, J = 8.2 Hz, 1H), 3.36 (dd, J = 9.2, 6.2 Hz, 2H), 2.56 – 2.36 (m, 2H), 2.34 – 2.22 (m, 1H), 1.93 (dt, J = 13.6, 6.5 Hz, 1H), 1.85 (td, J = 9.4, 2.9 Hz, 1H), 1.45 (s, 9H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 178.8, 154.6, 118.8, 80.9, 41.0, 40.3, 37.7, 34.3, 28.2. HRMS (ESI/Q-TOF) m/z: [M + Na] ⁺ calcd for C ₁₂ H ₁₉ N ₃ O ₃ Na 276.1319, found: 276.1322. Preparation of Compound F: [00166] Following the procedure described for the preparation of nitrile D using boc- protected amino ester E (150 mg, 0.5 mmol), afforded the nitrile F (60 mg, 45%) as fluffy white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.61 (s, 1H), 6.21 (d, J = 7.6 Hz, 1H), 4.68 (d, J = 8.6 Hz, 1H), 3.29 (ddt, J = 9.0, 4.8, 2.1 Hz, 2H), 2.46 – 2.26 (m, 2H), 2.10 – 1.96 (m, 1H), 1.87 (dq, J = 13.6, 4.5 Hz, 2H), 1.80 – 1.64 (m, 1H), 1.55 (ddd, J = 13.8, 8.1, 3.0 Hz, 1H), 1.43 (s, 9H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 173.9, 154.8, 119.1, 80.7, 42.1, 40.9, 37.7, 34.9, 28.2, 27.1, 21.5. HRMS (ESI/LTQ) m/z: [M + H] ⁺ calcd for C ₁₃ H ₂₂ N ₃ O ₃ 268.16609, found: 268.16614. Preparation of compounds G and H: Preparation of Compound G: [00167] To a solution of tert-butyl ((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)carbamate D (77 mg, 0.30 mmol) in CH ₂ Cl ₂ (2 mL) at 0 °C was added trifluoroacetic acid (1.2 mL) and the solution was stirred for 2 h at 23 °C. After evaporating the solvent under reduced pressure, the corresponding deprotected lactam residue I (47 mg, 0.30 mmol) was dissolved in DMF (4 mL) and acid L (77 mg, 0.30 mmol), EDC. HCl (70 mg, 0.37 mmol), HOBt (47 mg, 0.30 mmol), and N-methylmorpholine (83 µL, 0.76 mmol) were added at 0°C. After 10 minutes, the ice bath was removed, and the reaction mixture was stirred at 23°C for 12h. The solvent was then evaporated under high vacuum, and the residue was dissolved in ethyl acetate. The organic layer was washed with water, 1N HCl, and brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure and the residue was purified by column chromatography (1-2% MeOH/ CH ₂ Cl ₂ ) to give the Boc-protected amide G (85 mg, 71%) as white fluffy solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.54 (d, J = 7.4 Hz, 1H), 6.94 (s, 1H), 4.86 (ddd, J = 10.8, 7.5, 5.4 Hz, 1H), 4.10 (s, 1H), 3.56 (dd, J = 6.6, 4.5 Hz, 1H), 3.48 (d, J = 11.2 Hz, 1H), 3.40 – 3.34 (m, 2H), 2.66 (ddd, J = 13.8, 10.8, 5.0 Hz, 1H), 2.39 (qd, J = 10.3, 9.0, 3.1 Hz, 2H), 1.99 – 1.91 (m, 1H), 1.87 – 1.80 (m, 1H), 1.48 (d, J = 7.4 Hz, 1H), 1.43 (s, 9H), 1.28 (dd, J = 7.4, 5.1 Hz, 1H), 1.02 (s, 3H), 0.90 (s, 3H). ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 178.7, 173.1, 153.9, 118.4, 81.2, 61.8, 46.3, 40.4, 38.9, 37.7, 33.2, 32.6, 28.2, 27.5, 25.9, 19.1, 12.2. ESI-MS (m/z): [M + H] ⁺ 391.2 Preparation of Compound H: [00168] Following the procedure described for the preparation of nitrile G using boc- protected amine F (38 mg, 0.14 mmol) and acid L (36 mg, 0.14 mmol) afforded the coupled amide H (27 mg, 47%) as fluffy white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.56 (d, J = 7.8 Hz, 1H), 6.86 (s, 1H), 5.03 – 4.92 (m, 1H), 4.06 (d, J = 3.8 Hz, 1H), 3.63 (dt, J = 13.1, 6.2 Hz, 1H), 3.46 (d, J = 11.1 Hz, 1H), 3.35 – 3.23 (m, 2H), 2.69 (ddt, J = 14.6, 11.4, 5.8 Hz, 1H), 2.31 – 2.07 (m, 2H), 2.04 – 1.82 (m, 3H), 1.78 – 1.62 (m, 1H), 1.54 (dd, J = 18.5, 7.3 Hz, 1H), 1.40 (d, J = 4.1 Hz, 9H), 1.23 (s, 1H), 1.01 (s, 3H), 0.89 (s, 3H). ¹³ C{ ¹ H} NMR (100 MHz, CDCl ₃ ) δ 173.5, 173.0, 153.8, 118.6, 81.0, 61.7, 46.3, 42.0, 38.4, 37.6, 33.8, 32.7, 28.17, 26.5, 26.0, 25.9, 21.5, 19.1, 12.3. ESI-MS (m/z): [M + H] ⁺ 405.3 Synthesis of inhibitor 19: [00169] To a solution of amide G (13 mg, 0.03 mmol) in CH ₂ Cl ₂ (200 µL) at 0 °C was added trifluoroacetic acid (130 µL) and the solution was stirred for 2 h at 23 °C. After evaporating the solvent under reduced pressure, the corresponding deprotected lactam residue M (9.7 mg, 0.03 mmol) was dissolved in DMF (0.5 mL) and acid B (9 mg, 0.03 mmol), HATU (15 mg, 0.04 mmol), and N,N-diisopropylethylamine (14 µL, 0.08 mmol) were added at 0°C. After 10 minutes, the ice bath was removed, and the reaction mixture was stirred at 23°C for 15h. The solvent was then evaporated under high vacuum, and the residue was dissolved in ethyl acetate. The organic layer was washed with water, 1N HCl, and brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure and the residue was purified by column chromatography (1-4% MeOH/ CH ₂ Cl ₂ ) to give the inhibitor 19 (9 mg, 51%) as white fluffy solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (d, J = 5.6 Hz, 2H), 8.27 (d, J = 6.6 Hz, 1H), 7.23 (d, J = 5.3 Hz, 2H), 5.97 (s, 1H), 5.55 (d, J = 9.8 Hz, 1H), 5.12 (d, J = 6.1 Hz, 1H), 5.06 (d, J = 3.3 Hz, 1H), 4.86 (dt, J = 11.3, 6.2 Hz, 1H), 4.26 (s, 1H), 4.24 – 4.21 (m, 1H), 3.92 (t, J = 5.0 Hz, 1H), 3.85 (d, J = 10.2 Hz, 1H), 3.36 (d, J = 6.7 Hz, 2H), 2.56 (t, J = 9.3 Hz, 1H), 2.40 (d, J = 6.1 Hz, 1H), 2.36 – 2.31 (m, 1H), 2.04 – 1.98 (m, 1H), 1.87 (s, 1H), 1.06 (s, 1H), 1.04 (s, 3H), 1.01 (s, 9H), 0.85 (d, J = 7.2 Hz, 1H), 0.81 (s, 3H). ESI-MS (m/z): [M + H] ⁺ 539.3 Synthesis of inhibitor 20: [00170] Following the procedure described for the preparation of inhibitor 19 using amide H (15 mg, 0.04 mmol) and acid B (10 mg, 0.04 mmol), afforded inhibitor 20 (4 mg, 20%) as fluffy white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.60 (s, 2H), 8.31 (d, J = 6.6 Hz, 1H), 7.21 (s, 2H), 6.15 (s, 1H), 5.55 (d, J = 10.1 Hz, 1H), 5.11 (s, 1H), 5.06 (d, J = 6.0 Hz, 1H), 4.92 – 4.81 (m, 1H), 4.25 (d, J = 3.9 Hz, 1H), 4.22 (s, 1H), 3.93 (dd, J = 10.4, 4.8 Hz, 1H), 3.84 (d, J = 9.9 Hz, 1H), 3.31 (s, 2H), 2.40 (d, J = 9.7 Hz, 1H), 2.33 (t, J = 7.6 Hz, 1H), 2.08 – 2.00 (m, 2H), 1.94 (dd, J = 9.3, 4.1 Hz, 1H), 1.89 – 1.83 (m, 2H), 1.03 (d, J = 1.9 Hz, 3H), 1.01 (s, 9H), 0.85 (d, J = 7.0 Hz, 2H), 0.81 (s, 3H). ESI-MS (m/z): [M + H] ⁺ 553.2 [00171] Synthesis of inhibitor 21. To a solution of acid O (40 mg, 0.084 mmol, 1 equiv.) in dry DMF (2.5 mL), corresponding amine I (25.4 mg, 0.10 mmol, 1.2 equiv.), HATU (38.7 mg, 0.10 mmol, 1.2 equiv.) and DIPEA (55 mg, 0.42 mmol, 5 equiv.) were added at 0 °C. The reaction was stirred at room temperature for 12 h. After this period, the reaction was quenched with water, the reaction mixture was extracted with ethyl acetate and brine. The reaction product was purified using flash column chromatography (DCM: MeOH) (98:2) to furnish inhibitor 21 (8 mg) as a colorless solid. Yield: 23%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.10 (s, 1H), 6.80 (d, J = 7.7 Hz, 1H), 5.32 (d, J = 18.5 Hz, 1H), 4.60 (s, 1H), 4.17 – 3.98 (m, 1H), 3.35 (s, 1H), 2.45 (s, 1H), 2.31 (d, J = 7.6 Hz, 2H), 2.01 (m, 3H), 1.70 – 1.53 (m, 9H), 1.29 (d, J = 33.8 Hz, 17H), 1.03 (d, J = 15.1 Hz, 2H), 0.86 (dt, J = 13.4, 8.1 Hz, 6H). [00172] Synthesis of inhibitor 22. To a solution of amine P (25 mg, 0.061 mmol, 1 equiv.) in dry DMF (2.5 mL), N-Boc-L-tert-leucine Q (17 mg, 0.074 mmol, 1.2 equiv.), HATU (28 mg, 0.074 mmol, 1.2 equiv.) and DIPEA (40 mg, 0.31 mmol, 5 equiv.) were added at 0 °C. The reaction was stirred at room temperature for 12 h. After this period, the reaction was quenched with water, the reaction mixture was extracted with ethyl acetate and brine. The reaction product was purified using flash column chromatography (DCM: MeOH) (98:2) to furnish inhibitor 22 (13 mg) as a colorless solid. Yield: 40%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 7.3 Hz, 1H), 6.28 (s, 1H), 5.44 – 5.21 (m, 1H), 4.90 (d, J = 6.1 Hz, 1H), 4.45 (t, J = 7.9 Hz, 1H), 4.29 (d, J = 9.9 Hz, 1H), 4.10 (dd, J = 14.3, 7.1 Hz, 2H), 3.98 (d, J = 10.9 Hz, 1H), 3.64 (dd, J = 10.8, 3.3 Hz, 1H), 3.40 – 3.22 (m, 4H), 2.65 (d, J = 8.2 Hz, 1H), 2.45 – 2.30 (m, 2H), 2.29 – 2.13 (m, 2H), 1.97 – 1.70 (m, 2H), 1.63 – 1.49 (m, 2H), 1.49 – 1.31 (m, 11H), 1.01 – 0.80 (m, 13H). [00173] Synthesis of inhibitor 22. To a solution of amine R (20 mg, 0.049 mmol, 1 equiv.) in dry DMF (2.0 mL), acid B (16 mg, 0.059 mmol, 1.2 equiv.), HATU (23 mg, 0.059 mmol, 1.2 equiv.) and DIPEA (31.9 mg, 0.25 mmol, 5 equiv.) were added at 0 °C. The reaction was stirred at room temperature for 12 h. After this period, the reaction was quenched with water, the reaction mixture was extracted with ethyl acetate and brine. The reaction product was purified using flash column chromatography (DCM: MeOH) (98:2) to furnish inhibitor 22 (13 mg) as a colorless solid. Yield: 55%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.59 (s, 2H), 8.27 (d, J = 7.2 Hz, 1H), 7.33 – 7.25 (m, 2H), 6.07 (d, J = 18.8 Hz, 1H), 5.85 (dd, J = 22.8, 9.4 Hz, 1H), 5.18 – 5.00 (m, 2H), 4.89 (dd, J = 10.8, 5.5 Hz, 1H), 4.64 – 4.39 (m, 1H), 4.40 – 4.15 (m, 2H), 3.82 (d, J = 10.7 Hz, 1H), 3.77 – 3.53 (m, 2H), 3.30 (dd, J = 19.2, 11.8 Hz, 2H), 2.67 (d, J = 8.8 Hz, 1H), 2.45 – 2.31 (m, 2H), 2.18 (ddd, J = 43.5, 26.0, 4.0 Hz, 4H), 1.96 – 1.73 (m, 2H), 1.36 (s, 1H), 1.13 – 0.81 (m, 15H). [00174] Synthesis of inhibitor 26. To a solution of amine R (30 mg, 0.073 mmol, 1 equiv.) in dry DMF (3.0 mL), acid (21 mg, 0.086 mmol, 1.2 equiv.), HATU (34 mg, 0.086 mmol, 1.2 equiv.) and DIPEA (48 mg, 0.37 mmol, 5 equiv.) were added at 0 °C. The reaction was stirred at room temperature for 12 h. After this period, the reaction was quenched with water, the reaction mixture was extracted with ethyl acetate and brine. The reaction product was purified using flash column chromatography (DCM: MeOH) (98:2) to furnish inhibitor 26 (15 mg) as a colorless solid. Yield: 39%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.10 (dd, J = 64.4, 41.3 Hz, 1H), 5.41 – 5.09 (m, 1H), 4.49 (t, J = 37.0 Hz, 1H), 4.38 – 4.03 (m, 2H), 3.98 – 3.79 (m, 1H), 3.64 (ddd, J = 15.8, 9.9, 5.4 Hz, 2H), 3.43 – 3.20 (m, 2H), 2.72 – 2.50 (m, 1H), 2.50 – 2.25 (m, 2H), 2.26 – 2.02 (m, 2H), 1.98 – 1.73 (m, 2H), 1.54 – 1.24 (m, 15H), 1.22 – 0.79 (m, 15H). [00175] Synthesis of inhibitor 29. To a solution of compound 26 (20 mg, 0.038 mmol, 1 equiv.) in dry DCM (3.0 mL), Trifluoroacetic anhydride (40 mg, 0.19 mmol, 5.0 equiv.), ZnCl ₂ (2 mg, 0.002 mmol, 0.2 equiv.) were added at 0 °C. The reaction was stirred at room temperature for 12 h. After this period, the reaction was quenched with water, the reaction mixture was extracted with ethyl acetate and brine. The reaction product was purified using flash column chromatography (DCM: MeOH) (98:2) to furnish inhibitor 26 (6 mg) as a colorless solid. Yield: 30%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.11 – 7.02 (m, 1H), 6.13 – 5.71 (m, 2H), 4.95 – 4.73 (m, 1H), 4.73 – 4.54 (m, 2H), 4.54 – 4.39 (m, 1H), 4.27 (dd, J = 22.1, 13.0 Hz, 2H), 3.90 – 3.71 (m, 2H), 3.63 (ddd, J = 9.7, 6.1, 4.4 Hz, 1H), 3.44 – 3.27 (m, 3H), 2.84 (d, J = 14.4 Hz, 1H), 2.43 – 2.27 (m, 2H), 2.27 – 2.10 (m, 2H), 2.08 – 1.83 (m, 3H), 1.76 (s, 2H), 1.18 – 1.06 (m, 7H), 1.05 – 0.95 (m, 11H). IC ₅₀ value (SARS-Cov-23CLpro inhibition) determination. [00176] IC50 values were determined for compounds that covalently inhibit SARS-CoV- 23CLpro using a recently described assay (Ghosh, A. K. et al. Bioorg. Med. Chem. Lett.2007, 17, 5876–5880) and data fitting methods that were derived from our previous work on SARS- CoV 3CLpro. The only differences were that pre-incubation of the enzyme with the compounds was 10 minutes instead of 20 minutes. In addition, the Morrison Equation was only used to determine the IC50 value when they were below 1 µM. Determination of Antiviral activity. [00177] Antiviral assay was carried out as described recently. (Hattori, S.-I et al. Nat. Commun. 2021, 12, 668; Hattori, S.-i. et al. mBio 2020, 11, e01833-20) [00178] Cells were seeded in a 96-well plate (2x10 ⁴ cells/well) and incubated. After 24 h, virus was inoculated into cells at multiplicity of infection (MOI) of 0.05. After an additional 72 h, cell culture supernatants were harvested and viral RNA was extracted using a QIAamp viral RNA minikit (Qiagen, Hilden, Germany), and quantitative RT-PCR (RT-qPCR) was then performed using One Step PrimeScript III RT-qPCR mix (TaKaRa Bio, Shiga, Japan) following the instructions of the manufacturers. The primers and probe used for detecting SARS-CoV-2 envelope (6) were 5’-ACT TCT TTT TCT TGC TTT CGT GGT-3’ (forward), 5’-GCA GCA GTA CGC ACA CAA TC-3’ (reverse), and 5’-FAM-CTA GTT ACA CTA GCC ATC CTT ACT GC-black hole quencher 1 (BHQ1)-3’ (probe). To determine the cytotoxicity of each compound, cells were seeded in a 96-well plate (2x10 ⁴ cells/well). One day later, various concentrations of each compound were added, and cells were incubated for additional 3 days. The 50% cytotoxic concentrations (CC50) values were determined using the WST-8 assay and Cell Counting Kit-8 (Dojindo, Kumamoto, Japan). [00179] Table 1. Biological Evaluation Data Range Key: 0.1 - 999 nM ++++ 1.0 - 10 µM +++ 10.1 – 100 µM ++ >100 µM +