Patent Publication Number: US-2023151019-A1

Title: Novel spiropyrrolidine derived antiviral agents

Description:
RELATED APPLICATION 
     This application claims the benefit of U.S. Provisional Application No. 63/278,917, filed on Nov. 12, 2021. The entire teachings of the above application are incorporated herein by reference. 
    
    
     TECHNICAL FIELD 
     The invention relates to compounds and methods of inhibiting coronavirus replication activity by targeting the 3C-Like protease (sometimes referred to as “3CLpro”, “Main protease”, or “Mpro”) with a therapeutically effective amount of a 3C-Like protease inhibitor. The invention further relates to pharmaceutical compositions containing the coronavirus 3C-Like protease inhibitor in a mammal by administering effective amounts of such coronavirus 3C-Like protease inhibitor. 
     BACKGROUND OF THE INVENTION 
     Coronaviruses are family of single-stranded, positive-strand RNA viruses with viral envelopes, classified within the Nidovirales order. The coronavirus family comprises pathogens of many animal species, including humans, horses, cattle, pigs, birds, cats and monkeys, and have been known for more than 60 years. The isolation of the prototype murine coronavirus strain JHM, for example, was reported in 1949. Coronaviruses are common viruses that generally cause mild to moderate upper-respiratory tract illnesses in humans and are named for the crown-like spikes on their envelope surface. There are four major sub-groups known as alpha, beta, gamma and delta coronaviruses, with the first coronaviruses identified in the mid-1960s. The coronaviruses known to infect humans include alpha coronaviruses 229E and NL63; and beta coronaviruses OC43, HKU1, SARS-CoV (the coronavirus that causes severe acute respiratory syndrome, or SARS), and MERS-CoV (the coronavirus that causes Middle East Respiratory Syndrome, or MERS). People are commonly infected with human coronaviruses 229E, NL63, 0C43 and HKU1, and symptoms usually include mild to moderate upper-respiratory tract illnesses of short duration, such as runny nose, cough, sore throat and fever. Occasionally human coronaviruses result in lower-respiratory tract illnesses, such as pneumonia, although this is more common in people with cardiopulmonary disease or compromised immune systems, or in the elderly. Transmission of the common human coronaviruses is not fully understood. However, it is likely that human coronaviruses spread from an infected person to others through the air by coughing and sneezing, and through close personal contact, such as touching or shaking hands. These viruses may also spread by touching contaminated objects or surfaces then touching the mouth, nose, or eyes. 
     Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. The genomic RNA of CoVs has a 5′-cap structure and 3′-poly-A tail and contains at least 6 open reading frames (ORFs). The first ORF (ORF 1a/b) directly translates two polyproteins: pp1a and pp1ab. These polyproteins are processed by a 3C-Like protease (3CLpro), also known as the main protease (Mpro), into 16 non-structural proteins. These non-structural proteins engage in the production of subgenomic RNAs that encode four structural proteins, namely envelope, membrane, spike, and nucleocapsid proteins, among other accessory proteins. As a result, it is understood that 3C-Like protease has a critical role in the coronavirus life cycle. 
     3CLpro is a cysteine protease involved in most cleavage events within the precursor polyprotein. Active 3CLpro is a homodimer containing two protomers and features a Cys-His dyad located in between domains I and II. 3CLpro is conserved among coronaviruses and several common features are shared among the substrates of 3CLpro in different coronaviruses. As there is no human homolog of 3CLpro, it is an ideal antiviral target. Although compounds have been reported to inhibit 3CLpro activity, only one has been approved as a coronavirus therapy. (Refer to WO2004101742 A2, US 2005/0143320 A1, US 2006/0014821 A1, US 2009/0137818 A1, WO2013/049382 A2, WO2013/166319 A1, WO2018042343 A1, WO2018023054 A1, WO2005113580 A1, WO2006061714 A1, WO2021/205296 A1, WO2021/206876 A1, WO2021/206877 A1, WO2021/207409 A2, WO2021/176369, WO2021/191827, WO2021/212039, WO2021/252491, WO2022/020242, WO2022/020711, WO2022/036018, WO2022/109360, WO2022/109363, U.S. Pat. No. 11,124,497 B1, U.S. Pat. No. 11,174,231 B1 and U.S. Pat. No. 11,351,149 B1). 
     More effective therapies for coronavirus infections are needed due to this high unmet clinical need. 
     SUMMARY OF THE INVENTION 
     The present invention relates to novel antiviral compounds, pharmaceutical compositions comprising such compounds, as well as methods for treating or preventing a viral (particularly coronavirus) infection in a subject in need of such therapy with said compounds. Compounds of the present invention inhibit the protein(s) encoded by a coronavirus or interfere with the life cycle of a coronavirus and are also useful as antiviral agents. In addition, the present invention provides processes for the preparation of said compounds. 
     In certain embodiments, the present invention provides compounds represented by Formula (I), and pharmaceutically acceptable salts, esters and prodrugs thereof, 
     
       
         
         
             
             
         
       
     
     wherein:
 
A is selected from:
 
     1) —R 11 ; 
     2) —OR 12 ; and 
     3) —NR 13 R 14 ; 
     -L 1 - is 
     
       
         
         
             
             
         
       
     
     -L 2 - is 
     
       
         
         
             
             
         
       
     
     B is an optionally substituted aryl or optionally substituted heteroaryl;
 
X is selected from:
 
     1) —CN; 
     2) —C(O)R 15 ; 
     3) —CH(OH)SO 3 R 16 ; 
     4) —C(O)NR 13 R 14 ;
         5) —C(O)C(O)NR 13 R 14 ; and   6) —C≡C—R 17 ;
 
R 1 , R 2 , R 3 , R 5 , R 6 , and R 17  are each independently selected from:
       

     1) Hydrogen; 
     2) Optionally substituted —C 1 -C 8  alkyl; 
     3) Optionally substituted —C 2 -C 8  alkenyl; 
     4) Optionally substituted —C 2 -C 8  alkynyl; 
     5) Optionally substituted —C 3 -C 8  cycloalkyl; 
     6) Optionally substituted 3- to 8-membered heterocycloalkyl; 
     7) Optionally substituted aryl; 
     8) Optionally substituted arylalkyl; 
     9) Optionally substituted heteroaryl; and 
     10) Optionally substituted heteroarylalkyl; 
     alternatively, R 1  and R 2  are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 8-membered carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring; 
     alternatively, R 2  and R 3  are taken together with the atoms to which they are attached to form an optionally substituted 4- to 8-membered heterocyclic ring; 
     alternatively, R 5  and R 6  are taken together with the carbon atom to which they are attached to form an optionally substituted 3- to 8-membered carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring; 
     R 4  is hydrogen, optionally substituted —C 1 -C 4  alkyl, optionally substituted C 2 -C 4 -alkenyl, or optionally substituted —C 3 -C 6  cycloalkyl;
 
R 11  is selected from:
 
     1) Optionally substituted —C 1 -C 8  alkyl; 
     2) Optionally substituted —C 2 -C 8  alkenyl; 
     3) Optionally substituted —C 2 -C 8  alkynyl; 
     4) Optionally substituted —C 3 -C 8  cycloalkyl; 
     5) Optionally substituted 3- to 8-membered heterocycloalkyl; 
     6) Optionally substituted aryl; 
     7) Optionally substituted arylalkyl; 
     8) Optionally substituted heteroaryl; and 
     9) Optionally substituted heteroarylalkyl; 
     R 12 , R 13 , and R 14  are each independently selected from: 
     1) Hydrogen; 
     2) Optionally substituted —C 1 -C 8  alkyl; 
     3) Optionally substituted —C 2 -C 8  alkenyl; 
     4) Optionally substituted —C 2 -C 8  alkynyl; 
     5) Optionally substituted —C 3 -C 8  cycloalkyl; 
     6) Optionally substituted 3- to 8-membered heterocycloalkyl; 
     7) Optionally substituted aryl; 
     8) Optionally substituted arylalkyl; 
     9) Optionally substituted heteroaryl; and 
     10) Optionally substituted heteroarylalkyl; 
     alternatively, R 13  and R 14  are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 8-membered heterocyclic ring; 
     R 15  is hydrogen, hydroxy, optionally substituted —C 1 -C 8  alkyl, or optionally substituted heteroary; preferably R 15  is hydrogen, hydroxy, CH 2 OH, CH 2 F, CH 2 Cl or benzothiazole, and R 16  is hydrogen or Na + . 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     In one embodiment, the present invention provides a compound of Formula (I) as described above, or a pharmaceutically acceptable salt thereof. 
     In one embodiment of the present invention, the compound of Formula (I) is represented by Formula (I-A) or Formula (I-B), or a pharmaceutically acceptable salt, ester or prodrug thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, B, L 1 , L 2 , X, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are as previously defined. 
     In a preferred embodiment, the compound of Formula (I) has the stereochemistry shown in Formula (I-A). 
     In certain embodiments of the compounds of Formula (I), R 1  is hydrogen, optionally substituted —C 1 -C 6  alkyl; optionally substituted —C 3 -C 6  cycloalkyl; optionally substituted C 3 -C 6  cycloalkyl-C 1 -C 2 -alkyl; optionally substituted aryl; optionally substituted arylalkyl; or optionally substituted heteroarylalkyl. 
     In certain embodiments of the compounds of Formula (I), R 1  is selected from the groups below: 
     
       
         
         
             
             
         
       
     
     In certain embodiments of the compounds of Formula (I), R 2  is hydrogen, optionally substituted —C 1 -C 6  alkyl; optionally substituted —C 3 -C 6  cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; or optionally substituted heteroarylalkyl. 
     In certain embodiments of the compounds of Formula (I), R 3  is hydrogen, -Me, -Et, —Pr, -i-Pr, -allyl, —CF 3 , —CD 3 , —CH 2 CF 3 , —CH 2 CHF 2  or cyclopropyl. 
     In certain embodiments of the compounds of Formula (I), R 4  is hydrogen, -Me, -Et, —Pr, -i-Pr, -allyl, —CF 3  or cyclopropyl. 
     In certain embodiments of the compounds of Formula (I), R 3  is hydrogen or optionally substituted —C 1 -C 4  alkyl; and R 4  is hydrogen or optionally substituted —C 1 -C 4  alkyl. 
     In certain embodiments of the compounds of Formula (I), R 5  is hydrogen, optionally substituted —C 1 -C 6  alkyl; optionally substituted —C 3 -C 6  cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; or optionally substituted heteroarylalkyl. 
     In certain embodiments of the compounds of Formula (I), R 6  is hydrogen, optionally substituted —C 1 -C 6  alkyl; optionally substituted —C 3 -C 6  cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; or optionally substituted heteroarylalkyl. 
     In certain embodiments of the compounds of Formula (I), R 5  and R 6  are both hydrogen; R 5  and R 6  are both methyl; or R 5  and R 6  are taken together with the carbon atom to which they are attached to form 3- to 7-membered cycloalkyl. 
     In certain embodiments of the compounds of Formula (I), L 1  is 
     
       
         
         
             
             
         
       
     
     and L 2  is 
     
       
         
         
             
             
         
       
     
     In certain embodiments of the compounds of Formula (I), L 1  is 
     
       
         
         
             
             
         
       
     
     L 2  is 
     
       
         
         
             
             
         
       
     
     In certain embodiments of the compounds of Formula (I), L 1  is 
     
       
         
         
             
             
         
       
     
     and L 2  is 
     
       
         
         
             
             
         
       
     
     In certain embodiments of the compounds of Formula (I), L 1  is 
     
       
         
         
             
             
         
       
     
     and L 2  is 
     
       
         
         
             
             
         
       
     
     In certain embodiments of the compounds of Formula (I), X is —CN. 
     In certain embodiments of the compounds of Formula (I), X is —C(O)H. 
     In certain embodiments of the compounds of Formula (I), X is —C(O)CH 2 OH, —C(O)CH 2 Cl, or —C(O)CH 2 F. 
     In certain embodiments of the compounds of Formula (I), X is —C(O)C(O)NR 13 R 14 , wherein R 13  and R 14  are previously defined. 
     In certain embodiments of the compounds of Formula (I), R 2  is hydrogen; and R 4  is hydrogen. 
     In certain embodiments of the compounds of Formula (I), L 1  is 
     
       
         
         
             
             
         
       
     
     L 2  is 
     
       
         
         
             
             
         
       
     
     R 1  is optionally substituted —C 1 -C 6  alkyl; optionally substituted —C 3 -C 6  cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; optionally substituted heteroarylalkyl; R 2  is hydrogen; R 3  is hydrogen, -Me, -Et, —Pr, -i-Pr, -allyl, —CF 3 , —CD 3 , —CH 2 CHF 2  or cyclopropyl; R 4  is hydrogen; and X is —CN. 
     In certain embodiments of the compounds of Formula (I), L 1  is 
     
       
         
         
             
             
         
       
     
     L 2  is 
     
       
         
         
             
             
         
       
     
     R 2  is hydrogen; R 3  is hydrogen, -Me, -Et, —Pr, -i-Pr, -allyl, —CF 3 , —CD 3 , or cyclopropyl; R 4  is hydrogen; X is —CN; and R 1  is selected from the groups below: 
     
       
         
         
             
             
         
       
     
     In certain embodiments of the compounds of Formula (I), L 1  is 
     
       
         
         
             
             
         
       
     
     L 2  is 
     
       
         
         
             
             
         
       
     
     R 2  is hydrogen; R 3  is hydrogen, -Me, -Et, —Pr, -i-Pr, -allyl, —CF 3 , —CD 3 , or cyclopropyl; R 4  is hydrogen; R 5  is n-butyl, 
     
       
         
         
             
             
         
       
     
     R 6  is hydrogen; X is —CN; and R 1  is selected from the groups below: 
     
       
         
         
             
             
         
       
     
     In certain embodiments of the compounds of Formula (I), A is derived from one of the following by removal of a hydrogen atom and is optionally substituted: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In certain embodiments of the compounds of Formula (I), A is selected from the following groups, and A is optionally substituted: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Preferably there are 0, 1, 2 or 3 substituents. Preferably the substituents are independently selected from halogen, optionally substituted —C 1 -C 3  alkoxy, optionally substituted —C 1 -C 3  alkyl, optionally substituted —C 3 -C 6  cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. 
     In certain embodiments of the compounds of Formula (I), A is selected from the following groups, and A is optionally substituted: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Preferably there are 0, 1, 2 or 3 substituents. Preferably the substituents are independently selected from halogen, CN, NH 2 , optionally substituted —C 1 -C 3  alkoxy, optionally substituted —C 1 -C 3  alkyl, optionally substituted —C 3 -C 6  cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. 
     In certain embodiments of the compounds of Formula (I), A is selected from the following groups, and A is optionally substituted: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     In certain embodiments of the compounds of Formula (I), B is selected from the following groups, and B is optionally substituted: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (II-1)˜(II-3), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (III-1)˜(III-3), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, B, R 1 , R 2 , R 3 , R 5 , R 6  and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (IV-1)˜(IV-3), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, B, R 1 , R 3 , R 5 , R 6  and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (IV-1a)˜(IV-3a), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, B, R 1 , R 3 , R 5 , R 6  and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (V-1)˜(V-3), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, B, R 1 , R 3 , R 5 , and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (VI-1)˜(VI-9), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein A, B, R 1 , R 5 , R 6  and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (VII-1)˜(VII-9), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, B, R 1 , R 5 , and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (VIII-1)˜(VIII-3), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and X are as previously defined, and
 
each R 9  is independently selected from:
 
     1) Halogen; 
     2) —CN; 
     3) —OR 13 ; 
     4) —SR 13 ; 
     5) —NR 13 R 14 ; 
     6) —OC(O)NR 13 R 14 ; 
     7) Optionally substituted —C 1 -C 6  alkyl; 
     8) Optionally substituted —C 3 -C 8  cycloalkyl; 
     9) Optionally substituted 3- to 8-membered heterocycloalkyl; 
     10) Optionally substituted aryl; and 
     11) Optionally substituted heteroaryl; 
     and n is 0, 1, 2, 3, or 4. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (IX-1)˜(IX-3), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 3 , R 4 , R 5 , R 6 , R 9 , n and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (X-1)˜(X-3), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 3 , R 5 , R 9 , n and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XI-1)˜(XI-3), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 3 , R 5 , R 6 , and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XI-1a)˜(XI-3a), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 3 , R 5 , R 6 , and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XII-1)˜(XII-9), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 5 , R 6 , and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XI-1a)˜(XI-3a) or one of Formulae (XII-1)˜(XII-9), wherein A is selected from the groups below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and R 1  is selected from the groups below: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, the compound of Formula (I) is represented by one of Formula (XIII-1) to (XIII-6): 
     
       
         
         
             
             
         
       
     
     wherein A, B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 13 , R 14 , L 1 , and L 2 , are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formula (XIV-1) to (XIV-6): 
     
       
         
         
             
             
         
       
     
     wherein A, B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 13  and R 14  are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XV-1) to (XV-6), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R 13 , R 14 , L 1  and L 2 , are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XVI-1) to (XVI-6), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 3 , R 5 , and R 6  are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XVI-1a) to (XVI-6a), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 3 , R 5 , and R 6  are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XVII-1) to (XVII-5), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 3 , and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XVII-1a) to (XVII-5a), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , R 3 , and X are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XVII-1)˜(XVII-5) or Formulae (XVII-1a)˜(XVII-5a), wherein A is selected from the groups below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     R 1  is selected from the groups below: 
     
       
         
         
             
             
         
       
     
     and X is selected from the groups below: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, the compound of Formula (I) is represented by one of Formulae (XVII-1b) to (XVII-5b), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein A, R 1 , and R 3 , are as previously defined. 
     In certain embodiments, the compound of Formula (I) is represented by Formula (XVIII-1) to (XVIII-15), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein A and R 1  are as previously defined. Preferably, R 1  is selected from the groups below: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, the compound of Formula (I) is represented by Formula (XVIII-1a) to (XVIII-15a), or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     wherein A and R 1  are as previously defined. Preferably, R 1  is selected from the groups below: 
     
       
         
         
             
             
         
       
     
     It will be appreciated that the description of the present invention herein should be construed in congruity with the laws and principles of chemical bonding. In some instances, it may be necessary to remove a hydrogen atom to accommodate a substituent at any given location. 
     It will be yet appreciated that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention. 
     In certain embodiments, the invention provides a method of treating or preventing a coronavirus infection in a subject, such as a human, in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The coronavirus can be an alpha, beta, gamma or delta coronavirus. In certain embodiments, the coronavirus is one which infects humans, such as coronavirus 229E, coronavirus NL63, coronavirus OC43, coronavirus HKU1, SARS-CoV-1, SARS-CoV-2, and MERS-CoV. In certain embodiments, the coronavirus is SARS-CoV-1, SARS-CoV-2, or MERS-CoV. Preferably the coronavirus is SARS-CoV-2. 
     Embodiments of the present invention provide administration of a compound to a healthy or virus-infected patient, either as a single agent or in combination with (1) another agent that is effective in treating or preventing coronavirus infections, (2) another agent that improves immune response and robustness, or (3) another agent that reduces inflammation and/or pain. 
     The compounds described herein, or salts, solvates or hydrates thereof, are believed to have activity in preventing, halting or reducing the effects of coronavirus by inhibiting the viral 3C or 3C-Like protease, thereby interfering with or preventing the polyprotein processing of the translated viral genome, in the host cell, rendering the virus unable to replicate. 
     In a further aspect, this invention provides for a method of treating a respiratory disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Such respiratory disorders include, but are not limited to, an acute airway disease or a chronic airway disease. Examples of such respiratory disorders include acute asthma, lung disease secondary to environmental exposures, acute lung infection, and chronic lung infection. 
     The compounds of the present invention and any other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compounds of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in combination of a compound of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds. 
     In certain embodiments of the combination therapy, the additional therapeutic agent is administered at a lower dose and/or dosing frequency as compared to dose and/or dosing frequency of the additional therapeutic agent required to achieve similar results in treating or preventing coronavirus when administered as a single agent. It should be understood that the compounds encompassed by the present invention are those that are suitably stable for use as pharmaceutical agent. 
     Definitions 
     Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group. 
     The term “aryl,” as used herein, refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring. Preferred aryl groups are C 6 -C 12 -aryl groups, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring. Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof. 
     The term “heteroaryl,” as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. In certain embodiments, a heteroaryl group is a 5- to 10-membered heteroaryl, such as a 5- or 6-membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl. Heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. A heteroaryl group can be C-attached or N-attached where possible. 
     In accordance with the invention, aryl and heteroaryl groups can be substituted or unsubstituted. 
     The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and the two rings can be fused or covalently attached. 
     The term “alkyl” as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals. “C 1 -C 4  alkyl,” “C 1 -C 6  alkyl,” “C 1 -C 8  alkyl,” “C 1 -C 12  alkyl,” “C 2 -C 4  alkyl,” and “C 3 -C 6  alkyl,” refer to alkyl groups containing from 1 to 4, 1 to 6, 1 to 8, 1 to 12, 2 to 4 and 3 to 6 carbon atoms respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl and n-octyl radicals. 
     The term “alkenyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond. “C 2 -C 8  alkenyl,” “C 2 -C 12  alkenyl,” “C 2 —C 4  alkenyl,” “C 3 -C 4  alkenyl,” and “C 3 -C 6  alkenyl,” refer to alkenyl groups containing from 2 to 8, 2 to 12, 2 to 4, 3 to 4 or 3 to 6 carbon atoms respectively. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, octenyl, and the like. 
     The term “alkynyl” as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond. “C 2 -C 8  alkynyl,” “C 2 -C 12  alkynyl,” “C 2 -C 4  alkynyl,” “C 3 -C 4  alkynyl,” and “C 3 -C 6  alkynyl,” refer to alkynyl groups containing from 2 to 8, 2 to 12, 2 to 4, 3 to 4 or 3 to 6 carbon atoms respectively. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, heptynyl, octynyl, and the like. 
     The term “cycloalkyl”, as used herein, refers to a monocyclic or polycyclic saturated carbocyclic ring, such as a bi- or tri-cyclic fused, bridged or spiro system. The ring carbon atoms are optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkyl groups include C 3 -C 12  cycloalkyl, C 3 -C 6  cycloalkyl, C 3 -C 8  cycloalkyl and C 4 -C 7  cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like. 
     The term “cycloalkenyl”, as used herein, refers to monocyclic or polycyclic carbocyclic ring, such as a bi- or tri-cyclic fused, bridged or spiro system having at least one carbon-carbon double bond. The ring carbon atoms are optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkenyl groups include C 3 -C 12  cycloalkenyl, C 4 -C 12 -cycloalkenyl, C 3 -C 8  cycloalkenyl, C 4 -C 8  cycloalkenyl and C 5 -C 7  cycloalkenyl groups. Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-2-enyl, bicyclo[4.2.1]non-3-en-12-yl, and the like. 
     As used herein, the term “arylalkyl” means a functional group wherein an alkylene chain is attached to an aryl group, e.g., —(CH 2 ) n -phenyl, where n is 1 to 12, preferably 1 to 6 and more preferably 1 or 2. The term “substituted arylalkyl” means an arylalkyl functional group in which the aryl group is substituted. Similarly, the term “heteroarylalkyl” means a functional group wherein an alkylene chain, is attached to a heteroaryl group, e.g., —(CH 2 ) n -heteroaryl, where n is 1 to 12, preferably 1 to 6 and more preferably 1 or 2. The term “substituted heteroarylalkyl” means a heteroarylalkyl functional group in which the heteroaryl group is substituted. 
     As used herein, the term “alkoxy” refers to a radical in which an alkyl group having the designated number of carbon atoms is connected to the rest of the molecule via an oxygen atom. Alkoxy groups include C 1 -C 12 -alkoxy, C 1 -C 8 -alkoxy, C 1 -C 6 -alkoxy, C 1 -C 4 -alkoxy and C 1 -C 3 -alkoxy groups. Examples of alkoxy groups includes, but are not limited to, methoxy, ethoxy, n-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred alkoxy groups include C 1 -C 3 -alkoxy. 
     An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds. Examples of aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH 2 , C(O), S(O) 2 , C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH 2 , S(O) 2 NH, S(O) 2 NH 2 , NHC(O)NH 2 , NHC(O)C(O)NH, NHS(O) 2 NH, NHS(O) 2 NH 2 , C(O)NHS(O) 2 , C(O)NHS(O) 2 NH or C(O)NHS(O) 2 NH 2 , and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group. Carbon atoms of an aliphatic group can be optionally oxo-substituted. An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted. 
     The terms “heterocyclic” and “heterocycloalkyl” can be used interchangeably and refer to a non-aromatic ring or a polycyclic ring system, such as a bi- or tri-cyclic fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted or optionally substituted with exocyclic olefinic double bond. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 2-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic or heterocycloalkyl groups may be further substituted. A heterocycloalkyl or heterocyclic group can be C-attached or N-attached where possible. 
     It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s). One of skill in the art can readily determine the valence of any such group from the context in which it occurs. 
     The term “substituted” refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, —F, —C 1 , —Br, —I, —OH, C 1 -C 12 -alkyl; C 2 -C 12 -alkenyl, C 2 -C 12 -alkynyl, —C 3 -C 12 -cycloalkyl, protected hydroxy, —NO 2 , —N 3 , —CN, —NH 2 , protected amino, oxo, thioxo, —NH—C 1 -C 12 -alkyl, —NH—C 2 -C 8 -alkenyl, —NH—C 2 -C 8 -alkynyl, —NH—C 3 -C 12 -cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C 1 -C 12 -alkyl, —O—C 2 -C 8 -alkenyl, —O—C 2 -C 8 -alkynyl, —O—C 3 -C 12 -cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —C(O)—C 1 -C 12 -alkyl, —C(O)—C 2 -C 8 -alkenyl, —C(O)—C 2 -C 8 -alkynyl, —C(O)—C 3 -C 12 -cycloalkyl, —C(O)-aryl, —C(O)— heteroaryl, —C(O)-heterocycloalkyl, —CONH 2 , —CONH—C 1 -C 12 -alkyl, —CONH—C 2 -C 8 -alkenyl, —CONH—C 2 -C 8 -alkynyl, —CONH—C 3 -C 12 -cycloalkyl, —CONH-aryl, —CONH-heteroaryl, —CONH— heterocycloalkyl, —OCO 2 —C 1 -C 12 -alkyl, —OCO 2 —C 2 -C 8 -alkenyl, —OCO 2 —C 2 -C 8 -alkynyl, —OCO 2 —C 3 -C 12 -cycloalkyl, —OCO 2 -aryl, —OCO 2 -heteroaryl, —OCO 2 -heterocycloalkyl, —CO 2 —C 1 -C 12  alkyl, —CO 2 —C 2 -C 8  alkenyl, —CO 2 —C 2 -C 8  alkynyl, —CO 2 —C 3 -C 12 -cycloalkyl, —CO 2 -aryl, —CO 2 -heteroaryl, —CO 2 -heterocyloalkyl, —OCONH 2 , —OCONH—C 1 -C 12 -alkyl, —OCONH—C 2 -C 8 -alkenyl, —OCONH—C 2 -C 8 -alkynyl, —OCONH—C 3 -C 12 -cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —OCONH— heterocycloalkyl, —NHC(O)H, —NHC(O)—C 1 -C 12 -alkyl, —NHC(O)—C 2 -C 8 -alkenyl, —NHC(O)—C 2 -C 8 -alkynyl, —NHC(O)—C 3 -C 12 -cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)— heterocycloalkyl, —NHCO 2 —C 1 -C 12 -alkyl, —NHCO 2 —C 2 -C 8 -alkenyl, —NHCO 2 —C 2 -C 8 -alkynyl, —NHCO 2 —C 3 -C 12 -cycloalkyl, —NHCO 2 -aryl, —NHCO 2 -heteroaryl, —NHCO 2 — heterocycloalkyl, —NHC(O)NH 2 , —NHC(O)NH—C 1 -C 12 -alkyl, —NHC(O)NH—C 2 -C 8 -alkenyl, —NHC(O)NH—C 2 -C 8 -alkynyl, —NHC(O)NH—C 3 -C 12 -cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, —NHC(S)NH 2 , —NHC(S)NH—C 1 -C 12 -alkyl, —NHC(S)NH—C 2 -C 8 -alkenyl, —NHC(S)NH—C 2 -C 8 -alkynyl, —NHC(S)NH—C 3 -C 12 -cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH 2 , —NHC(NH)NH—C 1 -C 12 -alkyl, —NHC(NH)NH—C 2 -C 8 -alkenyl, —NHC(NH)NH—C 2 -C 8 -alkynyl, —NHC(NH)NH—C 3 -C 12 -cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C 1 -C 12 -alkyl, —NHC(NH)—C 2 -C 8 -alkenyl, —NHC(NH)—C 2 -C 8 -alkynyl, —NHC(NH)—C 3 -C 12 -cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)-heterocycloalkyl, —C(NH)NH 2 , —C(NH)NH—C 1 -C 12 -alkyl, —C(NH)NH—C 2 -C 8 -alkenyl, —C(NH)NH—C 2 -C 8 -alkynyl, —C(NH)NH—C 3 -C 12 -cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH— heterocycloalkyl, —S(O)—C 1 -C 12 -alkyl, —S(O)—C 2 -C 8 -alkenyl, —S(O)—C 2 -C 8 -alkynyl, —S(O)—C 3 -C 12 -cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO 2 NH 2 , —SO 2 NH—C 1 -C 12 -alkyl, —SO 2 NH—C 2 -C 8 -alkenyl, —SO 2 NH—C 2 -C 8 -alkynyl, —SO 2 —C 1 -C 12 -alkyl, —SO 2 —C 2 -C 8 -alkenyl, —SO 2 —C 2 -C 8 -alkynyl, —SO 2 —C 3 -C 12 -cycloalkyl, —SO 2 -aryl, —SO 2 -heteroaryl, —SO 2 -heterocycloalkyl, —SO 2 NH—C 3 -C 12 -cycloalkyl, —SO 2 NH-aryl, —SO 2 NH-heteroaryl, —SO 2 NH-heterocycloalkyl, —NHSO 2 —C 1 -C 12 -alkyl, —NHSO 2 —C 2 -C 8 -alkenyl, —NHSO 2 —C 2 -C 8 -alkynyl, —NHSO 2 —C 3 -C 12 -cycloalkyl, —NHSO 2 -aryl, —NHSO 2 -heteroaryl, —NHSO 2 -heterocycloalkyl, —CH 2 NH 2 , —CH 2 SO 2 CH 3 , -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C 3 -C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH, —S—C 1 -C 12 -alkyl, —S—C 2 -C 8 -alkenyl, —S—C 2 -C 8 -alkynyl, —S—C 3 -C 12 -cycloalkyl, —S-aryl, —S-heteroaryl, —S— heterocycloalkyl, or methylthio-methyl. In certain embodiments, the substituents are independently selected from halo, preferably C 1  and F; C 1 -C 4 -alkyl, preferably methyl and ethyl; halo-C 1 -C 4 -alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C 2 -C 4 -alkenyl; halo-C 2 -C 4 -alkenyl; C 3 -C 6 -cycloalkyl, such as cyclopropyl; C 1 -C 4 -alkoxy, such as methoxy and ethoxy; halo-C 1 -C 4 -alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy; —CN; —OH; NH 2 ; C 1 -C 4 -alkylamino; di(C 1 -C 4 -alkyl)amino; and NO 2 . It is understood that an aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl in a substituent can be further substituted. In certain embodiments, a substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from C 1 -C 4 -alkyl; —CF 3 , —OCH 3 , —OCF 3 , —F, —C 1 , —Br, —I, —OH, —NO 2 , —CN, and —NH 2 . Preferably, a substituted alkyl group is substituted with one or more halogen atoms, more preferably one or more fluorine or chlorine atoms. 
     The term “halo” or halogen” alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom. 
     The term “optionally substituted”, as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein. 
     The term “hydrogen” includes hydrogen and deuterium. In addition, the recitation of an element includes all isotopes of that element so long as the resulting compound is pharmaceutically acceptable. In certain embodiments, the isotopes of an element are present at a particular position according to their natural abundance. In other embodiments, one or more isotopes of an element at a particular position are enriched beyond their natural abundance. 
     The term “hydroxy activating group,” as used herein, refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction. Examples of hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate and the like. 
     The term “activated hydroxyl,” as used herein, refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including, but not limited to mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups. 
     The term “hydroxy protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in P. G. M. Wuts,  Greene&#39;s Protective Groups in Organic Synthesis,  5th edition, John Wiley &amp; Sons, Hoboken, N.J. (2014). Examples of hydroxyl protecting groups include, but not limited to, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl, benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like. 
     The term “protected hydroxy,” as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including but not limited to, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example. 
     The term “hydroxy prodrug group,” as used herein, refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan,  Prodrugs. Topical and Ocular Drug Delivery , (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992). 
     The term “amino protecting group,” as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed. Amino protecting groups as known in the art are described generally in P. G. M. Wuts,  Greene&#39;s Protective Groups in Organic Synthesis,  5th edition, John Wiley &amp; Sons, Hoboken, N.J. (2014). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 12-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like. 
     The term “protected amino,” as used herein, refers to an amino group protected with an amino protecting group as defined above. 
     The term “leaving group” means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like. 
     The term “aprotic solvent,” as used herein, refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of aprotic solvents may be found in organic chemistry textbooks or in specialized monographs, for example:  Organic Solvents Physical Properties and Methods of Purification,  4th ed., edited by John A. Riddick et al., Vol. II, in the  Techniques of Chemistry Series , John Wiley &amp; Sons, N Y, 1986. 
     The term “protic solvent,” as used herein, refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example:  Organic Solvents Physical Properties and Methods of Purification,  4th ed., edited by John A. Riddick et al., Vol. II, in the  Techniques of Chemistry Series , John Wiley &amp; Sons, N Y, 1986. 
     Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. The term “stable,” as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). 
     The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds disclosed herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock,  Comprehensive Organic Transformations,  2 nd  Ed. Wiley-VCH (1999); P. G. M. Wuts,  Greene&#39;s Protective Groups in Organic Synthesis,  5th edition, John Wiley &amp; Sons, Hoboken, N.J. (2014); L. Fieser and M. Fieser,  Fieser and Fieser&#39;s Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette, ed.,  Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995), and subsequent editions thereof. 
     The term “subject,” as used herein, refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. A subject also refers to, for example, a dog, cat, horse, cow, pig, guinea pig, fish, bird and the like. 
     The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion. 
     The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al.,  Enantiomers, Racemates, and Resolutions  (John Wiley &amp; Sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers or cis- and trans-isomers. Likewise, all tautomeric forms are also intended to be included. Tautomers may be in cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon-heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. 
     Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof. 
     As used herein, the term “pharmaceutically acceptable salt,” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 2-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. 
     As used herein, the term “pharmaceutically acceptable ester” refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. 
     Pharmaceutical Compositions 
     The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients. 
     As used herein, the term “pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer&#39;s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. 
     The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. 
     Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. 
     Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer&#39;s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable. 
     The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. 
     In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. 
     Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. 
     Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. 
     Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. 
     The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. 
     Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. 
     The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. 
     Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. 
     Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. 
     For pulmonary delivery, a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system. Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No. 5,767,068 to Van Devanter et al., U.S. Pat. No. 5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of which are incorporated herein by reference). 
     Antiviral Activity 
     In certain embodiments, the present invention provides a method of treating or preventing a viral infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The viral infection is preferably a coronavirus infection. In certain embodiments, the coronavirus is SARS—CoV-1, SARS—CoV-2, or MERS—CoV. Preferably the coronavirus is SARS—CoV-2. 
     A viral inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. 
     According to the methods of treatment of the present invention, viral infections are treated or prevented in a patient such as a human or another animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. 
     By a “therapeutically effective amount” of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). A therapeutically effective amount of the compound described above may range, for example, from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts. 
     The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses. 
     The compounds of the present invention described herein can, for example, be administered by injection, intravenously, intra-arterial, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with pharmaceutically excipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations may contain from about 20% to about 80% active compound. 
     Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient&#39;s disposition to the disease, condition or symptoms, and the judgment of the treating physician. 
     Upon improvement of a patient&#39;s condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. 
     Combination and Alternation Therapy 
     The compounds of the present invention may be used in combination with one or more antiviral therapeutic agents or anti-inflammatory agents useful in the prevention or treatment of viral diseases or associated pathophysiology. Thus, the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof, may be employed alone or in combination with other antiviral or anti-inflammatory therapeutic agents. The compounds herein and pharmaceutically acceptable salts thereof may be used in combination with one or more other agents which may be useful in the prevention or treatment of respiratory disease, inflammatory disease, autoimmune disease, for example; anti-histamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, Ieukotriene modulators (e.g., montelukast, zafirlukast.pranlukast), tryptase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors such as elastase inhibitors, integrin antagonists (e.g., beta-2 integrin antagonists), adenosine A2a agonists, mediator release inhibitors such as sodium chromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (Iysophosphatidic) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors (e.g., sodium 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-ethylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate), bronchodilators (e.g., muscarinic antagonists, beta-2 agonists), methotrexate, and similar agents; monoclonal antibody therapy such as anti-1gE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; cytokine receptor therapies e.g. etanercept and similar agents; antigen non-specific immunotherapies (e.g. interferon or other cytokines/chemokines, chemokine receptor modulators such as CCR3, CCR4 or CXCR2 antagonists, other cytokine/chemokine agonists or antagonists, TLR agonists and similar agents), suitable anti-infective agents including antibiotic agents, antifungal agents, antheimintic agents, antimalarial agents, antiprotozoal agents, antitubercuiosis agents, and antiviral agents, including those listed at https://www.drugs.com/drug-class/anti-infectives.html. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus. 
     When the compositions of this invention comprise a combination of a compound of the Formula described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. 
     The “additional therapeutic or prophylactic agents” include but are not limited to, immune therapies (e.g. interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (e.g. N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (e.g. ribavirin and amantidine). The compositions according to the invention may also be used in combination with gene replacement therapy. 
     Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims. 
     Abbreviations 
     Abbreviations which may be used in the descriptions of the scheme and the examples that follow are: Ac for acetyl; AcOH for acetic acid; Boc 2 O for di-tert-butyl-dicarbonaste; Boc for t-butoxycarbonyl; Bz for benzoyl; Bn for benzyl; t-BuOK for potassium tert-butoxide; Brine for sodium chloride solution in water; CDI for carbonyldiimidazole; DCM or CH 2 Cl 2  for dichloromethane; CH 3  for methyl; CH 3 CN for acetonitrile; Cs 2 CO 3  for cesium carbonate; CuCl for copper (I) chloride; CuI for copper (I) iodide; dba for dibenzylidene acetone; DBU for 1,8-diazabicyclo[5.4.0]-undec-7-ene; DEAD for diethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIPEA or (i-Pr) 2 EtN for N,N,-diisopropylethyl amine; DMP or Dess-Martin periodinane for 1,1,2-tris(acetyloxy)-1,2-dihydro-1,2-benziodoxol-3-(1H)-one; DMAP for 4-dimethylamino-pyridine; DME for 1,2-dimethoxyethane; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH for ethanol; Et 2 O for diethyl ether; HATU for O-(7-azabenzotriazol-2-yl)-N,N,N′,N′,-tetramethyluronium Hexafluoro-phosphate; HCl for hydrogen chloride; K 2 CO 3  for potassium carbonate; n-BuLi for n-butyl lithium; DDQ for 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; LDA for lithium diisopropylamide; LiTMP for lithium 2,2,6,6-tetramethyl-piperidinate; MeOH for methanol; Mg for magnesium; MOM for methoxymethyl; Ms for mesyl or —SO 2 —CH 3 ; NaHMDS for sodium bis(trimethylsilyl)amide; NaCl for sodium chloride; NaH for sodium hydride; NaHCO 3  for sodium bicarbonate or sodium hydrogen carbonate; Na 2 CO 3  sodium carbonate; NaOH for sodium hydroxide; Na 2 SO 4  for sodium sulfate; NaHSO 3  for sodium bisulfite or sodium hydrogen sulfite; Na 2 S 2 O 3  for sodium thiosulfate; NH 2 NH 2  for hydrazine; NH 4 Cl for ammonium chloride; Ni for nickel; OH for hydroxyl; OsO 4  for osmium tetroxide; OTf for triflate; PPA for polyphosphoric acid; PTSA for p-toluenesulfonic acid; PPTS for pyridinium p-toluenesulfonate; TBAF for tetrabutylammonium fluoride; TEA or Et 3 N for triethylamine; TES for triethylsilyl; TESCl for triethylsilyl chloride; TESOTf for triethylsilyl trifluoromethanesulfonate; TFA for trifluoroacetic acid; THF for tetrahydrofuran; TMEDA for N,N,N′,N′-tetramethylethylene-diamine; TPP or PPh 3  for triphenyl-phosphine; Tos or Ts for tosyl or —SO 2 —C 6 H 4 CH 3 ; Ts 2 O for tolylsulfonic anhydride or tosyl-anhydride; TsOH for p-tolylsulfonic acid; Pd for palladium; Ph for phenyl; Pd 2 (dba) 3  for tris(diben-zylideneacetone) dipalladium (0); Pd(PPh 3 ) 4  for tetrakis(triphenylphosphine)-palladium (0); PdCl 2 (PPh 3 ) 2  for trans-dichlorobis-(triphenylphosphine)palladium (II); Pt for platinum; Rh for rhodium; rt for room temperature; Ru for ruthenium; TBS for tert-butyl dimethylsilyl; TMS for trimethylsilyl; and TMSCl for trimethylsilyl chloride. 
     Synthetic Methods 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Scheme 1 illustrates a general method to prepare the compound of formular (XII-1), starting with the amino ester compound (1-1), wherein B is as previously defined and PG 1  is C 1 -C 4  alkyl or Bn. Treatment of (1-1) with formaldehyde affords the cyclized amine (1-2), which is converted to (1-3) using appropriate protecting group PG 2  (e.g. Boc). Treatment of (1-3) with NBS in solvents containing AcOH at low temperature provides the rearranged spiral proline derivative (1-4). Examples of this sequence of transformation have been reported in the literature (Pellegrini C. et al. “Synthesis of the Oxindole Alkaloid (−)-Horsfiline” Tetrahedron Asymmetry, 1994, vol. 5, No. 10, pp 1979-1992; Efremov, I. V. et al. “Discovery and Optimization of a Novel Spiropyrrolidine Inhibitor of β-Secretase (BACE1) through Fragment-Based Drug Design” Journal of Medicinal Chemistry, 2012, 55, 9069-9088). Treatment of ester (1-4) with NH 3  (e. g. ammonia in MeOH, NH 30 H, etc.) affords the amide compound (1-5), which is converted to amine compound (1-6) by removal of protecting group PG 2  (e.g. TFA, HCl, etc). Condensation of the amine (1-6) with acid (1-7) wherein R 1 , R 2 , and R 3  are previously defined and PG 3  is appropriate protecting group (e.g. Cbz or Boc), under amide coupling conditions (e.g. HATU, EDC, DCC, etc) provides amide (1-8). Removal of PG 3  (e.g. hydrogenation for Cbz, or HCl, TFA for Boc) affords amine compound (1-9). Condensation of amine (1-9) with acid (1-10), wherein, R′ is methyl, ethyl, or t-Butyl, R 5 , R 6  is previously defined, which are commercially available, or can be prepared from corresponding malonates, under amide coupling conditions (e.g. HATU, EDC, DCC, etc.) or other acid activating conditions such as acylhalide (SOCl 2 , ClCOCOCl and Ghosez&#39;s reagent), or acyl imidazole (carbonyl diimidazole) provides amide (1-11). The ester in (1-11) is converted to acid (1-12) under basic condition, such as LiOH, NaOH in solvent such as MeOH/water, THF/water; or in the case, R′ is t-Butyl, under acidic conditions (HCl, TFA). The acid (1-12) is reacted with any amine under amide coupling conditions (e.g. HATU, EDC, DCC, etc) or other acid activating conditions such as acylhalide (SOCl 2 , ClCOCOCl and Ghosez&#39;s reagent), or acyl imidazole (carbonyl diimidazole) provides amide (1-13). Amide (1-13) is converted to the nitrile compound (XII-1) under dehydration conditions, such as TFAA/Et 3 N, Burgess reagent or Pd(OCOCF 3 ) 2 /Cl 2 CHCN. 
     
       
         
         
             
             
         
       
     
     Alternatively, as shown in scheme 2, condensation of the amine (1-9) with acid (2-2) wherein A, R 5 , R 6 , are as previously defined, under amide coupling conditions (e.g. HATU, EDC, DCC, etc) or other acid activating conditions such as acylhalide (SOCl 2 , ClCOCOCl and Ghosez&#39;s reagent), or acyl imidazole (carbonyl diimidazole) provides amide (1-13), which can be converted to (XII-1) under conditions described above. 
     When A is an amine, the acid (1-10) reacts with A under either amide formation conditions (e.g. HATU, EDC, DCC, etc) or other acid activating conditions such as acylhalide (SOCl 2 , ClCOCOCl and Ghosez&#39;s reagent) to afford the ester (2-1). Removal of R′ under aforementioned conditions will provides the acid (2-2). 
     When A is an alkyl, aryl, heteroaryl, one general approach to (2-2) is also shown. The commercially available acid A-COOH (2-3) is activated with carbonyl diimidazole to afford the acyl imidazole intermediate (2-4), which is reacted with the alpha lithium salt of acetate (2-5) (generated from alpha bromoacetate and LDA) at low temperature in aprotic solvent such as THF and diethyl ether to afford the ester (2-1). Removal of R′ under aforementioned conditions will provides the acid (2-2). Another general approach (2-2) is also described in Scheme 2, when A is an aryl or heteroaryl, it is converted to (2-1) by reaction with the 3-chloro-3-oxopropanoate, which is commercially available or generated from corresponding acid with SOCl 2 , ClCOCOCl or Ghosez&#39;s reagent, in the presence of a Lewis acid such as AClC 3 , or SnCl 4 . 
     
       
         
         
             
             
         
       
     
     Scheme 3 illustrates a general method to synthesize the aldehyde compound (XII-2), wherein A, R 1 , R 2 , R 3 , R 5 , R 6  and B are previously defined. The ester (1-4), wherein B, PG 1  and PG 2  are previously defined, is reduced to the alcohol (3-1) employing a reducing reagent such as, but not limited to, LiBH 4 , NaBH 4 , or DIBAL-H. The protecting group PG 2  (e.g. Boc) of (3-1) is removed under acidic conditions using an acid such as TFA, HCl, formic acid, TMSOTf/lutidine, etc. Coupling of the amine (3-2) with the acid (1-7) wherein PG 3 , R 1 , R 2 , and R 3  are previously defined, using coupling reagents such as HATU, EDC, or DCC, provides compound (3-3). Following the approaches illustrated in Scheme 1 and 2, intermediate (3-3) can be converted to (3-4). Oxidation of the alcohol of (3-4) with mild oxidation reagents such as DMSO/Ac 2 O, Dess-Martin periodinane, IBX, SO 3 -pyridine/DMSO/Et 3 N, produces the aldehyde (XII-2). 
     
       
         
         
             
             
         
       
     
     Scheme 4 illustrates a general method to synthesize the hydroxymethylketone of formula (XII-3). Hydrolysis of the ester compound (1-4), wherein B, PG 1  and PG 2  are previously defined, provides the acid compound (4-1). Amide (4-2) can be obtained from the acid (4-1) by coupling with N,O-dimethylhydroxyamine using reagents such as HATU, EDC, DCC, etc. Treatment of amide (4-2) at low temperature (e.g. −60° C.) with an organometallic reagent generated by BOM-Cl, Mg, and HgCl 2  affords the ketone (4-3). Removal of PG 2  (e.g. PTSA if PG 2  is BOC) provides amine (4-4). Coupling of amine (4-4) with acid (1-7), wherein R 1 , R 2 , and R 3  are previously defined, affords compound (4-5) using amide coupling reagents such as HATU, EDC, DCC, etc. Following the approaches illustrated in Scheme 1 and 2, intermediate (4-5) can be converted to (4-6). Removal of the benzyl group in (4-6) under hydrogenation conditions (Pd/C, H 2 ) provides compound of formula (XII-3). 
     
       
         
         
             
             
         
       
     
     Scheme 5 illustrates a general method to synthesize the chloromethylketone compound of formula (XII-4). Treatment of the ester compound (1-4) with an organometallic reagent generated by ICH 2 Cl and appropriate base, such as LDA, MeLi/LiBr, or BuLi, provides the chloroketone compound (5-1). Removal of PG 2  (e.g. PTSA if PG 2  is BOC) provides amine compound (5-2). Coupling of amine (5-2) with acid (1-7), wherein R 1 , R 2 , and R 3  are previously defined, affords compound (5-3) using coupling reagents such as HATU, EDC, DCC, etc. Following the approaches illustrated in Scheme 1 and 2, intermediate (5-3) can be converted to (XII-4). 
     
       
         
         
             
             
         
       
     
     Scheme 6 illustrates a general method to synthesize the fluoromethylketone compound of formula (XII-5). Removal of the Bn group of compound (4-3) with Pd-catalyzed hydrogenation provides alcohol (6-1). Alcohol (6-1) is converted to fluoromethylketone compound (6-2) under conditions such as SF 4 , Tf 2 O/lutidine/TBAF, C 4 F 9 SO 2 F/HF-Et 3 N, etc. Removal of PG 2  (e.g. PTSA if PG 2  is BOC) provides amine compound (6-3). Coupling of amine (6-3) with acid (1-7), wherein R 2 , and R 3  are previously defined, affords compound (6-4) using amide coupling reagents such as HATU, EDC, DCC, etc. Following the approaches illustrated in Scheme 1 and 2, intermediate (6-4) can be converted to (XII-5). 
     
       
         
         
             
             
         
       
     
     Scheme 7 illustrates a general method to synthesize the α-ketoamide compound of formula (XII-6′). Treatment of the aldehyde compound of formula (XII-2), wherein A, R 1 , R 2 , R 3 , and B are previously defined, with isonitrile compound (7-1), wherein R 13  is previously defined, affords α-hydroxylamide (7-2). Oxidation of compound (7-2) with appropriate oxidants such as Dess-Martin periodinane, (COCl) 2 /DMSO/Et 3 N, PCC, SO 3 -pyridine/DMSO/Et 3 N, affords α-ketoamide of formula XII-6′). 
     
       
         
         
             
             
         
       
     
     Alternatively, nitrile compound (XII-1) can be synthesized from aldehyde compound (XII-2) using the method shown in Scheme 7. Condensation of aldehyde (XII-2) with hydroxyamine hydrochloride in appropriate solvents such as DMSO, i-PrOH, pyridine, etc. provides oxime compound (8-1). Treatment of the oxime compound (XVI-1) under acid-catalyzed dehydration conditions such as (Cu(OAc) 2 /MeCN, HCl, etc.) affords the nitrile compound (XII-1). 
     EXAMPLES 
     The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Starting materials were either available from a commercial vendor or produced by methods well known to those skilled in the art. 
     General Conditions: 
     Mass spectra were run on LC-MS systems using electrospray ionization. These were Agilent 1290 Infinity II systems with an Agilent 6120 Quadrupole detector. Spectra were obtained using a ZORBAX Eclipse XDB-C18 column (4.6×30 mm, 1.8 micron). Spectra were obtained at 298K using a mobile phase of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). Spectra were obtained with the following solvent gradient: 5% (B) from 0-1.5 min, 5-95% (B) from 1.5-4.5 min, and 95% (B) from 4.5-6 min. The solvent flowrate was 1.2 mL/min. Compounds were detected at 210 nm and 254 nm wavelengths. [M+H] +  refers to mono-isotopic molecular weights. 
     NMR spectra were run on a Bruker 400 MHz spectrometer. Spectra were measured at 298K and referenced using the solvent peak. Chemical shifts for  1 H NMR are reported in parts per million (ppm). 
     Compounds were purified via reverse-phase high-performance liquid chromatography (RPHPLC) using a Gilson GX-281 automated liquid handling system. Compounds were purified on a Phenomenex Kinetex EVO C18 column (250×21.2 mm, 5 micron), unless otherwise specified. Compounds were purified at 298K using a mobile phase of water (A) and acetonitrile (B) using gradient elution between 0% and 100% (B), unless otherwise specified. The solvent flowrate was 20 mL/min and compounds were detected at 254 nm wavelength. 
     Alternatively, compounds were purified via normal-phase liquid chromatography (NPLC) using a Teledyne ISCO Combiflash purification system. Compounds were purified on a REDISEP silica gel cartridge. Compounds were purified at 298K and detected at 254 nm wavelength. 
     Example 1 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     Step 1-a 
     To a stirred solution of-ethoxy-3-oxopropanoic acid (200 mg, 1.51 mmol, 1.0 equiv), 2,5-difluoroaniline (205 mg, 1.55 mmol, 1.05 equiv), HATU (604 mg, 1.55 mmol, 1.05 equiv) in DMF (3 mL) was added DIPEA (0.79 mL, 4.54 mmol, 3 equiv) at 0° C. The resulting mixture was warmed to rt and stirred for 3 h. The reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with hexanes/EtOAc (0-60%) to afford Compound (1-a) (110 mg mg) as a colorless oil and used without further purification. 
     Step 1-b 
     To a stirred solution of Compound (1-1) (110 mg, 0.45 mmol) in MeOH (25 mL) was added aq. LiOH (1 M, 0.91 mL, 2 equiv) at rt. The resulting mixture was stirred for 2 h at rt. The reaction was acidified to pH=3 with 3N HCl solution and extracted with EtOAc. The organic was washed with brine concentrated to afford desired product Compound (1-b) (92 mg, white solid) was collected by filtration. 
     Step 1-c 
     Methyl (S)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate hydrochloride (500 mg, 1.875 mmol) was dissolved in CH 2 Cl 2  (10 ml). Triethylamine (523 μl, 3.75 mmol) and a 2.0 M solution of di-tert-butyl dicarbonate in DCM (1031 μl, 2.062 mmol) was added. The mixture was stirred at rt for 3 h, quenched with sat. NaHCO 3 , and extracted with DCM. The organic layer was washed with brine, dried over MgSO 4 , and concentrated in vacuo. Purification of the residue on silica gel with 0-30% EtOAc/cyclohexane provided compound (1-c) (578 mg, 1.749 mmol, 93% yield). 
     Step 1-d 
     Compound (1-c) was dissolved in THF (15 ml), AcOH (10 ml), and water (10 ml). The solution was cooled to −15° C. A solution of NBS (328 mg, 1.843 mmol) in THF (5 mL) was added dropwise. The mixture was slowly warmed to 5° C. over 1 h. The reaction was quenched with Na 2 SO 3  and sat. NaHCO 3 , and extracted with DCM. The organic layer was washed with brine, dried with MgSO 4 , and concentrated in vacuo. Purification of the residue on silica gel with 0-50% EtOAc/cyclohexane provided compound (1-d) (328 mg, 0.947 mmol, 53.9% yield). 
     Step 1-e 
     Compound (1-d) (328 mg, 0.947 mmol) was dissolved in MeOH (3 ml). A solution of 7 N ammonia in MeOH (5 mL, 35.0 mmol) was added. The mixture was stirred at rt for 5 days. Solvent was removed in vacuo. Purification of the residue on silica gel with 0-10% MeOH/DCM, and on C 18  column with 0-50% MeCN/H 2 O provided compound (1-e) (101 mg, 0.305 mmol, 32.2% yield). 
     Step 1-f 
     Compound (1-e) (100 mg, 0.302 mmol) was dissolved in DCM and trifluoroacetic acid (232 μl, 3.02 mmol) was added. The mixture was stirred at 0° C. for 1 h, and at rt for 2 h. DCM (10 mL) and toluene (10 mL) were added. Solvent was removed in vacuo. The residue was dissolved in MeOH and 1 M HCl (0.6 mL, 2 eq) was added. Solvent was removed. The obtained compound (1-f) (91 mg, 0.340 mmol, quantitative yield) was used for next step. 
     Step 1-g 
     To a stirred solution of Compound (1-f) (4.65 g, 17.37 mmol, 1.0 equiv) and N-((benzyloxy)carbonyl)-N-methyl-L-leucine (5.34 g, 19.11 mmol, 1.1 equiv) in DCM (80 mL) and DMF (8 mL) was added DIEA (6.37 g, 52.11 mmol, 3 equiv) and HATU (7.26 g, 19.11 mmol, 1.1 equiv) at 0° C. The resulting mixture was warmed to rt. and stirred for 1 h. The reaction was quenched with 10% citric acid at rt. The resulting mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with cyclohexane/acetone (0-50%) to afford Compound (1-g) (6.95 g) as an off-white solid. 
     Step 1-h 
     To a solution of Compound (1-g) (500.00 mg, 1.015 mmol, 1.00 equiv) in 10 mL MeOH was added Pd/C (10%, 50 mg) under nitrogen atmosphere in a 50 mL round-bottom flask. The mixture was hydrogenated at rt. for 1 h under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. This resulted in Compound (1-h) (345 mg) as an off-white solid. LC-MS, ES+: 359.43 [M+1] + . 
     Step 1-i 
     A solution of Compound (1-b) (86 mg, 0.409 mmol, 1.0 equiv), Compound (1-h) (147 mg, 0.409 mmol, 1.0 eq), HATU (156 mg, 0.409 mmol, 1.0 eq) and DIPEA (0.22 mL, 1.23 mmol, 3.0 equiv) in DMF was stirred at rt for 3 hours. The reaction was quenched with sat. NaHCO 3  (aq.) and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure. The crude product Compound (1-i) as a light-yellow solid was used in the next step directly without further purification. 
     Step 1-j 
     To a stirred mixture of Compound (1-i) (130 mg, 0.23 mmol, 1.0 equiv) and Et 3 N (0.17 mL, 1.18 mmol, 5.00 equiv) in DCM (2 mL) was added TFAA (0.067 mL, 0.46 mmol, 2.0 equiv) at rt. The resulting mixture was stirred for 30 min at rt. The reaction was quenched with sat. NaHCO 3  (aq.) and extracted with DCM. The combined organic layers were concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford the title compound (11 mg) as a white solid. LC-MS, ES+: 538.41 [M+1] + . 
     Example 2 
     
       
         
         
             
             
         
       
     
     Step 2-a 
     Into the solution of diethyl 2-isobutylmalonate (5.15 ml, 23.12 mmol) in Ethanol (35 ml). 
     Was added potassium hydroxide (1.297 g, 23.12 mmol, 1 equiv)) in several portions. The reaction was stirred overnight, it was concentrated, and water added. It was acidified to pH 3 by addition of 1 M HCl, extracted with EtOAc twice. The organic layer was dried and concentrated to give the compound (2-a) 4.3 g. 
     The title compound was synthesized from intermediate 2-a and 1-h following the sequence of step 1-i and 1-j. LC-MS, ES−: 594.57[M+1] + . 
     Example 3 and 4 
     
       
         
         
             
             
         
       
     
     Example 2 was passed through a prep-HPLC eluting with 20 nM NH 4 HCO 3  and acetonitrile to afford both title compounds. 
     Example 5 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized from 3-(tert-butoxy)-3-oxopropanoic acid and intermediate 1-h following the sequence of step 1-i and 1-j. LC-MS, ES−: 481.41 [M−1] − . 
     Example 6 
     
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
     
     Step 6-a 
     To a slurry of 4,6-difluoro-1H-indole-2-carboxylic acid (5 g, 25.4 mmol) in benzene (30 ml) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (24.27 ml, 101 mmol). The mixture was heated to 80° C. and stirred for 2 h. The reaction was concentrated and purified by chromatography on silica eluting with EtOAc and cyclohexane afford Compound (6-a) (4.6 g) as an off-white solid. LC-MS, ES−: 251.78 [M−1] − . 
     Step 6-b 
     To the solution of compound (6-a) (702 mg, 2.77 mmol) in DMF (6 mL) at) 0° C., NaH (60% 144 mg, 3.60 mmol) was added, and stirred 30 mins. CBz-Cl (0.51 mL, 3.60 mmol) was added and stirred o/n at rt. To it, water was added and extracted with MTBE*2. The organic was washed with water*2, brine and dried concentrated. The crude was chromatographed on silica eluting with MTBE-cyclohexane to afford the desired (6-b) (1.19 g). 
     Step 6-c 
     To the solution of compound (6-b) (1.19 g, 3.07 mmol) in DCM (5 mL) at) TFA (1.18 mL, 15.4 mmol) was added, and stirred 3 hours. It was concentrated. The crude was chromatographed on silica eluting with EtOAc-cyclohexane to afford the desired (6-c) (570 mg) at a yield of 56% for two steps. LC-MS, ES−: 330.14[M−1] − . 
     Step 6-d 
     To the solution of compound (6-c) (570 mg, 1.72 mmol) in THF (6 mL) was added CDI (307 mg, 1.85 mmol), and stirred at rt. In another flask, t-butyl acetate (700 mg, 6.02 mmol) was added to the solution of LDA (5.68 mmol) in THF (6 mL) at −78° C. and stirred at such temperature for 1 h. The solution from the first reaction was transferred into the second reaction at −78° C. It was further stirred at such temperature for two hours before being quenched with water (6 mL) and warmed up to rt. It was extracted with EtOAc twice. The organic was washed with brine and dried. After being concentrated, the crude was chromatographed on silica eluting with EtOAc-cyclohexane to afford the desired (6-d) (210 mg) at a yield of 41%. LC-MS, ES−: 294.11 [M−1]. 
     Step 6-e 
     To the solution of compound (6-d) (65 mg, 0.22 mmol) in DCM (2 mL) at room temperature, TFA (0.17 mL, 2.2 mmol) was added, and stirred 4 hours. It was concentrated and used as crude directly in the next steps. 
     Step 6-f 
     The title compound was synthesized from intermediate 6-e and 1-h following the sequence of step 1-i and 1-j. LC-MS, ES−: 560.39 [M−1] − . 
     Example 7 
     
       
         
         
             
             
         
       
     
     Step 7-a 
     To the solution of compound (1-h) (260 mg, 0.725 mmol and DIPEA (0.25 mL, 1.5 mmol) in DMF (1 mL) at 0° C. was added methyl 3-chloro-2,2-dimethyl-3-oxopropanoate (131 mg) and stirred 1 h. It was concentrated and chromatographed on silica eluting with DCM/MeOH to afford the desired (7-a) (160 mg) at a yield of 43%. LC-MS, ES+: 487.42 [M+1] + . 
     Step 7-b 
     To the solution of compound (7-a) (117 mg, 0.24 mmol) in THF (2 mL) at room temperature, TMSOK (93 mg, 0.72 mmol) was added, and stirred 4 hours. It was acidified with 1 M HCl to pH 3, and extracted with EtOAc. The organic was washed with brine and dried. After being concentrated the crude was chromatographed on silica eluting with EtOAc-cyclohexane to afford the desired (7-b) (57 mg) at a yield of 50%. LC-MS, ES−: 471.37 [M−1] − . 
     Step 7-c 
     The title compound was synthesized from intermediate 7-b following the procedure described in 1-j. LC-MS, ES+: 477.46 [M+1] + . 
     Example 8 
     
       
         
         
             
             
         
       
     
     Step 8-a 
     To the solution of 3,5-difluoroaniline (124 mg, 0.79 mmol and DIPEA (0.35 mL, 2.0 mmol) in was (1 mL) at 0° C. was added methyl 3-chloro-2,2-dimethyl-3-oxopropanoate (0.7 mmol) and stirred 1 h. It was concentrated and chromatographed on silica eluting with EtOAc-cylohexane to afford the desired (8-a) (175 mg). LC-MS, ES+: 258.28 [M+1] + . 
     Step 8-b 
     To the solution of compound (8-a) (175 mg, 0.68 mmol) in THF (3 mL) at room temperature, LiOH (1 M, 1.02 mL) was added, and stirred o/n. It was acidified with 1 M HCl to pH 3, and extracted with EtOAc. The organic was washed with brine and dried. After being concentrated the crude was chromatographed on silica eluting with EtOAc-cyclohexane to afford the desired (8-b) (102 mg) at a yield of 61% over two steps. LC-MS, ES+: 244.18 [M−1] − . 
     Step 8-c 
     To the solution of compound (8-b) (48 mg, 0.20 mmol) in DCM (1 mL) at room temperature, one drop DMF was added followed by oxalyl chloride (52 μL, 0.59 mmol), and stirred 1 h. It was concentrated. To it, THF (1 mL) was added and cooled to 0° C. Compound (1 h 71 mg, 0.19 mmol) and DIPEA (0.103 mL, 0.59 mmol) in THF was added into above solution and stirred 30 mins. Aq. NaHCO 3  was added and extracted with EtOAc. The organic was washed with brine and dried. After being concentrated, the crude was chromatographed on silica eluting with MeOH/DCM to afford the desired (8-c) (20 mg) at a yield of 18%. LC-MS, ES+: 584.44 [M−1] − . 
     Step 8-d 
     The title compound was synthesized from intermediate 8-c following the procedure described in 1-j. LC-MS, ES+: 588.46 [M+Na] + . 
     Example 9 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized from 2,6-difluoroaniline following the procedures described in example 8. LC-MS, ES+: 580.52 [M+Na] + . 
     Example 10 
     
       
         
         
             
             
         
       
     
     Step 10-a 
     To the solution of 3-ethoxy-3-oxopropanoic acid (122 mg, 0.92 mmol), Compound (1-h) (300 mg, 0.84 mmol), HATU (350 mg, 0.92 mmol) in DMF (3 mL) was added DIPEA (0.37 mL, 2.1 mmol), and stirred at rt for 3 hours. The reaction was quenched with sat. NaHCO 3  (aq.) and extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure. The crude was chromatographed on silica eluting with MeOH/DCM to afford the desired (10-a) (243 mg) at a yield of 62%. LC-MS, ES+: 473.41[M+1] + . 
     Step 10-b 
     To the solution of compound (10-a) (238 mg, 0.50 mmol) in THF (3 mL) at room temperature, LiOH (1 M, 1.0 mL) was added, and stirred 5 h. It was acidified with 1 M HCl to pH 3, and extracted with EtOAc then DCM. The organic was washed with brine and dried. After concentrated to afford the desired (10-b) (205 mg) at a yield of 92%. The crude was used directly in the next step. LC-MS, ES+: 445.37 [M+1] + . 
     Step 10-c 
     To the solution of compound (10-b) (50 mg, 0.11 mmol), 2,6-dimethylaniline (14 mg, 0.12 mmol), HATU (47 mg, 0.124 mmol) in DMF (1 mL) was added DIPEA (0.08 mL, 0.45 mmol), and stirred at rt for 3 hours. The reaction concentrated under reduced pressure. The crude was chromatographed on silica eluting with MeOH/DCM to afford the desired (10-c) (46 mg) at a yield of 74%. LC-MS, ES+: 548.63 [M+1] + . 
     Step 10-d 
     To the solution of compound (10-c) (46 mg, 0.084 mmol) in THF (1 mL) was added Burgess reagent (40 mg, 0.17 mmol), and stirred at rt for 3 hours. The reaction concentrated under reduced pressure. The crude was chromatographed on silica eluting with EtOAc-cyclohexane to afford the title compound (9 mg) at a yield of 20%. LC-MS, ES+: 530.47 [M+1] + . Example 11 
     
       
         
         
             
             
         
       
     
     Step 11-a 
     To a mixture of compound 1-h (1.7 g, 5.07 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanoic acid (1.367 g, 5.57 mmol) in dry CH 2 Cl 2  (17 mL) and DMF (3 mL) at 0° C. were added 4-methylmorpholine (1.67 mL, 15.2 mmol) and HATU (2.119 g, 5.57 mmol). The resulting mixture was stirred at 0° C. for ˜30 min and then at rt for several hours until LC-MS indicated the reaction was completed. The reaction mixture was diluted with DCM, washed with 5% NaHCO 3 , water, brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by silica gel chromatography (0 to 10% MeOH/DCM) to afford the desired compound 11-a (1.7 g, 3.71 mmol, 73.2% yield) as a white solid. LC-MS, ES+: 456.3 [M+1]. 
     Step 11-b 
     Compound 11-a (1.0 g, 2.181 mmol) was added to 4M HCl (10.90 ml, 43.6 mmol) at 0° C. After stirring for 15 min, then at rt for 15 min, MTBE (60 mL) was added to the reaction mixture. The resulting white precipitate was collected via filtration under N 2  and rinsed with MTBE (3×), The collected solid was further dried under high vacuum to provide the desired compound 11-b (860 mg, 2.15 mmol, 100% yield) as white solid. LC-MS, ES+: 359.49 [M+1]. 
     Step 11-c 
     The title compound was synthesized from 8-b and 11-b following the procedures described in steps 10-c and 10-d. LC-MS, ES+: 566.57 [M+1] + . 
     Example 12 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized from 2-6-dimethylamine and 11b by following the procedures described in steps 8a, 8b, 10c and 10-d. LC-MS, ES+: 558.55 [M+1] + . 
     Example 13 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized from methyl 2-(chlorosulfonyl)acetate following the procedure described in example 8. LC-MS, ES+: 564.38 [M−1] − . 
     Example 14 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized from methyl 2-(chlorosulfonyl)acetate following the procedure described in example 10. LC-MS, ES+: 564.30 [M−1] − . 
     The following examples were prepared employing similar protocol as described above. 
     
       
         
           
               
               
               
             
               
                   
               
               
                 Example 
                   
                   
               
               
                 # 
                 Structure 
                 MS 
               
               
                   
               
             
            
               
                 15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] −  = 496.32 
               
               
                   
               
               
                 16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 502.30 
               
               
                   
               
               
                 17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 516.30 
               
               
                   
               
               
                 18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 530.25 
               
               
                   
               
               
                 19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 552.20 
               
               
                   
               
               
                 20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 530.30 
               
               
                   
               
               
                 21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 503.35 
               
               
                   
               
               
                 22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 503.25 
               
               
                   
               
               
                 23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 503.20 
               
               
                   
               
               
                 24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 520.40 
               
               
                   
               
               
                 25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 520.40 
               
               
                   
               
               
                 26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 520.40 
               
               
                   
               
               
                 27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 492.25 
               
               
                   
               
               
                 28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 570.39 
               
               
                   
               
               
                 29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 556.45 
               
               
                   
               
               
                 30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + Na] +  = 592.36 
               
               
                   
               
               
                 31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 484.20 
               
               
                   
               
               
                 32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] +  = 482.20 
               
               
                   
               
               
                 33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 484.20 
               
               
                   
               
               
                 34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 484.20 
               
               
                   
               
               
                 35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 490.25 
               
               
                   
               
               
                 36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] +  = 593.3 
               
               
                   
               
               
                 37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] +  = 593.3 
               
               
                   
               
               
                 38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 586.41 
               
               
                   
               
               
                 39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + Na] +  = 546.27 
               
               
                   
               
               
                 40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 600.37 
               
               
                   
               
               
                 41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 510.04 
               
               
                   
               
               
                 42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 510.35 
               
               
                   
               
               
                 43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 510.30 
               
               
                   
               
               
                 44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 510.40 
               
               
                   
               
               
                 45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 510.20 
               
               
                   
               
               
                 46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M − H] +  = 508.20 
               
               
                   
               
               
                 47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 510.35 
               
               
                   
               
               
                 48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 510.30 
               
               
                   
               
               
                 49 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 522.20 
               
               
                   
               
               
                 50 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 [M + H] +  = 522.20 
               
               
                   
               
            
           
         
       
     
     Biological Activity 
     SARS—CoV-2 3C-like (3CL) protease fluorescence assay (FRET): Recombinant SARS—CoV-2 3CL-protease was expressed and purified. TAMRA-SITSAVLQSGFRKMK-Dabcyl-OH peptide 3CLpro substrate was synthesized. Black, low volume, round-bottom, 384 well microplates were used. In a typical assay, 0.85 μL of test compound was dissolved in DMSO then incubated with SARS—CoV-2 3CL-protease (10 nM) in 10 μL assay buffer (50 mM HEPES [pH 7.5], 1 mM DTT, 0.01% BSA, 0.01% Triton-X 100) for 30 min at RT. Next, 10 μL of 3CL-protease substrate (40 μM) in assay buffer was added and the assays were monitored continuously for 1 h in an Envision multimode plate reader operating in fluorescence kinetics mode with excitation at 540 nm and emission at 580 nm at RT. No compound (DMSO only) and no enzyme controls were routinely included in each plate. All experiments were run in duplicate. 
     Data Analysis: SARS—CoV-2 3CL-protease enzyme activity was measured as initial velocity of the linear phase (RFU/s) and normalized to controlled samples DMSO (100% activity) and no enzyme (0% activity) to determine percent residual activity at various concentrations of test compounds (0-10 μM). Data were fitted to normalized activity (variable slope) versus concentration fit in GraphPad Prism 7 to determine IC 50 . All experiments were run in duplicate, and IC 50  ranges are reported as follows: A&lt;0.1 μM; B 0.1-1 μM; C&gt;1 μM. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Summary of Activities 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Compound 
                 FRET IC 50   
                 Compound 
                 FRET IC 50   
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1 
                 A 
                 2 
                 A 
               
               
                   
                 3 
                 A 
                 4 
                 A 
               
               
                   
                 5 
                 A 
                 6 
                 A 
               
               
                   
                 7 
                 C 
                 8 
                 B 
               
               
                   
                 9 
                 B 
                 10 
                 A 
               
               
                   
                 11 
                 A 
                 12 
                 A 
               
               
                   
                 13 
                 A 
                 14 
                 A 
               
               
                   
                 15 
                 A 
                 16 
                 A 
               
               
                   
                 17 
                 A 
                 18 
                 A 
               
               
                   
                 19 
                 A 
                 20 
                 B 
               
               
                   
                 21 
                 A 
                 22 
                 A 
               
               
                   
                 23 
                 A 
                 24 
                 A 
               
               
                   
                 25 
                 A 
                 26 
                 A 
               
               
                   
                 27 
                 A 
                 28 
                 A 
               
               
                   
                 29 
                 A 
                 30 
                 A 
               
               
                   
                 31 
                 A 
                 32 
                 A 
               
               
                   
                 33 
                 A 
                 34 
                 A 
               
               
                   
                 35 
                 A 
                 36 
                 B 
               
               
                   
                 37 
                 A 
                 38 
                 A 
               
               
                   
                 39 
                 A 
                 40 
                 A 
               
               
                   
                 41 
                 A 
                 42 
                 A 
               
               
                   
                 43 
                 A 
                 44 
                 A 
               
               
                   
                 45 
                 A 
                 46 
                 A 
               
               
                   
                 47 
                 A 
                 48 
                 A 
               
               
                   
                 49 
                 A 
                 50 
                 A 
               
               
                   
                   
               
            
           
         
       
     
     229E Assay Protocol 
     Viral stock preparation: MRC-5 cells, (a diploid cell culture line composed of fibroblasts, originally developed from the lung tissue of a 14-week-old aborted Caucasian male fetus), were used for the culturing of 229E human corona virus (hCoV). Flasks were inoculated with hCoV-229E and viral stocks were collected once cytopathic effect (CPE) was greater than 70%. Viral stocks in Growth Media (EMEM, 1% Penn/Strep, 1% nonessential amino acids, 10% heat-inactivated FBS) plus 5% glycerol were snap frozen using liquid nitrogen and stored at −80° C. Viral stock titers were quantified by a TCID 50  (50% median tissue culture infectious dose) assay, as described elsewhere. 
     229E live virus assay: 384-well black cell-culture-treated plastic clear-bottom plates are used in this assay. Using an ECHO liquid dispenser, 3-fold serial dilutions of control and test compounds suspended in DMSO are added to the plate wells in duplicate in a total volume of 125 nL per well. MRC-5 cells below passage 17 are seeded into the inner 240 wells of the 384-well plate at 1,500 cells per well in a volume of 12.5 μL using Growth Media. Viral stock is then added to the wells at a multiplicity of infection (MOI) of 0.05 in a volume of 12.5 μL per well, bringing the total volume of each well to ˜25 μL. Each plate has a control row of 20 wells with cells plus DMSO and virus but no compound (positive control, max CPE, minimum ATPlite signal), and a row with cells plus DMSO but no compound or virus (negative control, minimum CPE, maximum ATPlite signal), and a row with no cells or virus or compound (background plate/reagent control). The control wells with cells but no virus are given an additional 12.5 μL of growth media containing an equal quantity of glycerol as those wells receiving the viral stock in order to keep consistent in media and volume conditions. The outer 2 rows/columns of wells are filled with 30 μL of moat media (DMEM, 1% Penn/Strep) to act as a thermal and evaporative barrier around the test wells. Following addition of all components, the sides of the plates are gently tapped by hand to promote even cell distribution across the wells. Upon confirmation of cell distribution, plates are incubated at 34° C. in a CO 2  humidity-controlled incubator for 6 days. Following the 6-day incubation period, the plates are read using ATPlite (12.5 μL added per well), which quantifies the amount of ATP (a measure of cell health) present in each well. Assay plates are read using an Envision luminometer. These data are used to calculate the percent cell health per well relative to the negative control wells and the EC 50  of each compound is calculated using ExcelFit software and 4-parameter logistical curve fitting analysis. 
     All experiments were run in duplicate, and EC 50  ranges are reported as follows: A&lt;0.1 μM; B 0.1-1 μM; C&gt;1 μM. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Summary of Activities 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Compound 
                 229E EC 50   
                 Compound 
                 229E EC 50   
               
               
                   
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 1 
                 A 
                 2 
                 B 
               
               
                   
                 3 
                 B 
                 4 
                 A 
               
               
                   
                 5 
                 A 
                 6 
                 A 
               
               
                   
                 11 
                 B 
               
               
                   
                   
               
            
           
         
       
     
     All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications. 
     Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims. 
     Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims.