Novel spiropyrrolidine-derived antiviral agents

Abstract

The present invention discloses compounds of formula (I) and their pharma- ceutically acceptable salts, which inhibit coronavirus replicative activity. [Formula 1] JPEG2024529476000214.jpg3268 The present invention further relates to pharmaceutical compositions comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, and to a method of treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

Description

[Technical field]

[0001] Related Applications This application is a continuation-in-part of U.S. Provisional Application No. 17 / 479,248, filed September 20, 2021, which claims the benefit of U.S. Provisional Application No. 63 / 227,206, filed July 29, 2021. This application also claims the benefit of U.S. Provisional Application No. 63 / 324,367, filed March 28, 2022. The entire teachings of the above applications are incorporated herein by reference.

[0002] The present invention relates to compounds and methods for inhibiting coronavirus replication activity by contacting 3C-like protease (sometimes referred to as "3CLpro", "main protease", or "Mpro") with a therapeutically effective amount of a 3C-like protease inhibitor. The present invention further relates to pharmaceutical compositions containing coronavirus 3C-like protease inhibitors in mammals by administering an effective amount of such a coronavirus 3C-like protease inhibitor. [Background technology]

[0003] Coronaviruses are a family of enveloped, single-stranded, positive-stranded RNA viruses classified in the order Nidovirales. The coronavirus family includes pathogens of humans and many animal species, including horses, cattle, pigs, birds, cats, and monkeys, and has been known for over 60 years. For example, the isolation of the prototype murine coronavirus strain JHM was reported in 1949. Coronaviruses are common viruses that generally cause mild to moderate upper respiratory tract disease in humans and are named for the crown-like spikes on their envelope surface. There are four main subgroups, known as alpha-, beta-, gamma-, and delta-coronaviruses, with the first coronaviruses identified in the mid-1960s. Coronaviruses known to infect humans include alphacoronavirus 229E and NL63; and betacoronavirus OC43, HKU1, SARS-CoV (coronavirus that causes severe acute respiratory syndrome or SARS) and MERS-CoV (coronavirus that causes Middle East respiratory syndrome or MERS). Human coronaviruses 229E, NL63, 0C43, and HKU1 are commonly transmitted, and symptoms usually include mild to moderate, short-term upper respiratory illness, such as runny nose, cough, sore throat, and fever. Occasionally, human coronaviruses cause lower respiratory illness, such as pneumonia, which is more common in people with cardiopulmonary disease or compromised immune systems, or in the elderly. Transmission of common human coronaviruses is not fully understood. However, human coronaviruses likely spread from infected individuals to others through the air, by coughing or sneezing, or through close personal contact, such as shaking hands. These viruses can also be spread by touching a contaminated object or surface and then touching the mouth, nose, or eyes.

[0004] Coronaviruses are enveloped, positively directed, single-stranded RNA viruses. The genomic RNA of CoVs has a 5' cap structure and a 3' polyA tail and contains at least six open reading frames (ORFs). The first ORF (ORF 1a / b) directly translates two polyproteins: pp1a and pp1ab. These polyproteins are processed into 16 nonstructural proteins by papain-like proteases and 3C-like proteases (3CLpro), also known as main proteases (Mpro). These nonstructural proteins are involved in the production of subgenomic RNAs that code for the four structural proteins, namely the envelope, membrane, spike and nucleocapsid proteins, among other accessory proteins. As a result, it is understood that 3C-like proteases play a key role in the coronavirus life cycle.

[0005] 3CLpro is a cysteine ​​protease responsible for most cleavage events within the precursor polyprotein. Active 3CLpro is a homodimer containing two protomers and is characterized by a Cys-His dyad located between domains I and II. 3CLpro is conserved among coronaviruses, and several common features are shared among the substrates of 3CLpro in various coronaviruses. The absence of a human homolog of 3CLpro makes it an ideal antiviral target. Compounds have been reported to inhibit 3CLpro activity, but they have not been approved as coronavirus therapies. (See WO 2004101742 A2, U.S. Patent No. 2005 / 0143320 A1, U.S. Patent No. 2006 / 0014821 A1, U.S. Patent No. 2009 / 0137818 A1, WO 2013 / 049382 A2, WO 2013 / 166319 A1, WO 2018042343, WO 2018023054, WO 2005113580 and WO 2006061714).

[0006] More effective therapies against coronavirus infections are needed due to this high unmet medical need. The present invention provides compounds that inhibit the coronavirus life cycle, as well as methods for preparing and using these compounds. These compounds are useful for treating or preventing coronavirus infections and reducing the incidence of disease complications, such as organ failure or death. Summary of the Invention

[0007] The present invention relates to novel antiviral compounds, pharmaceutical compositions containing such compounds, and methods for treating or preventing viral, particularly coronavirus, infectivity in subjects in need of such treatment with said compounds. The compounds of the present invention inhibit proteins encoded by coronaviruses or interfere with the life cycle of coronaviruses and are also useful as antiviral agents. Additionally, the present invention provides methods for preparing said compounds.

[0008] The present invention provides compounds represented by formula (I), and pharma- ceutically acceptable salts, esters, and prodrugs thereof: [ka] During the ceremony R1, R2, R3, R 21 , R 22 and R 23 are each independently 1) Hydrogen; 2) optionally substituted -C1-C8 alkyl; 3) optionally substituted -C2-C8 alkenyl; 4) optionally substituted -C2-C8 alkynyl; 5) optionally substituted -C3-C8 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 is selected from.

[0009] Alternatively, R1 and R2 together with the carbon atom to which they are attached form an optionally substituted 3- to 8-membered carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring.

[0010] Alternatively, R1 and R3 together with the atoms to which they are attached form an optionally substituted 3- to 8-membered heterocyclic ring.

[0011] Or, R 21 and R3 together with the intervening atom form an optionally substituted 4- to 8-membered heterocyclic ring.

[0012] Or, R 22 does not exist, and R 21 and R3 together with the intervening atom form an optionally substituted 4- to 8-membered partially unsaturated heterocyclic ring or an optionally substituted 5- to 6-membered heteroaryl ring.

[0013] Or, R 21 and R 22 together with the carbon atom to which they are attached form an optionally substituted 3- to 8-membered carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring.

[0014] R 24 is selected from: 1)-C(O)R 25 ; 2)-C(O)OR 25 ; 3) -C(O)NR 13 R 14 ; 4)-S(O)2R 25 ; 5) Hydrogen; 6) optionally substituted -C1-C8 alkyl; 7) optionally substituted -C2-C8 alkenyl; 8) optionally substituted -C2-C8 alkynyl; 9) optionally substituted -C3-C 12 Cycloalkyl; 10) optionally substituted 3- to 12-membered heterocycloalkyl; 11) optionally substituted aryl; 12) optionally substituted arylalkyl; 13) optionally substituted heteroaryl; 14) optionally substituted heteroarylalkyl; 15)-(CO)(CO)NR 13 R 14 ; 16)-(CO)(CO)R 25 ; 17)-S(O)NR 13 R 14 ; 18)-C(S)R 25 and 19)-C(S)NR 13 R 14 ; Or, R 23 and R 24 form, together with the nitrogen atom to which they are attached, an optionally substituted 3- to 12-membered heterocyclic ring or an optionally substituted 5- to 12-membered heteroaryl ring; R 25 is selected from: 1) optionally substituted -C1-C8 alkyl; 2) optionally substituted -C2-C8 alkenyl; 3) optionally substituted -C2-C8 alkynyl; 4) optionally substituted -C3-C 12 Cycloalkyl; 5) optionally substituted 3- to 12-membered heterocycloalkyl; 6) optionally substituted aryl; 7) optionally substituted arylalkyl; 8) optionally substituted heteroaryl; and 9) optionally substituted heteroarylalkyl; R4 is hydrogen, optionally substituted -C1-C4 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, halogen, -CN, -OH, or a prodrug moiety; B is optionally substituted aryl or optionally substituted heteroaryl; Or, R 21 and R 24 is L-, where L is a saturated or unsaturated linker 4 to 20 atoms in length attached to B; X is selected from: 1)-CN; 2)-C(O)R 15 ; 3)-CH(OH)SO3R 16 ; 4)-C(O)NR 13 R 14 ; 5)-C(O)C(O)NR 13 R 14 ; 6) -CH=CH-C(O)OR 25 , 7) -CH=CH-C(O)NR 13 R 14 , 8)-CH=CH-S(O)NR 13 R 14 , 9)-B(OR 13 )2; 10)-C≡CR 13 ; 11)-C≡CC(O)OR 25 ; 12)-C≡CC(O)NR 13 R 14 ; 13)-C≡CS(O)2NR 13 R 14 ; 14)-(CR 13 R 14 ) w -CN; and 15)-(CR 13 R 14) w -(C=O)-R 25 ; w is 1, 2, 3, 4 or 5; R 13 and R 14 are each independently selected from: 1) Hydrogen; 2) optionally substituted -C1-C8 alkyl; 3) optionally substituted -C2-C8 alkenyl; 4) optionally substituted -C2-C8 alkynyl; 5) optionally substituted -C3-C8 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; Or, R 13 and R 14 together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclic ring; R 15 is hydrogen, hydroxy, optionally substituted -C1-C8 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl; R 16 is hydrogen or Na + It is. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] In one embodiment of the present invention is a compound of formula (I) above or a pharma- ceutically acceptable salt thereof.

[0016] In certain embodiments of compounds of formula (I), R4 is hydrogen, an optionally substituted -C1-C4 alkyl, an optionally substituted -C2-C4 alkenyl, or an optionally substituted -C3-C6 cycloalkyl; and X is selected from: 1)-CN; 2)-C(O)R 15 ; 3)-CH(OH)SO3R 16 ; 4)-C(O)NR 13 R 14 and 5)-C(O)C(O)NR 13 R 14 ; R 24 is selected from: 1)-C(O)R 25 ; 2)-C(O)OR 25 ; 3) -C(O)NR 13 R 14 ; 4)-S(O)2R 25 ; 5) Hydrogen; 6) optionally substituted -C1-C8 alkyl; 7) optionally substituted -C2-C8 alkenyl; 8) optionally substituted -C2-C8 alkynyl; 9) optionally substituted -C3-C8 cycloalkyl; 10) optionally substituted 3- to 8-membered heterocycloalkyl; 11) optionally substituted aryl; 12) optionally substituted arylalkyl; 13) optionally substituted heteroaryl; and 14) optionally substituted heteroarylalkyl; R 25 is selected from: 1) optionally substituted -C1-C8 alkyl; 2) optionally substituted -C2-C8 alkenyl; 3) optionally substituted -C2-C8 alkynyl; 4) optionally substituted -C3-C8 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 15 is hydrogen, hydroxy, or optionally substituted -C1-C8 alkyl.

[0017] In one embodiment of the invention, the compound of formula (I) is represented by formula (IA) or formula (IB) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, B, X, R1, R2, R3, R4, R 21 , R 22 , R 23 and R 24 is as defined above.

[0018] In a preferred embodiment, the compound of formula (I) has the stereochemistry shown in formula (IA).

[0019] In one embodiment of the invention, the compound of formula (I) is represented by formula (II) or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, B, X, R1, R2, R3, R 21 , R 22 , R 23 and R 24 is as defined above.

[0020] In one embodiment of the present invention, the compound of formula (I) is represented by formula (II-A) or formula (II-B), or a pharma-ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, B, X, R1, R2, R3, R 21 , R 22 , R 23 and R 24 is as defined above.

[0021] In certain embodiments of the compound of formula (I), R1 is hydrogen, an optionally substituted -C1-C6 alkyl; an optionally substituted -C3-C6 cycloalkyl; an optionally substituted aryl; an optionally substituted arylalkyl; or an optionally substituted heteroarylalkyl.

[0022] In certain embodiments, R1 is -C1-C6-alkyl, preferably branched -C3-C6-alkyl, such as isobutyl or neopentyl. In certain embodiments, R1 is optionally substituted benzyl.

[0023] In a particular embodiment, R1 is optionally substituted -C1-C6-alkyl, preferably R1 is 2-fluoro-2-methylpropyl or cyclopropylmethyl.

[0024] In certain embodiments of the compound of formula (I), R2 is hydrogen or optionally substituted -C1-C4 alkyl; optionally substituted -C3-C6 cycloalkyl; optionally substituted aryl; optionally substituted arylalkyl; or optionally substituted heteroarylalkyl. In certain embodiments, R2 is hydrogen.

[0025] In certain embodiments of a compound of formula (I), R3 is hydrogen or optionally substituted -C1-C4 alkyl and R4 is hydrogen or optionally substituted -C1-C4 alkyl.

[0026] In certain embodiments of compounds of Formula (I), R3 is hydrogen, -Me, -Et, -Pr, -i-Pr, -allyl, -CF 3、 -CD3 or cyclopropyl.

[0027] In certain embodiments of a compound of Formula (I), R4 is hydrogen, -Me, -Et, -Pr, -i-Pr, -allyl, -CF3, or cyclopropyl.

[0028] In certain embodiments, R3 and R4 are each independently hydrogen or methyl.

[0029] In certain embodiments of compounds of Formula (I), X is --CN.

[0030] In certain embodiments of compounds of Formula (I), X is -C(O)H.

[0031] In certain embodiments of a compound of Formula (I), X is -C(O)CH2OH, -C(O)CH2Cl, or -C(O)CH2F.

[0032] In certain embodiments of compounds of Formula (I), X is -C(O)CHFCl.

[0033] In certain embodiments of compounds of Formula (I), X is -C(O)C(O)NR 13 R 14 where R 13 and R 14 is as defined above.

[0034] In certain embodiments of compounds of Formula (I), X is -C≡CR 13 where R 13 is as defined above. Preferably, R 13 is hydrogen.

[0035] In certain embodiments of the compounds of formula (I), R 21is hydrogen, an optionally substituted -C1-C4 alkyl; an optionally substituted -C3-C6 cycloalkyl; an optionally substituted aryl; an optionally substituted heteroaryl; an optionally substituted arylalkyl; or an optionally substituted heteroarylalkyl. In certain embodiments, R 21 is an optionally substituted phenyl, an optionally substituted benzyl, an optionally substituted methyl, a t-butyl, an isopropyl, a neopentyl, [ka] It is.

[0036] In certain embodiments of the compounds of formula (I), R 22 is hydrogen or an optionally substituted -C1-C4 alkyl; an optionally substituted -C3-C6 cycloalkyl; an optionally substituted aryl; an optionally substituted heteroaryl; an optionally substituted arylalkyl; an optionally substituted heteroarylalkyl. In certain embodiments, R 22 is hydrogen.

[0037] In certain embodiments of the compounds of formula (I), R and R 21 are each independently C1-C4 alkyl substituted with one or more fluorine atoms; C3-C6 cycloalkyl substituted with one or more fluorine atoms; aryl substituted with one or more fluorine atoms; heteroaryl substituted with one or more fluorine atoms; arylalkyl substituted with one or more fluorine atoms; or heteroarylalkyl substituted with one or more fluorine atoms. Each of the aforementioned groups can be substituted with a number of fluorine atoms ranging from 1 to the maximum number possible, i.e., all hydrogen atoms can be replaced with fluorine atoms. In certain embodiments, R1 and R 21 are each independently -CF3, -CF2-CF3, -CH2CH(CF3)2, [ka] where m is 1, 2, 3, 4 or 5.

[0038] In certain embodiments of the compounds of formula (I), R 23 is hydrogen or optionally substituted -C1-C4 alkyl. In certain embodiments, R 23 is hydrogen.

[0039] In certain embodiments of the compounds of formula (I), R 24 is -C(O)R 25 , -C(O)OR 25 or -C(O)NR 13 R 14 where R 13 , R 14 and R 25 is as defined above.

[0040] In certain embodiments of compounds of Formula (I), R2 is hydrogen, R3 is hydrogen, R4 is hydrogen, and R 22 is hydrogen.

[0041] In certain embodiments of compounds of formula (I), R4 is hydrogen or optionally substituted -C1-C4 alkyl, e.g., methyl; R 23 is hydrogen or optionally substituted -C1-C4 alkyl, e.g., methyl; R 24 is -C(O)R 25 , -C(O)OR 25 or -C(O)NR 13 R 14 where R 13 , R 14 and R 25 is as defined above.

[0042] In certain embodiments of compounds of formula (I), R4 is cyano-C1-C4 alkyl, cyano-C3-C6 cycloalkyl, hydroxy-C1-C4 alkyl, or optionally substituted hydroxy-C3-C6 cycloalkyl, each of the above optionally further substituted.

[0043] In certain embodiments of a compound of Formula (I), R4 is a prodrug moiety, said prodrug moiety being an amino acid residue, preferably a naturally occurring L-amino acid residue.

[0044] In certain embodiments of compounds of Formula (I), R4 is a prodrug moiety selected from the group consisting of: 1)-C(O)R 25 ; 2)-S(O)2R 25 ; 3)-P(O)(R 25 )2; 4)-C(O)OR 25 ; 5)-S(O)2OR 25 and 6)-P(O)(OR 25 )2, In the formula, each R 25 are the same or different.

[0045] In certain embodiments of compounds of Formula (I), R4 is a prodrug moiety selected from the group consisting of: 1)-CHR 13 O(CO)R 25 ; 2)-CHR 13 O(CO)CH(NH2)R 25 ; 3)-CHR 13 O(CO)OR 25 and 4)-CHR 13 O(PO)(OR 14 )2, In the formula, each R 14 are the same or different.

[0046] In certain embodiments of a compound of Formula (I), R2 is hydrogen, R3 is methyl, R4 is hydrogen or a prodrug moiety, and R 22 is hydrogen, and R 23 is hydrogen, and R 24 HA-C(O)R 25 , -C(O)OR 25 or -C(O)NR 13R 14 where R 13 , R 14 and R 25 is as defined above.

[0047] In certain embodiments of compounds of formula (I), R2 is hydrogen, R3 and R4 are independently hydrogen or optionally substituted -C1-C4 alkyl, e.g., methyl; R 23 is hydrogen; R 24 HA-C(O)R 25 , -C(O)OR 25 or -C(O)NR 13 R 14 where R 13 , R 14 and R 25 is as defined above.

[0048] In certain embodiments of the compounds of formula (I), R 24 is -C(O)R 25 ;C(O)OR 25 ; or -S(O)R 25 ;R 25 is selected from the following groups by removal of a hydrogen atom, R 25 may be substituted. [ka]

[0049] In certain embodiments of the compounds of formula (I), R 24 is -C(O)R 25 ;C(O)OR 25 ; or -S(O)R 25 ;R 25 is selected from the following groups, R 25 may be substituted. [ka]

[0050] Preferably, the substituents are independently selected from halogen, CN, NH2, optionally substituted -C1-C3 alkoxy, optionally substituted -C1-C3 alkyl, optionally substituted -C3-C6 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. Preferably, the number of the substituents is 0 to 3.

[0051] In certain embodiments of the compounds of formula (I), R 24 is optionally substituted -C1-C8 alkyl, optionally substituted -C3-C 12 Cycloalkyl, -C(O)R 25 , C(O)OR 25 or -S(O)2R 25 ;R 25 is optionally substituted -C1-C8 alkyl or optionally substituted -C3-C 12 cycloalkyl; preferably, R 25 is optionally substituted -C1-C8 alkyl.

[0052] In certain embodiments of the compounds of Formula (I), B is selected from the following groups, where B is optionally substituted: [ka]

[0053] In certain embodiments of the present invention, the compound of formula (I) is represented by one of formulas (III-1) to (III-4), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, B, X, R1, R2, R3, R 13 , R 14 , R 21 , R 22 , R 23 and R 25 is as defined above.

[0054] In certain embodiments of the present invention, the compound of formula (I) is represented by formula (III-5) or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, B, X, R1, R2, R3, R 13 , R 14 , R 21 , R 22 , and R 23 is as defined above.

[0055] In certain embodiments of the present invention, the compound of formula (I) is represented by one of formulae (III-1A) to (III-4A) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, B, X, R1, R2, R3, R 13 , R 14 , R 21 , R 22 , R 23 and R 25 is as defined above.

[0056] In certain embodiments of the present invention, the compound of formula (I) is represented by formula (III-5A) or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, B, X, R1, R2, R3, R 13 , R 14 , R 21 , R 22 , and R 23 is as defined above.

[0057] In certain embodiments of the present invention, the compound of formula (I) is represented by one of formulas (IV-1) to (IV-4), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, B, X, R1, R3, R 13 , R 14 , R 21 , and R 25 is as defined above.

[0058] In certain embodiments of the present invention, the compound of formula (I) is represented by formula (IV-5) or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, B, X, R1, R3, R 13 , R 14 , and R 21 is as defined above.

[0059] In certain embodiments of the present invention, the compound of formula (I) is represented by one of formulae (IV-1A) to (IV-4A) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, B, X, R1, R3, R 13 , R 14 , R 21 , and R 25 is as defined above.

[0060] In certain embodiments of the present invention, the compound of formula (I) is represented by formula (IV-5A) or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, B, X, R1, R3, R 13 , R 14 , and R 21 is as defined above.

[0061] In certain embodiments, the compound of formula (I) has formula (V): [ka] In the formula, R1, R2, R3, R4, R 21 , R 22 , R 23 , R 24 and X are as defined above, preferably R4 is hydrogen and each R9 is 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 -C1-C6 alkyl; 8) optionally substituted -C3-C8 cycloalkyl; 9) optionally substituted 3- to 8-membered heterocycloalkyl; 10) optionally substituted aryl; and 11) Optionally substituted heteroaryl are independently selected from n is 0, 1, 2, 3, or 4.

[0062] In certain embodiments, the compound of formula (I) has formula (V): [ka] In the formula, n, R1, R2, R3, R4, R 21 , R 22 , R 23 , R24 and X are as defined above, preferably R4 is hydrogen; each R9 is 1)-OC(O)R 25 ; 2) -C(O)NR 13 R 14 ; 3)-S(O)R 25 ; 4)-S(O)2R 25 ; 5)-S(O)(NH)R 25 ; 6)-S(O)2-NR 13 R 14 ; 7)-NR 13 (C=O)R 25 ; 8)-NR 13 (C=O)OR 25 ; 9)-NR 13 (C=O)NR 13 R 14 ; 10)-NR 13 -S(O)2-R 25 and 11)-NR 13 -S(O)2-NR 13 R 14 ; are independently selected from R 13 , R 14 , R 25 is as defined above.

[0063] In certain embodiments, the compound of formula (I) has formula (VI): [ka] In the formula, R1, R3, R9, R 21 , R 22 , R 23 , R 24 and n is as defined above. Preferably, n is 0 or 1.

[0064] In certain embodiments, the compound of formula (I) has formula (VI-A) or formula (VI-B): [ka] In the formula, R1, R3, R9, R 21 , R 22 , R 23 , R 24 and n is as defined above. Preferably, n is 0 or 1.

[0065] In certain embodiments, the compound of formula (I) has the formulas (VII-1) to (VII-4): [ka] wherein R1, R3, R 21 , R 23 , R 25 , R 13 and R 14 is as defined above. Preferably, R3 is hydrogen, Me.

[0066] In certain embodiments, the compound of formula (I) is represented by one of formulas (VII-1) to (VII-4), wherein R, R 21 , R 23 , R 25 , R 13 and R 14 is as defined above and R3 is CD3.

[0067] In certain embodiments of the present invention, the compound of formula (I) is represented by formula (VII-5) or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, R1, R3, R 21 , R 23 , R 25 , R 13 and R 14 is as defined above. Preferably, R3 is hydrogen, Me or CD3.

[0068] In certain embodiments, the compound of formula (I) has the formula (VII-1A) to (VII-4A): [ka] wherein R1, R3, R 21 , R 23 , R 25 , R 13 and R 14 is as defined above. Preferably, R3 is hydrogen, Me.

[0069] In certain embodiments, the compound of formula (I) is represented by one of formulas (VII-1A) to (VII-4A), wherein R, R 21 , R 23 , R 25 , R 13 and R 14 is as defined above and R3 is CD3.

[0070] In certain embodiments of the present invention, the compound of formula (I) is represented by formula (VII-5A) or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, R1, R3, R 21 , R 23 , R 25 , R 13 and R 14 is as defined above. Preferably, R3 is hydrogen, Me or CD3.

[0071] In certain embodiments of the present invention, the compound of formula (I) is represented by one of formulae (VIII-1) to (VIII-3), or a pharma- ceutically acceptable salt, ester or prodrug thereof: [ka] In the formula, A1 is an optionally substituted 4- to 8-membered lactam; A2 is an optionally substituted 3- to 12-membered heterocyclic ring or an optionally substituted 5- to 12-membered heteroaryl ring; A3 is an optionally substituted 3- to 8-membered heterocyclic ring; B, X, R1, R2, R3, R4, R 21 , R 22 , R 23 , and R 24 is as defined above.

[0072] In a particular embodiment of the present invention, the compound of formula (I) is represented by one of formulae (VIII-1) to (VIII-3), or a pharma- ceutically acceptable salt, ester or prodrug thereof, wherein A1 is 2-pyridone; A2 is an optionally substituted 3- to 12-membered heterocyclic ring or an optionally substituted 5- to 12-membered heteroaryl ring; A3 is an optionally substituted 3- to 8-membered heterocyclic ring; and B, X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R61, R62, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R79, R79, R71, R72, R75, R79, R79, R79, R79, R71, 21 , R 22 , R 23 , and R 24 is as defined above.

[0073] In certain embodiments of the present invention, the compound of formula (I) is represented by one of formulas (IX-1) to (IX-3), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, A1, A2, A3, B, R1, R3, R 21 , R 23 , and R 24 is as defined above.

[0074] In certain embodiments of the present invention, the compound of formula (I) is represented by one of formulas (X-1) to (X-3), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, A1, A2, A3, X, R1, R2, R3, R4, R9, R 21 , R 22 , R 23 , and R 24 is as defined above.

[0075] In certain embodiments of the present invention, the compound of formula (I) is represented by one of formulas (XI-1) to (XI-3), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, A1, A2, A3, R1, R3, R 21 , R 23 , and R 24 is as defined above.

[0076] In certain embodiments of the present invention, the compound of formula (I) is represented by one of formulas (XII-1) to (XII-10), or a pharma- ceutically acceptable salt, ester, or prodrug thereof: [ka] In the formula, A1, A3, R1, R 13 , R 14 , R 21 , R 23 , and R 25 is as defined above.

[0077] In certain embodiments of the present invention, the compound of formula (I) is represented by one of formulae (XII-11) to (XII-12), or a pharma- ceutically acceptable salt, ester, or prodrug thereof; [ka] In the formula, A1, A3, R1, R 13 , R 14 , R 21 , and R 23 is as defined above.

[0078] In a particular embodiment of the invention, the compound of formula (I) is represented by formula (XIII): [ka] In the formula, q is 1 or 2; R 21 , R 22 , R 23 and R 24 is as defined above.

[0079] In a particular embodiment of the present invention, the compound of formula (I) is represented by one of the formulae (XIV-1) to (XIV-5): [ka] In the formula, q, R 13 , R 14 , R 21 , R 23 and R 25 is as defined above.

[0080] In a particular embodiment of the present invention, the compound of formula (I) is represented by formula (XIV-6): [ka] In the formula, q, R 13 , R 14 , R 21 , and R 23 is as defined above.

[0081] In a particular embodiment of the invention, the compound of formula (I) is represented by one of the formulae (XV-1) to (XV-4): [ka] In the formula, R 21 , R 22 , R 23 , R 24and R4 is as defined above; preferably, R4 is hydrogen or a prodrug moiety.

[0082] In a particular embodiment of the present invention, the compound of formula (I) is represented by one of the formulae (XVI-1) to (XVI-6): [ka] In the formula, R1, R4, R 13 , R 14 , R 23 and R 25 is as defined above; preferably, R4 is hydrogen or a prodrug moiety.

[0083] In a particular embodiment of the present invention, the compound of formula (I) is represented by one of formulae (XVII-1) to (XVII-2): [ka] In the formula, r is 1, 2, 3 or 4; n, R1, R3, R4, R9 and R 21 is as defined above; preferably, R4 is hydrogen or a prodrug moiety.

[0084] In a particular embodiment of the invention, the compound of formula (I) is represented by one of the formulae (XVIII-1) to (XVIII-4): [ka] In the formula, n, R1, R3, R9, R 13 , R 14 , R 21 , R 22 , R 23 , R 24 and R 25 is as defined above.

[0085] In a particular embodiment of the invention, the compound of formula (I) is represented by one of formulae (XVIII-1a) to (XVIII-4a): [ka] In the formula, R1, R3, R 13 , R 14 , R 21 , R 22 , R 23 , R 24 and R 25 is as defined above.

[0086] In certain embodiments, the compound of formula (I) has formula (XIX): [ka] In the formula, R1, R3, R4, R9, R 21 , R 22 , R 23 , R 24 and n is as defined above. Preferably, n is 0 or 1 and R4 is hydrogen or a prodrug moiety.

[0087] In certain embodiments, the compound of formula (I) is represented by formula (XIX-A) or (XIX-B): [ka] In the formula, R1, R3, R4, R9, R 21 , R 22 , R 23 , R 24 and n is as defined above. Preferably, n is 0 or 1 and R4 is hydrogen or a prodrug moiety.

[0088] In certain embodiments, the compound of formula (I) is represented by one of formulas (XX-1) to (XX-5): [ka] In the formula, R1, R3, R4, R 21 , R 23 , R 25 , R 13 and R 14is as defined above. Preferably, R3 is hydrogen or Me or CD3 and R4 is hydrogen or a prodrug moiety.

[0089] In certain embodiments, the compound of formula (I) has the formula (XX-1A) to (XX-5A): [ka] wherein R1, R3, R 21 , R 23 , R 25 , R 13 and R 14 is as defined above. Preferably, R3 is hydrogen, Me or CD3 and R4 is hydrogen or a prodrug moiety.

[0090] In a particular embodiment of the invention, the compound of formula (I) is represented by formula (XXI): [ka] In the formula, q is 1 or 2; R, R 21 , R 22 , R 23 and R 24 is as defined above. Preferably, R4 is hydrogen or a prodrug moiety.

[0091] In a particular embodiment of the invention, the compound of formula (I) is represented by formula (XXII): [ka] In the formula, B, X, R1, R2, R3, R4, R 22 , R 23 , and R 24 is as defined above, and L is -R a -QR b -, wherein R a If exists, R a is connected to B, and R a is not present, then Q is linked to B; Ra is selected from the group consisting of absent, optionally substituted -C1-C8 alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; in some embodiments, R a is non-existent; R b is selected from the group consisting of optionally substituted -C1-C8 alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; Q is -CR 31 =CR 32 -, -CR 31 R 33 -CR 32 R 34 -, -CR 31 R 33 C(O)-, -CR 31 R 33 -O-, -CR 31 R 33 -S-, -CR 31 R 33 N(R 17 )-, -NR 13 C(O)-, -NR 13 C(O)O-, -NR 13 C(O)NR 14 -, -C(O)O-, -C(O)S-, -OC(O)O-, -C(O)-, O-, -S-, -S(O)-, -S(O)2-, -S(O)(NH)-, -N(R 17)-, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted -C3-C8 cycloalkyl, and optionally substituted 3- to 8-membered heterocycloalkyl.

[0092] In certain embodiments, L is an optionally substituted C-C 10 Alkylene or optionally substituted C4-C 10 alkenylene, 10 Alkylene or C4-C 10 In the alkenylene, one CH2 group may be replaced by an oxygen atom or an NH group; preferably L is a C4-C8 alkylene or a C4-C8 alkenylene, said C4-C8-alkylene or C4-C8-alkenylene being optionally substituted by oxo; R 31 and R 32 is each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C1-C8 alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; in certain embodiments, R 31 and R 32 are both hydrogen; R 33 and R 34 is hydrogen, halogen, -OH, -OR in each occurrence. 12 , -OC(O)R 11 , -OC(O)OR 12 , -OC(O)NR 13 R 14 , -NR 13 R 17, -N3, -CN, optionally substituted -C1-C8 alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; in certain embodiments, R 33 and R 34 are both hydrogen; R 11 and R 12 are each independently selected from the group consisting of optionally substituted -C1-C8 alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R 13 and R 14 is independently selected at each occurrence from the group consisting of hydrogen, optionally substituted -C1-C8 alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; or R 13 and R 14 together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclic ring; R 17is hydrogen, optionally substituted -C1-C8 alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -C(O)R 11 , -C(O)OR 12 , -C(O)NR 13 R 14 , -C(O)C(O)NR 13 R 14、 -S(O)2R 11 , and -S(O)NR 13 R 14 is selected from the group consisting of:

[0093] In a particular embodiment of the invention, the compound of formula (I) is represented by formula (XXIII): [ka] In the formula, B, X, R1, R2, R3, R4, R 21 , R 22 , R 23 and L is as defined above.

[0094] In certain embodiments, the compound of formula (I) is represented by one of formulas (XXIV-1) to (XXIV-5): [ka] In the formula, R1, R3, R4, R 22 , R 23 , R 25 , R 13 and R 14 is as defined above. Preferably, R3 is hydrogen or Me or CD3 and R4 is hydrogen or a prodrug moiety.

[0095] In certain embodiments, the compound of formula (I) is represented by one of formulas (XXV-1) to (XXV-5): [ka] In the formula, R1, R3, R4, R 21 , R 23 , and R 14 is as defined above. Preferably, R3 is hydrogen or Me or CD3 and R4 is hydrogen or a prodrug moiety.

[0096] It will be understood that the description of the invention herein is to be interpreted in accordance with the laws and principles of chemical bonding. In some cases, it may be necessary to remove a hydrogen atom to accommodate a substituent at any given position.

[0097] It is intended that the definition of any substituent or variable (e.g., R1, R2, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. For example, in formula (V) where n is 2, each of the two R9 groups can be the same or different.

[0098] It will be further understood that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereomeric and optically active forms.It will still be understood that certain compounds of the present invention may exist in different tautomeric forms.All tautomers are intended to be within the scope of the present invention.

[0099] definition Listed below are definitions of various terms used to describe this invention. These definitions apply to those terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0100] The term "aryl" as used herein refers to a monocyclic or polycyclic carbocyclic ring system containing at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system containing at least one aromatic ring. A polycyclic aryl can contain fused rings, covalently bonded rings, or combinations thereof.

[0101] The term "heteroaryl" as used herein refers to a monocyclic or polycyclic aromatic radical having one or more ring atoms selected from S, O, and N, with the remaining ring atoms being carbon, and any N or S contained within the ring being optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. Polycyclic heteroaryl can include fused rings, covalently bonded rings, or combinations thereof.

[0102] According to the present invention, the aromatic group can be substituted or unsubstituted.

[0103] The term "bicyclic aryl" or "bicyclic heteroaryl" refers to a ring system consisting of two rings, at least one of which is aromatic, and which may be fused or covalently linked.

[0104] The term "alkyl" as used herein refers to a straight or branched chain hydrocarbon radical. 1- C4 alkyl", "C 1- C6 alkyl", "C 1- C8 alkyl", "C 1- C 12"Alkyl," "C2-C4 alkyl," or "C3-C6 alkyl" refer to alkyl groups containing 1 to 4, 1 to 6, 1 to 8, 1 to 12, 2 to 4, and 3 to 6 carbon atoms, respectively. Examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl groups.

[0105] The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond formed by the removal of a single hydrogen atom. 12 "Alkenyl", "C2-C4 alkenyl", "C3-C4 alkenyl" or "C3-C6 alkenyl" refers to an alkenyl group containing 2 to 8, 2 to 12, 2 to 4, 3 to 4 or 3 to 6 carbon atoms, respectively. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, octenyl, and the like.

[0106] The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond formed by the removal of a single hydrogen atom. 12 "Alkynyl", "C2-C4 alkynyl", "C3-C4 alkynyl" or "C3-C6 alkynyl" refers to an alkynyl group containing 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, for example, ethynyl, 2-propynyl, 2-butynyl, heptynyl, octynyl, and the like.

[0107] The term "cycloalkyl" as used herein refers to a monocyclic or polycyclic saturated carbocyclic ring, or a bicyclic or tricyclic fused, bridged, or spiro system, in which the carbon atoms may be oxo-substituted or substituted with an exocyclic olefinic double bond. Preferred cycloalkyl groups include C3-C12 Cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl. 12 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.

[0108] The term "cycloalkenyl" as used herein refers to a monocyclic or polycyclic carbocyclic ring, or a bicyclic or tricyclic fused, bridged, or spiro system having at least one carbon-carbon double bond, the carbon atoms of which may be oxo-substituted or substituted with an exocyclic olefinic double bond. Preferred cycloalkenyl groups include those having C3-C 12 Cycloalkenyl, C3-C8 cycloalkenyl or C5-C7 cycloalkenyl groups. 12 Examples of cycloalkenyls 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.

[0109] The term "arylalkyl" as used herein refers to a functional group in which an alkylene chain is attached to an aryl group, e.g., -CH2CH2-phenyl. The term "substituted arylalkyl" refers to an arylalkyl functional group in which the aryl group is substituted. Similarly, the term "heteroarylalkyl" refers to a functional group in which an alkylene chain is attached to a heteroaryl group. The term "substituted heteroarylalkyl" refers to a heteroarylalkyl functional group in which the heteroaryl group is substituted. Preferably, as used herein, an arylalkyl is an aryl-C1-C6 alkyl and a heteroarylalkyl is a heteroaryl-C1-C6 alkyl.

[0110] As used herein, the term "alkoxy", used alone or in combination with other terms, unless otherwise specified, refers to an alkyl group having the specified number of carbon atoms attached to the remainder of the molecule through an oxygen atom, such as methoxy, ethoxy, 2-propoxy, 2-propoxy (isopropoxy) and higher homologs and isomers. Preferred alkoxy is (C2-C3)alkoxy.

[0111] It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkenyl moiety described herein can also be an aliphatic or alicyclic group.

[0112] An "aliphatic" group is a non-aromatic moiety composed of any combination of carbon, hydrogen, halogen, oxygen, nitrogen, or other atoms, and may contain one or more units of unsaturation, such as double and / or triple bonds. Examples of aliphatic groups include alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O)2NH2, NHC(O)NH2, NHC(O)C(O)NH, NHS(O)2NH, NHS(O)2NH2, C(O)NHS(O)2, C(O)NHS(O)2NH or C(O)NHS(O)2NH2, groups containing one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups in which one or more carbons of a non-aromatic hydrocarbon (optionally substituted) are replaced by a functional group. The carbon atoms of the aliphatic group may be oxo-substituted. The aliphatic group may be linear, branched, cyclic, or a combination thereof, and preferably contains from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyl, polyalkoxyalkyl, such as polyalkylene glycols, polyamines, and polyimines. The aliphatic group is optionally substituted.

[0113] The terms "heterocyclic" or "heterocycloalkyl" may be used interchangeably and refer to non-aromatic rings or bicyclic or tricyclic fused, bridged, or spiro systems, 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 can be optionally oxidized, (iv) the nitrogen heteroatom can be optionally quaternized, (v) any of the above rings can be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms that can be optionally oxo-substituted or optionally substituted with an 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, quinozalinyl, 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-oxoxoxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups may be C-attached or N-attached (where possible).

[0114] It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety, etc. described herein may also be a divalent or polyvalent group when used as a bond to connect two or more groups or substituents, which may be on the same atom or different atoms. One skilled in the art can readily determine the valency of any such group from the context in which it occurs.

[0115] The term "substituted" refers to the replacement of one, two, or more hydrogen atoms with, but not limited to, -F, -Cl, -Br, -I, -OH, C 1- C 12 -Alkyl; C2-C12 -Alkenyl, C2-C 12 -Alkynyl, -C3-C 12 -Cycloalkyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thio, -NH-C 1- C 12 -Alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C 12 -Cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -OC 1- C 12 -Alkyl, -O-C2-C8-alkenyl, -O-C2-C8-alkynyl, -O-C3-C 12 -Cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C 1- C 12 -Alkyl, -C(O)-C2-C8-alkenyl, -C(O)-C2-C8-alkynyl, -C(O)-C3-C 12 -Cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C 1- C 12 -Alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 -Cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C 1- C 12 -Alkyl, -OCO2-C2-C8-alkenyl, -OCO2-C2-C8-alkynyl, -OCO2-C3-C 12 -Cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C 1- C 12 Alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2-C3-C 12-Cycloalkyl, -CO2-aryl, CO2-heteroaryl, CO2-heterocycloalkyl, -OCONH2, -OCONH-C1C 12 -Alkyl, -OCONH-C2-C8-alkenyl, -OCONH-C2-C8-alkynyl, -OCONH-C3-C 12 -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclo-alkyl, -NHC(O)H, -NHC(O)-C 1- C 12 -Alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C 12 -Cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclo-alkyl, -NHCO2-C 1- C 12 -Alkyl, -NHCO2-C2-C8-alkenyl, -NHCO2-C2-C8-alkynyl, -NHCO2-C3-C 12 -Cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-C 1- C 12 -Alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12 -Cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C 1- C 12 -Alkyl, -NHC(S)NH-C2-C8-alkenyl, -NHC(S)NH-C2-C8-alkynyl, -NHC(S)NH-C3-C 12 -Cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C 1- C 12-Alkyl, -NHC(NH)NH-C2-C8-alkenyl, -NHC(NH)NH-C2-C8-alkynyl, -NHC(NH)NH-C3-C 12 -cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C 1- C 12 -Alkyl, -NHC(NH)-C2-C8-alkenyl, -NHC(NH)-C2-C8-alkynyl, -NHC(NH)-C3-C 12 -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C 1- C 12 -Alkyl, -C(NH)NH-C2-C8-alkenyl, -C(NH)NH-C2-C8-alkynyl, -C(NH)NH-C3-C 12 -cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C 1- C 12 -Alkyl, -S(O)-C2-C8-alkenyl, -S(O)-C2-C8-alkynyl, -S(O)-C3-C 12 -Cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-C 1- C 12 -Alkyl, -SO2NH-C2-C8-alkenyl, -SO2NH-C2-C8-alkynyl, -SO2NH-C3-C 12 -Cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C 1- C 12 -Alkyl, -NHSO2-C2-C8-alkenyl, -NHSO2-C2-C8-alkynyl, -NHSO2-C3-C 12-Cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C 12 -Cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -SC 1- C 12 -Alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-C 12 In certain embodiments, the substituents are halo, preferably Cl and F; 1- C4-Alkyl, preferably methyl and ethyl; halo-C 1- C4-Alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C2-C4-Alkenyl; Halo-C2-C4-Alkenyl; C3-C6-Cycloalkyl, such as cyclopropyl; C 1- C4-alkoxy, such as methoxy and ethoxy; halo-C 1- C4-alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy; acetyl; -CN; -OH; NH2; C 1- C4-Alkylamino; Di(C 1- C4-alkyl)amino; and NO2. It is understood that the aryl, heteroaryl, alkyl, etc. may be further substituted. In some cases, each substituent in the substituted moiety may be further substituted with one or more groups, each group being independently selected from C4-alkyl)amino; and NO2. 1-C4-alkyl is independently selected from -CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN and -NH2. Preferably, the substituted alkyl group is substituted with one or more halogen atoms, more preferably one or more fluorine or chlorine atoms. The terms "halo" or "halogen," as used herein alone or as part of another substituent, refer to a fluorine, chlorine, bromine or iodine atom.

[0116] The term "optionally substituted" as used herein means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group may be substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group may be substituted with one or more additional groups individually and independently selected from the groups described herein.

[0117] The term "hydrogen" includes hydrogen and deuterium. Furthermore, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharma- cetically acceptable.

[0118] As used herein, the term "hydroxy activating group" refers to a labile chemical moiety, which is known in the art to activate a hydroxyl group so that it is eliminated during a synthetic procedure, such as a substitution or elimination reaction. Examples of hydroxyl activating groups include, but are not limited to, mesylates, tosylates, triflates, p-nitrobenzoates, phosphonates, and the like.

[0119] The term "activated hydroxyl" as used herein refers to a hydroxy group that has been activated with a hydroxyl activating group as defined above, including, for example, a mesylate, tosylate, triflate, p-nitrobenzoate, or phosphonate group.

[0120] The term "hydroxy protecting group" as used herein refers to a labile chemical moiety, which is known in the art to protect hydroxyl groups from undesired reactions during synthetic procedures. After said synthetic procedures, the hydroxy protecting groups described herein can be selectively removed. Hydroxy protecting groups known in the art are generally described in TH Greene and PG M Huts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include 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-trimethylsilylethyl, allyl, benzyl, triphenyl-methyl(trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

[0121] The term "protected hydroxy" as used herein refers to a hydroxy group protected with a hydroxy-protecting group, as defined above, which includes, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.

[0122] The term "hydroxy prodrug group" as used herein refers to a promoiety group, which is known in the art to temporarily change the physicochemical and therefore biological properties of the parent drug by covering or masking the hydroxy group. After the synthetic procedure, the hydroxy prodrug group described herein must be able to revert back to the hydroxy group in vivo. Hydroxy prodrug groups known in the art are generally described in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992). Preferably, the hydroxy prodrug group is a phosphate, sulfamate, or an acyl group derived from an amino acid, preferably an α-amino acid.

[0123] The term "amino protecting group" as used herein refers to a labile chemical moiety, which is known in the art to protect amino groups from undesired reactions during synthetic procedures. After said synthetic procedures, the amino protecting groups described herein can be selectively removed. Amino protecting groups known in the art are generally described in TH Greene and PGM Huts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 12-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.

[0124] The term "protected amino" as used herein refers to an amino group protected with an amino-protecting group as defined above.

[0125] The term "leaving group" means a functional group or atom that 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; sulfonate ester groups, such as mesylate, tosylate, brosylate, nosylate; and acyloxy groups, such as acetoxy, trifluoroacetoxy, and the like.

[0126] The term "aprotic solvent" as used herein refers to a solvent that is relatively inert to proton activity, i.e., does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene, halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, heterocyclic compounds such as 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 apparent to those skilled in the art that individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions, depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of aprotic solvents can be found in organic chemistry textbooks or specialized monographs, such as Organic Solvents Physical Properties and Methods of Purification, 4th ed. (edited by John A. Riddick et al.), Vol. II in Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0127] The term "protic solvent" as used herein refers to a solvent that tends to donate a proton, such as an alcohol, e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, etc. Such solvents are well known to those skilled in the art, and it will be apparent to those skilled in the art that individual solvents or mixtures thereof may be preferred for particular compounds and reaction conditions, depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of protogenic solvents can be found in organic chemistry textbooks or specialized monographs, such as Organic Solvents Physical Properties and Methods of Purification, 4th ed. (edited by John A. Riddick et al.), Vol. II, in Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0128] Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to a compound that has sufficient stability to permit its manufacture and maintains its integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0129] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by those skilled in the art, additional methods of synthesizing the compounds of the formulas herein will be apparent to those skilled in the art. Furthermore, the various synthetic steps can be performed in an alternative order or sequence to obtain the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful for synthesizing the compounds described herein are known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations, 2001, Vol. 1, No. 1, pp. 111-115, 2001. ndEd. Wiley-VCH (1999); T. W. Greene and P. G. Muts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser'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 successive editions thereof.

[0130] The term "subject" as used herein refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. Subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, etc.

[0131] The compounds of the present invention can be modified by appending appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and can include those that increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), those that increase oral availability, those that increase solubility to allow administration by injection, those that modify metabolism, and those that modify excretion rate.

[0132] The compounds described herein contain one or more asymmetric centers and therefore give rise to enantiomers, diastereomers, and other stereoisomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. 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. Resolution may be carried out in the presence of a resolving agent, by chromatography, or by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding resolution may be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometrical asymmetry, it is intended that the compounds include both E and Z geometric isomers or cis and trans isomers, unless otherwise specified. Likewise, all tautomeric forms are intended to be included. Tautomers may be cyclic or acyclic. Any carbon-carbon double bond configurations appearing herein are merely chosen for convenience and are not intended to designate a particular configuration unless so indicated in the context. Thus, any carbon-carbon double bond or carbon-heteroatom double bond shown herein as trans may be cis, trans, or a mixture of the two in any ratio.

[0133] Certain compounds of the present invention may also exist in different stable conformational forms that may be separable. Torsional asymmetry due to restricted rotation around a chiral single bond, for example due to steric hindrance or ring strain, may allow the separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

[0134] The term "pharmaceutically acceptable salts" as used herein refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment, 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. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:2-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compounds of the present 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, non-toxic acid addition salts that are salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or 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 pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobiotin, and the like. Representative salts include, but are not limited to, phosphate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, picrate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.Further pharma- ceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates, and arylsulfonates.

[0135] The term "pharmaceutically acceptable ester" as used herein refers to an ester that hydrolyzes in vivo, including those that decompose easily in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acids, alkenoic acids, cycloalkanoic acids and alkanedioic acids, each alkyl or alkenyl moiety advantageously having 6 or less carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[0136] As used herein, the term "pharmaceutical acceptable prodrugs" refers to prodrugs of the compounds of the present invention that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals having excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, and where possible, zwitterionic forms of the compounds of the present invention.

[0137] The term "prodrug," as used herein, means a compound that is convertible in vivo to a compound of formula I by metabolic means (eg, by hydrolysis). Various forms of prodrugs are known in the art and are described, for example, in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed.). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug These and other related compounds are discussed in Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002). For example, a compound of formula (I) having a free amino, amide, hydroxy, or carboxylic acid group can be converted into a prodrug. Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., 2, 3, or 4) amino acid residues, is covalently bonded to a free amino, hydroxy, or carboxylic acid group of a compound of formula (I) via an amide or ester bond.Amino acid residues include, but are not limited to, the 20 natural amino acids, commonly referred to by their three-letter symbols, including 4-hydroxyproline, hydroxyisine, demosine, isodemosine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Additional types of prodrugs are also included. For example, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxyl groups can be derivatized using groups including, but not limited to, hemisuccinate, ethylsuccinate, phosphate ester, dimethylaminoacetate, and phosphoryloxymethyloxycarbonyl, as reviewed in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as well as carbonate prodrugs, sulfonate esters, and sulfate esters of hydroxy groups. Also included are derivatizations of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl group may be an alkyl ester, optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including, but not limited to, ether, amine and carboxylic acid functionalities.

[0138] The term "amino acid" refers to naturally occurring and synthetic alpha, beta, gamma or delta amino acids, including, but not limited to, amino acids found in proteins or intermediates in amino acid or protein metabolism, namely glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, citrulline, arginine and histidine. In certain embodiments, the amino acid is in the L-configuration. In certain embodiments, the amino acid is in the D-configuration. In certain embodiments, an amino acid is provided as a substituent of the compounds described herein, wherein the amino acid is a residue selected from the group consisting of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threonyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycinyl, β-serinyl, β-threoninyl, β-cysteinyl, β-tyrosinyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaroyl, β-lysinyl, β-arginyl, and β-histidinyl.

[0139] The term "amino acid derivative" refers to a group derivable from a natural or unnatural amino acid, as described and exemplified herein. Amino acid derivatives will be apparent to those of skill in the art and include, but are not limited to, esters, amino alcohols, amino aldehydes, amino lactones, and N-methyl derivatives of natural and unnatural amino acids. In one embodiment, amino acid derivatives are provided as substituents on the compounds described herein, where the substituent is -NR u -G(S c )-C(O)-Q 1 And Q 1 Ha-SR v , -NR v R vor alkoxyl, R v is hydrogen or alkyl; S c is the side chain of a natural or unnatural amino acid, and G is C l -C2 alkyl, R u is hydrogen or R u and S c are taken together with the atoms to which they are attached to form a 5-membered heterocyclic ring. In one embodiment, amino acid derivatives are provided as substituents on the compounds described herein, the substituent being -OC(O)-G(S c )-NH-Q 2 And Q 2 is hydrogen or alkoxyl, S c is the side chain of a natural or unnatural amino acid, and G is C1-C2 alkyl. 2 and S c together with the atoms to which they are attached form a 5-membered heterocyclic ring. In certain embodiments, G is an optionally substituted methylene and S c is selected from the group consisting of hydrogen, alkyl, arylalkyl, heterocycloalkyl, carboxyalkyl, heteroarylalkyl, aminoalkyl, hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl, sulfanylalkyl, carbamoylalkyl, alkylsulfanylalkyl, and hydroxyarylalkyl. In one embodiment, an amino acid derivative is provided as a substituent on a compound described herein, wherein the amino acid derivative is in the D configuration. In one embodiment, an amino acid derivative is provided as a substituent on a compound described herein, wherein the amino acid derivative is in the L configuration.

[0140] Pharmaceutical Compositions Pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharma- ceutically acceptable carriers or excipients.

[0141] 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 may serve as pharma- ceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch, potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; glycols such as propylene glycol; esters such as ethyl oleate, ethyl laurate; agar; buffers such as magnesium hydroxide, aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers, 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 agents, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition according to the judgment of the formulator.

[0142] The pharmaceutical composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir, preferably by oral administration or injection.The pharmaceutical composition of the present invention can contain any conventional non-toxic pharma- ceutically acceptable carrier, adjuvant, or vehicle.In some cases, the pH of the formulation can be adjusted with pharma- ceutically 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, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0143] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings and aromatics.

[0144] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in injectable preparations.

[0145] Injectable preparations 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.

[0146] 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 can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug depends on its rate of dissolution, which in turn may depend on 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 on the ratio of drug to polymer and the nature of the particular polymer used, 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.

[0147] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0148] 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 pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarders, In the case of capsules, tablets and pills, the dosage form may also include buffering agents.

[0149] 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.

[0150] 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 formulation art. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient alone, 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.

[0151] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharma- ceutically acceptable carrier and any needed preservatives or buffers, as required. Ophthalmic preparations, ear drops, eye ointments, powders and solutions are also contemplated within the scope of the present invention.

[0152] The ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0153] 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 conventional propellants such as chlorofluorohydrocarbons.

[0154] Transdermal patches have the added advantage of controlling the delivery of compounds to the body. Such dosage forms can be made by dissolving or dispensing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compounds in a polymer matrix or gel.

[0155] For pulmonary delivery, the therapeutic compositions of the present invention are formulated and administered to patients in solid or liquid particle form by direct administration, e.g., inhalation into the respiratory system. The solid or liquid particle form of the active compound prepared to practice the present invention includes particles of respirable size, i.e., particles small enough to pass through the mouth and larynx upon inhalation and enter the bronchi and alveoli of the lungs. The delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, e.g., 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 to Montgomery, all of which are incorporated herein by reference).

[0156] 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 pharma- ceutically 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.

[0157] A viral inhibitory amount or dose of a compound of the invention may range from about 0.01 mg / Kg to about 500 mg / Kg, alternatively from about 1 to about 50 mg / Kg. The inhibitory amount or dose will also vary depending on the route of administration, as well as the possibility of co-administration with other drugs.

[0158] In accordance with the therapeutic methods of the 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 an amount and for a time necessary to achieve the desired result.

[0159] A "therapeutically effective amount" of a compound of the present invention means an amount of the compound that 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., the subject shows 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. The effective dose will also vary depending on the route of administration, as well as the possibility of co-administration with other drugs. However, it will be understood that the total daily usage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the age, weight, general health, sex and diet of the patient; the time of administration, route of administration, and excretion rate of the particular compound used; the duration of treatment; drugs used in combination or simultaneously with the particular compound used; and similar factors well known in the medical art.

[0160] The total daily dose of the compounds of this invention administered to a human or other animal in single or divided doses may be, for example, in an amount of 0.01 to 50 mg / kg body weight or more, usually 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 of from about 10 mg to about 1000 mg of the compounds of this invention per day, in single or multiple doses.

[0161] The compounds of the invention described herein may be administered, for example, by intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or subcutaneous injection, or orally, bucally, nasally, mucosally, topically, in ophthalmic preparations, or by inhalation, at dosages ranging from about 0.1 to about 500 mg / kg body weight, or at dosages of 1 mg to 1000 mg / administration, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administering an effective amount of the compound or compound composition to achieve the desired or described effect. Typically, the pharmaceutical compositions of the invention are administered 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 can be combined with pharmaceutical excipients or carriers to produce a single dosage form will vary depending on the host treated and the particular mode of administration. A typical preparation contains about 5% to about 95% active compound (w / w). Alternatively, such preparations may contain from about 20% to about 80% active compound.

[0162] Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, concomitant medications, the severity and course of the disease, condition or symptom, the patient's disposition to the disease, condition or symptom, and the judgment of the treating physician.

[0163] Once the patient's condition has improved, a maintenance dose of the compound, composition or combination of the present invention may be administered as necessary. Thereafter, the dosage or frequency of administration, or both, may be reduced, depending on the symptoms, until the symptoms have been alleviated to a desired level and the improved condition is maintained. However, the patient may require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[0164] Combination and Alternative Therapies The compounds of the present invention may be used in combination with one or more antiviral or anti-inflammatory therapeutic 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 pharma- ceutically acceptable derivatives thereof may be used alone or in combination with other antiviral or anti-inflammatory therapeutic agents.The compounds and pharma- ceutically acceptable salts thereof described herein may be used in combination with one or more other agents useful in the prophylaxis or treatment of respiratory disorders, inflammatory disorders, and autoimmune disorders, such as; antihistamines, corticosteroids, (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene 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 cromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidic) inhibitors or FLAP (5-lipoxygenase activating protein) inhibitors (e.g. sodium 3-(3-(t ert-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, e.g., anti-lgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1, and similar agents; cytokine receptor therapy, e.g., etanercept, and similar agents; antigen non-specific immunotherapy. Therapies (e.g., interferons 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), may be used in combination with anti-infective agents including antibiotics, antifungals, antiparasitics, antimalarials, antiprotozoals, antituberculous agents, and antivirals, including those listed at https: / / www.drugs.com / drug-class / anti-infectives.html.In general, combination therapy is typically preferred over alternation therapy since it induces multiple simultaneous stresses on the virus.

[0165] When the compositions of the invention include a combination of a compound of the formulas described herein with one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at dosage levels of about 1-100%, more preferably about 5-95%, of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately from the compounds of the invention as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, combined with the compounds of the invention in a single composition.

[0166] "Additional therapeutic or prophylactic agents" include, but are not limited to, immunotherapy (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, antimuscarinics, anti-leukotrienes, cell adhesion inhibitors (e.g., ICAM antagonists), antioxidants (e.g., N-acetylcysteine), cytokine agonists, cytokine antagonists, pulmonary surfactants, and / or antibacterial and antiviral agents (e.g., ribavirin and amantidine). The compositions according to the invention may also be used in combination with gene replacement therapy.

[0167] Abbreviation Abbreviations that may be used in the description of the following schemes and examples are as follows: Ac, acetyl; AcOH, acetic acid; Boc2O, di-tert-butyl dicarbonate; Boc, t-butoxycarbonyl; Bz, benzoyl; Bn, benzyl; t-BuOK, potassium tert-butoxide; Brine, aqueous sodium chloride; CDI, carbonyldiimidazole; DCM or CH2Cl2, dichloromethane; CH3, methyl; CH3CN, acetonitrile; Cs2CO3, cesium carbonate; CuCl, copper(I) chloride; CuI, copper(I) iodide; dba, dibenzylideneacetone; DBU, 1,8-diazabicyclo[5.4.0]-undec-7-ene; DEAD, diethyl azodicarboxylate; DIAD, diisopropyl azodicarboxylate; DIPEA or (i-Pr)2EtN, N,N,-diisopropylethylamine; DMP or Dess-Martin periodinane, 1,1,2-tris(acetyloxy)-1,2-dihydro-1,2-benziodoxol-3-(1H)-one;DMAP, 4-dimethylamino-pyridine;DME, 1,2-dimethoxyethane;DMF, N,N-dimethylformamide;DMSO, dimethylsulfoxide;EtOAc, ethyl acetate;EtOH, ethanol;Et2O, diethyl ether;HATU, O-(7-azabenzotriazol-2-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate;HCl, hydrogen chloride;K2CO3, potassium carbonate;n-BuLi, n-butyllithium;D DQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; LDA, lithium diisopropylamide; LiTMP, lithium 2,2,6,6-tetramethyl-piperidinate; MeOH, methanol; Mg, magnesium; MOM, methoxymethyl; Ms, mesyl or -SO2-CH3; NaHMDS, sodium bis(trimethylsilyl)amide; NaCl, sodium chloride; NaH, sodium hydride; NaHCO3, sodium bicarbonate or sodium hydrogen carbonate; Na2CO3, sodium carbonate; NaOH, sodium hydroxide; Na2SO4, sodium sulfate; NaHSO 3、Sodium bisulfite or sodium hydrogen sulfite;Na2S2O3, sodium thiosulfate;NH2NH2, hydrazine;NH4Cl, ammonium chloride;Ni, nickel;OH, hydroxyl;OsO4, osmium tetroxide;OTf, triflate;PPA, polyphosphoric acid;PTSA, p-toluenesulfonic acid;PPTS, pyridinium p-toluenesulfonate;TBAF, tetrabutylammonium fluoride;TEA or Et3N, triethylamine;TES, triethylsilyl;TESCl, triethylsilyl chloride;TESOTf, triethylsilyl trifluoromethanesulfonate;TFA, trifluoroacetic acid;THF, tetrahydrofuran;TMEDA, N,N,N',N'-tetramethylethylene -diamine; TPP or PPh3, triphenyl-phosphine; Tos or Ts, tosyl or -SO2-C6H4CH3; Ts2O, tolylsulfonic anhydride or tosyl anhydride; TsOH, p-tolylsulfonic acid; Pd, palladium; Ph, phenyl; Pd2(dba)3, tris(dibenzylideneacetone)dipalladium(0); Pd(PPh3)4, tetrakis(triphenylphosphine)-palladium(0); PdCl2(PPh3)2, trans-dichlorobis-(triphenylphosphine)palladium(II); Pt, platinum; Rh, rhodium; rt, room temperature; Ru, ruthenium; TBS, tert-butyldimethylsilyl; TMS, trimethylsilyl; and TMSCl, trimethylsilyl chloride.

[0168] Synthesis method The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes (intended as examples only and not as limiting the scope of the invention) illustrating how the compounds of the present invention may be prepared. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives and / or methods of the invention, can be made without departing from the spirit of the invention and the scope of the appended claims.

[0169] Scheme 1 illustrates a general method for preparing compounds of formula (VI): [ka] In the formula, R1, R3, n, R 9、 R 21 , R 22 , R 23 , and R 24 is as defined above. Amide coupling of compound 1 with compound 2 under standard peptide coupling conditions gives compound 3. Standard peptide coupling conditions are summarized in Chem. Rev. 2011, 111, 11, 6557-6602 by Ayman El-Faham and Fernando Albericio. PG1 and PG2 are conventional protecting groups, such as, but not limited to, Cbz, Boc or Fmoc. PG1 and PG2 can be removed by standard deprotection conditions summarized in Greene's Protective Groups in Organic Synthesis, 5th Edition, Peter GMWuts, Wiley 2014. After removal of the PG1 protecting group of compound 3, compound 4 is obtained, which is again subjected to an amide coupling reaction with compound 5 using standard peptide coupling chemistry to give compound 6. Removal of the PG2 protecting group allows functionalization of the nitrogen group of compound 7 to provide a variety of R 24 Compound 8 having the substitution is obtained. Final conversion of the primary amide group in compound 8 to a CN group under dehydrating conditions such as, but not limited to, TFAA / NEt3, Burgess reagent, and Pd(OCOCF3)2 / Cl2CHCN, provides compound 9 having formula (VI).

[0170] Scheme 1 [ka]

[0171] Alternatively, as shown in Scheme 2, compound 7 can be first converted to nitrile compound 10 under standard dehydration conditions, including but not limited to TFAA / NEt3, Burgess reagent, and Pd(OCOCF3)2 / Cl2CHCN. Subsequent removal of the PG2 protecting group and attachment of the R to the NH 24 Introduction of the formula (VI) forms compound 9.

[0172] Scheme 2 [ka]

[0173] Scheme 3 illustrates a general method for preparing compounds of formula (V'). [ka] In the formula, R 23 and R 24together with the N atom to which they are attached form an optionally substituted 3-8 membered heterocyclic or heteroaryl ring. Compound 14 can be synthesized from compound 4 and compound 12 by an amide coupling reaction followed by removal of the PG2 protecting group. The primary amine group of compound 14 can then be converted to a variety of optionally substituted 3-8 membered heterocyclic or heteroaryl rings according to literature procedures to form compound 15, which can then be converted to compound 16 having formula (V'). Selected literature procedures can be found in the following references: Huang, P.-Q.; Fan, T., European Journal of Organic Chemistry 2017, 43, 6369-6374; Dhingra, S.K.; Arora, S.K.; Singh, K.; Prasad, M.; Kumar, Y., WO 2006090265; Mochizuki, A.; Kishida, M.; Kanno, H., WO 2008111300; Chen, K.X.; Njoroge, F.; George, S.; Mousumi, N; Latha G.; et al., WO 2005085242; Sugiyama, S.; Morishita, K.; Chiba, M.; Ishii, K., Heterocycles 2002,57,637-648;Meng, G., Guo, T., Ma, T. et al., Nature 2019,574,86-89.

[0174] Scheme 3 [ka]

[0175] The compound having the formula (VI') [ka] As shown in Scheme 4, it can be prepared from a compound having formula (VI') by reaction with a suitable alkylating agent, such as, but not limited to, Me2SO4, MeI, alkyl iodide, alkyl bromide, allyl bromide, in the presence of a suitable base, such as, but not limited to, K2CO3, NaH or KOt-Bu.

[0176] Scheme 4 [ka]

[0177] Alternatively, compounds having formula (VI') can be prepared from compound 21 following similar chemistry previously described for compound 9. Compound 21 can be obtained from compound 18 by alkylation, followed by functional group transformation and removal of the PG3 protecting group, as shown in Scheme 5.

[0178] Scheme 5 [ka]

[0179] The compound having the formula (VI") is [ka] Compound 18 can be prepared from aldehyde intermediate 25 using standard functional group transformations, where X is as previously described. Compound 18 is converted to alcohol compound 22 via reduction of the ester. The reducing agent can be, but is not limited to, LiBH4, DIBAL, NaBH4. Removal of the PG group of compound 22 gives intermediate 23, which is then converted to compound 24 using similar chemistry previously described. Aldehyde 25 is prepared from alcohol intermediate 24 via oxidation of the OH group using conditions such as, but not limited to, IBX oxidation, Swern oxidation, Dess-Martin oxidation, or Albright-Goldman oxidation. Compounds 26 having formula (VI") can then be synthesized from aldehyde intermediate 25 using appropriate chemistry depending on the nature of X. Selected chemistry and procedures are described in the following references: J. Med. Chem. 2020, 63, 4562-4578, WO 2020 / 030143, and J. Med. Chem. 2015, 58, 3144-3155.

[0180] Scheme 6 [ka]

[0181] example The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as illustrative only and not limiting the scope of the invention. Starting materials were available from commercial vendors or prepared by methods well known to those skilled in the art.

[0182] General conditions: Mass spectra were performed on an LC-MS system using electrospray ionization. These were Agilent 6120 Infinity II systems equipped with an Agilent 1290 Quadrupole detector. Spectra were obtained using a ZORBAX Eclipse XDB-C18 column (4.6 x 30 mm, 1.8 microns). Spectra were obtained at 298 K using mobile phases of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). Spectra were obtained using the following solvent gradients: 5% (B) from 0 to 1.5 min, 5 to 95% (B) from 1.5 to 4.5 min, and 95% (B) from 4.5 to 6 min. The solvent flow rate was 1.2 mL / min. Compounds were detected at wavelengths of 210 nm and 254 nm. [M+H] + refers to the monoisotopic molecular weight.

[0183] NMR spectra were performed on a Bruker 400 MHz spectrometer. Spectra were measured at 298 K and referenced using the solvent peak. 1 1 H NMR chemical shifts are reported in parts per million (ppm).

[0184] Compounds were purified by reversed-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 x 21.2 mm, 5 microns) unless otherwise stated. Compounds were purified at 298 K using a mobile phase of water (A) and acetonitrile (B) with a gradient elution from 0% to 100% (B) unless otherwise stated. The solvent flow rate was 20 mL / min and compounds were detected at a wavelength of 254 nm.

[0185] Alternatively, compounds were purified by normal phase liquid chromatography (NPLC) using a Teledyne ISCO Combiflash purification system. Compounds were purified on REDISEP silica gel cartridges. Compounds were purified at 298 K and detected at a wavelength of 254 nm.

[0186] Example 1 [ka] Steps 1-3: Synthesis of (3R,5'S)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide hydrochloride [ka]

[0187] Steps 1 and 2: Compound 1-2 was prepared according to literature reported procedures, such as those described in J. Med. Chem. 2012, 55, 9069.

[0188] Step 3: To a clear solution of compound 1-2 (45.0 g, 136 mmol) in THF (720 mL) in a three-neck 2000 mL flask at 0° C., water (90 mL) was added in one portion. Acetic acid (54.6 mL, 953 mmol) was added at 0° C. The cloudy mixture was cooled to −30° C. A solution of NBS (24.24 g, 136 mmol) in THF / H2O (8 / 1, 207 mL) was added dropwise over 30 min while maintaining the internal temperature below −30° C. The milky mixture became a yellow cloudy solution and was stirred at −30° C. (internal temperature) for 1.0 h. The cloudy yellow solution was warmed to −20° C. and poured in portions into a mixture of potassium carbonate (65.9 g, 477 mmol), saturated NaHCO3 solution (approx. 400 mL) and EtOAc (300 mL) in cold water (approx. 300 mL) with stirring. The mixture was further diluted with EtOAc (500 mL). The aqueous layer was extracted with EtOAc (1x). The combined organic layers were washed with brine (1x), dried over Na2SO4, filtered, and concentrated to give the crude product as a pale yellow sticky oil (56.0 g). The crude product was dissolved in DCM (60 mL) and filtered through a 330 g silica gel column (MTBE / cyclohexane) to give the desired product 1-3 as an off-white foam (48.20 g, 102%). 1 H NMR (400 MHz, DMSO-d6) showed dr 10 / 1 (1-3a / 1-3b).

[0189] Step 4: A clear, colorless solution of compound 1-3 (48.20 g, 139 mmol, dr 10 / 1) in 7N ammonia in MeOH (400 mL) was stirred in a sealed tube at 45° C. for 4 days. The mixture was cooled and concentrated. The solid was dried under vacuum to give the desired compound 1-4 as a yellow solid (42.80 g, 93%). 1 H NMR (400 MHz, DMSO-d6) showed dr 10 / 1 (1-4a / 1-4b).

[0190] Step 5: To a clear solution of compound 1-4 (42.80 g, 129 mmol, dr 10 / 1) in DMF (85 mL) at room temperature was added 4M HCl in 1,4-dioxane (323 mL, 1292 mmol). The resulting clear pale yellow solution was stirred at room temperature for 2.5 h and concentrated on a rotary evaporator. The resulting clear solution was poured into DCM (1700 mL) with stirring to form a slurry. The precipitated solid was collected by filtration and rinsed with DCM (x2). The solid was dried under vacuum to give crude product 1-5 as a pale yellow solid (35.20 g, 102%).

[0191] Recrystallization: 3 g of the above crude compound 1-5 was mixed with DMF (9 mL) and heated to form a nearly clear solution. A solid began to appear during heating. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and rinsed with DMF (1 mL) and DCM (2x). The solid was dried under vacuum to give the desired product, compound 1-5, as a white solid (2.14 g). 1 H NMR (400 MHz, DMSO-d6) showed clean product with approximately 0.9 equivalents of DMF, but no minor diastereomer. 1H NMR (400 MHz, DMSO-d6) δ 11.14 (brs, 1H), 10.81 (s, 1H), 9.08 (brs, 1H), 8.07 (s, 1H), 7.78 (s, 1H), 7.66 (d, J = 7.4 Hz, 1H), 7.27 (td, J = 7.7, 1.2 Hz, 1H), 7.04 (td, J = 7.6, 1.1 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 4.65 (dd, J = 11.2, 7.1 Hz, 1H), 3.59 (d, J = 12.3 Hz, 1H), 3.45 (d, J = 12.3 Hz, 1H), 2.50 (dd, J = 12.9, 11.2 Hz, 1H), 2.22 (dd, J = 12.9, 11.2 Hz, 1H).

[0192] Steps 6-9: Synthesis of Example 1 [ka]

[0193] Step 6: To a mixture of compound 1-5 (5 g, 14.90 mmol) and N-((benzyloxy)carbonyl)-N-methyl-L-leucine (4.29 g, 15.35 mmol) in dry CHCl (60 mL) and DMF (10 mL) at 0° C., 4-methylmorpholine (4.92 mL, 44.7 mmol) and HATU (5.84 g, 15.35 mmol) were added. The resulting mixture was stirred at 0° C. for 30 min and then at room temperature for 1 h. The reaction mixture was diluted with DCM (100 mL) and washed successively with 5% NaHCO (100 mL), water (100 mL) and brine (100 mL). The collected organic layer was dried over NaSO and concentrated in vacuum. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) to give the desired compound 1-6 (5.33 g, 10.82 mmol, 72.6% yield) as a white solid. LC-MS, ES+: 493.14 [M+1].

[0194] Step 7: To a solution of compound 1-6 (4.0 g, 7.63 mmol) in MeOH (76 mL) was added 10% Pd-C (0.406 g, 0.382 mmol). The mixture was stirred under a H2 balloon for 60 min. The mixture was then filtered through Celite and concentrated in vacuo to give compound 1-7 (2.7 g, 7.53 mmol, 99% yield), which was used in the next step without further purification.

[0195] Step 8: To a mixture of compound 1-7 (300 mg, 0.837 mmol) and (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-fluorophenyl)propanoic acid (279 mg, 0.879 mmol) in dry CHCl (7 mL) and DMF (1.4 mL) at 0° C., 4-methylmorpholine (184 μl, 1.674 mmol) and HATU (350 mg, 0.921 mmol) were added. The resulting mixture was stirred at 0° C. for 30 min and then at room temperature for several hours until LC-MS showed the reaction was complete. The reaction mixture was diluted with DCM and washed with 5% NaHCO, water and brine. The collected organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) to give the desired compound 1-8 (400 mg, 0.61 mmol, 73% yield) as a white solid. LC-MS, ES + : 658.26 [M+1].

[0196] Step 9: To a solution of compound 1-8 (28 mg, 0.043 mmol) and triethylamine (35.6 μL, 0.255 mmol) in dry CHCl (1 mL) at 0 °C, TFAA (17.75 μL, 0.128 mmol) was added dropwise. The mixture was then stirred at 0 °C for 30-60 min until LC-MS showed the reaction was complete. The reaction mixture was diluted with DCM, washed with 10% aqueous NaHCO, brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography (0-40% acetone / cyclohexane) to give Example 1 (18 mg, 0.028 mmol, 66.1% yield). LC-MS, ES - : 638.1 [MH].1 H NMR (400 MHz, Acetone-d6) δ 9.73 (s, 1H), 7.35 - 7.28 (m, 2H), 7.25 - 7.18 (m, 2H), 7.17 (dt, J = 7.9, 4.5 Hz, 1H), 7.10 - 6.92 (m, 3H), 6.40 (d, J = 9.0 Hz, 1H), 5.45 (dd, J = 9.3, 5.8 Hz, 1H), 5.21 (t, J = 8.5 Hz, 1H), 4.95 (d, J = 2.2 Hz, 2H), 4.63 (td, J = 9.7, 4.0 Hz, 1H), 4.04 (d, J = 10.7 Hz, 1H), 3.96 (d, J = 10.6 Hz, 1H), 3.15 (s, 3H), 2.82 - 2.63 (m, 2H), 2.44 (dd, J = 14.2, 10.3 Hz, 1H), 2.31 (dd, J= 14.3, 4.1 Hz, 1H), 1.78 (ddd, J = 14.2, 9.3, 5.0 Hz, 1H), 1.66 (ddd, J= 14.1, 8.8, 5.8 Hz, 1H), 1.53 (dd, J = 13.3, 6.9 Hz, 1H), 0.95 (d, J= 6.6 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H).

[0197] Example 2 [ka]

[0198] Step 1: A mixture of compound 1-8 (370 mg, 0.563 mmol) and 10% Pd-C (29.9 mg, 0.028 mmol) in MeOH (5.63 mL) was stirred under a H2 balloon for 60 min. The mixture was filtered through Celite and concentrated in vacuo to give compound 2-1 (290 mg, 98% yield), which was used directly without further purification. LC-MS, ES + : 524.13 [M+1].

[0199] Step 2: To a solution of compound 2-1 (30 mg, 0.057 mmol) and triethylamine (63.9 μL, 0.458 mmol) in CH2Cl2 (1.146 mL) at 0° C. was added TFAA (31.9 μL, 0.229 mmol) dropwise. The mixture was stirred at 0° C. for about 30 min, then at room temperature for about 60 min.

[0200] The reaction mixture was then diluted with DCM, washed with 10% aqueous NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0-50% acetone / cyclohexane) to give Example 2 (22 mg, 0.037 mmol, 63.8% yield). LC-MS, ES - : 600.0 [MH]. 1H NMR (400 MHz, Acetone-d6) δ 9.77 (s, 1H), 8.41 (d, J= 8.4 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.19 (ddd, J = 7.7, 6.9, 2.0 Hz, 1H), 7.12 - 7.02 (m, 4H), 6.97 (dt, J = 7.8, 0.9 Hz, 1H), 5.45 (dd, J = 9.3, 5.9 Hz, 1H), 5.22 (t, J = 8.5 Hz, 1H), 4.96 (td, J= 9.0, 4.8 Hz, 1H), 4.05 (d, J = 10.6 Hz, 1H), 3.99 (d, J = 10.5 Hz, 1H), 3.20 (s, 3H), 2.80 - 2.64 (m, 2H), 2.64 - 2.47 (m, 2H), 1.80 (ddd, J= 14.4, 9.3, 5.2 Hz, 1H), 1.70 (ddd, J = 14.2, 8.6, 5.9 Hz, 1H), 1.58 - 1.43 (m, 1H), 0.92 (dd, J= 26.3, 6.6 Hz, 6H).

[0201] Example 3 [ka]

[0202] To a solution of compound 2-1 (30 mg, 0.057 mmol) and triethylamine (63.9 μL, 0.458 mmol) in CH2Cl2 (1.146 mL) at 0° C. was added methyl chloroformate (4.43 μL, 0.057 mmol). After stirring at 0° C. for 45 min, TFAA (31.9 μL, 0.229 mmol) was added dropwise. After stirring at 0° C. for 30 min, the reaction was stirred at room temperature for approximately 60 min.

[0203] Work-up: The reaction mixture was diluted with DCM, washed with 10% aqueous NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0-50% acetone / cyclohexane) to give Example 3 (5 mg, 15% yield). LC-MS, ES - : 562.0 [MH]. 1 H NMR (400 MHz, Acetone-d6) δ 9.60 (s, 1H), 7.08 (dt, J = 12.9, 4.8 Hz, 2H), 7.01 (td, J = 5.2, 2.6 Hz, 1H), 6.93 - 6.85 (m, 4H), 6.80 (d, J = 7.7 Hz, 1H), 6.11 (d, J = 8.9 Hz, 1H), 5.29 (dd, J = 9.2, 6.0 Hz, 1H), 5.06 (t, J = 8.5 Hz, 1H), 4.45 (td, J = 9.6, 4.1 Hz, 1H), 3.88 (d, J = 10.7 Hz, 1H), 3.81 (d, J = 10.6 Hz, 1H), 3.31 (s, 3H), 3.00 (s, 3H), 2.63 - 2.45 (m, 2H), 2.27 (dd, J = 14.3, 10.1 Hz, 1H), 2.16 (dd, J = 14.2, 4.2 Hz, 1H), 1.61 (dt, J = 8.8, 5.1 Hz, 1H), 1.57 - 1.47 (m, 1H), 1.43-1.36 (m, 1H), 0.78 (dd, J = 24.7, 6.5 Hz, 6H).

[0204] Example 4 [ka]

[0205] Step 1: Compound 2-1 (25 mg, 0.048 mmol) and 5-methylisoxazole-3-carboxylic acid (6.37 mg, 0.050 mmol) were dissolved in CHCl (0.40 mL) and DMF (0.10 mL). 4-Methylmorpholine (10.50 μl, 0.095 mmol) and HATU (19.97 mg, 0.053 mmol) were added at 0° C. After stirring at 0° C. for 1 h, the reaction mixture was diluted with DCM, washed with 5% NaHCO, brine, dried over NaSO, and concentrated in vacuo. The crude compound 4-1 was used directly in the next step without purification. LC-MS, ES + : 633.20 [M+H].

[0206] Step 2: Compound 4-1 (0.030 g, 0.048 mmol) was dissolved in CHCl (0.96 mL). At 0° C., triethylamine (0.040 mL, 0.288 mmol) and TFAA (0.020 mL, 0.144 mmol) were added. The mixture was stirred at 0° C. for about 30 min, then at room temperature for about 60 min. 28% aqueous ammonia (19 uL, 0.29 mmol) was added. After stirring at room temperature for an additional 1 h, the reaction mixture was diluted with CHCl, washed with water, brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography (0-50% acetone / cyclohexane) to give Example 4 (22 mg, 75% yield for two steps). LC-MS, ES +: 615.2 [M+H]. 1H NMR (400 MHz, Acetone-d6) δ 9.76 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.18 (td, J = 7.3, 2.0 Hz, 1H), 7.11 - 6.91 (m, 5H), 6.35 (s, 1H), 5.45 (dd, J = 9.2, 6.0 Hz, 1H), 5.24 (t, J = 8.5 Hz, 1H), 5.10 (td, J = 8.9, 4.3 Hz, 1H), 4.07 (d, J = 10.7Hz, 1H), 4.00 (d, J = 10.6 Hz, 1H), 3.23 (s, 3H), 2.83 - 2.65 (m, 3H), 2.57 (dd, J = 14.2, 4.3 Hz, 1H), 2.44 (s, 3H), 1.87 - 1.63 (m, 2H), 1.63 - 1.48 (m, 1H), 0.91 (dd, J = 25.8, 6.6 Hz, 6H).

[0207] Example 5 [ka]

[0208] Steps 1-4: Example 5 was prepared according to the same procedure as described in Example 1. ES - :651.99 [MH].

[0209] Example 6 [ka]

[0210] Step 1: Compound 5-4 (237 mg, 0.363 mmol) was dissolved in MeOH (4.53 mL). 10% Pd-C (19.29 mg, 0.018 mmol) was added. The mixture was stirred under a H2 balloon for 60 min. The mixture was filtered through Celite and concentrated in vacuo to give compound 6-2 (187 mg, 0.360 mmol, 99% yield), which was used in the next step without further purification. LC-MS, ES + : 520.24 [M+H].

[0211] Step 2: Compound 6-2 (20 mg, 0.038 mmol) was dissolved in CH2Cl2 (0.77 mL). At 0 °C, triethylamine (16.09 μL, 0.115 mmol) and TFAA (8.03 μL, 0.058 mmol) were added. The mixture was stirred at 0 °C for about 45 min. The reaction mixture was diluted with DCM, washed with 10% aqueous NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0-50% acetone / cyclohexane) to give Example 6. LC-MS, ES - : 614.06 [MH]. 1H NMR (400 MHz, Acetone-d6) δ 9.78 (s, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.25 (ddd, J= 8.4, 5.3, 2.5 Hz, 2H), 7.18 (ddd, J = 7.7, 5.1, 3.8 Hz, 1H), 7.11 - 7.01 (m, 4H), 6.98 (dt, J= 7.7, 0.9 Hz, 1H), 5.50 (dd, J = 6.8, 5.7 Hz, 1H), 5.22 (t, J = 8.6 Hz, 1H), 4.94 (td, J = 9.0, 5.6 Hz, 1H), 4.07 (d, J = 10.5 Hz, 1H), 4.00 (d, J = 10.5 Hz, 1H), 3.21 (s, 3H), 2.80 - 2.67 (m, 2H), 2.49 - 2.42 (m, 2H), 2.17 - 2.11 (m, 1H), 1.56 (dd, J= 14.2, 5.7 Hz, 1H), 0.94 (s, 9H).

[0212] Example 7 [ka]

[0213] Compound 6-2 (20 mg, 0.038 mmol) and 4,6,7-trifluoro-1H-indole-2-carboxylic acid (9.11 mg, 0.042 mmol) were dissolved in CHCl (0.321 mL) and DMF (0.064 mL). 4-Methylmorpholine (8.46 μl, 0.077 mmol) and HATU (16.83 mg, 0.044 mmol) were added at 0° C. The mixture was stirred at 0° C. to room temperature for 1 h. The reaction mixture was diluted with DCM and washed with brine. The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% acetone / cyclohexane) to give Example 7 (20 mg, 0.028 mmol, 72.5% yield). LC-MS, ES -: 715.09 [MH]. 1H NMR (400 MHz, Acetone-d6) δ 11.41 (s, 1H), 9.79 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.28 (td, J = 5.6, 2.5 Hz, 3H), 7.20 (ddd, J = 7.7, 5.9, 3.1 Hz, 1H), 7.13 -7.08 (m, 2H), 7.03 - 6.96 (m, 3H), 6.90 (ddd, J= 11.3, 9.6, 5.2 Hz, 1H), 5.53 (dd, J = 7.0, 5.5 Hz, 1H), 5.23 (t, J= 8.6 Hz, 1H), 5.12 (ddd, J = 10.8, 9.0, 3.8 Hz, 1H), 4.11 (d, J= 10.6 Hz, 1H), 4.01 (d, J = 10.5 Hz, 1H), 3.24 (s, 3H), 2.79 - 2.66 (m, 2H), 2.50 (dd, J = 14.2, 10.9 Hz, 1H), 2.39 (dd, J = 14.2, 3.9 Hz, 1H), 2.15 (dd, J = 14.2, 7.0 Hz, 1H), 1.52 (dd, J = 14.1, 5.5 Hz, 1H), 0.92 (s, 9H).

[0214] Example 8 [ka]

[0215] To a solution of compound 6-2 (20 mg, 0.038 mmol) in dry CH2Cl2 (0.77 mL) at 0 °C, triethylamine (21.46 μL, 0.154 mmol) was added, followed by isocyanatocyclopropane (3.49 μL, 0.050 mmol). The mixture was stirred at 0 °C for 1 h.

[0216] The reaction mixture was diluted with DCM and washed with 5% NaHCO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-50% acetone / cyclohexane) to give Example 8 (16 mg, 0.027 mmol, 69.0% yield). LC-MS, ES - : 601.13 [MH]. 1H NMR (400 MHz, Acetone-d6) δ 9.79 (s, 1H), 7.20-7.12 (m, 3H), 7.08 - 6.92 (m, 5H), 5.63 (s, 1H), 5.56 (d, J = 9.1 Hz, 1H), 5.48 (dd, J = 7.0, 5.5 Hz, 1H), 5.21 (t, J = 8.6 Hz, 1H), 4.78 (td, J = 9.1, 4.9 Hz, 1H), 4.06 (dd, J= 10.5, 1.2 Hz, 1H), 3.98 (d, J = 10.4 Hz, 1H), 3.17 (s, 3H), 2.79 - 2.63 (m, 2H), 2.39 -2.24 (m, 3H), 2.18 - 2.11 (m, 1H), 1.51 (dd, J= 14.2, 5.5 Hz, 1H), 0.94 (s, 9H), 0.64 -0.46 (m, 2H), 0.29 (ddt, J = 5.9, 3.8, 2.2 Hz, 2H).

[0217] Example 9 [ka]

[0218] Step 1: NSOF solution was prepared according to the procedure reported by Meng, G., Guo, T., Ma, T. et al. Nature 574, 86-89 (2019).

[0219] To a solution of sodium azide (100 mg, 1.538 mmol) in HO (4.05 mL) and MTBE (4.05 mL) at 0 °C in a plastic tube, ACN (0.4 mL, 1 / 10 water content) was added followed by solid 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate (606 mg, 1.846 mmol). The mixture was vigorously stirred at 0 °C for 10-15 min. After standing at room temperature for approximately 30 min, the organic phase was separated and kept at room temperature in a loosely sealed plastic bottle for at least 12 h. After standing beyond 12 h, the bottom reddish aqueous layer was removed. The desired product was diluted to a total volume of 5.1 mL with MTBE to make a 0.3 M NSOF solution and stored at 4 °C away from light.

[0220] Step 2: The amine was converted to the azide following the procedure reported by Meng, G., Guo, T., Ma, T. et al. Nature 574, 86-89 (2019).

[0221] To a solution of compound 6-2 (85 mg, 0.164 mmol) in DMF (0.61 mL) at room temperature was added the 0.3 M solution of sulfurazidic fluoride in MTBE formed above (1063 μL, 0.213 mmol), followed by KHCO3 (3.0 M in water, 218 μL, 0.654 mmol). The resulting suspension was stirred at room temperature for about 30 min. The mixture was diluted with EtOAc, washed with saturated NaHCO3, water, brine, dried and concentrated to give crude azide compound 9-1 (82 mg, 0.150 mmol, 92% yield), which was used directly in the next step. LC-MS, ES - (m / z): 544.1[MH].

[0222] Step 3: To a mixture of potassium carbonate (15.18 mg, 0.110 mmol), sodium ascorbate (6.10 mg, 0.031 mmol), CuSO4.5H2O (3.84 mg, 0.015 mmol) and cyclopropylacetylene (14.89 μl, 0.176 mmol) in water (0.34 mL) / DMF (0.34 mL) was added compound 9-1 (24 mg, 0.044 mmol). The reaction mixture was heated at 55° C. for 60 min and then cooled to room temperature.

[0223] The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, water, brine, dried and concentrated. The residue was purified by silica gel chromatography (0-70% EtoAc / cyclohexane) to give Example 9 (12 mg, 0.02 mmol, 45% yield). LC-MS, ES - : 610.19 [MH]. 1H NMR (400 MHz, Acetone-d6) δ 9.79 (s, 1H), 7.63 (s, 1H), 7.23 (dtd, J= 24.0, 7.6, 1.2 Hz, 2H), 7.13 - 6.87 (m, 6H), 5.73 (dd, J = 11.1, 4.4 Hz, 1H), 5.47 (t, J = 6.3 Hz, 1H), 5.22 (t, J= 8.6 Hz, 1H), 4.21 (d, J = 10.6 Hz, 1H), 4.00 (d, J = 10.5 Hz, 1H), 3.16 (s, 3H), 3.12 - 3.00 (m, 1H), 2.79 - 2.66 (m, 2H), 2.64 - 2.53 (m, 1H), 2.05 - 1.98 (m, 1H), 1.87 (ddd, J = 8.4, 6.8, 4.3 Hz, 1H), 1.48 (dd, J = 14.3, 6.2 Hz, 1H), 0.87 - 0.83 (m, 2H), 0.83 (s, 9H), 0.70 - 0.60 (m, 2H).

[0224] Example 10 [ka]

[0225] Step 1 Compound 1-5 (400 mg, 1.192 mmol) and Boc-Freidinger lactam (394 mg, 1.252 mmol) were dissolved in CH2Cl2 (4.97 mL) and DMF (0.994 mL) at 0° C. 4-Methylmorpholine (393 μL, 3.58 mmol) and HATU (499 mg, 1.312 mmol) were added at 0° C. The reaction was stirred at 0° C. for about 30 min, then warmed to room temperature and stirred for 90 min.

[0226] The mixture was diluted with DCM and washed with water and brine. The collected organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH in DCM) to give the desired compound 10-1 (600 mg, 1.137 mmol, 95% yield) as a white solid. LC-MS, ES + : 528.15 [M+H].

[0227] Step 2: To a solution of compound 10-1 (188 mg, 0.356 mmol) in CH2Cl2 (3.56 mL) at 0° C. was added triethylamine (298 μL, 2.138 mmol), followed by TFAA (149 μL, 1.069 mmol). The mixture was stirred at 0° C. for about 45 min.

[0228] The reaction mixture was diluted with DCM, washed with 10% aqueous NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0-40% acetone / cyclohexane) to give the desired compound example 10 (82 mg, 45% yield). LC-MS, ES + : 510.12 [M+H]. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] Example 55 [ka]

[0229] Step 1: (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid (305 mg, 1.150 mmol) and L-methyl proline hydrochloride (209 mg, 1.265 mmol) were dissolved in CHCl (5.75 mL). DIPEA (531 μL, 2.87 mmol) and HATU (481 mg, 1.265 mmol) were added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and washed successively with 1M HCl, 5% NaHCO, and brine. The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by silica gel chromatography using 0-100% EtOAc / cyclohexane to give compound 55-1 (316 mg, 0.839 mmol, 73.0% yield).

[0230] Step 2: Compound 55-1 (316 mg, 0.839 mmol) was dissolved in THF (5.60 mL) and water (2.80 mL). At 0° C., lithium hydroxide hydrate (88 mg, 2.099 mmol) was added. The mixture was stirred at 0° C. for 2 h and at room temperature for 30 min. The reaction was quenched with 1M HCl (2 mL) and extracted with MTBE. The organic layer was dried over Na2SO4 and concentrated in vacuo to give compound 55-2 (308 mg, 0.850 mmol, quantitative yield).

[0231] Step 3: Compound 55-2 (250 mg, 0.690 mmol) and compound 1-5 (231 mg, 0.690 mmol) were dissolved in DCM (5 mL) and DMF (2 mL). 4-Methylmorpholine (283 μL, 2.069 mmol) and HATU (262 mg, 0.690 mmol) were added and the mixture was stirred at room temperature for 90 min. The reaction mixture was diluted with DCM and washed successively with 1M HCl, 5% NaHCO3, and brine. The collected organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography using 0-100% acetone / cyclohexane to give compound 55-3 (308 mg, 0.535 mmol, 78% yield). LC-MS, ES + : 576.3 [M+H].

[0232] Step 4: Compound 55-3 (308 mg, 0.535 mmol) was dissolved in DCM (3 mL). At 0° C., triethylamine (447 μL, 3.21 mmol) and TFAA (227 μL, 1.605 mmol) were added. The mixture was stirred at 0° C. for 20 min and quenched with 5% NaHCO3. The organic layer was loaded onto silica gel and eluted with 0-50% acetone / cyclohexane to give Example 55 (282 mg, 0.506 mmol, 95% yield). LC-MS, ES+: 580.26 [M+Na + ]; 1H NMR (400 MHz, Acetone-d6) δ 9.67 (s, 1H), 7.51 - 7.34 (m, 2H), 7.34 (t, J= 0.9 Hz, 2H), 7.34 - 7.27 (m, 1H), 7.31 - 7.22 (m, 2H), 7.08 - 6.96 (m, 2H), 6.17 (d, J= 9.4 Hz, 1H), 5.09 (td, J = 9.7, 3.0 Hz, 2H), 5.03 - 4.93 (m, 1H), 4.63 (t, J= 6.9 Hz, 1H), 4.39 (d, J = 9.4 Hz, 1H), 4.29 (d, J = 10.2 Hz, 1H), 4.02 (m, 1H), 3.91 (s, 1H), 3.82 - 3.74 (m, 1H), 2.78 - 2.58 (m, 2H), 2.32 (s, 1H), 2.19 (s, 1H), 2.01 (m, 2H), 1.11 (s, 9H).

[0233] Example 56 [ka]

[0234] Example 55 (282 mg, 0.506 mmol) was dissolved in MeOH (5 mL). 10% Pd-C (26.9 mg, 0.025 mmol) was added. The mixture was stirred under hydrogen (balloon) for 1 h. The mixture was filtered through Celite and concentrated in vacuo to give Example 56 (199 mg, 0.470 mmol, 93% yield) as a white solid. LC-MS, ES + : 424.29 [M+H]; 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 7.30 - 7.17 (m, 2H), 7.01 - 6.86 (m, 2H), 5.07 (dd, J= 8.5, 6.9 Hz, 1H), 4.53 (dd, J = 8.3, 5.2 Hz, 1H), 4.09 (d, J = 10.4 Hz, 1H), 3.89 (d, J = 10.4 Hz, 1H), 3.83 - 3.66 (m, 1H), 3.56 (dt, J = 9.8, 6.9 Hz, 1H), 3.17 (m, 1 H), 2.67 - 2.57 (m, 1H), 2.47 (dd, J = 13.1, 6.9 Hz, 1H), 2.26 - 2.11 (m, 1H), 2.00 (dt, J = 12.7, 6.7 Hz, 1H), 1.81 (dtd, J = 33.8, 12.2, 6.7 Hz, 2H), 0.95 (s, 9H).

[0235] Example 57 [ka]

[0236] Example 56 (20 mg, 0.047 mmol) was dissolved in DCM (0.472 mL). Hunig's base (24.74 μL, 0.142 mmol) and benzenesulfonyl chloride (7.25 μL, 0.057 mmol) were added. The mixture was stirred at room temperature for 10 min, quenched with 5% NaHCO3, and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone / cyclohexane to give Example 57 (24 mg, 0.043 mmol, 90% yield). LC-MS, ES + : 586.23 [M+Na + ].

[0237] Example 58 [ka]

[0238] Example 56 (20 mg, 0.047 mmol) was dissolved in DCM (0.472 mL). Hunig's base (24.74 μL, 0.142 mmol) and 4-fluorobenzoyl chloride (6.70 μL, 0.057 mmol) were added. The mixture was stirred at room temperature for 10 min, quenched with 5% NaHCO3, and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone / cyclohexane to give Example 58 (22 mg, 0.040 mmol, 85% yield). LC-MS, ES + : 568.24 [M+Na].

[0239] Example 59 [ka]

[0240] Example 56 (20 mg, 0.047 mmol) was dissolved in DCM (0.472 mL). Hunig's base (24.74 μL, 0.142 mmol) and a 1.0 M solution of isopropyl carbonochloridate in toluene (56.7 μL, 0.057 mmol) were added. The mixture was stirred at room temperature for 10 min, quenched with 5% NaHCO3, and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone / cyclohexane to give Example 59 (22 mg, 0.043 mmol, 91% yield). LC-MS, ES + : 532.25 [M+Na].

[0241] Example 60 [ka]

[0242] Example 56 (22 mg, 0.052 mmol) was dissolved in DCM (0.519 mL). (Isocyanatomethyl)benzene (7.70 μL, 0.062 mmol) was added. The mixture was stirred for 20 min at room temperature, loaded onto silica gel, and eluted with 0-50% acetone / cyclohexane to give Example 60 (28 mg, 0.050 mmol, 97% yield). LC-MS, ES +: 579.27 [M+Na + ].

[0243] Example 61 [ka]

[0244] Example 56 (22 mg, 0.052 mmol) was dissolved in DCM (0.519 mL). 2,4,5-Trifluorobenzaldehyde (8.91 μL, 0.078 mmol) was added. The mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (1M in THF) (51.9 μL, 0.052 mmol) was added. The mixture was stirred at room temperature for 30 min, quenched with 5% NaHCO3, and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone / cyclohexane to give Example 61 (8.6 mg, 0.015 mmol, 29.2% yield). LC-MS, ES + : 568.25 [M+H].

[0245] Example 62 [ka]

[0246] Step 1: To a mixture of compound 1-5 (1.7 g, 5.07 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-4,4-dimethylpentanoic acid (1.367 g, 5.57 mmol) in dry CHCl (17 mL) and DMF (3 mL) at 0° C., 4-methylmorpholine (1.67 mL, 15.2 mmol) and HATU (2.119 g, 5.57 mmol) were added. The resulting mixture was stirred at 0° C. for about 30 min and then at room temperature for several hours until LC-MS showed the reaction was complete. The reaction mixture was diluted with DCM, washed with 5% NaHCO, water, brine, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) to give the desired compound 62-1 (1.7 g, 3.71 mmol, 73.2% yield) as a white solid. LC-MS, ES+: 456.3 [M+1].

[0247] Step 2: Compound 62-1 (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, it was transferred to an ice bath and stirred at room temperature for 15 min.

[0248] MTBE (60 mL) was added to the reaction mixture. The resulting white precipitate was collected by filtration under N2 and rinsed with MTBE (3x). The collected solid was further dried under high vacuum to give the desired compound 62-2 (860 mg, 2.15 mmol, 100% yield) as a fine solid. LC-MS, ES+: 359.49 [M+H].

[0249] Step 3: To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-(4-fluorophenyl)propanoic acid (0.726 g, 2.289 mmol) and 4-methylmorpholine (0.959 ml, 8.72 mmol) in DCM (18.17 ml) and DMF (3.63 ml) at room temperature, HATU (0.912 g, 2.398 mmol) was added. The reaction mixture was stirred at room temperature for about 20 minutes and then cooled to 0° C. Compound 62-2 (0.86 g, 2.18 mmol) was added and the resulting mixture was stirred at 0° C. for about 1 hour and then at room temperature for several hours until LC-MS showed the reaction was complete. The reaction mixture was diluted with DCM, washed with 5% NaHCO3, water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) to give the desired compound 62-3 (958 mg, 1.456 mmol, 66.8% yield) as a white solid. LC-MS, ES + : 658.26 [M+1].

[0250] Step 4: Compound 62-3 (473 mg, 0.719 mmol) was dissolved in DCM (7.2 mL). At 0° C., triethylamine (501 μL, 3.60 mmol) and TFAA (225 μL, 1.618 mmol) were added. The mixture was stirred at 0° C. for about 30 min. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0-40% acetone / cyclohexane) to give Example 62 (400 mg, 0.719 mmol, 87% yield). LC-MS, ES-: 638.44 [MH].

[0251] Example 63 [ka]

[0252] Step 1: Example 62 (372 mg, 0.581 mmol) was dissolved in MeOH (7.27 mL). 10% Pd-C (30.9 mg, 0.029 mmol) was added. The mixture was stirred under H2 (balloon) for 90 min. The mixture was filtered through Celite and concentrated in vacuo to give compound 63-1 (280 mg, 0.554 mmol, 95% yield) as a solid. LC-MS, ES-: 504.5 [MH].

[0253] Step 2: Compound 63-1 (30 mg, 0.059 mmol) was dissolved in DMF (0.2 mL) and ethyl 2,2,2-trifluoroacetate (0.2 mL, 1.661 mmol) at room temperature. Hunig's base (46.6 μL, 0.267 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and concentrated to dryness. The residue was purified by silica gel chromatography (0-40% acetone / cyclohexane) to give Example 63 (22 mg, 0.059 mmol, 62% yield). LC-MS, ES-: 600.4 [MH]. 1H NMR (400 MHz, Acetone-d6) δ 9.78 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.04 (s, 1H), 7.35 - 7.31 (m, 2H), 7.25 (td, J = 7.7, 1.2 Hz, 1H), 7.11 - 7.03 (m, 3H), 7.02 - 6.94 (m, 2H), 5.18 (t, J = 8.4 Hz, 1H), 4.80 (dtd, J= 12.7, 8.7, 8.2, 4.4 Hz, 2H), 4.26 (d, J = 10.2 Hz, 1H), 4.04 (d, J= 10.2 Hz, 1H), 3.16 (dd, J = 14.2, 4.4 Hz, 1H), 2.91-2.88 (m, 1H), 2.75 - 2.69 (m, 2H), 1.96 - 1.88 (m, 1H), 1.64 (dd, J= 14.4, 8.3 Hz, 1H), 0.99 (s, 9H). [Table 2-1]

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 2-45

Table 2-46

Table 2-47

Table 2-48

Table 2-49

Table 2-50

Table 2-51

Table 2-52

Table 2-53

Table 2-54

Table 2-55

Table 2-56

Table 2-57

Table 2-58

Table 2-59

Table 2-60

Table 2-61

Table 2-62

[0254] Example 348

change

[0255] To a solution of compound 1-1 (15 mg, 0.026 mmol) in acetone (0.131 mL) was added K2CO3 (5.44 mg, 0.039 mmol) and dimethyl sulfate (3.73 μL, 0.039 mmol) at room temperature. The reaction mixture was then heated under reflux for about 3 h and monitored by LC-MS. The mixture was concentrated to remove acetone, then diluted with EtOAc, washed with water, brine, dried and concentrated. The crude product was purified by silica gel column eluted with 0-50% acetone / cyclohexane to give Example 348 (3.5 mg, 5.98 μmol) in 22.8% yield. LC-MS, ES-: 584.09 [M-1]. 1H NMR (400 MHz, Acetone-d6) 1H NMR (400 MHz, Acetone-d6) δ 8.22 (s, 1H), 7.24 (td, J = 7.7, 1.4 Hz, 1H), 7.01 - 6.89 (m, 2H), 5.29 (dd, J = 7.5, 4.8 Hz, 1H), 5.04 (t, J = 8.5 Hz, 1H), 4.60 (t, J = 7.0 Hz, 1H), 3.88 - 3.75 (m, 2H), 3.11 (s, 2H), 2.96 (s, 2H), 2.85 (s, 1H), 2.56 (dd, J = 8.3, 6.1 Hz, 3H), 1.16 (s, 3H), 0.77 (d, J = 14.3 Hz, 8H). [Table 3]

[0256] Example 353 [ka]

[0257] Process 1-1 Compound (1-1) (6.2 g) was dissolved in methanol (250 ml). Thionyl chloride (10 ml) was added and the mixture was stirred at room temperature overnight. The volatiles were then removed to give compound (1-2) (6 g), which was used directly in the next step without further purification.

[0258] Process 1-2 Compound (1-3) (1.5 g) was dissolved in DMF (15 ml) at 0° C., then 90% NaH powder (500 mg) was added under an inert nitrogen atmosphere. After 1 h, a solution of compound (1-2) (2 g) in DMF (30 ml) was added at 0° C. The mixture was allowed to reach room temperature and then heated to 80° C. for 20 h. The volatiles were removed and the residue was purified on silica gel to give the product compound (1-4) (50 mg).

[0259] Process 1-3 Compound (1-4) (690 mg) was dissolved in MeOH (50 mL). 10% Pd / C (50 mg) was added and the mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. The reaction was then opened to air and filtered through Celite. The filtrate was concentrated and purified on silica gel to give compound (1-5) (300 mg).

[0260] Process 1-4 To a solution of compound (1-5) (190 mg) and Et3N (161 mg) in DCM (3 mL) was added cyclopropanesulfonyl chloride (125 mg) at 0°C. The mixture was then stirred at room temperature for 2 h. The mixture was poured into water (20 mL) and the aqueous layer was extracted with DCM (10 mL x 2). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column eluted with (0-40% EtOAc in petroleum ether) to give compound (1-6) (50 mg) as a yellow oil.

[0261] Process 1-5 To a solution of compound (1-6) (110 mg) in THF (2 mL), MeOH (2 mL) and HO (2 mL) was added LiOH·HO (67 mg). The mixture was then stirred at 50° C. for 3 h. The mixture was poured into water (20 mL) and the aqueous was acidified to pH 2-3 with 2N HCl. Extraction was performed with EtOAc (10 mL×3). The combined organic phase was dried over Na2SO4 and concentrated to give compound (1-7) (130 mg), which was used directly without further purification.

[0262] Process 1-6 To a solution of compound (1-7) (130 mg) in DMF (3 mL), compound (1-8) (91 mg), EDCI (228 mg), HOBT (107 mg), DIEA (102 mg) were added, and the reaction mixture was then stirred at room temperature for 4 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The organic layer was dried over Na2SO4 and evaporated in vacuum. The residue was purified by silica column eluted with (0-5% MeOH in DCM) to give compound (1-9) (88 mg) as a yellow solid.

[0263] Process 1-7 To a solution of compound (1-9) (88 mg) in THF (2 mL) was added TEA (49 mg) and TFAA (51 mg). The reaction was stirred at room temperature for 12 h, then it was poured into water and extracted with EtOAc (10 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by reverse phase HPLC to give Example 353 (7.9 mg) as a white solid along with the corresponding epimer (7.5 mg). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.53 (m, 2H), 7.46-7.30 (m, 2H), 7.22-6.88 (m, 4H), 6.37 (td, J= 7.2, 1.8 Hz, 1H), 6.08-4.98 (m, [MH] - m / z 521.8. [Table 4-1] [Table 4-2] [Table 4-3]

[0264] Example 361 [ka]

[0265] Process 1 Methyl L-leucinate hydrochloride (1036 mg, 5.70 mmol) was dissolved in DCM (25 ml) and MeOH (5.00 ml). At 0° C., triethylamine (1590 μl, 11.41 mmol), sodium cyanotrihydroborate (287 mg, 4.56 mmol) and acetaldehyde (384 μl, 6.84 mmol) were added. The mixture was stirred at 0° C. for 2 h, warmed to room temperature and stirred for 18 h. The reaction was quenched with 5% NaHCO3 and extracted with DCM. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue on silica gel with 0-10% MeOH / DCM gave methyl ethyl-L-leucinate (787 mg, 4.54 mmol, 80% yield) as an oil. 1H NMR (400 MHz, Chloroform-d) δ 3.74 (s, 3H), 3.34 (td, J= 7.3, 1.3 Hz, 1H), 2.73 - 2.48 (m, 2H), 1.80 - 1.59 (m, 1H), 1.59 - 1.42 (m, 2H), 1.13 (td, J = 7.2, 1.3 Hz, 3H), 0.94 (ddd, J = 10.0, 6.6, 1.0 Hz, 6H).

[0266] Process 2 Methyl ethyl-L-leucinate (582 mg, 3.36 mmol) was dissolved in DMF (7 ml). ((benzyloxy)carbonyl)-L-alanine (750 mg, 3.36 mmol), Hunig's base (587 μl, 3.36 mmol) and HATU (1277 mg, 3.36 mmol) were added. The mixture was stirred at room temperature for 5 min, heated to 80 °C and stirred for 70 min. The reaction mixture was cooled to room temperature, diluted with MTBE and quenched with 5% NaHCO3. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel using 0-50% EtOAc / cyclohexane to give methyl N-(((benzyloxy)carbonyl)-L-alanyl)-N-ethyl-L-leucinate (774 mg, 2.045 mmol, 60.9% yield). 1 H NMR (400 MHz, Chloroform-d) δ 7.43 - 7.28 (m, 5H), 5.68 (d, J = 8.4 Hz, 1H), 5.18 - 5.07 (m, 2H), 4.85 (dd, J = 9.7, 5.1 Hz, 1H), 4.67 (dt, J= 8.2, 6.7 Hz, 1H), 3.70 (s, 3H), 3.51 (dq, J = 14.5, 7.1 Hz, 1H), 3.35 - 3.21 (m, 1H), 1.88 (ddd, J = 14.2, 9.2, 5.1 Hz, 1H), 1.71 (ddd, J = 14.3, 9.8, 4.6 Hz, 1H), 1.42 - 1.24 (m, 6H), 1.05 - 0.91 (m, 6H).

[0267] Process 3 Methyl N-(((benzyloxy)carbonyl)-L-alanyl)-N-ethyl-L-leucinate (963 mg, 2.54 mmol) was dissolved in THF (13 ml) and water (13.00 ml). At 0° C. lithium hydroxide hydrate (214 mg, 5.09 mmol) was added. The mixture was stirred at 0° C. for 2 h and diluted with cyclohexane / water (10 mL each). The collected aqueous layers were quenched with 1 M HCl (6 mL) and extracted with DCM (2×) and EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. N-(((benzyloxy)carbonyl)-L-alanyl)-N-ethyl-L-leucine (649 mg, 1.781 mmol, 70.0% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.28 (m, 5H), 5.81 (d, J = 8.3 Hz, 1H), 5.18 - 5.06 (m, 2H), 4.77 - 4.60 (m, 2H), 3.54 (dq, J = 14.4, 7.1 Hz, 1H), 3.30 (dq, J = 14.8, 7.2 Hz, 1H), 1.92 (ddd, J = 14.3, 8.9, 5.5 Hz, 1H), 1.75 (ddd, J = 14.3, 9.4, 5.1 Hz, 1H), 1.62 (m, 1H), 1.42 - 1.24 (m, 6H), 1.04 - 0.92 (m, 6H).

[0268] Process 4 Compound 1-5 (496 mg, 1.482 mmol) and N-(((benzyloxy)carbonyl)-L-alanyl)-N-ethyl-L-leucine (540 mg, 1.482 mmol) were dissolved in DMF (5 ml). At 0° C., HOAt (0.6 M in DMF) (494 μl, 0.296 mmol), 2,4,6-trimethylpyridine (431 μl, 3.26 mmol), and HATU (620 mg, 1.630 mmol) were added. The mixture was stirred at 0° C. for 3.5 h, warmed to room temperature, and stirred for 1 h. The reaction was quenched with 5% NaHCO3 at 0° C. and extracted with DCM (2×). The organic layer was washed with 1M HCl, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified on silica gel with 0-100% acetone / cyclohexane to give 361-1 (823 mg, 1.425 mmol, 96% yield). 1 H NMR (400 MHz, Acetone-d6) δ 9.67 (s, 1H), 7.37 - 7.23 (m, 5H), 7.08 (m, 2H), 7.08 - 6.92 (m, 3H), 6.40 (s, 1H), 6.27 (d, J = 8.2 Hz, 1H), 5.44 (t, J = 7.2 Hz, 1H), 5.03 (s, 2H), 4.84 - 4.75 (m, 1H), 4.40 (p, J = 7.1 Hz, 1H), 3.89 (d, J = 10.1 Hz, 1H), 3.79 (d, J = 10.2 Hz, 1H), 3.67 (dq, J = 14.7, 7.4 Hz, 1H), 3.36 (dt, J = 15.5, 7.2 Hz, 1H), 2.51 (dd, J = 12.7, 9.9 Hz, 1H), 2.38 (m, 1H), 1.82 - 1.73 (m, 1H), 1.55 (dq, J = [M+H] + ] 578.3.

[0269] Process 5 Compound 361-1 (823 mg, 1.425 mmol) was dissolved in CHCl (7.12 mL). At 0 °C, triethylamine (993 μL, 7.12 mmol) and TFAA (443 μL, 3.13 mmol) were added dropwise. The mixture was stirred at 0 °C for 15 min, quenched with 5% NaHCO and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone / cyclohexane to give 361-2 (530 mg, 0.947 mmol, 66.5% yield). 1 H NMR (400 MHz, Acetone-d6) δ 9.72 (s, 1H), 7.37 - 7.24 (m, 6H), 7.12 - 6.93 (m, 3H), 6.33 (d, J= 8.2 Hz, 1H), 5.46 (t, J = 7.4 Hz, 1H), 5.16 (t, J = 8.4 Hz, 1H), 5.04 (d, J = 2.1 Hz, 2H), 4.46 (p, J = 7.1 Hz, 1H), 3.96 (d, J = 10.5 Hz, 1H), 3.85 (d, J = 10.5 Hz, 1H), 3.66 (dq, J = 14.5, 7.1 Hz, 1H), 3.40 (dq, J = 14.7, 7.1 Hz, 1H), 2.82 - 2.63 (m, 2H), 1.80 (dt, J= 14.2, 7.5 Hz, 1H), 1.61 (m, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.94 (dd, J= 10.7, 6.5 Hz, 6H), 0.79 (d, J = 6.9 Hz, 3H). [M+Na + ] 582.2.

[0270] Process 6 Compound 361-2 (530 mg, 0.947 mmol) was dissolved in MeOH (9.47 mL). 10% Pd-C (50.4 mg, 0.047 mmol) was added. The mixture was stirred at room temperature under hydrogen (balloon) for 90 min, filtered through Celite, and concentrated in vacuo. 361-3 (430 mg, 1.010 mmol, quantitative yield) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.23 (td, J = 7.6, 1.4 Hz, 1H), 7.00 (dd, J = 7.5, 1.4 Hz, 1H), 6.98 - 6.91 (m, 1H), 6.88 (d, J = 7.7 Hz, 1H), 5.26 (t, J = 7.2 Hz, 1H), 5.15 (t, J = 8.0 Hz, 1H), 3.76 (d, J = 10.6 Hz, 1H), 3.55 (d, J = 10.5 Hz, 1H), 3.42 (m, 1H), 3.29 - 3.15 (m, 1H), 2.63 (m, 1H), 2.51 - 2.43 (m, 1H), 1.71 (dt, J = 13.8, 7.3 Hz, 1H), 1.47 (m, 2H), 1.14 (t, J = 7.1 Hz, 3H), 0.89 (dt, J = 9.4, 4.7 Hz, 6H), 0.55 (d, J = 6.5 Hz, 3H). [M+H + ] 426.3.

[0271] Process 7 Compound 361-3 (16 mg, 0.038 mmol) was dissolved in CHCl (0.313 mL) and DMF (0.063 ml). 4-(Trifluoromethoxy)benzoic acid (7.75 mg, 0.038 mmol), 4-methylmorpholine (8.27 μl, 0.075 mmol) and HATU (14.30 mg, 0.038 mmol) were added. The mixture was stirred at room temperature for 1 h, quenched with 5% NaHCO and extracted with DCM. The organic layer was loaded onto silica gel and eluted with 0-50% acetone to give example 361 (20 mg, 0.033 mmol, 87% yield). 1H NMR (400 MHz, Acetone-d6) δ 9.74 (s, 1H), 8.05 - 7.97 (m, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.31 (td, J = 7.6, 1.6 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.11 - 7.03 (m, 1H), 7.03 (d, J = 7.8 Hz, 1H), 5.48 (t, J = 7.4 Hz, 1H), 5.18 (t, J = 8.4 Hz, 1H), 4.88 (p, J = 7.1 Hz, 1H), 3.98 (d, J = 10.5 Hz, 1H), 3.89 (d, J = 10.5 Hz, 1H), 3.74 (dq, J = 14.4, 7.1 Hz, 1H), 3.46 (dq, J = 14.6, 7.1 Hz, 1H), 2.75 (d, J = 8.5 Hz, 1H), 2.69 (dd, J = 13.2, 8.4 Hz, 1H), 1.82 (dt, J = 14.7, 7.5 Hz, 1H), 1.72 - 1.53 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H), 0.97 - 0.87 (m, 9H).[M+Na + ] 636.2.

Table 5-1

Table 5-2

Table 5-3

[0272] The following example is the same as the one mentioned above.

Table 6

[0273] Example 373 [ka]

[0274] Step 373-1: A clear, colorless solution of the mixture of compounds from steps 1-3 (3.94 g, 11.4 mmol, dr 10 / 1) in acetonitrile (40 mL) was treated with NBS (2.23 g, 12.5 mmol) in three portions at room temperature. The reaction was stirred at room temperature for 3 h. It became a pale yellow solution. LCMS showed no SM. The reaction was quenched with aqueous Na2S2O3. The mixture was stirred at room temperature for another 30 min. The cloudy mixture was further diluted with EtOAc (80 mL). The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product as an off-white solid. The crude product was dissolved in DCM (10 mL) and filtered through an 80 g silica gel pad (MTBE) to give the desired product (dr 10 / 1) as a white solid. The product was treated with MTBE / Hexane (2:1) (30 mL). The mixture was sonicated for 10 min to form a milky suspension, which was filtered and washed with MTBE / Hexane (2:1) to give the desired product as a white solid (4.23 g, 10.0 mmol, dr>100 / 1). ESI MS m / z = 422.74, 424.64 [MH] - .

[0275] Step 373-2: A clear colorless solution of the compound from step 373-1 (4.2 g, 9.9 mmol) in n-PrOH (35 mL) was treated with triethylamine (1.7 mL, 11.9 mmol), potassium vinyltrifluoroborate (1.6 g, 11.9 mmol) and PdCl2(dppf) (290 mg, 0.4 mmol) under N2. The mixture was degassed and filled with N2 (*3). The resulting orange suspension was bubbled with N2 for 10 min. The reaction was warmed to 100 °C and stirred for 20 min. A dark red / brown mixture was obtained. TLC (CH / EtOAc 2:1) showed no SM. The reaction was diluted with ethyl acetate (100 mL) and quenched with aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate (*2). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was redissolved in ethyl acetate (20 mL) and treated with SiliaMetS DMT (8 g) as a metal scavenger. The mixture was stirred at room temperature for 16 h, then filtered, rinsed with MTBE / CH (2:1) (200 mL) and concentrated in vacuo. The brownish crude product was redissolved in ethyl acetate (20 mL), treated with activated charcoal and warmed to 60° C. for 1 h. After cooling, the mixture was filtered to give a pale yellow solution which was further concentrated in vacuo to give the desired product (3.3 g, 8.7 mmol, 90%) as an off-white foam. ESI MS m / z = 370.79 [MH] - .

[0276] Step 373-3: A clear pale yellow solution of the compound from step 373-2 (3.3 g, 8.9 mmol) in 7N ammonia in MeOH (80 ml, 560 mmol) was stirred at 50° C. in a sealed pressure vessel over the weekend (3d). LCMS showed no SM. The mixture was cooled and concentrated in vacuo to give a yellow gel-like solid. The solid was redissolved in 30 mL of MeOH / dioxane (1:10) and coevaporated in vacuo to give a pale yellow solid. The crude product was dried under high vacuum for 1 h, then crushed into small pieces and dried under high vacuum overnight to give a pale yellow powder. The powder was washed with 10 mL of DCM / MTBE (1:2), sonicated, and filtered to give the desired product (3.05 g, 8.5 mmol, 96%) as an off-white solid. ESI MS m / z = 355.79 [MH] - .

[0277] Step 373-4: To a clear solution of the compound from step 373-3 (1.15 g, 3.22 mmol) in DMF (2 mL) at room temperature was added 4M HCl in 1,4-dioxane (8 mL, 32 mmol). The resulting clear yellow solution was stirred at room temperature for 2 h. The mixture was concentrated on a rotavapor. The remaining clear DMF solution was poured into DCM (150 ml) with stirring to give a white slurry. The mixture was sonicated to form a cloudy suspension. The solid was collected by filtration and washed with DCM and then MTBE. The solid was dried under vacuum to give the desired product as an off-white powder (862 mg, 2.93 mmol, 91%). 1 g of the above product was mixed with DMF (2 ml) and heated with a heat gun to give a nearly clear solution. A solid started to appear during heating. The mixture was cooled to room temperature. The solid was collected by filtration and washed with DMF (0.2 ml), DCM and MTBE. The solid was dried under vacuum to give the desired product as a white solid (771 mg). ESI MS m / z = 257.77 [MH] - .

[0278] Step 373-5: A suspension of (S)-2-((tert-butoxycarbonyl)amino)hept-6-enoic acid (1 g, 4.11 mmol) and methylmethyl-L-leucinate hydrochloride (0.81 g, 4.14 mmol) in CHCl (12 ml) and DMF (3 ml) was treated with N-methylmorpholine (1.8 ml, 16.37 mmol) and HATU (1.71 g, 4.50 mmol) at room temperature. The reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo and the reaction was quenched with a saturated solution of sodium bicarbonate. The mixture was stirred at room temperature for an additional 30 minutes and diluted with ethyl acetate. The organic layer was washed three times with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was loaded onto a 40 g silica gel column and eluted with 0%-25% ethyl acetate / cyclohexane to give the desired compound (1.12 g, 2.91 mmol, 71% yield) as a colorless syrup. ESI MS m / z = 384.95 [M+H] + .

[0279] Step 373-6: A solution of compound from step 373-5 (1.1 g, 2.86 mmol) in THF (6 ml) and water (3 ml) was treated with lithium hydroxide (200 mg, 8.35 mmol) at 0° C. The reaction was stirred at 0° C. for 5 h and neutralized to pH=2 with 6N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired compound (1.05 g, 2.83 mmol, 99% yield) as a white solid. ESI MS m / z = 369.25 [MH] - .

[0280] Step 373-7: A suspension of compound from step 373-6 (285 mg, 0.77 mmol) and compound from step 373-4 (221 mg, 0.75 mmol) in DMF (0.6 ml) and DCM (1.8 ml) was treated with N-methylmorpholine (330 μl, 3.00 mmol) and HATU (318 mg, 0.836 mmol). The reaction was stirred at room temperature for 1 h. The reaction was quenched with a saturated solution of sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed three times with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was loaded onto a 24 g silica gel column and eluted with 0%-100% dichloromethane / methanol to give the desired product (77 mg, 0.126 mmol, 17% yield) as a white solid. ESI MS m / z = 608.33 [MH] - .

[0281] Step 373-8: A solution of compound from step 373-7 (77 mg, 0.126 mmol) in toluene (125 ml) was treated with Zhan 1B cat. (17 mg, 0.023 mmol). The mixture was degassed and backfilled with N2 by freeze-pump thaw at -78 °C. The reaction was warmed to 90 °C and stirred overnight. The mixture was concentrated in vacuo. The crude product was loaded onto a 4 g silica gel column and eluted with 0%-100% dichloromethane / methanol to give the desired product (7 mg, 0.012 mmol, 10% yield) as a black foam. ESI MS m / z = 580.19 [MH] - .

[0282] Step 373-9: A solution of compound from step 373-8 (7 mg, 0.012 mmol) in MeOH (0.5 ml) was treated with Pd-C (2.7 mg, 2.54 μmol) under 1 atm H2 (0.024 mg, 0.012 mmol). The reaction was stirred at room temperature overnight. The mixture was filtered through Celite and rinsed with methanol. The filtrate was concentrated in vacuo to give the desired product (7 mg, 0.012 mmol, 100% yield) as a black foam. ESI MS m / z = 582.33 [MH]- .

[0283] Step 373-10: A solution of the compound from step 373-9 (7 mg, 0.012 mmol) in CH2Cl2 (0.3 mL) was treated dropwise with TEA (15 μl, 0.108 mmol) and TFAA (6 μl, 0.042 mmol) at 0° C. The reaction was stirred at 0° C. for 30 min and then quenched with ammonium hydroxide. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was loaded onto a 4 g silica gel column and eluted with 0% to 100% ethyl acetate / cyclohexane to give Example 373 (1.7 mg, 3.01 μmol, 25% yield) as a white solid. ESI MS m / z = 564.22 [MH] - .

[0284] Example 374 [ka]

[0285] Step 374-To a solution of tert-butyl (2S)-2-amino-4,4-dimethylpentanoate (0.974 g, 4.84 mmol) and pent-4-enoyl-L-alanine (0.753 g, 4.40 mmol) in DCM (30 ml) at 1.0° C., 4-methylmorpholine (1.451 ml, 13.20 mmol) was added followed by HATU (1.840 g, 4.84 mmol). The resulting yellow milky solution was stirred at 0° C. for 5 min and then at room temperature for 2 h. The mixture was diluted with EtOAc and saturated aqueous NaHCO3 solution. The organic layer was washed with brine (*1), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica, cyclohexane / EtOAc) to give the desired compound as a sticky colorless oil (1.280 g, 82%). ESI MS m / z = 355.43 [M+H] + .

[0286] Step 374-2. At room temperature, TFA (5.56 ml, 72.2 mmol) was added to a solution of the compound obtained from step 374-1 (1.280 g, 3.61 mmol) in DCM (6 ml). The solution was stirred at room temperature for 1 h and then concentrated. The residue was co-evaporated with toluene (*2), DCM (*1) and dried under vacuum to give the desired compound as a sticky colorless oil (1.240 g, 100%), which was used directly in the next step. ESI MS m / z = 299.37 [M+H] + .

[0287] step 374-To a suspension of compound from 373-4 (1.060 g, 3.61 mmol) and compound from step 374-2 (1.077 g, 3.61 mmol) in DCM (10 ml) and DMF (2.000 ml) at 3.0°C, 4-methylmorpholine (1.191 ml, 10.83 mmol) was added followed by HATU (1.922 g, 5.05 mmol). The reaction mixture was stirred at 0°C for 5 min and then at room temperature overnight. The mixture was diluted with saturated NaHCO3 solution and EtOAc. The aqueous layer was extracted with DCM (*1). The combined organic layers were washed with brine (*1), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica, cyclohexane / acetone) to give the desired compound as a white solid (0.290 g, 15%). ESI MS m / z = 538.31 [M+H] + .

[0288] Step 374-4. To a solution of the compound from step 374-3 (0.120 g, 0.223 mmol) in CH2Cl2 (5 ml) and DMF (1.000 ml) at room temperature, Burgess reagent (0.067 g, 0.268 mmol) was added. The resulting clear solution was stirred at room temperature for 1.5 h. Additional Burgess reagent (0.067 g, 0.268 mmol) was added. The mixture was stirred at room temperature for 2 h. It was quenched with water and extracted with DCM (*2). The combined organic layers were dried over Na2SO4, then filtered and concentrated. The residue was purified by flash column chromatography (silica, cyclohexane / acetone) to give the desired compound as a yellow solid (40.0 mg, 35%). ESI MS m / z = 520.29 [M+H] + .

[0289] step 374-5. To a solution of the compound from step 374-4 (0.0400 g, 0.077 mmol) in toluene (77 ml) was added Zhan 1B cat. (0.011 g, 0.015 mmol). The mixture was purged with N2 and then heated at 85° C. overnight. The mixture was cooled and concentrated. The residue was dissolved in DCM (10 ml) at room temperature. 2-Mercaptonicotinic acid (0.024 g, 0.154 mmol) and Et3N (0.021 ml, 0.154 mmol) were added. The mixture was stirred at 40° C. for 30 min, after which most of the DCM was evaporated. The residue was filtered through a 1 g silica column and washed with acetone. The filtrate was concentrated. The residue was purified by flash column chromatography (silica, cyclohexane / acetone) to give the desired compound as a yellow solid (19.0 mg, 50%). ESI MS m / z = 492.47 [M+H] + .

[0290] Step 374-6. At room temperature, 10% Pd / C (4.11 mg, 3.86 μmol) was added to a solution of the compound obtained from step 374-5 (19.0 mg, 0.039 mmol) in MeOH (2.0 ml). The mixture was purged with H2 and then stirred at room temperature for 2 h with a hydrogen balloon. LC-MS showed mostly SM, traces of DP. The mixture was diluted with DCM (4 ml), filtered through a short Celite pad, and washed with DCM / MeOH (2 / 1). The filtrate was concentrated. The residue was resubmitted to the above hydrogenation conditions at 60 psi overnight. The mixture was diluted with DCM (4 ml), filtered through a short Celite pad, and washed with DCM / MeOH (2 / 1). The filtrate was concentrated. The residue was purified by flash column chromatography (silica, cyclohexane / acetone) to give Example 374 as a white solid (6.0 mg, 31%). ESI MS m / z = 494.28 [M+H] + .

[0291] The following compounds were prepared following a procedure similar to Example 374. Example 375 [ka] Example 376 [ka] Example 377 [ka] Example 378 [ka] Example 379 [ka]

[0292] 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 3CL pro substrate was synthesized. Black, small volume, round bottom, 384-well microplates were used. In a typical assay, 0.85 μL of test compound was dissolved in DMSO and then incubated with SARS-CoV-2 3CL-protease (10 nM) in 10 μL of assay buffer (50 mM HEPES [pH 7.5], 1 mM DTT, 0.01% BSA, 0.01% Triton-X 100) for 30 min at room temperature. Next, 10 μL of 3CL-protease substrate (40 μM) in assay buffer was added and the assay was continuously monitored for 1 h on an Envision multimode plate reader operated in fluorescence kinetic mode with excitation at 540 nm and emission at 580 nm at room temperature. No compound (DMSO only) and no enzyme controls were routinely included on each plate. All experiments were performed in duplicate.

[0293] Data Analysis: SARS-CoV-2 3CL-protease enzyme activity was measured as the initial velocity of the linear phase (RFU / s) and normalized to control samples DMSO (100% activity) and no enzyme (0% activity) to determine percent residual activity at various concentrations of test compound (0-10 μM). Data were fitted to a normalized activity (variable slope) versus concentration fit in GraphPad Prism 7 to determine IC 50 All experiments were performed in duplicate and IC 50 Ranges are reported as follows: A<0.1 μM; B 0.1-1 μM; C>1 μM. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0294] 229E Assay Protocol Virus stock preparation: MRC-5 cells (a diploid cell culture line composed of fibroblasts, originally developed from lung tissue of an aborted 14-week-old Caucasian male fetus) were used to culture 229E human coronavirus (hCoV). Flasks were inoculated with hCoV-229E and virus stocks were harvested when cytopathic effect (CPE) exceeded 70%. Virus stocks in growth medium (EMEM, 1% Penn / Strep, 1% non-essential amino acids, 10% heat-inactivated FBS) supplemented with 5% glycerol were snap frozen using liquid nitrogen and stored at -80°C. Virus stock titers were calculated as TCID 50 (median 50% tissue culture infectious dose) assay.

[0295] 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 plate wells in duplicate in a total volume of 125 nL per well. MRC-5 cells less than passage 17 are seeded in the inner 240 wells of a 384-well plate at 1,500 cells per well in a volume of 12.5 μL using growth medium. Virus stock is then added at a multiplicity of infection (MOI) of 0.05 at 12.5 μL per well, bringing the total volume of each well to approximately 25 μL. Each plate has a 20-well control row containing cells with DMSO and virus but no compound (positive control, maximum CPE, minimum ATPlite signal), as well as a row containing cells with DMSO but no compound or virus (negative control, minimum CPE, maximum ATPlite signal), as well as a row with no cells or virus or compound (background plate / reagent control). Control wells containing cells but no virus receive an additional 12.5 μL of growth media containing an equal amount of glycerol as the wells receiving the virus stock to keep media and volume conditions constant. The outer two rows / tiers of wells are filled with 30 μL of moat media (DMEM, 1% Penn / Strep) to act as a heat and evaporation barrier around the test wells. After all components are added, the sides of the plate are gently tapped with the hand to encourage even cell distribution across the wells. Once cell distribution has been confirmed, the plates are incubated for 6 days at 34°C in a CO2 humidity controlled incubator. After the 6-day incubation period, the plates are read using ATPlite (12.5 μL added per well), which quantifies the amount of ATP present in each well (a measure of cell health). The 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 is calculated using ExcelFit software and a four-parameter logistic curve fitting analysis.

[0296] All experiments were performed in duplicate and EC 50 Ranges are reported as follows: A<0.1 μM; B 0.1-1 μM; C>1 μM. [Table 8-1] [Table 8-2] [Table 8-3]

[0297] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. Represented by formula (I), 【Chemistry 1】 During the ceremony: R １ , R ２ , R ３ , R ２１ , R ２２ , and R ２３ are each independently selected from the following: 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; Or, R １ and R ２ together with the carbon atoms to which they are attached form an optionally substituted 3- to 8-membered carbocyclic ring or an optionally substituted 3- to 8-membered heterocyclic ring; Or, R １ and R ３ together with the atoms to which they are attached form an optionally substituted 3- to 8-membered heterocyclic ring; Or, R ２１ and R ３ together with the intervening atoms form an optionally substituted 4- to 8-membered heterocyclic ring; Or, R ２２ does not exist, and R ２１ and R ３ together with the intervening atoms form an optionally substituted 4- to 8-membered partially unsaturated heterocyclic ring or an optionally substituted 5- to 6-membered heterocyclic ring; Or, R ２１ and R ２２ together with the carbon atoms to which they are attached form an optionally substituted 3- to 8-membered carbocyclic ring or an optionally substituted 3- to 8-membered heteroaryl ring; R ２４ is selected from: 1)-C(O)R ２５ ; 2)-C(O)OR ２５ ; 3)-C(O)NR １３ R １４ ; 4)-S(O) ２ R ２５ ; 5) Hydrogen; 6) optionally substituted -C １ -C ８ Alkyl; 7) optionally substituted -C ２ -C ８ Alkenyl; 8) optionally substituted -C ２ -C ８ Alkynyl; 9) optionally substituted -C ３ -C １２ Cycloalkyl; 10) optionally substituted 3- to 12-membered heterocycloalkyl; 11) optionally substituted aryl; 12) optionally substituted arylalkyl; 13) optionally substituted heteroaryl; 14) optionally substituted heteroarylalkyl; 15)-(CO)(CO)NR １３ R １４ ; 16)-(CO)(CO)R ２５ ; 17)-S(O) ２ NR １３ R １４ ; 18) -C(S)R ２５ and 19)-C(S)NR １３ R １４ ; Or, R ２３ and R ２４ together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclic ring or an optionally substituted 5- to 12-membered heteroaryl ring; R ２５ 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 １２ Cycloalkyl; 5) optionally substituted 3- to 12-membered heterocycloalkyl; 6) optionally substituted aryl; 7) optionally substituted arylalkyl; 8) optionally substituted heteroaryl; and 9) optionally substituted heteroarylalkyl; R ４ is hydrogen, optionally substituted -C １ -C ４ Alkyl, optionally substituted -C ２ -C ４ Alkenyl, optionally substituted -C ３ -C ６ cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, halogen, -CN, -OH, or a prodrug moiety; B is optionally substituted aryl or optionally substituted heteroaryl; Or, R ２１ and R ２４ is L-, where L is a saturated or unsaturated linker 4 to 20 atoms in length attached to B; 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 ; 6)-CH=CH-C(O)OR ２５ , 7)-CH=CH-C(O)NR １３ R １４ , 8)-CH=CH-S(O) ２ NR １３ R １４ , 9)-B(OR １３ ) ２ ; 10)-C≡CR １３ ; 11)-C≡C-C(O)OR ２５ ; 12)-C≡C-C(O)NR １３ R １４ ; 13)-C≡C-S(O) ２ NR １３ R １４ ; 14) - (CR １３ R １４ ) ｗ -CN; and 15)-(CR １３ R １４ ) ｗ -(C=O)-R ２５ ; w is 1, 2, 3, 4 or 5; R １３ and R １４ are each independently selected from the following: 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; Or, R １３ and R １４ together with the nitrogen atom to which they are attached form an optionally substituted 3- to 8-membered heterocyclic ring; R １５ is hydrogen, hydroxy, optionally substituted -C １ -C ８ alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or heteroarylalkyl; R １６ is hydrogen or Na ＋ That is, A compound or a pharma- ceutically acceptable salt thereof.

2. Represented by one of formulas (IV-1) to (IV-4): 【Chemistry 2】 In the formula, B, X, R １ , R ３ , R １３ , R １４ , R ２１ , and R ２５ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

3. Represented by one of the formulas (V): 【Chemistry 3】 Each R ９ are 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; 11) optionally substituted heteroaryl 12)-OC(O)R ２５ ; 13)-C(O)NR １３ R １４ ; 14)-S(O)R ２５ ; 15)-S(O) ２ -R ２５ ; 16)-S(O)(NH)R ２５ ; 17)-S(O) ２ -NR １３ R １４ ; 18)-NR １３ (C=O)R ２５ ; 19)-NR １３ (C=O)OR ２５ ; 20)-NR １３ (C=O)NR １３ R １４ ; 21) -NR １３ -S (O) ２ -R ２５ and 22)-NR １３ -S(O) ２ -NR １３ R １４ ; n is 0, 1, 2, 3, or 4; R １ , R ２ , R ３ , R ４ , R １３ , R １４ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ and X is as defined in claim 1; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

4. Represented by formula (XIX): 【Chemistry 4】 Each R ９ are 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; 11) optionally substituted heteroaryl 12)-OC(O)R ２５ ; 13)-C(O)NR １３ R １４ ; 14)-S(O)R ２５ ; 15)-S(O) ２ -R ２５ ; 16)-S(O)(NH)R ２５ ; 17)-S(O) ２ -NR １３ R １４ ; 18)-NR １３ (C=O)R ２５ ; 19)-NR １３ (C=O)OR ２５ ; 20)-NR １３ (C=O)NR １３ R １４ ; 21) -NR １３ -S (O) ２ R ２５ and 22)-NR １３ -S(O) ２ NR １３ R １４ ; n is 0, 1, 2, 3, or 4; R １ , R ３ , R ４ , R ２１ , R ２２ , R ２３ , and R ２４ is as defined in claim 1, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

5. Represented by one of formulas (VII-1) to (VII-5): 【Chemistry 5】 In the formula, R １ , R ３ , R ２１ , R ２３ , R ２５ , R １３ , and R １４ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

6. Represented by one of formulas (XI-1) to (XI-3): 【Chemistry 6】 In the formula, A1 is an optionally substituted 4- to 8-membered lactam or an optionally substituted 2-pyridone; A2 is an optionally substituted 3- to 12-membered heterocyclic ring or an optionally substituted 5- to 12-membered heteroaryl ring; A3 is a 3- to 8-membered heterocyclic ring; R １ , R ３ , R ２１ , R ２３ , and R ２４ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

7. Represented by one of formulas (XVII-1) to (XVII-2): 【Chemistry 7】 In the formula, each R ９ are 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; 11) optionally substituted heteroaryl 12)-OC(O)R ２５ ; 13)-C(O)NR １３ R １４ ; 14)-S(O)R ２５ ; 15)-S(O) ２ -R ２５ ; 16)-S(O)(NH)R ２５ ; 17)-S(O) ２ -NR １３ R １４ ; 18)-NR １３ (C=O)R ２５ ; 19)-NR １３ (C=O)OR ２５ ; 20)-NR １３ (C=O)NR １３ R １４ ; 21) -NR １３ -S (O) ２ R ２５ and 22)-NR １３ -S(O) ２ NR １３ R １４ ; n is 0, 1, 2, 3, or 4; r is 1, 2, 3, or 4; R １ , R ３ , R ４ , and R ２１ is as defined in claim 1, The compound of claim 1.

8. Represented by one of formulas (XVIII-1) to (XVIII-4): 【Chemistry 8】 In the formula, each R ９ are 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; 11) optionally substituted heteroaryl 12)-OC(O)R ２５ ; 13)-C(O)NR １３ R １４ ; 14)-S(O)R ２５ ; 15)-S(O) ２ -R ２５ ; 16)-S(O)(NH)R ２５ ; 17)-S(O) ２ -NR １３ R １４ ; 18)-NR １３ (C=O)R ２５ ; 19)-NR １３ (C=O)OR ２５ ; 20)-NR １３ (C=O)NR １３ R １４ ; 21) -NR １３ -S (O) ２ R ２５ and 22)-NR １３ -S(O) ２ NR １３ R １４ ; n is 0, 1, 2, 3, or 4; R １ , R ３ , R １３ , R １４ , R ２１ , R ２２ , R ２３ , R ２４ and R ２５ is as defined in claim 1, The compound of claim 1.

9. 2. The compound of claim 1, selected from the following compounds: or a pharma- ceutically acceptable salt thereof: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier or excipient.

11. 10. A method of treating or preventing viral infections from RNA-based viruses, coronaviruses, rhinoviruses and noroviruses in a subject susceptible to or suffering from said viral infection, comprising administering to said subject an effective amount of a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof.

12. 10. A method of treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or combination of compounds according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof.

13. 13. The method of claim 12, wherein the coronavirus is 229E, NL63, OC43, HKU1, SARS-CoV or MERS coronavirus.

14. 10. A method of treating or preventing a viral infection in a subject susceptible to or suffering from said viral infection, comprising administering to said subject an effective amount of a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof.

15. 10. A method for inhibiting viral 3C protease or viral 3CL protease in a subject, comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt thereof.

16. 10. A method of treating a respiratory disease, including acute asthma, lung disease due to environmental exposure, acute pulmonary infection, and chronic pulmonary infection, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof.

17. 12. The method of claim 11, wherein the compound or a pharma- ceutically acceptable salt thereof is administered orally, subcutaneously, intravenously or by inhalation.

Images