Functionalized peptides as antiviral agents

Abstract

This invention provides a compound and method for inhibiting coronavirus replication activity by contact with a 3C-like protease inhibitor. [Solution] The present invention discloses a compound of formula (I) and a pharmaceutically acceptable salt thereof that inhibits coronavirus replication activity. The present invention further relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a method for treating or preventing coronavirus infection in a subject requiring such treatment, comprising the step of administering a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. JPEG2026053472000099.jpg34166

Description

[Technical Field]

[0001] Related applications This application claims the benefits of U.S. Provisional Patent Application No. 63 / 054,048, filed on 20 July 2020. All teachings of the said application are incorporated herein by reference.

[0002] The present invention relates to compounds and methods for inhibiting coronavirus replication activity by contacting a 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 a coronavirus 3C-like protease inhibitor in mammals, obtained by administering an effective amount of such a coronavirus 3C-like protease inhibitor. [Background technology]

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

[0004] Coronaviruses are enveloped, single-stranded positive-sense RNA viruses. The genomic RNA of CoV has a 5' cap structure and a 3' poly-A 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 non-structural proteins by a 3C-like protease (3CLpro), also known as the main protease (Mpro). These non-structural proteins are involved in the production of subgenomic RNAs encoding four structural proteins, namely the envelope, membrane, spike, and nucleocapsid proteins, among other accessory proteins. Consequently, it is understood that the 3C-like protease plays a crucial role in the life cycle of coronaviruses.

[0005] 3CLpro is a cysteine ​​protease involved in most cleavage events within precursor polyproteins. Active 3CLpro is a homodimer containing two protomers, characterized by a Cys-His dimer located between domains I and II. 3CLpro is conserved among coronaviruses, and several common features are shared between 3CLpro substrates in different coronaviruses. Since no human homolog of 3CLpro exists, it is an ideal antiviral target. Compounds have been reported to inhibit 3CLpro activity, but they are not approved as coronavirus therapies. (See International Publication Nos. 2018042343, 2018023054, 2005113580, and 2006061714).

[0006] More effective treatments for coronavirus infection are needed due to the high level of unmet clinical need. This invention describes a method for preparing compounds that are thought to inhibit the life cycle of the coronavirus and methods for using them. This type of compound may be used to treat coronavirus infection and reduce the occurrence of disease complications such as organ failure or death.

[0007] In this field, there is a need for novel therapeutic agents to treat, alleviate, or prevent coronavirus infection. When administered to patients with coronavirus infection, either as monotherapy or in combination with other coronavirus treatments or adjunctive therapies, these agents result in significant improvements in prognosis, reduced disease progression, and increased antibody seroconversion rates. [Overview of the project]

[0008] The present invention relates to novel antiviral compounds, pharmaceutical compositions comprising such compounds, and methods for treating or preventing viral (particularly coronavirus) infections in subjects requiring such treatment with these 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. Furthermore, the present invention provides methods for preparing these compounds.

[0009] The present invention provides compounds represented by formula (I), as well as pharmaceutically acceptable salts, N-oxides, esters, and prodrugs thereof. [ka] During the ceremony, A is 1) Arbitrarily substituted -C1-C8 alkyl, 2) Arbitrarily substituted -C3-C 12 Cycloalkyl, 3) 3-12 member heterocycloalkyl groups that are optionally substituted, 4) Arbitrarily substituted, and 5) optionally substituted heteroaryl, L1 is -C(R 11 R 12 )-, L2 is -C(R 11 R 12 )-, n1 is 0, 1, 2, 3 or 4, X is optionally substituted -C1-C6 alkyl, -CN, -C(O)R 15 , C(O)NR 13 R 14 , or C(O)C(O)NR 13 R 14 and, each Q is -C(R 11 ’R 12 ’)-, n2 is 0, 1, 2, 3 or 4, preferably n2 is not 0, each R 11 , R 11 ’, R 12 and R 12 ’ is independently selected from the following, 1) hydrogen, 2) halogen, 3) -OR 16 , 4) -SR 16 , 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, or, R 11 and R 12 together with the carbon atom to which they are attached form an optionally substituted 3- to 8-membered carbocyclic or heterocyclic ring, Alternatively, if n1 is not 0, two adjacent R 11 The groups, together with the carbon atoms to which they are bonded, form optionally substituted 3- to 8-membered carbon rings or heterocycles. Alternatively, n1 is 2, 3, or 4, and R is on two non-adjacent carbon atoms. 11 The groups, together with the carbon atoms to which they are bonded, form optionally substituted bridging portions, and in this embodiment, [ka] Preferably, it is an optionally substituted 6-12 membered bridged heterocyclic system, R 13 and R 14 Each of these is independently selected from the following: 1) Hydrogen, 2) Arbitrarily substituted -C1-C6 alkyl, 3) -C3-C8 cycloalkyl groups that are optionally substituted 4) 3- to 8-membered heterocycloalkyl groups that are optionally substituted. 5) Arbitrari that has been arbitrarily substituted, 6) Arbitrarily substituted arylalkyls, 7) Heteroaryl compounds that are arbitrarily substituted, 8) Heteroarylalkyls that are optionally substituted, 9)-C(O)R 15 , 10)-S(O)2R 16 , and 11)-NH2, Alternatively, R 13 and R 14 These, together with the nitrogen atoms to which they are bonded, form arbitrarily substituted 3- to 8-membered heterocycles.

[0010] R 15 The following can be selected: 1) Hydrogen, 2) Halogen, 3)-OH, 4) Arbitrarily substituted -C1-C6 alkyl, 5) Arbitrarily substituted -C1-C6 alkoxy, 6) -C3-C8 cycloalkyl groups that are optionally substituted 7) 3- to 8-membered heterocycloalkyl groups that are optionally substituted, 8) Arbitrari that have been arbitrarily substituted, 9) Arbitrarily substituted arylalkyls, 10) Optionally substituted heteroaryls, and 11) Optionally substituted heteroarylalkyls, R 16 The following can be selected. 1) Hydrogen, 2)-OH, 3) Arbitrarily substituted -C1-C6 alkyl, 4) -C3-C8 cycloalkyl groups that are optionally substituted 5) 3- to 8-membered heterocycloalkyl groups that are optionally substituted. 6) Arbitrarily substituted, 7) Arbitrarily substituted arylalkyls, 8) Heteroaryls that are arbitrarily substituted, and 9) Heteroarylalkyls that are arbitrarily substituted. [Modes for carrying out the invention]

[0011] One embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] In certain embodiments of the compound of formula (I), R 13 and R 14 These are, independently, hydrogen, optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3-8 member heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and -C(O)R 15 -S(O)2R 16 , and selected from NH2, or R 13 and R 14These, together with the nitrogen atoms to which they are bonded, form an arbitrarily substituted 3- to 8-membered heterocycle, R 15 R is selected from hydrogen, halogen, -OH, optionally substituted -C1-C6 alkyl, optionally substituted -C1-C6 alkoxy, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. 16 The group is selected from hydrogen, -OH, optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0013] In certain embodiments of the compound of formula (I), X is -CN.

[0014] In certain embodiments of the compound of formula (I), X is -C(O)CH2OC(O)R 21 -C(O)CH2C(O)2R 21 -C(O)CH2OR 21 Or C(O)CH2R 22 And R 21 R is hydrogen, optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. 22 is halogen or NR 13 R 14 That is the case.

[0015] In certain embodiments of the compound of formula (I), X is -C(O)C(O)NHR 21 And R 21 This is as previously defined. Preferably, R 21 This is optionally substituted benzyl, optionally substituted methyl, optionally substituted isopropyl, optionally substituted t-butyl, or optionally substituted cyclohexyl.

[0016] In certain embodiments of the compound of formula (I), X is -C(O)R 21 And R 21 This has already been defined.

[0017] In certain embodiments of the compound of formula (I), X is -CHR 21 OC(O)R 21 ,-CHR 21 C(O)2R 21 ,-CHR 21 (OR 21 ), or CH(OR 21 )2, R 21 This has already been defined.

[0018] In certain embodiments, X is -CN, -C(O)H, [ka] Selected from. In a preferred embodiment, X is -CN.

[0019] In certain embodiments of the compound of formula (I), A is optionally substituted by the removal of a hydrogen atom, and is derived from one of the following: [ka]

[0020] In certain embodiments of the compound of formula (I), A is selected from the following groups, and A is optionally substituted. [ka]

[0021] Preferably, A has 0, 1, or 2 substituents. Preferably, the substituents are independently selected from fluoro, chloro, hydroxy, methoxy, fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0022] In certain embodiments of the compound of formula (I), A is -CH2R 23 And R 23 -NR 13 R 14 , arbitrarily substituted -C3-C 12 The components are cycloalkyl groups, optionally substituted 3- to 12-membered heterocycloalkyl groups, optionally substituted aryl groups, or optionally substituted heteroaryl groups.

[0023] In certain embodiments of the compound of formula (I), A is -CR 23 R 24 R 25 And in the formula, R 24 This includes hydrogen, halogens, optionally substituted -C1-C6 alkyl groups, optionally substituted -C1-C6 alkoxy groups, and optionally substituted -C3-C6 groups. 12 Cycloalkyl, optionally substituted 3-12 member heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl, R 25 is hydrogen or halogen, R 23 This is as defined earlier.

[0024] In certain embodiments of the compound of formula (I), A is -C(NR 13 R 14 )R 24 R 25 And R 13 , R 14 , R 24 and R 25 This is as defined earlier.

[0025] In a particular embodiment of the compound of formula (I), A is [ka] And in the formula, R 14 , R 15 , R 24 and R 25 This is as previously defined. In a particular embodiment, R14 and R 25 is hydrogen and R 24 is C1-C6-alkyl, preferably t-butyl. R 15 is preferably benzyl, C1-C6-alkyl or C3-C8-cycloalkyl.

[0026] In certain embodiments of the compound of formula (I), at least one Q is -CH2-. In certain embodiments of the compound of formula (I), all Q are -CH2-.

[0027] In certain embodiments, the compound of formula (I) is represented by one of formulas (II-1) to (II-2) or a pharmaceutically acceptable salt thereof,

Chemical formula

[0028] In certain embodiments, the compound of formula (I) is represented by one of formulas (II-1a) to (II-2a) or a pharmaceutically acceptable salt thereof,

Chemical formula

[0029] In certain embodiments, the compound of formula (I) is represented by one of formulas (III-1) to (III-2) or a pharmaceutically acceptable salt thereof,

Chemical formula

[0030] In certain embodiments, the compound of formula (I) is represented by one of formulas (IV-1) to (IV-4), or a pharmaceutically acceptable salt thereof. [ka] In the formula, A, R 17 , R 11 ', m1, m2 and X are as defined above.

[0031] In certain embodiments, the compound of formula (I) is represented by one of formulas (IV-1a) to (IV-4a), or a pharmaceutically acceptable salt thereof. [ka] In the formula, A and X are as defined above.

[0032] In certain embodiments, the compound of formula (I) is represented by one of formulas (V-1) to (V-4), or a pharmaceutically acceptable salt thereof. [ka] In the formula, each T is CR 11 And each U is -C(R 11 R 12 )- and each V is -O-, -S-, -C(R 11 R 12 )-, or N(R 13 R 14)- where m is 0, 1 or 2, m' is 0, 1, 2 or 3, A, Q, n2, R 11 , R 12 , R 13 , R 14 And X is as defined above.

[0033] In certain embodiments, the compound of formula (I) is represented by one of formulas (VI-1) to (VI-6), or a pharmaceutically acceptable salt thereof. [ka] In the formula, A, R 11 ', V, m, and X are as defined above.

[0034] In certain embodiments, the compound of formula (I) is represented by one of formulas (VI-1a) to (VI-8a), or a pharmaceutically acceptable salt thereof. [ka] In the formula, A and X are as defined above.

[0035] In certain embodiments, the compound of formula (I) is represented by one of formulas (VII-1) to (VII-6), or a pharmaceutically acceptable salt thereof. [ka] In the formula, A, R 11 ', V, m, and X are as defined above.

[0036] In certain embodiments, the compound of formula (I) is represented by one of formulas (VII-1a) to (VII-6a), or a pharmaceutically acceptable salt thereof. [ka] In the formula, A and X are as defined above.

[0037] In certain embodiments, the present invention relates to compounds of formulas (VI-1) to (VI-4) or (VII-1) to (VII-4), and pharmaceutically acceptable salts thereof. [ka] The following are selected from the following bases: [ka] Each of these groups is optionally substituted.

[0038] In certain embodiments, the present invention relates to compounds of formulas (VI-5) to (VI-6) or (VII-5) to (VII-6), and pharmaceutically acceptable salts thereof. [ka] The following are selected from the following bases: [ka] Each of these groups is optionally substituted.

[0039] In certain embodiments, the present invention relates to compounds of formulas (VI-1) to (VI-6) or (VII-1) to (VII-6), and pharmaceutically acceptable salts thereof, wherein A is selected from the following groups: [ka] Each of these groups is optionally substituted. Preferably, A has 0, 1, or 2 substituents. Preferably, the substituents are independently selected from fluoro, chloro, hydroxy, methoxy, fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0040] In certain embodiments, the present invention relates to one compound of formulas (VI-1) to (VI-6) and formulas (VII-1) to (VII-6) or a pharmaceutically acceptable salt thereof, where A is -CH2R 23 And R 23 This has already been defined.

[0041] In certain embodiments, the present invention relates to one compound of formulas (VI-1) to (VI-6) and (VII-1) to (VII-6) or a pharmaceutically acceptable salt thereof, where X is -CN, -C(O)CH2OC(O)R 21 -C(O)CH2C(O)2R 21 -C(O)CH2OR 21 -C(O)CH2R 22 -C(O)C(O)NHR 21 , -C(O)R 21 ,-CHR 21 OC(O)R 21 ,-CHR 21 C(O)2R 21 ,-CHR 21 (OR 21 ), or CH(OR 21 )2, R 21 and R 22 This is as defined earlier.

[0042] In certain embodiments, the compound of formula (I) is represented by one of formulas (VIII-1) to (VIII-12), or a pharmaceutically acceptable salt thereof. [ka] In the formula, R 31 is hydrogen, -F, -Cl, -OCH3, or OCHF2, and X is as defined above. Preferably, X is -CN, -C(O)CH2OC(O)R 21 -C(O)CH2C(O)2R 21 -C(O)CH2OR 21 -C(O)CH2R 22 -C(O)C(O)NHR 21 , -C(O)R 21 ,-CHR 21 OC(O)R21 ,-CHR 21 C(O)2R 21 ,-CHR 21 (OR 21 ), or CH(OR 21 )2, R 21 and R 22 This is as defined earlier.

[0043] In certain embodiments, the compound of formula (I) is represented by one of formulas (IX-1) to (IX-8), or a pharmaceutically acceptable salt thereof. [ka] In the formula, R 32 R is hydrogen, -F, Cl, -CH3, -CF3 or OR, 33 -Cl, -Br, -OR 21 , -NHR 21 Or OC(O)R 21 And R 34 is R 21 Preferably, R 34 is an optionally substituted -C1-C6 alkyl, an optionally substituted -C3-C8 cycloalkyl, or an optionally substituted 3- to 8-membered heterocycloalkyl, more preferably R 34 R is benzyl, cyclohexyl, isopropyl, t-butyl, or optionally substituted methyl, 21 And A is as defined above.

[0044] In a particular embodiment, the compound of formula (I) is represented by one of formulas (IX-1) to (IX-8), or a pharmaceutically acceptable salt thereof, and R 32 , R 33 and R 34 As defined above, A is selected from the following bases, [ka] Each of these is optionally substituted. Preferably, A has 0, 1, or 2 substituents. Preferably, the substituents are independently selected from fluoro, chloro, hydroxy, methoxy, fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

[0045] In certain embodiments, the compound of formula (I) is represented by one of formulas (IX-1) to (IX-8), where A is -CH2R 23 And R 23 , R 32 , R 33 and R 34 This is as defined earlier.

[0046] In certain embodiments, the compound of formula (I) is represented by formula (Xa) or a pharmaceutically acceptable salt thereof, where A and X are as previously defined. [ka]

[0047] Representative compounds of the present invention include, but are not limited to, compounds of formula (Xa) and their pharmaceutically acceptable salts, where A and X are described in Table 1 for each compound. [Table 1-1] [Table 1-2]

[0048] In certain embodiments, the compound of formula (I) is represented by formula (Xb) or a pharmaceutically acceptable salt thereof, where A and X are as previously defined. [ka]

[0049] Representative compounds of the present invention include, but are not limited to, compounds of formula (Xb) and their pharmaceutically acceptable salts, where A and X are described in Table 2 for each compound. [Table 2-1] [Table 2-2]

[0050] In certain embodiments, the compound of formula (I) is represented by formula (Xc) or a pharmaceutically acceptable salt thereof, where A and X are defined previously. [ka]

[0051] Representative compounds of the present invention include, but are not limited to, compounds of formula (Xc) and their pharmaceutically acceptable salts, where A and X are described in Table 3 for each compound. [Table 3-1] [Table 3-2]

[0052] In certain embodiments, the compound of formula (I) is represented by formula (Xd) or a pharmaceutically acceptable salt thereof, where A and X are defined previously. [ka]

[0053] Representative compounds of the present invention include, but are not limited to, compounds of formula (Xd) and their pharmaceutically acceptable salts, where A and X are described in Table 4 for each compound. [Table 4-1] [Table 4-2] [Table 4-3]

[0054] In certain embodiments, the compound of formula (I) is represented by formula (Xe) or a pharmaceutically acceptable salt thereof, where A and X are defined previously. [ka]

[0055] Representative compounds of the present invention include, but are not limited to, compounds of formula (Xe) and their pharmaceutically acceptable salts, where A and X are described in Table 5 for each compound. [Table 5-1] [Table 5-2]

[0056] In certain embodiments, the compound of formula (I) is represented by formula (Xf) or a pharmaceutically acceptable salt thereof, where A and X are defined previously. [ka]

[0057] Representative compounds of the present invention include, but are not limited to, compounds of formula (Xf) and their pharmaceutically acceptable salts, where A and X are described in Table 6 for each compound. [Table 6-1] [Table 6-2]

[0058] In certain embodiments, the compound of formula (I) is represented by one of formulas (XI-1) to (XI-8), or a pharmaceutically acceptable salt thereof. [ka] In the formula, R 13 , R 14 , R 24 , R 25 And X is as defined above.

[0059] In certain embodiments, the compound of formula (I) is represented by one of formulas (XII-1) to (XII-4), or a pharmaceutically acceptable salt thereof. [ka] In the formula, R 14 , R 15 , R 24 , R 25 And X is as defined above.

[0060] In certain embodiments, the compound of formula (I) is represented by one of formulas (XIII-1) to (XIII-4), or a pharmaceutically acceptable salt thereof. [ka] In the formula, R 15 , R 24 And X is as defined above. Preferably, X is -CN and R 24 This is an optionally substituted -C1-C6 alkyl group, such as t-butyl.

[0061] It will be understood that the description of the present invention herein should be interpreted in accordance with the laws and principles of chemical bonding. In some cases, it may be necessary to remove a hydrogen atom in order to accommodate a substituent at any given position.

[0062] It will be further understood that the compounds of the present invention may contain one or more chiral carbon atoms and may exist in racemic, diastereoisomer, and optically active forms. It will also be understood that certain compounds of the present invention may exist in different tautomeral forms. All tautomers are considered to be within the scope of the present invention.

[0063] In certain embodiments, the present invention provides a method for treating or preventing coronavirus infection in a subject requiring it, such as a human, comprising the step of administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. The coronavirus may be alpha, beta, gamma, or delta coronavirus. In certain embodiments, the coronavirus is one that infects humans, such as coronavirus 229E, coronavirus NL63, coronavirus OC43, coronavirus HKU1, SARS-CoV-1, SARS-CoV-2, and MERS-CoV. In certain embodiments, the coronavirus is SARS-CoV-1, SARS-CoV-2, or MERS-CoV. Preferably, the coronavirus is SARS-CoV-2.

[0064] Embodiments of the present invention provide administering the compound to a healthy patient or a patient with a viral infection, either as a single agent or in combination with another agent effective in treating or preventing coronavirus infection, (2) another agent that improves the immune response and robustness, or (3) another agent that reduces inflammation and / or pain.

[0065] The compounds described herein, or their salts, solvates, or hydrates, are thought to have the activity to prevent, halt, or reduce the effects of coronavirus by inhibiting the virus's 3C or 3C-like proteases, thereby interfering with or preventing polyprotein processing of the translated viral genome in host cells and rendering the virus unable to replicate.

[0066] In a further embodiment, the present invention provides a method for treating respiratory disorders in subjects requiring treatment of respiratory disorders, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. Such respiratory disorders include, but are not limited to, acute or chronic airway diseases. Examples of such respiratory disorders include acute asthma, lung diseases secondary to environmental exposure, acute lung infections, and chronic lung infections.

[0067] The compounds of the present invention and any other pharmaceutically active agents may be administered together or separately, and if administered separately, the administration may be simultaneous or sequential in any order. The amounts of the compounds of the present invention and the other pharmaceutically active agents and the relative timing of administration are selected to achieve the desired combined therapeutic effect. The administration of the compounds of the present invention and their salts, solvates or other pharmaceutically acceptable derivatives in combination with other therapeutic agents may be combined by administering them simultaneously in (1) a single pharmaceutical composition containing both compounds, or (2) separate pharmaceutical compositions, each containing one of the compounds.

[0068] In another embodiment of combination therapy, administration of the compound of the present invention makes it possible to administer additional therapeutic agents to individuals requiring prophylactic treatment for coronavirus infection at lower doses or frequencies than administering at least one additional therapeutic agent alone to achieve similar results in prophylactic treatment for coronavirus infection.

[0069] It should be understood that the compounds included in this invention are stable compounds suitable for use as pharmaceuticals.

[0070] definition The following lists the definitions of various terms used to describe the present invention. These definitions apply to the terms used herein and throughout the claims, unless specifically limited in particular cases, individually or as part of a larger group.

[0071] As used herein, the term "aryl" refers to a monocyclic or polycyclic carbocyclic 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 may include fused rings, covalent rings, or combinations thereof.

[0072] As used herein, the term “heteroaryl” refers to a monocyclic or polycyclic aromatic radical having one or more ring atoms selected from S, O, and N, the remaining ring atoms being carbon, and either N or S within the ring may be optionally oxidized. Heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimizolyl, benzoxazolyl, and quinoxalinyl. Polycyclic heteroaryls may include fused rings, covalent rings, or combinations thereof.

[0073] According to the present invention, the aromatic group may be substituted or unsubstituted.

[0074] As used herein, the term "alkyl" refers to saturated linear or branched hydrocarbon radicals. This includes "C1-C4 alkyl," "C1-C6 alkyl," "C1-C8 alkyl," and "C2-C 12 "Alkyl," "C2-C4 alkyl," or "C3-C6 alkyl" refers to alkyl groups containing 1-4, 1-6, 1-8, 1-12, 2-4, and 3-6 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 radicals.

[0075] As used herein, the term "alkenyl" refers to a linear or branched hydrocarbon radical having at least one carbon-carbon double bond by the removal of a single hydrogen atom. "C2-C8 alkenyl," "C2-C 12 "Alkenyl," "C2-C4 alkenyl," "C3-C4 alkenyl," or "C3-C6 alkenyl" refers to an alkenyl group containing 2-8, 2-12, 2-4, 3-4, or 3-6 carbon atoms, respectively. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, and octenyl.

[0076] As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon radical having at least one carbon-carbon double bond by the removal of a single hydrogen atom. "C2-C8 alkynyl," "C2-C 12 "Alkynyl," "C2-C4 alkynyl," "C3-C4 alkynyl," or "C3-C6 alkynyl" refers to an alkynyl group containing 2-8, 2-12, 2-4, 3-4, or 3-6 carbon atoms, respectively. Typical alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, heptynyl, and octynyl.

[0077] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring, or a condensed, cross-linked, or spiro-type bicyclic or tricyclic group, where the carbon atoms are optionally oxosubstituted or optionally substituted with extracyclic olefin double bonds. Preferred cycloalkyl groups include C3-C 12 This includes cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl, and C4-C7 cycloalkyl. 12Examples of cycloalkyl compounds 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, and spiro[4.4]nonanyl.

[0078] As used herein, the term "cycloalkenyl" refers to a monocyclic or polycyclic carbocyclic ring having at least one carbon-carbon double bond, or a condensed, bridged, or spiro-type bicyclic or tricyclic group, wherein the carbon atoms are optionally oxosubstituted or optionally substituted with extracyclic olefin double bonds. Preferred cycloalkenyl groups include C3-C 12 It contains a cycloalkenyl, C3-C8 cycloalkenyl, or C5-C7 cycloalkenyl group. 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]hexa-2-enyl, spiro[2.5]octo-4-enyl, spiro[4.4]non-2-enyl, and bicyclo[4.2.1]non-3-en-12-yl.

[0079] As used herein, the term "arylalkyl" means a functional group in which an alkylene chain is bonded to an aryl group, for example, -CH2CH2-phenyl. The term "substituted arylalkyl" means an arylalkyl functional group in which an aryl group is substituted. Similarly, the term "heteroarylalkyl" means a functional group in which an alkylene chain is bonded to a heteroaryl group. The term "substituted heteroarylalkyl" means a heteroarylalkyl functional group in which a heteroaryl group is substituted.

[0080] As used herein, the term “alkoxy,” whether used alone or in combination with other terms, means an alkyl group having a specified number of carbon atoms bonded to the rest of the molecule via an oxygen atom, unless otherwise specified, such as methoxy, ethoxy, 2-propoxy, 2-propoxy (isopropoxy), and higher-order congeners and isomers. Preferred alkoxys are (C2-C3)alkoxys.

[0081] It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, and cycloalkenyl moieties described herein may also be aliphatic or alicyclic groups.

[0082] An "aliphatic" group is a non-aromatic moiety containing any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen, or other atoms, and optionally containing one or more unsaturated units, such as double and / or triple bonds. Examples of aliphatic groups include functional groups such as 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 carbon atoms of non-aromatic hydrocarbons (optionally substituted) are replaced by functional groups. The carbon atoms of aliphatic groups are oxo-substituted as desired. The aliphatic group may be linear, branched, cyclic, or a combination thereof, and preferably contains about 1 to about 24 carbon atoms, more typically about 1 to about 12 carbon atoms. In addition to the aliphatic hydrocarbon groups used herein, the aliphatic groups clearly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines. The aliphatic group is optionally substituted.

[0083] The terms “heterocyclic” or “heterocycloalkyl” are interchangeable and refer to a non-aromatic ring or a bicyclic or tricyclic group of a condensed, bridged, or spirosystem, wherein (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur, and nitrogen; (ii) each ring system may be saturated or unsaturated; (iii) the nitrogen and sulfur heteroatoms may be optionally oxidized; (iv) the nitrogen heteroatom may be optionally quaternized; (v) any of the above rings may be condensed to an aromatic ring; and (vi) the remaining ring atoms are optionally oxosubstituted or optionally substituted with an extracyclic olefin double bond. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridadinyl, 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-oxooxepant-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups can be bonded by C or N bonds (where possible).

[0084] Any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moieties described herein may be divalent or polyvalent when used as linkers to connect two or more groups or substituents, and these may be on the same or different atoms. Those skilled in the art can readily determine the valency of any such group from the context in which it arises.

[0085] The term "substituted" refers to a substitution in which one, two, or three or more hydrogen atoms are independently replaced by substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, C 1- C12 -Alkyl, C2-C 12 -Alkenyl, C2-C 12 -Alkinyl, -C3-C 12 -Cycloalkyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -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-C 1- C 12 -alkyl, -OCONH-C2-C8-alkenyl, -OCONH-C2-C8-alkynyl, -OCONH-C3-C 12 -Cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, OCONH-heterocycloalkyl, -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, -methoxyethoxy, -SH, -SC 1- C 12 -alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-C 12 -Cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. In certain embodiments, the substituent is a halo, preferably Cl and F;C 1- C4-alkyl, preferably methyl and ethyl; halo-C 1- C4-alkyl, e.g., fluoromethyl, difluoromethyl and trifluoromethyl; C2-C4-alkenyl; halo-C2-C4-alkenyl; C3-C6-cycloalkyl, e.g., cyclopropyl; C 1- C4-alkoxy, e.g., methoxy and ethoxy; halo-C 1- C4-alkoxy, for example, fluoromethoxy, difluoromethoxy and trifluoromethoxy, -CN;-OH;NH2;C 1- C4-alkylamino;di(C 1- The C4-alkyl)amino and NO2 groups are independently selected. It is understood that aryl, heteroaryl, alkyl, etc., can be further substituted. In some cases, each substituent of the substituted moiety may be optionally further substituted with one or more groups, each of which is C1-C4-alkyl, CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO 2、 -CN, or NH2, can be selected independently. Preferably, the substituted alkyl group is substituted with one or more halogen atoms, more preferably with one or more fluorine atoms or chlorine atoms.

[0086] The terms "halo" or "halogen," when used herein, either alone or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0087] As used herein, the term “optionally substituted” means that the group referred to may be substituted or unsubstituted. In one embodiment, the group referred to is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional groups selected individually and independently from the groups described herein.

[0088] The term "hydrogen" includes both hydrogen and deuterium. Furthermore, the enumeration of atoms includes other isotopes of that atom, as long as the resulting compound is pharmaceutically acceptable.

[0089] As used herein, the term “hydroxyl-activating group” refers to an unstable chemical moiety known in the art to activate a hydroxyl group and detach during synthetic procedures such as substitution or elimination reactions. Examples of hydroxyl-activating groups include, but are not limited to, mesylates, tosylates, triflates, p-nitrobenzoates, and phosphonates.

[0090] As used herein, the term "activated hydroxyl" refers to a hydroxyl group activated by a hydroxyl activating group as defined above, including, for example, mesylate, tosylate, triflate, p-nitrobenzoate, and phosphonate groups.

[0091] As used herein, the term “hydroxy protecting group” refers to an unstable chemical moiety known in the art to protect a hydroxyl group from undesirable reactions during a synthetic procedure. After the synthetic procedure, the hydroxy protecting groups described herein can be selectively removed. Hydroxy protecting groups known in the art are described in T. Greene and P. G. M. W. Uts' "Protecting Groups in Organic Synthesis." Protective Groups in Organic Synthesis ) is generally described in the 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl, 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, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

[0092] As used herein, the term "protected hydroxy" refers to a hydroxy group protected with a hydroxy protecting group as defined above, including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, and methoxymethyl groups.

[0093] As used herein, the term "hydroxy prodrug group" refers to a promoiety group known in the art to temporarily change the physicochemical and thus the biological properties of the parent drug by covering or masking a hydroxy group. After the synthetic procedure, the hydroxy prodrug groups described herein must be able to return 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 ( Products, Topical and Ocular Drug Delivery )" (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992).

[0094] As used herein, the term “amino protecting group” refers to an unstable chemical moiety known in the art to protect an amino group from undesirable reactions during a synthetic procedure. After the synthetic procedure, the amino protecting groups described herein can be selectively removed. Hydroxy protecting groups known in the art are described in T. Greene and P. G. M. W. Uts “Protecting Groups in Organic Synthesis” Protective Groups in Organic Synthesis This is commonly described in "The 3rd edition of 'The 3rd edition of 'The 3rd edition of 'The 3rd edition of ', John Wiley & Sons, New York (1999)'." Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 12-fluorenyl-methoxycarbonyl, and benzyloxycarbonyl.

[0095] As used herein, the term "protected amino" refers to an amino group protected by the amino protecting group defined above.

[0096] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom in substitution reactions such as nucleophilic substitution reactions. Examples of typical leaving groups include chloro, bromo, and iodine groups, sulfonic acid ester groups (such as mesylate, tosylate, brosylate, and nosylate), and acyloxy groups (such as acetoxy and trifluoroacetoxy).

[0097] As used herein, the term “aprotic solvent” 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, and chloroform), heterocyclic compounds (such as tetrahydrofuran and N-methylpyrrolidinone), and ethers (such as diethyl ether and 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, depending on factors such as reagent solubility, reagent reactivity, and preferred temperature range, individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions. A detailed description of aprotic solvents can be found in organic chemistry textbooks or specialized papers, e.g., “Physical Properties and Purification Methods of Organic Solvents.” Organic Solvents Physical Properties and Methods of Purco )" 4th edition, edited by John A. Riddick et al., Vol. II, Techniques of Chemistry Series This can be found in John Wiley & Sons, NY, 1986.

[0098] As used herein, the term “protic solvent” refers to solvents that tend to yield protons, such as alcohols, 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, depending on factors such as reagent solubility, reagent reactivity, and preferred temperature range, individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions. A detailed description of protic solvents can be found in organic chemistry textbooks or specialized papers, e.g., “Physical Properties and Purification Methods of Organic Solvents.” Organic Solvents Physical Properties and Methods of Purco ) Fourth Edition, edited by John A. Riddick et al., Vol. II, Techniques of Chemistry Series , can be found in John Wiley & Sons, NY, 1986.

[0099] The combinations of substituents and variables contemplated in the present invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds having sufficient stability to allow for their manufacture and that maintain their integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0100] 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 will be appreciated by those skilled in the art, additional methods for synthesizing the compounds of the formulas herein will be apparent to those skilled in the art. In addition, the various synthetic steps can be carried out in alternative sequences or orders to obtain the desired compounds. Synthetic chemical transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art, for example, R. Larock, "Comprehensive Organic Transformations ( Comprehensive Organic Transformations )" 2 nd Ed. Wiley-VCH (1999); T.W. Greene and P.G.M. Wuts "Protecting Groups in Organic Synthesis ( 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 ( FENER and Fieser's Reagents for Organic Synthesis)" John Wiley and Sons (1994); and L. Paquette, ed. "Dictionary of Reagents for Organic Synthesis" Encyclopedia of Reagents for Organic Synthesis This includes what is written in John Wiley and Sons (1995) and subsequent editions.

[0101] As used herein, the term “subject” refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. The subject also refers to, for example, dogs, cats, horses, cattle, pigs, guinea pigs, fish, birds, and so on.

[0102] The compounds of the present invention can be modified by adding appropriate functional groups to enhance their selective biological properties. Such modifications are known in the art and may include increasing biopenetration into specific biological systems (e.g., blood, lymphatic system, central nervous system), improving oral availability, increasing solubility to enable injection, altering metabolism, and altering excretion rates.

[0103] The compounds described herein contain one or more chiral centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers that can be defined with respect to absolute stereochemistry as (R)- or (S)-, or (D)- or (L)-amino acids. The present invention means that it includes all such possible isomers, as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the above procedure or by splitting the racemic mixture. Splitting can be carried out by chromatography in the presence of a splitting agent, by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details regarding splitting can be found in Jacques et al. "Enantiomers, Racemic and Splitting ( Enantiomers, Racemates, and ResolutionsThis can be found in (John Wiley & Sons, 1981). Where a compound described herein contains an olefinic double bond, other unsaturated or other geometrically asymmetric center, unless otherwise specified, the compound is intended to include both E and Z geometric isomers or cis and trans isomers. Similarly, all tautomers are also intended to be included. Tautomers may be cyclic or acyclic. The carbon-carbon double bond configurations appearing herein are selected for convenience only and are not intended to specify any particular configuration unless otherwise specified herein. Thus, a carbon-carbon double bond or carbon-heteroatom double bond optionally indicated as trans herein may be cis, trans, or a mixture of the two in any proportion.

[0104] Certain compounds of the present invention may also exist in different stable conformations that may be separable. For example, torsional asymmetry due to restricted rotation around an asymmetric single bond, such as due to steric hindrance or ring strain, may allow for the separation of different conformational isomers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

[0105] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, or allergic reactions, and that is commensurate with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al., J. Pharmaceutical Sciences, 66:2-19 (1977), describe pharmaceutically acceptable salts in detail. Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by the reaction of a free basic functional group with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, and 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 other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include azipart, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and lactobionic acid. This includes, but is not limited to, salts, lactates, laurates, lauryl sulfate, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valersates, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium.Further pharmaceutically 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, sulfons, and arylsulfons having 1 to 6 carbon atoms.

[0106] As used herein, the term “pharmaceutically acceptable ester” refers to an ester that hydrolyzes in vivo, including those that readily decompose in the human body, leaving a parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanes, alkenes, cycloalkanoates, and alkanedioates, where each alkyl or alkenyl moiety preferably has six or fewer carbon atoms. Examples of specific esters include, but are not limited to, formate esters, acetate esters, propionate esters, butyrate esters, acrylic esters, and ethyl succinate esters.

[0107] Pharmaceutical composition The pharmaceutical composition of the present invention comprises a therapeutically effective amount of the compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.

[0108] 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 any type of formulation aid. Some examples of materials that function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and 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, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; water free of pyrogens; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solution. Other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings, fragrances, preservatives, and antioxidants may also be present in the composition at the discretion of the compounder.

[0109] The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, transrectally, transnasally, intraoral, transvaginally, or via an implanted reservoir, preferably by oral administration or injection. The pharmaceutical compositions of the present invention may comprise any conventional non-toxic, pharmaceutically acceptable carrier, adjuvant, or vehicle. In some cases, the pH of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the compound being formulated or its delivery form. As used herein, the term parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intrafocal, and intracranial injection or infusion techniques.

[0110] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form 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 sorbitan, and mixtures thereof. In addition to inert diluents, the oral composition may also contain adjuvants such as wetting agents, emulsifiers and suspension agents, sweeteners, flavorings, and fragrances.

[0111] Injectable preparations, such as sterile injectable aqueous or oily suspensions, may be formulated according to known techniques using appropriate dispersants or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as a solution of 1,3-butanediol. Acceptable vehicles and solvents include water, Ringer's solution, United States Pharmacopeia (USP), and isotonic sodium chloride solution. In addition, sterile fixatives have conventionally been used as solvents or suspension media. For this purpose, any non-irritating fixative, including synthetic mono or diglycerides, may be used. Furthermore, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0112] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injection medium before use.

[0113] To prolong the effects of a drug, it is often desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low solubility in water. In this case, the rate of drug absorption depends on its dissolution rate, which may depend on the crystal size and morphology. Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oily vehicle. Injectable depot formulations are made by forming a microencapsulation matrix of the drug with biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydrous). Injectable depot formulations can also be prepared by encapsulating the drug in liposomes or microemulsions that conform to body tissues.

[0114] The compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or suppository wax, which are solid at ambient temperature but liquid at body temperature, and thus dissolve in the rectum or vaginal cavity to release the active compound.

[0115] 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 and pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or with a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, arginate, 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) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also include a buffering agent.

[0116] Similar solid compositions may also be used as fillers for soft and hard gelatin capsules, for example, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0117] Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in pharmaceutical formulation techniques. The dosage forms may optionally contain opacifiers and may be compositions that release the active ingredient only in specific parts of the intestinal tract, or preferentially, optionally, in a delayed manner. Examples of usable embedding compositions may include polymeric substances and waxes.

[0118] 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 pharmaceutically acceptable carrier and, if necessary, required preservatives or buffers. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also considered to be within the scope of the present invention.

[0119] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0120] The powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof, in addition to the compounds of the present invention. The sprays may also contain conventional propellants such as chlorofluorohydrocarbons.

[0121] Transdermal patches offer the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms can be created by dissolving or distributing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0122] For pulmonary delivery, the therapeutic compositions of the present invention are formulated and administered to the patient in solid or liquid particle form by direct administration, for example, by inhalation into the respiratory system. The solid or liquid particle form of the active compound prepared for carrying out the present invention includes breathable-sized particles, i.e., particles small enough to pass through the mouth and larynx and enter the bronchi and alveoli of the lungs upon inhalation. The delivery of aerosolized therapeutics, in particular aerosolized antibiotics, is known in the art (see, for example, National Patent No. 5,767,068 by Van Devanter et al., U.S. Patent No. 5,508,269 by Smith et al., and International Publication No. 98 / 43650 by Montgomery, all of which are incorporated herein by reference).

[0123] Combination therapy and alternating therapy The compounds of the present invention may be used in combination with one or more antiviral or anti-inflammatory agents useful for the prevention or treatment of viral diseases or related pathophysiology. Accordingly, the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives may be used alone or in combination with other antiviral or anti-inflammatory agents.The compounds herein and their pharmaceutically acceptable salts may be used in combination with one or more other agents that may be useful for the prevention or treatment of: respiratory diseases, inflammatory diseases, autoimmune diseases, e.g., antihistamines, corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, ciclesonide, mometasone furoate, triamcinolone, flunisolide), NSAIDs, leukotriene modulators (e.g., montelukast, zafirlukast, pranlukast), tripe Tase inhibitors, IKK2 inhibitors, p38 inhibitors, Syk inhibitors, protease inhibitors, e.g., elastase inhibitors, integrin antagonists (e.g., β-2 integrin antagonists), adenosine A2α agonists, mediator release inhibitors, e.g., sodium cromoglycate, 5-lipoxygenase inhibitors (zyflo), DP1 antagonists, DP2 antagonists, PI3K delta inhibitors, ITK inhibitors, LP (lysophosphatidyl) inhibitors, or FLAP (5-lipoxygenase activating protein) inhibitors (e.g., , sodium 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridine-3-yl)benzyl)-5-((5-ethylpyridine-2-yl)methoxy)-1H-indole-2-yl)-2,2-dimethylpropanoate), bronchodilators (e.g., muscarinic antagonists, β-2 agonists), methotrexate and similar drugs; monoclonal antibody therapies such as anti-IgE, anti-TNF, anti-IL-5, anti-IL-6, anti-IL-12, anti-IL-1 and similar drugs; cytokine receptor therapies, e.g., etanercept and similar drugs; anti Proto-nonspecific immunotherapies (e.g., interferon or other cytokines / chemokines, chemokine receptor modulators, e.g., CCR3, CCR4 or CXCR2 antagonists, other cytokine / chemokine agonists or antagonists, TLR agonists and similar agents), appropriate anti-infective agents including antibiotics, antifungals, anthelmintics, antimalarials, antiparasitic agents, antituberculosis agents, and antivirals including those listed at https: / / www.drugs.com / drug-class / anti-infectives.html.Generally, combination therapy is preferred over alternating therapy because it typically induces multiple simultaneous stresses on the virus.

[0124] While the present invention has been described in relation to various preferred embodiments, it is not intended to be limited thereto. Rather, those skilled in the art will recognize that modifications and alterations can be made within the spirit of the invention and the scope of the appended claims.

[0125] Antiviral activity The inhibitory amount or dose of the compound of the present invention may range from about 0.01 mg / kg to about 500 mg / kg, or from about 1 to about 50 mg / kg. The inhibitory amount or dose also varies depending on the route of administration and the possibility of concomitant use with other drugs.

[0126] According to the therapeutic method of the present invention, viral infection is treated or prevented in a patient, such as a human or another animal, by administering a therapeutically effective amount of the compound of the present invention to the patient in the amount and time necessary to achieve the desired result.

[0127] The “therapeutic effective dose” of the compounds of the present invention means the amount of the compound that confers a therapeutic effect to the subject being treated in a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by several tests or markers) or subjective (i.e., the subject shows signs of or feels an effect). The effective dose of the above compounds may range from about 0.1 mg / kg to about 500 mg / kg, preferably from about 1 to about 50 mg / kg. The effective dose also varies depending on the route of administration and the possibility of concomitant use with other drugs. However, it will be understood that the total daily dose of the compounds and compositions of the present invention should be determined by the attending physician within the bounds of sound medical judgment. The specific therapeutic effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and its severity; the activity of the particular compound used; the particular composition used; the patient’s age, weight, overall health, sex, and diet; the timing of administration, route of administration, and excretion rate of the particular compound used; the duration of treatment; drugs used in combination with or concurrently with the particular compound used; and similar factors well known in the medical field.

[0128] The total daily dose of the compound of the present invention administered to humans or other animals in single or divided doses may be, for example, 0.01 to 50 mg / kg body weight or more, usually 0.1 to 25 mg / kg body weight. A single-dose composition may contain such an amount or a fraction thereof to constitute a daily dose. Generally, a therapeutic regimen according to the present invention involves administering to a patient requiring such treatment about 10 mg to about 1000 mg of the compound of the present invention per day in single or multiple doses.

[0129] The compounds of the present invention described herein may be administered, for example, by injection, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or subcutaneously; or orally, orally, nasally, transmucosally, topically, in ophthalmic preparations, or by inhalation, in doses ranging from about 0.1 to about 500 mg / kg body weight, or 1 mg to 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods described herein are intended to administer an effective amount of the compound or compound composition to achieve the desired or described effect. Typically, the pharmaceutical compositions of the present invention are administered about 1 to about 6 times per day, or instead as continuous infusions. Such administrations can be used as chronic or acute treatment. The amount of active ingredient that can be combined with pharmaceutically active excipients or carriers to produce a single dosage form varies depending on the host being treated and the specific mode of administration. Typical preparations contain about 5% to about 95% (w / w) of the active compound. Alternatively, such preparations may contain approximately 20% to 80% of the active compound.

[0130] Lower or higher doses than those listed above may be required. The specific dosage and treatment regimen for any particular patient depends on a variety of factors, including the activity of the specific compound used, age, weight, overall health, sex, diet, administration time, excretion rate, drug combination, severity and course of the disease, condition or symptom, the patient's nature to the disease, condition or symptom, and the judgment of the treating physician.

[0131] If the patient's condition improves, a maintenance dose of the compound, composition, or combination of the present invention may be administered as needed. Thereafter, the dose, frequency, or both may be reduced as a function of symptoms to a level at which the improved state is maintained when symptoms are alleviated to a desired level. However, patients may require long-term, intermittent treatment based on relapses of disease symptoms.

[0132] When the composition of the present invention comprises a combination of a compound of a formula described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at a dosage level of about 1 to 100%, more preferably about 5 to 95%, of the dosage typically administered in a monotherapy regimen. The additional agents may be administered separately from the compound of the present invention as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form mixed with the compound of the present invention in a single composition.

[0133] "Further therapeutic or prophylactic agents" include, but are not limited to, immunotherapies (e.g., interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as β-2 adrenergic agonists and xanthines (e.g., theophylline), mucolytics, antimuscarinic agents, 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). Compositions according to the present invention may also be used in combination with gene replacement therapy.

[0134] Abbreviation The following abbreviations may be used in the following explanation of schemes and examples: Acetyl Ac; AcOH acetate; Di-tert-butyl dicarbonate Boc2O; t-butoxycarbonyl Boc; Benzoyl Bz; Benzyl Bn; Potassium tert-butoxide t-BuOK; Sodium chloride aqueous solution brine; Carbonyl diimidazole CDI; Dichloromethane DCM or CH2Cl2; Methyl CH3; Acetonitrile CH3CN; Cesium carbonate Cs2CO3; Copper(I) chloride CuCl; Copper(I) iodide CuI; Dibenzylideneacetone dba; 1,8-dia Zabicyclo[5.4.0]-undeka-7-ene DBU; diethyl azodicarboxylate DEAD; diisopropyl azodicarboxylate DIAD; N,N,-diisopropylethylamine DIPEA or (i-Pr)2EtN; 1,1,2-tris(acetyloxy)-1,2-dihydro-1,2-benzoiodoxol-3-(1H)-one DMP or des-martin periodinane; 4-dimethylaminopyridine DMAP; 1,2-dimethoxyethane DME; N,N-dimethylformamide DMF; dimethyl sulfoxide DMSO; acetate Tyl ethyl ethyl; Ethanol EtOH; Diethyl ether Et2O; O-(7-azabenzotriazol-2-yl)-N,N,N',N',-tetramethyluronium hexafluorophosphate HATU; Hydrogen chloride HCl; Potassium carbonate K2CO3; n-Butyllithium n-BuLi; 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DDQ; Lithium diisopropylamide LDA; Lithium 2,2,6,6-tetramethyl-piperidinate LiTMP; Methanol MeOH; Magnesium Mg; Methoxymethyl MOM; Mesyl or SO2-CH3 is Ms; sodium bis(trimethylsilyl)amide NaHMDS; sodium chloride NaCl; sodium hydride NaH; sodium bicarbonate or sodium bicarbonate NaHCO3; sodium carbonate Na2CO3; sodium hydroxide NaOH; sodium sulfate Na2SO4; sodium bisulfite or sodium bisulfite NaHSO3; sodium thiosulfate Na2S2O3; hydrazine NH2NH2; ammonium chloride NH4Cl; nickel Ni; hydroxyl OH; osmium tetroxide OsO4; triflate OTf; polyphosphate PPA;p-toluenesulfonate PTSA; p-toluenesulfonate pyridinium PPTS; tetrabutylammonium fluoride TBAF; triethylamine TEA or Et3N; triethylsilyl TES; triethylsilyl chloride TESCl; triethylsilyl trifluoromethanesulfonate TESOTf; trifluoroacetate TFA; tetrahydrofuran THF; N,N,N',N'-tetramethylethylene-diamine TMEDA; triphenylphosphine TPP or PPh3; tosyl or SO2-C6H4CH3 is Tos or Ts; torylsul Tosyl anhydride or phosphate anhydride Ts2O; p-tolylsulfonic acid TsOH; palladium Pd; phenyl Ph; tris(dibenzylideneacetone)dipalladium(0) is Pd2(dba)3; tetrakis(triphenylphosphine)-palladium(0) is Pd(PPh3)4; trans-dichlorobis-(triphenylphosphine)palladium(II) is PdCl2(PPh3)2; platinum Pt; rhodium Rh; room temperature rt; ruthenium Ru; tert-butyldimethylsilyl TBS; trimethylsilyl TMS; trimethylsilyl chloride TMSCl.

[0135] Synthesis method The compounds and methods of the present invention will be better understood in relation to the following synthetic schemes illustrating methods for preparing the compounds of the present invention. These schemes are illustrative and are not intended to limit the scope of the present invention. Without departing from the general range of synthetic methods, equivalent, similar or suitable solvents, reagents or reaction conditions may be used instead of the specific solvents, reagents or reaction conditions described herein.

[0136] Scheme 1: [ka] As shown in Scheme 1, compounds such as 5 (where Q1 is defined as Q and Q2 as Q; R is defined as H, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heterocycle) can be prepared according to the synthetic methods shown herein or by similar methods known to those skilled in the art. Intermediate 1 (where R1 is defined as H, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heterocycle; J is defined as an amino protecting group) can be reacted with nitrile 2 (where X is defined as a halogen, OMs, OAc, OTf, OTs, or OTf) in a carbon-carbon bond formation reaction, typically mediated by a base (indicated as [base]), including but not limited to LDA, LiHMDS, or LiTMP. Intermediate 3 can be reduced (indicated as [reduction]), typically mediated by a reducing agent (including but not limited to LiBH4 or NaBH4). Lactam 4 can be reacted in a deprotection step (indicated as [deprotection]) typically mediated by an acidic reagent containing, but not limited to, TFA or HCl, to produce compound 5. Alternatively, lactam 4 can be reacted in a deprotection step (indicated as [deprotection]) mediated by a reducing agent containing, but not limited to, hydrogen on palladium carbon, to produce compound 5.

[0137] Scheme 2: [ka] As shown in Scheme 2, compounds such as 3 (where Q1 is defined as Q, Q2 as Q, and A, L1 and L2 are as previously defined) can be prepared according to the synthesis methods shown herein or by similar methods known to those skilled in the art. Acid 1 can be reacted in a coupling reaction with amine 2 (X as previously defined) typically mediated by a base (indicated as [base]) including but not limited to DIPEA, Et3N, or DBU, and an activator (indicated as [activator]) including but not limited to HATU or EDC.

[0138] Scheme 3: [ka] As shown in Scheme 3, compounds such as 3 (where Q1 is defined as Q, Q2 as Q, A, L1 and L2 are as previously defined, and R is defined as H, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heterocycle) can be prepared according to the synthetic methods shown herein or by similar methods known to those skilled in the art. Acid 1 can be reacted in a coupling reaction with amine 2, typically mediated by a base (indicated as [base]) including but not limited to DIPEA, Et3N, or DBU, and an activator (indicated as [activator]) including but not limited to HATU or EDC.

[0139] Scheme 4: [ka] As shown in Scheme 4, compounds such as 4 (A, L1 and L2 as previously defined) can be prepared according to the synthetic methods described herein or by similar methods known to those skilled in the art. Amine 1 (R is defined as H, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heterocycle) can be coupled with acid 2 (A as previously defined) typically mediated by a base (indicated as [base]) containing, but not limited to, DIPEA, Et3N, or DBU, and an activator (indicated as [activator]) containing, but not limited to, HATU, or EDC. Ester 3 can react in a hydrolysis reaction (indicated as [hydrolysis]) typically mediated by an acidic reagent containing, but not limited to, TFA or HCl, to produce acid 4. Alternatively, ester 3 can react in a hydrolysis reaction (indicated as [hydrolysis]) typically mediated by a basic reagent containing, but not limited to, NaOH, LiOH, or Me3SnOH, to produce acid 4. Alternatively, ester 3 can react in a hydrolysis reaction (indicated as [hydrolysis]) typically mediated by a reducing agent containing hydrogen on the palladium carbon, but not limited to this case, to produce acid 4.

[0140] Scheme 4b: [ka] As shown in Scheme 4b, compounds such as 3 (A, L1 and L2 as previously defined) can be prepared according to the synthetic methods described herein or by similar methods known to those skilled in the art. Amine 1 (R is defined as H, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocycle) can be reacted in a coupling reaction with the activated form of acid 2 (A as previously defined), the acid activation occurring in reaction with an activator (indicated as [activator]) to produce an activated ester intermediate. The aforementioned coupling reaction between amine 1 and the activated form of acid 2 is mediated by a base (indicated as [base]), including but not limited to NaOH, NaHCO3, or KOH, to produce amide 3.

[0141] Scheme 5: [ka] As shown in Scheme 5, compounds such as 3 (where Q1 is defined as Q, Q2 as Q, and A, L1 and L2 are as previously defined) can be prepared according to the synthetic methods described herein or by similar methods known to those skilled in the art. Intermediate 1 (where R is defined as H, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heterocycle) can be reacted in a reduction reaction using a reagent including but not limited to LiBH4 or NaBH4 (indicated as [reducing agent]) to produce alcohol 2. This can then be oxidized using a reagent, or a group of reagents including but not limited to SO3-pyridine, DMP, or Ac2O / DMSO (indicated as [oxidizing agent]) to produce aldehyde 3.

[0142] Scheme 6: [ka] As shown in Scheme 6, compounds such as 2 (where Q1 is defined as Q, Q2 as Q, and A, L1 and L2 are as previously defined) can be prepared according to the synthetic methods shown herein or by similar methods known to those skilled in the art. Ester 1 (where R is defined as H, an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted heterocycle) can be reacted with ICH2Cl and a basic reagent (indicated as [base]), such as LDA or nBuLi, to produce 2.

[0143] Scheme 7: [ka] As shown in Scheme 7, compounds such as 3 (where Q1 is defined as Q, Q2 as Q, A, L1 and L2 are as previously defined, and R is defined as an optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocycle) can be prepared according to the synthetic methods shown herein or by similar methods known to those skilled in the art. Halide 1 can be reacted with acid 2 and a basic reagent (indicated as [base]) containing but not limited to CsF or NaF to produce ester 3.

[0144] Scheme 8: [ka] As shown in Scheme 8, compounds such as 3 (where Q1 is defined as Q, Q2 as Q, and A, L1 and L2 are as previously defined) can be prepared according to the synthesis methods shown herein or by similar methods known to those skilled in the art. Halide 1 can react with acid 2 and a basic reagent (indicated as [base]) containing but not limited to CsF or NaF to produce an intermediate ester, which can then be reacted with a hydrolysis reaction (indicated as [hydrolysis]) mediated by a reagent containing but not limited to K2CO3 or Cs2CO3 to produce alcohol 3.

[0145] Scheme 9: [ka] As shown in Scheme 9, compounds such as 3 (where Q1 is defined as Q and Q2 as Q) can be prepared according to the synthetic methods described herein or by similar methods known to those skilled in the art. Ester 1 (where R is defined as an optionally substituted aryl or alkyl group and PG is defined as a nitrogen-based protecting group) can be reacted with ammonia to produce an intermediate amide, which can then undergo a dehydration reaction indicated as [dehydration] mediated by a reagent including, but not limited to, Pd(CO2CF3)2 or TFAA to produce nitrile 2. This can then undergo a deprotection reaction indicated as [deprotection] mediated by a reagent including, but not limited to, TFA, HCl, palladium, or platinum to produce primary amine 3.

[0146] Scheme 10: [ka] As shown in Scheme 10, compounds such as 4 (where Q1 is defined as Q, Q2 as Q, A, L1 and L2 are as previously defined, and R is defined as an optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycle) can be prepared according to the synthetic methods shown herein or by similar methods known to those skilled in the art. Aldehyde 1 can be reacted with isonitrile 2 to form the intermediate hydroxyamide 3. This intermediate can undergo an oxidation reaction, indicated as [oxidation], mediated by reagents including but not limited to sulfur trioxide pyridine complex (Py-SO3), DMSO, oxalyl chloride, and / or acetic anhydride, to produce ketoamide 4.

[0147] All references cited herein, whether in print, electronic, computer-readable storage media, or other form, including but not limited to abstracts, articles, journals, publications, texts, papers, internet websites, databases, patents, and patent gazettes, are expressly incorporated by reference in their entirety.

[0148] 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 structure, substituents, derivatives, formulations and / or methods of the present invention, can be made without departing from the spirit of the invention and the scope of the appended claims.

[0149] While the present invention has been described in relation to various preferred embodiments, it is not intended to be limited thereto. Rather, those skilled in the art will recognize that modifications and alterations can be made within the spirit of the invention and the scope of the appended claims.

[0150] example The compounds and methods of the present invention will be better understood in relation to the following examples, but these are for illustrative purposes only and do not limit the scope of the invention. The starting materials were available from commercial distributors or were prepared by methods well known to those skilled in the art.

[0151] General conditions: Mass spectra were performed using an LC-MS system with electrospray ionization. These were Agilent 1290 Infinity II systems equipped with an Agilent 6120 Quadrupole detector. Spectra were obtained using a ZORBAX Eclipse XDB-C18 column (4.6 × 30 mm, 1.8 micron). Spectra were obtained at 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: 0–1.5 min 5% (B), 1.5–4.5 min 5–95% (B), and 4.5–6 min 95% (B). The solvent flow rate was 1.2 mL / min. The compound was detected at wavelengths of 210 nm and 254 nm. [M+H] + This refers to the molecular weight of a monoisotope.

[0152] NMR spectra were obtained using a Bruker 400 MHz spectrometer. Spectra were measured at 298 K and referenced using solvent peaks. 1 The chemical shifts in 1H NMR are reported in parts per million (ppm).

[0153] Compounds were purified by reversed-phase high-performance liquid chromatography (RPHPLC) using a Gilson GX-281 automated liquid processing system. Unless otherwise specified, compounds were purified using a Phenomenex Kinetex EVO C18 column (250 × 21.2 mm, 5 micron). Unless otherwise specified, compounds were purified at 298 K using a 0% to 100% (B) gradient elution with water (A) and acetonitrile (B) mobile phases. The solvent flow rate was 20 mL / min, and the compounds were detected at a wavelength of 254 nm.

[0154] Alternatively, the compound was purified by normal-phase liquid chromatography (NPLC) using a Teledyne ISCO Combiflash purification system. The compound was also purified using a REDISEP silica gel cartridge. The compound was purified at 298K and detected at a wavelength of 254nm.

[0155] Example 1: Synthesis of (1S,3aR,6aS)-N-((S)-4-chloro-3-oxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide [ka]

[0156] Step 1: A suspension of 4-methoxy-1H-indole-2-carboxylic acid (3.6 g) in DCM (94 mL) was cooled to 0°C. Next, tert-butyl(1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate oxalate (6.81 g) was added, followed by the addition of DMAP (0.690 g). Next, EDC (7.22 g) was added, and the reaction mixture was stirred at 0°C for 30 minutes, then stirred overnight at room temperature. The mixture was then washed with water (1 × 30 mL), the organic layer was dried over Na₂SO₄, filtered, and concentrated. The crude product was used directly in the next step.

[0157] Step 2: Trifluoroacetic acid (32.6 mL) was added at room temperature to a solution of methyl (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylate (7.24 g) in DCM (106 mL). The resulting solution was stirred at room temperature for 2 hours and then concentrated. The crude residue was purified with silica gel (ethyl acetate:cyclohexane 0-100%) to obtain (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (4 g, 58% yield in 2 steps).

[0158] Step 3: (S)-3-((S)-2-amino-4-chloro-3-oxobutyl)pyrrolidine-2-one hydrochloride (150 mg), DMF (3 mL), HATU (239 mg), and (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (212 mg) were placed in a vial and cooled to 0°C. Next, Hünig base (261 mg) was added. The reaction mixture was stirred for 75 minutes, then diluted with ethyl acetate and washed three times with saturated NaHCO3, water, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified with silica gel to obtain (1S,3aR,6aS)-N-((S)-4-chloro-3-oxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide as a light brown foam (195 mg, yield 61%). ESI MS m / z=516.1 [M+H] + .

[0159] Example 2: Synthesis of (S)-3-((1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide)-2-oxo-4-((S)-2-oxopyrrolidine-3-yl)butyl2,6-dichlorobenzoate [ka]

[0160] Step 1: A vial was loaded with 2,6-dichlorobenzoic acid (62 mg), cesium fluoride (91 mg), and (1S,3aR,6aS)-N-((S)-4-chloro-3-oxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (140 mg). The vial was purged with nitrogen gas, and then DMF (2 mL) was added. The reaction mixture was heated at 65°C for 1 hour. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaHCO3, water, and brine. The organic layer was concentrated, and the residue was purified on silica gel to obtain (S)-3-((1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide)-2-oxo-4-((S)-2-oxopyrrolidine-3-yl)butyl2,6-dichlorobenzoate (115 mg, yield 63%). ESI MS m / z=670.1 [M+H] + .

[0161] Example 3: Synthesis of (1S,3aR,6aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide. [ka]

[0162] Step 1: A solution of methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2-oxopyrrolidine-3-yl]propanoate (25.00 g, 87.312 mmol, 1.00 equivalent) in NH3 (g) in MeOH (250 mL, 7 mol / L) was placed in a 350 mL sealed tube. The resulting solution was stirred at 70°C for 16 hours. The reaction product was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH = 1:0~10:1). This yielded 15 g (63.32%) of tert-butyl N-[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl]carbamate as a white solid.

[0163] Step 2: In a 3 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, 900 mL of ACN containing tert-butyl N-[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidine-3-yl]ethyl]carbamate (150.00 g, 552.859 mmol, 1.00 equivalent), dichloroacetonitrile (607.81 g, 5528.590 mmol, 10.00 equivalent), and 900 mL of water were added. Subsequently, Pd(CO2CF3)2 (11.03 g, 33.172 mmol, 0.06 equivalent) was added at room temperature. The resulting solution was stirred at room temperature for 16 hours. The resulting mixture was extracted with DCM (3 × 600 mL). The combined organic layers were washed with brine (1 × 1 L) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (2:1). After concentrating the combined product fraction, the residue was polished under DCM, the resulting solid was isolated, and dried under vacuum. This yielded (51 g, 36.42%) tert-butyl((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl) carbamate as a white solid. ESI MS m / z=254.1 [M+H] +.1HNMR(CDCl3)δ 6.30(s,1H),5.90(s,1H),4.77-4.59(m,1H),3.48-3.31(m,2H),2.49(dddd,J=23.7,11.8,7.3,2.7 Hz,2H),2.38-2.23(m,1H),2.02-1.79(m,2H),1.48(s,9H).

[0164] Step 3: Trifluoroacetic acid (790 μL) was added at 22°C to a solution of tert-butyl((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl) carbamate (20 mg, 0.079 mmol) and DCM (0.790 mL). After 15 minutes, the resulting solution was concentrated directly under vacuum. The residue was redissolved in methanol (2 mL), concentrated under vacuum, then redissolved in ethyl acetate (2 mL), and concentrated again. Crude (S)-2-amino-3-((S)-2-oxopyrrolidine-3-yl)propanenitrile 2,2,2-trifluoroacetate was used without further purification. 1HNMR(DMSO-d6)δ 8.94(bs,2H),4.80(dd,J=8.7,6.6 Hz,1H),3.24-3.16(m,2H),2.50(m,1H),2.30(dddd,J=12.1,8.8,5.6,3.4 Hz,1H),2.15(ddd,J=14.5,8.1,6.6 Hz,1H),1.97-1.91(m,1H),1.74(ddt,J=12.5,10.5,9.0 Hz,1H).

[0165] Step 4: 4-(difluoromethoxy)-1H-indole-2-carboxylic acid (3.5 g, 15.41 mmol) was suspended in 25 mL of DCM and 4.5 mL of THF. Next, oxalyl chloride (1.618 mL, 18.49 mmol) was added dropwise at 22°C, followed by the addition of DMF (3 drops). After 15 minutes, the mixture became homogeneous, and TLC analysis (aliquots quenched with MeOH) showed complete conversion. The resulting solution was directly concentrated to obtain crude 4-(difluoromethoxy)-1H-indole-2-carbonyl chloride as a red oil, which was used immediately without further purification.

[0166] Step 5: Ethyl (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride (9.57 g, 43.6 mmol) was suspended in EtOH (87 mL), and then 5N sodium hydroxide aqueous solution (37 mL, 185 mmol) was added at 22°C with vigorous stirring. After 1 hour, the ethanol was distilled under vacuum to obtain approximately 40 mL of a viscous aqueous solution containing sodium (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate, which was used directly.

[0167] Step 6: Crude 4-(difluoromethoxy)-1H-indole-2-carbonyl chloride (2.161 g, 8.8 mmol) was dissolved in THF (5 mL) at 22°C. Next, an aqueous solution of sodium (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate (16 mL) was added at 22°C with vigorous stirring. After stirring for 1 hour, 1 N HCl was added until the pH of the solution was approximately 1. The resulting aqueous suspension was extracted twice by DCM, and then the pooled organic fraction was dried over MgSO4, filtered, and concentrated. The resulting oily substance was subjected to silica gel chromatography to obtain (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (2.67 g, 7.33 mmol, yield 83%) as a pale yellow solid. 1HNMR(DMSO-d6)δ 12.64(bs,1H),11.88(s,1H),7.38-7.29(m,1H),7.20(m,1H),7.00-6.95(m,1H),6.82(m,1H),4.36(d,J=3.6 Hz,1H),4.13(dd,J=10.5,8.2 Hz,1H),3.81(dd,J=10.5,4.3 Hz,1H),3.70(m,1H),2.90-2.79(m,1H),2.64(m,1H),2.02-1.90(m,1H),1.88-1.66(m,3H),1.58(m,4H).

[0168] Step 7: HATU (69.6 mg, 0.183 mmol) was added at 22°C to a solution of (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (57.8 mg, 0.159 mmol), (S)-2-amino-3-((S)-2-oxopyrrolidine-3-yl)propanenitrile 2,2,2-trifluoroacetate (32.6 mg, 0.122 mmol), DMF (0.407 mL), and Et3N (150 μl, 1.08 mmol). The resulting solution was stirred at 22°C for 24 hours and then directly purified via RPHPLC to obtain (1S,3aR,6aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide as a white solid (2 mg). ESI MS m / z=500.1 [M+H] + .

[0169] Example 4: Synthesis of (1S,3aR,6aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide. [ka]

[0170] The synthesis in Example 4 had similar properties to the synthesis in Example 3, but with the following changes: 1. In step 4, 4-methoxy-1H-indole-2-carboxylic acid was used instead of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid.

[0171] Characteristic data for Example 4 was obtained: ESI MS m / z = 464.1 [M+H] +. 1HNMR (chloroform-d)δ 9.77(s,1H),8.18(d,J=7.1 Hz,1H),7.22(t,J=8.1 Hz,1H),7.11-7.00(m,2H),6.76(s,1H),6.50(d,J=7.7 Hz,1H),4.92(t,J=8.3 Hz,1H),4.54(d,J=3.2 Hz,1H),4.24(t,J=9.4 Hz,1H),3.96(s,3H),3.84(dd,J=10.8,4.8 Hz,1H),3.32(m,2H),3.04(m,1H),2.87(m,1H),2.65(m,1H),2.33(m,2H),2.11-1.50(m,10H).

[0172] Example 5: Synthesis of (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide [ka]

[0173] Step 1: Methyl(S)-2-amino-3-((S)-2-oxopyrrolidine-3-yl)propanoate hydrochloride (0.880 g, 3.95 mmol) and (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (1.01 g, 2.77 mmol) were dissolved in a mixture of DMF and DCM (1:1 v / v, 26 mL), and the resulting solution was cooled to 0°C under a nitrogen atmosphere. Next, HATU (1.126 g, 2.96 mmol) was added all at once. After stirring for 3 minutes, Hünig base (1.656 mL, 9.48 mmol) was added dropwise. After stirring at 0°C for 30 minutes, pre-cooled 1 N HCl (15 mL) was added, followed by water (40 mL). The resulting mixture was extracted twice with DCM. The pooled organic fraction was washed twice with saturated NaHCO3 aqueous solution, then with brine, dried over MgSO4, and concentrated. The resulting brown oily substance was subjected to silica gel chromatography to obtain (S)-2-((1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide)-3-((S)-2-oxopyrrolidine-3-yl)propanoate (1.42 g, 2.67 mmol, yield 96%) as a white foam. ¹H NMR (chloroform-d)δ 9.87 (s, ¹H), 7.85 (d, J=7.2 Hz, ¹H), 7.29 (d, J=8.2 Hz, ¹H), 7.20 (d, J=8.0 Hz, ¹H), 6.97 (s, ¹H), 6.90-6.45 (m, ³H), 6.01 (s, ¹H), 4.63 (app s, ¹H), 4.56 (m, ¹H), 4.22 (t, J=9.4 Hz, ¹H), 3.80 (dd, J=10.5, 4.6 Hz,1H),3.73(m,4H),3.26(m,2H),3.00(m,1H),2.86(m,1H),2.55(m,1H),2.41-2.30(m,1H),2 .23-2.11(m,1H),2.04(m,2H),1.98-1.85(m,3H),1.85-1.72(m,3H),1.48(m,2H),1.43(m,1H).

[0174] Step 2: Methyl(S)-2-((1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide)-3-((S)-2-oxopyrrolidine-3-yl)propanoate (1.42 g, 2.67 mmol) was dissolved in THF (26.7 mL) and cooled to 0°C with stirring under a nitrogen atmosphere. Next, lithium borohydride (2 M, 6.67 mL, 13.33 mmol in THF) was added dropwise over 4-5 minutes. After 40 minutes at 0°C, 1 M HCl (1 equivalent, 13.5 mL) was slowly added over 5 minutes. The resulting turbid solution was partitioned into ethyl acetate and water to separate the phases. The aqueous phase was extracted three times with ELISA, and the pooled organic fraction was dried over MgSO4 and concentrated. The residue was subjected to silica gel chromatography to obtain (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (965 mg, 1.913 mmol, yield 71.7%) as a white solid. 1HNMR (chloroform-d)δ 10.45(s,1H),7.95(d,J=8.0 Hz,1H),7.29(app d,J=8.3 Hz,1H),7.19(t,J=8.0 Hz,1H),6.99(s,1H),6.85-6.47(m,2H),6.12(s,1H),4.51(d,J=3.4 Hz,1H),4.27(t,J=9.4 Hz,1H),4.01(m,1H),3.74(td,J=11.1,4.3 Hz,2H),3.61(dd,J=11.6,4.2 Hz,1H),3.22(m,2H),3.06-2.93(m,1H),2.75(m,1H),2.60-2.50(m,1H),2.34 (m,1H),2.17(m,3H),1.95-1.83(m,3H),1.83-1.67(m,3H),1.67-1.45(m,5H).

[0175] Step 3: (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)-N-((S)-1-hydroxy-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (0.958 g, 1.899 mmol) was dissolved in DCM (12.66 mL) and then cooled to 0°C under a nitrogen atmosphere. Next, Des-Martin periodinane (1.127 g, 2.66 mmol) was added all at once. After 1 hour, saturated Na2S2O3 aqueous solution was poured over the resulting brown suspension. The phases were separated, and the organic phase was washed with saturated NaHCO3 aqueous solution and then brine, dried over MgSO4, and concentrated. The residue was then subjected to silica gel chromatography eluted with DCM / MeOH. The fraction containing the product was concentrated, and the resulting brown foam was subjected to a second silica gel chromatography with MTBE / acetone elution to obtain (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (390 mg, 0.776 mmol, yield 40.9%) as a colorless foam. ¹H NMR (chloroform-d)δ 9.82(s,¹H), 9.52(s,¹H), 8.42(s,¹H), 7.28(app d,J=8.4 Hz,¹H), 7.21(t,J=7.9 Hz,¹H), 7.02(s,¹H), 6.87-6.43(m,³H), 5.90(s,¹H), 4.69(s,¹H), 4.35(s,¹H), 4.26(t,J=9.4 Hz,¹H), 3.82(dd,J=10.3,4.6 Hz,1H),3.49(s,1H),3.28(m,2H),2.99(s,1H),2.87(s,1H),2.54(s,1H),2.34(m,1H),2.11-1.49(m,17H).ESI MS m / z=503.1 [M+H] + .

[0176] Example 6: Synthesis of (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide [ka]

[0177] The synthesis in Example 6 had similar properties to the synthesis in Example 5, but with the following changes: 1. In step 1, (1S,3aR,6aS)-2-(4-(methoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid was used instead of (1S,3aR,6aS)-2-(4-(methoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid.

[0178] Characteristic data for Example 6 was obtained: ESI MS m / z = 464.1 [M+H] + .

[0179] Example 7: Synthesis of (1S,3aR,6aS)-N-((S)-1-cyano-2-((S)-2-oxopiperidine-3-yl)ethyl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide. [ka]

[0180] Step 1: Dimethyl (tert-butoxycarbonyl)-L-glutamate (6.5 g) and THF (70 mL) were placed in a flask. The flask was cooled to -78°C under a nitrogen atmosphere. Next, LiHMDS (52 mL, 1 M in THF) was added over 5 minutes. After 1 hour, 3-bromopropannitrile (3 mL) was added dropwise. After 90 minutes, the reaction mixture was heated to -55°C and then quenched with NH4Cl aqueous solution. The reaction mixture was allowed to reach room temperature and then diluted with 20 mL of water. The product was extracted with MTBE and then concentrated. A further 30 mL of MTBE was added, and a precipitate was formed. This was filtered off, and the filtrate was concentrated to obtain an orange oily substance, which was used directly in the next step.

[0181] Step 2: Cobalt(II) chloride hexahydrate (2.8 g) was placed in a flask. Next, a solution of the product from Step 1 in THF (20 mL) was transferred to this flask using MeOH washing (140 mL). After cooling the flask to 0°C, sodium borohydride (3.6 g) was added over 20 minutes. The reaction mixture was allowed to reach room temperature and stirred for 24 hours. Next, most of the volatile substances were removed under reduced pressure. HCl (100 mL) and 1 M HCl (40 mL) were added. The product was extracted with HCl, and the combined organic layer was washed with 1 M HCl and brine, then concentrated. The residue was purified with silica gel to obtain methyl(S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidine-3-yl)propanoate (1.4 g, 20% in 2 steps). ESI MS m / z=301.1 [M+H] + .

[0182] Step 3: Methyl(S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidine-3-yl)propanoate (421 mg) was placed in a flask, and then 4 M ammonia in MeOH (2.8 mL) was added. The reaction mixture was stirred for 72 hours, and then heated at 65°C for 1.5 hours. After removing volatile substances, the residue was purified with silica gel to obtain tert-butyl((S)-1-amino-1-oxo-3-((S)-2-oxopiperidine-3-yl)propan-2-yl)carbamate (237 mg). This was added to a flask containing Pd(CO2CF3)2 (28 mg) and MeCN (5 mL). Next, water (2 mL) and 2,2-dichloroacetonitrile (1.3 mL) were added. After purging with nitrogen gas, the flask was heated at 60°C for 2 hours. The reaction mixture was diluted with toluene, washed with water, and then washed with brine. The organic extract was concentrated, and the residue was purified over silica gel to obtain tert-butyl((S)-1-cyano-2-((S)-2-oxopiperidine-3-yl)ethyl)carbamate (88 mg).

[0183] Step 4: tert-butyl((S)-1-cyano-2-((S)-2-oxopiperidine-3-yl)ethyl) carbamate (88 mg) and DCM (1 mL) were placed in a vial. Then TFA (2 mL) was added. After 1 hour, volatile substances were removed, and the product (S)-2-amino-3-((S)-2-oxopiperidine-3-yl)propanenitrile 2,2,2-trifluoroacetate was used without further purification.

[0184] Step 5: The vial was loaded with (1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid (50 mg), (S)-2-amino-3-((S)-2-oxopiperidine-3-yl)propanenitrile 2,2,2-trifluoroacetate (20 mg), DMF (1 mL), and DIPEA (0.1 mL). Next, HATU (40 mg) was added. After 30 minutes, the reaction mixture was purified by RPHPLC to obtain the product (1S,3aR,6aS)-N-((S)-1-cyano-2-((S)-2-oxopiperidine-3-yl)ethyl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (3 mg). ESI MS m / z = 478.1 [M+H] + .

[0185] Example 8: Synthesis of (1S,3aR,6aS)-N-((S)-4-(cyclohexylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide [ka]

[0186] Step 1: (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide (58 mg) and DCM (1 mL) were placed in a vial. The flask was cooled to 0°C under a nitrogen atmosphere. Next, acetic acid (0.3 mL) was added as a solution in DCM (1 mL). Next, isocyanocyclohexane (0.3 mL) was added and the reaction mixture was brought to room temperature. After 2 hours, volatile substances were removed. The residue was dissolved in MeOH (1 mL) and cooled to -40°C. Potassium carbonate (23 mg) was added and the reaction mixture was warmed to 0°C. Next, water (0.2 mL) was added, followed by 3 M aqueous HCl (0.5 mL). The product was extracted with ethyl acetate and concentrated. The residue was purified with silica gel to obtain the product (1S,3aR,6aS)-N-((2S)-4-(cyclohexylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (39 mg). ESI MS m / z = 630.1 [M+H] + .

[0187] Step 2: (1S,3aR,6aS)-N-((2S)-4-(cyclohexylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (39 mg), DCM (1 mL), and Huenig base (0.033 mL) were charged into a vial at 0°C. Py-SO3 (30 mg) was added as a solution in DMSO (1 mL). Further amounts of Huenig base (0.033 mL) and Py-SO3 (30 mg) in DMSO (1 mL) were added. The reaction mixture was diluted with ethyl acetate and water. The organic layer was removed, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated, and the residue was crystallized twice from diethyl ether:THF to obtain the product (1S,3aR,6aS)-N-((S)-4-(cyclohexylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (2 mg). ESI MS m / z = 628.1 [M+H] + .

[0188] Example 9: Synthesis of (1S,3aR,6aS)-N-((S)-4-(cyclohexylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide [ka]

[0189] The synthesis in Example 9 had similar properties to the synthesis in Example 8, but with the following changes: 1. In step 1, (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide was used instead of (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)-N-((S)-1-oxo-3-((S)-2-oxopyrrolidine-3-yl)propan-2-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide.

[0190] Characteristic data for Example 9 was obtained: ESI MS m / z = 592.1 [M+H] + .

[0191] Example 10: Synthesis of (1S,3aR,6aS)-N-((S)-4-hydroxy-3-oxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide [ka]

[0192] Step 1: A vial was loaded with (1S,3aR,6aS)-N-((S)-4-chloro-3-oxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (99 mg), cesium fluoride (67 mg), 2-oxo-2-phenylacetic acid (38 mg), and DMF (2 mL). The flask was heated to 65°C for 75 minutes. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate and water. The product was extracted with ethyl acetate, and the combined organic matter was concentrated. The product (S)-3-((1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide)-2-oxo-4-((S)-2-oxopyrrolidine-3-yl)butyl 2-oxo-2-phenyl acetate was used in the next step without further purification.

[0193] Step 2: (S)-3-((1S,3aR,6aS)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide)-2-oxo-4-((S)-2-oxopyrrolidine-3-yl)butyl 2-oxo-2-phenylacetate (121 mg) and MeOH (3 mL) were placed in a vial. Next, potassium carbonate (27 mg) was added. After 1 hour, 0.5 mL of 1 M aqueous HCl was added. The reaction mixture was filtered and concentrated. The residue was purified by RPHPLC to obtain the product (1S,3aR,6aS)-N-((S)-4-hydroxy-3-oxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-methoxy-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide (3 mg). ESI MS m / z = 497.1 [M+H] + .

[0194] Example 11: Synthesis of (1S,2S,5R)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-(4-(difluoromethoxy)-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide. [ka]

[0195] The synthesis in Example 11 had similar properties to the synthesis in Example 3, but with the following changes: 1. In step 7, (1S,2S,5R)-3-(4-(difluoromethoxy)-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid was used instead of (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid.

[0196] Characteristic data for Example 11 was obtained: ESI MS m / z = 500.1 [M+H] + .

[0197] Example 12: Synthesis of (S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-1-(4-(difluoromethoxy)-1H-indole-2-carbonyl)pyrrolidine-2-carboxamide [ka]

[0198] The synthesis in Example 12 had similar properties to the synthesis in Example 3, with the following changes: 1. In step 7, (4-(difluoromethoxy)-1H-indole-2-carbonyl)-L-proline was used instead of (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid.

[0199] Characteristic data for Example 12 was obtained: ESI MS m / z = 460.1 [M+H] + .

[0200] Example 13: Synthesis of (1S,3aR,6aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-2-(4,6-difluoro-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide. [ka]

[0201] The synthesis in Example 13 had similar properties to the synthesis in Example 3, but with the following changes: 1. In step 7, (1S,3aR,6aS)-2-(4,6-difluoro-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid was used instead of (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid.

[0202] Characteristic data for Example 13 was obtained: ESI MS m / z = 470.1 [M+H] + .

[0203] Example 14: Synthesis of (1S,3aR,6aS)-2-(4-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)octahydrocyclopenta[c]pyrrole-1-carboxamide. [ka]

[0204] The synthesis in Example 14 had similar properties to the synthesis in Example 3, but with the following changes: 1. In step 7, (1S,3aR,6aS)-2-(4-chloro-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid was used instead of (1S,3aR,6aS)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxylic acid.

[0205] Characteristic data for Example 14 was obtained: ESI MS m / z = 469.1 [M+H] + .

[0206] Example 15: Synthesis of (1S,3aR,6aS)-N-((S)-4-(benzylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidine-3-yl)butan-2-yl)-2-(4-(difluoromethoxy)-1H-indole-2-carbonyl)octahydrocyclopenta[c]pyrrole-1-carboxamide [ka]

[0207] The synthesis in Example 15 had similar properties to the synthesis in Example 8, but with the following changes: 1. In step 1, (isocyanomethyl)benzene was used instead of isocyanocyclohexane.

[0208] Characteristic data for Example 15 was obtained: ESI MS m / z = 636.1 [M+H] + .

[0209] Example 16: Synthesis of (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-(5,7-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0210] The synthesis in Example 16 had similar properties to the synthesis in Example 3, but with the following changes: 1. In step 4, 5,7-difluoro-1H-indole-2-carboxylic acid was used instead of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid. 2. In step 5, ethyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride was used instead of ethyl(1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride.

[0211] Characteristic data for Example 16 was obtained: ESI MS m / z = 470.1 [M+H] + .

[0212] Example 17: Synthesis of (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-(5,6-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0213] The synthesis in Example 17 had similar properties to the synthesis in Example 3, but with the following changes: 1. In step 4, 5,6-difluoro-1H-indole-2-carboxylic acid was used instead of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid. 2. In step 5, ethyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride was used instead of ethyl(1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride.

[0214] Characteristic data for Example 17 was obtained: ESI MS m / z = 470.1 [M+H] + .

[0215] Example 18: Synthesis of (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-(4,6-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0216] The synthesis in Example 18 had similar properties to the synthesis in Example 3, but with the following changes: 1. In step 4, 4,6-difluoro-1H-indole-2-carboxylic acid was used instead of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid. 2. In step 5, ethyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride was used instead of ethyl(1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride.

[0217] Characteristic data for Example 18 was obtained: ESI MS m / z = 470.1 [M+H] + .

[0218] Example 19: Synthesis of (2S,4S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-1-(4-(difluoromethoxy)-1H-indole-2-carbonyl)-4-phenoxypyrrolidine-2-carboxamide [ka]

[0219] The synthesis in Example 19 had similar properties to the synthesis in Example 3, with the following changes: 1. In step 5, ethyl(2S,4S)-4-phenoxypyrrolidine-2-carboxylate hydrochloride was used instead of ethyl(1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride.

[0220] Characteristic data for Example 19 was obtained: ESI MS m / z = 552.1 [M+H] + .

[0221] Example 20: Synthesis of (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-(4,7-difluoro-1H-indole-2-carbonyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0222] The synthesis in Example 20 had similar properties to the synthesis in Example 3, but with the following changes: 1. In step 4, 4,7-difluoro-1H-indole-2-carboxylic acid was used instead of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid. 2. In step 5, ethyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride was used instead of ethyl(1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride.

[0223] Characteristic data for Example 20 was obtained: ESI MS m / z = 470.1 [M+H] + .

[0224] Example 21: Synthesis of (1R,2S,5S)-3-(4-chloro-1H-indole-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide. [ka]

[0225] The synthesis in Example 21 had similar properties to the synthesis in Example 3, with the following changes: 1. In step 4, 4-chloro-1H-indole-2-carboxylic acid was used instead of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid. 2. In step 5, ethyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride was used instead of ethyl(1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride.

[0226] Characteristic data for Example 21 was obtained: ESI MS m / z = 469.1 [M+H] + .

[0227] Example 22: Synthesis of (1R,2S,5S)-3-(4-chlorobenzofuran-2-carbonyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide. [ka]

[0228] The synthesis in Example 22 had similar properties to the synthesis in Example 3, with the following changes: 1. In step 4, 4-chlorobenzofuran-2-carboxylic acid was used instead of 4-(difluoromethoxy)-1H-indole-2-carboxylic acid. 2. In step 5, ethyl(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride was used instead of ethyl(1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride.

[0229] Characteristic data for Example 22 was obtained: ESI MS m / z = 470.1 [M+H] + .

[0230] Example 23: Synthesis of (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-((S)-2-(cyclopentanecarboxamide)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide. [ka]

[0231] Step 1: Boc-L-tert-leucine (1.55 g), DCM (20 mL), and DMF (5 mL) were placed in a vial. The vial was cooled to 0°C, and then HATU (2.2 g) was added. Next, Hünig base (1.8 g) was added. After stirring the yellow suspension for 2 minutes, methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride was added. Next, Hünig base (1.8 g) was added, and the reaction mixture was allowed to reach room temperature. After 2 hours, the reaction mixture was diluted with ethyl acetate and partitioned with water. The product was extracted with ethyl acetate. The combined organic layers were concentrated, and the residue was purified over silica gel to obtain the product methyl(1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.5 g). ESI MS m / z = 383.1 [M+H] + .

[0232] Step 2: Methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (300 mg) and MeOH (4 mL) were placed in a vial. The vial was cooled to 0°C, and then 2 mL of 2.5 M aqueous LiOH was added. After 3.5 hours, the reaction mixture was concentrated. Next, 5.5 mL of 4 M HCl in dioxane was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was then concentrated to obtain the product (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, which was used in its crude form without further purification. ESI MS m / z=269.1 [M+H] + .

[0233] Step 3: (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (304 mg), triethylamine (0.42 mL), and MeCN (6 mL) were placed in a vial. The vial was stirred at 0°C, and then cyclopentane carbonyl chloride (147 mg) was added dropwise under a nitrogen atmosphere. After 1 hour, DCM (25 mL) was added. The reaction mixture was partitioned with water (25 mL) and stirred at room temperature. After 10 minutes, the organic layer was removed. The aqueous layer was acidified to pH 5 with 1 M aqueous HCl. The product was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated. The product (1R,2S,5S)-3-((S)-2-(cyclopentanecarboxamide)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid was used in its crude form without further purification. ESI MS m / z=365.1 [M+H] + .

[0234] Step 4: (1R,2S,5S)-3-((S)-2-(cyclopentanecarboxamide)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (130 mg) and DMF (5 mL) were placed in a vial. Next, DIEA (139 mg) was added. Then HATU (274 mg) was added at room temperature, and the reaction mixture was stirred for 10 minutes. Next, tert-butyl((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)carbamate (155 mg) was added. After 1 hour, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by RPHPLC to obtain the product (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-((S)-2-(cyclopentanecarboxamide)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (45 mg). ESI MS m / z=500.1 [M+H] + .1H NMR(300 MHz,DMSO-d6)δ 8.96(d,J=8.5 Hz,1H),7.76(d,J=9.2 Hz,1H),7.66(s,1H),5.04-4.89(m,1H),4.38(d,J=9.2 Hz,1H),4.12(s,1H),3.91-3.76(m,2H),3.20-2.98(m,2H),2.82-2.66(m,1 H),2.47-2.37(m,1H),2.23-2.01(m,2H),1.76-1.42(m,11H),1.28(d,J=7.6 Hz,1H),1.02(s,3H),0.94(s,9H),0.82(s,3H).

[0235] Example 24: Synthesis of (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-(2-phenylacetamide)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0236] The synthesis in Example 24 is similar in properties to the synthesis in Example 23, with the following changes: 1. In step 3, 2-phenylacetyl chloride was used instead of cyclopentane carbonyl chloride.

[0237] Characteristic data for Example 24 was obtained: ESI MS m / z = 522.1 [M+H] + . 1H NMR(300 MHz,DMSO-d6)δ 8.97(d,J=8.6 Hz,1H),8.13(d,J=9.0 Hz,1H),7.66(s,1H),7.30-7.14(m,6H),5.03-4.88(m,1H),4.36(d,J=6.0 Hz,1H),4.11(s,1H),3.90-3.81(m,1H),3.74(d,J=10.4 Hz,1H),3.56-3.41(m,2H),3.19-2.99(m,2H),2.27-1.99(m,3H),1.77-1.63(m,2H),1.54-1.48(m,1H),1.27(d,J=7.6 Hz,1H),1.01(s,3H),0.91(s,9H),0.74(s,3H).

[0238] Example 25: Synthesis of (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-((S)-2-(cyclohexanecarboxamide)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide. [ka]

[0239] The synthesis in Example 25 is similar in properties to the synthesis in Example 23, with the following changes: 1. In step 3, cyclohexanecarbonyl chloride was used instead of cyclopentanecarbonyl chloride.

[0240] Characteristic data for Example 25 was obtained: ESI MS m / z = 514.1 [M+H] + . 1H NMR(300 MHz,DMSO-d6)δ 8.95(d,J=8.5 Hz,1H),7.73-7.62(m,2H),5.00-4.90(m,1H),4.35(d,J=9.2 Hz,1H),4.11(s,1H),3.90-3.77(m,4H),3.19-2.99(m,2H),2.45-2.24(m,2H),2.22-2. 00(m,2H),1.75-1.47(m,8H),1.24-1.10(m,4H),1.01(s,3H),0.93(s,9H),0.82(s,3H).

[0241] Example 26: Synthesis of (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-propionamide butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0242] The synthesis in Example 26 is similar in properties to the synthesis in Example 23, with the following changes: 1. In step 3, propionyl chloride was used instead of cyclopentane carbonyl chloride.

[0243] Characteristic data for Example 26 was obtained: ESI MS m / z = 460.1 [M+H] +. 1H NMR(300 MHz,DMSO-d6)δ 8.96(d,J=8.6 Hz,1H),7.79(d,J=8.9 Hz,1H),7.65(s,1H),5.01-4.90(m,1H),4.34(d,J=9.0 Hz,1H),4.11(s,1H),3.89-3.76(m,2H),3.08(dq,J=16.4,9.4 Hz,2H),2.45-2.35(m,1H),2.19-2.01(m,4H),1.78-1.63(m,2H),1.58-1.50(m,1H),1.28(d,J=7.7 Hz,1H),1.02(s,3H),0.94(t,J=6.0 Hz,1H),0.92(s,9H),0.84(s,3H).

[0244] Example 27: Synthesis of (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-((S)-2-(isobutylamide-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide. [ka]

[0245] The synthesis in Example 27 is similar in properties to the synthesis in Example 23, with the following changes: 1. In step 3, isobutyryl chloride was used instead of cyclopentane carbonyl chloride.

[0246] Characteristic data for Example 27 was obtained: ESI MS m / z = 474.1 [M+H] +. 1H NMR(300 MHz,DMSO-d6)δ 8.95(d,J=8.5 Hz,1H),7.76(d,J=9.2 Hz,1H),7.65(s,1H),5.01-4.89(m,1H),4.39(d,J=9.2 Hz,1H),4.12(s,1H),3.91-3.75(m,2H),3.20-2.97(m,2H),2.58(dd,J=13.6,6.8 Hz,1H),2.46-2.36(m,1H),2.23-2.02(m,2H),1.78-1.63(m,2H),1.56-1.49(m,1H),1.28(d,J=7.6 Hz,1H),1.02(s,3H),1.00-0.85(m,15H),0.82(s,3H).

[0247] Example 28: Synthesis of (1R,2S,5S)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-3-((S)-3,3-dimethyl-2-pivalamidobutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0248] The synthesis in Example 28 is similar in properties to the synthesis in Example 23, with the following changes: 1. In step 3, pivaloyl chloride was used instead of cyclopentane carbonyl chloride.

[0249] Characteristic data for Example 28 was obtained: ESI MS m / z = 488.1 [M+H] +. 1H NMR(300 MHz,DMSO-d6)δ 8.95(d,J=8.5 Hz,1H),7.67(s,1H),6.88(d,J=7.3 Hz,1H),5.02-4.89(m,1H),4.46(s,1H),4.13(s,1H),3.93-3.81(m,1H),3.73(d,J=10.3 Hz,1H),3.21-2.98(m,2H),2.45-2.36(m,1H),2.19-2.04(m,2H),1.79-1.63(m,2H),1.58-1.49(m,1H),1.29(d,J=7.6 Hz,1H),1.08(s,9H),1.02(s,3H),0.92(s,9H),0.81(s,3H).

[0250] Example 29: Synthesis of (1R,2S,5S)-3-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidine-3-yl)ethyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0251] The synthesis in Example 29 is similar in properties to the synthesis in Example 23, with the following changes: 1. In step 3, acetyl chloride was used instead of cyclopentane carbonyl chloride.

[0252] Characteristic data for Example 29 was obtained: ESI MS m / z = 446.1 [M+H] +. 1H NMR(300 MHz,DMSO-d6)δ 8.97(d,J=8.6 Hz,1H),7.87(d,J=8.7 Hz,1H),7.65(brs,1H),4.99-4.92(m,1H),4.30(d,J=8.7 Hz,1H),4.11(s,1H),3.90-3.75(m,2H),3.18-2.99(m,2H),2.45-2.35(m,1H),2. 20-1.98(m,2H),1.83(s,3H),1.79-1.62(m,2H),1.57-1.50(m,1H),1.28(d,J=7.7 Hz,1H),1.02(s,3H),0.94(s,9H),0.86(s,3H).

[0253] biological activity SARS-CoV-2 3C-like (3CL) protease fluorescence assay (FRET): Recombinant SARS-CoV-2 3CL protease was expressed and purified. The TAMRA-SITSAVLQSGFRKMK-Dabcyl-OH peptide 3CLpro substrate was synthesized. A black, small-volume, round-bottom, 384-well microplate was used. In a typical assay, 0.85 μL of the 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) at room temperature for 30 minutes. Next, 10 μL of 3CL protease substrate (40 μM) was added to the assay buffer, and the assay was monitored continuously for 1 hour using an Envision multimode plate reader operating in fluorescence dynamics mode, excited at 540 nm and emitted at 580 nm at room temperature. Compounds (DMSO only) and enzyme controls were not routinely included in each plate. All experiments were performed in pairs.

[0254] Data Analysis: SARS-CoV-2 3Cl-protease enzyme activity was measured as the initial rate (RFU / s) of the linear phase. This was normalized against the control sample DMSO (100% activity) and no enzyme (0% activity) to determine the percentage residual activity at various concentrations of the test compound (0-10 μM). The data was then fitted to the normalized activity (variable gradient) versus concentration fitting in GraphPad Prism 7 to determine IC50. 50 This was decided. All experiments were conducted in pairs, and IC 50 Report the range as follows: A < 0.1 μM; B 0.1 ~ 1 μM; C > 1 μM. [Table 7]

[0255] Although the present invention has been specifically shown and described with reference to its preferred embodiments, those skilled in the art will understand that various modifications of form and detail can be made without departing from the scope of the invention as set forth in the appended claims.

Claims

1. Compound represented by formula (I): 【Chemistry 1】 or its pharmaceutically acceptable salt During the ceremony: A is selected from the following: 1) Arbitrarily substituted -C １ -C ８ Alkyl; 2) Arbitrarily substituted -C ３ -C １２ Cycloalkyl; 3) 3- to 12-membered heterocycloalkyl groups that are optionally substituted; 4) Arbitrarily substituted; and 5) Heteroaryl compounds that are arbitrarily substituted; L １ -C(R １１ R １２ ) - and; L ２ is -C(R １１ R １２ )-; n1 is 0, 1, 2, 3 or 4, X is arbitrarily substituted -C １ -C ６ Alkyl, -CN, -C(O)R １５ , -C(O)NR １３ R １４ Or C(O)C(O)NR １３ R １４ And; Q is -C(R １１ 'R １２ ') - and; n2 is 0, 1, 2, 3, or 4; Each R １１ , R １１ ', R １２ and R １２ Each of the following is selected independently: 1) Hydrogen; 2) Halogen; 3)-OR １６ ; 4)-SR １６ ; 5)-NR １３ R １４ ; 6)-OC(O)NR １３ R １４ ; 7) Arbitrarily substituted -C １ -C ６ Alkyl; 8) Arbitrarily substituted -C ３ -C ８ Cycloalkyl; 9) Optionally substituted 3- to 8-membered heterocycloalkyl groups; 10) Arbitrarily substituted; and 11) Heteroaryl compounds that are arbitrarily substituted; Alternatively, R １１ and R １２ These, together with the carbon atoms to which they are bonded, form optionally substituted 3- to 8-membered carbon rings or heterocycles; Alternatively, if n1 is not 0, two adjacent R １１ The groups, together with the carbon atoms to which they are bonded, form optionally substituted 3- to 8-membered carbon rings or heterocycles; Alternatively, n1 is 2, 3, or 4, and R is on two non-adjacent carbon atoms. １１ The groups, together with the carbon atoms to which they are bonded, form optionally substituted bridging regions; R １３ and R １４ Each of these is independently selected from the following: 1) Hydrogen; 2) Arbitrarily substituted -C １ -C ６ Alkyl; 3) Arbitrarily substituted -C ３ -C ８ Cycloalkyl; 4) 3- to 8-membered heterocycloalkyl groups that are optionally substituted; 5) Arbitrarily substituted; 6) Arbitrarily substituted arylalkyls; 7) Heteroaryl compounds that are arbitrarily substituted; 8) Heteroarylalkyls that are optionally substituted; 9)-C(O)R １５ ; 10) -S(O) ２ R １６ and 11)-NH ２ ; Alternatively, R １３ and R １４ These, together with the nitrogen atoms to which they are bonded, form arbitrarily substituted 3- to 8-membered heterocycles. R １５ The following can be selected: 1) Hydrogen; 2) Halogen; 3) -OH; 4) Arbitrarily substituted -C １ -C ６ Alkyl; 5) Arbitrarily substituted -C １ -C ６ Alkoxy; 6) Arbitrarily substituted -C ３ -C ８ Cycloalkyl; 7) Optionally substituted 3- to 8-membered heterocycloalkyl groups; 8) Arbitrarily substituted; 9) Arbitrarily substituted arylalkyls; 10) Optionally substituted heteroaryls; and 11) Optionally substituted heteroarylalkyls; R １６ The following can be selected: 1) Hydrogen; 2) -OH; 3) Arbitrarily substituted -C １ -C ６ Alkyl; 4) Arbitrarily substituted -C ３ -C ８ Cycloalkyl; 5) 3- to 8-membered heterocycloalkyl groups that are optionally substituted; 6) Arrays that have been arbitrarily substituted; 7) Arbitrarily substituted arylalkyls; 8) Heteroaryl compounds that are arbitrarily substituted; and 9) A heteroarylalkyl that is arbitrarily substituted.

2. The compound according to claim 1, wherein A is derived from and optionally substituted with one of the following: 【Chemistry 2】 。

3. A is (NR １３ R １４ ) R ２４ R ２５ And, R ２４ -C is substituted with hydrogen, halogen, or any other element. １ -C ６ Alkyl, optionally substituted -C １ -C ６ Alkoxy, arbitrarily substituted -C ３ -C １２ Cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl. R ２５ is hydrogen or halogen, R １３ and R １４ This is as defined in claim 1, The compound according to claim 1.

4. X is -CN, -C(O)CH ２ OC(O)R ２１ 、 -C(O)CH ２ C(O) ２ R ２１ 、 -C(O)CH ２ OR ２１ 、 -C(O)CH ２ R ２２ 、 -C(O)C(O)NHR ２１ 、 -C(O)R ２１ 、 -CHR ２１ OC(O)R ２１ 、 -CHR ２１ C(O) ２ R ２１ 、 -CHR ２１ (OR ２１ )又はCH(OR ２１ ) ２ and is R ２１ is hydrogen, optionally substituted -C １ -C ６ alkyl, optionally substituted -C ３ -C ８ cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl, R ２２ is halogen or NR １３ R １４ And, R １３ and R １４ This is as defined in claim 1, The compound according to claim 1.

5. A compound according to claim 1, represented by one of formulas (IV-1) to (IV-4), or a pharmaceutically acceptable salt thereof: 【Transformation 3】 In the formula, R １７ is halogen, -OR １６ ,-SR １６ , -NR １３ R １４ , -OC(O)NR １３ R １４ , arbitrarily substituted -C １ -C ６ Alkyl, optionally substituted -C ３ -C ８ A cycloalkyl group, an optionally substituted 3- to 8-membered heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. m1 is 0, 1, 2, or 3. m2 is 0, 1, 2, 3, or 4. A, R １１ , R １１ ' and X are as defined in claim 1.

6. A compound according to claim 1, represented by one of formulas (V-1), (V-2), (V-3), or (V-4), or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 In the formula, each T is CR １１ And, Each U is -C(R １１ R １２ ) - and Each V is -O-, -S-, -C(R １１ R １２ )-, or N(R １３ R １４ ) - and m is 0, 1, or 2. m' is 0, 1, 2, or 3. A, Q, n2, R １１ , R １２ , R １３ , R １４ And X is as defined in claim 1.

7. A compound according to claim 1, represented by one of formulas (VI-1a) to (VI-8a), or a pharmaceutically acceptable salt thereof: 【Transformation 5】 In the formula, X and A are as defined in claim 1.

8. A compound according to claim 1, represented by one of formulas (IX-1) to (IX-8), or a pharmaceutically acceptable salt thereof: 【Transformation 6】 During the ceremony, R ３２ These are hydrogen, -F, Cl, and -CH ３ , -CF ３ OR, R ３３ -Cl, -Br, -OR ２１ , - NHR ２１ or OC(O)R ２１ And, R ３４ is R ２１ And, R ２１ is hydrogen, optionally substituted with -C １ -C ６ Alkyl, optionally substituted -C ３ -C ８ A cycloalkyl group, an optionally substituted 3- to 8-membered heterocycloalkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. A is as defined in claim 1.

9. A compound according to claim 1, represented by one of formulas (IX-1) to (IX-8), or a pharmaceutically acceptable salt thereof: 【Transformation 7】 In the formula, R ２４ -C is hydrogen, halogen, or optionally substituted. １ -C ６ Alkyl, optionally substituted -C １ -C ６ Alkoxy, arbitrarily substituted -C ３ -C １２ Cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl. R ２５ is hydrogen or halogen, X, R １３ and R １４ This is as defined in claim 1.

10. A compound according to claim 1, represented by one of formulas (XIII-1) to (XIII-4), or a pharmaceutically acceptable salt thereof: 【Transformation 8】 In the formula, R ２４ -C is hydrogen, halogen, or optionally substituted. １ -C ６ Alkyl, optionally substituted -C １ -C ６ Alkoxy, arbitrarily substituted -C ３ -C １２ Cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl. R １５ And X is as defined in claim 1.

11. A compound according to claim 1, selected from the compounds listed below, or a pharmaceutically acceptable salt thereof: Table 1-1 Table 1-2 Table 1-3

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.

13. A method for treating or preventing a viral infection, including viral infections from RNA-based viruses, coronaviruses, rhinoviruses, and noroviruses, in a subject susceptible to or suffering from such a viral infection, wherein the method comprises the step of administering a 3C protease enzyme inhibitor to the subject, wherein the inhibitor is a compound or pharmaceutically acceptable salt according to any one of claims 1 to 11.

14. A method for treating or preventing coronavirus infection in a subject requiring treatment or prevention of coronavirus infection, comprising the step of administering a therapeutically effective amount of a compound or combination of compounds according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, to a subject.

15. The method according to claim 13, wherein the virus is a coronavirus selected from 229E, NL63, OC43, HKU1, SARS-CoV, or MERS coronavirus.

16. A method for treating or preventing a viral infection in a subject susceptible to or suffering from a viral infection, comprising the step of administering a 3C protease enzyme inhibitor to the subject, wherein the inhibitor comprises a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

17. A method for inhibiting viral 3C protease or viral 3CL protease in a mammal, comprising the step of administering an effective amount of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof to the target.

18. The method according to claim 17, wherein the subject is a human.

19. Methods for treating respiratory disorders, However, the aforementioned respiratory disorders include acute asthma, lung diseases secondary to environmental exposure, acute lung infections, and chronic lung infections, and include administering the compound described in any of claims 1 to 11 to the target population as needed.

20. The method according to claim 19, wherein the compound or pharmaceutical composition is administered orally, subcutaneously, intravenously, or by inhalation.

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