PLpro inhibitors

Abstract

The present disclosure provides novel compounds (e.g., Formula X, or Formula Y), pharmaceutical compositions, and methods of use thereof. The compounds of the present disclosure can generally inhibit the activity of PLpro. The compounds of the present disclosure can also be used to treat a number of diseases or conditions, such as viral infections caused by coronaviruses, such as SARS-CoV-2.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This invention claims the benefit of U.S. Provisional Application No. 63 / 290,337, filed December 16, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates generally to PLpro inhibitors and compositions, methods of preparation, and methods of use, such as for example, for the treatment of viral infections. [Background technology]

[0003] In the past two decades, there have been two coronavirus outbreaks: SARS-CoV (2002) and MERS (2012). The most recent coronavirus outbreak is called the 2019-nCoV outbreak, which was recently renamed SARS-CoV-2. Human coronaviruses (HCoVs) belong to two genera: alphacoronaviruses and betacoronaviruses. The alphacoronaviruses that infect humans are HCoV-229E, and HCoV-NL63, while the betacoronaviruses that infect humans are HCoV-HKU1, HCoV-OC43, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), and SARS-CoV-2.

[0004] Coronaviruses encode two large polyproteins that are further processed by virally encoded cysteine ​​proteases, namely, papain-like protease (PLpro) and 3-chymotrypsin-like protease (3CLpro, also called main protease-Mpro). Processing of viral polyproteins is important for viral maturation and infectivity. SARS-CoV-2 PLpro is responsible for processing the three cleavage sites of the viral polyprotein to release the mature nonstructural proteins 1, 2, and 3. In addition to hydrolytic processing of proteins, PLpro also has deubiquitinating and deISGylating activities [1-4]. These two proteases play important roles in the viral life cycle and therefore are important targets for antiviral drug design.

[0005] PLpro is important for viral protein production and infectivity, as shown by studies with SARS CoV protease. Small molecule inhibitors of SARS CoV PLpro protease have been shown to have antiviral activity against SARS CoV and SARS CoV-2 [5-7]. PLpro is required for viral polyprotein maturation and cleaves ubiquitin from various substrates involved in maintaining host cell immunity, for example, by the production of interferon [8]. The net effect of these various functions contributes to SARS-CoV's inhibition of the establishment of an antiviral state in the host [2-4]. PLpro inhibits the host immune response by blocking interferon (IFN) signaling, a major antiviral response pathway [9].

[0006] Previous attempts at designed SARS-CoV PL inhibitors have yielded some promising results in the class of naphthalene inhibitors, although no PL inhibitors have been approved as antivirals.[10,11] As the 2003 SARS-CoV outbreak was effectively contained and no recurrences have emerged, these potential anti-CoV therapeutics were gradually abandoned.

[0007] Coronavirus infections, such as the COVID-19 pandemic, have medical, social and economic [12,13] Therefore, there is an urgent need to develop effective therapies to treat such infections. Summary of the Invention

[0008] The present invention is based in part on the discovery of novel small molecule PLpro inhibitors. In various embodiments, the present invention generally relates to compounds and compositions for use in the treatment of viral infections, such as SARS-CoV-2 infections. Without wishing to be bound by theory, it is believed that the compounds and compositions of the present invention can inhibit viral PLpro activity, thereby inhibiting viral replication. In some embodiments, the compounds of the present invention can be characterized as irreversible inhibitors, which can provide advantages over reversible inhibitors, including a long duration of action after a short exposure to the target. Thus, if the irreversible inhibitor has a short t1 / 2, the potential for off-target toxicity is also minimized.

[0009] In some embodiments, the present invention provides a compound according to formula X or Y, or a pharma- ceutically acceptable salt thereof.

[0010] [ka] where A, L, W, and X are the variables. 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , Rg, and R 10are defined herein for the corresponding formula. In some embodiments, the compound is characterized by having a sub-formula according to formula Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7, as defined herein. In some embodiments, the invention also provides compounds of formula I, II, III, IV, V, as defined herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the invention provides a compound selected from the compounds set forth in Table A herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the invention provides a compound selected from compounds 1-177, or a pharma- ceutically acceptable salt thereof.

[0011] In embodiments, the invention provides pharmaceutical compositions comprising a compound of the invention (e.g., a compound of Formula X, Formula Y (e.g., Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Formula I, II, III, IV, or V, any compound described in Table A herein, or any compound among Compounds 1-177, or a pharma- ceutically acceptable salt thereof), and any pharma- ceutically acceptable carrier, excipient, or diluent, and any additional bioactive agent. In some embodiments, the additional bioactive agent is an antiviral agent. In some embodiments, the pharmaceutical composition is in a form selected from a tablet, a powder, a microparticle, a nanoparticle, a granule, a capsule, a liquid, an aqueous solution, a suspension, or a dispersion.

[0012] In embodiments, the present invention provides a method for treating a coronavirus infection and symptoms associated therewith to a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention (e.g., a compound of Formula X, Formula Y (e.g., Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Formula I, II, III, IV, or V, any compound described in Table A herein, or any compound among Compounds 1-177, or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound of the present invention. In some embodiments, the coronavirus infection is caused by a virus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2. In some embodiments, the coronavirus infection is caused by SARS-CoV-2. In some embodiments, the compound of the present invention is administered in an amount that effectively modulates the amount or activity of a viral protein encoded by a coronavirus in a subject, wherein the viral protein is responsible for viral replication. In some embodiments, the viral protein comprises a papain-like protease (PLpro) encoded by a coronavirus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2. In some embodiments, the viral protein comprises a PLpro encoded by SARS-CoV-2.

[0013] In some embodiments, the present invention provides a method for inhibiting papain-like protease (PLpro), comprising administering to a subject in need thereof an effective amount of a compound of the present invention (e.g., a compound of formula X, formula Y (e.g., Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), a compound of formula I, II, III, IV, or V, any compound described in Table A herein, or any compound of compounds 1-177, or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound of the present invention. In some embodiments, the subject suffers from a viral infection caused by a virus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2. In some preferred embodiments, the subject suffers from a SARS-CoV-2 infection. In some embodiments, the papain-like protease (PLpro) is encoded by a virus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2, e.g., SARS-CoV-2.

[0014] The administration in the method of the present specification is not limited to a specific administration route.For example, in some embodiments, administration can be oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral.In some embodiments, administration can be injection, infusion, oral, or inhalation.

[0015] The compounds of the invention can be used as monotherapy or in combination therapy, for example, the compounds of the invention can be used in combination therapy with one or more other antiviral agents (such as those described herein).

[0016] It is to be understood that the foregoing summary of the invention and the following detailed description are exemplary and explanatory only and are not restrictive of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Coronavirus (CoV) genomes encode polyproteins consisting of structural proteins, replicase proteins, and proteases. Compared to SARS-CoV and MERS-CoV, SARS-CoV-2 has a lower genetic similarity, with 79% genetic similarity to SARS-CoV and 50% genetic similarity to MERS-CoV. However, the coding region of SARS-CoV-2 has a similar genomic organization to bat coronaviruses and SARS-CoV. The only major difference is that the S protein of SARS-CoV-2 is longer than the S proteins encoded by bat coronaviruses, SARS-CoV, and MERS-CoV. Although phylogenetic analysis has classified SARS-CoV-2 and SARS-CoV into different clades, both of these two viruses have about 50 conserved amino acids in the S1 domain of the S protein. The receptor-binding domain (S1) of SARS-CoV-2 is highly similar to the S1 domain of SARS-CoV. SARS-CoV-2 is more similar to SARS-CoV than to MERS-CoV in terms of structure and pathogenicity: both CoVs bind to host cells with the same spike (S) protein, and both CoVs utilize similar cellular proteases to activate the S protein

[15] .

[0018] Recently, the crystal structure of SARS-CoV PLpro in complex with ubiquitin (Ub) was determined. The PLpro-Ub complex crystal structure could provide a snapshot of the transition of PLpro from the "FQ" to the "E+Q" state, reaffirming the high plasticity of the BL2 loop and its interactions with substrates, intermediates, products, and inhibitors.

[0019] PLpro dissociates ubiquitin and the ubiquitin-like protein ISG15 from host cell proteins, allowing coronaviruses to evade the host's innate immune response. Host defense mechanisms are characterized by the production of inflammatory cytokines, including type I b-interferon (IFN-b) and chemokines such as CCL5 and CXCL10

[16] . A recent review

[17] lists the known effects of SARS-CoV on host cell defense mechanisms, as reported in various cellular studies, specifically, the inhibition of the expression of inflammatory cytokines (e.g., IFN-b) and the establishment of an antiviral state. SARS-CoV PLpro interferes with the activation of the transcription factors IRF3

[18] and NF-kB

[17] . Specifically, SARS-CoV inhibits the phosphorylation, homodimerization, and subsequent nuclear translocation of IRF3, thereby inhibiting cytokine expression. The protease stabilizes NF-κB and IκBa, preventing activation of the NF-κB signaling pathway.

[20] Finally, SARS-CoV PLpro reduces endogenous levels of inflammatory cytokines and chemokines in activated cells.

[16] Similar effects have been observed with SARS-CoV-2 PLpro.[2-4]

[0020] Therefore, antiviral drugs targeting PLpro may exert a dual mechanism of action, not only inhibiting viral replication but also inhibiting virus-induced cell signaling events that impair host defense [2, 17].

[0021] In a broad aspect, the present invention provides compounds and compositions for inhibiting the activity of PLpro, such as those useful for selectively covalently inhibiting the PLpro enzyme, which can overcome problems associated with existing non-covalent enzyme inhibitors. In some embodiments, the present invention also provides methods of using the compounds and compositions herein to treat viral infections, such as SARS-CoV-2 infections. In some embodiments, the compounds and compositions herein may be irreversible inhibitors that inhibit PLpro enzyme activity. Compared to the reversible inhibition of non-covalent inhibitors, irreversible inhibition can improve therapeutic efficacy.

[0022] As used herein, an "irreversible inhibitor" is an inhibitor that can covalently bind to a target protein and inhibit the activity of the target protein for a period longer than the functional life of the target protein. An irreversible inhibitor is usually characterized by a time dependency. When inhibited by an irreversible inhibitor, the recovery of the activity of the target protein depends on the synthesis of new protein. Suitable methods for determining whether a compound is an irreversible inhibitor by kinetic analysis are well known in the art. As used herein, a "reversible inhibitor" is a compound that reversibly binds to a target protein and inhibits the activity of the target protein. When inhibited by a reversible inhibitor, the recovery of the activity of the target protein can be achieved by dissociating the reversible inhibitor from the target protein.

[0023] formula As described herein, in some embodiments, the compounds of the present invention are typically designed so that the PLpro inhibitor can be covalently linked to a "warhead" that can form a covalent bond with PLpro via a suitable linker. PLpro inhibitors, linkers, and warheads suitable for this design are not particularly limited and are exemplified herein.

[0024] In some embodiments, the present invention provides a compound of formula X:

[0025] [ka] Where: A represents a residue of a papain-like protease (PLpro) inhibitor; W represents a group capable of forming a covalent bond with PLpro, preferably a group capable of forming a covalent bond with the SH group of a cysteine ​​residue in PLpro; L represents a linker that covalently bonds A and W.

[0026] In some embodiments, A may be characterized as having a structure according to formula A-1: [ka] Where: X 1 , non-existent, CR 11 R 12 , N.R. 13 , C(O), or -C(O)N(R 13 )-and X 2 is absent, optionally substituted C 1-4 Alkylene group, or optionally substituted C 1-4 is a heteroalkylene group, Rg is an optionally substituted ring structure having 4 to 10 ring atoms, preferably an optionally substituted 4-10 membered heterocycle; Where: R 10 is an optionally substituted aryl group or an optionally substituted heteroaryl group; R 11 and R 12 are each independently hydrogen, halogen, OH, or NH 2 , COOH, CONH 2 , S.O. 2 NH 2 , G A , O.G. A , NH(G A ), N(G A )(G A), COOG A , CONH(G A ), CON(G A )(G A ), SO 2 NH(G A ), SO 2 N(G A )(G A ), NHCOG A , N(G A )COG A , N.H.S.O. 2 (G A ), N(G A )SO 2 (G A ), COG A , or SO 2 (G A ) or R 11 and R 12 are bonded to form a 3- to 8-membered ring structure, R 13 is hydrogen, G A , COOG A ,CONH 2 , CONH(G A ), CON(G A )(G A ), SO 2 NH 2 , S.O. 2 NH(G A ), SO 2 N(G A )(G A ), COG A , or SO 2 (G A ) and Here, G A each independently represents an optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl Groups, Optionally Substituted C 2-6 Alkynyl Group, Optionally Substituted C 1-6A heteroalkyl group or an optionally substituted ring structure having 4 to 10 ring atoms. As used herein, unless otherwise specified or contrary to the context, "ring structure" includes carbocyclic and heterocyclic rings, which may be saturated, partially unsaturated, or aromatic, and the ring structure may contain a single ring or two or more rings. For example, as used herein, "an optionally substituted ring structure having 4 to 10 ring atoms" includes C 4-10 These include carbocyclic rings and 4-10 membered heterocyclic rings, which may be aromatic or non-aromatic and may be optionally substituted with one or more suitable substituents as described herein. Divalent ring structures herein should be understood to be linked to the remainder of the molecule via a ring atom, which may be a heteroatom such as carbon or nitrogen. For example, ring Rg may be linked to X via one or two, usually two, ring atoms of Rg (e.g., ring nitrogen atoms or ring carbon atoms, etc.). 1 and X 2 It should be understood that the compound is bound to

[0027] Typically, in formula A-1, Rg is an optionally substituted 4-10 membered heterocycle. More preferably, Rg is an optionally substituted 4-7 membered monocyclic heterocycle having one or two ring heteroatoms, such as, for example, a saturated 4-7 membered monocyclic heterocycle such as a piperidine, piperazine, or pyrrolidine ring, where the ring heteroatoms are independently O, S, or N. In a preferred embodiment, Rg is a non-aromatic ring. In some embodiments, Rg may be an unsubstituted 4-10 membered heterocycle. When substituted, Rg may be substituted with one or more, typically, for example, 1-3, substituents, where the substituents are independently F, Cl, -OH, a protected hydroxyl group, oxo (where applicable), NH 2 , protected amino group, NH(C 1-4 alkyl group) or its protected derivative, N(C 1-4 Alkyl group)(C 1-4 Alkyl group), C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 and cycloalkoxy groups, phenyl groups, 5- or 6-membered heteroaryl groups containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclyl groups containing 1 or 2 ring heteroatoms independently selected from O, S, and N, where the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl groups are each optionally substituted with 1, 2, or 3 substituents, said substituents being independently selected from F, -OH, oxo (where applicable), C, -CO ... 1-4 Alkyl groups, fluorine-substituted C 1-4 Alkyl groups (e.g., CF 3 ), C 1-4 Alkoxy groups and fluorine-substituted C 1-4 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0028] For example, in some embodiments, formula A-1 may be characterized as having a structure according to formula A-2: [ka] where Het is linked to X via the indicated ring nitrogen atom. 2 is bonded to X through another ring atom 1 wherein the 4-10 membered heterocycle has 0-3 ring heteroatoms in addition to the indicated ring nitrogen atom, each of the ring heteroatoms being independently O, S, or N. In preferred embodiments, Het is a non-aromatic ring, e.g., a 4-7 membered saturated monocyclic heterocycle having 0 or 1 ring heteroatom in addition to the nitrogen atom, as shown in formula A-2. In some embodiments, Het is unsubstituted. In some embodiments, Het may be substituted with one or more, e.g., 1-3, substituents. Suitable substituents are described herein, such as those described in connection with Rg.

[0029] In some specific embodiments, formula A-1 may be characterized as having a structure according to formula A-3: [ka] X in formula A-1 (including subformula A-2 or A-3) 2 is usually an arbitrarily substituted C 1-4 For example, in some embodiments, X 2 is a straight or branched chain, unsubstituted C 1-4 Alkylene groups (e.g., CH 2 , CH(CH 3 ), CH(C 2 H 5 ) etc.) If replaced, C 1-4 An alkylene group may be substituted, typically with one or more, e.g., 1 to 3, substituents, which may be independently selected from F, Cl, -OH, a protected hydroxyl group, oxo (where applicable), NH 2 , protected amino group, NH(C 1-4 alkyl group) or its protected derivative, N(C 1-4 Alkyl group)(C 1-4 Alkyl group), C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 and cycloalkoxy groups, phenyl groups, 5- or 6-membered heteroaryl groups containing 1, 2, or 3 ring heteroatoms independently selected from O, S, and N, and 3- to 7-membered heterocyclyl groups containing 1 or 2 ring heteroatoms independently selected from O, S, and N, where the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl groups are each optionally substituted with 1, 2, or 3 substituents, said substituents being independently selected from F, -OH, oxo (where applicable), C, -CO ... 1-4Alkyl groups, fluorine-substituted C 1-4 Alkyl groups (e.g., CF 3 ), C 1-4 Alkoxy groups and fluorine-substituted C 1-4 In some embodiments, C is selected from the group consisting of alkoxy groups. 1-4 Two or more substituents of an alkylene group may, for example, be linked to form a ring structure, such as a 3- to 7-membered ring structure, for example: [ka] is regarded as a methylene group, and the two geminal substituents are linked to form a three-membered ring structure.

[0030] In some embodiments, X in formula A-1 (including subformula A-2 or A-3) 2 may be non-existent. In other words, R 10 binds directly to Rg.

[0031] In some more specific embodiments, X in formula A-1 (including subformula A-2 or A-3) 2 CR 14 R 15 where R 14 and R 15 each independently represents hydrogen, optionally substituted C 1-4 Alkyl groups, optionally substituted C 2-4 Alkenyl Groups, Optionally Substituted C 2-4 In some more specific embodiments, X in formula A-1 (including subformula A-2 or A-3) is an alkynyl group or an optionally substituted ring structure having 4 to 10 ring atoms. 2 CR 14 R 15 where R 14 and R 15 is COOH or an ester or amide thereof, and R 14 and R 15The other of is defined as above. In some embodiments, X in formula A-1 (including subformula A-2 or A-3) 2 CR 14 R 15 where R 14 and R 15 together with the carbons to which they are both attached form an optionally substituted 3- to 6-membered ring. For example, in some embodiments, R 14 and R 15 is hydrogen, and R 14 and R 15 The other of the two is hydrogen, optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group, optionally 1 to 3 G S1 C replaced with 3-6 Cycloalkyl group or optionally 1 to 3 G S1 is a phenyl group substituted with S1 are each independently a halogen (preferably F), NH 2 , O.H., C. 1-4 Alkyl group, or C 1-4 In some embodiments, R 14 and R 15 is hydrogen, and R 14 and R 15 The other of R is hydrogen, a methyl group, or a phenyl group. 14 and R 15 is hydrogen, and R 14 and R 15 The other of R is hydrogen, a methyl group, an ethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, an aminomethyl group, or a 2-aminoethyl group. 14 and R 15 is hydrogen, and R 14 and R 15 The other one is CH 2 F, C.H. 2 OH, CHF 2 , CD 3 , C.F. 3, ethyl group, CN, cyclopropyl group, COOH, or COOCH 3 In some embodiments, R 14 and R 15 together with the carbons to which they are both attached form a cyclopropyl group.

[0032] R in formula A-1 (including subformula A-2 or A-3) 10 is typically an optionally substituted aryl group. For example, in some embodiments, R in formula A-1 (including subformula A-2 or A-3) 10 may be an optionally substituted phenyl group or an optionally substituted naphthyl group. In some embodiments, the phenyl or naphthyl group is unsubstituted. When substituted, the phenyl or naphthyl group may typically be substituted with one or more substituents (e.g., 1 to 3 substituents), the substituents being, independently, F, Cl, Br, -OH, -CN, NH 2 , protected amino group, NH(C 1-4 alkyl group) or its protected derivative, N(C 1-4 Alkyl group)(C 1-4 alkyl group), -S(=O)(C 1-4 Alkyl group), -SO 2 (C 1-4 Alkyl group), C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 3-6 Cycloalkyl groups, C 3-6 A cycloalkoxy group, a phenyl group, a 5- or 6-membered heteroaryl group containing 1, 2 or 3 ring heteroatoms independently selected from O, S, and N, and a 3- to 7-membered heterocyclyl group containing 1 or 2 ring heteroatoms independently selected from O, S, and N. In this case, the alkyl group, alkenyl group, The alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl groups are each optionally substituted with 1, 2, or 3 substituents, the substituents being independently selected from F, -OH, oxo (where applicable), C 1-4 Alkyl groups, fluorine-substituted C 1-4 Alkyl group, C 1-4 Alkoxy groups and fluorine-substituted C 1-4 The alkoxy group is selected from the group consisting of aryl, ... and aryl groups.

[0033] In a more specific embodiment, R in formula A-1 (including subformula A-2 or A-3) 10 For example, 1 to 3 G S1 Optionally substituted, such as [ka] where G S1 are each independently a halogen (preferably F or Cl), OH, C 1-4 Alkyl group, or C 1-4 In a more specific embodiment, R in formula A-1 (including subformula A-2 or A-3) is an alkoxy group (e.g., a methoxy group). 10 For example, 1 to 3 G S1A Optionally substituted, such as [ka] where G S1A are each independently selected from halogen (preferably F or Cl), OH, and C optionally substituted with 1 to 3 F. 1-4 Alkyl groups (e.g., methyl, CF 3 ), C optionally substituted with 1 to 3 F 1-4 In a more specific embodiment, R in formula A-1 (including subformula A-2 or A-3) is an alkoxy group (e.g., a methoxy group), or an optionally substituted 3- to 7-membered ring. 10 For example, 1 to 3 GS1A Optionally substituted, such as [ka] where G S1A are each independently selected from halogen (preferably F or Cl), OH, and C optionally substituted with 1 to 3 F. 1-4 Alkyl groups (e.g., methyl, CF 3 ), C optionally substituted with 1 to 3 F 1-4 It is an alkoxy group (eg, a methoxy group), or an optionally substituted 3- to 7-membered ring.

[0034] In a more specific embodiment, R in formula A-1 (including subformula A-2 or A-3) 10 For example, 1 to 3 G S1B optionally substituted phenyl groups, such as those substituted with [ka] where G S1B are each independently selected from halogen (e.g., F, Cl, or Br), OH, C optionally substituted with 1 to 3 F 1-4 Alkyl groups (e.g., methyl, CF 3 ), C optionally substituted with 1 to 3 F 1-4 It is an alkoxy group (eg, a methoxy group), or an optionally substituted 3- to 7-membered ring (eg, a phenyl group, a thienyl group, etc.).

[0035] In some preferred embodiments, X in formula A-1 (including subformula A-2 or A-3) 2 -R 10 teeth, [ka] In some embodiments, X in formula A-1 (including subformula A-2 or A-3) may be 2 -R 10 teeth, [ka] In some embodiments, X in formula A-1 (including subformula A-2 or A-3) may be 2 -R 10 teeth, [ka] As used herein, when stereochemistry is specifically depicted, it should be understood that, unless the context indicates otherwise, for a particular chiral center or axial chirality, the compound exists predominantly as the depicted stereoisomer, e.g., the compound has less than 20%, less than 10%, less than 5%, less than 1% of the stereoisomer by weight, HPLC area, or both, or has undetectable amounts of other stereoisomers, e.g., the compound can have an enantiomeric excess (ee) of at least 60%, preferably at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, etc. In accordance with the present invention, the presence and / or amount of stereoisomers can be readily determined by one of skill in the art by using chiral HPLC or any other suitable method.

[0036] In some embodiments, R in formula A-1 (including subformula A-2 or A-3) 10 may be, for example, an optionally substituted heteroaryl group, such as a quinolyl group, an isoquinolyl group, or a quinazolinyl group. In some embodiments, R in formula A-1 (including subformula A-2 or A-3) 10 may be a heteroaryl ring, e.g., a bicyclic heteroaryl group having 9 or 10 ring atoms and 1 to 3 ring heteroatoms, such as quinoline, isoquinoline, benzo[d]thiazole, etc., with each ring heteroatom being independently selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 29, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 Each of the radicals is independently N, O, or S. For example, in some embodiments, R in formula A-1 (including subformula A-2 or A-3) is10 For example, 1 to 3 G S1A Optionally substituted, such as [ka] where G S1A are each independently selected from halogen (preferably F or Cl), OH, and C optionally substituted with 1 to 3 F. 1-4 Alkyl groups (e.g., methyl, CF 3 ), C optionally substituted with 1 to 3 F 1-4 It is an alkoxy group (eg, a methoxy group), or an optionally substituted 3- to 7-membered ring.

[0037] In some embodiments, X in formula A-1 (including subformula A-2 or A-3) 1 is NR 13 where R 13 is defined as herein. In some preferred embodiments, R 13 is hydrogen, optionally substituted C 1-6 Alkyl group, COG A , or SO 2 G A where G A may include any group described herein. In some embodiments, R 13 is an arbitrarily substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, or optionally substituted C 2-6 Alkynyl groups, such as COG as defined herein. A1 , COG A2 , COG A3 , S.O. 2 G A1 , S.O. 2 G A4 , or SO 2 G A5 COG A or SO 2 G A For example, R 13 teeth, [ka] may be also possible.

[0038] For example, in some embodiments, X in formula A-1 (including subformula A-2 or A-3) 1 is NR 13 where R 13 COG A1 where G A1 is an arbitrarily substituted C 1-6 Alkyl groups, optionally substituted C 3-6 In some embodiments, R is an optionally substituted cyclic ring structure having 4 to 10 ring atoms and 1 to 3 ring heteroatoms. 13 COG A2 where G A2 is optionally 1 to 3 G S2 C replaced with 1-6 is an alkyl group, Here, G S2 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkoxy group, optionally 1 to 5 G S3 C replaced with 3-6 Cycloalkyl group, optionally 1 to 5 G S3 or a phenyl group substituted with 1 to 3 ring heteroatoms, optionally 1 to 5 G S3 wherein the ring heteroatoms are independently O, S, or N; Where: G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 is an alkoxy group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 is bonded to an optionally substituted 3- In some embodiments, R 13 COG A2 where G A2 is optionally 1 to 3 G S2A C replaced with 1-6 is an alkyl group, where G S2A are each independently a halogen (preferably F), OH, COOH, CONH 2 , G S2B , CONHG. S2B , CONG S2B G S2B , S.O. 2 NH 2 , S.O. 2 NHG S2B , S.O. 2 NG S2B G S2B , COG S2B , CO 2 G S2B , or SO 2 G S2B where G S2B each independently represents 1 to 3 G S1 C replaced with 1-4 Alkyl group, optionally 1 to 3 G S1 C replaced with 1-4 Alkoxy group, optionally 1 to 5 G S3 C replaced with 3-6 Cycloalkyl group, optionally 1 to 5 G S3 or a phenyl group substituted with 1 to 3 ring heteroatoms, optionally 1 to 5 G S3 wherein the ring heteroatoms are independently O, S, or N, and wherein G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 is an alkoxy group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure. In some embodiments, R 13 COG A3 where G A3 is any combination of 1 to 5 G S3 C replaced with 3-6 is a cycloalkyl group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure, G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 In any embodiment described herein, unless otherwise indicated or contrary to context, R 13 teeth, [ka] is selected from.

[0039] In some embodiments, X in formula A-1 (including subformula A-2 or A-3) 1 is NR 13 where R 13 SO 2 G A1 where G A1 is an arbitrarily substituted C1-6 Alkyl groups, optionally substituted C 3-6 In some embodiments, R is an optionally substituted cyclic ring structure having 4 to 10 ring atoms and 1 to 3 ring heteroatoms. 13 SO 2 G A4 and G A4 is optionally 1 to 3 G S2 C replaced with 1-6 is an alkyl group, where G S2 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkoxy group, optionally 1 to 5 G S3 C replaced with 3-6 Cycloalkyl group, optionally 1 to 5 G S3 or a phenyl group substituted with 1 to 3 ring heteroatoms, optionally 1 to 5 G S3 wherein the ring heteroatoms are independently O, S, or N, and G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 is an alkoxy group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure. In some embodiments, R 13 SO 2 G A4 G A4 is optionally 1 to 3 G S2A C replaced with 1-6 is an alkyl group, where G S2Aare each independently a halogen (preferably F), OH, COOH, CONH 2 , G S2B , CONHG. S2B , CONG S2B G S2B , S.O. 2 NH 2 , S.O. 2 NHG S2B , S.O. 2 NG S2B G S2B , COG S2B , CO 2 G S2B , or SO 2 G S2B where G S2B each independently represents 1 to 3 G S1 C replaced with 1-4 Alkyl group, optionally 1 to 3 G S1 C replaced with 1-4 Alkoxy group, optionally 1 to 5 G S3 C replaced with 3-6 Cycloalkyl group, optionally 1 to 5 G S3 or a phenyl group substituted with 1 to 3 ring heteroatoms, optionally 1 to 5 G S3 wherein the ring heteroatoms are independently O, S, or N, and G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 is an alkoxy group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure. In some embodiments, R 13 SO 2 G A5 where GA5 is any combination of 1 to 5 G S3 C replaced with 3-6 a cycloalkyl group or a phenyl group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 an alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure, G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 In some embodiments, R 13 SO 2 G A5 where G A5 is a 4-7 membered heterocycle having 1 or 2 ring heteroatoms, such as, for example, pyrrolidine, piperidine or piperazine, which ring heteroatoms are independently N, O, or S. wherein the 4-7 membered heterocycle is optionally substituted with 1 to 3 substituents, which are independently selected from the group consisting of G S3A , (C 1-4 Alkylene group)-G S3A , O.G. S3A , N.H.G. S3A , N.G. S3A G S3A , or (C 1-4 Heteroalkylene group)-G S3A Selected from G S3A are each independently a halogen (preferably F), OH, COOH, CONH 2 , G S2B , CONHG. S2B , CONG S2B G S2B , S.O. 2 NH 2 , S.O. 2 NHG S2B , S.O. 2 NG S2B GS2B , COG S2B , CO 2 G S2B , or SO 2 G S2B where G S2B each independently represents 1 to 3 G S1 C replaced with 1-4 Alkyl group, optionally 1 to 3 G S1 C replaced with 1-4 Alkoxy group, optionally 1 to 5 G S3 C replaced with 3-6 Cycloalkyl group, optionally 1 to 5 G S3 or a phenyl group substituted with 1 to 3 ring heteroatoms, optionally 1 to 5 G S3 wherein the ring heteroatoms are independently O, S, or N, and G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 is an alkoxy group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure. In some embodiments, the formula A-1 (subformula X in (including A-2 or A-3) 1 is NR 13 where R 13 COOG A ,CONH 2 , CONH(G A ), CON(G A )(G A ), SO 2 NH 2 , S.O. 2 NH(G A ), or SO 2 N(GA )(G A ), where G A is defined herein. In any embodiment described herein, unless otherwise indicated or contrary to the context, R 13 teeth, [ka] is selected from.

[0040] In any embodiment described herein, unless otherwise indicated or contrary to the context, R 13 teeth, [ka] is selected from.

[0041] In some embodiments, X in formula A-1 (including subformula A-2 or A-3) 1 CR 11 R 12 where R 11 and R 12 is defined as herein. For example, in some embodiments, R 11 and R 12 is hydrogen, and R 11 and R 12 The other is hydrogen, NH 2 , NH(G A ), N(G A )(G A ), NHCO(G A ), or N(G A )CO(G A ), where G A is defined herein. In some embodiments, R 11 and R 12 is hydrogen, and R 11 and R 12 The other is hydrogen, NH 2 , NH(G A6), or N(G A6 )(G A6 ), where G A6 each independently represents 1 to 3 G S2 C replaced with 1-6 is an alkyl group, Here, G S2 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkoxy group, optionally 1 to 5 G S3 C replaced with 3-6 Cycloalkyl group, optionally 1 to 5 G S3 or a phenyl group substituted with 1 to 3 ring heteroatoms, optionally 1 to 5 G S3 wherein the ring heteroatoms are independently O, S, or N; Where: G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 is an alkoxy group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure.

[0042] In some embodiments, L in formula X may be characterized as having a structure shown in formula L-1, where A and W as shown indicate the bond direction: [ka] Where: Y 1 and Y 9 each independently represents absent, an optionally substituted C1-4 Alkylene Group, Optionally Substituted C 1-4 a heteroalkylene group or an optionally substituted 3- to 8-membered ring structure;

[0043] Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 are independently absent, CR 20 R 21 , C(O), C(S), O, NR 22 , S, SO, or SO 2 where Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 up to four of may be absent, where (i) Two adjacent CRs 20 R 21 The unit may optionally form a double bond to form -C(R 20 )=C(R 21 )- or -C≡C-; (ii) Two adjacent CRs 20 R 21 and N.R. 22 The unit may optionally form a double bond to form -C(R 20 )=N-, or (iii) Two adjacent NRs 22 The units may optionally form a double bond to form -N=N-; Or, three or four consecutive Y's 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 (For example, Y 4 , Y 5 , and Y 6 , Y 5 , Y 6 , and Y7 , or Y 6 , Y 7 , and Y 8 etc.) together represent a 3- to 10-membered ring structure, and the remaining Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 is defined as above,

[0044] Where: R 20 and R 21 are each independently hydrogen, halogen, OH, or NH 2 , COOH, CONH 2 , S.O. 2 NH 2 , G A , O.G. A , NH(G A ), N(G A )(G A ), COOG A , CONH(G A ), CON(G A )(G A ), SO 2 NH(G A ), SO 2 N(G A )(G A ), NHCOG A , N(G A )COG A , N.H.S.O. 2 (G A ), N(G A )SO 2 (G A ), COG A , or SO 2 (G A ) and R 22 are each independently hydrogen, G A , COOG A ,CONH 2 , CONH(G A ), CON(G A )(G A ), SO 2 NH 2, S.O. 2 NH(G A ), SO 2 N(G A )(G A ), COG A , or SO 2 (G A ) and Here, G A each independently represents an optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl Groups, Optionally Substituted C 2-6 Alkynyl Group, Optionally Substituted C 1-6 a heteroalkyl group or an optionally substituted ring structure having 4 to 10 ring atoms; Or, two or more R 20 , R 21 , and R 22 (For example, R on the same carbon 20 and R 21 , R on two different carbons 20 and R 20 , R 20 and R 22 etc.) can be linked to form a 3- to 8-membered ring structure.

[0045] In some embodiments, Y 1 may be absent. In some embodiments, Y 1 For example, CH 2 or CD 2 Any substitution of C, such as 1-4 In some embodiments, Y is an alkylene group. 1 For example, [ka] and the like, wherein said ring heteroatoms are independently O, S, or N.

[0046] In some embodiments, Y 9 is absent, e.g., CH 2, CD 2 Or CF 2 Any substitution of C such as 1-4 In some embodiments, Y may be an alkylene group or an optionally substituted 4-8 membered heterocycle having 1 or 2 ring heteroatoms, which are independently O, S, or N. 9 For example, [ka] C etc. 3-6 In some embodiments, Y may be a 3-membered carbocyclic ring. 9 For example, oxo, F, CF 3 C, optionally substituted with 1-4 Heteroalkylene groups (e.g., -NH-CH 2 -, -CH 2 -NH-CH 2 Generally, C 1-4 A heteroalkylene group, excluding substituents, has 1 or 2 heteroatoms, e.g., 1 oxygen, 1 nitrogen, 2 oxygen, 2 nitrogen, or 1 oxygen and 1 nitrogen. In some embodiments, C 1-4 The heteroalkylene group may be substituted with oxo and includes, for example, -C(O)-NH-CH 2 - etc.

[0047] In some embodiments, Y 2 is CH 2 Or for example, CH(CH 3 ) and other CH(C 1-4 alkyl group), where C 1-4 Alkyl groups include, for example, F, OH, and NH 2 In some embodiments, Y is optionally substituted with a substituent independently selected from 2 In some embodiments, Y 2 is CH(CH 3 ), C(CH 3 )2 , CD 2 ,or [ka] It is.

[0048] In some embodiments, Y 3 is C(O). In some embodiments, Y 3 In some embodiments, Y 3 is CH(OH) or CH(C 1-4 alkyl group), where C 1-4 Alkyl groups include, for example, F, OH, and NH 2 and optionally substituted with substituents independently selected from, for example, Y 3 is CH(CF 3 ).

[0049] In some embodiments, Y 4 NH, CH 2 , or CH(C 1-4 In some embodiments, Y is an alkyl group. 4 In some embodiments, Y 4 For example, NCH 3 N(C 1-4 Each C in this section is an alkyl group. 1-4 Alkyl groups include, for example, F, OH, and NH 2 It should be understood that the substituted or unsubstituted groups may be optionally substituted with substituents independently selected from:

[0050] In some embodiments, Y 5 NH, CH 2 , CH(C 1-4 alkyl group), C(C 1-4 Alkyl group)(C 1-4 alkyl group), or [ka] In some embodiments, Y 5 In some embodiments, Y 5 is CH(CH 3 ), C(CH 3 ) 2 , CD 2 ,or [ka] It is.

[0051] In some embodiments, Y 6 is C(O), CH 2 , or CH(C 1-4 In some embodiments, Y is an alkyl group. 6 In some embodiments, Y 6 is CH(OH) or CH(C 1-4 alkyl group), where C 1-4 Alkyl groups include, for example, F, OH, and NH 2 and optionally substituted with substituents independently selected from, for example, Y 6 is CH(CF 3 ).

[0052] In some embodiments, Y 7 NH, CH 2 , or CH(C 1-4 In some embodiments, Y is an alkyl group. 7 In some embodiments, Y 7 For example, NCH 3 , CH(CH 3 ), C(CH 3 ) 2 , or CD 2 N(C 1-4 Each C in this section is an alkyl group. 1-4 Alkyl groups include, for example, F, OH, and NH 2 It should be understood that the substituted or unsubstituted groups may be optionally substituted with substituents independently selected from:

[0053] In some embodiments, Y 8 is NH. In some embodiments, Y 8 For example, O or NCH 3 N(C 1-4 alkyl group), where C 1-4 Alkyl groups include, for example, F, OH, and NH 2 In some embodiments, Y is optionally substituted with a substituent independently selected from 8 is CH 2 , or CH(C 1-4 In some embodiments, Y is an alkyl group. 8 is CO. In some embodiments, Y 8 is CH(CH 3 ), C(CH 3 ) 2 , CD 2 ,or [ka] In some embodiments, Y 8 may be non-existent.

[0054] In some embodiments, the linker of formula L-1 is characterized by one or more of the following features:

[0055] (i)Y 2 is CH 2 , or CH(C 1-4 alkyl group), (ii) Y 3 is C(O), (iii) Y 4 NH, CH 2 , or CH(C 1-4 alkyl group), (iv) Y 5 NH, CH 2 , CH(C 1-4 alkyl group), C(C 1-4 Alkyl group)(C1-4 alkyl group), or [ka] That is, (v) Y 6 is C(O), CH 2 , or CH(C 1-4 alkyl group), (vi) Y 7 is absent, C(O), NH, CH 2 , or CH(C 1-4 alkyl group), and / or (vii) Y 8 NH, CH 2 , CH(C 1-4 alkyl group) or absent.

[0056] "C(C 1-4 Alkyl group)(C 1-4 Two C's in "alkyl group" 1-4 It is to be understood that the alkyl groups are independently selected and may be the same or different, and other similar expressions are to be understood as well.

[0057] In some embodiments, the linker of formula L-1 is Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 Two of them are C(O), for example, Y 3 and Y 6 is C(O). In some embodiments, the linker of formula L-1 is 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 In some embodiments, the linker of formula L-1 is characterized in that one of Y 2 , Y 3 , Y4 , Y 5 , Y 6 , Y 7 , and Y 8 One of them is SO 2 In some embodiments, the linker of formula L-1 is Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 Up to four of the following (e.g., one, two, three, or four) are NR 22 In some embodiments, the linker of formula L-1 may be Y 3 is C(O) and Y 4 NR 22 It is characterized in that:

[0058] In some embodiments, the linker of formula L-1 is Y 4 , Y 5 , and Y 6 are bonded to form a 3- to 10-membered ring, and the 3- to 10-membered ring is, for example, [ka] or a 4-, 5-, or 6-membered heterocycle having 1 to 3 ring heteroatoms, such as for example, [ka] wherein the ring heteroatoms are independently selected from N, O, and S. Be selected.

[0059] In some embodiments, the linker of formula L-1 is Y 5 , Y 6 , and Y 7 are bonded to form a 3- to 6-membered ring, and the 3- to 6-membered ring is, for example, [ka] or a 5-membered heteroaryl ring having 1 to 3 ring heteroatoms, such as, for example, [ka] and the like, wherein the ring heteroatoms are independently selected from N, O, and S.

[0060] In some embodiments, the linker of formula L-1 is Y 6 , Y 7 , and Y 8 are bonded to form a 3- to 6-membered ring, the 3- to 6-membered ring being, for example, a 4- or 5-membered heterocycle having 1 to 3 ring heteroatoms, the ring heteroatoms being independently selected from N, O, and S.

[0061] In some embodiments, the linker of formula L-1 is Y 6 is C(O) and Y 7 NR 22 In some embodiments, the linker of formula L-1 is Y 7 is C(O) and Y 8 NR 22 In some embodiments, the linker of formula L-1 is Y 8 is absent, CH 2 , or CH(C 1-4 alkyl group).

[0062] Combinations of features of formula L-1 are not particularly limited and include the specific compounds shown in Table A and those listed in compounds 1-177 herein. For example, in some embodiments, formula A has a structure shown in formula A-1, and the linker of formula L-1 is a structure shown in formula L-2, a structure shown in formula L-2A, a structure shown in formula L-3, a structure shown in formula L-3A, a structure shown in formula L-4, a structure shown in formula L-4A, a structure shown in formula L-5, or a structure shown in formula L-6 (X shown). 1 and W indicates the orientation of the linker attached to A and W. [ka]

[0063] Here, in formula L-2A, each G 10 are independently hydrogen, deuterium, or a methyl group, or two G 10 is a cyclopropylene group together with the carbons attached to both of these, [ka] and each G 11 is hydrogen or a methyl group, However, G 10 and G 11 In all combinations of 10 and G 11 is not hydrogen or deuterium, preferably up to three G 10 and G 11 is not hydrogen or deuterium, and more preferably has one or two G 10 and G 11 Only hydrogen or deuterium is not where the other variables are defined as elsewhere in this specification.

[0064] In some embodiments, R 20 and R 21each independently represents hydrogen or an optionally substituted C 1-4 Alkyl groups (e.g., CF 3 In some embodiments, R 20 and R 21 are each independently hydrogen, deuterium, OH, or optionally substituted C 1-4 Alkyl groups (e.g., CF 3 In some embodiments, R 22 each independently represents hydrogen or an optionally substituted C 1-4 It is an alkyl group. 20 , R 21 , and R 22 Other definitions are given.

[0065] In some embodiments, a linker of formula L-1 (eg, L-2, L-3, L-4, or L-5) may be characterized as having one or more of the following applicable features.

[0066] (i)Y 1 is non-existent, (ii) Y 2 is CH 2 , or CH(C 1-4 alkyl group), (iii) Y 3 is C(O), (iv) Y 4 NH, CH 2 , or CH(C 1-4 alkyl group), (v) Y 5 NH, CH 2 , CH(C 1-4 alkyl group), C(C 1-4 Alkyl group)(C 1-4 alkyl group), or [ka] and (vi) Y 6 is C(O), CH 2 , or CH(C 1-4alkyl group), (vii) Y 7 NH, CH 2 , or CH(C 1-4 alkyl group), or Y 7 is C(O), (viii) Y 8 is NH, or Y 8 is CH 2 , or CH(C 1-4 alkyl group), or Y 8 is non-existent, and (xi) Y 9 is absent, optionally substituted C 1-4 an alkylene group or an optionally substituted 4-8 membered heterocycle having 1 or 2 ring heteroatoms which are independently O, S, or N;

[0067] In some embodiments, the linker L in formula X may have the following structure: [ka]

[0068] (The indicated A and W indicate the bond direction.) In some embodiments, the linker L in formula X may have the following structure: [ka]

[0069] (The indicated A and W indicate the bond direction.) In some embodiments, the linker L in formula X may have the following structure: [ka]

[0070] (The indicated A and W indicate the bond direction). In some embodiments, Y 1 In some embodiments, Y9 In some embodiments, Y 9 is C 1-4 Alkylene group, or C 1-4 Heteroalkylene groups, each of which may be branched or straight-chained.

[0071] In some embodiments, W in formula X is one or more of the following moieties: [ka] Alternatively, they may be characterized as having protected or masked derivatives thereof.

[0072] Where: EWG is an electron withdrawing group such as, for example, aldehyde, ester, amide, sulfone, sulfonamide, CN, etc. Lg is OH, CN or a leaving group such as, for example, F, Cl; R 30 and R 31 are each independently B or an electron-withdrawing group, R 30 And, R 31 or EWG combines to form a non-aromatic ring structure, or R 31 and EWG are linked to form a non-aromatic ring structure, R 31A and R 31B are each independently B or an electron-withdrawing group, R 30 and R 31B are linked to form a non-aromatic ring structure, or R 31A and R 31B are linked to form a non-aromatic ring structure, J 1 , O, NR 36 , C 1-4 Alkylene group, C 1-4 a heteroalkylene group, or absent, J 2 is absent, C(O), SO, or SO 2 and R 32 is G B or an electron withdrawing group, R 33 and R 34 are independently hydrogen or optionally substituted C 1-4 is an alkyl group, R 35 is G B , O.G. B , NH(G B ), N(G B )(G B ) and R 36 is hydrogen, optionally substituted C 1-4 is an alkyl group or an electron withdrawing group, Here, G B each independently represents hydrogen, optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl Groups, Optionally Substituted C 2-6 An alkynyl group or an optionally substituted ring structure having from 4 to 10 ring atoms.

[0073] For example, in some embodiments, W is [ka] or CN, Where: EWG is a COOG A ,CONH 2 , CONH(G A ), CON(G A )(G A ), SO 2 NH 2 , S.O. 2 NH(G A ), SO 2 N(G A )(G A ), COG A , or SO 2 (G A ), Here, G A each independently represents an optionally substituted C1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl Groups, Optionally Substituted C 2-6 Alkynyl Group, Optionally Substituted C 1-6 A heteroalkyl group or an optionally substituted ring structure having 4 to 10 ring atoms. For example, in some embodiments, R 30 and R 31 are both hydrogen. 32 is hydrogen or C 1-4 In some embodiments, W is an alkyl group. [ka] , C(O)R 35 ,or [ka] where G A7 is an arbitrarily substituted C 1-6 is an alkyl group, R 35 is hydrogen or C 1-4 is an alkyl group, and R 32 is hydrogen or C 1-4 In some embodiments, Y is an alkyl group. 9 -W is -(C 1-4 Alkylene group)-CN, CN, [ka] In some embodiments, Y 9 -W is the masked CH 2 In some embodiments, W is a C(O)H group. [ka] In some embodiments, W may be [ka] In some embodiments, W may be [ka] In some preferred embodiments, W may be [ka] In some embodiments, W may be [ka] In some preferred embodiments, W may be [ka] may be also possible.

[0074] Formula Y In some embodiments, the present invention provides a compound of formula Y, or a pharma- ceutically acceptable salt thereof: [ka] Where: X 1 , non-existent, CR 11 R 12 , N.R. 13 , C(O), or -C(O)N(R 13 )-and X 2 is absent, optionally substituted C 1-4 Alkylene group, or optionally substituted C 1-4 is a heteroalkylene group, Rg is an optionally substituted ring structure having 4 to 10 ring atoms, preferably an optionally substituted 4-10 membered heterocycle; Y 1 and Y 9each independently represents absent, an optionally substituted C 1-4 Alkylene Group, Optionally Substituted C 1-4 a heteroalkylene group or an optionally substituted 3- to 8-membered ring structure; Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 are independently absent, CR 20 R 21 , C(O), O, NR 22 , S, SO, or SO 2 where Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 up to four (e.g., one, two, three, or four) of (i) Two adjacent CRs 20 R 21 The unit may optionally form a double bond to form -C(R 20 )=C(R 21 )- or -C≡C-; (ii) Two adjacent CRs 20 R 21 and N.R. 22 The unit may optionally form a double bond to form -C(R 20 )=N-, or (iii) Two adjacent NRs 22 The units may optionally form a double bond to form -N=N-; Or three or four consecutive Y's 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 (For example, Y 4 , Y 5 , and Y 6 , or Y 5 , Y 6, and Y 7 etc.) together represent a 3- to 10-membered ring structure, and the remaining Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 is defined as above, W is [ka] , CN, or a protected or masked derivative thereof; R 10 is an optionally substituted aryl group or an optionally substituted heteroaryl group; Where: R 11 and R 12 are each independently hydrogen, halogen, OH, or NH 2 , COOH, CONH 2 , S.O. 2 NH 2 , G A , O.G. A , NH(G A ), N(G A )(G A ), COOG A , CONH(G A ), CON(G A )(G A ), SO 2 NH(G A ), SO 2 N(G A )(G A ), NHCOG A , N(G A )COG A , N.H.S.O. 2 (G A ), N(G A )SO 2 (G A ), COG A , or SO 2 (G A ) or R 11 and R 12 are bonded to form a 3- to 8-membered ring structure, R 13 is hydrogen, G A , COOG A ,CONH 2 , CONH(G A ), CON(G A )(G A ), SO 2 NH 2 , S.O. 2 NH(G A ), SO 2 N(G A )(G A ), COG A , or SO 2 (G A ) and R 20 and R 21 are each independently hydrogen, halogen, OH, or NH 2 , COOH, CONH 2 , G A , O.G. A , NH(G A ), N(G A )(G A ), COOG A ,CONH 2 , CONH(G A ), CON(G A )(G A ), SO 2 NH 2 , S.O. 2 NH(G A ), SO 2 N(G A )(G A ), NHCOG A , N(G A )COG A , N.H.S.O. 2 (G A ), N(G A )SO 2 (G A ), COG A , or SO 2 (G A ) and R 22 are each independently hydrogen, G A , COOG A ,CONH 2 , CONH(GA ), CON(G A )(G A ), SO 2 NH 2 , S.O. 2 NH(G A ), SO 2 N(G A )(G A ), COG A , or SO 2 (G A ), Or, two or more R 20 , R 21 , and R 22 (For example, R on the same carbon 20 and R 21 , R on two different carbons 20 and R 20 , R 20 and R 22 etc.) can be combined to form a 3- to 8-membered ring structure, EWG is an electron withdrawing group such as, for example, aldehyde, ester, amide, sulfone, sulfonamide, CN, etc. R 30 and R 31 are each independently hydrogen, G A or an electron-withdrawing group, R 30 And, R 31 or EWG combines to form a non-aromatic ring structure, or R 31 and EWG are linked to form a non-aromatic ring structure, R 31A and R 31B are each independently hydrogen, G A or an electron withdrawing group, R 30 and R 31B are linked together to form a non-aromatic ring structure, or R 31A and R 31B are linked to form a non-aromatic ring structure, J 1 , O, NR 36 , C 1-4 Alkylene group, C 1-4 a heteroalkylene group, or absent, where R 36is hydrogen, optionally substituted C 1-4 an alkyl group, or is an electron withdrawing group, J 2 is absent, C(O), SO, or SO 2 and R 32 is hydrogen, G A or an electron withdrawing group, Lg is OH, CN or a leaving group such as, for example, F, Cl; R 33 and R 34 are independently hydrogen or optionally substituted C 1-4 is an alkyl group, R 35 is G B , O.G. B , NH(G B ), N(G B )(G B ) and R 36 is hydrogen, optionally substituted C 1-4 is an alkyl group or an electron withdrawing group, Here, G B each independently represents hydrogen, optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl Groups, Optionally Substituted C 2-6 an alkynyl group or an optionally substituted ring structure having 4 to 10 ring atoms; Here, G A each independently represents an optionally substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl Groups, Optionally Substituted C 2-6 Alkynyl Group, Optionally Substituted C 1-6 A heteroalkyl group or an optionally substituted ring structure having from 4 to 10 ring atoms.

[0075] In some embodiments, the compound of formula Y may be characterized as having a structure of formula Y-1, a structure of formula Y-2, a structure of formula Y-2-E, a structure of formula Y-2-F, a structure of formula Y-3, a structure of formula Y-3A, a structure of formula Y-3B, a structure of formula Y-3C, a structure of formula Y-4, a structure of formula Y-5, a structure of formula Y-6, or a structure of formula Y-7. [ka] [ka] [ka] [ka] where Het is linked to X via the indicated ring nitrogen atom. 2 is bonded to X through another ring atom 1 represents an optionally substituted 4- to 10-membered heterocycle bonded to has 0-3 ring heteroatoms in addition to the indicated ring nitrogen atom, each of which is independently O, S, or N; Here, in the formula Y-2-E or Y-3B, each G 10 are independently hydrogen, deuterium, or a methyl group, or two G 10 is a cyclopropylene group together with the carbons attached to both of these, [ka] and each G 11 is hydrogen or a methyl group, However, G 10 and G 11 In all combinations of 10and G 11 is not hydrogen or deuterium, preferably up to three G 10 and G 11 is not hydrogen or deuterium, and more preferably has one or two G 10 and G 11 Only hydrogen or deuterium is not In the formula Y-3A, Y-3B, or Y-3C, (i) R 14 and R 15 each independently represents hydrogen, optionally substituted C 1-4 Alkyl groups, optionally substituted C 2-4 Alkenyl Groups, Optionally Substituted C 2-4 (ii) R is an alkynyl group or an optionally substituted ring structure having 4 to 10 ring atoms; 14 and R 15 is COOH or an ester or amide thereof, and R 14 and R 15 the other of which is defined as in (i), or (iii) R 14 and R 15 forms an optionally substituted 3- to 6-membered ring together with the carbons to which they are both attached, where n is 0, 1, 2, 3, or 4, preferably 0, 1, or 2, and G S1A are each independently selected from halogen (preferably F or Cl), OH, and C optionally substituted with 1 to 3 F. 1-4 Alkyl groups (e.g., methyl, CF 3 ), C optionally substituted with 1 to 3 F 1-4 An alkoxy group (e.g., a methoxy group), or an optionally substituted 3- to 7-membered ring. For clarity, each G in formula Y-3A, Y-3B, or Y-3C may be S1A It should be understood that may be attached to any available position on the naphthyl ring.

[0076] A variable in the formula Y, e.g., X 1 , X 2 , Rg, R 10 , Y 1 , Y2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 and W may have any of the definitions corresponding to those described for formula X herein, or a subformula or substructure thereof. 1 , X 2 , Rg, R 10 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 and W also include any of the definitions corresponding to those given for specific compounds in Table A herein or in the Examples, such as, for example, compounds 1-177.

[0077] In some preferred embodiments, X in formula Y (e.g., any subformula) 2 is a CR as defined herein 14 R 15 For example, in some embodiments, R 14 and R 15 is hydrogen, and R 14 and R 15 The other one is CH 2 F, C.H. 2 OH, CHF 2 , CD 3 , C.F. 3 , ethyl group, CN, cyclopropyl group, COOH, or COOCH 3 It is.

[0078] In some preferred embodiments, R in formula Y (e.g., any subformula) 10 may be an optionally substituted phenyl group or an optionally substituted naphthyl group, as defined herein. For example, in some embodiments, R 10For example, 1 to 3 G S1A Optionally substituted, such as [ka] where G S1A are each independently selected from halogen (preferably F or Cl), OH, and C optionally substituted with 1 to 3 F. 1-4 Alkyl groups (e.g., methyl, CF 3 ), C optionally substituted with 1 to 3 F 1-4 In some embodiments, R is an alkoxy group (e.g., a methoxy group), or an optionally substituted 3- to 7-membered ring. 10 For example, 1 to 3 G S1A Optionally substituted, such as [ka] where G S1A are each independently selected from halogen (preferably F or Cl), OH, and C optionally substituted with 1 to 3 F. 1-4 Alkyl groups (e.g., methyl, CF 3 ), C optionally substituted with 1 to 3 F 1-4 In another embodiment, R is an optionally substituted 3- to 7-membered ring. 10 For example, 1 to 3 G S1B optionally substituted phenyl groups, such as those substituted with [ka] where G S1B each independently represents a halogen (preferably F, Cl, or Br), OH, or C optionally substituted with 1 to 3 F 1-4 Alkyl groups (e.g., methyl, CF 3 ), C optionally substituted with 1 to 3 F 1-4an alkoxy group (e.g., a methoxy group), or an optionally substituted 3- to 7-membered ring (e.g., a phenyl group, a thienyl group, etc.), such as R 10 teeth, [ka] may be also possible.

[0079] In some preferred embodiments, X in formula Y (including subformulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7) 2 -R 10 teeth, [ka] In some embodiments, X in formula Y (including subformulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7) may be 2 -R 10 teeth, [ka] In some embodiments, X in formula Y (including subformulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7) may be 2 -R 10 teeth, [ka] may be also possible.

[0080] In some embodiments, X in formula Y (including subformulas Y-1, Y-2, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7) 1 is NR 13 where R 13 is defined as herein. For example, in some embodiments, R 13 is hydrogen, optionally substituted C 1-6 Alkyl group, COG A , or SO 2 G A where G A is defined herein. In some embodiments, R 13 is an arbitrarily substituted C 1-6 Alkyl groups, optionally substituted C 2-6 Alkenyl group, or optionally substituted C 2-6 It may be an alkynyl group, for example, as described herein: [ka] In some embodiments, R 13 COG A1 where G A1 is an arbitrarily substituted C 1-6 Alkyl groups, optionally substituted C 3-6 In some embodiments, R is an optionally substituted cyclic ring structure having 4 to 10 ring atoms and 1 to 3 ring heteroatoms. 13 COG A2 where: (i) G A2 is optionally 1 to 3 G S2 C replaced with 1-6 is an alkyl group, where G S2 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4Alkoxy group, optionally 1 to 5 G S3 C replaced with 3-6 Cycloalkyl group, optionally 1 to 5 G S3 or a phenyl group substituted with 1 to 3 ring heteroatoms, optionally 1 to 5 G S3 wherein the ring heteroatoms are independently O, S, or N; or (ii) G A2 is optionally 1 to 3 G S2A C replaced with 1-6 is an alkyl group, where G S2A are each independently a halogen (preferably F), OH, COOH, CONH 2 , G S2B , CONHG. S2B , CONG S2B G S2B , S.O. 2 NH 2 , S.O. 2 NHG S2B , S.O. 2 NG S2B G S2B , COG S2B , CO 2 G S2B , or SO 2 G S2B where G S2B each independently represents 1 to 3 G S1 C replaced with 1-4 Alkyl group, optionally 1 to 3 G S1 C replaced with 1-4 Alkoxy group, optionally 1 to 5 G S3 C replaced with 3-6 Cycloalkyl group, optionally 1 to 5 G S3 or a phenyl group substituted with 1 to 3 ring heteroatoms, optionally 1 to 5 G S3 wherein the ring heteroatoms are independently O, S, or N; Where: G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 is an alkoxy group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure. In some embodiments, R 13 COG A3 where G A3 is any combination of 1 to 5 G S3 C replaced with 3-6 is a cycloalkyl group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure, G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 In any embodiment described herein, unless otherwise indicated or contrary to context, R 13 teeth, [ka] is selected from.

[0081] In some embodiments, X in formula Y (including subformulas Y-1, Y-2, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7) 1 is NR 13 where R 13 SO 2 GA1 where G A1 is an arbitrarily substituted C 1-6 Alkyl groups, optionally substituted C 3-6 a cycloalkyl group, an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted ring structure having 4 to 10 ring atoms and 1 to 3 ring heteroatoms; In some embodiments, R 13 SO 2 G A4 and (i) G A4 is optionally 1 to 3 G S2 C replaced with 1-6 is an alkyl group, where G S2 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkoxy group, optionally 1 to 5 G S3 C replaced with 3-6 Cycloalkyl group, optionally 1 to 5 G S3 or a phenyl group substituted with 1 to 3 ring heteroatoms, optionally 1 to 5 G S3 wherein the ring heteroatoms are independently O, S, or N; or (ii) G A4 is optionally 1 to 3 G S2A C replaced with 1-6 is an alkyl group, where G S2A are each independently a halogen (preferably F), OH, COOH, CONH 2 , G S2B , CONHG. S2B , CONG S2B G S2B , S.O. 2 NH 2 , S.O. 2 NHG S2B , S.O. 2 NG S2B G S2B , COG S2B , CO 2 G S2B , or SO 2 GS2B where G S2B each independently represents 1 to 3 G S1 C replaced with 1-4 Alkyl group, optionally 1 to 3 G S1 C replaced with 1-4 Alkoxy group, optionally 1 to 5 G S3 C replaced with 3-6 Cycloalkyl group, optionally 1 to 5 G S3 or a phenyl group substituted with 1 to 3 ring heteroatoms, optionally 1 to 5 G S3 wherein the ring heteroatoms are independently O, S, or N, and G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 is an alkoxy group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure. In some embodiments, R 13 SO 2 G A5 where G A5 is any combination of 1 to 5 G S3 C replaced with 3-6 is a cycloalkyl group or a phenyl group, G S3 each independently represents halogen (preferably F), OH, or optionally 1 to 3 G S1 C replaced with 1-4 Alkyl group or optionally 1 to 3 G S1 C replaced with 1-4 An alkoxy group, or two G S3 can be linked to form an optionally substituted 3- to 6-membered ring structure, G S1 are each independently halogen (preferably F), OH, C 1-4 Alkyl group, or C 1-4 In some embodiments, R 13 SO 2 G A5 where G A5 is a 4-7 membered heterocycle having 1 or 2 ring heteroatoms, such as, for example, pyrrolidine, piperidine, or piperazine, which ring heteroatoms are independently N, O, or S. wherein the 4-7 membered heterocycle is optionally substituted with 1 to 3 substituents, which are independently selected from the group consisting of G S3A , (C 1-4 Alkylene group)-G S3A , O.G. S3A , N.H.G. S3A , N.G. S3A G S3A , or (C 1-4 Heteroalkylene group)-G S3A Selected from G S3A are each independently a halogen (preferably F), OH, COOH, CONH 2 , G S2B , CONHG. S2B , CONG S2B G S2B , S.O. 2 NH 2 , S.O. 2 NHG S2B , S.O. 2 NG S2B G S2B , COG S2B , CO 2 G S2B , or SO 2 G S2B where G S2B are each independently defined as above. In some embodiments, X in formula A-1 (including subformula A-2 or A-3) 1 is NR 13 where R 13 COOG A ,CONH 2 , CONH(G A), CON(G A )(G A ), SO 2 NH 2 , S.O. 2 NH(G A ), or SO 2 N(G A )(G A ), where G A is defined herein. In any embodiment described herein, unless otherwise indicated or contrary to context, R 13 teeth, [ka] In any embodiment described herein, unless otherwise indicated or contrary to context, R 13 teeth, [ka] is selected from.

[0082] In some embodiments, the compound of formula Y-1 may have a structure represented by formula Y-1-A, a structure represented by formula Y-1-B, a structure represented by formula Y-1-C, or a structure represented by formula Y-1-D.

[0083] [ka]

[0084] Here, the variable X 2 ,Het,R. 10 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , G A , J 1 , J 2 , R 30 , R 31A, R 31B , and R 32 includes any of the corresponding definitions set forth in formula Y herein, or in the applicable subformula, in any combination.

[0085] In some embodiments, in formula Y, and any applicable subformula, [ka] The linker of formula L-1 may have any of the definitions of formula L-1 (e.g., formula L-2, L-2A, L-3, L-3A, L-4, L-4A, L-5, or L-6) described herein for formula X. In some embodiments, Y in formula Y (including subformula Y-1 or Y-2) may have any of the definitions of formula L-1 (e.g., formula L-2, L-2A, L-3, L-3A, L-4, L-4A, L-5, or L-6) described herein for formula X. 1 ~Y 9 is the formula in Eq. [ka] The linker can be characterized by having the following structure: [ka]

[0086] Here, the variable R 20 , R 21 , R 22 , Y 3 , Y 5 , Y 6 , Y 7 , and Y 8 includes any combination of those described herein, for example, combinations described in formula Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, or Y-6.

[0087] In some embodiments, Y in formula Y (including, as applicable, sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7) 1 ~Y 9 may be characterized as having any combination of one or more (e.g., two, three, four, five, six, seven, eight, or all) of the following applicable features.

[0088] (i)Y 1 is non-existent, (ii) Y 2 is CH 2 , or CH(C 1-4 alkyl group), (iii) Y 3 is C(O), (iv) Y 4 NH, CH 2 , or CH(C 1-4 alkyl group), (v) Y 5 NH, CH 2 , CH(C 1-4 alkyl group), C(C 1-4 Alkyl group)(C 1-4 alkyl group), or [ka] and (vi) Y 6 is C(O), CH 2 , or CH(C 1-4 alkyl group), (vii) Y 7 NH, CH 2 , or CH(C 1-4 alkyl group), or Y 7 is C(O), (viii) Y 8 is NH, or Y 8 is CH 2, or CH(C 1-4 alkyl group), or Y 8 is non-existent, and (ix) Y 9 is absent, optionally substituted C 1-4 an alkylene group or an optionally substituted 4-8 membered heterocycle having 1 or 2 ring heteroatoms which are independently O, S, or N;

[0089] In some embodiments, in formula Y (including, as applicable, sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 In some embodiments, none of the formula Y (where applicable, the sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D) is absent. , Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 In some embodiments, one or two of Y 2 In some embodiments, Y 3 In some embodiments, Y 4 In some embodiments, Y 5 In some embodiments, Y 6 In some embodiments, Y 7In some embodiments, Y 8 is non-existent.

[0090] In some embodiments, in formula Y (including, as applicable, sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 In some embodiments, in formula Y (including, as applicable, sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 In some embodiments, in formula Y (including, as applicable, sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 One of them is SO 2In some embodiments, in formula Y (including, as applicable, sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , and Y 8 Up to four of them are NR 22 In some embodiments, in formula Y (including, as applicable, sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 3 is C(O) and Y 4 is NR 22 In some embodiments, in formula Y (including, as applicable, sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 4 , Y 5 , and Y 6 are joined to form a 3-6 membered ring, for example a 4- or 5-membered heterocycle having 1-3 ring heteroatoms, the ring heteroatoms being independently selected from N, O, and S. In some embodiments, in formula Y (including subformulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7, as applicable), Y 5 , Y 6 , and Y 7are joined to form a 3-6 membered ring, for example a 5 membered heteroaryl ring having 1-3 ring heteroatoms, said ring heteroatoms being independently selected from N, O, and S. In some embodiments, in formula Y (including subformulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7, as applicable), Y 6 , Y 7 , and Y 8 are joined to form a 3-6 membered ring, for example a 4- or 5-membered heterocycle having 1-3 ring heteroatoms, said ring heteroatoms being independently selected from N, O, and S. In some embodiments, the formula Y (including, where applicable, subformulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 6 is C(O) and Y 7 is NR 22 In some embodiments, in formula Y (including, as applicable, sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 7 is C(O) and Y 8 is NR 22 In some embodiments, in formula Y (including, as applicable, sub-formulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Y 8 is non-existent, CH 2 or CH(C 1-4 Y is an alkyl group. 2 ~Y8 Other definitions of include any of the corresponding definitions of formula L-1 (e.g., formulas L-2, L-2A, L-3, L-3A, L-4, L-4A, L-5, or L-6) set forth in formula X herein.

[0091] In some embodiments, in formula Y (including, as applicable, subformulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), R 20 and R 21 each independently represents hydrogen or an optionally substituted C 1-4 In some embodiments, in formula Y (including, as applicable, subformulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), R 22 each independently represents hydrogen or an optionally substituted C 1-4 It is an alkyl group. 20 , R 21 , and R 22 Other definitions are given.

[0092] In some embodiments, in formula Y and any applicable subformula [ka] Part of the structure is [ka] (Y shown 1 and Y 9 In some embodiments, Y 1 In some embodiments, Y 9In some embodiments, Y 9 is C 1-4 Alkylene group, or C 1-4 In some embodiments, the formula Y and any applicable subformulas are [ka] The linker may have the following structure: [ka]

[0093] (X shown 1 and W indicates the bond direction. In some embodiments, in formula Y and any applicable subformula [ka] The linker may have the following structure: [ka]

[0094] (X shown 1 and W indicates the bond direction. In some embodiments, in formula Y and any applicable subformula [ka] The linker may have the following structure: [ka]

[0095] (X shown 1 and W indicates the bond direction. In some embodiments, Y 1 In some embodiments, Y 9In some embodiments, Y 9 is C 1-4 Alkylene group, or C 1-4 In some embodiments, the formula Y and any applicable subformulas are heteroalkylene groups, each of which may be branched or straight chain. [ka] The linker may be any of the formulas I, II, III, IV, or V defined in any of the embodiments 1-14 herein, or as described in Table A herein, or in the specific compounds of the Examples. 10 -Linker-Y 10 It may have the following structure.

[0096] Suitable W groups for formula Y are not particularly limited and include any of the groups described in formula X herein.

[0097] For example, in some embodiments, the compound of formula Y-2 may have a structure represented by formula Y-2-A, a structure represented by formula Y-2-B, a structure represented by formula Y-2-C, or a structure represented by formula Y-2-D. [ka] [ka]

[0098] Here, the variable X 2 , R 10 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , G A , R 30 , R 31 , EWG, and R 32includes any of the corresponding definitions set forth in formula Y, or applicable subformulas herein, in any combination. For example, in some embodiments, X in formula Y-2-A, Y-2-B, Y-2-C, or Y-2-D 2 -R 10 teeth, [ka] In some embodiments, X in formula Y-2-A, Y-2-B, Y-2-C, or Y-2-D may be 2 -R 10 teeth, [ka] In some embodiments, X in formula Y-2-A, Y-2-B, Y-2-C, or Y-2-D may be 2 -R 10 teeth, [ka] In some embodiments, R 30 and R 31 are both hydrogen, and EWG is COOH, COO(C 1-4 alkyl group), CONH 2 , CONH(C 1-4 alkyl group), CON(C 1-4 Alkyl group)(C 1-4 (alkyl group) , CN, or SO 2 (C 1-4 In some embodiments, R 32 is hydrogen or C 1-4 In some embodiments, Y-2-A, Y-2-B, Y-2-C, or Y-2-D is an alkyl group. [ka] may have the following structure: [ka]

[0099] In some embodiments, Y 1 In some embodiments, Y 9 In some embodiments, Y 9 is C 1-4 Alkylene group, or C 1-4 In some embodiments, G is a heteroalkylene group. A is optionally 1 to 3 G S2 C replaced with 1-6 is an alkyl group, where G S2 is defined herein. In some embodiments, G A is any combination of 1 to 5 G S3 C replaced with 3-6 A cycloalkyl group, where G S3 is defined herein. In some embodiments, G A is any combination of 1 to 5 G S3 is a phenyl group substituted with S3 is defined as herein.

[0100] In some embodiments, W in formula Y (including, as applicable, subformulas Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7) is [ka] , C(O)R 35 ,or [ka] where G A7 is an arbitrarily substituted C1-6 is an alkyl group, R 35 is hydrogen or C 1-4 is an alkyl group, R 32 is hydrogen or C 1-4 It is an alkyl group.

[0101] In some embodiments, in formula Y (including subformulas Y-1, Y-2, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7, as applicable), Y 9 -W is -(C 1-4 Alkylene group)-CN, CN, [ka] In some embodiments, Y 9 -W is [ka] may be a masked CH 2 In some embodiments, W in formula Y (including subformulas Y-1, Y-2, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7, as applicable) is C(O)H, [ka] In some embodiments, W may be [ka] In some embodiments, W may be [ka] In some preferred embodiments, W in formula Y (including subformulas Y-1, Y-2, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7, as applicable) may be: [ka] In some embodiments, W may be [ka] In some preferred embodiments, W in formula Y (including subformulas Y-1, Y-2, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7, as applicable) may be: [ka] may be also possible.

[0102] Formula I, II, III, IV, or V In some embodiments, the present invention also provides compounds having Formula I, II, III, IV, or V. Particularly preferred compounds of the present invention include those set forth in Table A.

[0103] In some embodiments, the present invention provides the following exemplary embodiments.

[0104] Embodiment 1. A compound of formula I, or a pharma- ceutically acceptable salt thereof: [ka] Here, R 1 is selected from an aryl group, or a heteroaryl group, each of which is optionally substituted. 2 is selected from hydrogen, an alkyl, a halogenated alkyl group, a heteroalkyl group, a hydroxyl group, an alkoxy group, or a prodrug moiety, each of which is optionally substituted.

[0105] Here, R 3 is hydrogen, -C(=O)-R 5A1 , -SO2 -R 5A1 , -NHC(=O)-R 5A1 , -NHSO 2 -R 5A1 , -C(=O)-(CH 2 ) n -R 5A1 , -NHCH 2 -R 5A1 , -(CH 2 ) n -C(=O)-R 5A1 , -(CH 2 ) n -SO 2 -R 5A1 , -SO 2 -(CH 2 ) n -R 5A1 , -C(=O)-CH 2 -R 5A1 , -C(=O)-NH-R 5A1 , -SO 2 -NH-R 5A1 , or -SO 2 -CH 2 -R 5A1 is selected from.

[0106] where X 3 is CH or N. Here, each Y 10 is independently absent, or -C(=O)-, -CHR 5A2 -, -CH 2 CHR 5A2 -, -NR 5A2 -, -CHR 5A2 -NH-.

[0107] where the linker is -(C=O)-NR 5A2 -(CH 2 ) n -(C=O)-, -(C=O)-NR 5A2 -(CH 2 ) n -(C=O)-Heteroalkyl group-, -(C=O)-NR 5A2 -(CH 2 ) n -(C=O)-heteroaryl group, -(C=O)-NR 5A2 -, -SO2 -NR 5A2 -(CH 2 ) n -(C=O)-, -(C=O)-NR 5A2 -(CH 2 ) n -SO 2 -, -SO 2 -NR 5A2 -(CH 2 ) n -SO 2 -, -NR 5A2 -, -(C=O)-NR 5A2 -(CH 2 ) n -heteroaryl group-, -(C=O) -NR 5A2 -(CH 2 ) n -Heterocycloalkyl group-, -(OCH 2 CH 2 ) n -(PEG), an alkyl group linker, an aminoalkyl group linker, a cycloalkyl group linker, a heterocycloalkyl group linker, an aryl group linker, and a heteroaryl group linker, where n is an integer of 0 to 7.

[0108] Here, R 4 is selected from functional groups used in reversible and irreversible covalent interactions, -CR 5A3 -C≡CR 6 , -C≡CR 6 , -CR 5A3 -CH=CH-C(=O)-R 6 , -CH=CH-C(=O)-R 6 , -CR 5A3 -CH=CH-C(=O)-ZR 6 , -CH=CH-C(=O)-ZR 6 , -CR 5A3 -CH=CH-SO 2 -R 6 , -CH=CH-SO 2 -R 6 , -CR 5A3 -CH=CH-SO 3 -R 6 , -CH=CH-SO 3-R 6 , -CR 5A3 Including, but not limited to, -C≡N, or -C≡N.

[0109] where Z is NH, N(R 5B ), O, or S.

[0110] In some preferred embodiments, R 3 is -C(=O)-R 5A1 , or -SO 2 -R 5A1 Here, R 5A1 -R 5A3 each independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a halogen atom, or -CH 2 N(R 6 ) 2 , -CH 2 NHR 6 In some preferred embodiments, R 5A1 -R 5A3 are each independently hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or phenyl, each of which is optionally substituted. In some preferred embodiments, X 3 is N. In some preferred embodiments, Y 10 -CHR 5A2 Here, R 5A2 is hydrogen, a methyl group, an ethyl group, a cyclopropyl group, or a halogen (preferably, F). In some preferred embodiments, the linker is -(C=O)-NR 5A2 -(CH 2 ) n -(C=O)-, where R 5A2 represents hydrogen, a methyl group, an ethyl group, or a cyclopropyl group, and n is an integer of 0 to 3.

[0111] Here, R 6is selected from hydrogen, halogen, an alkyl group, an alkenyl group, an acyl group, an aryl group, or a heteroaryl group. In some preferred embodiments, R 4 is -C≡CR 6 , or -CH=CH-C(=O)-ZR 6 Here, R 6 is hydrogen, methyl, ethyl, cyclopropyl, or phenyl, each of which is optionally substituted, where Z is O or NH.

[0112] Embodiment 2.R 1 And, R 2 and are different, or a pharma- ceutically acceptable salt thereof.

[0113] Embodiment 3.R 1 And, R 2 or a pharma- ceutically acceptable salt thereof.

[0114] Embodiment 4.R 1 The compound according to any one of embodiments 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein R is an aryl group. 1 is a naphthyl group, or a phenyl group, each of which is optionally substituted.

[0115] Embodiment 5.R 1 The compound according to any one of embodiments 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein R is a heteroaryl group. In some preferred embodiments, R 1 is a quinolyl group, an isoquinolyl group, or a quinazolinyl group, each of which is optionally substituted.

[0116] Embodiment 6.R 2

[0023] In some preferred embodiments, R is an alkyl group, or a pharma- ceutically acceptable salt thereof. 2is hydrogen, a methyl group, an ethyl group, a hydroxymethyl group, a 2-hydroxyethyl group, an aminomethyl group, or a 2-aminomethyl group.

[0117] Embodiment 7.R 2 is in the (R)-configuration; or a pharma- ceutically acceptable salt thereof.

[0118] Embodiment 8.R 1 is an aryl group, R 2 is an alkyl group, or a pharma- ceutically acceptable salt thereof. 1 is a naphthyl group, and R 2 is a methyl group, each of which is optionally substituted.

[0119] Embodiment 9.R 3 is -C(=O)-R 5A1 or a pharma- ceutically acceptable salt thereof.

[0120] Embodiment 10.R 3 -SO 2 -R 5A1 or a pharma- ceutically acceptable salt thereof.

[0121] Embodiment 11. A compound having a structure according to formula II: [ka] Here, R 5B1 -R 5B4 each independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a halogen atom, or -CH 2 N(R 6 ) 2 , -CH 2 NHR 6or -C≡N, or a pharma- ceutically acceptable salt thereof. 5B1 and R 5B3 is independently selected from hydrogen, a methyl group, a halogen (preferably F), a hydroxymethyl group, a 2-hydroxymethyl group, an aminomethyl group, or a 2-aminomethyl group. In some preferred embodiments, R 5B2 and R 5B4 is independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0122] Embodiment 12. A compound having a structure according to formula III: [ka] Here, R 5C1 -R 5C4 each independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a halogen atom, or -CH 2 N(R 6 ) 2 , -CH 2 NHR 6 or -C≡N, or a pharma- ceutically acceptable salt thereof. 5C1 and R 5C2 is independently selected from hydrogen, a methyl group, a halogen (preferably F), a hydroxymethyl group, a 2-hydroxymethyl group, an aminomethyl group, or a 2-aminomethyl group. In some preferred embodiments, R 5C3 and R 5C4 is independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0123] Embodiment 13. A compound having a structure according to formula IV, [ka] Here, R 5D1 -R 5D5 each independently represents a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, a halogen atom, or -CH 2 N(R 6 ) 2 , -CH 2 NHR 6 or -C≡N, or a pharma- ceutically acceptable salt thereof. 5D1 , R 5D3 and R 5D4 is independently selected from hydrogen, a methyl group, a halogen (preferably F), a hydroxymethyl group, a 2-hydroxymethyl group, an aminomethyl group, or a 2-aminomethyl group. In some preferred embodiments, R 5D2 and R 5D5 is independently selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0124] Embodiment 14. A compound having a structure according to formula V: [ka] Here, Y 11 -Y 14 are each absent or independently -C(=O)-, -C(=O)NH-, -CHR 5A2 -, -CH 2 CHR 5A2 -, -NR 5A2 -, -CHR 5A2 -NH- or a pharma- ceutically acceptable salt thereof. 11 -CHR 5A2 - and Y 12 is -C(=O)NH-. In some preferred embodiments, Y 13 -NR 5A2 - and Y 14is -C(=O)-, -C(=O)NH-, or -CHR 5A2 In some preferred embodiments, R 5A2 is hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or phenyl, each of which is optionally substituted; 7 is selected from an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group. In some preferred embodiments, R 7 is a 3-8 membered heterocycle. In some preferred embodiments, R 7 teeth, [ka] It is.

[0125] Embodiment 15. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 14, a pharma- ceutically acceptable carrier, excipient, or vehicle, and optionally, an additional bioactive agent.

[0126] Embodiment 16. The pharmaceutical composition of embodiment 15, wherein the additional bioactive agent is an antiviral agent.

[0127] Embodiment 17. The pharmaceutical composition of embodiment 15 or 16, wherein the pharmaceutical composition is in a form selected from a tablet, a powder, a microparticle, a nanoparticle, a granule, a capsule, a liquid, an aqueous solution, a suspension, or a dispersion.

[0128] Embodiment 18. A method for treating a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of embodiments 1 to 14.

[0129] Embodiment 19. The method comprises administering to the subject an effective amount of the compound, 19. The method of embodiment 18, wherein a dysregulated viral protein encoded by the coronavirus is responsible for the infection and the compound modulates the activity of the viral protein in the subject.

[0130] Embodiment 20. The method of embodiment 18 or 19, wherein the coronavirus infection is selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2.

[0131] Embodiment 21. The method of any one of embodiments 18 to 20, wherein the coronavirus infection is SARS-CoV-2.

[0132] Embodiment 22. The method of any one of embodiments 19 to 21, wherein the viral protein comprises a papain-like protease (PLpro) encoded by a coronavirus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2.

[0133] Embodiment 23. The method of embodiment 22, wherein the viral protein comprises PLpro encoded by SARS-CoV-2.

[0134] Embodiment 24. The method of any one of embodiments 18-23, wherein the compound is administered to the subject by injection, infusion, oral administration, or inhalation.

[0135] Exemplary Compounds and Embodiments In some embodiments, the present invention further provides compounds as set forth in the following exemplary embodiments.

[0136] A compound of formula Y, Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7, or a pharma- ceutically acceptable salt thereof, wherein the variables are defined as herein.

[0137] EM2.X 1 is NR 13 and preferably R 13 is hydrogen, optionally substituted C 1-6 Alkyl group, COG A , or SO 2 G A or a pharma- ceutically acceptable salt thereof.

[0138] EM3.X 1 is NR 13 and R 13 teeth, [ka] or R 13 teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0139] EM4.X 1 is NR 13 And R 13 teeth, [ka] or a pharma- ceutically acceptable salt thereof.

[0140] EM5.(i)Y 1 is non-existent, (ii) Y 1 For example, CH 2 Or CD 2 Any substitution of C, such as 1-4 an alkylene group, or (iii) Y 1 For example, [ka] and the like, wherein the ring heteroatoms are independently O, S, or N.

[0141] EM6.(i)Y 2 is CH 2 Or for example, CH(CH 3 ) and other CH(C 1-4 alkyl group), where C 1-4 Alkyl groups include, for example, F, OH, and NH 2 Optionally substituted with substituents independently selected from (ii) Y 2 is non-existent, or (iii) Y 2 is CH(CH 3 ), C(CH 3 ) 2 , CD 2 ,or [ka] The compound according to any one of EM1 to EM5, wherein:

[0142] EM7.(i)Y 3 is C(O), (ii) Y 3 is non-existent, or (iii) Y 3 is CH(OH) or CH(C 1-4alkyl group), where C 1-4 Alkyl groups include, for example, F, OH, and NH 2 The compound according to any one of claims EM1 to EM6, or a pharma- ceutically acceptable salt thereof, wherein the compound is optionally substituted with a substituent independently selected from the following:

[0143] EM8.(i)Y 4 NH, CH 2 , or CH(C 1-4 alkyl group), (ii) Y 4 is non-existent, or (iii) Y 4 For example, NCH 3 N(C 1-4 alkyl group), Here, each C in (i) and (iii) 1-4 Alkyl groups include, for example, F, OH, and NH 2 or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims EM1 to EM7, wherein the compound is optionally substituted with a substituent independently selected from the following:

[0144] EM9.(i)Y 5 NH, CH 2 , CH(C 1-4 alkyl group), C(C 1-4 Alkyl group)(C 1-4 alkyl group), or [ka] That is, (ii) Y 5 is non-existent, or (iii) Y 5 is CH(CH 3 ), C(CH 3 ) 2 , CD 2 ,or [ka] The compound according to any one of items EM1 to EM8, which is: or a pharma- ceutically acceptable salt thereof.

[0145] EM10.(i)Y 6 is C(O), CH 2 , or CH(C 1-4 alkyl group), (ii) Y 6 is non-existent, or (iii) Y 6 is CH(OH) or CH(C 1-4 alkyl group), where C 1-4 Alkyl groups include, for example, F, OH, and NH 2 and optionally substituted with substituents independently selected from, for example, Y 6 is CH(CF 3 EM1 to EM9, or a pharma- ceutically acceptable salt thereof.

[0146] EM11.(i)Y 7 NH, CH 2 , or CH(C 1-4 alkyl group), (ii) Y 7 is non-existent, or (iii) Y 7 is N(C 1-4 alkyl group), for example, Y 7 NCH 3 , CH(CH 3 ), C(CH 3 ) 2 , or CD 2 where each C in (i) and (iii) 1-4 Alkyl groups include, for example, F, OH, and NH 2 The compound according to any one of claims EM1 to EM10, or a pharma- ceutically acceptable salt thereof, wherein the compound is optionally substituted with a substituent independently selected from the following:

[0147] EM12.Y 7The compound according to any one of items EM1 to EM10, wherein is C(O), or a pharma- ceutically acceptable salt thereof.

[0148] EM13.Y 8 is NH, or Y 8 is O or, for example, NCH 3 N(C 1-4 alkyl group), wherein the C 1-4 Alkyl groups include, for example, F, OH, and NH 2 The compound according to any one of claims EM1 to EM12, or a pharma- ceutically acceptable salt thereof, wherein the compound is optionally substituted with a substituent independently selected from:

[0149] EM14.(i)Y 8 is CH 2 , or CH(C 1-4 alkyl group), (ii) Y 8 is CO, or (iii) Y 8 is CH(CH 3 ), C(CH 3 ) 2 , CD 2 ,or [ka] The compound according to any one of EM1 to EM12, which is: or a pharma- ceutically acceptable salt thereof.

[0150] EM15.Y 8 The compound according to any one of EM1 to EM12, or a pharma- ceutically acceptable salt thereof, wherein is absent.

[0151] EM16.(i)Y 9 is absent, e.g., CH 2 , or CD 2 Any substitution of C, such as 1-4an alkylene group or an optionally substituted 4-8 membered heterocycle having 1 or 2 ring heteroatoms, said ring heteroatoms being independently O, S, or N; (ii) Y 9 For example, [ka] C 3-6 or (iii) Y 9 is optionally, for example, oxo, F, CF 3 C replaced by 1-4 The compound according to any one of EM1 to EM15, which is a heteroalkylene group, or a pharma- ceutically acceptable salt thereof.

[0152] EM17. In formula Y [ka] The linker is [ka] (X shown 1 and W indicates the bond direction), or a pharma- ceutically acceptable salt thereof.

[0153] EM18.W is, [ka] , C(O)R 35 ,or [ka] where G A7 is an arbitrarily substituted C 1-6 is an alkyl group, R 35 is hydrogen or C 1-4 is an alkyl group, and R32 is hydrogen or C 1-4 The compound according to any one of EM1 to EM17, which is an alkyl group, or a pharma- ceutically acceptable salt thereof.

[0154] EM19.W is, [ka] or W is [ka] The compound according to any one of EM1 to EM17, which is: or a pharma- ceutically acceptable salt thereof.

[0155] The EM20.W is [ka] The compound according to any one of EM1 to EM17, which is: or a pharma- ceutically acceptable salt thereof.

[0156] EM21.Y 9 -W is -(C 1-4 Alkylene group)-CN, CN, [ka] or Y 9 -W is [ka] The compound according to any one of EM1 to EM17, which is: or a pharma- ceutically acceptable salt thereof.

[0157] EM22.W is C(O)H, [ka] or W is [ka] or W is [ka] The compound according to any one of EM1 to EM17, which is: or a pharma- ceutically acceptable salt thereof.

[0158] In some embodiments, the present invention also provides a compound selected from the compounds set forth in Table A, or a pharma- ceutically acceptable salt thereof.

[0159] Table A. List of Exemplary Compounds

[0160] [Table 1-1]

[0161] [Table 1-2]

[0162] [Table 1-3]

[0163] [Table 1-4]

[0164] [Table 1-5]

[0165] [Table 1-6]

[0166] [Table 1-7]

[0167]

Table 1-8

[0168]

Table 1-9

[0169]

Table 1-10

[0170]

Table 1-11

[0171]

Table 1-12

[0172]

Table 1-13

[0173]

Table 1-14

[0174]

Table 1-15

[0175]

Table 1-16

[0176]

Table 1-17

[0177] [Table 1-18]

[0178] [Table 1-19]

[0179] [Table 1-20]

[0180] [Table 1-21]

[0181] Abbreviations used herein have the meanings commonly understood in the art unless otherwise defined or contrary to the context. For example, Ms is commonly used in the art to represent a mesyl group or -SO 2 Me and Boc means a tert-butoxycarbonyl group.

[0182] The compounds of the present invention can be easily synthesized in light of the teachings of the present invention. Exemplary syntheses are also shown in the Examples section. The reagents used in the reactions described herein are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers such as, for example, Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Sigma (St. Louis, Missouri, USA). Others may be prepared by methods described in standard references such as, for example, Fieser and Fieser's Reagents for Organic Synthesis, volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, volumes 1-5 and supplements (Elsevier Science Publishers, 1989), Organic Reactions, volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (Wiley, 7th edition), Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), and any updates available at the time of this filing, or obvious modifications thereof. obtain.

[0183] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of this specification belongs. Unless otherwise explained to the contrary, the following terms used in the specification and the appended claims have the meanings set forth to facilitate understanding of the present invention.

[0184] As used in the specification and the appended claims, singular elements include plural elements unless the context dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions, reference to "an inhibitor" includes mixtures of two or more such inhibitors, and so forth.

[0185] Headings and subheadings are used for convenience and / or formal compliance only and are not intended to limit the subject technology or relate to the interpretation of the description of the subject technology. In various embodiments, features described under one heading or subheading disclosed in this subject matter may be combined with features described under other headings or subheadings. Also, not all features under a single heading or subheading may necessarily be used together in an embodiment.

[0186] It is to be understood that for all moieties and combinations thereof, appropriate atomic valences are maintained.

[0187] It should also be understood that a specific embodiment of a variable herein may be the same or different from another specific embodiment having the same designation.

[0188] Where applicable, suitable groups for the variables of the compounds of formula X, Y, I, II, III, IV, or V, or subformulas thereof, are independently selected. Non-limiting useful groups for the variables of the compounds of formula X, Y, I, II, III, IV, or V, or subformulas thereof, where applicable, include any or any combination of the groups set forth in the compounds of Table A or specific compounds 1-177 herein.

[0189] The embodiments described in this invention can be combined. Such combinations are contemplated and are within the scope of the invention. For example, X of formula Y 1 , X 2 , Rg, R 10 , Y 1 , Y 2 , Y3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 , and one or more of the definitions of W, X, 1 , X 2 , Rg, R 10 , Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , Y 7 , Y 8 , Y 9 and W may be combined with any one or more of the definitions, and compounds resulting from such combinations are envisaged to be within the scope of the present invention.

[0190] symbol [ka] When shown perpendicular (or crossing) a bond, it indicates the point at which the shown moiety is attached to the remainder of the molecule. For bivalent (or multivalent) structures, one or more of the directly bonded groups or appropriate variables shown in the formula may be replaced with the symbol ( ) to indicate the direction of the bond. [ka] It should be noted that the heteroarylene group may be represented in a bivalent (or multivalent) structure other than the above. When no groups are shown directly attached to either of the two attachment points of a bivalent structure, this means that either orientation of the attachment to the rest of the molecule is possible, unless otherwise stated or contrary to the context. For example, in the structure "A-heteroarylene group-B", the heteroarylene group is [ka] When the structure is defined as: [ka] may be also possible.

[0191] symbol [ka] It is to be understood that when is used as a bond in a structure, the stereochemistry of the structure can be any of the chemically possible stereoisomers. For example, the moiety [ka] As mentioned above, cross the upper left bond [ka] is R 30 The carbon atom attached to the is to be understood as the point of attachment of that moiety to the remainder of the molecule. [ka] indicates that the stereochemistry of the double bond can be either E or Z.

[0192] Definitions of specific functional groups and chemical terms are discussed in more detail below. Chemical elements are determined in accordance with the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as set forth therein. For further information regarding general principles of organic chemistry, as well as the moieties and reactivity of specific functional groups, see Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and d March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. The subject matter of the present invention is not intended to be limited in any way by the exemplary list of substituents set forth herein.

[0193] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Preferred isomers can also be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers, including racemic mixtures. Where stereochemistry is specifically depicted, it is to be understood that, unless the context explains to the contrary, for a particular chiral center or axial chirality, the compound exists predominantly as the depicted stereoisomer, e.g., the compound has less than 20%, less than 10%, less than 5%, less than 1% of that stereoisomer by weight, HPLC area, or both, or has undetectable amounts of the other stereoisomer, e.g., the compound can have an enantiomeric excess (ee) of greater than 60%, e.g., greater than 80%, greater than 90%, greater than 95%, greater than 98%, greater than 99%, etc.In accordance with the present invention, one of ordinary skill in the art can determine the presence and / or amount of stereoisomers by using chiral HPLC or other methods.

[0194] When a range of values ​​is listed, it is intended to include each value and subrange within the range. For example, "C 1-6 " is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 is intended to include.

[0195] As used herein, the term "a compound of the invention" refers to any compound according to formula X, formula Y (e.g., Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), formula I, II, III, IV, or V, any compound described in Table A herein, or compounds 1-177, isotopically labeled compounds thereof (e.g., deuterated analogs in which one or more hydrogen atoms are replaced with deuterium atoms having an abundance greater than their natural abundance, e.g., compounds in which the compound is CH 3 CD with a group 3 analogues), and their possible positional variations The term "deuterium" refers to any of the compounds of the formula (I), their possible isomers, their possible geometric isomers, their possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), their tautomers, their conformers, and / or their possible pharma- ceutically acceptable salts (e.g., acid addition salts such as HCl, methanesulfonate, or base addition salts such as Na salt). When a particular position of a structure, or substructure (e.g., a compound or substituent herein) is designated as containing deuterium (referred to as "D" or "deuterium"), it is to be understood that the abundance of deuterium at that position is greater than the natural abundance of deuterium, which is about 0.0156%, and preferably, the abundance of deuterium at that position is significantly greater than its natural abundance, e.g., the inclusion concentration of deuterium at that position is at least 50.1%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%. Hydrates and solvates of the compounds of the present invention are considered compositions of the present invention, where the compounds are combined with water or solvent, respectively. In any embodiment described herein, unless otherwise stated or contrary to the context, the compound or its pharma- ceutically acceptable salt may be selected from exemplary embodiments EM1-EM22 described herein. In some preferred embodiments, the compound or its pharma- ceutically acceptable salt for the pharmaceutical composition or treatment method herein may have an IC50 of less than 100 nM when measured under the PLpro enzyme inhibition test herein.

[0196] The compounds of the present invention may exist in isotopically enriched or enriched forms containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. The isotopes may be radioactive or non-radioactive isotopes. Isotopes of atoms (e.g., hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine) are 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 32 P, 35 S, 18F, 36 Cl, and 125 Compounds that contain other isotopes of these atoms and / or other atoms are within the scope of this invention, including, but not limited to, I.

[0197] As used herein, the term "alkyl group" refers to a saturated, linear or branched, monovalent hydrocarbyl group. In some embodiments, an alkyl group refers to a linear or branched C1-C32 alkyl group, a C1-C24 alkyl group, a C1-C12 alkyl group, a C1-C8 alkyl group, or a C1-C6 alkyl group. In some embodiments, an alkyl group refers to a linear or branched C1-C6 alkyl group. Examples of alkyl groups include methyl, ethyl, 1-propyl, 2-propyl, i-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. In some embodiments, the alkyl group is a C1-C3 alkyl group. In some embodiments, the alkyl group is a C1-C2 alkyl group.

[0198] As used herein, the term "alkylene group" refers to a straight or branched divalent hydrocarbon chain that is attached to the remainder of the molecule, consisting solely of carbon and hydrogen, contains no unsaturated bonds, and has 1 to 12 carbon atoms, such as, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the remainder of the molecule through a single bond and may be attached to a group through a single bond. In some embodiments, an alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene group). In some embodiments, the alkylene group contains 1 to 8 carbon atoms (C1-C8 alkylene group). In embodiments, the alkylene group contains 1 to 6 carbon atoms (C1-C6 alkylene group). In some embodiments, the alkylene group contains 1 to 5 carbon atoms (C1-C5 alkylene group). In some embodiments, the alkylene group contains 1 to 4 carbon atoms (C1-C4 alkylene group). In some embodiments, the alkylene group contains 1 to 3 carbon atoms (C1-C3 alkylene group). In some embodiments, the alkylene group contains 1 to 2 carbon atoms (C1-C2 alkylene group). In some embodiments, the alkylene group contains one carbon atom (C1 alkylene group).

[0199] As used herein, the term "carbocyclyl" (also referred to as a "carbocyclyl group"), used alone or as part of a larger moiety, refers to a group that includes saturated, partially unsaturated, or aromatic ring systems having 3 to 20 carbon atoms, i.e., alone or as part of a larger moiety (e.g., an alkylcarbocyclyl group). In some embodiments, a "carbocyclyl group" is fully saturated. The term "carbocyclyl group" includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In one embodiment, a carbocyclyl group contains 3 to 15 carbon atoms (C3-C15). In one embodiment, a carbocyclyl group contains 3 to 12 carbon atoms (C3-C12). In another embodiment, a carbocyclyl group contains C3-C8, C3-C10, or C5-C10. In other embodiments, a carbocyclyl group that is a monocyclic ring comprises C3-C8, C3-C6, or C5-C6. In some embodiments, a carbocyclyl group that is a bicyclic ring comprises C7-C12. In some embodiments, a carbocyclyl group that is a spiro ring system comprises C5-C12. Representative examples of monocyclic carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, phenyl, and cyclododecyl. Bicyclic carbocyclyl groups having 7 to 12 ring atoms include, for example, [4,3], [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, naphthalene, and bicyclo[3.2.2]nonane. Representative examples of spirocarbocyclyl groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane.The term carbocyclyl group includes aromatic ring systems as defined herein. The term carbocyclyl group also includes cycloalkyl rings (e.g., saturated or partially unsaturated monocyclic, bicyclic, or spirocarbocyclic rings). The term carbocyclyl group also includes carbocyclic rings fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., aromatic or heterocyclic rings) where the groups or points of attachment are on the carbocyclic ring.

[0200] As used herein, the term "halogen" (or "halide" or "halide") refers to fluorine, chlorine, bromine, or iodine.

[0201] As used herein, the term "alkoxy group" when used by itself or as part of another group means R a1 is an alkyl group, a1 This refers to the group.

[0202] As used herein, the term "cycloalkoxy group" when used by itself or as part of another group means R a1 is a cycloalkyl group, a1 This refers to the group.

[0203] As used herein, the term "haloalkyl group," when used alone or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and / or iodine atoms. In preferred embodiments, a haloalkyl group is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, a haloalkyl group is a C 1-10 In one embodiment, the haloalkyl group is 1-6 In one embodiment, the haloalkyl group is 1-4 It is a haloalkyl group.

[0204] As used herein, unless otherwise indicated, the term "heteroalkyl group", by itself or in combination with another term, means a stable straight or branched chain alkyl group having, for example, 2 to 14 carbons in the chain, e.g., 2 to 10 carbons, one or more of the carbons being replaced with a heteroatom selected from S, O, P and N, wherein the nitrogen, phosphorus, and sulfur atoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. The heteroatoms S, O, P and N can be located at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. When a heteroalkyl group is described as substituted, the substituents can replace one or more hydrogen atoms bonded to the carbon atoms and / or heteroatoms of the heteroalkyl group. In some embodiments, a heteroalkyl group is an alkyl group having, for example, C 1-4 Heteroalkyl group, 1-4 Heteroalkyl group refers to a heteroalkyl group having 1 to 4 carbon atoms, as defined herein. 1-4 Illustrative examples of heteroalkyl groups are, for example, -CH 2 -CH 2 -N(CH 3 )-CH 3 C etc. 4 Heteroalkyl groups, such as -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 C etc. 3 Heteroalkyl, e.g. -CH 2 -CH 2 -OH, -CH 2 -CH 2 -NH 2 , -CH 2 -NH(CH3 ), -O-CH 2 -CH 3 C etc. 2 Heteroalkyl, and for example -CH 2 -OH, -CH 2 -NH 2 , -O-CH 3 C etc. 1 Similarly, the term "heteroalkylene group" when used alone or as part of another substituent means a divalent group derived from a heteroalkyl group, but said divalent group is not limited to -CH 2 -CH 2 -O-CH 2 -CH 2 - and -O-CH 2 -CH 2 -NH-CH 2 -, but are not limited to. For heteroalkylene groups, heteroatoms may occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Also, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the molecular formula of the linking group is drawn. When a "heteroalkyl group" is described and then a specific heteroalkyl group, such as -NR'R'', it should be understood that the terms heteroalkyl group and -NR'R'' are not overlapping or mutually exclusive. Rather, the specific heteroalkyl groups are recited for greater clarity. Thus, the term "heteroalkyl group" should not be construed herein as a heteroalkyl group that excludes specific heteroalkyl groups, such as -NR'R''.

[0205] As used herein, the term "heterocyclyl group," used alone or as part of a larger moiety, includes saturated, partially unsaturated, or aromatic ring systems in which one or more (e.g., one, two, three, or four) carbon atoms are heteroatoms (e.g., O, N, N(O), S, S(O), or S(O)). 2) substituted with 5-, 6- or 7-membered heterocyclyl groups. The term heterocyclyl group includes monocyclic, bicyclic, tricyclic, fused, bridged, and spiro ring systems, and combinations thereof. In some embodiments, the heterocyclyl group refers to a 3- to 15-membered heterocyclyl ring system. In some embodiments, the heterocyclyl group refers to a 3- to 12-membered heterocyclyl ring system. In some embodiments, the heterocyclyl group refers to a saturated ring system, such as, for example, a 3- to 12-membered saturated heterocyclyl ring system. In some embodiments, the heterocyclyl group refers to a saturated ring system, such as, for example, a 5- to 12-membered saturated heterocyclyl ring system. It refers to a heteroaryl ring system, such as a 4-membered heteroaryl ring system. The term heterocyclyl group also includes C3-C8 heterocycloalkyl groups, which are saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic ring systems containing 3 to 8 carbons and one or more (one, two, three, or four) heteroatoms.

[0206] In some embodiments, the heterocyclyl group contains 3-12 ring atoms, including monocyclic, bicyclic, tricyclic, and spirocyclic ring systems, where the ring atoms are carbon and 1-5 ring atoms are heteroatoms, such as, for example, nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl group contains a 3- to 7-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl group contains a 4- to 6-membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In some embodiments, the heterocyclyl group contains a 3-membered monocyclic ring. In some embodiments, the heterocyclyl group contains a 4-membered monocyclic ring. In some embodiments, the heterocyclyl group contains a 5- to 6-membered monocyclic ring. In some embodiments, the heterocyclyl group contains 0-3 double bonds. In any of the foregoing embodiments, the heterocyclyl group contains one, two, three, or four heteroatoms. Any nitrogen or sulfur heteroatoms may be optionally oxidized (e.g., NO, SO, SO 2 ), and any nitrogen heteroatom may be optionally quaternized (e.g., [NR 4 ] + Br, [NR4 ] +Representative examples of heterocyclyl groups are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydropyranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothio, and the like. Pyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydrothiopyranyl, Hydro[2H]indazolyl group, tetrahydrobenzimidazolyl group, 4,5,6,7-tetrahydrobenzo[d]imidazolyl group, 1,6-dihydroimidazole[4,5-d]pyrrolo[2,3-b]pyridinyl group, thiazinyl group, oxazinyl group, thiadiazinyl group, oxadiazinyl group, dithiazinyl group, dioxazinyl group, oxathiazinyl group, thiatriazinyl group, oxatriazinyl group, dithiadiazinyl group, imidazolinyl group, dihydropyrimidyl group, tetrahydropyrimidyl group, 1-pyrrolinyl group, 2-pyrrolinyl group, 3-pyridinyl group, lolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperazinonyl, piperazidionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl. Examples of 5-membered heterocyclyl groups containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl groups, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl groups, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl groups, such as oxazol-2-yl, and oxadiazolyl groups, such as 1,3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl. Examples of 5-membered heterocyclyl groups containing 2 to 4 nitrogen atoms include imidazolyl groups, such as imidazol-2-yl, triazolyl groups, such as 1,3,4-triazol-5-yl, and tetrazolyl groups, such as 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and 1H-tetrazol-5-yl. Representative examples of benzo-fused 5-membered heterocyclyl groups are benzoxazol-2-yl, benzthiazol-2-yl, and benzimidazol-2-yl. Examples of 6-membered heterocyclyl groups containing one to three nitrogen atoms and optionally sulfur or oxygen atoms include pyridyl groups, for example pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl, pyrimidyl groups, for example pyrimid-2-yl, pyrimid-4-yl, triazinyl groups, for example 1,3,4-triazin-2-yl, and 1,3,5-triazin-4-yl, pyridazinyl groups, especially pyridazin-3-yl, and pyrazinyl groups. Pyridine N-oxide and pyridazine N-oxide, as well as pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl, and 1,3,4-triazin-2-yl groups, are further examples of heterocyclyl groups. In some embodiments, a heterocyclyl group comprises a heterocycle fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., carbocycles or heterocycles) where the group or point of attachment is on the carbocycle, and in some embodiments, the point of attachment is a heteroatom contained in the heterocycle.

[0207] Thus, the term heterocycle includes N-heterocyclyl groups, which as used herein refer to heterocyclyl groups containing at least one nitrogen, where the point of attachment of the heterocyclyl group to the remainder of the molecule is a nitrogen atom in the heterocyclyl group. Representative examples of N-heterocyclyl groups include 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl groups. The term heterocycle also includes C-heterocyclyl groups, which as used herein refer to heterocyclyl groups containing at least one heteroatom, where the point of attachment of the heterocyclyl group to the remainder of the molecule is a carbon atom in the heterocyclyl group. Representative examples of C-heterocyclyl groups include 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, and 2- or 3-pyrrolidinyl groups.

[0208] In some embodiments, a heterocyclyl group refers to a heteroaryl ring system, such as, for example, a 5-14 membered heteroaryl ring system. The term heterocyclyl group also includes C3-C8 heterocycloalkyl groups, which are saturated or partially unsaturated monocyclic, bicyclic, or spirocyclic ring systems containing 3-8 carbons and one or more (one, two, three, or four) heteroatoms.

[0209] As used herein, the term "heteroarylene group" refers to a divalent heteroaryl group, which may be optionally substituted. The term "heteroaryl group" (e.g., a "heteroarylalkyl group" (also referred to as a "heteroaralkyl group"), or a "heteroarylalkoxy group" (also referred to as a "heteroaralkoxy group"), used alone or as part of a larger moiety, refers to a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 ring atoms, in which at least one ring is aromatic and contains at least one heteroatom. In one embodiment, a heteroaryl group is a 4-6 membered monocyclic ring. Heteroaryl groups include aromatic groups where one or more ring atoms are independently optionally substituted nitrogen, sulfur, or oxygen. In another embodiment, the heteroaryl group includes a 5-6 membered monocyclic aromatic group where one or more ring atoms are nitrogen, sulfur, or oxygen. Representative examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, purinyl, benzoxazolyl, benzofuran ... The heteroaryl groups include aryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, indolyl, 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl, and pyrid-2-yl N-oxide. The term "heteroaryl group" also includes groups in which a heteroaryl group is fused to one or more rings (e.g., a carbocyclyl group, or a heterocyclyl group) where the group or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups may be monocyclic, bicyclic, or tricyclic.In some embodiments, a heteroaryl group comprises a heteroaryl ring fused to one or more (e.g., one, two, or three) different cyclic groups (e.g., carbocyclic or heterocyclic rings), where the group or point of attachment is on the heteroaryl ring, and in some examples, the point of attachment is a heteroatom contained in the heterocyclic ring.

[0210] Thus, the term heteroaryl group includes N-heteroaryl groups, which as used herein refer to heteroaryl groups as defined above containing at least one nitrogen, where the point of attachment of the heteroaryl group to the remainder of the molecule is a nitrogen atom in the heteroaryl group. The term heteroaryl group, as used herein, also includes C-heteroaryl groups, which as used herein refer to heteroaryl groups as defined above, where the point of attachment of the heteroaryl group to the remainder of the molecule is a carbon atom in the heteroaryl group.

[0211] Typically, the salts of the present invention are pharma- ceutically acceptable salts. As used herein, the term "pharma- ceutically acceptable salts" refers to non-toxic salts of the PLpro compounds described herein. The salts of the PLpro compounds described herein can include acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium salt, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, and hydrobromide. , Hydrochloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Magnesium, Methyl Bromide, Methyl Nitrate, Methyl Sulfate, Potassium Hydrogen Maleate, Mucate, Napsylate, Nitrate, N-Methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate / Diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium Examples of suitable salts include acetamide, stearate, diacetate, succinate, sulfate, tannate, tartrate, thioacetate, tosylate, triethiodide, trimethylammonium, and valerate. Other salts, which are not pharmaceutically acceptable, may be used in the preparation of compounds of the invention and should be considered to form a further aspect of the invention.

[0212] As used herein, the term "prodrug" refers to a derivative of any biologically active compound that has a reactive functional group (e.g., -COOH from naproxen, aspirin). When administered to a site of action, the derivative is degraded by hydrolysis and / or enzymatic action to release the biologically active agent at its target or active site, and the remaining residue is non-toxic or is metabolized to a non-toxic compound. Particularly preferred prodrugs are those that increase the bioavailability of the compounds of the invention when the compounds of the invention are administered to a mammal, for example, by allowing an orally administered compound to be more readily absorbed into the blood or by enhancing delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) compared to the parent species.

[0213] As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, the compound of the present invention) and a solvent. Such a solvent must not interfere with the biological activity of the solute for the purposes of the present invention. Non-limiting examples of suitable solvents include, but are not limited to, water, methanol, ethanol, and acetic acid. The solvent preferably used is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include, but are not limited to, water, ethanol, acetic acid. The most preferably used solvent is water. In some embodiments, the solvate of the compound of the present invention includes, but is not limited to, a hemihydrate, a monohydrate, or a trihydrate, etc.

[0214] For example, an "optionally substituted" group, such as an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted carbocyclyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, and an optionally substituted heteroaryl group, refers to a group that is unsubstituted or substituted. In general, the term "substituted," whether preceded by the term "optionally," refers to at least one hydrogen present in the group (e.g., a carbon or nitrogen atom) being replaced with an acceptable substituent, e.g., a substituent that, upon substitution, produces a stable compound that does not spontaneously undergo transformation (e.g., rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any particular structure is substituted, the substituent may be the same or different at each position. In general, when substituted, an optionally substituted group herein may be substituted with 1 to 5 substituents. Where applicable, the substituents may be carbon atom, nitrogen atom, oxygen atom, or sulfur atom substituents. Two optional substituents may be combined to form an optionally substituted cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl ring. Substitution may occur at any available carbon, oxygen, or nitrogen atom and may form a spiro ring. Typically, substitutions herein include O-SO 2 -O, O-SO 2 -N, and N-SO 2 -N, OO, ON, SS, SN(SO 2 does not produce a -N bond), heteroatom-halogen, or -C(O)-S bond or three or more consecutive heteroatoms, unless it is permitted that part of such bond or linkage is in a stable aromatic system.

[0215] In a broad aspect, permissible substituents in the general formulae described herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. For suitable organic compounds, the permissible substituents used in conjunction with the general formulae described herein may be one or more and may be the same or different. For purposes of this invention, heteroatoms such as nitrogen may be substituted with hydrogen and / or aryl groups. The substituents may include any of the permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms or heteroatoms. The substituents may include any of the substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (carboxyl groups, alkoxycarbonyl groups, formyl groups, or acyl groups), thiocarbonyl groups (thioesters, thioacetates, or thioformates), alkoxy groups, cycloalkoxy groups, phosphoryl groups, phosphates, phosphonates, phosphinates, amino groups, amido groups, amidines, imines, cyano groups, nitro groups, azido groups, sulfhydryl groups, alkylthio groups, sulfates, sulfonates, sulfamoyl groups, sulfonamide groups, sulfonyl groups, heterocyclyl groups, aralkyl groups, aryl groups, and heteroaryl groups, each of which may be substituted, if applicable.

[0216] Exemplary substituents suitable for the general formulas described herein include alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, acyl, -C(O)-aryl, halogen, -NO 2 , -CN, -SF 5 , -C(O)OH, -C(O)O-alkyl group, -C(O)O-aryl group, -C(O)O-alkylene group-aryl group, -S(O)-alkyl group, -S(O) 2 -Alkyl group, -S(O)-Aryl group, -S(O)2 -aryl group, -S(O)-heteroaryl group, -S(O) 2 -heteroaryl group, -S-alkyl group, -S-aryl group, -S-heteroaryl group, -S-alkylene group-aryl group, -S-alkylene group-heteroaryl group, -S(O) 2 -Alkylene group-aryl group, -S(O) 2 -Alkylene group-heteroaryl group, cycloalkyl group, heterocycloalkyl group, -OC(O)-alkyl group, -OC(O)-aryl group, -OC(O)-cycloalkyl group, -C(=N-CN)-NH 2 , -C(=NH)-NH 2 , -C(=NH)-NH(alkyl group), -N(Y 1 )(Y 2 ), -alkylene group -N(Y 1 )(Y 2 ), -C(O)N(Y 1 )(Y 2 ), and -S(O) 2 N(Y 1 )(Y 2 ), including, but not limited to, where Y 1 and Y 2 may be the same or different and are independently selected from hydrogen, an alkyl group, an aryl group, a cycloalkyl group, and an -alkylene group-aryl group.

[0217] Some illustrative examples of suitable substituents for use in conjunction with the general formulae described herein are: 1 -C 8 ) alkyl group, (C 2 -C 8 ) alkenyl group, (C 2 -C 8 ) alkynyl group, (C 3 -C 10 ) cycloalkyl groups, halogen (F, Cl, Br, or I), halogenated (C 1 -C 8 ) alkyl group (e.g. -CF 3 but is not limited to these), -O-(C 1 -C 8 ) alkyl group, -OH, -S-(C1 -C 8 ) alkyl group, -SH, -NH(C 1 -C 8 ) alkyl group, -N((C 1 -C 8 ) alkyl group) 2 , -NH 2 , -C(O)NH 2 , -C(O)NH(C 1 -C 8 ) alkyl group, -C(O)N((C 1 -C 8 ) alkyl group) 2 , -NHC(O)H, -NHC(O)(C 1 -C 8 ) alkyl group, -NHC(O)(C 3 -C 8 ) cycloalkyl group, -N((C 1 -C 8 ) alkyl group) C(O)H, -N((C 1 -C 8 ) alkyl group) C(O)(C 1 -C 8 ) alkyl group, -NHC(O)NH 2 , -NHC(O)NH(C 1 -C 8 ) alkyl group, -N((C 1 -C 8 )Alkyl group)C(O)NH 2 , -NHC(O)N((C 1 -C 8 ) alkyl group) 2 , -N((C 1 -C 8 ) alkyl group)C(O)N((C 1 -C 8 ) alkyl group) 2 , -N((C 1 -C 8 ) alkyl group)C(O)NH((C 1 -C 8 ) alkyl group), -C(O)H, -C(O)(C 1 -C 8 ) Alkyl group, -CN, -NO 2 , -S(O)(C 1 -C 8 ) alkyl group, -S(O) 2 (C1 -C 8 ) alkyl group, -S(O) 2 N((C 1 -C 8 ) alkyl group) 2 , -S(O) 2 NH(C 1 -C 8 ) alkyl group, -S(O) 2 NH(C 3 -C 8 ) cycloalkyl group, -S(O) 2 NH 2 , -NHS(O) 2 (C 1 -C 8 ) alkyl group, -N((C 1 -C 8 )Alkyl group)S(O) 2 (C 1 -C 8 ) alkyl group, -(C 1 - C 8 )Alkyl group -O-(C 1 -C 8 ) alkyl group, -O-(C 1 -C 8 )Alkyl group -O-(C 1 -C 8 ) alkyl group, -C(O)OH, -C(O)O(C 1 -C 8 ) alkyl group, NHOH, NHO(C 1 -C 8 ) alkyl group, -O-halogenated (C 1 -C 8 ) alkyl group (e.g. -OCF 3 (but is not limited to these), -S(O) 2 -Halogenated (C 1 -C 8 ) alkyl group (e.g. -S(O) 2 CF 3 (but not limited to) -S-halogenated (C 1 -C 8 ) alkyl group (e.g. -SCF 3-(C1-C6)heterocycle (such as, but not limited to, pyrrolidine, tetrahydrofuran, pyran, or morpholine), -(C 1 -C 6 ) heteroaryl groups (such as, but not limited to, tetrazole, imidazole, furan, pyrazine, or pyrazole), -phenyl groups, -NHC(O)O-(C 1 -C 6 ) alkyl group, -N((C 1 -C 6 ) alkyl group) C(O) O-(C 1 -C 6 ) alkyl group, -C(=NH)-(C 1 -C 6 ) alkyl group, -C(=NOH)-(C 1 -C 6 ) alkyl group, or -C(=NO-(C 1 -C 6 )alkyl)-(C 1 -C 6 ) alkyl groups, but are not limited to.

[0218] Exemplary carbon atom substituents suitable for the general formulae described herein are halogen, -CN, -NO 2 , -N 3 , hydroxyl group, alkoxy group, cycloalkoxy group, aryloxy group, amino group, monoalkylamino group, dialkylamino group, amide, sulfonamide, thiol, acyl group, carboxylic acid, ester, sulfone, sulfoxide, alkyl group, haloalkyl group, alkenyl group, alkynyl group, C 3-10 Carbocyclyl group, C 6-10 Examples of the carbon atom substituents include, but are not limited to, aryl groups, 3-10 membered heterocyclyl groups, 5-10 membered heteroaryl groups, etc. For example, exemplary carbon atom substituents are F, Cl, -CN, -SO 2 H, -SO 3 H, -OH, -OC 1-6 Alkyl group, -NH 2 , -N(C 1-6 (alkyl group) 2 , -NH(C 1-6Alkyl group), -SH, -SC 1-6 Alkyl group, -C(=O)(C 1-6 alkyl group), -CO 2 H, -CO 2 (C 1-6 alkyl group), -OC(=O)(C 1-6 alkyl group), -OCO 2 (C 1-6 alkyl group), -C(=O)NH 2 , -C(=O)N(C 1-6 (alkyl group) 2 , -OC(=O)NH(C 1-6 alkyl group), -NHC(=O)(C 1-6 alkyl group), -N(C 1-6 Alkyl group)C(=O)(C 1-6 alkyl group), -NHCO 2 (C 1-6 alkyl group), -NHC(=O)N(C 1-6 (alkyl group) 2 , -NHC(=O)NH(C 1-6 alkyl group), -NHC(=O)NH 2 , -NHSO 2 (C 1-6 Alkyl group), -SO 2 N(C 1-6 (alkyl group) 2 , -SO 2 NH(C 1-6 Alkyl group), -SO 2 NH 2 ,-SO 2 C 1-6 Alkyl group, -SO 2 O.C. 1-6 Alkyl group, -OSO 2 C 1-6 Alkyl group, -SOC 1-6 Alkyl group, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Carbocyclyl group, C 6-10 It may include an aryl group, a 3- to 10-membered heterocyclyl group, a 5- to 10-membered heteroaryl group, or two geminal substituents may combine to form =O.

[0219] Where valences permit, nitrogen atoms may be substituted or unsubstituted, including primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents suitable for the general formulae described herein are hydrogen, acyl groups, esters, sulfones, sulfoxides, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Carbocyclyl groups, 3-14 membered heterocyclyl groups, C 6-14 Examples of substituents that may be present at the nitrogen atom include, but are not limited to, aryl groups, and 5-14 membered heteroaryl groups. Alternatively, the two substituents attached to the nitrogen atom may combine to form a 3-14 membered heterocyclyl group or a 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group may be further substituted as defined herein. In some embodiments, the substituent present at the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and are incorporated herein by reference. Such nitrogen protecting groups include, but are not limited to, aryl, aryl, and 5-14 membered heteroaryl groups. Alternatively, the two substituents attached to the nitrogen atom may combine to form a 3-14 membered heterocyclyl group or a 5-14 membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group may be further substituted as defined herein. In some embodiments, the substituent present at the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and are incorporated herein by reference. Groups include those described in detail in Protective Groups in Organic Synthesis, TW Greene and PG M Huts, 3rd Edition, John Wiley & Sons, 1999. Exemplary nitrogen protecting groups include, but are not limited to, groups that form carbamates, e.g., carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), Troc, 9-fluorenylmethyloxycarbonyl (Fmoc), groups that form amides, e.g., acetyl, benzoyl, groups that form benzylamines, e.g., benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, groups that form sulfonamides, e.g., tosyl, nosyl, and other groups, e.g., p-methoxyphenyl. thing,

[0220] Exemplary oxygen atom substituents suitable for the general formulae described herein are acyl groups, esters, sulfonates, C 1-10 Alkyl group, C 1-10 Haloalkyl group, C 2-10 Alkenyl group, C 2-10 Alkynyl group, C 3-10 Carbocyclyl groups, 3-14 membered heterocyclyl groups, C 6-14 The oxygen protecting groups include, but are not limited to, aryl groups, and 5-14 membered heteroaryl groups, where each alkyl group, alkenyl group, alkynyl group, carbocyclyl group, heterocyclyl group, aryl group, and heteroaryl group may be further substituted as defined herein. In some embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and are incorporated herein by reference. Such oxygen protecting groups include those described in detail in Protective Groups in Organic Synthesis, TW Greene and PG M Huts, 3rd Edition, John Wiley & Sons, 1999. Exemplary oxygen protecting groups include, but are not limited to, groups that form alkyl ethers or substituted alkyl ethers, e.g., methyl, allyl, benzyl, substituted benzyl groups such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), silyl ethers, e.g., trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), acetals or ketals, e.g., tetrahydropyranyl (THP), esters, e.g., formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, carbonates or sulfonates, e.g., methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0221] Unless expressly stated to the contrary, combinations of substituents and / or variables are permissible only if such combinations are chemically permissible and produce stable compounds. A "stable" compound is one which may be prepared and isolated and whose structure and properties will be maintained or remain essentially unchanged for a period of time sufficient to enable the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0222] As used herein, the term "subject" refers to a tissue, system, animal, mammal, or human, for example, in which a researcher or clinician seeks to elicit a biological or medical response with a bioactive agent, such as a therapeutic agent. In some embodiments, a subject refers to a mammal. In some embodiments, a subject refers to a human.

[0223] As used herein, the terms "treatment" and "treat" refer to therapeutic treatment, the purpose of which is to reverse, alleviate, or ameliorate the progression or severity of a disease or symptoms associated therewith. The term "treatment" includes reducing or alleviating at least one side effect or symptom of a condition, disease or disorder (e.g., coronavirus infection). Treatment is generally "effective" if one or more symptoms or clinical markers are reduced. Alternatively, treatment is "effective" if the progression of the disease is reduced or stopped. That is, "treatment" includes not only improvement of symptoms or markers, but also at least a delay in the progression of the condition or a halt in the worsening of the condition that would be expected in the absence of treatment. Beneficial or desirable clinical results include, but are not limited to, alleviation of one or more symptoms, reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), delay or reduction in the progression of the disease, improvement or reduction in the disease state, and alleviation (partial or complete), whether detectable or undetectable. The term "treatment" of a disease also includes alleviation of symptoms or side effects of the disease (including palliative treatment).

[0224] As used herein, the term "therapeutically effective amount" refers to an amount of a drug or pharmaceutical agent that induces a biological or medical response in a tissue, system, animal, mammal, or human that is being sought, for example, by a researcher or clinician. The biological or medical response may be considered a preventative or therapeutic response. The term "therapeutically effective amount" refers to an amount that improves the treatment, cure, prevention, or amelioration of a disease, condition, or side effect, or results in a slowing of the progression of a disease or condition, compared to a corresponding subject not administered such amount. The term also includes within its scope an amount effective to enhance normal physiological function. As used herein, an effective amount also includes an amount sufficient to slow the development of a disease symptom, alter the course of a disease symptom (e.g., but not limited to, slowing the progression of a disease symptom), or reverse a disease symptom.

[0225] Pharmaceutical compositions and their use as therapeutics for treating coronavirus infections - Patents.com In some embodiments, the present invention also provides pharmaceutical compositions comprising a compound of the invention (e.g., a compound of Formula X, Formula Y (e.g., Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Formula I, II, III, IV, or V, any compound described in Table A herein, or any compound among Compounds 1-177, or a pharma- ceutically acceptable salt thereof), and any one or more pharma- ceutically acceptable excipients. In any embodiment described herein, unless otherwise indicated or contrary to context, the pharmaceutical composition can include a compound selected from the compounds described in Table A herein, or a pharma- ceutically acceptable salt thereof.

[0226] In one embodiment, the invention also provides a pharmaceutical composition comprising an effective amount of a compound of the invention (e.g., a compound of Formula X, Formula Y (e.g., Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Formula I, II, III, IV, or V, any compound described in Table A herein, or any compound of Compounds 1-177, or a pharma- ceutically acceptable salt thereof) and one or more pharma- ceutically acceptable carriers, diluents, or excipients. In some embodiments, the pharmaceutical compositions herein comprise a compound of the invention (e.g., a compound of Formula X, Formula Y (e.g., Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Formula I, II, III, IV, or V, any compound described in Table A herein, or any compound among Compounds 1-177, or a pharma- ceutically acceptable salt thereof) in an amount effective to treat coronavirus infection and symptoms associated therewith in a subject in need of such treatment. In some embodiments, In some embodiments, the coronavirus infection and symptoms associated therewith are caused by a coronavirus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2. In some embodiments, the coronavirus infection and symptoms associated therewith are caused by SARS-CoV-2. In some embodiments, the pharmaceutical compositions herein comprise a compound of the invention in an amount that effectively reduces the activity of a viral PLpro, which activity of the viral PLpro can lead to inhibiting SRAS-CoV-2 viral replication, thereby treating the infection and symptoms associated therewith caused by the SRAS-CoV-2 virus.

[0227] Pharmaceutical preparations may be provided in unit dose forms containing a predetermined amount of active ingredient per unit dose. As a non-limiting example, such a unit may contain 0.5 mg to 1 g of one or more of the compounds of the present invention, depending on the disease to be treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dose formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of the active ingredient as described above. Such pharmaceutical preparations may be prepared by any of the methods known in the art of pharmacy.

[0228] Pharmaceutical formulations can be adapted to be administered by any suitable route, such as, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes. Such formulations can be prepared by any method known in the art of pharmacy, for example, by combining the active ingredient with the carrier or excipient.

[0229] In some embodiments, the present invention provides pharmaceutical compositions suitable for injection, comprising one or more compounds of the present invention and a liquid carrier. In some embodiments, compositions used for injection include sterile aqueous solutions (if water soluble) or dispersions, and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the present invention provides pharmaceutical compositions suitable for intravenous administration, comprising one or more compounds of the present invention and a carrier selected from saline, sterile water, Cremophor® EL.TM. (BASF, Parsippany, NJ), and phosphate buffered saline (PBS). In all cases, the injectable pharmaceutical compositions are sterile and sufficiently fluid for administration by syringe. In all cases, the injectable pharmaceutical compositions are stable under the conditions of manufacture and storage, and free of contamination by microorganisms, such as bacteria and fungi.

[0230] In some embodiments, the carrier used in the injectable pharmaceutical composition comprises a solvent or dispersion medium, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent in the composition, for example, sugar, polyalcohol such as mannitol, sorbitol, or sodium chloride. Prolonged absorption of the injectable composition can be achieved by including in the composition an agent that delays absorption (e.g., aluminum monostearate or gelatin).

[0231] Sterile injectable solutions can be prepared by incorporating the compound in the desired amount in the appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.

[0232] Generally, the dispersion is prepared by incorporating one or more compounds of the present invention into a sterile carrier containing a basic dispersion medium and other necessary ingredients as enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of one or more compounds of the present invention and any other suitable formulation ingredients from a previously sterile-filtered solution.

[0233] In some embodiments, the present invention provides a pharmaceutical composition suitable for oral administration (oral pharmaceutical dose), comprising one or more compounds of the present invention and an inert diluent or edible carrier. For oral administration, one or more compounds of the present invention are mixed with an excipient and formulated into the form of a tablet, an orally disintegrating tablet, a capsule, an oral liquid, comprising a solution or suspension, each comprising an aqueous or non-aqueous liquid, a soft gelatin capsule (soft capsule), an effervescent tablet, a chewable tablet, an oral spray, a thin film, a powder or granules, an edible foam or whip, an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, or a loosely compressed tablet. Pharmaceutically compatible binders and / or auxiliary substances can be optionally used as part of the oral pharmaceutical dose. Tablets, pills, capsules, troches, and the like can contain any of the following ingredients: binders such as microcrystalline cellulose or gelatin, excipients such as starch or lactose, disintegrants such as alginic acid, primogel, or corn starch, lubricants such as magnesium stearate, glidants such as colloidal silica, sweeteners such as sucrose or saccharin, flavorings such as peppermint, methyl salicylate, or orange flavoring, or compounds of similar nature. For example, for oral administration in the form of a tablet or capsule, the active drug ingredient can be combined with an oral non-toxic pharma- ceutically acceptable inert carrier, such as, for example, ethanol, glycerol, water, and the like.

[0234] Capsules are manufactured by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or other suitable shell material. Glidants and lubricants, such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol, may be added to the mixture before encapsulation. Disintegrants or solubilizers, such as agar-agar, calcium carbonate, or sodium carbonate, may also be added to improve the availability of the drug when the capsule is ingested. Furthermore, suitable binders, lubricants, disintegrants, and coloring agents may be incorporated into the mixture, if desired or necessary. Examples of suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants suitable for these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. The disintegrants include, without being restricted thereto, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

[0235] Tablets can be formulated, for example, by preparing a powder mixture, granulating or grinding, adding a lubricant and disintegrant, and compressing into tablets. Powder mixtures can be prepared by mixing the appropriately ground compound with a diluent or base as described above. Optional ingredients include binders such as carboxymethylcellulose, alginates, gelatin, or polyvinylpyrrolidone, dissolution retarders such as paraffin, resorption accelerators such as quaternary ammonium salts, and / or absorbents such as bentonite, kaolin, or dicalcium phosphate. Powder mixtures can be wet granulated using binders such as syrup, starch paste, acadia mucilage, or cellulose, or solutions of polymeric materials, and forced through a screen. As an alternative to granulation, the powder mixture can be passed through a tablet press, resulting in imperfectly formed blocks broken into granules. The granules can be coated with stearic acid, stearates, taurants, or other additives to prevent sticking to the tablet forming dies. The mixture may be lubricated by adding grease, grease powder, or mineral oil. The lubricated mixture is then compressed into tablets. One or more compounds of the present invention may be combined with a free-flowing inert carrier and directly compressed into tablets without going through a granulation or tableting step. A clear or opaque protective coating consisting of a sealing coating of shellac, a coating of sugar or polymeric material, and a polish coating of wax may be provided. Dyes may be added to these coatings to distinguish different unit doses.

[0236] Oral liquids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given amount contains a predetermined amount of the compound.Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, and elixirs can be prepared by using a non-toxic alcoholic carrier.Suspensions can generally be prepared by dispersing the compound in a non-toxic carrier.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavorings such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, or their analogs can also be added.

[0237] Where appropriate, dosage unit formulations for oral administration may be microencapsulated. The formulations may also be prepared to provide extended or sustained release, for example by coating or embedding particulate matter in polymers, waxes, etc.

[0238] One or more compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations are clear to those skilled in the art. These materials are commercially available from Alza Corporation or Nova Pharmaceuticals, Inc. Liposomal suspensions, including liposomes targeted to infected cells with monoclonal antibodies against viral antigens, can be used as pharma- ceutically acceptable carriers. They can be prepared according to methods known to those skilled in the art.

[0239] In some embodiments, the present invention provides pharmaceutical compositions suitable for inhalation administration comprising one or more compounds of the present invention (inhalation compositions). In some embodiments, the inhalation compositions are formulated in the form of an aerosol spray generated from a pressurized container or dispenser containing a suitable propellant, or a nebulizer. The propellant can be, for example, a gas such as carbon dioxide, a C3-C5 alkane (propane, butane, or heptane), CHF 2 CHF, CF 3 CH 2 F, CHF 2 CH 3 , C.F. 3 CHFCF 3 and mixtures thereof.

[0240] In some embodiments, the present invention provides pharmaceutical compositions suitable for topical, transmucosal, or transdermal administration, comprising one or more compounds of the present invention and a transdermal permeation enhancer. Such transdermal permeation enhancers are known in the art, such as dimethylsulfone (DMSO), emu oil, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished using nasal sprays or suppositories. For transdermal administration, the compounds are formulated into ointments, salves, gels, hydrogels, or creams, as known in the art. Pharmaceutical formulations suitable for transdermal administration can be present as dispersion patches intended to remain in intimate contact with the epidermis of the recipient for an extended period of time. For example, the active ingredient can be delivered by iontophoretic transfer, as described in Pharmaceutical Research, 3(6), 318 (1986). The pharmaceutical composition may be delivered from a patch by a liquid transporter. The contents relating to such delivery systems are incorporated herein by reference. Pharmaceutical formulations suitable for topical administration can be prepared into ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.

[0241] For treatment of the eye or other external tissues, such as the mouth and skin, the formulations can be administered as a topical ointment or cream. When prepared in an ointment, the active ingredient can be used with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water base or a water-in-oil base.

[0242] Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

[0243] Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, tablets, mouthwashes, and the like.

[0244] Pharmaceutical formulations suitable for nasal administration (wherein the carrier is a solid) include coarse powders having a particle size of, for example, from 20 to 500 microns. Such powders are administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose. Where the carrier is a liquid, suitable formulations for administration as a nasal spray or nasal drops include aqueous or oil solutions of the active ingredient.

[0245] In some embodiments, the present invention provides pharma- ceutically acceptable suppository compositions (e.g., containing conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery comprising one or more compounds of the present invention.

[0246] In some embodiments, one or more compounds of the present invention may be coupled with a soluble polymer as a targeted drug carrier. Such polymers may include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethylene oxide polylysine substituted with palmitoyl residues. One or more compounds of the present invention may also be coupled with crosslinked or amphiphilic block copolymers of biodegradable polymer classes used to achieve controlled release of drugs, such as polylactic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.

[0247] In some embodiments, pharmaceutical preparations are formulated for parenteral administration, including aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bactericides, and solutes that render the preparation isotonic with the subject's blood, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0248] The formulations may be present in unit-dose or multi-dose containers, for example, sealed ampoules or vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, such as water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0249] For the sake of easy administration and uniformity of dosage, it is advantageous to formulate oral or parenteral compositions into unitary dosage form.As used herein, the term "unitary dosage form" refers to a physically separate unit suitable for therapeutic object, each unit contains a predetermined amount of active compound combined with the required pharmaceutical carrier that can be calculated to produce desired therapeutic effect.

[0250] The therapeutically effective amount of one or more compounds of the present invention depends on several factors.For example, the recipient's species, age, weight, the exact condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered.The therapeutically effective amount should ultimately be left to the discretion of the attending physician or veterinarian.In some embodiments, one or more compounds of the present invention may be effective in a wide range of doses.

[0251] In one embodiment, the present invention provides a compound of the present invention for use in medical treatment, particularly in the treatment of viral infections, such as coronavirus infections. The compounds of the present invention have shown activity against SRAS-CoV-2 infection.

[0252] The compounds of the present invention are particularly suitable for the treatment of SRAS-CoV-2 infection and associated conditions. The treatment referred to herein extends to the treatment of established infection, symptoms, and associated clinical conditions such as cytokine storm.

[0253] The compounds of the invention may also be used as adjunctive therapy in the treatment of coronavirus infection or related symptoms and effects (e.g., coronavirus-induced cytokine storm)

[21] .

[0254] The compounds of the present invention can be used alone or in combination with other therapeutic agents. The compounds of the present invention and other pharma- ceutical active agents can be administered together or separately, and when administered separately, administration can be performed simultaneously or sequentially in any order. The amounts and relative administration times of one or more compounds of the present invention and other pharma- ceutical active agents can be selected to achieve a desired overall therapeutic effect. The co-administration of one or more compounds of the present invention and other therapeutic agents can be combined by simultaneous administration in (1) a single pharmaceutical composition containing the two compounds, or (2) separate pharmaceutical compositions, each containing one compound. Alternatively, the combinations can be administered in a sequential manner, with one therapeutic agent administered first and then the other therapeutic agent, or can be administered separately in the reverse order. Such sequential administration can be close in time or distant in time.

[0255] One or more compounds of the present invention may be used in combination with one or more pharmaceutical agents used to prevent or treat coronavirus infection. Examples of such pharmaceutical agents include, but are not limited to, interferons, remdesivir, favipiravir, ribavirin or analogs thereof, protease inhibitors, 3CLpro inhibitors such as nilmatrellvir, α-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of SARS coronavirus polymerase, non-nucleoside inhibitors of SARS coronavirus polymerase, SARS coronavirus helicase inhibitors, TLR-7 agonists, cyclophilin inhibitors, pharmacokinetic enhancers, and other agents for treating SARS coronavirus, or mixtures thereof. Combinations of one or more compounds of the present invention are typically selected based on the condition to be treated, cross-reactivity of the components, and the pharmacological properties of the combination. For example, when treating an infection (e.g., SARS CoV-2), one or more compounds of the present invention can be combined with other active therapeutic agents (e.g., those described herein).

[0256] Suitable active therapeutic agents or components that can be combined with one or more compounds of the invention include, for example, pegylated rIFN-alpha 2a, PEGylated rIFN-alpha 2a, rIFN-alpha 2b, IFN-alpha-2b XL, rIFN-alpha 2a, consensus IFN-alpha, interferon alpha 1 (infergen), interferon beta 1a (Rebif), interferon alpha 2b (Locteron), AV Interferons such as I-005, PEG-interferon alpha 1, PEGylated IFN-beta, oral interferon alpha, interferon, alpha 2a interferon, intermax alpha, r-EFN-beta, interferon alpha 1 + interferon gamma 1b, IFN-omega + DUROS, and Albuferon; remdesivir, remdesivir analogs, favipiravir, favipiravir analogs, ribavirin, ribavirin analogs, hepatoprotectants such as 1DN-6556, ME 3738, MitoQ, and LB-84451, non-nucleoside inhibitors of SARS coronavirus.

[0257] In another embodiment, the present invention provides pharmaceutical compositions comprising one or more compounds of the present invention in combination with at least one other therapeutic agent and a pharma- ceutically acceptable carrier or excipient.

[0258] In another embodiment, the present invention provides pharmaceutical compositions comprising one or more compounds of the present invention in combination with at least one other therapeutic agent selected from biologics, interleukin-6 inhibitors, sarilumab, siltuximab, tocilizumab, TNFα inhibitors, adalimumab, etanercept, infliximab, certolizumab, interleukin-12 / 23 inhibitors, ustekinumab, interleukin-17A inhibitors, secukinumab, brodalumab, ixekizumab, interleukin-23 inhibitors, guselkumab, tildrakizumab, risankizumab.

[0259] One or more compounds of the present invention may also be combined with one or more other active therapeutic agents in a unit dosage form and administered to a subject simultaneously or sequentially. The combination therapy may be administered simultaneously or sequentially. When administered sequentially, the combination may be administered in two or more doses.

[0260] Co-administration of one or more compounds of the present invention with one or more other active therapeutic agents generally refers to the simultaneous or sequential administration of one or more compounds of the present invention and one or more other active therapeutic agents such that therapeutically effective amounts of both the compounds of the present invention and the one or more other active therapeutic agents are present in the subject's body.

[0261] Coadministration includes administering a unit dose of one or more compounds of the invention before or after administering a unit dose of one or more other active therapeutic agents, for example, administering one or more compounds of the invention within seconds, minutes, or hours after administering one or more other active therapeutic agents. For example, a unit dose of one or more compounds of the invention can be administered first, followed by administration of one or more unit doses of the other active therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more other active therapeutic agents can be administered first, followed by administration of one or more compounds of the invention within seconds or minutes. In some cases, it is necessary to administer a unit dose of one or more compounds of the invention first, followed by administration of a unit dose of one or more other active therapeutic agents after a certain time (e.g., 1 to 12 hours). In other cases, it is necessary to administer a unit dose of one or more other active therapeutic agents first, followed by administration of a unit dose of one or more compounds of the invention after a certain time (e.g., 1 to 12 hours).

[0262] Combination therapy can provide "synergy" and "synergistic effects" in which the effect achieved when the active ingredients are used together is greater than the sum of the effects that would result if the compounds were used alone. The combination therapy can provide "synergistic effects" and "synergistic effects" in which the active ingredients are (I) coformulated in a combination formulation and administered or delivered simultaneously, (2) delivered alternately or in parallel as separate formulations, or (3) administered in combination with other active ingredients. When other treatment methods are adopted, synergistic effects are obtained.When compounds are delivered in alternating therapy, synergistic effects are obtained when the compounds are administered or delivered sequentially, for example, in separate tablets, pills or capsules, or by different injections in separate syringes.Generally, during alternating therapy, the effective dose of each active ingredient is administered sequentially, i.e., sequentially, whereas in combination therapy, the effective doses of two or more active ingredients are administered together.Synergistic antiviral effect means that the antiviral effect is greater than the expected pure additive effect of each compound in combination.

[0263] In one embodiment, the present invention provides a process for preparing a pharmaceutical formulation comprising mixing one or more compounds of the present invention with one or more pharma- ceutically acceptable carriers, diluents, or excipients.

[0264] In some embodiments, the invention provides a method of treating coronavirus infection and associated conditions (or the use of one or more compounds of the invention in the preparation of a medicament for treating coronavirus infection and associated conditions) in a subject in need thereof, such as an infected animal or a mammal, including a human, comprising administering to the subject a therapeutically effective amount of one or more compounds of the invention. In some embodiments, the invention provides a method of inhibiting SARS-coronavirus protease in a cell comprising contacting a coronavirus-infected cell with an effective amount of one or more compounds of the invention and at least one other active therapeutic agent, wherein the active therapeutic agent is selected from interferon, remdesivir, flavipiravir, ribavirin or an analog thereof, a protease inhibitor, an alpha-glucosidase 1 inhibitor, a hepatoprotectant, a nucleoside or nucleotide inhibitor of coronavirus polymerase, a non-nucleoside inhibitor of coronavirus polymerase, a pharmacokinetic enhancer, and other agents for treating SARS-coronavirus, or mixtures thereof.

[0265] In some embodiments, the methods include administering to a subject an effective amount of one or more compounds of the invention that modulate the activity of a viral protein in the subject.

[0266] Without wishing to be bound by theory, it is believed that the one or more compounds can be used to modulate the activity of a viral protein encoded by a coronavirus that causes an infection, and that when the one or more compounds modulate the activity of the viral protein in a subject, inflammation and / or immunomodulatory activity due to the coronavirus can be prevented and treated.

[0267] In some embodiments, the invention provides a method of treating or preventing a viral infection comprising administering to a subject in need thereof an effective amount of a compound of the invention (e.g., a compound of Formula X, Formula Y (e.g., Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y-2-A, Y-2-B, Y-2-C, Y-2-D, Y-2-E, Y-2-F, Y-3, Y-3A, Y-3B, Y-3C, Y-4, Y-5, Y-6, or Y-7), Formula I, II, III, IV, or V, any compound described in Table A herein, or any compound among Compounds 1-177, or a pharma- ceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound of the invention. In some embodiments, the method further comprises administering to the subject one or more other antiviral agents described herein. In some embodiments, the viral infection is caused by a virus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2. In some preferred embodiments, the viral infection is a SARS-CoV-2 infection.

[0268] In some embodiments, the present invention provides a compound of the present invention, comprising an effective amount of a compound of the present invention (e.g., a compound of formula X, a compound of formula Y (e.g., Y-1, Y-1-A, Y-1-B, Y-1-C, Y-1-D, Y-2, Y- The present invention provides a method for inhibiting papain-like protease (PLpro), comprising administering to a subject in need thereof a compound of formula I, II, III, IV, or V, any compound described in Table A herein, or any compound among compounds 1-177, or a pharma- ceutical acceptable salt thereof, or a pharmaceutical composition comprising a compound of the present invention. In some embodiments, the subject is suffering from a viral infection caused by a virus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2. In some preferred embodiments, the subject is suffering from a SARS-CoV-2 infection.

[0269] Working Example The definitions of terms and abbreviations used in this specification are as follows:

[0270] ●A549: hACE2 A549 cells overexpressing human ACE2 receptor ●BSA Bovine serum albumin ●DAB 3,3′-diaminobenzidine DCM Dichloromethane ●DMEM Dulbecco's Modified Eagle Medium ●DIPEA Diisopropylethylamine ●DMF N,N-Dimethylformamide ●DMSO Dimethyl sulfoxide Ethyl acetate (EtOAc) EtOH Ethanol ●H 2 O water ●HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) Hex ● HPLC High-performance liquid chromatography ●HRP Horseradish peroxidase ●IC50 half inhibitory concentration ●K 2 CO 3 Potassium carbonate ●LC-MS Liquid Chromatography-Mass Spectrometry LiOH Lithium hydroxide ●MeOH Methanol ●MOI Multiplicity of infection ●MS Mass Spectrum ●N 2 Nitrogen gas ●PBS Phosphate buffered saline ●PBST Phosphate buffered saline / Tween ●PLpro papain-like protease ●rt room temperature ●rac racemic ●RT retention time THF Tetrahydrofuran ●TFA Trifluoroacetic acid ●FA Formic acid ●UV Ultraviolet rays

[0271] Chemical Experiment General. All reactions using air- or moisture-sensitive reagents should be carried out in dry glassware with dry N 2The experiments were carried out at room temperature. Solvents were purchased from Sigma-Aldrich or Oakwood Chemical and used without further purification. Reagents and other chemicals were purchased from commercial sources with purity of >95% and did not require further purification. Flash column chromatography was performed using Combi-Flash NextGen 300+ and RediSep columns with EA / Hexane or MeOH / DCM as eluents. Purity was assessed by LC / MS / UV using UHPLC-MS (a Thermo Scientific Ultimate 3000 high performance liquid chromatography (HPLC) system coupled with a ThermoScientific mass spectrometer (LTQ XL MS) for qualitative analysis). Compounds were detected by fluorescence under UV light at 220 nm and 254 nm. All compounds were confirmed to be 95% or higher purity before testing. Compounds with purity less than 95% were marked separately with (*).

[0272] LC-MS conditions: Thermo Scientific Ultimate 3000 high performance liquid chromatography (HPLC) system coupled with a ThermoScientific mass spectrometer (LTQ XL MS). Detection wavelengths: 220 nM and 254 nM. Method 1: Column: Phenomenex Luna® (C18, 5 μm 50x2 mm); Mobile phase A: H 2 O / 0.1% FA; Mobile phase B: CH 3 CN / 0.1% FA; Flow rate: 0.400 ml / min; Gradient: 5% B at 0 min, 95% B at 6.0 min, 95% B at 8.0 min, 5% B at 8.1 min, stop at 10.0 min; Column temperature: 40° C. Method 2: Column: Water ACQUITY UPLC® (C18, 1.7 μm 50x2.1 mm); Mobile phase A: H 2 O / 0.1% FA; Mobile phase B: CH 3CN / 0.1% FA; flow rate: 0.400 ml / min; gradient: 5% B at 0 min, 95% B at 6.0 min, 95% B at 8.0 min, 5% B at 8.1 min, stop at 10.0 min; column temperature: 40° C. Method 3: Column: Phenomenex Luna® (C18, 5 μm 50x2 mm); mobile phase A: H 2 O / 0.1% FA; Mobile phase B: CH 3 CN / 0.1% FA; flow rate: 1.000 ml / min; gradient: 5% B at 0 min, 95% B at 4.0 min, 95% B at 4.8 min, 5% B at 4.9 min, stop at 6.0 min; column temperature: 40°C.

[0273] Illustrative examples of compounds of the present invention include, but are not limited to, one or more of the compounds shown in Table 1 below.

[0274] [Table 2-1]

[0275] [Table 2-2]

[0276] a. PLpro enzyme inhibition level is IC 50 +++(IC 50 : Less than 100 nM), ++ (IC 50 : 0.1 μM to less than 1 μM), or + (IC 50 : 1 μM to 10 μM).

[0277] General scheme 1 [ka]

[0278] Reagents and conditions: (a) acetone, CH 3 I, 0℃~rt, 16 hours; (b)K 2 CO 3 , EtOH, reflux, 2 h; (c) NaBH 3CN, MeOH, rt, 16 h; (d) HATU, DIPEA, DMF, rt, 1 h; (e) DIPEA, DCM, rt, 1 h; (f) i) LiOH H 2 O, THF, H 2 O, rt, 1 hour, ii) HATU, DIPEA, DMF, rt, 1 hour.

[0279] General scheme 2 [ka]

[0280] Reagents and conditions: (a) NaBH 3 CN, MeOH, rt, 16 h; (b) HATU, DIPEA, DMF, rt, 1 h; (c) DIPEA, DCM, rt, 1 h; (d) HCl in dioxane, DCM; (e) K 2 CO 3 , ACN, 50℃, 16 hours; (f)i)Ti(Oi-Pr) 4 , DCM, reflux, 16 h; ii) NaBH 3 CN, MeOH , rt, 16 h; (g)i)LiOH·H 2 O, THF, H 2 O, rt, 1 hour, ii) HATU, DIPEA, DMF, rt, 1 hour.

[0281] The following examples detail the specific synthetic methods shown in the schemes that were used to synthesize some preferred compounds of the invention. However, one of ordinary skill in the art should understand that the chemical reactions may be modified slightly for the synthesis of other compounds of the invention. A , R 10 and W include any of the respective definitions described herein. C is, where applicable, R 14 or R 15 For example, G C can be an optionally substituted C alkyl group or an optionally substituted C cycloalkyl group. In some embodiments, R10 is an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted ring structure having 4 to 10 ring atoms and 1 to 3 ring heteroatoms.

[0282] These examples are not intended to limit the scope of the present invention in any way, but are only used to illustrate the present invention.

[0283] General Procedure A. Synthesis of 1,1-dimethyl-4-oxopiperidin-1-ium iodide (I-1) by alkylation [ka] To a solution of 1-methyl-4-piperidone (30 mmol, 1.0 eq) in acetone (15.0 mL) was added iodomethane (33 mmol, 1.1 eq) at 0° C. and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and dried under reduced pressure. The compound was used without further purification.

[0284] B. Synthesis of (R)-1-(1-(1-naphthyl)ethyl)piperidin-4-one (I-2) by substitution [ka] To a solution (100.0 mL) of (R)-1-(1-naphthyl)ethylamine (20 mmol, 1.0 eq) (or (S) or DL-1-(1-naphthyl)ethylamine) in EtOH / water (2:1), 2 CO 3 (50 mmol, 2.5 eq) and compound I-1 (21 mmol, 1.05 eq) were added, and the mixture was stirred at 110° C. for 2 h. Then, EtOH was removed under reduced pressure, and the aqueous layer was extracted with EtOAc. The organic layer was diluted with Na 2 SO 4 The crude product was then purified by flash column chromatography.

[0285] HPLC (Method 1) RT=3.52 min, purity >99.9%, MS(ESI+) m / z is C 17 H 20 NO + [M+H] + It was calculated as 254.4 and measured as 254.2.

[0286] C. Synthesis of methyl (R)-(R)-(1-(1-(1-naphthyl)ethyl)piperidin-4-yl)glycylglycinate (I-3) or tert-butyl 4-((2-((2-methoxy-2-oxoethyl)amino)-2-oxoethyl)amino)piperidine-1-carboxylate (I-6) by reductive amination [ka] To a suspension of compound I-2, 1-Boc-4-piperidone, or the corresponding ketone (2 mmol, 1.0 eq) in methanol (4.0 mL) was added methyl ((aminoacetyl)amino)acetate hydrochloride, or the corresponding amine (2 mmol, 1.0 eq) and sodium cyanoborohydride (4 mmol, 2.0 eq), and the mixture was stirred at room temperature for 1 h. The methanol was then removed under reduced pressure, and the reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate and extracted with EtOAc. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0287] HPLC (Method 1) RT=2.44 min, purity >99.9%, MS(ESI+) m / z is C 22 H 30 N 3 O 3 + [M+H] + Calculated to be 384.5 and measured to be 384.3. - Compound I-3

[0288] HPLC (Method 1) RT=3.51 min, purity >99.9%, MS(ESI+) m / z is C 15 H 28 N3 O 5 + [M+H] + Calculated: 330.2, Measured: 330.2. - Compound I-6

[0289] D. Synthesis of amides or sulfonamides (I-4, I-7) To a solution of compound I-3, I-6, or the corresponding intermediate (0.1 mmol, 1.0 eq) in DMF (0.3 mL) was added the corresponding carboxylic or sulfonic acid (0.1 mmol, 1.0 eq), and DIPEA (0.2 mmol, 2.0 eq). Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was purified by NaCl distillation. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0290] When the corresponding reagent was a carbonyl chloride or sulfonyl chloride, the substitution procedure shown below was used. To a solution of compound (I-3) (0.1 mmol, 1.0 eq) in DCM (0.3 mL) was added DIPEA (0.2 mmol, 2.0 eq). The corresponding carbonyl chloride or sulfonyl chloride (0.1 mmol, 1.0 eq) was slowly added to the mixture at 0° C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0291] E. Hydrolysis and Amide Coupling (I-5, I-9) To a solution of compound I-4, I-8, or the corresponding ester (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0292] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL), DIPEA (0.2 mmol, 2.0 eq) and the corresponding amine, or its salt form (0.1 mmol, 1.0 eq) was added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc and washed several times with brine. The organic layer was purified by filtration using NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0293] F. Synthesis of I-8 by reductive amination or substitution A solution of compound (I-7) (0.1 mmol, 1.0 eq) in ACN (0.3 mL) was added to the 2 CO 3 (0.2 mmol, 2.0 eq) and the corresponding halide, mesylate, or tosylate (0.1 mmol, 1.0 eq) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then heated to 50° C. and left overnight. The reaction mixture was quenched with water and extracted with DCM. The organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0294] When the corresponding reagent was a ketone, the reductive amination procedure shown below was used: A solution of compound (I-7) (0.1 mmol, 1.0 eq) and the corresponding ketone (0.1 mmol, 1.0 eq) in DCM (0.3 mL) was treated with Ti(Oi-Pr)4 (0.1 mmol, 1.0 eq) was added. The reaction mixture was refluxed overnight. The reaction mixture was then concentrated under reduced pressure. The mixture was diluted with MeOH (0.3 mL). The mixture was diluted with NaBH 3 CN (0.3 mmol, 3.0 eq) was added and the mixture was refluxed for 4 h. The solvent was removed under reduced pressure and the reaction mixture was quenched with water and extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0295] Synthesis of Compound I-3-Racemate [ka] To a suspension of compound I-2-racemate (2 mmol, 1.0 eq) in MeOH (4.0 mL) was added methyl ((aminoacetyl)amino)acetate hydrochloride (2 mmol, 1.0 eq) and sodium cyanoborohydride (4 mmol, 2.0 eq) and the mixture was stirred at room temperature for 1 h. MeOH was then removed under reduced pressure and the reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate and extracted with EtOAc. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0296] HPLC (Method 1) RT=2.44 min, purity >99.9%, MS(ESI+) m / z is C 22 H 30 N 3 O 3 + [M+H] + The calculated value was 384.5 and the measured value was 384.3.

[0297] Synthesis of compound I-10 [ka] To a solution of compound I-3-racemate (0.1 mmol, 1.0 eq) in DMF (0.3 mL) was added 1,3-benzodioxole-5-acetic acid (0.1 mmol, 1.0 eq) and DIPEA (0.2 mmol, 2.0 eq). Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0298] HPLC (Method 1) RT=4.30 min, purity >99.9%, MS(ESI+) m / z is C 31 H 36 N 3 O 6 + [M+H] + The calculated value was 546.3 and the measured value was 546.4.

[0299] Synthesis of compound 1 [ka] To a solution of compound I-10 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0300] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq) and (E)-4-amino-2-butenoic acid, 4-amino-, methyl ester, (E)-, trifluoroacetate (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was washed with NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0301] Synthesis of compound 12 [ka] To a solution of compound I-3 (0.1 mmol, 1.0 eq) in DMF (0.3 mL) was added propargylamine (0.1 mmol, 1.0 eq) and DIPEA (0.2 mmol, 2.0 eq). Then, HATU (0.1 mmol, 1.0 eq) was slowly added to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0302] Synthesis of compound 63 [ka] To a solution of compound (12) (0.1 mmol, 1.0 eq) in DCM (0.3 mL) was added DIPEA (0.2 mmol, 2.0 eq). Benzenesulfonyl chloride (0.1 mmol, 1.0 eq) was slowly added to the mixture at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0303] Synthesis of compound 60 [ka] To a solution of compound (12) (0.1 mmol, 1.0 eq) in DCM (0.3 mL) was added DIPEA (0.2 mmol, 2.0 eq). Cyclopropanesulfonyl chloride (0.1 mmol, 1.0 eq) was added slowly to the mixture at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0304] Synthesis of compound I-11 [ka] To a solution of compound (I-3) (0.1 mmol, 1.0 eq) in DCM (0.3 mL) was added DIPEA (0.2 mmol, 2.0 eq). Methanesulfonyl chloride or methanesulfonic anhydride (0.1 mmol, 1.0 eq) was slowly added to the mixture at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0305] HPLC (Method 1) RT=3.98 min, purity >99.9%, MS(ESI+) m / z is C 23 H 32 N 3 O 5 + [M+H] + The calculated value was 462.2 and the measured value was 462.3.

[0306] Synthesis of Compound I-11-Racemate [ka] To a solution of compound (I-3-racemate) (0.1 mmol, 1.0 eq) in DCM (0.3 mL) was added DIPEA (0.2 mmol, 2.0 eq). Methanesulfonyl chloride or methanesulfonic anhydride (0.1 mmol, 1.0 eq) was added slowly to the mixture at 0° C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0307] HPLC (Method 1) RT=3.98 min, purity >99.9%, MS(ESI+) m / z is C 23 H 32 N 3 O 5 + [M+H] + The calculated value was 462.2 and the measured value was 462.3.

[0308] Synthesis of compound 20 [ka] To a solution of compound I-11 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0309] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq), and (E) 4-amino-2-butenoic acid methyl trifluoroacetate (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was concentrated with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0310] Synthesis of compound 21 [ka] To a solution of compound I-11 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0311] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq) and propargylamine (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was concentrated with Na2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0312] Synthesis of compound 127 [ka] To a solution of compound I-11 (0.1 mmol, 1.0 eq) in DMF (0.3 mL), but-3-yn-1-amine hydrochloride (0.1 mmol, 1.0 eq) and DIPEA (0.2 mmol, 2.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was purified by NaCl distillation. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0313] Synthesis of compound I-12 [ka] To a solution of compound (I-3) (0.1 mmol, 1.0 eq) in DCM (0.3 mL) was added DIPEA (0.2 mmol, 2.0 eq). Pyrrolidine-1-sulfonyl chloride (0.1 mmol, 1.0 eq) was slowly added to the mixture at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0314] HPLC (Method 1) RT=4.33 min, purity >99.9%, MS(ESI+) m / z is C 26 H 37 N 4 O 5 S + [M+H] +The calculated value was 517.2 and the measured value was 517.4.

[0315] Synthesis of compound 65 [ka] To a solution of compound I-12 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0316] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq) and propargylamine (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was concentrated with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0317] Synthesis of compound I-13 [ka] To a solution of compound I-3 (0.1 mmol, 1.0 eq) in DMF (0.3 mL), cyclobutanecarboxylic acid (0.1 mmol, 1.0 eq) and DIPEA (0.2 mmol, 2.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was slowly added to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0318] HPLC (Method 1) RT=4.13 min, purity >99.9%, MS(ESI+) m / z is C 27 H 36 N 3 O 4 + [M+H] + The calculated value was 466.3 and the measured value was 466.5.

[0319] Synthesis of compound 7 [ka] To a solution of compound I-13 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0320] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq), and (E) 4-amino-2-butenoic acid methyl trifluoroacetate (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was concentrated with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0321] Synthesis of compound I-14 [ka] To a solution of diethyl(methylsulfonylmethyl)phosphonate (1 mmol, 1.0 eq) in THF (10 mL) was slowly added 60% NaH (1.3 mmol, 1.3 eq) at 0° C. The reaction mixture was stirred for 10 min at 0° C. Then, N-Boc-2-aminoacetaldehyde (190 mg, 1.2 mmol, 1.2 eq) in THF (1 mL) was slowly added to the mixture. The reaction was allowed to warm to room temperature and stirred for 1 h. The excess solvent was then dried under reduced pressure. The mixture was extracted with EtOAc and washed with MgSO 4 The crude material was then purified by flash column chromatography. To a solution of the purified boc-protected amine (0.2 mmol) in DCM (0.3 mL) was added TFA (0.1 mL) slowly at 0° C. The reaction mixture was stirred at room temperature for 30 min. The excess solvent was then dried under reduced pressure. The compound was used without further purification.

[0322] Synthesis of Compound I-13-Racemate [ka] To a solution of compound I-3-racemate (0.1 mmol, 1.0 eq) in DMF (0.3 mL) was added cyclobutanecarboxylic acid (0.1 mmol, 1.0 eq) and DIPEA (0.2 mmol, 2.0 eq). Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0323] HPLC (Method 1) RT=4.17 min, purity=88.4%, MS(ESI+) m / z is C 27 H 36 N 3 O 4 + [M+H] + The calculated value was 466.3 and the measured value was 466.4.

[0324] Synthesis of compound 9 [ka] To a solution of compound I-13-racemate (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0325] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq) and compound I-14 (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was purified by filtration using NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0326] Synthesis of compound 59 [ka] To a solution of compound I-11 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0327] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq) and compound I-14 (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was purified by filtration using NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0328] Synthesis of compound I-15 [ka] To a solution of compound I-11 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0329] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq) and H-Gly-OMe HCl (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was concentrated with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0330] HPLC (Method 1) RT=4.17 min, purity=87.5%, MS(ESI+)m / z is C 25 H 35 N 4 O 6 S+ [M+H] + The calculated value was 519.2 and the measured value was 519.4.

[0331] Synthesis of compound I-16 [ka] To a solution of compound I-15 (0.1 mmol, 1.0 eq) in THF (0.1 mL) was added lithium aluminum hydride (0.3 mmol, 3.0 eq) at 0° C. and the reaction mixture was stirred for 1 h. The reaction mixture was quenched with 1N NaOH solution (0.1 mL), filtered, extracted with EtOAc, washed with brine, and diluted with Na 2 SO 4 The crude material was then purified by flash column chromatography.

[0332] HPLC (Method 1) RT=3.73 min, purity >99.9%, MS(ESI+) m / z is C 24 H 35 N 4 O 5 S + [M+H] + The calculated value was 491.2 and the measured value was 491.4.

[0333] Synthesis of compound 64 [ka] To a solution of compound I-16 (0.1 mmol, 1.0 eq) in DCM (0.4 mL) and DMSO (0.1 mL), SO3Py complex (0.3 mmol, 3.0 eq) and TEA (0.6 mmol, 6.0 eq) were added at 0° C., and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with EtOAc, washed with brine, and then washed with Na 2 SO 4 The crude material was then purified by flash column chromatography. Mass spectrum showed the hydroxyacetal (MS=507), and the protonated form (MS=489).

[0334] Synthesis of compound I-17 [ka] To a solution of compound (I-3-racemate) (0.1 mmol, 1.0 eq) in DCM (0.3 mL) was added DIPEA (0.2 mmol, 2.0 eq). Acetyl chloride or acetic anhydride (0.1 mmol, 1.0 eq) was added slowly to the mixture at 0° C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0335] HPLC (Method 1) RT=3.75 min, purity=88.4%, MS(ESI+) m / z is C 24 H 32 N 3 O 4 + [M+H] + The calculated value was 426.2 and the measured value was 426.3.

[0336] Synthesis of compound 13 [ka] To a solution of compound I-17 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0337] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq) and (E) 4-amino-2-butenoic acid methyl trifluoroacetate (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was washed with NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0338] Synthesis of compound I-18 [ka] To a solution of compound (I-6) (0.1 mmol, 1.0 eq) in DCM (0.3 mL) was added DIPEA (0.2 mmol, 2.0 eq). Methanesulfonyl chloride or methanesulfonic anhydride (0.1 mmol, 1.0 eq) was slowly added to the mixture at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water and extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0339] To a solution of the methanesulfonylated intermediate (1 mmol, 1.0 eq) in DCM (3 mL) was added a solution of 4 M HCl in 1,4-dioxane (3 mmol, 3.0 eq) at 0° C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 1 h. The mixture was diluted with DCM and filtered to collect the precipitate. The crude product was used without further purification.

[0340] HPLC (Method 1) MS(ESI+)m / z is C 11 H 22 N 3 O 5 S + [M+H] +The calculated value was 308.1 and the measured value was 308.2.

[0341] Synthesis of compound I-19 [ka] A solution of 1-(4-fluoro-1-naphthyl)ethanone (1 mmol, 1.0 eq) in MeOH (3 mL) was added to NaBH 4 (2 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with 1N HCl, concentrated, diluted and extracted with DCM. The organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0342] To a solution of the hydroxyl intermediate (0.1 mmol) in DCM (0.3 mL), SOCl 2 (0.6 mmol, 6.0 eq) and DMF (0.01 mmol, 0.1 eq) were added. The reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated and dried under reduced pressure. The crude mixture was used without further purification.

[0343] Synthesis of compound I-20 [ka] A solution of compound I-18 (0.1 mmol, 1.0 eq) in ACN (0.3 mL) was 2 CO 3 (0.2 mmol, 2.0 eq) and compound I-19 (0.1 mmol, 1.0 eq) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then heated to 50° C. and stirred overnight. The reaction mixture was quenched with water and extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0344] HPLC (Method 1) RT=4.11 min, MS(ESI+) m / z is C 23 H 31 FN 3 O 5 S + [M+H] + The calculated value was 480.2 and the measured value was 480.2.

[0345] Synthesis of compound 107 [ka] To a solution of compound I-20 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0346] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and mixed with DIPEA (0.2 mmol, 2.0 eq) and propargylamine (0.1 mmol, 1 0.0eq) was added. Then HATU (0.1mmol, 1.0eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0347] Synthesis of compound I-21 [ka] A solution of 2'-chloroacetophenone (0.1 mmol, 1.0 eq) and compound I-18 in DCM (0.3 mL) was added to Ti(Oi-Pr) 4(0.1 mmol, 1.0 eq) was added. The reaction mixture was refluxed overnight. The reaction mixture was then concentrated under reduced pressure. The mixture was diluted with MeOH (0.3 mL). The mixture was diluted with NaBH 3 CN (0.3 mmol, 3.0 eq) was added and the mixture was stirred for 16 h. The solvent was removed under reduced pressure and the reaction mixture was quenched with water and extracted with DCM. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0348] HPLC (Method 1) RT=3.59 min, purity >99.9%, MS(ESI+) m / z is C 19 H 29 ClN 3 O 5 S + [M+H] + The calculated value was 446.2 and the measured value was 446.1.

[0349] Synthesis of Compound 101 [ka] To a solution of compound I-21 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0350] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq) and propargylamine (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was concentrated with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0351] Synthesis of compound I-22 [ka] To a suspension of compound I-2 (2 mmol, 1.0 eq) in MeOH (4.0 mL), N-methylglycine methyl ester hydrochloride (2 mmol, 1.0 eq) and sodium cyanoborohydride (4 mmol, 2.0 eq) were added and the mixture was stirred at room temperature for 1 h. Then, the methanol was removed under reduced pressure and the reaction mixture was diluted with saturated NaHCO 3 The mixture was quenched with ethyl acetate and extracted with EtOAc. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0352] HPLC (Method 1) RT=3.02 min, purity=92.6%, MS(ESI+) m / z is C 21 H 29 N 2 O 2 + [M+H] + The calculated value was 341.2 and the measured value was 341.2.

[0353] Synthesis of compound I-23 [ka] To a solution of compound I-22 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0354] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and mixed with DIPEA (0.2 mmol, 2.0 eq) and glycine ethyl ester hydrochloride (0.1 mmol, 1.0 eq). mol, 1.0 eq) was added. Then, HATU (0.1 mmol, 1.0 eq) was slowly added to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0355] HPLC (Method 1) RT=3.34 min, purity=92.9%, MS(ESI+) m / z is C 24 H 34 N 3 O 3 + [M+H] + The calculated value was 412.3 and the measured value was 412.4.

[0356] Synthesis of compound 25 [ka] To a solution of compound I-23 (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0357] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq) and glycine ethyl ester hydrochloride (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was concentrated with Na 2 SO4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0358] Synthesis of compound I-24 [ka] LiAlD in anhydrous THF (5 mL) 4 To the suspension of (12 mmol, 1.7 eq) was added dropwise a solution of 2,2-diethoxyacetamide (6.8 mmol, 1.0 eq) in dry THF (0.60 mL) at 0° C. The resulting mixture was stirred at 25° C. for 30 min and then heated at 75° C. for 2 h. The mixture was cooled and purified by H 2 The mixture was quenched with 2M NaOH (1 mL) and 3M HO (1 ml). After stirring for 30 min, the mixture was filtered through a silica gel filter (peddle of The white precipitate was removed by filtration through silica gel and washing with a small amount of ethyl ether. The mother liquor was evaporated and the residue was dissolved in 2 mL of DCM and added Na 2 SO 4 Dry with , filtered and concentrated.

[0359] Synthesis of compound 158 [ka] To a solution of compound I-11-racemate (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0360] The carboxylic acid (0.1 mmol, 1.0 eq) was redissolved in DMF (0.3 mL) and DIPEA (0.2 mmol, 2.0 eq) and compound I-24 (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was added slowly to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was purified by filtration using NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0361] Synthesis of compound 153 [ka] Compound 158 (0.1 mmol, 1.0 eq) in DCM (0.8 mL) and D 2 To a solution of 2O (0.2 mL) was added TFA (0.5 mmol, 5.0 eq) at 0° C. and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM, cooled to 0° C. and diluted with NaHCO 3 / D 2 Neutralized with 20H2O solution (10%, 3 ml), extracted with DCM, and 2 SO 4 The crude product was dried under reduced pressure and used in the next step without further purification.

[0362] To a solution of KOt-Bu (0.2 mmol, 2.0 eq) in THF (3.0 mL) was added Bestmann's reagent (0.2 mmol, 2.0 eq) at -78 °C. The reaction mixture was stirred at the same temperature for 5 min. To the mixture was added the aldehyde in THF (1.5 mL) from the previous step dropwise. The reaction mixture was allowed to warm slowly to room temperature. The reaction was diluted with DCM and quenched with water at 0 °C. The reaction mixture was extracted with DCM and washed several times with water. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0363] Synthesis of compound I-25 [ka] To a solution of potassium phthalimide (1.0 mmol, 1.0 eq) in DMF (1.0 mL) was added 1-chloro-3-fluoro-2-propanol (1.0 mmol, 1.0 eq). The reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was extracted with EtOAc and washed several times with water. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0364] To a solution of the potassium phthalimide protected compound from the previous step (1.0 mmol, 1.0 eq) in MeOH (2.0 mL) was added hydrazine monohydrate (1.0 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 16 h. Concentrated liquid HCl (2 mL) was added to the reaction mixture and the reaction mixture was stirred for 3 h. The precipitate was then collected by filtration and dried under reduced pressure.

[0365] Synthesis of compound 116 [ka] To a solution of compound I-11-racemate (0.1 mmol, 1.0 eq) in THF / water (4:1, 0.5 mL) was added lithium hydroxide monohydrate (0.1 mmol, 1.0 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was filtered through a thin layer of silica pad and washed with methanol. The filtrate was concentrated and dried thoroughly under reduced pressure. The hydrolyzed carboxylic acid was used without further purification.

[0366] Redissolve the carboxylic acid (0.1 mmol, 1.0 eq) in DMF (0.3 mL) and DI PEA (0.2 mmol, 2.0 eq) and compound I-25 (0.1 mmol, 1.0 eq) were added. Then, HATU (0.1 mmol, 1.0 eq) was slowly added to the mixture at room temperature. The mixture was stirred for 1 h. The reaction mixture was quenched with water, extracted with EtOAc, and washed several times with brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0367] Synthesis of compound 132 [ka] To a solution of compound 116 (0.1 mmol, 1.0 eq) in DCM (0.3 mL) was added DMP (0.2 mmol, 2.0 eq) at 0° C. and the reaction mixture was stirred for 1 h. The reaction mixture was then diluted with saturated NaHCO 3 The mixture was quenched with a solution of 1,000 ml of ethyl acetate, extracted with DCM, and washed several times with water. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and the crude material was then purified by flash column chromatography.

[0368] PLpro Inhibitors--Examples Examples of compounds according to formula I include, but are not limited to, one or more of the compounds listed below as "Examples of PLpro Inhibitors". Some compounds are synthesized according to the general schemes and procedures described above using the corresponding reagents.

[0369] Compound 1, methyl (E)-4-(2-(2-(2-(benzo[d][1,3]dioxol-5-yl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 2) RT=4.78 min, purity 95.0%, MS(ESI+) m / z is C35 H 41 N 4 O 7 + [M+H] + The calculated value was 629.7 and the measured value was 629.4.

[0370] Compound 2, methyl (R,E)-4-(2-(2-(2-(benzo[d][1,3]dioxol-5-yl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.42 min, purity 95.0%, MS(ESI+) m / z is C 35 H 41 N 4 O 7 + [M+H] + The calculated value was 629.7 and the measured value was 629.6.

[0371] Compound 3, methyl (R,E)-4-(2-(2-(2-(3-fluorophenyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.51 min, purity >99.9%, MS(ESI+) m / z is C 34 H 40 FN 4 O 5 + [M+H] + The calculated value was 603.7 and the measured value was 603.5.

[0372] Compound 4, methyl(E)-4-(2-(2-(N-(1-(1-(naphthalene-1-yl) ethyl)piperidin-4-yl)-2-phenylacetamide)acetamide)acetamide)but-2-enoate [ka] HPLC (Method 1) RT=4.44 min, purity >99.9%, MS(ESI+) m / z is C 34 H 40 N 4 O 5 + [M+H] + The calculated value was 585.7 and the measured value was 585.5.

[0373] Compound 5, methyl (R,E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclopropanecarboxamide)acetamide)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.11 min, purity >99.9%, MS(ESI+) m / z is C 30 H 39 N 4 O 5 + [M+H] + The calculated value was 535.7 and the measured value was 535.5.

[0374] Compound 6, methyl (E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.26 min, purity >99.9%, MS(ESI+) m / z is C 31 H 41 N 4 O 5 + [M+H] +The calculated value was 549.7 and the measured value was 549.5.

[0375] Compound 7, methyl (R,E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.28 min, purity >99.9%, MS(ESI+) m / z is C 31 H 41 N 4 O 5 + [M+H] + The calculated value was 549.7 and the measured value was 549.5.

[0376] Compound 8, (E)-N-(2-((2-((4-amino-4-oxobut-2-en-1-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamide [ka] HPLC (Method 1) RT=3.93 min, purity >96.6%, MS(ESI+) m / z is C 30 H 40 N 5 O 4 + [M+H] + The calculated value was 534.7 and the measured value was 534.5.

[0377] Compound 9, (E)-N-(2-((2-((3-(methylsulfonyl)allyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamide [ka] HPLC (Method 1) RT=4.23 min, purity 97.7%, MS(ESI+) m / z is C 30 H 41 N 4 O 5 S + [M+H] + The calculated value was 569.7 and the measured value was 569.5.

[0378] Compound 10, methyl (R,E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclopentanecarboxamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.41 min, purity >99.9%, MS(ESI+) m / z is C 32 H 43 N 4 O 5 + [M+H] + The calculated value was 563.7 and the measured value was 563.6.

[0379] Compound 11, methyl (R,E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclohexanecarboxamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.53 min, purity >99.9%, MS(ESI+) m / z is C 33 H 45 N 4 O 5 + [M+H] + The calculated value was 577.7 and the measured value was 577.6.

[0380] Compound 12, (R)-2-((1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=2.81 min, purity >99.9%, MS(ESI+) m / z is C 24 H 31 N 4 O 2 + [M+H] + The calculated value was 407.4 and the measured value was 407.5.

[0381] Compound 13, methyl (E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=3.94 min, purity >99.9%, MS(ESI+) m / z is C 29 H 39 N 4 O 5 + [M+H] + It was calculated as 509.3 and measured as 509.3.

[0382] Compound 14, methyl (R,E)-4-(2-(2-(2,2,2-trifluoro-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.30 min, purity >99.9%, MS(ESI+) m / z is C 28 H 34 F 3 N4 O 5 + [M+H] + The calculated value was 563.6 and the measured value was 563.4.

[0383] Compound 15, methyl (E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)propionamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.05 min, purity >99.9%, MS(ESI+) m / z is C 29 H 39 N 4 O 5 + [M+H] + The calculated value was 523.3 and the measured value was 523.5.

[0384] Compound 16, methyl (E)-4-(2-(2-(3,3,3-trifluoro-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)propanamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.28 min, *91.09% purity, MS(ESI+) m / z is C 29 H 36 F 3 N 4 O 5 + [M+H] + The calculated value was 577.6 and the measured value was 577.5.

[0385] Compound 17, methyl (R,E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)isobutyramido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.18 min, purity >99.9%, MS(ESI+) m / z is C 30 H 41 N 4 O 5 + [M+H] + The calculated value was 537.7 and the measured value was 537.4.

[0386] Compound 18, methyl (R,E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)butyramido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.21 min, purity >99.9%, MS(ESI+) m / z is C 30 H 41 N 4 O 5 + [M+H] + The calculated value was 537.7 and the measured value was 537.4.

[0387] Compound 19, methyl (R,E)-4-(2-(2-(3-methyl-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)isobutanamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.37 min, purity >99.9%, MS(ESI+) m / z is C 31 H 43 N 4 O 5 + [M+H] + The calculated value was 551.7 and the measured value was 551.5.

[0388] Compound 20, methyl (R,E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.08 min, purity >99.9%, MS(ESI+) m / z is C 27 H 37 N 4 O 6 S + [M+H] + The calculated value was 545.7 and the measured value was 545.4.

[0389] Compound 21, (R)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.96 min, purity >99.9%, MS(ESI+) m / z is C 25 H 33 N 4 O 4 S + [M+H] + The calculated value was 485.6 and the measured value was 485.4.

[0390] Compound 22, methyl (R,E)-4-(2-(2-((1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)(sulfamoyl)amino)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=3.97 min, purity >99.9%, MS(ESI+) m / z is C 26 H 36 N 5O 6 S + [M+H] + The calculated value was 546.7 and the measured value was 546.3.

[0391] Compound 23, methyl (R,E)-4-(2-(2-((N-(tert-butoxycarbonyl)sulfamoyl)(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.53 min, purity >99.9%, MS(ESI+) m / z is C 31 H 44 N 5 O 8 S + [M+H] + The calculated value was 646.8 and the measured value was 646.4.

[0392] Compound 24, methyl (R,E)-4-(2-(2-((1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=3.21 min, purity >99.9%, MS(ESI+) m / z is C 26 H 35 N 4 O 4 + [M+H] + The calculated value was 467.6 and the measured value was 467.5.

[0393] Compound 25, methyl (R,E)-4-(2-(2-(methyl(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=3.38 min, purity >99.9%, MS(ESI+) m / z is C 27 H 37 N 4 O 4 + [M+H] + The calculated value was 481.7 and the measured value was 481.4.

[0394] Compound 26, methyl (E)-4-(2-((S)-3-amino-2-((1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)propanamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=3.42 min, purity 97.1%, MS(ESI+) m / z is C 27 H 38 N 5 O 4 + [M+H] + The calculated value was 496.6 and the measured value was 496.5.

[0395] Compound 27, methyl (S,E)-2,2-dimethyl-7-((1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)-4,8,11-trioxo-3-oxa-5,9,12-triazahexadec-14-en-16-oate [ka] HPLC (Method 1) RT=4.07 min, purity >99.9%, MS(ESI+) m / z is C 32 H 46 N 5 O 6 + [M+H] + The calculated value was 596.7 and the measured value was 596.6.

[0396] Compound 28, methyl (E)-4-(2-((R)-2-((1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)propanamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=3.38 min, purity >99.9%, MS(ESI+) m / z is C 27 H 37 N 4 O 4 + [M+H] + The calculated value was 481.6 and the measured value was 481.3.

[0397] Compound 29, methyl (E)-4-(2-((3S)-3-((benzo[d][1,3]dioxol-5-ylmethyl)amino)-3-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)propanamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=3.70 min, purity 95.0%, MS(ESI+) m / z is C 35 H 43 N 4 O 6 + [M+H] + The calculated value was 615.7 and the measured value was 615.5.

[0398] Compound 30, 2-(benzo[d][1,3]dioxol-5-yl)-N-(2-((2-((1-cyanopiperidin-4-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamide [ka] HPLC (Method 2) RT=4.70 min, purity >99.9%, MS(ESI+) m / z is C 36 H 43 N 6 O 5 + [M+H] + The calculated value was 639.8 and the measured value was 639.4.

[0399] Compound 31, 2-(benzo[d][1,3]dioxol-5-yl)-N-(2-((2-((1-cyanopyrrolidin-3-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamide [ka] HPLC (Method 1) RT=4.35 min, purity >99.9%, MS(ESI+) m / z is C 35 H 41 N 6 O 5 + [M+H] + The calculated value was 625.7 and the measured value was 625.5.

[0400] Compound 32, (R)-N-(3-(2-((1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)acetamido)isoxazol-5-yl)acrylamide [ka] HPLC (Method 1) RT=3.42 min, purity 95.0%, MS(ESI+) m / z is C 25 H 30 N 5 O 3 + [M+H] + The calculated value was 448.5 and the measured value was 448.3.

[0401] Compound 33, 2-(benzo[d][1,3]dioxol-5-yl)-N-(2-((2-((1-cyanocyclopropyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamide [ka] HPLC RT=4.76 min, purity >99.9%, MS(ESI+) m / z is C 34 H 38 N 5 O 5 + [M+H] + The calculated value was 596.7 and the measured value was 596.4.

[0402] Compound 34, 2-(benzo[d][1,3]dioxol-5-yl)-N-(2-((2-((S)-2-cyanopyrrolidin-1-yl)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamide [ka] HPLC (Method 1) RT=4.81 min, purity 95.0%, MS(ESI+) m / z is C 35 H 40 N 5 O 5 + [M+H] + The calculated value was 610.7 and the measured value was 610.5.

[0403] Compound 35, methyl (E)-4-(1-(2-((1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)acetamido)cyclopropane-1-carboxamide)but-2-enoate [ka] HPLC (Method 1) RT=3.25 min, purity >99.9%, MS(ESI+) m / z is C 28 H 37 N 4 O 4 + [M+H] + The calculated value was 493.6 and the measured value was 493.5.

[0404] Compound 36, methyl (E)-4-(1-(2-((tert-butoxycarbonyl)(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)acetamido)cyclopropane-1-carboxamide)but-2-enoate [ka] HPLC (Method 1) RT=4.50 min, purity >99.9%, MS(ESI+) m / z is C 33 H 45 N 4 O 6 + [M+H] + The calculated value was 593.7 and the measured value was 593.5.

[0405] Compound 37, methyl (E)-4-(2-methyl-2-(2-((1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)acetamido)propanamido)but-2-enoate [ka] HPLC (Method 1) RT=3.34 min, purity >99.9%, MS(ESI+) m / z is C 28 H 39 N 4 O 4 + [M+H] + The calculated value was 495.6 and the measured value was 495.4.

[0406] Compound 38, methyl (E)-2,2,9,9-tetramethyl-5-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-4,7,10-trioxo-3-oxa-5,8,11-triazapentadec-13-en-15-oate [ka] HPLC (Method 1) RT=4.50 min, purity >99.9%, MS(ESI+) m / z is C 33 H 47 N 4 O 6 + [M+H] + The calculated value was 595.8 and the measured value was 595.5.

[0407] Compound 39, (E)-4-(2-(2-(2-(benzo[d][1,3]dioxol-5-yl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamide)acetamide)acetamide)-N,N-dimethylbut-2-enamide [ka] HPLC (Method 1) RT=4.34 min, purity 95.0%, MS(ESI+) m / z is C 36 H 44 N 5 O 6 + [M+H] + The calculated value was 642.8 and the measured value was 642.6.

[0408] Compound 40, (E)-4-(2-(2-(benzo[d][1,3]dioxole -5-yl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamido)acetamido)acetamido)but-2-enoic acid [ka] HPLC (Method 1) RT=4.22 min, purity >99.9%, MS(ESI+) m / z is C 34 H 39 N 4 O 7 + [M+H] + The calculated value was 615.7 and the measured value was 615.5.

[0409] Compound 41, 2-(benzo[d][1,3]dioxol-5-yl)-N-(2-((2-((2-cyanoethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamide [ka] HPLC (Method 1) RT=4.26 min, purity 95.0%, MS(ESI+) m / z is C 33 H 38 N 5 O 5 + [M+H] + The calculated value was 584.7 and the measured value was 584.5.

[0410] Compound 42, 2-(benzo[d][1,3]dioxol-5-yl)-N-(2-((2-((cyanomethyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)acetamide [ka] HPLC (Method 1) RT=4.28 min, purity 95.0%, MS(ESI+) m / z is C 32 H 36 N 5 O 5 + [M+H] + The calculated value was 570.7 and the measured value was 570.4.

[0411] Compound 43, methyl (E)-4-((R)-2-(2-((1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)acetamido)propanamido)but-2-enoate [ka] HPLC (Method 1) RT=3.36 min, purity 97.24%, MS(ESI+) m / z is C 27 H 37 N 4 O 4 + [M+H] + The calculated value was 481.6 and the measured value was 481.4.

[0412] Compound 44, methyl (E)-4-((R)-2-((R)-2-((1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)propanamido)propanamido)but-2-enoate [ka] HPLC (Method 1) RT=3.38 min, purity >99.9%, MS(ESI+) m / z is C 28 H 39 N 4 O 4 + [M+H] + The calculated value was 495.6 and the measured value was 495.4.

[0413] Compound 45, methyl (E)-4-(2-(2-((1-benzhydrylpiperidin-4-yl)amino)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=3.49 min, purity >99.9%, MS(ESI+) m / z is C 27 H 35 N 4 O 4 +[M+H] + The calculated value was 479.6 and the measured value was 479.4.

[0414] Compound 46, methyl (E)-4-((2R)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamido)acetamido)propanamido)but-2-enoate [ka] HPLC (Method 1) RT=4.22 min, purity 99.8%, MS(ESI+) m / z is C 32 H 43 N 4 O 5 + [M+H] + The calculated value was 563.7 and the measured value was 563.5.

[0415] Compound 47, methyl (E)-4-((2S)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamido)acetamido)propanamido)but-2-enoate [ka] HPLC (Method 1) RT=4.29 min, purity 95.7%, MS(ESI+) m / z is C 32 H 43 N 4 O 5 + [M+H] + The calculated value was 563.7 and the measured value was 563.5.

[0416] Compound 48, (R,E)-4-(2-(2-((1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)acetamide)acetamido)but-2-enamide [ka] HPLC (Method 1) RT=2.44 min, purity >99.9%, MS(ESI+) m / z is C 25 H 34 N 5 O 3 + [M+H] + The calculated value was 452.6 and the measured value was 452.4.

[0417] Compound 49, (R)-N-(2-((3-acrylamidopropyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamide [ka] HPLC (Method 1) RT=4.12 min, purity >99.9%, MS(ESI+) m / z is C 30 H 41 N 4 O 3 + [M+H] + The calculated value was 505.7 and the measured value was 505.5.

[0418] Compound 50, methyl (R,E)-4-(2-(N-methyl-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.14 min, purity >99.9%, MS(ESI+) m / z is C 28 H 39 N 4 O 6 S + [M+H] + The calculated value was 559.7 and the measured value was 559.4.

[0419] Compound 51, (E)-N-(2-((2-((4-methylamino)-4-oxobut-2-en-1-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamide [ka] HPLC (Method 1) RT=3.99 min, purity 97.7%, MS(ESI+) m / z is C 31 H 42 N 5 O 4 + [M+H] + The calculated value was 548.7 and the measured value was 548.5.

[0420] Compound 52, N-((S)-1-(cyanomethyl)-2-oxopyrrolidin-3-yl)-2-(N-(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamide [ka] HPLC (Method 1) RT=3.96 min, purity 96.1%, MS(ESI+) m / z is C 26 H 34 N 5 O 4 S + [M+H] + The calculated value was 512.6 and the measured value was 512.4.

[0421] Compound 53, (E)-N-(2-((2-((3-cyanoallyl)amino)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamide [ka] HPLC (Method 1) RT=4.31 min, purity >99.9%, MS(ESI+) m / z is C 30 H 38 N 5 O 3 + [M+H] + The calculated value was 516.6 and the measured value was 516.4.

[0422] Compound 54, (R)-N-(2-((2-(allylamino)-2-oxoethyl)amino)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamide [ka] HPLC (Method 1) RT=4.58 min, purity 98.2%, MS(ESI+) m / z is C 29 H 39 N 4 O 3 + [M+H] + The calculated value was 491.6 and the measured value was 491.5.

[0423] Compound 55, isopropyl (R,E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclobutanecarboxamide)acetamide)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.68 min, purity 98.8%, MS(ESI+) m / z is C 33 H 45 N 4 O 5 + [M+H] + The calculated value was 577.7 and the measured value was 577.5.

[0424] Compound 56, (R,E)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-N-(2-oxo-2-((2-oxo-2-((4-oxo-4-(phenylamino)but-2-en-1-yl)amino)ethyl)amino)ethyl)cyclobutanecarboxamide [ka] HPLC (Method 1) RT=4.62 min, purity 95.1%, MS(ESI+) m / z is C 36 H 44 N 5 O 4 + [M+H] + The calculated value was 610.8 and the measured value was 610.6.

[0425] Compound 57, (R)-3-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)-N-(prop-2-yn-1-yl)propanamide [ka] HPLC (Method 1) RT=3.95 min, purity 98.6%, MS(ESI+) m / z is C 26 H 35 N 4 O 4 S + [M+H] + The calculated value was 499.6 and the measured value was 499.6.

[0426] Compound 58, (R)-3-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)propanamide [ka] HPLC (Method 1) RT=3.97 min, purity 97.6%, MS(ESI+) m / z is C26 H 35 N 4 O 4 S + [M+H] + The calculated value was 499.6 and the measured value was 499.4.

[0427] Compound 59, (R,E)-N-(3-(methylsulfonyl)allyl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=3.90 min, purity >99.9%, MS(ESI+) m / z is C 26 H 37 N 4 O 6 S 2 + [M+H] + The calculated value was 565.7 and the measured value was 565.3.

[0428] Compound 60, (R)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclopropanesulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.16 min, purity >99.9%, MS(ESI+) m / z is C 27 H 35 N 4 O 4 S + [M+H] + The calculated value was 511.7 and the measured value was 511.5.

[0429] Compound 61, (R)-N-(but-2-yn-1-yl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=4.09 min, purity >99.9%, MS(ESI+) m / z is C 26 H 35 N 4 O 4 S + [M+H] + The calculated value was 499.6 and the measured value was 499.4.

[0430] Compound 62, (R)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-((3-phenylprop-2-yn-1-yl)amino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.63 min, purity >99.9%, MS(ESI+) m / z is C 31 H 37 N 4 O 4 S + [M+H] + The calculated value was 561.7 and the measured value was 561.3.

[0431] Compound 63, (R)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)phenylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.43 min, purity >99.9%, MS(ESI+) m / z is C 30 H 35 N 4 O 4 S + [M+H] + The calculated value was 546.7 and the measured value was 547.4.

[0432] Compound 64, (R)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-((2-oxoethyl)amino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.67 min, purity >99.9%, MS(ESI+) m / z is C 24 H 33 N 4 O 5 S + [M+H] + The calculated value was 489.6 and the measured value was 489.4.

[0433] Compound 65, (R)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)pyrrolidine-1-sulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.36 min, purity >99.9%, MS(ESI+) m / z is C 28 H 38 N 5 O 4 S + [M+H] + The calculated value was 540.7 and the measured value was 540.5.

[0434] Compound 66, N-(2-hydroxy-3-(3-(prop-2-yn-1-yl)ureido)propyl)-N-(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methanesulfonamide [ka] HPLC (Method 1) RT=3.96 min, purity >99.9%, MS(ESI+) m / z is C25 H 35 N 4 O 4 S + [M+H] + The calculated value was 487.6 and the measured value was 487.4.

[0435] Compound 67, methyl (E)-4-(2-(2-((1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)((E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl)amino)acetamide)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.33 min, purity=98.5%, MS(ESI+) m / z is C 30 H 36 F 3 N 4 O 5 + [M+H] + It was calculated as 589.3, 589. The actual measurement was 5.

[0436] Compound 68, 1-(2-hydroxy-3-((1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)amino)propyl)-3-(prop-2-yn-1-yl)urea [ka] HPLC (Method 1) RT=2.89 min, purity=99.4%, MS(ESI+) m / z is C 24 H 33 N 4 O 2 + [M+H] + The calculated value was 409.3 and the measured value was 409.4.

[0437] Compound 69, tert-butyl (2-hydroxy-3-(3-(prop-2-yn-1-yl)ureido)propyl)(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)carbamate [ka] HPLC (Method 1) RT=4.46 min, purity=96.4%, MS(ESI+) m / z is C 29 H 41 N 4 O 4 + [M+H] + The calculated value was 509.3 and the measured value was 509.5.

[0438] Compound 70, 2-(N-(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-((S)-2-oxo-1-(prop-2-yn-1-yl)pyrrolidin-3-yl)acetamide [ka] HPLC (Method 1) RT=4.12 min, purity >99.9%, MS(ESI+) m / z is C 27 H 35 N 4 O 4 S + [M+H] + The calculated value was 511.2 and the measured value was 511.4.

[0439] Compound 71, (R)-N-methyl-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)-N-(prop-2-yn-1-yl)acetamido [ka] HPLC (Method 1) RT=4.11 min, purity >99.9%, MS(ESI+) m / z is C 26 H 35 N 4O 4 S + [M+H] + The calculated value was 499.2 and the measured value was 499.4.

[0440] Compound 72, (R)-N-(2-methylbut-3-yn-2-yl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=4.24 min, purity >99.9%, MS(ESI+) m / z is C 27 H 37 N 4 O 4 S + [M+H] + The calculated value was 513.3 and the measured value was 513.4.

[0441] Compound 73, (R)-N-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)ethyl)propiolamide [ka] HPLC (Method 1) RT=3.94 min, purity >99.9%, MS(ESI+) m / z is C 25 H 33 N 4 O 4 S + [M+H] + The calculated value was 485.2 and the measured value was 485.4.

[0442] Compound 74, (R)-N-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)ethyl)cinnamamide [ka] HPLC (Method 1) RT=4.59 min, purity >99.9%, MS(ESI+) m / z is C 31 H 39 N 4 O 4 S + [M+H] + The calculated value was 563.3 and the measured value was 563.4.

[0443] Compound 75, (R)-N-(1-ethynylcyclopropyl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=4.12 min, purity >99.9%, MS(ESI+) m / z is C 27 H 35 N 4 O 4 S + [M+H] + The calculated value was 511.2 and the measured value was 511.4.

[0444] Compound 76, (R)-1-((R)-N-(methylsulfonyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)glycyl)-N-(prop-2-yn-1-yl)azetidine-3-carboxamide [ka] HPLC (Method 1) RT=4.03 min, purity=99.6%, MS(ESI+) m / z is C 27 H 35 N 4 O 4 S + [M+H] + The calculated value was 511.2 and the measured value was 511.5.

[0445] Compound 77, 1-(N-(methylsulfonyl)-N-(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)glycyl)-N-(prop-2-yn-1-yl)pyrrolidine-3-carboxamide [ka] HPLC (Method 1) RT=4.02 min, purity >98.8%, MS(ESI+) m / z is C 28 H 37 N 4 O 4 S + [M+H] + The calculated value was 525.2 and the measured value was 525.4.

[0446] Compound 78, (R)-5-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(prop-2-yn-1-yl)pentanamide [ka] HPLC (Method 1) RT=4.15 min, purity=98.2%, MS(ESI+) m / z is C 26 H 36 N 3 O 3 S + [M+H] + The calculated value was 470.2 and the measured value was 470.4.

[0447] Compound 79, (R)-2-((1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)(3-oxobutyl)amino)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.83 min, purity >99.9%, MS(ESI+) m / z is C 28 H 37 N 4 O3 + [M+H] + The calculated value was 477.3 and the measured value was 477.5.

[0448] Compound 80, (R)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-2-((1,1,1-trifluoro-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methyl)sulfonamido)acetamide [ka] HPLC (Method 1) RT=4.54 min, purity >99.9%, MS(ESI+) m / z is C 25 H 30 F 3 N 4 O 4 S + [M+H] + The calculated value was 539.2 and the measured value was 539.3.

[0449] Compound 81, (R)-5-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-4-oxo-N-(prop-2-yn-1-yl)pentanamide [ka] HPLC (Method 1) RT=4.20 min, purity >99.9%, MS(ESI+) m / z is C 26 H 34 N 3 O 4 S + [M+H] + The calculated value was 484.2 and the measured value was 484.4.

[0450] Compound 82, N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-2-(N-(1-(1-(quinolin-8-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamide [ka] HPLC (Method 1) RT=3.59 min, purity=97.6%, MS(ESI+) m / z is C 24 H 32 N 5 O 4 S + [M+H] + The calculated value was 486.2 and the measured value was 486.4.

[0451] Compound 83, 2-(N-(1-(1-(2-fluoronaphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.09 min, purity >99.9%, MS(ESI+) m / z is C 25 H 32 FN 4 O 4 S + [M+H] + The calculated value was 503.2 and the measured value was 503.3.

[0452] Compound 84, 2-(N-(1-(1-(7-chloronaphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.22 min, purity >99.9%, MS(ESI+) m / z is C 25 H 32 ClN 4 O 4 S + [M+H] + The calculated value was 519.2 and the measured value was 519.4.

[0453] Compound 85, N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-2-(N-(1-(1-(quinolin-4-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamide [ka] HPLC (Method 1) RT=2.93 min, purity >99.9%, MS(ESI+) m / z is C 24 H 32 N 5 O 4 S + [M+H] + The calculated value was 486.2 and the measured value was 486.4.

[0454] Compound 86, (R)-4-((R)-N-(methylsulfonyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)glycyl)-N-(prop-2-yn-1-yl)piperazine-1-carboxamide [ka] HPLC (Method 1) RT=4.03 min, purity >99.9%, MS(ESI+) m / z is C 28 H 38 N 5 O 4 S + [M+H] + The calculated value was 540.3 and the measured value was 540.4.

[0455] Compound 87, (R)-6-((R)-N-(methylsulfonyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)glycyl)-N-(prop-2-yn-1-yl)-2,6-diazaspiro[3.3]heptane-2-carboxamide [ka] HPLC (Method 1) RT=4.00 min, purity >99.9%, MS(ESI+) m / z is C 29H 38 N 5 O 4 S + [M+H] + The calculated value was 552.3 and the measured value was 552.4.

[0456] Compound 88, 2-(N-(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(5-oxo-1-(prop-2-yn-1-yl)pyrrolidin-3-yl)acetamide [ka] HPLC (Method 1) RT=3.99 min, purity >99.9%, MS(ESI+) m / z is C 27 H 35 N 4 O 4 S + [M+H] + The calculated value was 511.2 and the measured value was 511.3.

[0457] Compound 89, (S)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.95 min, purity=99.0%, MS(ESI+) m / z is C 25 H 33 N 4 O 4 S + [M+H] + The calculated value was 485.2 and the measured value was 485.4.

[0458] Compound 90, (S)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)cyclopropanesulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.13 min, purity=98.3%, MS(ESI+) m / z is C 27 H 35 N 4 O 4 S + [M+H] + The calculated value was 511.2 and the measured value was 511.4.

[0459] Compound 91, (S)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)pyrrolidine-1-sulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.28 min, purity=92.3%, MS(ESI+) m / z is C 28 H 38 N 5 O 4 S + [M+H] + The calculated value was 540.3 and the measured value was 540.5.

[0460] Compound 92, (S)-2-(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-1,2,5-thiadiazolidine-3-carboxamide 1,1-dioxide 2,2,2-trifluoroacetate [ka] HPLC (Method 1) RT=4.02 min, purity=97.2%, MS(ESI+) m / z is C 25 H 32 N 5 O 4 S + [M+H] +The calculated value was 498.2 and the measured value was 498.2.

[0461] Compound 93, 2-(N-(3-fluoro-1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.45 min, purity=95.9%, MS(ESI+) m / z is C 25 H 32 FN 4 O 4 S + [M+H] + It was calculated as 503.2 and measured as 503.2.

[0462] Compound 94, 2-(N-(1-(1-(2,3-dichlorophenyl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.92 min, purity >99.9%, MS(ESI+) m / z is C 21 H 29 Cl 2 N 4 O 4 S + [M+H] + It was calculated to be 503.1 and measured to be 503.1.

[0463] Compound 95, 1-((3-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-2-oxooxazolidin-5-yl)methyl)-3-(prop-2-yn-1-yl)urea [ka] HPLC (Method 1) RT=3.88 min, purity >99.9%, MS(ESI+) m / z is C 25 H 31 N 4 O 3 + [M+H] + It was calculated to be 435.2 and the actual measurement was 435.2.

[0464] Compound 96, 2-(N-(1-(1-(4-methoxynaphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.18 min, purity=97.0%, MS(ESI+) m / z is C 26 H 35 N 4 O 5 S + [M+H] + The calculated value was 515.2 and the measured value was 515.3.

[0465] Compound 97, 2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] 1 H NMR (400 MHz, CDCl 3 ) δ 1.46 (d, J = 8 Hz, 3H), 1.67 - 1.73 (m, 3H), 1.83-1.86 (m, 1H), 2.05 - 2.18 (m, 3H), 2.90 - 2.92 (m, 1H), 2.98 (s, 3H), 3.05 - 3.15 (m, 1H), 3.20 - 3.30 (m, 1H), 3.60 - 3.70 (m, 1H), 3.70 - 3.80 (m, 1H), 3.85 - 3.99 (m, 4H), 4.15(q, J = 8 Hz, 1H), 6.83 (s, 1H), 7.06 - 7.07 (m, 1H), 7.43 - 7.5 5 (m, 4H), 7.74 (d, J = 8 Hz, 1H), 7.85 (d, J = 8 Hz, 1H), 8.35 (d, J = 8 Hz,1H).

[0466] HPLC (Method 1) RT=3.94 min, purity=99.3%, MS(ESI+) m / z is C 25 H 33 N 4 O 4 S + [M+H] + The calculated value was 485.2 and the measured value was 485.2.

[0467] Compound 98, 2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)pyrrolidine-1-sulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.27 min, purity=98.8%, MS(ESI+) m / z is C 28 H 38 N 5 O 4 S + [M+H] + The calculated value was 540.3 and the measured value was 540.2.

[0468] Compound 99, 2-(N-(1-(1-(2,3-dimethylphenyl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.81 min, purity >99.9%, MS(ESI+) m / z is C 23 H 35 N 4 O 4 S + [M+H] + The calculated value was 463.2 and the measured value was 463.2.

[0469] Compound 100, N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-2-(N-(1-(2,2,2-trifluoro-1-(naphthalen-1-yl)ethyl) Piperidin-4-yl)methylsulfonamide)acetamide [ka] HPLC (Method 1) RT=6.20 min, purity >99.9%, MS(ESI+) m / z is C 25 H 30 F 3 N 4 O 4 S + [M+H] + The calculated value was 539.2 and the measured value was 539.20.

[0470] Compound 101, 2-(N-(1-(1-(2-chlorophenyl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.60 min, purity >99.9%, MS(ESI+) m / z is C 21 H 30 ClN 4 O 4 S + [M+H] + The calculated value was 469.2 and the measured value was 469.3.

[0471] Compound 102, N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-2-(N-(1-(1-(2-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)methylsulfonamido)acetamide [ka] HPLC (Method 1) RT=3.88 min, purity >99.9%, MS(ESI+) m / z is C 22 H 30 F 3 N 4 O 4 S + [M+H] + It was calculated as 503.2 and measured as 503.2.

[0472] Compound 103, 2-(N-(1-(1-(naphthalen-1-yl)propyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.10 min, purity >99.9%, MS(ESI+) m / z is C 26 H 35 N 4 O 4 S + [M+H] + The calculated value was 499.2 and the measured value was 499.2.

[0473] Compound 104, 2-(N-(1-(cyano(naphthalen-1-yl)methyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=5.69 min, purity >99.9%, MS(ESI+) m / z is C 25 H30 N 5 O 4 S + [M+H] + The calculated value was 496.2 and the measured value was 496.0.

[0474] Compound 105, 2-(N-(1-(1-(naphthalen-1-yl)cyclopropyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.13 min, purity >99.9%, MS(ESI+) m / z is C 26 H 33 N 4 O 4 S + [M+H] + The calculated value was 497.2 and the measured value was 497.2.

[0475] Compound 106, (R)-N-(2-amino-2-oxoethyl)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamide [ka] HPLC (Method 1) RT=3.67 min, purity >99.9%, MS(ESI+) m / z is C 22 H 31 N 4 O 4 S + [M+H] + The calculated value was 447.2 and the measured value was 447.2.

[0476] Compound 107, 2-(N-(1-(1-(4-fluoronaphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.09 min, purity >99.9%, MS(ESI+) m / z is C 25 H 32 FN 4 O 4 S + [M+H] + It was calculated as 503.2 and measured as 503.2.

[0477] Compound 108, 2-(N-(1-(1-(3-bromophenyl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.78 min, purity >99.9%, MS(ESI+) m / z is C 21 H 30 BrN 4 O 4 S + [M+H] + It was calculated to be 513.1 and was measured to be 513.1.

[0478] Compound 109, 2-(N-(1-(cyclopropyl(naphthalen-1-yl)methyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.39 min, purity >99.9%, MS(ESI+) m / z is C 27 H 35 N 4 O 4 S + [M+H] + The calculated value was 511.2 and the measured value was 511.3.

[0479] Compound 110, 2-(N-(1-(1-(naphthalen-2-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.03 min, purity >99.9%, MS(ESI+) m / z is C 25 H 33 N 4 O 4 S + [M+H] + The calculated value was 485.2 and the measured value was 485.2.

[0480] Compound 111, 2-(N-(1-(1-(isoquinolin-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.71 min, purity >99.9%, MS(ESI+) m / z is C 24 H 32 N 5 O 4 S + [M+H] + The calculated value was 486.2 and the measured value was 486.3.

[0481] Compound 112, 2-(N-(1-(1-([1,1'-biphenyl]-3-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.33 min, purity >99.9%, MS(ESI+) m / z is C 27 H 35 N4 O 4 S + [M+H] + The calculated value was 511.2 and the measured value was 511.3.

[0482] Compound 113, 2-(N-(1-(1-([1,1'-biphenyl]-2-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.23 min, purity >99.9%, MS(ESI+) m / z is C 27 H 35 N 4 O 4 S + [M+H] + The calculated value was 511.2 and the measured value was 511.3.

[0483] Compound 114, N-(cyanomethyl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=3.88 min, purity=95.1%, MS(ESI+) m / z is C 24 H 32 N 5 O 4 S + [M+H] + The calculated value was 486.2 and the measured value was 486.3.

[0484] Compound 115, ethyl 2-(4-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-N-(2-oxo-2-((2-oxo-2-(prop-2-yn-1-ylamino)ethyl)amino)ethyl)sulfamoyl)piperazin-1-yl)acetate [ka] HPLC (Method 1) RT=3.93 min, purity=97.1%, MS(ESI+) m / z is C 32 H 45 N 6 O 6 S + [M+H] + The calculated value was 641.3 and the measured value was 641.3.

[0485] Compound 116, N-(3-fluoro-2-hydroxypropyl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=3.83 min, purity >99.9%, MS(ESI+) m / z is C 25 H 36 FN 4 O 5 S + [M+H] + It was calculated to be 523.2 and the actual measurement was 523.2.

[0486] Compound 117, 2-(4-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-N-(2-oxo-2-((2-oxo-2-(prop-2-yn-1-ylamino)ethyl)amino)ethyl)sulfamoyl)piperazin-1-yl)acetic acid [ka] HPLC (Method 1) RT=3.68 min, purity=96.2%, MS(ESI+) m / z is C 30 H 41 N 6 O 6 S + [M+H] + The calculated value was 613.3 and the measured value was 613.4.

[0487] Compound 118, 4-((1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)(2-oxo-2-((2-oxo-2-(prop-2-yn-1-ylamino)ethyl)amino)ethyl)amino)-4-oxobutyric acid [ka] HPLC (Method 1) RT=3.86 min, purity=98.8%, MS(ESI+) m / z is C 28 H 35 N 4 O 5 + [M+H] + The calculated value was 507.3 and the measured value was 507.2.

[0488] Compound 119, 2-(N-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.77 min, purity >99.9%, MS(ESI+) m / z is C 20 H 26 N 5 O 4 S 2 + [M+H] + The calculated value was 464.1 and the measured value was 464.1.

[0489] Compound 120, 2-(N-(1-(1-(2,4-dichlorophenyl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.98 min, purity >99.9%, MS(ESI+) m / z is C 21 H 29 Cl 2 N 4 O 4 S + [M+H] + The calculated value was 503.1 and the measured value was 503.2.

[0490] Compound 121, 2-(N-(1-(1-(3-chloro-4-methoxyphenyl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.77 min, purity >99.9%, MS(ESI+) m / z is C 22 H 32 ClN 4 O 5 S + [M+H] + The calculated value was 499.2 and the measured value was 499.2.

[0491] Compound 122, 2-(N-(1-(1-(naphthalen-1-yl)ethyl)-2-oxopiperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=5.26 min, purity >99.9%, MS(ESI+) m / z is C 25 H 31 N 4 O 5 + [M+H] + The calculated value was 499.2 and the measured value was 499.2.

[0492] Compound 123, 2-(N-(1-(1-(2-chloro-3-methoxyphenyl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.66 min, purity >99.9%, MS(ESI+) m / z is C 22 H 32 ClN 4 O 5 S + [M+H] + The calculated value was 499.2 and the measured value was 499.2.

[0493] Compound 124, methyl 2-(naphthalen-1-yl)-2-(4-(N-(2-oxo-2-((2-oxo-2-(prop-2-yn-1-ylamino)ethyl)amino)ethyl)methylsulfonamido)piperidin-1-yl)acetate [ka] HPLC (Method 1) RT=4.30 min, purity >99.9%, MS(ESI+) m / z is C 26 H 33 N 4 O 6 S + [M+H] + The calculated value was 529.2 and the measured value was 529.3.

[0494] Compound 125, 2-(N-(1-(1-(2,6-dichlorophenyl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.58 min, purity >99.9%, MS(ESI+) m / z is C 21 H29 Cl 2 N 4 O 4 S + [M+H] + It was calculated to be 503.1 and measured to be 503.1.

[0495] Compound 126, 2-(N-(1-(5-chlorobenzo[d]thiazol-2-yl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=5.56 min, purity >99.9%, MS(ESI+) m / z is C 20 H 25 ClN 5 O 4 S 2 + [M+H] + The calculated value was 498.1 and the measured value was 498.2.

[0496] Compound 127, (R)-N-(but-3-yn-1-yl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=4.02 min, purity=98.6%, MS(ESI+) m / z is C 26 H 35 N 4 O 4 S + [M+H] + The calculated value was 499.2 and the measured value was 499.3.

[0497] Compound 128, N-(but-3-yn-2-yl)-2-(2-(N-(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=4.07 min, purity >99.9%, MS(ESI+) m / z is C 26 H 35 N 4 O 4 S + [M+H] + The calculated value was 499.2 and the measured value was 499.3.

[0498] Compound 129, 2-(N-(1-(1-(2-fluorophenyl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.22 min, purity >99.9%, MS(ESI+) m / z is C 21 H 30 FN 4 O 4 S + [M+H] + The calculated value was 453.2 and the measured value was 453.3.

[0499] Compound 130, 2-(N-(1-(1-(2-methoxyphenyl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.53 min, purity >99.9%, MS(ESI+) m / z is C 22 H 33 N 4 O 5 S + [M+H] + The calculated value was 465.2 and the measured value was 465.2.

[0500] Compound 131, methyl 3-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-N-(2-oxo-2-((2-oxo-2-(prop-2-yn-1-ylamino)ethyl)amino)ethyl)sulfamoyl)propanoate [ka] HPLC (Method 1) RT=4.21 min, purity=97.6%, MS(ESI+) m / z is C 28 H 37 N 4 O 6 S + [M+H] + The calculated value was 557.2 and the measured value was 55.3.

[0501] Compound 132, N-(3-fluoro-2-oxopropyl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=3.87 min, purity=96.8%, MS(ESI+) m / z is C 25 H 34 FN 4 O 5 S + [M+H] + It was calculated to be 521.2 and was measured to be 521.2.

[0502] Compound 133, JL-02-140, (R)-3-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-N-(2-oxo-2-((2-oxo-2-(prop-2-yn-1-ylamino)ethyl)amino)ethyl)sulfamoyl)propanamide [ka] HPLC (Method 1) RT=3.85 min, purity=96.4%, MS(ESI+) m / z is C 27 H 36 N 5 O 5 S + [M+H] + The calculated value was 542.2 and the measured value was 542.3.

[0503] Compound 134, methyl 1-(N-(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-N-(2-oxo-2-((2-oxo-2-(prop-2-yn-1-ylamino)ethyl)amino)ethyl)sulfamoyl)pyrrolidine-3-carboxylate [ka] HPLC (Method 1) RT=4.03 min, purity >99.9%, MS(ESI+) m / z is C 30 H 40 N 5 O 6 S + [M+H] + The calculated value was 598.3 and the measured value was 598.3.

[0504] Compound 135, (R)-2-((3-hydroxy-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)propyl)sulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.91 min, purity >99.9%, MS(ESI+) m / z is C 27 H 37 N 4 O 5 S + [M+H] + The calculated value was 529.2 and the measured value was 529.3.

[0505] Compound 136, methyl (E)-4-(5-((2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)methyl)-1,3,4-oxadiazole-2-carboxamido)but-2-enoate [ka] HPLC (Method 1) RT=4.14 min, purity=99.2%, MS(ESI+) m / z is C 29 H 37 N 6 O 7 S + [M+H] + The calculated value was 613.2 and the measured value was 613.3.

[0506] Compound 137, 1-(N-(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-N-(2-oxo-2-((2-oxo-2-(prop-2-yn-1-ylamino)ethyl)amino)ethyl)sulfamoyl)pyrrolidine-3-carboxylate Voxamide [ka] HPLC (Method 1) RT=3.95 min, purity >99.9%, MS(ESI+) m / z is C 29 H 39 N 6 O 5 S + [M+H] + The calculated value was 583.3 and the measured value was 583.4.

[0507] Compound 138, 2-(naphthalen-1-yl)-2-(4-(N-(2-oxo-2-((2-oxo-2-(prop-2-yn-1-ylamino)ethyl)amino)ethyl)methylsulfonamido)piperidin-1-yl)acetic acid [ka] HPLC (Method 1) RT=3.97 min, purity >99.9%, MS(ESI+) m / z is C 25 H 31 N 4 O 6 S + [M+H] + The calculated value was 515.2 and the measured value was 515.3.

[0508] Compound 139, 2-(N-(1-(1-(2-chloro-4-methoxyphenyl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.79 min, purity >99.9%, MS(ESI+) m / z is C 22 H 32 ClN 4 O 5 S + [M+H] + The calculated value was 499.2 and the measured value was 499.2.

[0509] Compound 140, 2-(N-(1-(1-(2,5-dichlorophenyl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.79 min, purity >99.9%, MS(ESI+) m / z is C 21 H 29 Cl 2 N 4 O 4 S + [M+H] + The calculated value was 503.1 and the measured value was 503.2.

[0510] Compound 141, N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-2-(N-(1-(1-(3-(thiophen-2-yl)phenyl)ethyl)piperidin-4-yl)methylsulfonamido)acetamide [ka] HPLC (Method 1) RT=4.20 min, purity >99.9%, MS(ESI+) m / z is C 25 H 33 N 4 O 4 S 2 + [M+H] + The calculated value was 517.2 and the measured value was 517.3.

[0511] Compound 142, 2-(N-(1-(1-(2-chloro-3-methylphenyl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.84 min, purity >99.9%, MS(ESI+) m / z is C 22 H 32 ClN 4 O 4 S + [M+H] + The calculated value was 483.2 and the measured value was 483.3.

[0512] Compound 143, 2-(N-(1-(2-hydroxy-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.68 min, purity >99.9%, MS(ESI+) m / z is C25 H 33 N 4 O 5 S + [M+H] + It was calculated to be 501.2 and measured to be 501.2.

[0513] Compound 144, KHS_NB6_066, 2-(N-(1-(2-fluoro-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.05 min, purity >99.9%, MS(ESI+) m / z is C 25 H 32 FN 4 O 4 S + [M+H] + It was calculated as 503.2 and measured as 503.2.

[0514] Compound 145, (R)-2-((1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)(sulfamoyl)amino)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide 2,2,2-trifluoroacetate [ka] HPLC (Method 1) RT=3.84 min, purity >99.9%, MS(ESI+) m / z is C 24 H 32 N 5 O 4 S + [M+H] + The calculated value was 486.2 and the measured value was 486.3.

[0515] Compound 146, (R)-N-(3-cyano-2-oxopropyl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=3.90 min, purity >99.9%, MS(ESI+) m / z is C 26 H 34 N 5 O 5 S + [M+H] + The calculated value was 528.2 and the measured value was 528.3.

[0516] Compound 147, (R)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-N-(2-oxo-2-(2-propioloylhydrazinyl)ethyl)methanesulfonamide [ka] HPLC (Method 1) RT=3.84 min, purity >99.9%, MS(ESI+) m / z is C 23 H 29 N 4 O 4 S + [M+H] + It was calculated to be 457.2 and measured to be 457.2.

[0517] Compound 148, 2-(N-(1-(2,2-difluoro-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=5.00 min, purity >99.9%, MS(ESI+) m / z is C 25 H 31 F2 N 4 O 4 S + [M+H] + The calculated value was 521.2 and the measured value was 521.3.

[0518] Compound 149, 5-((2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)methyl)-N-(prop-2-yn-1-yl)-1,3,4-oxadiazole-2-carboxamide [ka] HPLC (Method 1) RT=4.00 min, Purity=99.2%, MS(ESI+)m / z is C 27 H 33 N 6 O 5 S + [M+H] + The calculated value was 553.2 and the measured value was 553.3.

[0519] Compound 150, N-((1,3,4-oxadiazol-2-yl)methyl)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamide [ka] HPLC (Method 1) RT=3.79 min, purity=99.2%, MS(ESI+) m / z is C 23 H 30 N 5 O 4 S + [M+H] + The calculated value was 472.2 and the measured value was 472.2.

[0520] Compound 151, 2-(N-(1-(1-(naphthalen-1-yl)ethyl-2,2,2-d3)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.95 min, purity=97.0%, MS(ESI+) m / z is C 25 H 30 D 3 N 4 O 4 S + [M+H] + The calculated value was 488.2 and the measured value was 488.3.

[0521] Compound 152, (R)-2-(N-(1-((R)-1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)propanamide [ka] HPLC (Method 1) RT=3.99 min, purity=99.1%, MS(ESI+) m / z is C 26 H 35 N 4 O 4 S + [M+H] + The calculated value was 499.2 and the measured value was 499.3.

[0522] Compound 153, 2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-((prop-2-yn-1-yl-1,1-d2)amino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.95 min, purity >99.9%, MS(ESI+) m / z is C 25 H 31 D 2 N 4 O 4 S + [M+H] + The calculated value was 487.2 and the measured value was 487.3.

[0523] Compound 154, N-(2,2-dimethoxyethyl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=3.96 min, purity >99.9%, MS(ESI+) m / z is C 26 H 39 N 4 O 6 S + [M+H] + It was calculated as 535.3 and was measured as 535.3.

[0524] Compound 155, N-(2-methylpent-4-yn-2-yl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=4.39 min, purity >99.9%, MS(ESI+) m / z is C 28 H 39 N 4 O 4 S + [M+H] + It was calculated as 527.3 and was measured as 527.3.

[0525] Compound 156, N-(2,2-dimethylbut-3-yn-1-yl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=4.34 min, purity >99.9%, MS(ESI+) m / z is C 28 H 39 N 4 O 4 S + [M+H] + It was calculated as 527.3 and was measured as 527.3.

[0526] Compound 157, N-(but-3-yn-1-yl)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=4.05 min, purity=96.8%, MS(ESI+) m / z is C 26 H 35 N 4 O 4 S + [M+H] + The calculated value was 499.2 and the measured value was 499.2.

[0527] Compound 158, N-(2,2-diethoxyethyl-1,1-d2)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido [ka] HPLC (Method 1) RT=4.21 min, purity >99.9%, MS(ESI+) m / z is C 28 H 41 D 2 N4 O 6 S + [M+H] + The calculated value was 565.3 and the measured value was 565.2.

[0528] Compound 159, (E)-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido)but-2-enamido [ka] HPLC (Method 1) RT=3.69 min, purity >99.9%, MS(ESI+) m / z is C 26 H 36 N 5 O 5 S + [M+H] + The calculated value was 530.2 and the measured value was 530.3.

[0529] Compound 160, 2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-((3,3,3-trifluoro-2-oxopropyl)amino)ethyl)acetamide [ka] HPLC (Method 1) RT=5.58 min, purity=99.0%, MS(ESI+) m / z is C 25 H 32 F 3 N 4 O 5 S + [M+H] + The calculated value was 557.2 and the measured value was 557.3.

[0530] Compound 161, N-(2-cyanamido-2-oxoethyl)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamide [ka] HPLC (Method 1) RT=4.18 min, purity=97.4%, MS(ESI+) m / z is C 23 H 30 N 5 O 4 S + [M+H] + The calculated value was 472.2 and the measured value was 472.3.

[0531] Compound 162, methyl (E)-2-cyano-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=4.57 min, purity=94.3%, MS(ESI+) m / z is C 28 H 36 N 5 O 6 S + [M+H] + The calculated value was 570.2 and the measured value was 570.2.

[0532] Compound 163, methyl (E)-2-cyano-4-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido)but-2-enoate [ka] HPLC (Method 1) RT=3.79 min, purity >99.9%, MS(ESI+) m / z is C 26 H 35 N 4 O 6 S + [M+H] + The calculated value was 531.2 and the measured value was 531.3.

[0533] Compound 164, 2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-(prop-2-yn-1-ylamino)-2-thioxoethyl)acetamide [ka] HPLC (Method 1) RT=4.37 min, purity >99.9%, MS(ESI+) m / z is C 25 H 33 N 4 O 3 S 2 + [M+H] + It was calculated to be 501.2 and measured to be 501.2.

[0534] Compound 165, 2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(3,3,3-trifluoro-2-(prop-2-yn-1-ylamino)propyl)acetamide [ka] HPLC (Method 1) RT=4.33 min, purity >99.9%, MS(ESI+) m / z is C 26 H 34 F 3 N 4 O 3 S + [M+H] + The calculated value was 539.2 and the measured value was 539.3.

[0535] Compound 166, (2R)-2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)-N-(prop-2-yn-1-yl)propanamide [ka] HPLC (Method 1) RT=4.09 min, purity >99.9%, MS(ESI+) m / z is C26 H 35 N 4 O 4 S + [M+H] + The calculated value was 499.2 and the measured value was 499.2.

[0536] Compound 167, 2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(3,3,3-trifluoro-2-(prop-2-yn-1-yloxy)propyl)acetamide [ka] HPLC (Method 1) RT=4.63 min, purity=96.3%, MS(ESI+) m / z is C 26 H 33 F 3 N 3 O 4 S + [M+H] + The calculated value was 540.2 and the measured value was 540.3.

[0537] Compound 168, N-(2-(2-acryloylhydrazinyl)-2-oxoethyl)-N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methanesulfonamide [ka] HPLC (Method 1) RT=3.90 min, purity >99.9%, MS(ESI+) m / z is C 23 H 31 N 4 O 4 S + [M+H] + The calculated value was 459.2 and the measured value was 459.2.

[0538] Compound 169, N-benzyl-2-hydroxy-3-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)acetamido)acetamido)propanamide [ka] HPLC (Method 1) RT=4.30 min, purity=97.9%, MS(ESI+) m / z is C 32 H 42 N 5 O 6 S + [M+H] + The calculated value was 624.3 and the measured value was 624.4.

[0539] Compound 170, N-(5-ethynyl-1,3,4-oxadiazol-2-yl)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)acetamide [ka] HPLC (Method 1) RT=4.22 min, purity >99.9%, MS(ESI+) m / z is C 24 H 28 N 5 O 4 S + [M+H] + The calculated value was 482.2 and the measured value was 482.3.

[0540] Compound 171, N-(but-3-yn-1-yl)-2-(3-(methylsulfonyl)-3-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)ureido)acetamide [ka] HPLC (Method 1) RT=4.22 min, purity=98.2%, MS(ESI+) m / z is C 25 H 33 N 4 O 4 S + [M+H] + The calculated value was 485.2 and the measured value was 485.3.

[0541] Compound 172, N-(but-3-yn-1-yl)-3-hydroxy-4-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)butanamide [ka] HPLC (Method 1) RT=4.08 min, purity=99.4%, MS(ESI+) m / z is C 26 H 36 N 3 O 4 S + [M+H] + The calculated value was 486.2 and the measured value was 486.3.

[0542] Compound 173, (E)-N-((5-(2-methoxyvinyl)-1,3,4-oxadiazol-2-yl)methyl)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)acetamide [ka] HPLC (Method 1) RT=4.06 min, purity=82.1%, MS(ESI+) m / z is C 26 H 34 N 5 O 5 S + [M+H] + The calculated value was 528.2 and the measured value was 528.4.

[0543] Compound 174, (R)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)-N-(2-oxo-2-((prop-2-yn-1-yl-1,1-d2)amino)ethyl)acetamide [ka] HPLC (Method 1) RT=4.01 min, purity=99.7%, MS(ESI+) m / z is C 25 H31 D 2 N 4 O 4 S + [M+H] + The calculated value was 487.2 and the measured value was 487.3.

[0544] Compound 175, (S)-2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamide)-N-(2-oxo-2-((prop-2-yn-1-yl-1,1-d2)amino)ethyl)acetamide [ka] HPLC (Method 1) RT=3.99 min, purity >99.9%, MS(ESI+) m / z is C 25 H 31 D 2 N 4 O 4 S + [M+H] + The calculated value was 487.2 and the measured value was 487.2.

[0545] Compound 176, N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)-N-(2-oxo-2-(2-(vinylsulfonyl)hydrazinyl)ethyl)methanesulfonamide [ka] HPLC (Method 1) RT=4.02 min, purity >99.9%, MS(ESI+) m / z is C 22 H 31 N 4 O 5 S 2 + [M+H] + The calculated value was 495.2 and the measured value was 495.2.

[0546] Compound 177, N-benzyl-3-(2-(2-(N-(1-(1-(naphthalen-1-yl)ethyl)piperidin-4-yl)methylsulfonamido)acetamido)acetamido)-2-oxopropanamide [ka] HPLC (Method 3) RT=2.24 min, MS(ESI+) m / z is C 32 H 40 N 5 O 6 S + [M+H] + The calculated value was 622.3 and the measured value was 622.4.

[0547] biological analysis Biological Example 1. Preparation and Purification of PLpro PLpro(pp1ab 1564-1878) was codon-optimized, synthesized, and cloned into pET11a vector with a TEV-cleavable his6 tag at the N-terminus. The recombinant plasmid was transformed into BL21(DE3) expression cells and grown in Luria-Bertani (LB) medium containing carbenicillin (100 μg / mL) at 37°C with shaking at 220 rpm. When the OD600 reached 0.6, the cells were induced with 0.5 mM IPTG and further incubated at 18°C ​​for 16 h before harvesting. The cell pellet was resuspended and lysed by sonication in lysis buffer (50 mM Tris, pH 8.0, 500 mM NaCl, 20 mM imidazole, 5 mM β-MCE, 1 mg / mL lysozyme, 1% TritonX-100, and 0.025 mg / mL DNase I). His-tagged proteins were purified on a HisTrap HP column using a step gradient elution buffer (50 mM Tris, pH 8.0, 500 mM NaCl, 500 mM imidazole, and 5 mM β-MCE) on an AKTA Pure FPLC system. The his-TEV tag was removed by incubating the eluted protein with 1 unit / 100 μg TEV protease for 16 h at 4 °C. The digested protein was reloaded onto a HisTrap HP column equilibrated with 50 mM Tris, pH 8.0, 500 mM NaCl, and 5 mM β-MCE, and the his-TEV tagged cleaved PLpro was collected during the flow-through and loaded onto a HiLoad 16 / 60 Superdex 75 PG gel filtration column equilibrated with 50 mM Tris, pH 8.0, 200 mM NaCl, and 1 mM TCEP. Protein samples are analyzed by SDS-PAGE and the final purity is >95%.

[0548] Biological Example 2. Compound Inhibition and Determination of IC50 Values PLpro enzyme was purified as described above and prepared in assay buffer (50 mM HEPES, pH 7.5, 0.01% Triton X-100 (v / v), 0.1 mg mL-1 BSA, and 2 mM DTT). IC50 values ​​were measured in triplicate. A series of increasing concentrations (0–100 μM final concentrations when diluted in 3-fold steps) was prepared in 100% DMSO in a 384-well plate. 7 μL of 225 nM (3X) enzyme solution was dispensed into the wells, and 7 μL of various concentrations of 3X compounds were added and incubated for 10 and 60 min for non-covalent and covalent inhibitors, respectively. The enzyme reaction was initiated by adding 7 μL of 75 μM (3X) substrate, and its activity was continuously monitored for at least 10 min. IC50 values ​​were calculated by fitting the Hill equation (1) using Sigmaplotv 14. Here where y is the percent inhibition, x is the inhibitor concentration, n is the slope of the concentration-response curve (Hill slope), and Vmax is the maximum inhibition from three independent determinations.

number

[0549] The test results of compounds 1 to 177 in the enzyme inhibition test of the novel coronavirus SARS-CoV-2 PLpro are summarized in Table 1.

[0550] Biological Example 3. Compound binding assay and inactivation rate assay

[22] Using a Biacore T200 instrument, purified SARS-CoV-2 PLpro enzyme was immobilized on flow channels 2 and 4 of a CM5 sensor chip with standard amine coupling using running buffer HBS-P (10 mM HEPES, 150 mM NaCl, 0.05% surfactant P-20, pH 7.4). Flow channels 1 and 3 were used as control surfaces. PLpro enzyme was diluted in 10 mM sodium acetate (pH 5.0) and immobilized after activating the sensor surface with a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) / N-hydroxysuccinimide (NHS) mixture, followed by blocking the surface areas that were not coupled with ethanolamine (pH 8.5). Selected compounds were first diluted in 10 mM Compound solutions prepared as DMSO stock solutions and in a series of increasing concentrations (0-10 μM in 4-fold dilutions) were applied to all four channels at a flow rate of 30 μL / min at 25 °C. Single-cycle kinetic methods were performed and real-time response units were monitored. Sensorgrams were double-referenced with a blank channel and zero concentration response and fitted to a 1:1 Langmuir kinetic equation implemented in the Biacore Insight software.

[0551] Surface plasmon resonance (SPR) binding analysis demonstrated that selected PL inhibitors directly bind to immobilized SARS-CoV-2 PL protein using single-cycle kinetics over a series of increasing concentrations. Kd values ​​for representative compounds were measured to be less than 100 nM.

[0552] Purified SARS-CoV2-PLpro protein was prepared in assay buffer (50 mM HEPES, pH 7.5, 0.01% Triton X-100, 0.1 mg / mL BSA). The PLpro substrate, Z-RLRGG-AMC (Bachem Bioscience), is a small fluorescent peptide. PLpro cleavage of the substrate releases AMC (7-amido-4-methylcoumarin), which generates a fluorescent signal. Measurements were performed using black low-volume 384-well plates (Greiner). All compounds were initially prepared as 1 mM stock solutions in 100% DMSO. A series of increasing concentrations was prepared in 100% DMSO by two-fold serial dilutions. The final compound concentrations (1x) measured ranged from 1.5 to 1500 nM. 7 μL of compound (3x) solution and 7 μL of substrate (3x) solution were added to the wells. The reaction was started by adding 7 μL of SARS-CoV2-PLpro (3x) solution and mixing. The final concentration of SARS-CoV2-PLpro (1x) is 20 nM and the final concentration of substrate (1x) is 10 uM. Fluorescence intensity at 450 nm (excitation wavelength 360 nm) was continuously monitored for 1.5 h at 30 °C using a BMG LabTech PolarStar Optima plate reader. Kinetic curves were calculated using the equation F = F 0 +r P [S] 0 The value of the α parameter was derived by fitting {1-exp[-β(1-exp(-αt))]}. inact / K i is the hyperbolic equation α=K inact ([I] 0 / ([I] 0 +K i )) with α The results were obtained by fitting to a plot of the concentration of

[0553] Biological Example 4. Covalent Inhibition Modes Measured by MALDI Covalent binding and selectivity for the catalytic cysteine ​​were determined by comparing MALDI mass spectrometry of wild-type SARS-CoV-2 PLpro incubated with inhibitors with MALDI mass spectrometry of C111S-CoV-2 PLpro in which the catalytic cysteine ​​was converted to serine. Treatment of PLpro with representative compounds resulted in the formation of irreversible covalent adducts in the wild-type enzyme but not in the active site cysteine ​​mutant enzyme. Addition of the mass equivalent to one molecule of PLpro inhibitor to wild-type PLpro demonstrated selective covalent reaction with the catalytic cysteine ​​(C111 of PLpro).

[0554] Biological Example 5. SARS-CoV2 Antiviral Activity Analysis The antiviral activity of PLpro inhibitors was measured in a cell culture test on A549:hACE2 cells (Invivogen) by the following method. On the day before the test, 10K cells (A549:hACE2) were seeded per well. Then, serial dilutions of the drug were made in 2% DMEM medium and added to the cells. Before infection, the cells were incubated with the drug for 2 hours. Then, the cells were infected at 0.5 MOI (multiplicity of infection) and fixed with 10% formalin for 15-30 minutes after 48 hours. Then, immunohistochemical antibody staining was performed on the cells. The cells were blocked with 1% BSA + 0.025% saponin for 1 hour, washed with 3% hydrogen peroxide for 5 minutes, washed with PBS and PBST, then added the primary antibody [mouse anti-spike protein antibody (GTX632604, GeneTex)] in blocking buffer and spent overnight. The next day, further washed with PBS / PBST, added HRP secondary antibody for 1 hour, and then DAB staining was performed for 15 minutes. The percentage of spike protein-positive cells was then assessed microscopically. EC50 was determined using software such as Prism (Graphpad Software,) or the AAT Bioquest EC50 calculator (https: / / www.aatbio.com / tools / ec50-calculator) from the following formula (2): where [I] was the concentration of the inhibitor and n was the Hill coefficient.

number

[0555] The cellular EC50 results of selected PLpro compounds in the SARS-CoV2 antiviral cellular activity assay are summarized in Table 2.

[0556] Table 2 [Table 3]

[0557] a. SARS-CoV2 antiviral cellular activity is expressed in the EC50 range. +++ (EC 50 : <100 nM), or ++ (EC 50 : less than 0.1 μM to 1 μM).

[0558] The Summary and Abstract sections describe one or more exemplary embodiments of the invention as contemplated by the inventors, but are not intended to describe all of them, and are therefore not intended to be in any way limiting of the scope of the invention and the appended claims.

[0559] The present invention is described with the help of functional building blocks illustrating the implementation of certain functions and relationships thereof. For convenience of explanation, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries may be defined so long as the certain functions and relationships thereof are appropriately implemented.

[0560] For aspects of the invention described as genus, all individual species are each considered a separate aspect of the invention. When an aspect of the invention is described as "comprising" a feature, it is also envisioned that the embodiment "consists of" or "consists essentially of" that feature.

[0561] The foregoing description of the specific embodiments fully reveals the general nature of the present invention, so that those skilled in the art can easily modify and / or adapt such specific embodiments to various applications without undue experimentation by applying knowledge in the general art of the art, without departing from the general concept of the present invention. Therefore, based on the teaching and guidance presented herein, such adaptations and modifications are within the meaning and range of equivalents of the disclosed embodiments. It should be understood that the expressions or terms in this specification are intended to be illustrative, not limiting. Therefore, the terms or terms in this specification are to be interpreted by those skilled in the art based on the teaching and guidance.

[0562] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments.

[0563] The various aspects, embodiments, and options described herein may be combined in any desired manner and in any number of variations.

[0564] All publications, patents, and patent applications mentioned herein are incorporated by reference herein as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If any meaning or definition of a term in this specification conflicts with any meaning or definition of the same term in a document incorporated herein by reference, the meaning or definition assigned to that term in this specification shall control.

[0565] References 1.Lindner, HA, et al., Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch Biochem Biophys, 2007. 466(1): p. 8-14. 2.Liu, G., et al., ISG15-dependent activation of the sensor MDA5 is antagonized by the SARS-CoV-2 papain-like protease to evade host innate immunity. Nat Microbiol, 2021. 6(4): p. 467-478. 3.Freitas, B.T., et al., Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease. ACS Infect Dis, 2020. 6(8): p. 2099-2109. 4.Shin, D., et al., Papain-like proteas e regulates SARS-CoV-2 viral spread and innate immunity. Nature, 2020. 587(7835): p. 657-662. 5.Macchiagodena, M., M. Pagliai, and P. Procacci, Identification of Potential Binders of the Main Protease 3CL(pro) of the COVID-19 via Structure-Based Ligand Design and Molecular Modeling. Chem Phys Lett, 2020: p. 137489. 6.Ul Qamar, M.T., et al., Structural basis of SARS-CoV-2 3CL(pro) and anti-COVID-19 drug discovery from medicinal plants. J Pharm Anal, 2020. 7.Sisay, M., 3CL(pro) inhibitors as a potential therapeutic option for COVID-19: Available evidence and ongoing clinical trials. Pharmacol Res, 2020. 156: p. 104779. 8.Chen, X., et al., SARS coronavirus papain-like protease inhibits the type I interferon signaling pathway through interaction with the STING-TRAF3-TBK1 complex. Protein Cell, 2014. 5(5): p. 369-81. 9.Fung, T.S. and D.X. Liu, Human Coronavirus: Host-Pathogen Interaction. Annu Rev Microbiol, 2019. 73: p. 529-557. 10.Ghosh, A.K., et al., Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease. J Med Chem, 2009, 52(16): p. 5228- 5240. 11.Baez-Santos, Y.M., et al., X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases. J Med Chem, 2014, 57(6): p. 2393-2412. 12.Nicola, M., et al., The Socio-Economic Implications of the Coronavirus and COVID-19 Pandemic: A Review. Int J Surg, 2020. 13.Di Gennaro, F., et al., Coronavirus Diseases (COVID-19) Current Status and Future Perspectives: A Narrative Review. Int J Environ Res Public Health, 2020. 17(8). 14.Snijder, E.J., et al., Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J Mol Biol, 2003. 331(5): p. 991-1004. 15.Rabaan, A.A., et al., SARS-CoV-2, SARS-CoV, and MERS-COV: A comparative overview. Infez Med, 2020. 28(2): p. 174-184. 16.Mielech, A.M., et al., MERS-CoV papain-like protease has deISGylating and deubiquitinating activities. Virology, 2014. 450-451: p. 64-70. 17.Baez-Santos, Y.M., S.E. St John, and A.D. Mesecar, The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral Res, 2015. 115: p. 21-38. 18.Devaraj, S.G., et a...

Claims

1. A compound of formula Y-2-E or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 where: X １ is non-existent, CR １１ R １２ or NR13, X ２ is absent or optionally substituted C １－４ is an alkylene group, Y １ and Y ９ are each independently absent, optionally substituted C １－４ Alkylene group, optionally substituted C １－４ a heteroalkylene group or an optionally substituted 3- to 8-membered ring structure; W is 【Chemistry 2】 , or CN, R １０ is an optionally substituted aryl group or an optionally substituted heteroaryl group; each G 10 is independently hydrogen, deuterium, or a methyl group, or two G 10 s together with the carbons to which they are both attached form a cyclopropylene group; each G 11 is hydrogen or a methyl group; However, in all combinations of G 10 and G 11 , up to four of G 10 and G 11 are not hydrogen or deuterium, preferably up to three of G 10 and G 11 are not hydrogen or deuterium, and more preferably only one or two of G 10 and G 11 are not hydrogen or deuterium; R １１ and R １２ are each independently hydrogen, halogen, OH, NH ２ , COOH, CONH ２ , S.O. ２ NH ２ , G Ａ , O.G. Ａ , NH(G Ａ ), N(G Ａ ) (G Ａ ), COOG Ａ , CONH(G Ａ ), CON(G Ａ ) (G Ａ ), SO ２ NH (G Ａ ), SO ２ N (G Ａ ) (G Ａ ), NHCOG Ａ , N(G Ａ ) COG Ａ , NHSO ２ (G Ａ ), N(G Ａ ) SO ２ (G Ａ ), COG Ａ , or SO ２ (G Ａ ) or R １１ and R １２ are linked to form a 3- to 8-membered ring structure, R １３ is hydrogen, G Ａ , COOG Ａ , C.O.N.H. ２ , CONH(G Ａ ), CON(G Ａ ) (G Ａ ), SO ２ NH ２ , S.O. ２ NH (G Ａ ), SO ２ N (G Ａ ) (G Ａ ), COG Ａ , or SO ２ (G Ａ ) and EWG is an electron withdrawing group selected from an aldehyde group, an ester group, an amide group, a sulfone group, a sulfonamide group, or CN; R ３０ and R ３１ are each independently hydrogen, G Ａ or an electron withdrawing group, or R ３０ And, R ３１ or EWG bonded to form a non-aromatic ring structure, or R ３１ and EWG are linked to form a non-aromatic ring structure; R ３１Ａ and R ３１Ｂ are each independently hydrogen, G Ａ or an electron withdrawing group, or R ３０ and R ３１Ｂ are bonded to form a non-aromatic ring structure, or R ３１Ａ and R ３１Ｂ are bonded to form a non-aromatic ring structure, J １ , O, NR ３６ , C １－４ Alkylene group, C １－４ a heteroalkylene group, or absent, J ２ is absent, C(O), SO, or SO ２ and R ３２ is hydrogen, G Ａ or an electron-withdrawing group, Lg is a leaving group selected from F and Cl, OH, or CN; R ３３ and R ３４ are independently hydrogen or optionally substituted C １－４ is an alkyl group, R ３５ is G Ｂ , O.G. Ｂ , NH(G Ｂ ), N(G Ｂ ) (G Ｂ ) and R ３６ is hydrogen, optionally substituted C １－４ an alkyl group or an electron-withdrawing group, G Ｂ are each independently hydrogen, optionally substituted C １－６ alkyl groups, optionally substituted C ２－６ Alkenyl group, optionally substituted C ２－６ an alkynyl group or an optionally substituted ring structure having 4 to 10 ring atoms; and G Ａ each independently represents an optionally substituted C １－６ alkyl groups, optionally substituted C ２－６ Alkenyl group, optionally substituted C ２－６ Alkynyl group, optionally substituted C １－６ a heteroalkyl group or an optionally substituted ring structure having 4 to 10 ring atoms; A compound or a pharmaceutically acceptable salt thereof.

2. Having a structure represented by formula Y-2-F, 【Transformation 3】 wherein X 2 , R 10 , X 1 , Y 1 , Y 9 and W are defined as in claim 1; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. X 2 is an optionally substituted C 1-4 alkylene group, preferably a straight-chain or branched unsubstituted C 1-4 alkylene group, more preferably CH 2 , CH(CH 3 , or CH(C 2 H 5 ), or X 2 is represented by CR 14 R 15 , where (i) R 14 and R 15 are each independently hydrogen, an optionally substituted C 1-4 alkyl group, an optionally substituted C 2-4 alkenyl group, an optionally substituted C 2-4 alkynyl group, or an optionally substituted ring structure having 4 to 10 ring atoms; (ii) one of R 14 and R 15 is COOH, or an ester thereof, or an amide thereof, and the other of R 14 and R 15 is defined as in (i); or (iii) R 14 and R 15 together with the carbons to which they are both bonded form an optionally substituted 3- to 6-membered ring; and Preferably, one of R 14 and R 15 is hydrogen and the other of R 14 and R 15 is hydrogen, a C 1-4 alkyl group optionally substituted with 1 to 3 G S1 , a C 3-6 cycloalkyl group optionally substituted with 1 to 3 G S1 , or a phenyl group optionally substituted with 1 to 3 G S1 , where each G S1 is independently halogen (preferably F), NH 2 , OH, a C 1-4 alkyl group, or a C 1-4 alkoxy group; or (i) one of R14 and R15 is hydrogen and the other of R14 and R15 is hydrogen, a methyl group, or a phenyl group; (ii) one of R14 and R15 is hydrogen and the other of R14 and R15 is CH2F, CH2OH, CHF2, CD3, CF3, an ethyl group, CN, a cyclopropyl group, COOH, or COOCH3; or (iii) R14 and R15 together with the carbon to which they are both bonded form a cyclopropyl group.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. R 10 is an optionally substituted phenyl group or an optionally substituted naphthyl group; Preferably, (i) R 10 is optionally substituted, e.g., substituted with 1 to 3 G S1 . 【Chemistry 4】 wherein each G S1 is independently halogen (preferably F or Cl), OH, a C 1-4 alkyl group (eg, a methyl group), or a C 1-4 alkoxy group (eg, a methoxy group); (ii) R 10 is optionally substituted, for example, substituted with 1 to 3 G S1A . 【Transformation 5】 wherein each G S1A is independently halogen (preferably F or Cl), OH, a C 1-4 alkyl group optionally substituted with 1 to 3 F (e.g., methyl group, CF 3 ), a C 1-4 alkoxy group optionally substituted with 1 to 3 F (e.g., methoxy group), or an optionally substituted 3- to 7-membered ring; (iii) R 10 is optionally substituted, e.g., substituted with 1 to 3 G S1A . 【Transformation 6】 wherein each G S1A is independently halogen (preferably F or Cl), OH, a C 1-4 alkyl group optionally substituted with 1 to 3 F (e.g., methyl group, CF 3 ), a C 1-4 alkoxy group optionally substituted with 1 to 3 F (e.g., methoxy group), or an optionally substituted 3- to 7-membered ring; (iv) R 10 is optionally substituted, e.g., substituted with 1 to 3 G S1A . 【Transformation 7】 wherein each G S1A is independently halogen (preferably F or Cl), OH, a C 1-4 alkyl group optionally substituted with 1 to 3 F (e.g., a methyl group, CF 3 ), a C 1-4 alkoxy group optionally substituted with 1 to 3 F (e.g., a methoxy group), or an optionally substituted 3- to 7-membered ring; or (v) R 10 is optionally substituted, e.g., substituted with 1 to 3 G S1B . 【Transformation 8】 wherein each G S1B is independently halogen (e.g., F, Cl, or Br), OH, a C 1-4 alkyl group optionally substituted with 1 to 3 F (e.g., methyl group, CF 3 ), a C 1-4 alkoxy group optionally substituted with 1 to 3 F (e.g., methoxy group), or an optionally substituted 3- to 7-membered ring (e.g., phenyl group, thienyl group, etc.); 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. Having a structure represented by formula Y-3B or a structure represented by formula Y-3C, 【Chemistry 9】 where: (i) R １４ and R １５ are each independently hydrogen, optionally substituted C １－４ alkyl groups, optionally substituted C ２－４ Alkenyl group, optionally substituted C ２－４ an alkynyl group or an optionally substituted ring structure having 4 to 10 ring atoms; (ii) R １４ and R １５ is COOH or an ester or amide thereof, and R １４ and R １５ the other of which is defined as (i), or (iii) R １４ and R １５ together with the carbon atoms to which they are both attached form an optionally substituted 3- to 6-membered ring, n is 0, 1, 2, 3, or 4, preferably 0, 1, or 2; G Ｓ１Ａ are each independently selected from halogen (preferably F or Cl), OH, C optionally substituted with 1 to 3 F groups, １－４ Alkyl groups (e.g., methyl groups, CF ３ ), C optionally substituted with 1 to 3 F １－４ an alkoxy group (e.g., a methoxy group) or an optionally substituted 3- to 7-membered ring; and X 1 , Y 1 , Y 9 , W, G 10 and G 11 are defined as in claim 1; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. X 2 -R 10 is 【Chemistry 10】 and Preferably, X 2 -R 10 is 【Chemistry 11】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. X １ is NR １３ and (i) R １３ is hydrogen, optionally substituted C １－６ Alkyl group, COG Ａ , or SO ２ G Ａ is, or (ii) R １３ For example, 【Chemistry 12】 Optionally substituted C such as １－６ alkyl groups, optionally substituted C ２－６ alkenyl group or optionally substituted C ２－６ an alkynyl group, or (iii) R １３ teeth, 【Chemistry 13】 selected from, or R １３ teeth, 【Chemistry 14】 Selected from:

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. (i) Y ９ is absent, e.g., CH ２ Or CD ２ Optionally substituted C such as １－４ an alkylene group or an optionally substituted 4-8 membered heterocycle having 1 or 2 ring heteroatoms, said ring heteroatoms being independently O, S, or N; (ii) Y ９ For example, 【Chemistry 15】 C, etc. ３－６ is a 1-membered carbocyclic ring, or (iii) Y ９ is optionally, for example, oxo, F, CF ３ C substituted with １－４ is a heteroalkylene group, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. (i) Y １ is non-existent, (ii) Y １ For example, CH ２ or CD ２ Optionally substituted C such as １－４ an alkylene group, or (iii) Y １ For example, 【Chemistry 16】 and optionally substituted 4-8 membered heterocycles having 1-3 ring heteroatoms, such as, wherein said ring heteroatoms are independently O, S, or N; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. W is 【Chemistry 17】 , C(O)R ３５ ,or [Chemistry 18] where G Ａ７ is an optionally substituted C １－６ is an alkyl group, and R ３５ is hydrogen or C １－４ is an alkyl group, and R ３２ is hydrogen or C １－４ is an alkyl group, or W is 【Chemistry 19】 is, or W is 【Chemistry 20】 is, or W is 【Chemistry 21】 is, or W is C(O)H, 【Chemistry 22】 is, or W is 【Chemistry 23】 is, or W is 【Chemistry 24】 is, or Y ９ -W is -(C １－４ alkylene group)-CN, CN, 【Chemistry 25】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. A compound represented by formula Y-2-E or a pharmaceutically acceptable salt thereof, 【Chemistry 26】 where: X １ is NR １３ and R 13 is selected from hydrogen, an optionally substituted C 1-6 alkyl group, COG A , or SO 2 G A , where G A is an optionally substituted C 1-6 alkyl group; Preferably, R 13 is hydrogen, Me, Boc, 【Chemistry 27】 is selected from More preferably, R 13 is hydrogen, 【Chemistry 28】 is selected from X 2 -R 10 is 【Chemistry 29】 and Preferably, X 2 -R 10 is 【Transformation 30】 and Y 1 is absent; Y 9 is absent; W is 【Chemistry 31】 is selected from each G 10 is independently hydrogen, deuterium, or a methyl group, preferably G 10 is independently hydrogen or deuterium; and each G 11 is hydrogen or a methyl group; A compound or a pharmaceutically acceptable salt thereof.

12. A compound shown below 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 or a pharmaceutically acceptable salt thereof.

13. A composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient; Preferably, it further comprises one or more other antiviral agents. Pharmaceutical compositions.

14. 13. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a viral infection, comprising: Preferably, the viral infection is caused by a virus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2.

15. The pharmaceutical composition of claim 13 for treating or preventing a viral infection, comprising: Preferably, the viral infection is caused by a virus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2.

16. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting papain-like protease (PLpro) in a subject in need thereof. Use of salt, The subject is suffering from a viral infection caused by a virus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2.

17. The pharmaceutical composition of claim 13 for inhibiting papain-like protease (PLpro) in a subject in need thereof, comprising: The pharmaceutical composition, wherein the subject is suffering from a viral infection caused by a virus selected from SARS-CoV, HCoV-229E, HCoV-OC43, HCoV-NL63, MERS-CoV, HCoV-HKU1, and SARS-CoV-2.

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