2-Amino-N-(4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)benzamide derivatives as protease inhibitors for treating or preventing coronavirus infections

Abstract

The present invention provides compounds of Formula I (wherein R, R, R, R, R, R, R, R, and the subscripts x and n are as described herein), as well as pharmaceutical compositions comprising one or more of the compounds, and methods for using the compounds for the treatment, inhibition, or amelioration of one or more disease states that can benefit from the inhibition of coronaviruses (such as SARS-CoV, MERS-CoV, and SARS-CoV-2). The compounds of the present invention can further be used in combination with other therapeutically effective agents, including, but not limited to, other drugs useful in the treatment of coronavirus infections. The present invention further relates to processes for preparing compounds of Formula I, as well as pharmaceutical compositions comprising compounds of Formula I and pharmaceutically acceptable salts thereof. [Formula 1] TIFF2025530610000131.tif42146

Description

[Technical Field]

[0001] The present invention relates to certain protease inhibitors, pharmaceutical compositions containing such inhibitors, and methods for using the compounds for the treatment, inhibition, or amelioration of one or more disease states that can benefit from the inhibition of coronaviruses (such as SARS-CoV, MERS-CoV, and SARS-CoV-2). [Background technology]

[0002] Coronaviruses (CoVs) are large, enveloped, positive-strand RNA viruses that comprise the Coronavirinae subfamily in the Nirovirales order. CoVs are further classified into four genera: alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus. Alpha and beta CoVs infect humans and other mammals, whereas gamma and delta CoVs infect only animals (e.g., birds, marine mammals, and pigs). CoV infections can result in a wide range of acute to chronic respiratory, enteric, and central nervous system diseases (Fields Virology Emerging Viruses Vol. 1. 2021. pp. 410-412).

[0003] To date, seven different coronaviruses have been identified that cause disease in humans: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and most recently, SARS-CoV-2. HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1 circulate annually and cause mild symptoms similar to the common cold (Forni D, Cagliani R, Clerici M, and Sironi M. 2017. Trends in Microbiology, January 2017, Vol. 25, No. 1, 35-48). However, SARS-CoV, MERS-CoV, and SARS-CoV-2, which have emerged in three zoonotic CoV epidemic events over the past 21 years, are associated with mild to severe symptoms of respiratory infection, including fever, cough, difficulty breathing, pneumonia, and acute respiratory distress syndrome, which can ultimately lead to death.

[0004] This included the SARS-CoV epidemic from 2002 to 2003, which resulted in 8,000 cases of SARS-CoV infection and over 800 deaths (Fields Virology Emerging Viruses Vol. 1. 2021. pp. 438). Camel-human zoonotic transmission of MERS-CoV occurred in Saudi Arabia in 2012. While human-to-human transmission has been documented, most de novo infections occur as a result of camel-human interactions, and outbreaks are generally localized to the Arabian Peninsula (Zaki AM, van Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus A, Fouchier RAM. 2012 N Engl J Med 367:1814-1820). The case fatality rate of MERS infection is approximately 36% (http: / / www.who.int / csr / don / 16-october-2014-mers / en / ). SARS-CoV-2, the pandemic strain that causes COVID-19, originated in bats, and transmission from bats to humans may have occurred directly or via an unknown intermediate host animal (Lu R, Zhao X, Li J, et al. 2020. Lancet;395(10224):565-574). Currently, SARS-CoV-2 is a pandemic CoV, causing a global health and economic crisis in December 2021, with more than 5 million deaths worldwide (JHU CSSE COVID-19 Data https: / / github.com / CSSEGISandData / COVID-19). The well-characterized nature of these three zoonotic events, and the potential for future spillover events with novel CoVs, highlights the need for broad-spectrum CoV antiviral therapies that are active against both existing CoVs, such as MERS-CoV and SARS-CoV-2, as well as potential emerging CoVs.

[0005] CoV particles consist of a cell-derived lipid membrane containing the structural proteins spike (S), membrane (M), envelope (E), and nucleocapsid (N) (Fields Virology Emerging Viruses Vol. 1 2021 pp. 416-417). Virions also contain a large (25-32 kb), nonsegmented, positive-sense, single-stranded viral RNA genome that is 5'-capped, similar to cellular mRNA, and includes 5' and 3' untranslated regions (UTRs) and a 3' polyadenylated tail. All CoV viral genomes contain six basic common genes: two long open reading frames (1a and 1b) encoding two polypeptides that constitute the nonstructural proteins (nsp) that form the multiprotein replicase transcription complex (RTC), and four open reading frames for the structural proteins S, M, E, and N that constitute the virion. Depending on the CoV, one to eight additional genes, called accessory genes, may be encoded within the genome. The genome organization among all CoVs is conserved and invariant in different genera, such that the gene sequence is always 1a, 1b, S, M, E and N.

[0006] CoV replication is initiated by the binding of the S protein to specific cell surface receptors. For example, SARS-CoV and SARS-CoV-2 engage angiotensin-converting enzyme 2 (ACE-2) on upper respiratory tract cells (Lu R, Zhao X, Li J, et al. 2020. Lancet;395(10224):565-574). Viral attachment results in either endocytosis of the virus and subsequent fusion of the viral and endosomal membranes or direct fusion of the virus and cellular plasma membranes at the cell surface, releasing the virion into the cytoplasm. After entry, the viral genomic RNA is uncoated and serves as a template for cap-dependent translation of Orf 1a and Orf 1b to produce the viral polypeptides pp1a and pp1ab (Fung S, Liu D, 2019. Annu. Rev. Microbiol. 73:529-57). Cleavage of viral polypeptides to yield individual replisome proteins is carried out by the viral papain-like protease (PLPro or nsp3) and the 3CL main protease (Mpro or nsp5). nsp forms double-membrane vesicles that assemble to form the RTC, which is involved in genome replication, synthesis of subgenomic RNA (sgRNA), and transcription of sgRNA. The sgRNA serves as a template from which mRNAs encoding structural and accessory proteins are translated. Assembly of new viral particles occurs in the endoplasmic reticulum-Golgi intermediate complex, and mature particles are released via secretory vesicles.

[0007] Vaccines for preventing COVID-19 are being developed using the SARS-CoV-2 S protein as an antigen to elicit protective immune responses (Kryikidis et al. npj Vaccines 28(2021)6:28). Vaccines based on mRNA / lipid nanoparticle and replication-deficient adenovirus vector platforms have both proven highly effective in preventing severe disease. However, data on the efficacy of these vaccines against SARS-CoV-2 transmission are limited. A challenge with using the S protein for vaccine development is its highly variable amino acid sequence, which allows SARS-CoV-2 to adapt to immune pressure (Chen RE et al. Nature Medicine. March 4, 2021). Multiple independent spike mutations have been detected even in the absence of vaccine selection pressure, and some variants may be less effective in vaccine clinical trials conducted when those variants are circulating.

[0008] Given the limitations of current vaccines and the zoonotic potential of emerging pandemic strains, broad-spectrum anticoronavirus treatment and prevention regimens are urgently needed. Anticoronavirus interventions with efficacy against SARS-CoV, SARS-CoV-2, and the more distantly related MERS-CoV are expected to have broad-spectrum activity against both SARS-CoV-2 and future CoVs that may emerge via zoonotic transmission. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Fields Virology Emerging Viruses Vol.1.2021.pp.410-412 [Non-patent document 2] Forni D,Cagliani R,Clerici M,and Sironi M.2017.Trends in Microbiology,January 2017,Vol.25,No.1.35-48 [Non-licensed document 3] Fields Virology Emerging Viruses Vol.1.2021.pp.438

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[0010] The present invention relates to compounds of formula I: [ka] and pharmaceutically acceptable salts thereof. The compounds of Formula I are protease inhibitors and, therefore, may be useful in treating, inhibiting, or ameliorating one or more disease states that would benefit from the inhibition of coronaviruses, such as, for example, SARS-CoV, MERS-CoV, and SARS-CoV-2. Accordingly, the present invention also provides a method for preventing or treating a coronavirus infection (e.g., a SARS-CoV, SARS-CoV-2, or MERS-CoV infection), comprising administering to a patient in need thereof an effective amount of any of the compounds of Formula I disclosed herein, or a pharmaceutically acceptable salt thereof.

[0011] The compounds of the present invention can be further used in combination with other therapeutically effective agents (one or more additional therapeutic agents), including, but not limited to, other drugs useful in the treatment of coronavirus infections. Such additional therapeutic agents can include molnupiravir, pomotrervir, ensitrervir, nilmatrervir, and ritonavir. The present invention further relates to a compound of Formula I, and a process for preparing a pharmaceutical composition comprising the compound of Formula I and its pharmaceutically acceptable salts. DETAILED DESCRIPTION OF THE INVENTION

[0012] In one embodiment, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R1 is H; (C3-C6)cycloalkyl; (C1-C6)alkyl; (C1-C6)alkyl-OH; phenyl; (C1-C6)alkyl-phenyl; (C4-C6)heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, or S; (C1-C6)alkyl-(C4-C6)heterocycloalkyl containing 1 to 3 heteroatoms independently selected from N, O, or S; (C1-C6)alkyl-(C5-C6)heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, or S; (C5-C6)heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, or S; R2 is H; (C1-C6) alkyl; (C3-C6) cycloalkyl; or CF3; R3 is (C1-C6) alkyl; (C1-C6) alkyl-CF3; (C1-C6) alkyl-OH; (C1-C6) alkyl-O-CH3; (C1-C6) alkyl-O-CF3; OH, -(C1-C6) alkyl, CF3, -(C1-C6) alkyl-CF3, or (C1-C6) alkyl-O-(C3-C 10 )cycloalkyl; (CF2)-phenyl; (C1-C6)alkyl-phenyl; (C3-C6) optionally substituted with OH, -(C1-C6)alkyl, CF3, -(C1-C6)alkyl-CF3, or up to three halogens 10 )cycloalkyl; OH, —(C1-C6)alkyl, CF3, —(C1-C6)alkyl-CF3, or (C1-C6)alkyl-(C3-C 10 )cycloalkyl; containing up to three heteroatoms independently selected from N, O, and S, and optionally substituted with carbonyl, OH, —(C1-C6)alkyl, CF3, —(C1-C6)alkyl-CF3, or up to three halogens; (C4-C 10 ) heterocycle; containing up to three heteroatoms independently selected from N, O, and S, and optionally substituted with carbonyl, OH, —(C1-C6)alkyl, CF3, —(C1-C6)alkyl-CF3, or up to three halogens, (C1-C6)alkyl-(C4-C10 ) heterocycle; optionally substituted with OH, —(C1-C6) alkyl, CF3, —(C1-C6) alkyl-CF3, or up to three halogens (C6-C 10 )aryl; OH, —(C1-C6)alkyl, CF3, —(C1-C6)alkyl-CF3, or (C1-C6)alkyl-(C6-C 10 ) aryl; containing up to four heteroatoms independently selected from N, O, and S, and optionally substituted with OH, CN, CHF2, —(C1-C6)alkyl, CF3, —(C1-C6)alkyl-CF3, —(C3-C6)cycloalkyl, O—(C1-C6)alkyl, O—CF3, O—(C3-C6)cycloalkyl, or up to three halogens; (C5-C 10 )heteroaryl; containing up to four heteroatoms independently selected from N, O, and S, and optionally substituted with OH, CN, CHF2, (C3-C6)cycloalkyl, O-(C3-C6)cycloalkyl, -(C1-C6)alkyl, O-(C1-C6)alkyl, CF3, O-CF3, -(C1-C6)alkyl-CF3, or up to three halogens, (C1-C6)alkyl-(C5-C 10 ) heteroaryl; -O-(C1-C6) alkyl; OH, CF3, -(C1-C6) alkyl, -(C1-C6) alkyl-CF3, or -O-(C1-C6) alkyl-(C3-C6) cycloalkyl optionally substituted with up to three halogens; OH, CF3, -(C1-C6) alkyl, -(C1-C6) alkyl-CF3, or -O-(C3-C6) cycloalkyl optionally substituted with up to three halogens; CHF2; CF3; (C1-C6) alkyl-N(CH3)-C(O)-O-CH3; or N(R8)2; R4 is H; F; Cl; or (C1-C6) alkyl; R5 is H; F; Cl; or (C1-C6) alkyl; R6 is H; F; Cl; CN; CF3; O-CHF2; O-CF3; -(C1-C6)alkyl-CF3; CHF2; CF3; (C1-C6)alkyl; (C3-C6)cycloalkyl; -O-(C3-C6)cycloalkyl; or O-(C1-C6)alkyl; R7 is H; F; Cl; or (C1-C6) alkyl; R8 is independently H; (C1-C6) alkyl; OH, -(C1-C6) alkyl, CF3, -(C1-C6) alkyl-CF3, or optionally substituted with up to three halogens (C3-C 10 )cycloalkyl; OH, —(C1-C6)alkyl, CF3, —(C1-C6)alkyl-CF3, or (C1-C6)alkyl-(C3-C 10 )cycloalkyl; containing up to three heteroatoms selected from N, O and S, and optionally substituted with OH, —(C1-C6)alkyl, CF3, —(C1-C6)alkyl-CF3, or up to three halogens; (C4-C 10 ) heterocycle; containing up to three heteroatoms selected from N, O and S and optionally substituted with OH, —(C1-C6)alkyl, CF3, —(C1-C6)alkyl-CF3, or up to three halogens, (C1-C6)alkyl-(C4-C 10 ) heterocycle; optionally substituted with OH, —(C1-C6) alkyl, CF3, —(C1-C6) alkyl-CF3, or up to three halogens (C6-C 10 )aryl; OH, —(C1-C6)alkyl, CF3, —(C1-C6)alkyl-CF3, or (C1-C6)alkyl-(C6-C 10 ) aryl; containing up to three heteroatoms selected from N, O, and S, and optionally substituted with OH, —(C1-C6) alkyl, CF3, —(C1-C6) alkyl-CF3, or up to three halogens; (C5-C 10)heteroaryl; containing up to three heteroatoms selected from N, O and S and optionally substituted with OH, —(C1-C6)alkyl, CF3, —(C1-C6)alkyl-CF3, or up to three halogens; (C1-C6)alkyl-(C5-C 10 ) heteroaryl; A is C or N; B is C or N; D is C or N, provided that only one of A, B, or D can be N, and when A, B, or D is N, then the respective R4, R5, or R7 is absent; and x is 1 or 2.

[0013] In some embodiments of the present invention, R1 is H, (C3-C6)cycloalkyl, or (C1-C6)alkyl. In certain embodiments, R1 is H, CH3, or cyclopropyl.

[0014] In certain embodiments of the invention, R2 is CF3, CH3 or H.

[0015] In some embodiments of the invention, the group R3 is [ka] The file is TIFF0007744536000004.tif108154.

[0016] In certain embodiments of the invention, R4 is H, F, or Cl.

[0017] In certain embodiments of the invention, R5 is H, F, or Cl.

[0018] In certain embodiments of the invention, R6 is Cl, CHF2, or CN.

[0019] In certain embodiments of the invention, R7 is H, F, or Cl.

[0020] In certain embodiments of the invention, one of A, B, D is N.

[0021] In another embodiment of the invention, A, B and D are all C.

[0022] In certain embodiments of the invention, x is 1.

[0023] Reference to particular classes and subclasses above is meant to include all combinations of particular preferred groups unless otherwise specified.

[0024] Specific embodiments of the present invention include, but are not limited to, the compounds disclosed in Examples 1 to 100, or pharmaceutically acceptable salts thereof.

[0025] Other particular embodiments include the compounds listed below, or pharmaceutically acceptable salts thereof: 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, 2-[[3,5-bis(trifluoromethyl)benzoyl]amino]-5-cyano-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]amino]pyridine-3-carboxamide, isopropyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(2,2-difluoro-3-phenyl-propanoyl)amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[(1R)-2,2-difluorocyclopropanecarbonyl]amino]benzamide, methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-5-fluoro-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-cyano-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, 5-chloro-2-[(2,2-difluorocyclopropanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3,3,3-trifluoro-2,2-dimethyl-propanoyl)amino]benzamide, 5-chloro-2-[(3,3-difluorocyclopentanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, N-[4-cyano-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide, 5-(difluoromethoxy)-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3,3,3-trifluoro-2-methyl-propanoyl)amino]benzamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-(difluoromethoxy)-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, 5-chloro-2-[(3,3-difluorocyclobutanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]pyridine-3-carboxamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-fluoro-pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3,3,3-trifluoro-2-methyl-propanoyl)amino]benzamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-fluoro-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-2-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)amino]pyridine-3-carboxamide, 5-fluoro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, isopropyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-cyano-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3-fluorobenzoyl)amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-4-fluoro-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(trifluoromethyl)cyclobutanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[1-(2,2,2-trifluoroethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-(3,3,3-trifluoropropanoylamino)benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(4,4-difluorocyclohexanecarbonyl)amino]pyridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-2-carboxamide, 5-chloro-2-[(3,3-difluorocyclobutanecarbonyl)amino]-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl]methyl]propyl]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(3,3,3-trifluoropropanoylamino)benzamide, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl]methyl]propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-(difluoromethyl)-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, N-[(1S)-3-amino-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-chloro-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4,5-difluoro-phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, 5-chloro-2-[(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[(2,2,2-trifluoroacetyl)amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(4,4,4-trifluorobutanoylamino)pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-4-fluoro-2-(4,4,4-trifluorobutanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-4-fluoro-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-2-[(4-fluorobenzoyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3-fluorobenzoyl)amino]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3,3-difluorocyclobutanecarbonyl)amino]benzamide, 5-chloro-2-[(2,2-difluorocyclopropanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-cyano-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(2,2,2-trifluoroethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[(3,3-difluorocyclobutanecarbonyl)amino]benzamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-(trifluoromethyl)-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, 5-chloro-2-[(3,3-difluorocyclopentanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-fluoro-2-[[3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide, 5-(difluoromethyl)-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-4-(trifluoromethyl)pyridine-2-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3-fluorobenzoyl)amino]benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4-fluoro-phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-fluoro-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]-5-fluoro-phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide, N-[2,4-dichloro-6-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]spiro[2.2]pentane-2-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]spiro[2.2]pentane-2-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-4-(trifluoromethyl)pyridine-2-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-5-fluoro-phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, 5-cyano-N-[3-(methylamino)-2,3-dioxo-1-[[(5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(2-thiazol-4-ylpropanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(difluoromethyl)pyridine-4-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(2-thiazol-4-ylpropanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide, N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-5-(trifluoromethyl)-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, isopropyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4,5-difluoro-phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-3-carboxamide, methyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropyl(4-chloro-2-(((S)-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)phenyl)carbamate, cyclopropyl(4-chloro-2-(((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)carbamoyl)phenyl)carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, methyl N-[2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, methyl N-[2-[[(1S)-3-amino-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4-chloro-phenyl]carbamate, trideuteriomethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, methyl N-[4,5-difluoro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-2-(cyclopropanecarbonylamino)-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]benzamide, ethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, trideuteriomethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[6-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-3-pyridyl]carbamate, 5-chloro-N-[(1S)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-3-(4-pyridylmethylamino)propyl]-2-(4,4,4-trifluorobutanoylamino)benzamildé, 5-chloro-N-[(1S)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-3-(1H-1,2,4-triazol-3-ylmethylamino)propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-N-[(1S)-3-(2-hydroxyethylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, methyl N-[6-chloro-4-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-3-pyridyl]carbamate, methyl N-[5-chloro-3-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-2-pyridyl]carbamate, methyl N-[4,5-difluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropyl N-[4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-2-(cyclopropanecarbonylamino)-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, methyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, trideuteriomethyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(2-methylpropanoylamino)benzamide, 5-chloro-2-(2,2-dimethylpropanoylamino)-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]benzamide, cyclopropyl N-[4,5-difluoro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, isopropyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, ethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[4-(difluoromethyl)-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropyl N-[4-cyano-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[4-chloro-5-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[4-chloro-2-fluoro-6-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[5-chloro-4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]oxetane-3-carboxamide, cyclopropylmethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, cyclobutyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, (1-methylcyclopropyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, ethyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, cyclopropyl N-[5-chloro-3-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-2-pyridyl]carbamate, cyclopropyl N-[4,5-difluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, tert-butyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-2-[[(1R)-2,2-difluorocyclopropanecarbonyl]amino]-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]benzamide, methyl N-[4,5-dichloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-2-(cyclopropanecarbonylamino)-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, cyclopropyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(2-methylpropanoylamino)benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(dimethylcarbamoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-1-methyl-azetidine-3-carboxamide, cyclopropyl N-[2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]-4,5-difluoro-phenyl]carbamate, cyclobutyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropylmethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, tert-butyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropyl N-[4-chloro-5-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropyl N-[5-chloro-4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (2,2-difluorocyclopropyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, (2,2-difluorocyclopropyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, N-[(1S)-3-amino-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-chloro-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, cyclopropyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclobutyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, cyclopropylmethyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 2,2,2-trifluoroethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[(2R)-2-methoxypropanoyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(2-hydroxy-2-methyl-propanoyl)amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[(2S)-2-methoxypropanoyl]amino]benzamide, cyclopentyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[(1R)-2,2-difluorocyclopropanecarbonyl]amino]benzamide, cyclopropyl N-[2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4-(trifluoromethyl)phenyl]carbamate, cyclopropyl N-[4,5-dichloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (2,2-difluorocyclopropyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (2,2-difluorocyclopropyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (3,3-difluorocyclobutyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, benzyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(2,2,2-trifluoroacetyl)amino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-(2-thiazol-4-ylpropanoylamino)benzamide, (2,2,2-trifluoro-1-methyl-ethyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 2,2,2-trifluoroethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (5S)—N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-methyl-2-oxo-oxazolidine-5-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-cyano-pyridine-3-carboxamide, 5-chloro-2-[(2,2-difluorocyclopentanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-2-[(2,2-difluorocyclopentanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, (2,2-difluorocyclopropyl)methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (2,2-difluorocyclopropyl)methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (3,3-difluorocyclobutyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 2,2,2-trifluoroethyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]tetrahydropyran-4-carboxamide, (5S)—N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-oxo-oxazolidine-5-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]morpholine-4-carboxamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(2-thiazol-4-ylpropanoylamino)benzamide, N-[4-fluoro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, 5-chloro-2-[(4,4-difluorocyclohexanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-2-[(3,3-difluorocyclohexanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-2-[(3,3-difluorocyclohexanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, (3,3-difluorocyclopentyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (3,3-difluorocyclopentyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxopyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(2,2,2-trifluoroethyl)cyclopropanecarbonyl]amino]benzamide, 5-(difluoromethyl)-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, (5S)—N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-methyl-2-oxo-oxazolidine-5-carboxamide, (5R)-N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-methyl-2-oxo-oxazolidine-5-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-6-fluoro-phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, N-[4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[2-[[(1S)-3-amino-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4-chloro-phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[(2R)-4,4,4-trifluoro-2-methyl-butanoyl]amino]benzamide, (2,2,2-trifluoro-1-methyl-ethyl)N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (2,2,2-trifluoro-1-methyl-ethyl)N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (4S)—N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-1,3-dimethyl-2-oxo-imidazolidine-4-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-3-fluoro-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-4-fluoro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(2,2,2-trifluoroethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyrimidine-5-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-4-(trifluoromethyl)pyrimidine-2-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyrimidine-2-carboxamide, (3,3-difluorocyclohexyl)methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (3,3-difluorocyclohexyl)methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-(difluoromethyl)-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, methyl N-[(1S)-1-[[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamoyl]-2,2-dimethyl-propyl]-N-methyl-carbamate, N-[4-(difluoromethyl)-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-5-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide, N-[4-chloro-2-fluoro-6-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyrazine-2-carboxamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[2-[2-(trifluoromethyl)-4-pyridyl]propanoylamino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[2-[2-(trifluoromethyl)-4-pyridyl]propanoylamino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[2-[6-(trifluoromethyl)-3-pyridyl]propanoylamino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[2-[6-(trifluoromethyl)-3-pyridyl]propanoylamino]benzamide, N-[2,4-dichloro-6-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4-(difluoromethyl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-3,4,5-trifluoro-phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, and 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide.

[0026] In certain embodiments of the invention, the compound of formula I is selected from the group consisting of: [ka] TIFF0007744536000006.tif146158

[0027] Also included within the scope of the present invention is a pharmaceutical composition comprising a compound of Formula I above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.The pharmaceutical composition may be, for example, in the form of an orally administered tablet or capsule.The present invention is also intended to encompass pharmaceutical compositions comprising a pharmaceutically acceptable carrier and any of the compounds specifically disclosed in this application, including pharmaceutically acceptable salts thereof.These and other aspects of the present invention will be apparent from the teachings contained herein.

[0028] The present invention also includes compositions for inhibiting coronavirus proteases, treating diseases caused by coronaviruses, treating coronavirus infections, and preventing coronavirus infections in mammals, comprising a compound of the present invention in a pharmaceutically acceptable carrier. These compositions may optionally contain other antiviral agents. The compositions can be added to blood, blood products, or mammalian organs to achieve the desired inhibition.

[0029] The present invention further includes methods for preventing or treating a coronavirus infection by administering a compound of Formula I. Such coronavirus infections include SARS-CoV, SARS-CoV-2, or MERS-CoV infection.

[0030] The compound of the present invention can be administered in the form of pharmaceutically acceptable salts.The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, such as inorganic or organic bases and inorganic or organic acids.The salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" generally refer to non-toxic salts of the compound of the present invention, which are prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, acetate, ascorbate, adipate, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentanepropionate, diethylacetate, digluconate, dihydrochloride, dodecyl sulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinol, hydrabamine. abamine), hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic acid, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt , oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate / diphosphate, pimelic acid, phenylpropionate, polygalacturonate, propionate, salicylate, stearate, sulfate, acetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate, etc.Additionally, when a compound of the invention contains an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, mangamous, potassium, sodium, zinc, etc. Also included are ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexylamine, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Agents include basic nitrogen-containing groups that can be quaternized, such as lower alkyl halides, e.g., methyl, ethylpropyl, and butyl chlorides, bromides, iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl; and diamyl sulfates; long chain halides, e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, e.g., benzyl and phenethyl bromides; and the like.

[0031] These salts can be obtained by known methods, for example, by mixing the compound of the present invention with a solution containing an equivalent amount of the desired acid, base, etc., and then collecting the desired salt by filtering the salt or evaporating the solvent. The compound of the present invention and its salts can form solvates with solvents such as water, ethanol, or glycerol. The compound of the present invention may simultaneously form acid addition salts and base salts depending on the type of substituents on the side chain.

[0032] When the compounds of formula I contain simultaneously acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, also inner salts or betaines (zwitterions).

[0033] The present invention encompasses all stereoisomeric forms of the compounds of Formula I. Unless a specific stereochemistry is indicated, the present invention is meant to encompass all such isomeric forms of these compounds. All asymmetric centers present in the compounds of Formula I can, independently of one another, have either the (R) or (S) configuration. When a bond to a chiral carbon is shown as a straight line in the structural formulae of the present invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and thus both each individual enantiomer and mixtures thereof, are encompassed by the formula. When a specific configuration is shown, that enantiomer (either (R) or (S) at that center) is intended. Similarly, when a compound name is listed without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and thus each individual enantiomer and mixtures thereof, are encompassed by the name. The production of a specific stereoisomer or mixture thereof may be identified in the examples in which such stereoisomer or mixture was obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof within the scope of the present invention.

[0034] Unless a specific enantiomer or diastereomer is indicated, the present invention includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers, such as mixtures of enantiomers and / or diastereomers, in all ratios. Accordingly, enantiomers are subject of the present invention in enantiomerically pure form, both as levorotatory and dextrorotatory antipodes, in the form of racemates, and in the form of mixtures of the two enantiomers in all ratios. In the case of cis / trans isomerism, the present invention includes both cis and trans forms, as well as mixtures of these forms in all ratios. Individual stereoisomers can be prepared, if desired, by conventional methods, such as separation of mixtures by chromatography or crystallization, by using stereochemically uniform starting materials for synthesis, or by stereoselective synthesis. Optionally, derivatization can be carried out before the separation of stereoisomers. Separation of stereoisomeric mixtures can be carried out at an intermediate stage during the synthesis of the compound of Formula I, or on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Where the compounds of the present invention are capable of tautomerization, all individual tautomers and mixtures thereof are included within the scope of the present invention. The present invention includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0035] In the compounds of the present invention, atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The present invention is meant to include all suitable isotopic variants of the specifically and generically described compounds. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2H). Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) or may result in compounds useful as standards for characterizing biological samples. Isotopically enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by processes similar to those described in the general process schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0036] When any variable occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn from substituents into ring systems indicate that the indicated bond may be attached to any of the substitutable ring atoms. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.

[0037] It is understood by those skilled in the art that one or more silicon (Si) atoms can be incorporated into the compounds of the present invention instead of one or more carbon atoms, in order to provide compounds that are chemically stable and can be easily synthesized from readily available starting materials by techniques known in the art.Carbon and silicon have different covalent bond radii, so when comparing the bonds of similar C and Si elements, the bond distance and steric configuration are different.These differences result in subtle changes in the size and shape of silicon-containing compounds compared with carbon.Those skilled in the art will understand that size and shape differences can result in subtle or dramatic changes in potency, solubility, lack of off-target activity, packaging properties, etc. (Diass, JO et al. Organometallics (2006) 5:1188-1198; Showell, GA et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

[0038] It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by those skilled in the art to provide compounds that are chemically stable and can be easily synthesized by techniques known in the art, as well as the methods described below, from readily available starting materials. When a substituent itself is substituted with two or more groups, it is understood that these multiple groups can be on the same carbon or different carbons, as long as a stable structure is obtained. The phrase "optionally substituted" (with one or more substituents) should be understood to mean that the group in question can be unsubstituted or substituted with one or more substituents.

[0039] Furthermore, the compounds of the present invention may exist in amorphous form and / or one or more crystalline forms, and therefore, all amorphous and crystalline forms of the compounds of Formula I, as well as mixtures thereof, are intended to be included within the scope of the present invention. Furthermore, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates and hydrates of the compounds, particularly pharmaceutically acceptable solvates and hydrates, are also included within the scope of the present invention, along with unsolvated and anhydrous forms.

[0040] Also, when a carboxylic acid (—COOH) or alcohol group is present in the compounds of the invention, pharmaceutically acceptable esters of the carboxylic acid derivative, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of the alcohol, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can be used. Included are ester and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0041] Any pharmaceutically acceptable prodrug modification of the compounds of the present invention that results in in vivo conversion to a compound within the scope of the present invention is also within the scope of the present invention. For example, esters can optionally be made by esterification of available carboxylic acid groups or by forming esters on available hydroxy groups in the compounds. Similarly, unstable amides can be made. Pharmaceutically acceptable esters or amides of the compounds of the present invention can be prepared to act as prodrugs, particularly those that can be hydrolyzed in vivo back to the acid (or -COO-, depending on the pH of the fluid or tissue where the conversion occurs) or hydroxy form, and are therefore encompassed within the scope of the present invention. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C1-C6 alkyl esters and -C1-C6 substituted phenyl esters.

[0042] Thus, the compounds within the general structural formulas, embodiments and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, their physical forms (e.g., amorphous and crystalline forms), solvates and hydrate forms, and any combination of these forms, as well as salts thereof, prodrug forms thereof, and salts of the prodrug forms thereof, which forms are possible unless otherwise specified.

[0043] Terms used herein have their usual meanings, and the meaning of such terms is independent at each occurrence. Nevertheless, unless otherwise specified, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise specified. Thus, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portion of "hydroxyalkyl," "haloalkyl," "-O-alkyl," etc.

[0044] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0045] A "subject" is a human or non-human mammal. In one embodiment, the subject is a human. In another embodiment, the subject is a primate. In another embodiment, the subject is a monkey. In another embodiment, the subject is a chimpanzee. In yet another embodiment, the subject is a rhesus monkey.

[0046] As used herein, the terms "treatment" and "treating" refer to any process that may slow, interrupt, prevent, control, or stop the progression of a disease or disorder described herein. These terms do not necessarily indicate the complete elimination of all disease or disorder symptoms.

[0047] As used herein, the term "prevent" or "prevention" refers to reducing the likelihood of contracting a disease or disorder described herein or reducing the severity of a disease or disorder described herein.

[0048] The term "alkyl," as used herein, refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms has been replaced with an optional bond. An alkyl group can be straight-chained or branched and can contain from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, an alkyl group contains from 1 to 6 carbon atoms (C1-C6 alkyl) or from about 1 to about 4 carbon atoms (C1-C4 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl, and neohexyl. In one embodiment, an alkyl group is straight-chained. In another embodiment, an alkyl group is branched-chained. Unless otherwise indicated, an alkyl group is unsubstituted.

[0049] The term "fluoroalkyl," as used herein, refers to an alkyl group, as defined above, in which one or more of the alkyl group's hydrogen atoms have been replaced with fluorine. In one embodiment, a fluoroalkyl group has 1 to 6 carbon atoms. In another embodiment, a haloalkyl group is substituted with 1 to 3 F atoms. Non-limiting examples of fluoroalkyl groups include -CHF, -CHF, -CF, and -CHCF. The term "C1-C6 fluoroalkyl" refers to a fluoroalkyl group having 1 to 6 carbon atoms.

[0050] The term "halo" as used herein means -F, -Cl, -Br or -I.

[0051] The term "cycloalkyl" refers to a monocyclic or bicyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Bicyclic cycloalkyl ring systems include fused ring systems in which two rings share two atoms, spiro ring systems in which two rings share one atom, and bridged systems.

[0052] As used herein, the term "aryl" refers to a stable bicyclic or tricyclic ring system containing up to 10 atoms in each ring, in which at least one ring is aromatic and all of the ring atoms are carbon. Bicyclic and tricyclic ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom.

[0053] The term "heteroaryl," as used herein, refers to a stable monocyclic or bicyclic ring system of up to 10 atoms in each ring, in which at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Bicyclic heteroaryl ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom. Heteroaryl groups within this definition include, but are not limited to, azaindolyl, benzimidazolyl, benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, dihydroindenyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthalenyl, naphpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyrida Heteroaryl includes, for example, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, dihydrobenzodioxinyl, dihydropyrazolooxazinyl, dihydropyrazolothiazinedioxidyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, tetrahydroquinoline, and 3-oxo-3,4-dihydro-2N-benzo[b][1,4]thiazine. Where heteroaryl contains a nitrogen atom, it is understood that the corresponding N-oxide is also encompassed by this definition.

[0054] The terms "heterocycloalkyl," "heterocycle," or "heterocyclyl," as used herein, unless otherwise specified, are intended to mean a stable non-aromatic monocyclic or bicyclic ring system of up to 10 atoms in each ring, containing 1 to 4 heteroatoms selected from the group consisting of O, N, S, SO, or SO. In some embodiments, heterocycloalkyls are saturated. Bicyclic heterocyclic ring systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom. Thus, "heterocycloalkyl" includes, but is not limited to, azaspirononanyl, azaspirooctanyl, azetidinyl, dioxanyl, oxadiazaspirodecenyl, oxaspirooctanyl, oxazolidinonyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl, and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides are also encompassed by this definition.

[0055] "Celite®" (Fluka) is diatomaceous earth and may be referred to as "celite."

[0056] The term "substituted" means that one or more hydrogens on a specified atom are replaced with one selected from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom under the existing circumstances and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. A "stable compound" or "stable structure" means a compound that is sufficiently robust to survive isolation from a reaction mixture to a useful degree of purity and formulation into an efficacious therapeutic agent.

[0057] As used herein, the term "in substantially purified form" refers to the physical state of a compound after it has been isolated from a synthetic process (e.g., a reaction mixture), a natural source, or a combination thereof. The term "in substantially purified form" also refers to the physical state of a compound after it has been obtained from one or more purification processes (e.g., chromatography, recrystallization, etc.) described herein or known to those of skill in the art, with sufficient purity to be characterized by standard analytical techniques described herein or known to those of skill in the art.

[0058] It should also be noted that in the text, schemes, examples and tables herein, any carbon and heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0059] When a functional group in a compound is referred to as "protected," this means that the group is in a modified form to prevent undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art and by reference to standard textbooks, such as T.W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0060] When any substituent or variable (e.g., R2) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise stated.

[0061] As used herein, the term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product resulting from combining the specified ingredients in the specified amounts.

[0062] The present invention also relates to pharmaceutical products comprising at least one compound of formula I and / or a pharmaceutically acceptable salt of a compound of formula I and / or optionally a stereoisomeric form of a compound of formula I or a pharmaceutically acceptable salt of a stereoisomeric form of a compound of formula I, together with pharmaceutically suitable pharmaceutically acceptable vehicles, additives and / or other active substances and auxiliaries.

[0063] As used herein, the term "patient" is intended to mean mammals such as primates, humans, sheep, horses, cows, pigs, dogs, cats, rats, and mice.

[0064] The term "coronavirus" includes HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2.

[0065] The pharmaceutical preparations according to the invention can be administered orally, by inhalation, rectally or transdermally, or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred. Coating of stents with the compounds of formula (I) and other surfaces in contact with blood in the body is possible.

[0066] The present invention also relates to a process for producing a medicament, which comprises bringing at least one compound of formula (I) into a suitable administration form using pharmaceutically suitable and pharmaceutically acceptable carriers and optionally further suitable active substances, additives or auxiliaries.

[0067] Suitable solid or galenical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops, or injectable solutions and preparations with extended release of the active substance, which use excipients customary in such preparations, such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavors, sweeteners and solubilizers. Frequently used adjuvants that may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol and solvents, for example, sterile water and mono- or polyhydric alcohols such as glycerol.

[0068] Dosage regimens utilizing the protease inhibitors of the present invention are selected depending on a variety of factors, such as the type, species, age, weight, sex, and condition of the patient, the severity of the condition being treated, the route of administration, the renal and hepatic function of the patient, the particular compound or salt thereof being used, etc. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0069] Oral dosages of protease inhibitors, when used for the indicated effects, range from about 0.01 mg / kg body weight per day (mg / kg / day) to about 30 mg / kg / day, e.g., 0.01-20 mg / kg / day, 0.01-15 mg / kg / day, 0.01-10 mg / kg / day, or 0.01-5 mg / kg / day (amounts of active ingredient are on a free base basis unless otherwise specified). For example, an 80 kg patient would receive about 0.8 mg / day to 2.4 g / day, e.g., 0.8-1600 mg / day, 0.8-1200 mg / day, 0.8-800 mg / kg / day, or 0.8-400 mg / day. Thus, a suitable formulated medicament for once-daily administration may contain 0.8 mg to 2.4 g, 0.8 mg to 1600 mg, 0.8 mg to 1200 mg, 0.8 mg to 800 mg, or 0.8 mg to 400 mg, for example 1 mg, 4 mg, 8 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 200 mg, 300 mg, or 400 mg. Advantageously, the protease inhibitor may be administered in divided doses two, three, or four times daily. For twice daily administration, a suitable prepared pharmaceutical product contains 0.4 mg to 1.2 g, 0.4 mg to 800 mg, 0.4 mg to 600 mg, 0.4 mg to 400 mg, or 0.4 mg to 200 mg, for example, 0.5 mg, 2 mg, 4 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 150 mg, or 200 mg.

[0070] Intravenously, patients receive an amount of active ingredient sufficient to deliver 0.01-15 mg / kg / day, e.g., 0.01-7.5 mg / kg / day or 0.1-5 mg / kg / day. Such amounts can be administered in multiple suitable ways, e.g., a large amount of low-concentration active ingredient over a single extended period or several times daily, or a small amount of high-concentration active ingredient over a short period, e.g., once daily. Glucuronic acid, L-lactic acid, acetic acid, citric acid, or any pharmaceutically acceptable acid / conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration can be used as a buffer. Selection of an appropriate buffer and formulation pH based on the solubility of the drug to be administered can be readily determined by one of ordinary skill in the art.

[0071] The compounds of Formula I can be administered as monotherapy and in combination with an additional therapeutic agent (also referred to herein as a "second therapeutic agent"), such as another antiviral agent or treatment for a coronavirus infection.

[0072] The protease inhibitor of the present invention can also be co-administered with suitable antiviral drugs, including but not limited to agents that inhibit viral replication, such as nucleoside polymerase inhibitors, agents that induce viral error catastrophe protease inhibitors, eEF1A inhibitors, androgen receptor antagonists, dihydroorotate dehydrogenase (DHODH) inhibitors, sphingosine kinase inhibitors, MEK inhibitors, antimalarials, CCR5 inhibitors, PIKfyve kinase inhibitors, serine protease inhibitors and glycosylation inhibitors.In this class of the present invention, the protease inhibitor of the present invention can be co-administered with nucleoside polymerase inhibitors, protease inhibitors, or a combination thereof.Those skilled in the art will recognize that such antiviral drugs can be co-administered in some cases as prodrugs.

[0073] Polymerase inhibitors that can be co-administered with the protease inhibitors of the present invention include, but are not limited to, clevudine, remdesivir (VEKLURY), favipiravir (AVIGAN), and AT-527.

[0074] Protease inhibitors that can be co-administered with the protease inhibitors of the present invention include, but are not limited to, camostat mesylate, upamostat, SLV213, PF-0083523, CDI-45205, ALG-097111, GC-376, and TJC-0642.

[0075] Agents that induce viral error catastrophe that can be co-administered with the protease inhibitors of the present invention include molnupiravir and nilmatrervir.

[0076] eEF1A inhibitors that can be co-administered with the protease inhibitors of the present invention include, but are not limited to, plitidepsin.

[0077] Androgen receptor antagonists that may be co-administered with the protease inhibitors of the present invention include, but are not limited to, proxalutamide.

[0078] Dihydroorotate dehydrogenase (DHODH) inhibitors that can be co-administered with the protease inhibitors of the present invention include, but are not limited to, PTC299 and brequinlar.

[0079] Sphingosine kinase inhibitors that can be co-administered with the protease inhibitors of the present invention include, but are not limited to, opaganib.

[0080] MEK inhibitors that can be co-administered with the protease inhibitors of the present invention include, but are not limited to, ATR-002.

[0081] Antimalarials that may be co-administered with the protease inhibitors of the present invention include, but are not limited to, tafenoquine (ARAKODA).

[0082] CCR5 inhibitors that can be co-administered with the protease inhibitors of the present invention include, but are not limited to, maraviroc and vicriviroc.

[0083] PIKfyve kinase inhibitors that can be co-administered with the protease inhibitors of the present invention include, but are not limited to, opaganib.

[0084] Serine protease inhibitors that can be co-administered with the protease inhibitors of the present invention include, but are not limited to, nafamostat mesylate.

[0085] Glycosylation inhibitors that can be co-administered with the protease inhibitors of the present invention include, but are not limited to, WP1122.

[0086] Alternatively or additionally, one or more additional pharmacologically active agents can be administered in combination with the compound of the present invention.One or more additional active agents are intended to mean one or more pharmaceutically active agents that are active in the body, such as prodrugs that are converted into pharmaceutically active forms after administration, and this also includes the free acid, free base and pharmaceutically acceptable salts of the additional active agents, if these forms are commercially available or chemically possible, different from the compounds of the present invention. Generally, any suitable one or more additional active agents, including, but not limited to, polymerase nucleoside inhibitors, protease inhibitors, agents that induce viral error catastrophe, eEF1A inhibitors, androgen receptor antagonists, dihydroorotate dehydrogenase (DHODH) inhibitors, sphingosine kinase inhibitors, MEK inhibitors, antimalarials, CCR5 inhibitors, PIKfyve kinase inhibitors, serine protease inhibitors, and glycosylation inhibitors, can be used in any combination with the compounds of the invention in a single dosage formulation (fixed-dose drug combination) or can be administered to the patient in one or more separate dosage formulations that allow for simultaneous or sequential administration of the active agents (co-administration of separate active agents).

[0087] Typical doses of the protease inhibitors of the present invention in combination with other suitable polymerase nucleoside inhibitors, protease inhibitors, agents that induce viral error catastrophe, eEF1A inhibitors, androgen receptor antagonists, dihydroorotate dehydrogenase (DHODH) inhibitors, sphingosine kinase inhibitors, MEK inhibitors, antimalarials, CCR5 inhibitors, PIKfyve kinase inhibitors, serine protease inhibitors, and glycosylation inhibitors may vary depending on the therapeutic needs of the patient. ) inhibitor, sphingosine kinase inhibitor, MEK inhibitor, antimalarial drug, CCR5 inhibitor, PIKfyve kinase inhibitor, serine protease inhibitor and glycosylation inhibitor, or may be substantially less than the dose of the protease inhibitor administered without the concomitant administration of the polymerase nucleoside inhibitor, protease inhibitor, agent that induces viral catastrophe, eEF1A inhibitor, androgen receptor antagonist, dihydroorotate dehydrogenase (DHODH) inhibitor, sphingosine kinase inhibitor, MEK inhibitor, antimalarial drug, CCR5 inhibitor, PIKfyve kinase inhibitor, serine protease inhibitor and glycosylation inhibitor.

[0088] The compound is administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" is meant an amount of a compound of the invention that, when administered to a mammal alone or in combination with an additional therapeutic agent, is effective to treat (i.e., prevent, inhibit, or ameliorate) a viral condition or treat disease progression in the host.

[0089] The compounds of the present invention are preferably administered to mammals alone in a therapeutically effective amount. However, the compounds of the present invention can also be administered to mammals in a therapeutically effective amount in combination with an additional therapeutic agent as defined below. When administered in combination, the combination of compounds is preferably, but not necessarily, a synergistic combination. When the effect of the compounds administered in combination (in this case, inhibition of the desired target) is greater than the additive effect of each compound when administered individually as a single agent, a synergistic effect occurs, for example, as described in Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55. Generally, synergistic effects are most clearly demonstrated at suboptimal concentrations of the compounds. Synergistic effects can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of the combination compared to the individual components.

[0090] "Administered in combination" or "combination therapy" means that a compound of the present invention and one or more additional therapeutic agents are administered simultaneously to the mammal being treated. When administered in combination, each component can be administered simultaneously or sequentially in any order at different times. Thus, each component can be administered separately but sufficiently closely in time to provide the desired therapeutic effect.

[0091] The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of some aspects of the invention, and any embodiments which are functionally equivalent are within the scope of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to be included within the scope of the appended claims.

[0092] General Procedure Starting materials and intermediates were purchased, described in the chemical synthesis literature, or prepared using known procedures described otherwise. The preparation of the various starting materials used herein is well within the skill of one of ordinary skill in the art. The routes used in the synthesis of compounds of Formula I are described in the following schemes. In some cases, the order of reaction steps may be varied to facilitate the reaction or to avoid undesired reaction products. In some cases, the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions commonly known to those skilled in the art. Because the schemes are illustrative, the invention should not be construed as limited by the chemical reactions and conditions shown. The examples described below are provided so that the invention may be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

[0093] It is understood that chiral centers in compounds can exist in either the S or R absolute configuration, or as a mixture of both. Within a molecule, each bond drawn as a straight line from a chiral center includes both the R and S stereoisomers and mixtures thereof. An asterisk indicates a stereocenter in one configuration, either R or S. The absolute stereochemistry of the individual stereoisomers in the examples and intermediates is not determined unless otherwise specified in the examples or explicitly stated in the nomenclature.

[0094] The numbering of substituents shown in the schemes does not necessarily correlate to that used in the claims; in many cases, for clarity, one substituent attached to a compound is shown, with multiple substituents being possible under the definition above. The reactions used to produce the compounds of the invention are carried out by using the reactions shown in the schemes and examples herein, in addition to other standard manipulations such as ester hydrolysis, protecting group cleavage, etc., as are known in the literature or can be exemplified in experimental procedures.

[0095] Moisture- or air-sensitive reactions were performed under nitrogen or argon using anhydrous solvents and reagents. Reaction progress was monitored by liquid chromatography-mass spectrometry (LCMS) or Merck KGaA glass-backed TLC plates, silica gel 60F. 254 The results were determined by one of the routine analytical thin layer chromatography (TLC) methods using a .

[0096] Analytical LCMS was generally performed on a Waters SQD single quadrupole mass spectrometer (mass range 150-900 daltons, data collected in centroid mode, and scan time 0.2 seconds) equipped with electrospray ionization in positive ion detection mode and a Waters Acquity UPLC system (binary solvent manager, sample manager, and TUV). The column used was a Waters Acquity BEH C18 1 x 50 mm, 1.7 µm column heated to 50 °C. The mobile phase used was modified with an acidic or basic additive. The acidic mobile phase consisted of 0.1% aqueous trifluoroacetic acid for solvent A and 100% acetonitrile for solvent B. Initial conditions were 95% solvent A, ramped to 99% solvent B in 1.60 min, and held at 99% solvent B for 0.40 min. A 2-minute run was established at a flow rate of 0.3 mL / min. A partial loop needle overfill injection mode was used, with an injection volume of 0.5 µL. The TUV monitored wavelengths at 215 or 254 nm with a sampling rate of 20 points / s, a normal filter constant, and absorbance data mode. The basic mobile phase consisted of 0.1% aqueous ammonium hydroxide for solvent A and 100% acetonitrile for solvent B. Initial conditions were 99% solvent A, ramped to 99% solvent B at 1.90 min, and held at 99% solvent B for 0.10 min, establishing a 2-minute run at a flow rate of 0.3 mL / min. Initial conditions were 95% solvent A, ramped to 99% solvent B at 4.90 min, and held at 99% solvent B for 0.10 min, establishing a 5-minute run at a flow rate of 0.3 mL / min. For both methods, a partial loop needle overfill injection mode was used, with an injection volume of 5.0 μL. The TUV monitored wavelengths at 215 nm with a sampling rate of 20 points / s, a normal filter constant, and absorbance data mode. Alternatively, a commonly used system consisted of a Waters ZQ™ platform equipped with electrospray ionization in positive ion detection mode using an Agilent 1100 series HPLC equipped with an autosampler.The columns were typically Waters Xterra MS C18, 3.0 x 50 mm, 5 μm or Waters Acquity UPLC® BEH C18, 1.0 x 50 mm, 1.7 μm. The flow rate was 1 mL / min, with an injection volume of 10 μL. UV detection was in the 210-400 nm range. The mobile phase consisted of solvent A (water + 0.05% TFA) and solvent B (MeCN + 0.05% TFA), with a gradient of 100% solvent A over 0.7 min, followed by a change to 100% solvent B over 3.75 min, a 1.1 min hold, and then a 0.2 min return to 100% solvent A.

[0097] Preparative reversed-phase chromatography was generally performed on a Teledyne ISCO ACCQPrep HP125 or HP150 instrument equipped with UV and ELSD detectors. The UV detector typically monitored wavelengths of 215 nm and 254 nm. The columns were generally one of the following: Waters XBridge Prep C18 OBD 5 μm 30 × 150 mm, Waters XBridge Prep C18 OBD 5 μm 30 × 250 mm, Waters XBridge Prep C18 OBD 5 μm 50 × 250 mm, Waters SunFire Prep C18 OBD 5 μm 30 × 150 mm, Waters SunFire Prep C18 OBD 10 μm 30 × 150 mm, Waters SunFire Prep C18 OBD 5 μm 50 × 250 mm, Waters SunFire Prep C18 OBD 10 μm 50 × 250 mm, or Phenomenex Luna Prep C18 5 μm 50 × 250 mm. The mobile phase consisted of a mixture of acetonitrile with 0.1% TFA and water with 0.1% TFA, or a mixture of 100% acetonitrile and 5 mM (NH4)HCO3. Alternatively, a commonly used system was a Waters Chromatography Workstation, consisting of a Waters ZQ™ Single Quad MS system with electrospray ionization, a Waters 2525 gradient pump, a Waters 2767 injector / collector, and a Waters 996 PDA detector. MS conditions were 150-750 amu, positive charge electrospray, and MS-triggered collection. The columns used were generally a Waters SunFire C18 5 μm 30 x 150 mm, Boston Green ODS 5 μm 150 x 30 mm, or a YMC-Actus Triart C18 5 μm 150 x 30 mm column. The mobile phase consisted of a mixture of acetonitrile (10–100%) and water containing 0.1% TFA. The flow rate was maintained at 50 mL / min, and the UV detection range was 210–400 nm.The additional preparative HPLC system used was a Gilson Workstation consisting of a Gilson GX-281 injector / collector, a Gilson UV / VIS-155 detector, Gilson 333 and 334 pumps, and either a Phenomenex Gemini-NX C18 5 μm 50 × 250 mm column, a Waters XBridge Prep C18 OBD 5 μm 30 × 250 mm column, or a Welch Xtimate C18 5 μm 150 × 25 mm column. The mobile phase consisted of a mixture of acetonitrile (0–75%) and water containing 5 mM (NH4)HCO3. The flow rate was maintained at 50 mL / min for the Waters XBridge column, 90 mL / min for the Phenomenex Gemini column, and 25 mL / min for the Welch Xtimate column. The UV detection range was 210–400 nm. The mobile phase gradient was optimized for each compound.

[0098] Flash chromatography was typically performed on an ISCO CombiFlash Rf instrument, a Biotage® flash chromatography instrument (Dyax Corp.), or an ISCO CombiFlash® Companion XL instrument with pre-packed RediSep Rf, RediSep Rf Gold, or SepaFlash columns of silica gel (60 Å pore size). The mobile phase generally consisted of a mixture of hexane or dichloromethane with EtOAc, 3:1 EtOAc:EtOH, or MeOH. The mobile phase gradient was optimized for each compound.

[0099] Chiral chromatography was typically performed by supercritical fluid chromatography using a column selected from one of the following: Daicel CHIRALPAK AD-H 2 x 25 cm, Daicel CHIRALPAK AD-H 3 x 25 cm, YMC Chiral ART Cellulose-SC, Lux Cellulose-2 5 μm 30 x 250 mm, or Exsil Chiral-NR 8 μm 30 x 250 mm. The mobile phase consisted of a mixture of CO2 with methanol, ethanol, isopropanol + 0.1% diethylamine, isopropanol + 0.1% NH4OH, or 1:1 isopropanol:hexane + 0.1% 2M NH3 / MeOH. The mobile phase gradient was optimized for each compound. Pressure was typically maintained at 100 bar, and flow rates ranged from 50 to 200 mL / min. UV monitoring was typically performed at 220 or 205 nM.

[0100] 1 H NMR data were typically obtained at room temperature using a Bruker NEO 500 MHz NMR spectrometer equipped with a 5 mm BBF iProbe, a Bruker Avance NEO 400 MHz NMR spectrometer equipped with a Bruker PI HR-BBO400S1-BBF / H / D-5.0-Z SP probe, or a Bruker Avance III 500 MHz NMR spectrometer equipped with a Bruker 5 mm PABBO probe. Chemical shift values ​​are reported in delta (δ) units, parts per million (ppm). 1 Chemical shifts in H NMR spectra are given relative to the signals of residual non-deuterated solvents (CDCl3 referenced at δ 7.26 ppm, DMSO-d6 referenced at δ 2.50 ppm, and CD3OD referenced at δ 3.31 ppm). Multiplets are reported by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = overlap of multiplets or non-equivalent resonances. Coupling constants (J) are reported in Hertz (Hz). When a compound appears as a mixture of rotamers by NMR, the spectral data corresponding to the major species observed in solution are reported.

[0101] Abbreviations: ACN is acetonitrile. AOP is tris(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)phosphorus hexafluorophosphate. aq. is aqueous solution. Bn is benzyl. Boc is tert-butoxycarbonyl. Burgess reagent is methyl N-(triethylammonium sulfonyl)carbamate. Cbz is benzyloxycarbonyl. CDI is 1,1'-carbonyldiimidazole. DCM is dichloromethane. DIBAL or DIBAL-H is diisobutylaluminum hydride. DIEA or DIPEA is N,N-diisopropylethylamine. DMA is dimethylacetamide. DMF is N,N-dimethylformamide. DMP is Dess-Martin periodinane. DMSO is dimethyl sulfoxide. EDC or EDCI is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. ELSD is evaporative light scattering detector. Et is ethyl. EtOAc is ethyl acetate. HATU is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate. HOBt is hydroxybenzotriazole. HPLC is high pressure liquid chromatography. LAH is lithium aluminum hydride. LCMS is liquid chromatography-mass spectrometry. LiHMDS or LHMDS = lithium bis(trimethylsilyl)amide. LRMS is low resolution mass spectrometry. mCPBA is meta-chloroperbenzoic acid. Me is Methyl. MeCN is acetonitrile. MeOH is methanol. MTBE is methyl tert-butyl ether. OAc is acetate. OMe is methoxy. Na2CO3 is sodium carbonate. NaHCO3 is sodium bicarbonate. Na2SO4 is anhydrous sodium sulfate. NH4HCO3 is ammonium bicarbonate. NaOH is sodium hydroxide. NMP is N-methyl-2-pyrrolidone. NMR is nuclear magnetic resonance. Pd is palladium. Pd / C is palladium on carbon.PE is petroleum ether. Ph is phenyl. POCl3 is phosphorus oxychloride. Rochelle's salt is potassium sodium tartrate. RP HPLC is reversed-phase high-pressure liquid chromatography. RT or rt is room temperature. sat. is saturated. SFC is supercritical fluid chromatography. TEMPO is (2,2,6,6-tetramethylpiperidin-1-yl)oxy. t Bu is tert-butyl. TBS is tert-butyldimethylsilyl. TEA is triethylamine. TFA is trifluoroacetic acid. THF is tetrahydrofuran. TMS is trimethylsilyl. UV is ultraviolet light.

[0102] As shown in Scheme A, in general, compounds of the present invention can be prepared by acylation of an appropriately functionalized amine A-1 to provide a compound of formula A-2. Ester A-2 can be hydrolyzed to provide an acid of formula A-3, which can be coupled with an amine of formula INT-1 to provide a product of formula A-4. Hydroxyamide A-4 can be oxidized to provide a ketoamide of formula A-5. In some embodiments, stereoisomers can be separated during the course of the synthesis. Type A-1 amines, acylating agents, and type INT-1 amines are commercially available or can be synthesized from suitable intermediates.

[0103] Scheme A [ka]

[0104] As illustrated in Scheme B, in general, compounds of the present invention can be prepared by acylation of an appropriately functionalized amine B-1 to give a compound of formula B-2, which can be coupled with an amine of formula INT-1 to give a product of formula B-3. Hydroxyamide B-3 can be oxidized to give a ketoamide of formula B-4. In some embodiments, stereoisomers can be separated during the course of the synthesis. Type B-1 amines, acylating agents, and type INT-1 amines are commercially available or can be synthesized from suitable intermediates.

[0105] Scheme B [ka]

[0106] As illustrated in Scheme C, in general, compounds of the present invention can be prepared by amidating an appropriate aryl / heteroaryl halide C-1 (X=Cl or Br) with a suitable primary amide coupling partner to give a compound of formula C-2. Ester C-2 can be hydrolyzed to give an acid of formula C-3, which can be coupled with an amine of formula INT-1 to give a product of formula C-4. Hydroxyamide C-4 can be oxidized to give a ketoamide of formula C-5. In some embodiments, stereoisomers can be separated during the course of the synthesis. Aryl / heteroaryl halides of type C-1, primary amide coupling partners, and amines of type INT-1 are commercially available or can be synthesized from suitable intermediates.

[0107] Scheme C [ka]

[0108] Methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)propanoate [ka] TIFF0007744536000011.tif69163

[0109] Step 1: Dimethyl (2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-((R)-2-((tert-butoxycarbonyl)amino)propyl)pentanedioate To a mixture of dimethyl((benzyloxy)carbonyl)-L-glutamate (4 g, 12.93 mmol) in THF (26 mL) was added LiHMDS (28.4 mL, 28.4 mmol, 1 M in THF) at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1.5 hours. Then, tert-butyl (R)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylate (4.60 g, 19.40 mmol) was added to the mixture at −78° C. The reaction mixture was stirred at −78° C. for 2 hours. TLC showed that most of the starting material had been consumed. The reaction mixture was quenched at −78° C. with pre-cooled MeOH (2 mL) and stirred at −78° C. for 10 minutes. The resulting mixture was quenched with acetic acid in THF (1.8 mL acetic acid / 12 mL THF) and then stirred at -78°C for an additional 10 minutes. The mixture was warmed to 0°C, then brine (50 mL) was added, the mixture was warmed to room temperature, and then extracted with EtOAc (2 x 60 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified using silica gel chromatography eluting with 20% EtOAc / PE. The desired fractions were concentrated to give the title compound.

[0110] Step 2: Dimethyl (2S,4S)-2-((R)-2-aminopropyl)-4-(((benzyloxy)carbonyl)amino)pentanedioate To a solution of dimethyl (2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-((R)-2-((tert-butoxycarbonyl)amino)propyl)pentanedioate (3 g, 6.43 mmol) in EtOAc (10 mL) was added 4 M HCl in EtOAc (20 mL). The reaction mixture was stirred at 25° C. for 1 h. LC / MS showed that the starting material had been consumed. The reaction mixture was then concentrated to give the HCl salt of the title compound, which was used without further purification. LRMS m / z: (M+H) + Calculated value 367.1; measured value 367.3.

[0111] Step 3: Methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)propanoate To a solution of dimethyl (2S,4S)-2-((R)-2-aminopropyl)-4-(((benzyloxy)carbonyl)amino)pentanedioate HCl salt (2.3 g, 5.71 mmol) in MeOH (24 mL) and CHCl (2 mL) was added sodium acetate (2.342 g, 28.5 mmol). The reaction mixture was stirred at 75 °C for 12 h. TLC showed that the starting material was consumed. The reaction was then quenched with water (50 mL). The resulting suspension was extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated. The resulting residue was purified using silica gel chromatography eluting with 75% EtOAc / PE. The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 335.1; measured value 335.2.

[0112] 1H NMR(400MHz,CDCl3)δ=7.37-7.31(m,5H),5.96-5.95(br d,J=7.80Hz,1H),5.83(br d,J=7.80Hz,1H),5.12(s,2H),4.41-4.35(m,1H),3.76(s,4H),2.59-2.56(dq,J=5.00,8.80H z,1H),2.12-2.08(m,1H),2.06-2.05(m,2H),2.03-1.88(m,1H),1.22-1.19(d,J=6.40Hz,3H).

[0113] Intermediate 2 Benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3-oxopropan-2-yl)carbamate [ka] [ka]

[0114] Step 1: Benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3-oxopropan-2-yl)carbamate To a solution of methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)propanoate (2 g, 5.98 mmol) in THF (30 mL) was added DIBAL-H (23.93 mL, 23.93 mmol) (1 M in toluene) at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1 h. LC / MS showed that the starting material was consumed and the desired product was formed. MeOH (10 mL) was added to the mixture at −78° C., and then the mixture was warmed to room temperature and stirred at 25° C. for 15 min. The reaction mixture was then quenched with saturated Rochelle's salt (20 mL), followed by the addition of EtOAc (20 mL). After stirring at room temperature for 30 minutes, the mixture was then extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (2 x 20 mL). The organic layers were then dried over NaSO, filtered, and concentrated to give the title compound, which was used in the next step without further purification. LRMS m / z: (M+H) + Calculated value 305.1; measured value 305.1.

[0115] 1 H NMR (400MHz, chloroform-d) δ 9.55(s,1H),7.40-7.28(m,5H),6.60(br d,J=6.2Hz,1H),6.16(br s,1H),5.13(s,2H),4.24(br d,J=5.6Hz,1H),3.86-3.67(m,1H),2.66-2.51(m,1H),2.04-1.90(m,4H),1.19(br d,J=6.3Hz,3H).

[0116] Intermediate 3 (3S)-3-Amino-2-hydroxy-N-methyl-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide [ka] [ka]

[0117] Step 1: Benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3-oxopropan-2-yl)carbamate To a solution of benzyl ((S)-1,1-dimethoxy-3-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (2 g, 5.71 mmol) in acetone (20 mL) and water (20 mL) was added DOWEX® 50WX8(H) resin (20 g, 5.71 mmol). The resulting mixture was stirred at 40° C. for 16 hours. LC / MS showed that the starting material had been consumed and the desired product had formed. The resin was then filtered off and the filter cake was washed with 1:1 acetone / water (4×30 mL). The resulting residue was partially concentrated under a stream of nitrogen until the acetone was removed, and the aqueous layer was then lyophilized to give the title compound, which was used in the next step without further purification. LRMS m / z: (M+H) + Calculated value 305.1; measured value 305.1.

[0118] 1 H NMR (400MHz, chloroform-d) δ 9.55(s,1H),7.40-7.28(m,5H),6.60(br d,J=6.2Hz,1H),6.16(br s,1H),5.13(s,2H),4.24(br d,J=5.6Hz,1H),3.86-3.67(m,1H),2.66-2.51(m,1H),2.04-1.90(m,4H),1.19(br d,J=6.3Hz,3H).

[0119] Step 2: Benzyl ((2S)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-4-oxobutan-2-yl)carbamate To a mixture of benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3-oxopropan-2-yl)carbamate (1.7 g, 5.59 mmol) and isocyanomethane (0.333 mL, 6.14 mmol) in DCM (30 mL) was added TFA (0.764 g, 6.70 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 16 hours. LC / MS showed that the starting material was consumed and the desired MS was observed. Water (30 mL) was added, and then the mixture was extracted with DCM (3×20 mL). The organic layer was washed with brine (20 mL), then dried over MgSO4, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® silica flash column, eluent 10% MeOH / DCM gradient @ 24 mL / min). The desired fractions were concentrated and then re-purified by preparative HPLC (Column: Boston Green ODS 150*30 mm*5 μm, Conditions: (Water (TFA)-ACN start B60 end B80 gradient time (min) 10 100% B retention time (min) 2, flow rate (mL / min) 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 364.1; measured value 364.2.

[0120] 1 H NMR (500MHz, chloroform-d) δ 7.37-7.28(m,5H),6.89(br s,1H),5.76(br s,1H),5.06(br s,2H),4.24(br d,J=8.1Hz,2H),3.83-3.61(m,1H),2.79(br d,J=4.4Hz,3H),2.70-2.50(m,1H),2.03-1.79(m,4H),1.19(br d,J=5.3Hz,3H).

[0121] Step 3: (3S)-3-amino-2-hydroxy-N-methyl-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide To a solution of benzyl ((2S)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-4-oxobutan-2-yl)carbamate (800 mg, 2.201 mmol) in EtOAc (15 mL) was added 10% Pd on carbon (234 mg, 0.220 mmol). The mixture was degassed and backfilled with hydrogen (3 times). The reaction mixture was then stirred under a hydrogen atmosphere at 25° C. for 16 hours. LC / MS showed that the starting material was consumed and the desired MS was observed. The catalyst was filtered off and the filtrate was concentrated to give the title compound, which was used without further purification. LRMS m / z: (M+H) + Calculated value 230.1; measured value 230.1.

[0122] 1 H NMR (500MHz, methanol-d4) δ 4.24-4.14(m,1H),3.86-3.70(m,1H),2.90-2.81(m,1H),2.79(br d,J=4.4Hz,3H),2.03(br dd,J=1.4,2.4Hz,3H),1.91-1.52(m,2H),1.22(s,3H).

[0123] Intermediate 4 (3S)-3-Amino-2-hydroxy-N-methyl-4-((S)-2-oxopyrrolidin-3-yl)butanamide [ka] [ka]

[0124] Step 1: Benzyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate To a solution of benzyl ((S)-1,1-dimethoxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (5 g, 14.86 mmol) in acetone (25 mL) and water (25 mL) was added DOWEX® 50WX8(H) resin (50 g). The reaction mixture was then stirred at 40° C. for 16 hours. LC / MS showed that the starting material was consumed and the desired product was observed. The reaction mixture was filtered and the filter cake was washed with EtOAc (3×30 mL). The filtrate was concentrated to remove the organic solvent and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. LRMS m / z: (M+H) + Calculated value 291.1; measured value 291.1.

[0125] Step 2: Benzyl ((2S)-3-hydroxy-4-(methylamino)-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate To a mixture of benzyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (3 g, 10.33 mmol) in DCM (40 mL) was added TFA (0.921 mL, 12.40 mmol), followed by isocyanomethane (0.6 mL, 11.06 mmol). The reaction mixture was stirred at 25 °C for 3 h. LC / MS showed that the desired mass was observed. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (2 mL), basified with saturated Na2CO3 to pH = 10, and then stirred for 16 h. The mixture was extracted with EtOAc (3 x 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by RP-HPLC (column: Boston Green ODS 150*30mm*5μm, conditions: water (0.01% TFA)-ACN start B17 end B37 gradient time (min) 10, 100% B retention time 2, flow rate (mL / min): 25). The desired fraction was concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 350.1; measured value 350.2.

[0126] 1 H NMR(400MHz, methanol-d4)δ 7.38-7.22(m,5H),5.07-4.88(m,2H),4.18-3.90(m,2H),3.34-3.31(m,2H),3.25-3.17(m,1H), 2.72-2.65(m,3H),2.41-2.20(m,1H),2.13-1.99(m,1H),1.84-1.64(m,1H),1.47-1.03(m,1H).

[0127] Step 3: (3S)-3-amino-2-hydroxy-N-methyl-4-((S)-2-oxopyrrolidin-3-yl)butanamide To a solution of benzyl ((2S)-3-hydroxy-4-(methylamino)-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate (4.5 g, 12.88 mmol) in EtOAc (2 mL) was added 10% Pd on carbon (1.371 g). The reaction mixture was degassed and backfilled with hydrogen (3 times). The resulting mixture was stirred under a hydrogen atmosphere at 25° C. for 16 hours. LC / MS showed that the starting material was consumed and the desired mass was observed. The catalyst was filtered off and the filtrate was concentrated to give the title compound, which was used without further purification. LRMS m / z: (M+H) + Calculated value 216.1; measured value 216.1.

[0128] 1 H NMR (400 MHz, methanol-d₄) δ 4.08–3.89 (m, 1H), 3.34–3.32 (m, 1H), 3.16–3.05 (m, 1H), 2.82–2.73 (m, 3H), 2.69–2.58 (m, 1H), 2.43–2.29 (m, 1H), 1.96–1.65 (m, 2H), 1.47–118 (m, 1H).

[0129] Intermediate 5 (3S)-3-Amino-N-cyclopropyl-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide [ka] [ka] Step 1: Benzyl ((S)-1-hydroxy-3-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate To a 1 L three-neck flask was added methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)propanoate (50 g, 150 mmol) at 25 °C under a nitrogen atmosphere using a magnetic stirrer. DCM (500 mL, 10 V) was then added, followed by stirring for 10 minutes until solubilized. LiBH (6.6 g, 300 mol) was then added portionwise to the solution over 15 minutes at 0 °C. The reaction mixture was then warmed to 25 °C and stirred under a nitrogen atmosphere, followed by LC / MS. After 2 hours, the starting material was consumed and a mass of the desired product was observed. The reaction was then diluted with 10 wt% aqueous NH Cl (400 mL) at 25 °C. The reaction mixture was then stirred for 20 minutes, and the organic layer was then separated. The aqueous layer was extracted with DCM (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 100 / 1 to 5 / 1 DCM / MeOH. The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 307.1; measured value 307.1.

[0130] 1 H NMR(400MHz,DMSO-d6)δ:7.65(s,1H),7.34(s,5H),7.07(d,J=8.9Hz,1H),5.18-4.90(m,2H),4.67(t,J=5.7Hz,1H),3 .63-3.42(m,2H),3.40-3.20(m,4H),2.37-2.22(m,1H),1.88-1.60(m,3H),1.45-1.29(m,1H),1.04(d,J=6.3Hz,3H).

[0131] Step 2a: Benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3-oxopropan-2-yl)carbamate To a 500 mL three-neck flask was added benzyl ((S)-1-hydroxy-3-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (20 g, 65 mmol) at 25°C under a nitrogen atmosphere using a magnetic stirrer. DCM (200 mL) was then added to the flask and stirred for 10 minutes until solubilized. The reaction mixture was then cooled to 0°C. DMP (42 g, 98 mmol) was then added portionwise to the solution over 20 minutes, while maintaining the temperature between 0 and 10°C. The reaction mixture was then allowed to warm to 25°C with stirring, followed by LC / MS. After 3 hours, the reaction was filtered and the filter cake was washed with DCM (50 mL) to give the title compound, which was used without purification. LRMS m / z: (M+H) + Calculated value 305.1; measured value 305.1.

[0132] Step 2b: Isocyanocyclopropane To a 250 mL three-neck flask, under a nitrogen atmosphere, was added N-cyclopropylformamide (0.4 g, 122 mmol) followed by anhydrous DCM (100 mL) at 25 °C using a magnetic stirrer. Burgess reagent (29 g, 122 mmol) was then added portionwise to the solution with stirring at 25 °C, followed by LC / MS. After 1 h, 1H NMR indicated approximately 20% remaining starting material and approximately 80% desired product. The DCM (100 mL) solution was used directly in the next step without workup or purification.

[0133] Step 3: Benzyl ((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)carbamate To a flask containing the crude reaction mixture from step 2a containing benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3-oxopropan-2-yl)carbamate (65 mmol, theoretical yield) in DCM (250 mL), TFA (11.2 g, 98 mmol) was added dropwise into the organic layer at 25 °C. The crude solution of isocyanocyclopropane (122 mmol, theoretical yield) from step 2b was then added dropwise to the above solution over 20 min while maintaining the temperature at 25-30 °C, followed by LC / MS. After 1 h at 25 °C, the reaction mixture was quenched with 10 wt% aqueous NaCO to pH = 7. The organic layer was then separated, and the aqueous layer was extracted with DCM (3 × 80 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The resulting residue was then purified by preparative HPLC (water (NH4HCO3)-ACN). The desired fractions were then concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 390.2; measured value 390.2.

[0134] 1 H NMR(400MHz,MeOD)δ:7.61-7.19(m,5H),5.19-5.04(m,2H),4.20-3.94(m,2H),3.83-3.61(m,1H),2.82-2. 56(m,1H),2.55-2.34(m,1H),2.23-1.81(m,3H),1.56-0.97(m,4H),0.81-0.65(m,2H),0.63-0.39(m,2H).

[0135] Step 4: (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide To a 500 mL three-neck flask equipped with a magnetic stirrer was added benzyl ((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)carbamate (5.5 g, 14.1 mmol), 10 wt % Pd on carbon (20% loading), and CF3CH2OH (55 mL). The reaction mixture was then purged with hydrogen / vacuum, purged with hydrogen (3 times), and then stirred under a hydrogen atmosphere (hydrogen balloon) at 25 °C, followed by LC / MS. After 16 h, the reaction mixture was filtered. The filter cake was then washed with MeOH (50 mL). The combined organic layers were concentrated. The resulting residue was purified by preparative HPLC (eluted with water (NH4HCO3)-ACN)). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 256.1; measured value 256.3.

[0136] 1 H NMR(400MHz,MeOD)δ:4.08(d,J=3.7Hz,1H),3.95(d,J=3.4Hz,1H),3.82-3.64(m,1H),3.26-3.15(m,1H),2.86 -2.55(m,2H),2.11-1.74(m,3H),1.65-1.51(m,1H),1.63-1.10(m,1H),0.85-0.68(m,2H),0.63-0.41(m,2H).

[0137] Intermediate 6 (3S)-3-Amino-N-cyclopropyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide [ka] [ka]

[0138] Step 1: Benzyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate To a solution of benzyl ((S)-1,1-dimethoxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (5 g, 14.86 mmol) in acetone (25 mL) and water (25 mL) was added DOWEX® 50WX8(H) resin (50 g, 14.86 mmol). The resulting reaction mixture was stirred at 40° C., followed by LC / MS. After 16 h, the reaction mixture was filtered, and the resin was washed with EtOAc (3×30 mL). The filtrate was concentrated to remove organic solvents, and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound, which was used directly for the next step. LRMS m / z: (M+H)+ calculated 291.1; found 291.1.

[0139] 1 H NMR (400MHz, chloroform-d) δ 9.57(s,1H),7.45-7.28(m,5H),6.64(br d,J=6.0Hz,1H),6.10(br s,1H),5.24-5.04(m,2H),4.30-4.19(m,1H),3.44-3.21(m,2H),2.59-2.26(m,2H),2.04-1.76(m,3H).

[0140] Step 2: Benzyl ((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate To a mixture of benzyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (2 g, 6.89 mmol) in DCM (30 mL) was added TFA (0.614 mL, 8.27 mmol) and isocyanocyclopropane (0.761 mL, 10.33 mmol). The reaction mixture was stirred at 25 °C and then analyzed by LC / MS. After 3 h, the reaction mixture was concentrated and the resulting residue was treated with NaHCO (1.157 g, 13.78 mmol), MeOH (18 mL), and water (12 mL). The resulting mixture was stirred for 2 h. LC / MS showed the reaction was complete. The mixture was then concentrated and the residue was dissolved in water (10 mL) and EtOAc (20 mL). The organic layer was separated, the aqueous layer was re-extracted with EtOAc (3 x 10 mL), and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®, 20 g SepaFlash® silica flash column, eluent of 25% ethyl acetate / pet. ether gradient @ 50 mL / min). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 376.1; found 376.1.

[0141] Step 3: (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide To a solution of benzyl ((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate (600 mg, 1.598 mmol) in EtOAc (20 mL) under a nitrogen atmosphere was added 10% Pd on carbon (170 mg). The reaction mixture was degassed and backfilled with hydrogen / vacuum (3 times). The resulting mixture was stirred under hydrogen (balloon) at 25° C. and then subjected to LC / MS. After 1 h, the reaction mixture was filtered and the filtrate was concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 242.1; found 242.1.

[0142] [Example] [Example 1] 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-2-(1-(trifluoromethyl)cyclopropane-1-carboxamido)benzamide [ka]

[0143] Step 1: Methyl 5-chloro-2-(1-(trifluoromethyl)cyclopropane-1-carboxamido)benzoate To a vial containing methyl 2-amino-5-chlorobenzoate (304 mg, 1.638 mmol) and 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (415 mg, 2.69 mmol), 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.16 g, 2.62 mmol) was added, followed by NMP (4 mL), and finally DIPEA (450 μL, 2.58 mmol). The reaction mixture was then capped and immediately heated to 85 °C in a hood before being analyzed by LC / MS. After overnight at 85°C, the reaction mixture was diluted with 200 µL of MeOH and then purified (without workup) by reverse-phase chromatography (10-100% MeCN / HO, 0.1% TFA modifier, 30 min gradient, Waters 50 x 250 mm Sunfire 5 micron C18 column, flow rate = 118.1 mL / min). The desired fraction was the free base, suspended in EtOAc and washed with saturated NaHCO3, then water, then brine. The organic layer was then dried over Na2SO4, filtered, concentrated, then dissolved in DCM / MeOH and concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 322.6; measured value 322.0.

[0144] [ka]

[0145] Step 2: 5-chloro-2-(1-(trifluoromethyl)cyclopropane-1-carboxamido)benzoic acid To a flask containing methyl 5-chloro-2-(1-(trifluoromethyl)cyclopropane-1-carboxamido)benzoate (150 mg, 0.466 mmol) was added MeOH (4 mL), then water (2 mL), and finally 5N sodium hydroxide (350 μL, 1.750 mmol). The reaction mixture was then capped and stirred at room temperature before running LC / MS. After approximately 30 minutes at room temperature, the reaction mixture was diluted / acidified with 1N HCl, then suspended in EtOAc and washed with 1N HCl, then brine. The organic layer was then dried over NaSO, filtered, and concentrated to provide the title compound, which was used without further purification. LRMS m / z: (M+H) + Calculated value 308.6; measured value 308.1.

[0146] [ka] Step 3: 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-(1-(trifluoromethyl)cyclopropane-1-carboxamide)benzamide To a vial containing 5-chloro-2-(1-(trifluoromethyl)cyclopropane-1-carboxamido)benzoic acid (67 mg, 0.218 mmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (74 mg, 0.290 mmol) was added 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (162 mg, 0.365 mmol), followed by NMP (1.5 mL), and finally DIPEA (105 μL, 0.601 mmol). The reaction mixture was then capped and immediately heated to 85 °C in a hood prior to analysis by LC / MS. After overnight at 85°C, the reaction mixture was diluted with 200 µL of MeOH and then purified (without workup) by reverse-phase chromatography (5-60% MeCN / HO, 0.1% TFA modifier, 20 min gradient, Waters 30 x 150 mm Sunfire 5 micron C18 column, flow rate = 42.5 mL / min). The desired fractions were diluted with MeOH and concentrated, then dissolved in DCM / MeOH and concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 545.9; measured value 545.2.

[0147] [ka] Step 4: 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-2-(1-(trifluoromethyl)cyclopropane-1-carboxamido)benzamide To a vial containing 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-(1-(trifluoromethyl)cyclopropane-1-carboxamido)benzamide (100 mg, 0.184 mmol) was added Dess-Martin periodinane (138 mg, 0.325 mmol) and sodium bicarbonate (76 mg, 0.905 mmol), followed by DCM (5 mL). The reaction mixture was then capped and stirred at room temperature before being analyzed by LC / MS. After 30 min, the reaction mixture was quenched / diluted with 4 mL of saturated sodium thiosulfate, followed by 1 mL of water, and then diluted with 10 mL of EtOAc. The mixture was stirred for 10 minutes, then suspended in EtOAc and washed with saturated sodium thiosulfate, then water, then brine. The organic layer was then dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (30-100% EtOAc / Hex, 14 CV, 40 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 543.9; measured value 543.1.

[0148] 1 H NMR(500MHz,DMSO-d6)δ 9.65(d,J=6.6Hz,1H),8.81(d,J=5.1Hz,1H),8.36(d,J=9.0Hz,1H),7.97-7.89(m,2H), 7.63(dd,J=9.0,2.5Hz,1H),5.23-5.16(m,1H),3.69-3.57(m,1H),2.80-2.73(m,1H),2 .68-2.59(m,1H),2.03-1.94(m,2H),1.91-1.84(m,1H),1.78-1.71(m,1H),1.47-1.42( m,2H),1.41-1.36(m,2H),1.09(d,J=6.4Hz,3H),0.69-0.66(m,2H),0.61-0.56(m,2H).

[0149] [Example 2] N-(4-chloro-2-(((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)carbamoyl)phenyl)-2-(trifluoromethyl)isonicotinamide [ka]

[0150] Step 1: Methyl 5-chloro-2-(2-(trifluoromethyl)isonicotinamido)benzoate To a vial containing methyl 2-amino-5-chlorobenzoate (354 mg, 1.907 mmol) and 2-(trifluoromethyl)isonicotinic acid (507 mg, 2.65 mmol), 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (2.13 g, 4.81 mmol) was added, followed by NMP (6 mL), and finally DIPEA (850 μL, 4.87 mmol). The reaction mixture was then capped and immediately heated to 85 °C in a hood, followed by LC / MS analysis. After overnight at 85 °C, the reaction mixture was diluted with 200 μL of MeOH and then purified by reverse-phase chromatography (25–100% MeCN / HO; 0.1% TFA modifier, 30 min gradient, Waters 50 × 250 mm Sunfire 5 micron C18 column, flow rate = 118.1 mL / min) without workup. The desired fractions were concentrated, then dissolved in DCM / MeOH and concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 359.7; measured value 359.1.

[0151] [ka]

[0152] Step 2: 5-chloro-2-(2-(trifluoromethyl)isonicotinamido)benzoic acid To a flask containing methyl 5-chloro-2-(2-(trifluoromethyl)isonicotinamido)benzoate (432 mg, 1.204 mmol) was added MeOH (10 mL), then water (4 mL), and finally 5N sodium hydroxide (650 μL, 3.25 mmol). The reaction mixture was then capped and stirred at room temperature. After the addition of NaOH, the reaction mixture was still a suspension, so DCM (3 mL) was added, which immediately solubilized the mixture, followed by LC / MS. After 1.75 h at room temperature, the reaction mixture was diluted / acidified with 1N HCl, then suspended in EtOAc and washed with 1N HCl, then brine. The organic layer was then dried over NaSO, filtered, and concentrated to give the title compound, which was used without further purification. LRMS m / z: (M+H) + Calculated value 345.6; measured value 345.0.

[0153] [ka] Step 3: N-(4-chloro-2-(((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)carbamoyl)phenyl)-2-(trifluoromethyl)isonicotinamide To a vial containing 5-chloro-2-(2-(trifluoromethyl)isonicotinamido)benzoic acid (112 mg, 0.325 mmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (103 mg, 0.403 mmol) was added 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (383 mg, 0.864 mmol), followed by NMP (1.5 mL), and finally DIPEA (145 μL, 0.830 mmol). The reaction mixture was then capped and immediately heated to 85 °C in a hood prior to analysis by LC / MS. After overnight at 85°C, the reaction mixture was diluted with 200 µL of MeOH and then purified (without workup) by reverse-phase chromatography (10-60% MeCN / HO, 0.1% TFA modifier, 20 min gradient, Waters 30 x 150 mm Sunfire 5 micron C18 column, flow rate = 42.5 mL / min). The desired fractions were diluted with MeOH and concentrated, then dissolved in DCM / MeOH and concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 582.9; measured value 582.1.

[0154] [ka]

[0155] Step 4: N-(4-chloro-2-(((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)carbamoyl)phenyl)-2-(trifluoromethyl)isonicotinamide To a vial containing N-(4-chloro-2-(((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)carbamoyl)phenyl)-2-(trifluoromethyl)isonicotinamide (140 mg, 0.241 mmol) was added Dess-Martin periodinane (168 mg, 0.396 mmol) and sodium bicarbonate (42 mg, 0.500 mmol), followed by DCM (5 mL). The reaction mixture was then capped and stirred at room temperature before running LC / MS. After 60 minutes, the reaction mixture was quenched / diluted with 4 mL of saturated sodium thiosulfate, followed by 1 mL of water, then diluted with 10 mL of EtOAc. Stirred for 10 minutes, then suspended in EtOAc and washed with saturated sodium thiosulfate, then water, then brine. The organic layer was then dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (10-100% EtOAc / Hex, 14 CV, 40 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 580.9; measured value 580.1.

[0156] 1 H NMR(500MHz,DMSO-d6)δ 9.67(d,J=6.6Hz,1H),9.04(d,J=5.0Hz,1H),8.80(d,J=5.0Hz,1H),8.38(d,J=8.9Hz,1H),8.21 (s,1H),8.09(d,J=4.9Hz,1H),7.97(d,J=2.4Hz,1H),7.89(s,1H),7.72(dd,J=8.9,2.4Hz,1H),5 .22-5.13(m,1H),3.64-3.51(m,1H),2.76-2.69(m,1H),2.68-2.60(m,1H),2.02-1.93(m,2H),1. 86-1.79(m,1H),1.78-1.70(m,1H),1.00(d,J=6.3Hz,3H),0.67-0.62(m,2H),0.56-0.51(m,2H).

[0157] [Example 3] 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4- Dioxobutan-2-yl)-2-(4,4,4-trifluorobutanamido)benzamide [ka]

[0158] Step 1: 5-chloro-2-(4,4,4-trifluorobutanamido)benzoic acid To a solution of 2-amino-5-chlorobenzoic acid (150 mg, 0.874 mmol) in DCM (5 mL) was added triethylamine (0.366 mL, 2.62 mmol) and 4,4,4-trifluorobutanoyl chloride (154 mg, 0.962 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour, followed by LC / MS analysis. 0.5 M aqueous HCl (10 mL) was then added to quench the reaction. The mixture was extracted with DCM (2 × 10 mL). The separated organics were dried over Na SO , filtered, and concentrated. The resulting residue was purified by RP-HPLC (column: Boston Green ODS 150*30 mm*5 μm, condition: water (TFA)-ACN start B45 end B65, gradient time (min): 10 100% B, retention time (min): 2, flow rate (mL / min): 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 296.0; measured value 296.0.

[0159] [ka]

[0160] Step 2: 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-(4,4,4-trifluorobutanamido)benzamide To a mixture of 5-chloro-2-(4,4,4-trifluorobutanamido)benzoic acid (57.9 mg, 0.196 mmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (50 mg, 0.196 mmol) in DMF (1.5 mL) was added AOP (104 mg, 0.235 mmol) and DIPEA (0.103 mL, 0.588 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 12 hours, followed by LC / MS. The reaction mixture was then directly purified by RP-HPLC (column: Boston Green ODS 150*30mm*5μm, condition: water (TFA)-ACN start B33 end B53, gradient time (min): 10 100% B, retention time (min): 2, flow rate (mL / min) 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 533.1; found 533.2.

[0161] [ka]

[0162] Step 3: 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-2-(4,4,4-trifluorobutanamido)benzamide To a mixture of 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-(4,4,4-trifluorobutanamido)benzamide (55 mg, 0.103 mmol) and NaHCO (26.0 mg, 0.310 mmol) in DCM (1.5 mL) was added DMP (65.7 mg, 0.155 mmol) at 25° C. The resulting mixture was stirred at 25° C. for 2 hours, followed by LC / MS. The reaction mixture was then filtered, and the filtrate was concentrated. The resulting residue was purified by RP-HPLC (column: Welch Xtimate C18 150*25mm*5μm, condition: water (NH4HCO3)-ACN start B33 end B63, gradient time (min): 11 100% B, retention time (min): 2, flow rate (mL / min): 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 531.1; found 531.0.

[0163] 1 H NMR (500 MHz, chloroform-d) δ 11.53-11.34 (m, 1H), 9.93-9.92 (m, 1H), 8.56 (d, J = 9.0 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.43-7.40 (m, 1H), 6.98-6.97 (m, 1H), 6.04-5.90 (m, 1H), 5.34-5.30 (m, 1H), 3.87 -3.71(m,1H),2.94-2.72(m,2H),2.65-2.61(m,2H),2.57-2.49(m,2H),2.36-2.11( m,3H),1.94-1.87(m,1H),1.25-1.19(m,3H),0.91-0.80(m,2H),0.70-0.58(m,2H).

[0164] [Example 4] 2-(3,5-bis(trifluoromethyl)benzamido)-5-cyano-N-((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)nicotinamide [ka]

[0165] Step 1: 2-(3,5-bis(trifluoromethyl)benzamido)-5-bromonicotinic acid To a mixture of 2-amino-5-bromonicotinic acid (1 g, 4.61 mmol) and TEA (1.285 mL, 9.22 mmol) in DCM (25 mL) was added 3,5-bis(trifluoromethyl)benzoyl chloride (1.274 g, 4.61 mmol) slowly at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for a total of 16 hours before running LC / MS. The reaction mixture was then diluted with DCM (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give the title compound, which was used without further purification. LRMS m / z: (M+H)+ calculated 456.9; found 457.0.

[0166] [ka] Step 2: 2-(3,5-bis(trifluoromethyl)benzamido)-5-cyanonicotinic acid To a mixture of methyl 2-(3,5-bis(trifluoromethyl)benzamido)-5-bromonicotinate (470 mg, 0.998 mmol) and potassium hexacyanoferrate(II) trihydrate (527 mg, 1.247 mmol) in DMA (8 mL) and water (1 mL) was added dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (95 mg, 0.200 mmol) and allylpalladium(II) chloride (36.5 mg, 0.100 mmol) at 25 °C. The reaction mixture was then degassed and backfilled with nitrogen three times. The resulting mixture was stirred at 100 °C for 48 h, followed by LC / MS analysis. The reaction mixture was then filtered, and the solid was collected by filtration and then purified by RP-HPLC (Column: Boston Green ODS 150*30mm*5μm, Condition: Water (0.01% TFA)-ACN Start B42 End B62 Gradient time (min) 10 100% B Retention time 2 Flow rate (mL / min) 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 404.0; Found 404.0.

[0167] [ka] Step 3: 2-(3,5-bis(trifluoromethyl)benzamido)-5-cyano-N-((2S)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-4-oxobutan-2-yl)nicotinamide To a mixture of 2-(3,5-bis(trifluoromethyl)benzamido)-5-cyanonicotinic acid (65 mg, 0.161 mmol) and (3S)-3-amino-2-hydroxy-N-methyl-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (44.4 mg, 0.193 mmol) in DMF (2 mL) was added DIPEA (0.084 mL, 0.484 mmol) and AOP (86 mg, 0.193 mmol) at 25° C. The resulting mixture was stirred for 16 h and then analyzed by LC / MS. The reaction mixture was then purified by RP-HPLC (column: Boston Green ODS 150*30mm*5μm, condition: water (0.01% TFA)-ACN start B33 end B53 gradient time (min) 5 100% B hold time 2 flow rate (mL / min) 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 615.1; found 615.2.

[0168] [ka] Step 4: 2-(3,5-bis(trifluoromethyl)benzamido)-5-cyano-N-((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)nicotinamide To a mixture of 2-(3,5-bis(trifluoromethyl)benzamido)-5-cyano-N-((2S)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-4-oxobutan-2-yl)nicotinamide (45 mg, 0.073 mmol) and sodium bicarbonate (18.46 mg, 0.220 mmol) in DCM (2 mL) was added DMP (93 mg, 0.220 mmol) at 25° C., followed by LC / MS. After 3 h, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (column: Welch Xtimate C18 150*25mm*5μm, condition: water (10mM-NH4HCO3)-ACN start B25 end B55 gradient time (min) 11 100% B hold time 2 flow rate (mL / min) 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 613.1; found 613.3.

[0169] 1 H NMR(400MHz, methanol-d4)δ 9.01-8.41(m,4H),8.21(m,J=16.0Hz,1H),4.74-4.24(m,1H),3.81-3.47(m,1H),2.90-2.56(m,4H),2.21-1.43(m,4H),1.19-0.83(m,3H).

[0170] [Example 5] 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide)nicotinamide [ka]

[0171] Step 1: Methyl 5-chloro-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamido)nicotinate To a vial containing methyl 2-bromo-5-chloronicotinate (630 mg, 2.52 mmol) and 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide (570 mg, 3.18 mmol) was added cesium carbonate (2.65 g, 8.13 mmol), followed by Xantphos Pd G3 (405 mg, 0.427 mmol). The reaction mixture was then capped and anhydrous dioxane (10 mL) was added under a nitrogen atmosphere. Nitrogen was bubbled through the reaction mixture for 20 seconds, then heated to 85 °C in a hood, followed by LC / MS analysis. After 20 min, the reaction mixture was suspended in EtOAc, diluted with water, and washed with saturated NaHCO3 and then brine. The organic layer was then dried over Na2SO4, filtered, and concentrated. The resulting residue was then purified by silica gel chromatography (0-80% EtOAc / Hex, 14 CV, 80 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 349.0; found 349.1.

[0172] [ka] Step 2: 5-chloro-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamido)nicotinic acid To a flask containing methyl 5-chloro-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamido)nicotinate (634 mg, 1.818 mmol) was added MeOH (6 mL), then water (3 mL), and finally 5 N sodium hydroxide (750 μL, 3.75 mmol). The reaction mixture was then capped and stirred at room temperature before being followed by LC / MS. After 30 min at room temperature, the reaction mixture was diluted / acidified with 1 N HCl, then suspended in EtOAc and washed with 1 N HCl, then brine. The organic layer was then dried over Na2SO4, filtered, and concentrated to give the title compound, which was used without further purification. LRMS m / z: (M+H)+ calculated 335.0; found 335.0.

[0173] [ka] Step 3: 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide)nicotinamide To a vial containing 5-chloro-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamido)nicotinic acid (116 mg, 0.347 mmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (111 mg, 0.435 mmol) was added 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (251 mg, 0.566 mmol), followed by NMP (1.5 mL), and finally DIPEA (150 μL, 0.859 mmol). The reaction mixture was then capped and immediately heated to 85 °C in a hood before being analyzed by LC / MS. After overnight at 85°C, the reaction mixture was diluted with 200 µL of MeOH and then purified by reverse-phase chromatography (5-50% MeCN / HO, 0.1% TFA modifier, 20 min gradient, Waters 30 x 150 mm Sunfire 5 micron C18 column, flow rate = 42.5 mL / min). The desired fractions were diluted with MeOH and concentrated, then dissolved in DCM / MeOH and concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 572.1; found 570.2.

[0174] [ka] Step 4: 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide)nicotinamide To a vial containing 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamido)nicotinamide (114 mg, 0.199 mmol) was added Dess-Martin periodinane (168 mg, 0.396 mmol), followed by sodium bicarbonate (73 mg, 0.869 mmol), and finally DCM (5 mL). The reaction mixture was then capped and stirred at room temperature before being analyzed by LC / MS. After 30 min, the reaction mixture was quenched / diluted with 4 mL of saturated sodium thiosulfate, followed by 1 mL of water, and then diluted with 10 mL of EtOAc. The mixture was stirred for 10 minutes, then suspended in EtOAc and washed with saturated sodium thiosulfate, then water, then brine. The organic layer was then dried over Na2SO4, filtered, and concentrated. The resulting residue was then purified by silica gel chromatography (30-100% EtOAc / Hex, 14 CV, 40 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 570.9; found 570.1.

[0175] 1 H NMR(500MHz,DMSO-d6)δ 10.91(s,1H),9.29(d,J=7.1Hz,1H),8.80(d,J=5.0Hz,1H),8.58(d,J=2 .5Hz,1H),8.10(d,J=2.5Hz,1H),7.83(s,1H),5.13-5.05(m,1H),3.69- 3.56(m,1H),2.79-2.65(m,2H),2.26(s,6H),2.03-1.86(m,3H),1.74-1 .62(m,1H),1.10(d,J=6.3Hz,3H),0.69-0.63(m,2H),0.60-0.52(m,2H).

[0176] [Example 6] Isopropyl (4-chloro-2-(((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)carbamoyl)phenyl)carbamate [ka]

[0177] Step 1: Methyl 5-chloro-2-((isopropoxycarbonyl)amino)benzoate To a vial containing methyl 2-amino-5-chlorobenzoate (418 mg, 2.252 mmol), NMP (5 mL) was added, followed by DIPEA (0.8 mL, 4.58 mmol), and finally isopropyl chloroformate (2 mL, 4.00 mmol). The reaction mixture was then capped and stirred at room temperature before being analyzed by LC / MS. The reaction mixture was then diluted / quenched with 400 μL MeOH and then partially concentrated. The resulting residue was purified by reverse-phase chromatography (25–100% MeCN / HO, 0.1% TFA modifier, 30 min gradient, Waters 50 × 250 mm Sunfire 5 micron C18 column, flow rate = 118.1 mL / min). The desired fractions were diluted with MeOH and concentrated, then dissolved in MeOH / DCM and concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 272.0; found 272.0.

[0178] [ka] Step 2: 5-chloro-2-((isopropoxycarbonyl)amino)benzoic acid To a flask containing methyl 5-chloro-2-((isopropoxycarbonyl)amino)benzoate (455 mg, 1.675 mmol) was added MeOH (8 mL), followed by water (4 mL), and finally 5N sodium hydroxide (0.7 mL, 3.50 mmol). The reaction mixture was then capped and stirred at room temperature. After the NaOH addition, the reaction mixture was still a suspension, so DCM (3 mL) was added, which immediately solubilized the mixture, followed by LC / MS. After 3.5 h at room temperature, the reaction mixture was diluted / acidified with 1N HCl, then suspended in EtOAc and washed with 1N HCl, then brine. The organic layer was then dried over Na2SO4, filtered, and concentrated to give the title compound, which was used without further purification. LRMS m / z: (M+H)+ calculated 258.0; found 258.0.

[0179] [ka] Step 3: Isopropyl (4-chloro-2-(((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)carbamoyl)phenyl)carbamate To a vial containing 5-chloro-2-((isopropoxycarbonyl)amino)benzoic acid (81 mg, 0.314 mmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (101 mg, 0.396 mmol) was added 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (221 mg, 0.499 mmol), followed by NMP (1 mL), and finally DIPEA (145 μL, 0.830 mmol). The reaction mixture was then capped and immediately heated to 85 °C in a hood prior to analysis by LC / MS. After overnight at 85°C, the reaction mixture was diluted with 200 µL of MeOH and then purified by reverse-phase chromatography (5-50% MeCN / HO, 0.1% TFA modifier, 20 min gradient, Waters 30 x 150 mm Sunfire 5 micron C18 column, flow rate = 42.5 mL / min). The desired fractions were concentrated, then dissolved in DCM / MeOH and concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 495.1; found 495.3.

[0180] [ka] Step 4: Isopropyl (4-chloro-2-(((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)carbamoyl)phenyl)carbamate To a vial containing isopropyl (4-chloro-2-(((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)carbamoyl)phenyl)carbamate (113 mg, 0.228 mmol) was added Dess-Martin periodinane (190 mg, 0.448 mmol), followed by sodium bicarbonate (45 mg, 0.536 mmol), and finally DCM (5 mL). The reaction mixture was then capped and stirred at room temperature before running LC / MS. After 1 h, the reaction mixture was quenched / diluted with 4 mL of saturated sodium thiosulfate, followed by 1 mL of water, and then diluted with 10 mL of EtOAc. Stirred for 25 min, then suspended in EtOAc and washed with saturated sodium thiosulfate, followed by water, and then brine. The organic layer was then dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0-100% EtOAc / Hex; 14 CV; 40 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 493.9; found 493.1.

[0181] 1 H NMR(500MHz,DMSO-d6)δ 10.56(s,1H),9.66(d,J=5.9Hz,1H),8.82(d,J=4.8Hz,1H),8.25(d,J=9.0Hz,1H),8.01-7 .88(m,2H),7.60(d,J=9.0Hz,1H),5.16-5.05(m,1H),4.92-4.83(m,1H),3.68-3.57(m,1H) ,2.81-2.72(m,1H),2.71-2.61(m,1H),2.05-1.94(m,2H),1.93-1.85(m,1H),1.81-1.73(m ,1H),1.24(d,J=6.2Hz,6H),1.10(d,J=6.2Hz,3H),0.69-0.63-(m,2H),0.60-0.54(m,2H).

[0182] [Example 7] 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-2-(2,2-difluoro-3-phenylpropanamido)benzamide [ka]

[0183] Step 1: Ethyl 2,2-difluoro-3-phenylpropanoate To a solution of (bromomethyl)benzene (6.92 mL, 58.5 mmol) and ethyl 2-bromo-2,2-difluoroacetate (8.31 g, 40.9 mmol) in DMSO (10 mL), copper (8.55 g, 134 mmol), copper(I) bromide (0.419 g, 2.92 mmol), and 1,10-phenanthroline (2.107 g, 11.69 mmol) were added under a nitrogen atmosphere. The reaction mixture was then degassed and backfilled with nitrogen (three times). The resulting mixture was stirred under nitrogen at 50 °C for 16 h, followed by LC / MS analysis. The reaction mixture was then filtered. The filtrate was quenched with brine (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash silica gel chromatography (ISCO®, 80 g SepaFlash® silica flash column, eluent of 0-10% ethyl acetate / pet., ether gradient @ 100 mL / min). The desired fractions were concentrated to give the title compound.

[0184] 1 H NMR(400MHz,MeOD)δ 7.32-7.27(m,5H),4.22(q,J=7.2Hz,2H),3.40(t,J=16.8Hz,2H),1.22(t,J=7.2Hz,3H).. 19 F NMR (376 MHz, MeOD) δ 106.1.

[0185] [ka] Step 2: Benzyl 2,2-difluoro-3-phenylpropanoate To a solution of ethyl 2,2-difluoro-3-phenylpropanoate (4.5 g, 21.01 mmol) in THF (30 mL) and water (15 mL) was added lithium hydroxide monohydrate (5.29 g, 126 mmol). The reaction mixture was stirred at 25 °C for 24 hours, followed by LC / MS. The reaction mixture was then diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The aqueous layer was acidified to pH = 3-4 with 1N HCl. The resulting suspension was extracted with DCM (20 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound, which was used without further purification.

[0186] 1 H NMR(400MHz,MeOD)δ 7.32-7.27(m,5H),3.38(t,J=16.8Hz,2H). 19 F NMR (376 MHz, MeOD) δ 106.1.

[0187] [ka] Step 3: 5-chloro-2-(2,2-difluoro-3-phenylpropanamido)benzoic acid To a solution of 2,2-difluoro-3-phenylpropanoic acid (150 mg, 0.806 mmol) in THF (2 mL) was added CDI (392 mg, 2.417 mmol) and TEA (0.337 mL, 2.417 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 hours, and then 2-amino-5-chlorobenzoic acid (152 mg, 0.886 mmol) was added to the reaction. The mixture was then stirred at 25° C. for 16 hours, after which LC / MS analysis was performed. 1 M HCl (0.5 mL) was then added to the mixture, which was then concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (Column: Boston Green ODS 150 × 30 mm × 5 μm, Conditions: Water (TFA)-ACN Start B50 End B70, Gradient: Time (min) 10 100% B Retention Time (min) 2 Flow Rate (mL / min) 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 340.0; Found 340.0.

[0188] [ka] Step 4: 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-(2,2-difluoro-3-phenylpropanamido)benzamide To a mixture of 5-chloro-2-(2,2-difluoro-3-phenylpropanamido)benzoic acid (35 mg, 0.103 mmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (31.6 mg, 0.124 mmol) in DMF (3 mL) was added AOP (91 mg, 0.206 mmol) and DIPEA (0.054 mL, 0.309 mmol) at 25° C. The resulting reaction mixture was stirred at 25° C. for 16 hours, followed by LC / MS. Water (0.5 mL) was then added to the mixture, which was then purified by RP-HPLC (Column: Boston Green ODS 150 × 30 mm × 5 μm, Conditions: Water (TFA)-ACN Start B38 End B68, Gradient: Time (min) 10 100% B Retention Time (min) 2 Flow Rate (mL / min) 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 577.2; Found 577.2.

[0189] [ka] Step 5: 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-2-(2,2-difluoro-3-phenylpropanamido)benzamide To a solution of 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-(2,2-difluoro-3-phenylpropanamido)benzamide (45 mg, 0.078 mmol) in DCM (3 mL) was added NaHCO (19.89 mg, 0.234 mmol) and DMP (99 mg, 0.234 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 1 h, followed by LC / MS. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm, conditions: water (TFA)-ACN start B45 end B75, gradient: time (min) 10 100% B retention time (min) 2 flow rate (mL / min) 25) to give the title compound. LRMS m / z: (M+H)+ calculated 575.1; found 575.2.

[0190] 1 H NMR(400MHz,MeOD)δ 8.47-8.37(m,1H),7.92-7.71(m,1H),7.57-7.50(m,1H),7.31-7.22(m,5H),4.48-4.31(m,1H),3.87-3.68(m,1H),3.47(dt,J=9.1,16.9Hz ,2H),3.00-2.69(m,1H),2.69-2.48(m,1H),2.41-2.18(m,1H),2.14- 1.89(m,3H),1.24-1.11(m,3H),0.83-0.65(m,2H),0.64-0.40(m,2H).

[0191] [Example 8] 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-2-((R)-2,2-difluorocyclopropane-1-carboxamido)benzamide [ka] Step 1: Methyl (R)-5-chloro-2-(2,2-difluorocyclopropane-1-carboxamido)benzoate To a vial containing methyl 2-amino-5-chlorobenzoate (367 mg, 1.977 mmol) and (1R)-2,2-difluorocyclopropane-1-carboxylic acid (313 mg, 2.56 mmol), pyridine (6 mL) was added, followed by POCl3 (0.297 mL, 3.18 mmol). The reaction mixture was then capped and stirred at room temperature before analysis by LC / MS. After 20 min at room temperature, the reaction mixture was diluted with MeOH and purified by reverse-phase chromatography (10–100% MeCN / HO, 0.1% TFA modifier, 30 min gradient, Waters 50 × 250 mm Sunfire 5 micron C18 column, flow rate = 118.1 mL / min). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 290.0; found 290.1.

[0192] [ka] Step 2: (R)-5-chloro-2-(2,2-difluorocyclopropane-1-carboxamido)benzoic acid To a flask containing methyl (R)-5-chloro-2-(2,2-difluorocyclopropane-1-carboxamido)benzoate (450 mg, 1.554 mmol) was added MeOH (10 mL), followed by water (4 mL), and finally 5N sodium hydroxide (800 μL, 4.00 mmol). The reaction mixture was then capped and stirred at room temperature. DCM (3 mL) was then added, which immediately solubilized the mixture, followed by LC / MS. After 75 min at room temperature, the reaction mixture was diluted with 1N HCl, then suspended in EtOAc and washed with 1N HCl, then brine. The organic layer was then dried over NaSO, filtered, and concentrated to give the title compound, which was used without further purification. LRMS m / z: (M+H)+ calculated 276.0; found 276.0

[0193] [ka] Step 3: 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-((R)-2,2-difluorocyclopropane-1-carboxamide)benzamide To a vial containing (R)-5-chloro-2-(2,2-difluorocyclopropane-1-carboxamido)benzoic acid (71.5 mg, 0.259 mmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (71 mg, 0.278 mmol), 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (190 mg, 0.429 mmol) was added, followed by NMP (1 mL), and finally DIPEA (115 μL, 0.658 mmol). The reaction mixture was then capped and heated to 85 °C in a hood prior to analysis by LC / MS. After overnight at 85°C, the reaction mixture was diluted with 200 µL of MeOH and then purified by reverse-phase chromatography (10-70% MeCN / HO, 0.1% TFA modifier, 20 min gradient, Waters 30 x 150 mm Sunfire 5 micron C18 column, flow rate = 42.5 mL / min). The desired fractions were diluted with MeOH and concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 513.2; found 513.1

[0194] [ka] Step 4: 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-2-((R)-2,2-difluorocyclopropane-1-carboxamide)benzamide To a vial containing 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-((R)-2,2-difluorocyclopropane-1-carboxamido)benzamide (70 mg, 0.136 mmol) was added Dess-Martin periodinane (94 mg, 0.222 mmol), sodium bicarbonate (23 mg, 0.274 mmol), and finally DCM (5 mL). The reaction mixture was then capped and stirred at room temperature before being analyzed by LC / MS. After 60 min, the reaction mixture was quenched / diluted with 4 mL of saturated sodium thiosulfate, followed by 1 mL of water, and then diluted with 10 mL of EtOAc. The mixture was stirred for 10 minutes, then suspended in EtOAc and washed with saturated sodium thiosulfate, then water, then brine. The organic layer was then dried over Na2SO4, filtered, and concentrated. The resulting residue was then purified by silica gel chromatography (0-100% EtOAc / Hex, 14 CV, 40 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 511.2; found 511.1

[0195] 1 H NMR(500MHz,DMSO-d6)δ 11.09(s,1H),9.57(d,J=6.4Hz,1H),8.83(d,J=5.0Hz,1H),8.25(d,J=8.9Hz,1H),7.91(s ,1H),7.85(d,J=2.4Hz,1H),7.60(dd,J=8.9,2.4Hz,1H),5.18-5.10(m,1H),3.70-3.56(m ,1H),3.05-2.89(m,1H),2.80-2.72(m,1H),2.69-2.59(m,1H),2.05-1.92(m,3H),1.94-1 .85(m,1H),1.79-1.71(m,1H)1.09(d,J=6.3Hz,3H),0.71-0.62(m,2H),0.60-0.53(m,2H).

[0196] [Example 9] Methyl (4-chloro-2-(((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)carbamoyl)phenyl)carbamate [ka] TIFF0007744536000055.tif37165Step 1: 5-Chloro-2-((methoxycarbonyl)amino)benzoic acid To a solution of 2,5-dioxopyrrolidin-1-ylmethyl carbonate (133 mg, 0.769 mmol) and TEA (0.268 mL, 1.923 mmol) in DCM (3 mL) was added 2,5-dioxopyrrolidin-1-ylmethyl carbonate (133 mg, 0.769 mmol) at 20 ° C. The reaction mixture was then heated to 40 ° C. and stirred for 10 h, followed by LC / MS analysis. The reaction mixture was then concentrated, and the residue was purified by RP-HPLC (column: Boston Uni C18 150*40 mm*5 μm. Conditions: water (0.01% TFA)-ACN start B34 end B64 gradient time (min) 10 100% B retention time 2. Flow rate (mL / min): 60) to give the title compound. LRMS m / z: (M+H)+ calculated 230.0; found 230.0 1 H NMR(400MHz,DMSO-d6)δ 14.07(br s,1H),10.70(br s,1H),8.29(d,J=9.1Hz,1H),7.92(d,J=2.6Hz,1H),7.69(dd,J=2.6,9.1Hz,1H),3.72(s,3H).

[0197] [ka] Step 2: Methyl (4-chloro-2-(((2S)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-4-oxobutan-2-yl)carbamoyl)phenyl)carbamate A mixture of 5-chloro-2-((methoxycarbonyl)amino)benzoic acid (70 mg, 0.305 mmol), AOP (176 mg, 0.396 mmol), DIPEA (0.160 mL, 0.915 mmol), (3S)-3-amino-2-hydroxy-N-methyl-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (70 mg, 0.305 mmol) and DMF (3 mL) was stirred at 25° C. for 2 hours, followed by LC / MS. Then, water (0.2 mL) was added to the reaction mixture, which was purified by RP-HPLC (Column: Boston Uni C18 150*40 mm*5 μm. Conditions: Water (0.01% TFA)-ACN Start B14 End B44 Gradient time (min) 10 100% B Retention time 2. Flow rate (mL / min): 60) to give the title compound. LRMS m / z: (M+H)+ calculated 441.1; found 441.2

[0198] [ka] Step 3: Methyl (4-chloro-2-(((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)carbamoyl)phenyl)carbamate A mixture of methyl (4-chloro-2-(((2S)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-4-oxobutan-2-yl)carbamoyl)phenyl)carbamate (60 mg, 0.136 mmol), NaHCO3 (34.3 mg, 0.408 mmol), and DMP (115 mg, 0.272 mmol) in DCM / DMSO=3:1 (4 mL) was stirred at 20 °C for 1 h, followed by LC / MS. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (Column: Waters Xbridge BEH C18 100*40mm*10μm. Conditions: Water (10mM HCOONH4)-ACN Start B 22 End B 52 Gradient time (min) 11 100% B Retention time 3. Flow rate (mL / min): 50) to give the title compound. LRMS m / z: (M+H)+ calculated 439.1; found 439.2 1 H NMR(400MHz, methanol-d4)δ 8.26-8.11(m,1H),7.86-7.60(m,1H),7.53-7.44(m,1H),4.55-4.35(m,1H),3.84-3.70(m,4H), 2.87-2.75(m,3H),2.57-2.37(m,1H),2.18-1.93(m,4H),1.87-1.74(m,1H),1.37-1.15(m,3H).

[0199] [Example 10] Cyclopropyl(4-chloro-2-(((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)carbamoyl)phenyl)carbamate [ka] Step 1: 5-chloro-2-((cyclopropoxycarbonyl)amino)benzoic acid To a vial containing 2-amino-5-chlorobenzoic acid (2.21 g, 12.88 mmol), 2-MeTHF (40 mL) was added, followed by cyclopropyl chloroformate (1.92 g, 15.93 mmol). The reaction mixture was then capped and stirred at 65 °C, followed by LC / MS. After overnight at 65 °C, the reaction mixture was diluted / quenched with approximately 200 mL of water, then suspended in EtOAc and washed with 1N HCl, then brine. The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in DCM and then purified by silica gel chromatography (0-30% IPA / DCM, 14 CV, 120 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 256.0; Measured value 256.1

[0200] [ka] Step 2: Cyclopropyl (4-chloro-2-(((2S)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-4-oxobutan-2-yl)carbamoyl)phenyl)carbamate To a vial containing 5-chloro-2-((cyclopropoxycarbonyl)amino)benzoic acid (75 mg, 0.293 mmol) and (3S)-3-amino-2-hydroxy-N-methyl-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (77 mg, 0.336 mmol) was added 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (204 mg, 0.460 mmol), followed by NMP (1.5 mL), and finally DIPEA (135 μL, 0.773 mmol). The reaction mixture was then capped and heated to 85 °C prior to analysis by LC / MS. After overnight at 85°C, the reaction mixture was diluted with 200 µL MeOH, filtered (syringe filter), and the filtrate was purified (without workup) by reverse-phase chromatography (5-60% MeCN / HO, 0.1% TFA modifier, 20 min gradient, Waters 30 x 150 mm Sunfire 5 micron C18 column, flow rate = 42.5 mL / min). The desired fractions were concentrated, then dissolved in DCM / MeOH and concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 467.1; Measured value 467.4

[0201] [ka] Step 3: Cyclopropyl (4-chloro-2-(((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)carbamoyl)phenyl)carbamate To a vial containing cyclopropyl (4-chloro-2-(((2S)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-4-oxobutan-2-yl)carbamoyl)phenyl)carbamate (103 mg, 0.221 mmol) was added des-martine periodinane (172 mg, 0.406 mmol) and sodium bicarbonate (41 mg, 0.488 mmol), and finally DCM (5 mL). The reaction mixture was then capped and stirred at room temperature before running LC / MS. After 1.5 hours, the reaction mixture was quenched / diluted with 4 mL of saturated sodium thiosulfate, followed by 1 mL of water, and then diluted with 10 mL of EtOAc. The reaction mixture was stirred at room temperature for 15 minutes, then suspended in EtOAc and washed with saturated sodium thiosulfate, then water, then brine. The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in DCM and purified by silica gel chromatography (30-100% EtOAc / Hexanes, 14 CV, 40 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) + Calculated value 465.1; Measured value 465.4

[0202] 1 H NMR (500 MHz, DMSO-d6) δ 10.60(s,1H),9.67(d,J=5.9Hz,1H),8.74-8.69(m,1H),8.23(d,J=9.0Hz,1 H),8.02-7.87(m,2H),7.62(dd,J=9.0,2.4Hz,1H),5.18-5.10(m,1H),4.12 -4.03(m,1H),3.67-3.56(m,1H),2.70-2.64(m,4H),2.03-1.92(m,2H),1.9 1-1.84(m,1H),1.80-1.72(m,1H),1.09(d,J=6.4Hz,3H),0.73-0.64(m,4H).

[0203] [Example 11] Cyclopropyl(4-chloro-2-(((S)-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)phenyl)carbamate [ka] Step 1: 5-chloro-2-((cyclopropoxycarbonyl)amino)benzoic acid To a vial containing 2-amino-5-chlorobenzoic acid (2.21 g, 12.88 mmol), 2-MeTHF (40 mL) was added, followed by cyclopropyl chloroformate (1.92 g, 15.93 mmol). The reaction mixture was then capped and stirred at 65 °C before being analyzed by LC / MS. After overnight at 65 °C, the reaction mixture was diluted / quenched with approximately 200 mL of water, then suspended in EtOAc and washed with 1N HCl, then brine. The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in DCM and then purified by silica gel chromatography (0-30% IPA / DCM, 14 CV, 120 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 256.0; found 256.1

[0204] [ka] Step 2: Cyclopropyl (4-chloro-2-(((2S)-3-hydroxy-4-(methylamino)-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)phenyl)carbamate To a vial containing 5-chloro-2-((cyclopropoxycarbonyl)amino)benzoic acid (75 mg, 0.293 mmol) and (3S)-3-amino-2-hydroxy-N-methyl-4-((S)-2-oxopyrrolidin-3-yl)butanamide hydrochloride (94.7 mg, 0.376 mmol), 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.465 mmol) was added, followed by NMP (1 mL), and finally DIPEA (135 μL, 0.773 mmol). The reaction mixture was then capped and stirred at room temperature in a hood. LC / MS analysis was then performed. After overnight at room temperature, the reaction mixture was diluted with 200 μL MeOH, filtered (syringe filter), and the filtrate was then purified by reverse-phase chromatography (1×4.2 mL injection) (5-50% MeCN / HO, 0.1% TFA modifier, 20 min gradient, Waters 30×150 mm Sunfire 5 micron C18 column, flow rate = 42.5 mL / min) (no workup). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 453.1; found 453.4

[0205] [ka] Step 3: Cyclopropyl (4-chloro-2-(((S)-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)phenyl)carbamate To a flask containing cyclopropyl (4-chloro-2-(((2S)-3-hydroxy-4-(methylamino)-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)phenyl)carbamate (104 mg, 0.230 mmol) was added des-martine periodinane (146 mg, 0.344 mmol), sodium bicarbonate (28.9 mg, 0.344 mmol), and finally DCM (5 mL) (from a squirt bottle). The reaction mixture was then capped and stirred at room temperature before running LC / MS. After 1 h, the reaction mixture was quenched / diluted with 5 mL of saturated sodium thiosulfate, followed by 5 mL of water, then diluted with 10 mL of EtOAc and stirred at room temperature for 15 min. The reaction mixture was then suspended in EtOAc and washed with saturated sodium thiosulfate, then water, then brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was dissolved in DCM and purified by silica gel chromatography (50-100% EtOAc / Hexanes, 14 CV, 40 g ISCO column). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 451.1; found 451.3

[0206] 1 H NMR (500 MHz, DMSO-d6) δ 10.61(s,1H),9.66(d,J=6.0Hz,1H),8.76-8.69(m,1H),8.23(d,J=9.0Hz,1H), 7.95(d,J=2.5Hz,1H),7.85(s,1H),7.62(dd,J=9.0,2.4Hz,1H),5.18-5.11(m,1 H),4.11-4.04(m,1H),3.24-3.12(m,2H),2.67(d,J=4.8Hz,3H),2.61-2.52(m,1 H),2.30-2.22(m,1H),2.05-1.96(m,1H),1.80-1.71(m,2H),0.74-0.64(m,4H).

[0207] [Example 105] 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-2-(3-((4,4-difluorocyclohexyl)methyl)-3-methylureido)benzamide [ka] Step 1: Methyl 5-chloro-2-(3-((4,4-difluorocyclohexyl)methyl)-3-methylureido)benzoate To a vial containing methyl 2-amino-5-chlorobenzoate (202 mg, 1.088 mmol), triphosgene (123 mg, 0.415 mmol) was added, followed by MeCN (4 mL). The reaction mixture was then capped and stirred at room temperature, followed by LC / MS analysis. After overnight at room temperature, DIPEA (775 μL, 4.44 mmol) was added, followed by [(4,4-difluorocyclohexyl)methyl](methyl)amine hydrochloride (259 mg, 1.297 mmol). The mixture continued to stir at room temperature. After 1.5 h at room temperature, the reaction mixture was diluted / quenched with water, then suspended in EtOAc and washed with saturated sodium bicarbonate, then water, then brine. The organic layer was then dried over anhydrous sodium sulfate, then filtered, and concentrated. The resulting residue was purified by silica gel chromatography (0–10% IPA / DCM, 80 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 375.1; found 375.2.

[0208] [ka] Step 2: 5-chloro-2-(3-((4,4-difluorocyclohexyl)methyl)-3-methylureido)benzoic acid To a flask containing methyl 5-chloro-2-(3-((4,4-difluorocyclohexyl)methyl)-3-methylureido)benzoate (308 mg, 0.822 mmol) was added MeOH (8 mL), followed by DCM (2 mL), then water (2 mL), and finally 5 N sodium hydroxide (425 μL, 2.125 mmol). The reaction mixture was then capped and stirred at room temperature before running LC / MS. After 1.5 h at room temperature, the reaction mixture was diluted / quenched with 1 N HCl (10 mL, 10.00 mmol), then suspended in EtOAc and washed with 1 N HCl, then brine. The organic layer was dried over anhydrous sodium sulfate, then filtered and concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 361.1; found 361.2.

[0209] [ka] Step 3: 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-(3-((4,4-difluorocyclohexyl)methyl)-3-methylureido)benzamide To a vial containing 5-chloro-2-(3-((4,4-difluorocyclohexyl)methyl)-3-methylureido)benzoic acid (70 mg, 0.194 mmol) and (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanamide (61 mg, 0.239 mmol) was added 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (138 mg, 0.311 mmol), followed by NMP (1 mL), and finally DIPEA (90 μL, 0.515 mmol). The reaction mixture was then capped and immediately heated to 85 °C in a hood. LC / MS analysis followed. After overnight at 85°C, the reaction mixture was diluted with 200 µL MeOH and then purified (without workup) by reverse-phase chromatography (1 x 4.2 mL injection) (10-80% MeCN / HO, 0.1% TFA in AQ, 20 min gradient, Waters 30 x 150 mm Sunfire 5 micron C18 column, flow rate = 42.5 mL / min). The desired fractions were concentrated, then dissolved in DCM / MeOH and concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 598.2; found 598.4.

[0210] [ka] Step 4: 5-chloro-N-((S)-4-(cyclopropylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)- 3,4-Dioxobutan-2-yl)-2-(3-((4,4-difluorocyclohexyl)methyl)-3-methylureido)benzamide To a vial containing 5-chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-2-(3-((4,4-difluorocyclohexyl)methyl)-3-methylureido)benzamide (61 mg, 0.102 mmol) was added des-martine periodinane (83 mg, 0.196 mmol) and sodium bicarbonate (32 mg, 0.381 mmol), followed by DCM (5 mL). The reaction mixture was then capped and stirred at room temperature before being analyzed by LC / MS. After 1 h, the reaction mixture was quenched / diluted with 4 mL of saturated sodium thiosulfate, followed by 1 mL of water, and then diluted with 10 mL of EtOAc. The reaction mixture was stirred for 15 minutes, then suspended in EtOAc and washed with saturated sodium thiosulfate, then water, then brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was then dissolved in DCM and purified by silica gel chromatography (0-100% EtOAc / hexanes, 14 CV, 40 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 596.2; found 596.4.

[0211] 1 H NMR(500MHz,DMSO)d 10.75(s,1H),9.64(d,J=6.1Hz,1H),8.80(d,J=5.1Hz,1H),8.42(d,J=9.1Hz,1H),7.96(s,1H),7. 90(d,J=2.5Hz,1H),7.52(dd,J=9.1,2.5Hz,1H),5.21-5.09(m,1H),3.66-3.58(m,1H),3.25-3.12 (m,2H),2.94(s,3H),2.78-2.71(m,1H),2.70-2.61(m,1H),2.05-1.93(m,4H),1.91-1.82(m,1H), 1.82-1.65(m,5H),1.25-1.13(m,3H),1.09(d,J=6.3Hz,3H),0.70-0.63(m,2H),0.60-0.53(m,2H).

[0212] [Example 115] N-((S)-4-(benzylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-5-chloro-2-(4,4,4-trifluorobutanamido)benzamide [ka] Step 1: Benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3-oxopropan-2-yl)carbamate To a solution of methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)propanoate (3 g, 8.97 mmol) in THF (40 mL) was added DIBAL-H (44.9 mL, 44.9 mmol, 1 M in toluene) at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1 h, followed by LC / MS. The reaction mixture was quenched with anhydrous MeOH (10 mL) and saturated Rochelle's salt (30 mL) at −78° C., and the resulting mixture was warmed to room temperature. The reaction mixture was then diluted with EtOAc (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (2×30 mL), then dried over anhydrous NaSO, filtered, and concentrated to give the title compound, which was used directly in the next step without further purification. LRMS m / z: (M+H)+ calculated 305.1; found 305.1.

[0213] 1 H NMR (400 MHz, chloroform-d) δ 9.55 (s, 1H), 7.39-7.27 (m, 5H), 7.26-7.13 (m, 1H), 6.21 (s, 1H), 5.21-5.00 (m, 2H), 4.61-4.17 (m, 1H), 3.79-3.65 (m, 1H), 2.58 (t, J = 8.0 Hz, 1H), 2.05-1.83 (m, 4H), 1.20-1.06 (m, 3H).

[0214] [ka] Step 2: Benzyl ((2S)-1-cyano-1-hydroxy-3-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate To a stirred solution of benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3-oxopropan-2-yl)carbamate (2 g, 6.57 mmol) and ZnI (1.049 g, 3.29 mmol) in n-hexane (20 mL), TMS-CN (1.057 mL, 7.89 mmol) was added, and the mixture was stirred at 25 °C for 16 h. LC / MS was then performed. The reaction mixture was acidified to pH = 4-5 with 1 M HCl, and the mixture was stirred at 25 °C for 1 h. The mixture was then adjusted to approximately pH = 9 with saturated sodium bicarbonate. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent of 100% ethyl acetate / pet., ether gradient @ 500 mL / min). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 332.1; found 332.1.

[0215] [ka] Step 3: Methyl (3S)-3-amino-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanoate hydrochloride To a mixture of benzyl ((2S)-1-cyano-1-hydroxy-3-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)propan-2-yl)carbamate (1.1 g, 3.32 mmol) in MeOH (5 mL) was added 4 M HCl / MeOH (10 mL) at 25° C., and the resulting mixture was stirred at 50° C. for 16 hours. LC / MS analysis was then performed. The reaction mixture was then concentrated. The resulting residue was purified by RP-HPLC (column: YMC-Actus Triart C18 150*30 mm*5 μm, conditioned water (0.1% TFA)-ACN start B0 end B20 gradient time (min) 11.5 100% B retention time 1 flow rate (mL / min) 40). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 231.1; found 231.1.

[0216] 1 H NMR(400MHz,MeOD)δ 4.54-4.23(m,1H),3.83-3.75(m,3H),3.75-3.57(m,1H),3.54-3.36(m,1H), 2.92-2.60(m,1H),2.03-1.93(m,2H),1.92-1.62(m,2H),1.38-1.30(m,3H).

[0217] [ka] Step 4: Methyl (3S)-3-(5-chloro-2-(4,4,4-trifluorobutanamido)benzamido)-2-hydroxy-4-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanoate To a vial was added 5-chloro-2-(4,4,4-trifluorobutanamido)benzoic acid (100 mg, 0.338 mmol) and 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (169 mg, 0.507 mmol) in DMF (5 mL). The mixture was stirred at 45° C. for 16 hours. Methyl (3S)-3-amino-2-hydroxy-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanoate (101 mg, 0.440 mmol) and DIEA (0.177 mL, 1.015 mmol) were then added to the mixture. The mixture was stirred at 45° C. for 16 hours, after which LC / MS analysis was performed. Water (0.5 mL) was added to the mixture, and then the mixture was purified by RP-HPLC (Column: Welch Xtimate C18 150*25 mm*5 μm, Condition: Water (0.1% TFA)-ACN Start B32 End B62 Gradient time (min) 11 100% B Retention time 2 Flow rate (mL / min) 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H)+ calculated 508.1; Found 508.1.

[0218] [ka] Step 5: (3S)-3-(5-chloro-2-(4,4,4-trifluorobutanamido)benzamido)-2-hydroxy-4-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanoic acid To a solution of methyl (3S)-3-(5-chloro-2-(4,4,4-trifluorobutanamido)benzamido)-2-hydroxy-4-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanoate (20 mg, 0.039 mmol) in THF (1 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (3.30 mg, 0.079 mmol), and the reaction mixture was stirred at 25 °C for 2 h, followed by LC / MS. The mixture was then concentrated, and the residue was acidified with 1 M HCl to pH = 4-5, and then extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give the title compound, which was used without further purification. LRMS m / z: (M+H)+ calculated 494.1; found 494.1.

[0219] [ka] Step 6: N-((2S)-4-(benzylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-5-chloro-2-(4,4,4-trifluorobutanamido)benzamide To a solution of (3S)-3-(5-chloro-2-(4,4,4-trifluorobutanamido)benzamido)-2-hydroxy-4-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanoic acid (15 mg, 0.030 mmol) and phenylmethanamine (3.58 mg, 0.033 mmol) in DMF (1 mL) was added AOP (16.16 mg, 0.036 mmol) and DIEA (10.61 μL, 0.061 mmol) at 25° C., followed by LC / MS. After stirring at 25° C. for 16 h, water (0.5 mL) was added to the reaction mixture. The mixture was then purified by RP-HPLC (column: Welch Xtimate C18 150*25mm*5μm, condition: water (0.1% TFA)-ACN start B33 end B63 gradient time (min) 11 100% B retention time 2 flow rate (mL / min) 25) to give the title compound. LRMS m / z: (M+H)+ calculated 583.1; found 583.2.

[0220] [ka] Step 7: N-((S)-4-(benzylamino)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobutan-2-yl)-5-chloro-2-(4,4,4-trifluorobutanamido)benzamide A mixture of N-((2S)-4-(benzylamino)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutan-2-yl)-5-chloro-2-(4,4,4-trifluorobutanamido)benzamide (10 mg, 0.017 mmol), sodium bicarbonate (4.32 mg, 0.051 mmol), and DMP (21.83 mg, 0.051 mmol) in DCM (1 mL) was stirred at 25 °C for 1 h, followed by LC / MS. The reaction mixture was then diluted with DCM and quenched with saturated NaSO (4 mL) and saturated NaHCO (4 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated. The resulting residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® silica flash column, eluent: 50-100% ethyl acetate / pet., ether gradient @ 500 mL / min). The desired fractions were concentrated and then repurified by RP-HPLC (Column: Welch Xtimate C18 150*25 mm*5 μm, Condition: Water (0.1% TFA)-ACN Start B35 End B65 Gradient Time (min) 11 100% B Retention Time 2 Flow Rate (mL / min) 25) to give the title compound. LRMS m / z: (M+H)+ calculated 581.1; Found 581.3.

[0221] 1 H NMR(400MHz,MeOD)δ 8.45-8.13(m,1H),7.83-7.65(m,1H),7.54-7.44(m,1H),7.38-7.00(m,5H),5.52-5.02(m,1H),4.53-4.36(m,2) H),3.77(s,1H),2.71-2.63(m,2H),2.56(d,J=10.5Hz,2H),2.08-1.99(m,2H),1.34(s,3H),1.24-1.14(m,3H).

[0222] The following examples were prepared according to similar methods as above. [Table 1] TIFF0007744536000076.tif228153TIFF0007744536000077.tif228153TIFF0007744536000078.tif210154TIFF0007744536000079.tif219151TIFF0007744536000080.tif219153TIFF0007744536000081.tif224153TIFF0007744536000082.tif213153TIFF0007744536000083.tif215153TIFF0007744536000084.tif212154TIFF0007744536000085.tif219153TIFF0007744536000086.tif224153TIFF0007744536000087.tif219153TIFF0007744536000088.tif220153TIFF0007744536000089.tif231153TIFF0007744536000090.tif223153TIFF0007744536000091.tif215154TIFF0007744536000092.tif228154TIFF0007744536000093.tif223153TIFF0007744536000094.tif230156TIFF0007744536000095.tif235154TIFF0007744536000096.tif203153TIFF0007744536000097.tif232154TIFF0007744536000098.tif208153TIFF0007744536000099.tif233153TIFF0007744536000100.tif232153TIFF0007744536000101.tif211155TIFF0007744536000102.tif233154TIFF0007744536000103.tif237155TIFF0007744536000104.tif220154TIFF0007744536000105.tif232154TIFF0007744536000106.tif207153TIFF0007744536000107.tif219153TIFF0007744536000108.tif211153TIFF0007744536000109.tif212154TIFF0007744536000110.tif211153T IFF0007744536000111.tif232153TIFF0007744536000112.tif232152TIFF0007744 536000113.tif228154TIFF0007744536000114.tif232154TIFF0007744536000115. tif233153TIFF0007744536000116.tif220153TIFF0007744536000117.tif130166.

[0223] SARS2 coronavirus 3CL protease assay The enzymatic activity of SARS2 coronavirus 3CL protease was determined using a FRET (fluorescence resonance energy transfer)-based assay measuring the cleavage of a peptide substrate by recombinantly expressed and purified enzyme. Cleavage of the peptide SEQ ID NO:1 (CPC Scientific) by SARS2 3CL protease was measured in reaction buffer (50 mM Hepes pH 7.5, 0.01% Triton X-100, 0.01% BSA, 2 mM DTT). SARS2 3CL protease (final concentration 5 nM) was preincubated with compound for 30 minutes before initiating the reaction with the peptide substrate (final concentration 15 μM). Room temperature reactions (4 hours) were quenched by the addition of a high dose of inhibitor and read on an appropriate plate reader (excitation wavelength = 495 nm, emission wavelength = 520 nm). Data were analyzed using a standard four-parameter fit to determine IC values. 50 value was determined.

[0224] Compounds of the invention were tested in the above assays and the results are shown in the table below. [Table 2] TIFF0007744536000119.tif234153TIFF0007744536000120.tif233153TIFF0007744536000121.tif233152TIFF0007744536000122.tif233153TIFF0007744536000123.tif234151TIFF0007744536000124.tif148156

Claims

1. The group consisting of: 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, 2-[[3,5-bis(trifluoromethyl)benzoyl]amino]-5-cyano-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]amino]pyridine-3-carboxamide, isopropyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(2,2-difluoro-3-phenyl-propanoyl)amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[(1R)-2,2-difluorocyclopropanecarbonyl]amino]benzamide, methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-5-fluoro-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-cyano-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, 5-chloro-2-[(2,2-difluorocyclopropanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3,3,3-trifluoro-2,2-dimethyl-propanoyl)amino]benzamide, 5-chloro-2-[(3,3-difluorocyclopentanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, N-[4-cyano-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide, 5-(difluoromethoxy)-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3,3,3-trifluoro-2-methyl-propanoyl)amino]benzamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-(difluoromethoxy)-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, 5-chloro-2-[(3,3-difluorocyclobutanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]pyridine-3-carboxamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3,3-difluorocyclobutanecarbonyl)amino]-5-fluoro-pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3,3,3-trifluoro-2-methyl-propanoyl)amino]benzamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-fluoro-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-2-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)amino]pyridine-3-carboxamide, 5-fluoro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, isopropyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-cyano-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3-fluorobenzoyl)amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-4-fluoro-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(trifluoromethyl)cyclobutanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[1-(2,2,2-trifluoroethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-(3,3,3-trifluoropropanoylamino)benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(4,4-difluorocyclohexanecarbonyl)amino]pyridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-2-carboxamide, 5-chloro-2-[(3,3-difluorocyclobutanecarbonyl)amino]-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl]methyl]propyl]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(3,3,3-trifluoropropanoylamino)benzamide, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl]methyl]propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-(difluoromethyl)-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, N-[(1S)-3-amino-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-chloro-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4,5-difluoro-phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, 5-chloro-2-[(3-fluorobicyclo[1.1.1]pentane-1-carbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[(2,2,2-trifluoroacetyl)amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(4,4,4-trifluorobutanoylamino)pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-4-fluoro-2-(4,4,4-trifluorobutanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyridine-2-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-4-fluoro-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-2-[(4-fluorobenzoyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3-fluorobenzoyl)amino]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3,3-difluorocyclobutanecarbonyl)amino]benzamide, 5-chloro-2-[(2,2-difluorocyclopropanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-cyano-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(2,2,2-trifluoroethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[(3,3-difluorocyclobutanecarbonyl)amino]benzamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-(trifluoromethyl)-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, 5-chloro-2-[(3,3-difluorocyclopentanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-fluoro-2-[[3-(trifluoromethyl)benzoyl]amino]pyridine-3-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3R,5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide, 5-(difluoromethyl)-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-4-(trifluoromethyl)pyridine-2-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(3-fluorobenzoyl)amino]benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4-fluoro-phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-fluoro-2-[[3-(trifluoromethyl)benzoyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]-5-fluoro-phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide, N-[2,4-dichloro-6-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]spiro[2.2]pentane-2-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]spiro[2.2]pentane-2-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-4-(trifluoromethyl)pyridine-2-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-5-fluoro-phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, 5-cyano-N-[3-(methylamino)-2,3-dioxo-1-[[(5S)-2-oxo-5-(trifluoromethyl)pyrrolidin-3-yl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(2-thiazol-4-ylpropanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(difluoromethyl)pyridine-4-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(2-thiazol-4-ylpropanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide, N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-5-(trifluoromethyl)-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, isopropyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4,5-difluoro-phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-3-carboxamide, methyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropyl(4-chloro-2-(((S)-4-(methylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)phenyl)carbamate, cyclopropyl(4-chloro-2-(((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-3,4-dioxobutan-2-yl)carbamoyl)phenyl)carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, methyl N-[2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, methyl N-[2-[[(1S)-3-amino-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4-chloro-phenyl]carbamate, trideuteriomethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, methyl N-[4,5-difluoro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-2-(cyclopropanecarbonylamino)-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]benzamide, ethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, trideuteriomethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[6-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-3-pyridyl]carbamate, 5-chloro-N-[(1S)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-3-(4-pyridylmethylamino)propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-N-[(1S)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-3-(1H-1,2,4-triazol-3-ylmethylamino)propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-N-[(1S)-3-(2-hydroxyethylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, methyl N-[6-chloro-4-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-3-pyridyl]carbamate, methyl N-[5-chloro-3-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-2-pyridyl]carbamate, methyl N-[4,5-difluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropyl N-[4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-2-(cyclopropanecarbonylamino)-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, methyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, trideuteriomethyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(2-methylpropanoylamino)benzamide, 5-chloro-2-(2,2-dimethylpropanoylamino)-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]benzamide, cyclopropyl N-[4,5-difluoro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, isopropyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, ethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[4-(difluoromethyl)-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropyl N-[4-cyano-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[4-chloro-5-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[4-chloro-2-fluoro-6-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, methyl N-[5-chloro-4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]oxetane-3-carboxamide, cyclopropylmethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, cyclobutyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, (1-methylcyclopropyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, ethyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, cyclopropyl N-[5-chloro-3-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-2-pyridyl]carbamate, cyclopropyl N-[4,5-difluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, tert-butyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-2-[[(1R)-2,2-difluorocyclopropanecarbonyl]amino]-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]benzamide, methyl N-[4,5-dichloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-2-(cyclopropanecarbonylamino)-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, cyclopropyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(2-methylpropanoylamino)benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(dimethylcarbamoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-1-methyl-azetidine-3-carboxamide, cyclopropyl N-[2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]-4,5-difluoro-phenyl]carbamate, cyclobutyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropylmethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, tert-butyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropyl N-[4-chloro-5-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclopropyl N-[5-chloro-4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (2,2-difluorocyclopropyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, (2,2-difluorocyclopropyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, N-[(1S)-3-amino-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-chloro-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, cyclopropyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, cyclobutyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, cyclopropylmethyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 2,2,2-trifluoroethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[(2R)-2-methoxypropanoyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(2-hydroxy-2-methyl-propanoyl)amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[(2S)-2-methoxypropanoyl]amino]benzamide, cyclopentyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[(1R)-2,2-difluorocyclopropanecarbonyl]amino]benzamide, cyclopropyl N-[2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4-(trifluoromethyl)phenyl]carbamate, cyclopropyl N-[4,5-dichloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (2,2-difluorocyclopropyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (2,2-difluorocyclopropyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (3,3-difluorocyclobutyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, benzyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[(2,2,2-trifluoroacetyl)amino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-(2-thiazol-4-ylpropanoylamino)benzamide, (2,2,2-trifluoro-1-methyl-ethyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 2,2,2-trifluoroethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (5S)—N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-methyl-2-oxo-oxazolidine-5-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-cyano-pyridine-3-carboxamide, 5-chloro-2-[(2,2-difluorocyclopentanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-2-[(2,2-difluorocyclopentanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, (2,2-difluorocyclopropyl)methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (2,2-difluorocyclopropyl)methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (3,3-difluorocyclobutyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, 2,2,2-trifluoroethyl N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]tetrahydropyran-4-carboxamide, (5S)—N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-oxo-oxazolidine-5-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]morpholine-4-carboxamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-(2-thiazol-4-ylpropanoylamino)benzamide, N-[4-fluoro-2-[[(1S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, 5-chloro-2-[(4,4-difluorocyclohexanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-2-[(3,3-difluorocyclohexanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, 5-chloro-2-[(3,3-difluorocyclohexanecarbonyl)amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]benzamide, (3,3-difluorocyclopentyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (3,3-difluorocyclopentyl)N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxopyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(2,2,2-trifluoroethyl)cyclopropanecarbonyl]amino]benzamide, 5-(difluoromethyl)-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, (5S)—N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-methyl-2-oxo-oxazolidine-5-carboxamide, (5R)-N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-3-methyl-2-oxo-oxazolidine-5-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-6-fluoro-phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide, N-[4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[2-[[(1S)-3-amino-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4-chloro-phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[(2R)-4,4,4-trifluoro-2-methyl-butanoyl]amino]benzamide, (2,2,2-trifluoro-1-methyl-ethyl)N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (2,2,2-trifluoro-1-methyl-ethyl)N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (4S)—N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-1,3-dimethyl-2-oxo-imidazolidine-4-carboxamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-3-fluoro-2-(4,4,4-trifluorobutanoylamino)benzamide, 5-chloro-4-fluoro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[[1-(2,2,2-trifluoroethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyrimidine-5-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-4-(trifluoromethyl)pyrimidine-2-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyrimidine-2-carboxamide, (3,3-difluorocyclohexyl)methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, (3,3-difluorocyclohexyl)methyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5-(difluoromethyl)-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]benzamide, methyl N-[(1S)-1-[[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamoyl]-2,2-dimethyl-propyl]-N-methyl-carbamate, N-[4-(difluoromethyl)-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-5-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide, N-[4-chloro-2-fluoro-6-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyrazine-2-carboxamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[2-[2-(trifluoromethyl)-4-pyridyl]propanoylamino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[2-[2-(trifluoromethyl)-4-pyridyl]propanoylamino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[2-[6-(trifluoromethyl)-3-pyridyl]propanoylamino]benzamide, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-2-[2-[6-(trifluoromethyl)-3-pyridyl]propanoylamino]benzamide, N-[2,4-dichloro-6-[[(1S)-3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-4-(difluoromethyl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]-3,4,5-trifluoro-phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide, and 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide or a pharmaceutically acceptable salt thereof.

2. The group consisting of: 【Chemistry 3】 【change】 or a pharmaceutically acceptable salt thereof.

3. 3. A pharmaceutical composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. 4. The pharmaceutical composition of claim 3 in the form of an orally administered tablet or capsule.

5. 4. The pharmaceutical composition of claim 3, further comprising one or more additional therapeutic agents.

6. 6. The pharmaceutical composition of claim 5, wherein the one or more additional therapeutic agents are selected from molnupiravir, pomotrervir, ensitrervir, nilmatrervir, and ritonavir.

7. The pharmaceutical composition according to claim 3 for the prevention or treatment of coronavirus infections.

8. 8. The pharmaceutical composition of claim 7, wherein the coronavirus infection is SARS-CoV, SARS-CoV-2 or MERS-CoV infection.

9. The pharmaceutical composition of claim 8, wherein the coronavirus infection is SARS-CoV-2 infection.

10. 8. The pharmaceutical composition of claim 7, used in combination with one or more additional therapeutic agents.

11. 11. The pharmaceutical composition of claim 10, wherein the one or more additional therapeutic agents are selected from molnupiravir, pomotrervir, ensitrervir, nilmatrervir, and ritonavir.

12. 10. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of coronavirus infection.

13. The use according to claim 12, wherein the coronavirus infection is a SARS-CoV, SARS-CoV-2 or MERS-CoV infection.

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