2-amino-n-(4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)buthane-2-yl)benzamido derivative for treating or preventing corona virus infection as protease inhibitor

Abstract

To provide a compound for treating or preventing coronavirus infection.SOLUTION: This invention provides compounds of formula I, a pharmaceutical composition containing one or more of the aforementioned compounds, and methods for use of the compounds for treating, inhibiting, or improving one or more disease conditions 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 be further used in combination with other therapeutically effective agents, including but not limited to other drugs useful for the treatment of coronavirus infections. This invention further provides a process for preparing compounds of formula I, as well as pharmaceutical compositions containing compounds of formula I and their pharmaceutically acceptable salts.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] Coronaviruses (CoVs) are classified into the Coronavirinae subfamily. The Nirovirales order includes the Niloviridae family. CoVs are large enveloped, positive-stranded RNA viruses. CoVs are further divided into four genera: Facoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus They are classified as viruses. Alpha and beta CoVs infect humans and other mammals. However, gamma and delta CoVs only infect animals (e.g., birds, marine mammals, and pigs). CoV infections can cause a wide range of acute and chronic respiratory, intestinal and central nervous system diseases. Fields Virology Emerging Viruses Vol. l.1.2021.pp.410-412).

[0003] To date, seven different coronaviruses that cause disease in humans: HCoV- 229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, Severe acute illness SARS-CoV, Middle East Respiratory Syndrome Coronavirus (M ERS-CoV), and most recently SARS-CoV-2 have been identified. V-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1 circulate annually and cause mild symptoms similar to the common cold (Forni D, Caglia ni 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 in the past 21 years, are ultimately associated with mild to severe symptoms of respiratory infections such as fever, cough, dyspnea, pneumonia, and acute respiratory distress syndrome that can lead to death.

[0004] The 2002 - 2003 SARS-CoV epidemic was included, resulting in 8,000 cases of SARS-CoV infection and over 800 deaths ([[]]END]] Fields Virology Emerging Viruses Vol. 1.2 021. pp. 438). The camel - human zoonosis of MERS-CoV occurred in Saudi Arabia in 2012. Human - to - human transmission has been recorded, but most de novo infections occur as a result of camel - human interactions, and the outbreaks are generally localized to the Arabian Peninsula (Zaki AM, van Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus A, Fou chier RAM. 2012 N Engl J Med 367:1814 - 182 0). The fatality rate of MERS infection is approximately 36% (http: / / www.who.in t / csr / don / 16 - october - 2014 - mers / en / ). COVI SARS-CoV-2, the pandemic strain responsible for D-19, has a bat origin and the 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 and as of December 2021, it has caused a global health and economic crisis and the death toll worldwide has exceeded 5 million (JHU CSSE COVID-19 Da ta https: / / github.com / CSSEGISandData / COV ID-19). Given that these three zoonotic events are well-characterized and the potential for future spillover events due to novel CoVs, there is a strong emphasis on 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 any future emerging CoVs. CoV particles consist of a lipid membrane derived from the cell containing the structural proteins spike (S), membrane (M), envelope (E) and nucleocapsid (N) (Fields Virology Emerging Viruses Vol.1 2021 pp.416- 417). The virion is also 5’-capped like cellular mRNA and contains a large (25-32 kb) non-segmented positive-sense single-stranded viral RNA genome with 5’ and 3’ untranslated regions (UTRs) as well as a 3’ polyadenylated tail. All CoV viral

[0005] genomes contain six basic common genes: the polyprotein replicase transcription complex (RTC ​​​​​​​ encoding two polypeptides that make up the non-structural protein (nsp) that forms two long open reading frames (1a and 1b) and four open reading frames for the structural proteins S, M, E, and N that make up the virion. Depending on the CoV, one to eight additional genes called accessory genes can be encoded within the genome. The genomic organization among all CoVs is conserved and invariant across different genera such that the gene order 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 the angiotensin-converting enzyme 2 (ACE-2) on cells of the upper respiratory tract (Lu R, Zhao X, Li J, et al. 2020. Lancet; 395(10224):565-574). Viral attachment is followed by either viral endocytosis and subsequent fusion of the viral and endosomal membranes, or direct fusion of the virus and cell plasma membrane at the cell surface, which releases the virion into the cytoplasm. After entry, the viral genomic RNA is not capped and functions 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 obtain individual replicase proteins is mediated by the viral papain-like protease (PLPro or nsp3) and the 3CL main Performed by (Mpro or nsp5). Nsp forms double-membrane vesicles and associates to Involved in genomic replication, synthesis of subgenomic RNA (sgRNA) and transcription of sgRNA Form an RTC. The sgRNA serves as a template for translation of mRNAs encoding structural and accessory proteins. Assembly of new virus particles occurs in the endoplasmic reticulum-Golgi intermediate complex, and mature particles are released via secretory vesicles.

[0007] To induce a defensive immune response, the S protein of SARS-CoV-2 is used as an antigen To develop vaccines for the prevention of COVID-19 (Kryikidis et.al. npj Vaccines 28(2021)6:28). mRNA / Lipid nanoparticles and vaccines based on replication-deficient adenovirus vector platforms Both have been demonstrated to be highly effective in preventing severe disease. However Data on the effectiveness of these vaccines against SARS-CoV-2 infection are limited. The problem with using the S protein for vaccine development is that the amino acid sequence Is highly variable, which allows SARS-CoV-2 to adapt to immune pressure (Che n RE et al. Nature Medicine. March 4,2021) Multiple independent spike mutations have been detected even in the absence of vaccine selection pressure, and several Variants may have reduced efficacy in vaccine clinical Trials conducted when those variants are circulating.

[0008] Considering the limitations of current vaccines and the zoonotic potential of new pandemic strains ​​​And there is an urgent need for broad-spectrum anti-coronavirus treatment regimens and preventive regimens. Against SARS-CoV, SARS-CoV-2, and the more distantly related MERS-CoV Anti-coronavirus interventions that are effective are expected to have broad-spectrum activity against both SARS-CoV-2 and future CoVs that may emerge via zoonosis.

Prior Art Documents

Non-Patent Documents

[0009]

Non-Patent Document 1

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Summary of the Invention

[0010] The present invention provides a compound of formula I:

Chemical Formula

[0011] The compounds of the present invention are useful, although not limited, for the treatment of coronavirus disease and can be further used in combination with other therapeutically effective agents (one or more additional therapeutic agents), such as other drugs. Such additional therapeutic agents can include molnupiravir, pomotrelvir , ensitrelvir, nirmatrelvir, and ritonavir. The present invention further relates to a process for preparing a compound of formula I, and a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable salt thereof.

Mode for Carrying Out the Invention

[0012] In one aspect, the present invention provides a compound of formula I:

Chemical Formula

[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 cyclo propyl.

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

[0015] In some embodiments of the present invention, the group R3 is

Chemical formula

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

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

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

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

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

[0021] In other embodiments of the present invention, A, B, and D are all C.

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

[0023] References to the specific classes and subclasses above, unless otherwise specified, are meant to include all combinations of specific preferred groups.

[0024] Certain 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 specific embodiments include the compounds listed below or pharmaceutically acceptable salts thereof: include: 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]ben zamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 [(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-prop yl]-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-car boxamide, 5-Chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-Methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]-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-prop yl]-2-[(2,2-difluoro-3-phenyl-propanoyl)amino]benz amide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]-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-diox o-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-[[(3 S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dio xo-propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pe ntane-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-prop yl]-2-[(3,3,3-trifluoro-2,2-dimethyl-propanoyl)ami no]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-[[(3 S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dio xo-propyl]carbamoyl]phenyl]-3-(trifluoromethyl)bicyclo[1 .1.1]pentane-1-carboxamide, 5-(difluoromethoxy)-N-[(1S)-3-(methylamino)-1-[[(3 S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dio xo-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]benzami de, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-meth yl-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- [[1-(Pyrrolidin-3-yl)methyl]-2,3-dioxopropyl]benzamide, 5-Chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxopyrrolidin-3-yl]methyl]-2,3-dioxoprop yl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino]pyr idine-3-carboxamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-meth yl-2-oxopyrrolidin-3-yl]methyl]-2,3-dioxopropyl]-2 -[(3,3-difluorocyclobutanecarbonyl)amino]-5-fluoro-pyridin e-3-carboxamide, 5-Chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5- methyl-2-oxopyrrolidin-3-yl]methyl]-2,3-dioxopropyl] -2-[(3,3,3-trifluoro-2-methyl-propanoyl)amino]benzami de, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-meth yl-2-oxopyrrolidin-3-yl]methyl]-2,3-dioxopropyl]-5 -fluoro-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]amino] benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R )-5-methyl-2-oxopyrrolidin-3-yl]methyl]-2,3-dioxoprop yl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-2-carbo xamide, 5-Chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-[5-Methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]-2-[(3-Fluorobicyclo[1.1.1]pentane-1-carbonyl)a mino]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-carbox amide, 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]carb amoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carbox amide, 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-p ropyl]-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-prop yl]-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]benzami de, 5-Chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]-2-[[1-(trifluoromethyl)cyclobutanecarbonyl]amino]benz zamide, 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]carb amoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxa mide, 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-prop yl]-2-[(4,4-difluorocyclohexanecarbonyl)amino]pyridine- 3-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 S,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-prop yl]-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]ben zeneamide, 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-p ropyl]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-p yrrolidin-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-propy l]carbamoyl]-4,5-difluoro-phenyl]-2-(trifluoromethyl)py ridine-4-carboxamide, 5-chloro-2-[(3-fluorobicyclo[1.1.1]pentane-1-carbonyl )amino]-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5-me [[2-Oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]pi ridine-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-prop yl]-2-(4,4,4-trifluorobutanoylamino)pyridine-3-carbox amide, 5-Chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]-4-fluoro-2-(4,4,4-trifluorobutanoylamino)benzamide , N-[4-Chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo -propyl]carbamoyl]phenyl]-3-fluoro-bicyclo[1.1.1]pe ntane-1-carboxamide, N-[4-Chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]carbamoyl]phenyl]-5-(trifluoromethyl)pyridine-2-carbox amide, 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-(me thylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-i 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-p ropyl]-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-p ropyl]-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-p ropyl]-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-p Ropilyl-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-pro pyl]-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 d N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 (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 d 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, 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, amide, 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 N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R )-[5-Methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-carbo xamide, N-[4-Chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-dio xo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carb amoyl]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-prop yl]carbamoyl]phenyl]-6-(trifluoromethyl)pyridine-3-carbo xamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)- 5-Methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]carbamoyl]-4-fluoro-phenyl]-2-(trifluoromethyl)pyridine -4-carboxamide, N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-meth yl-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-dio xo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carb amoyl]-5-fluoro-phenyl]-5-(trifluoromethyl)pyridine-3-car boxamide, 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-(trif luoromethyl)cyclopropanecarbonyl]amino]benzamide, N-[4-Chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 (3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo -propyl]carbamoyl]phenyl]spiro[2.2]pentane-2-carboxa mide, N-[4-Chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 (3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo -propyl]carbamoyl]phenyl]spiro[2.2]pentane-2-carboxa mide, 5-Chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]be nzamide, 5-Chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop Ropilyl-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]benz amide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 (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-[[(3 (3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo propyl]carbamoyl]-5-fluoro-phenyl]-2-(trifluoromethyl yl)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-trifluorobutanoyl)aminobenzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]-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-prop Ropilyl]carbamoyl]phenyl]-5-(trifluoromethyl)pyridine-3-carbo xamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 S,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-prop ropyl]-2-(2-thiazol-4-ylpropanoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 S,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]pro pyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop Ropilyl-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]be nzamide, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-p ropilyl-2-[[2-(trifluoromethyl)cyclopropanecarbonyl]amino]be nzamide, N-[2-[[(1S)-3-(cyclopropylamino)-1-[[(3S,5R)- 5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]carbamoyl]-4,5-difluoro-phenyl]-5-(trifluoromethyl)pi ridine-3-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dio xo-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-dio xo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoy l)phenyl)carbamate, Cyclopropyl (4-chloro-2-(((S)-1-((3S,5R)-5-methyl- 2-oxopyrrolidin-3-yl)-4-(methylamino)-3,4-dioxobutane- 2-[(2-Iryl)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-[[(3 S,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 phenyl]-4-chloro-carbamate, Tritriuteriomethyl 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-(methyl amino)-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, Tritriomethylium N-[4-chloro-2-[[(1S)-3-(methylamino) -1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl] -2,3-dioxo-propyl]carbamoylphenyl]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)benzamylide(be nzamilde), 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-trifluorobutanoyl amino)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-(meth ylamino)-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, Tris(trimethyl) N-[4-chloro-2-[[(1S)-3-(cyclopropyl amino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]me thyl]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-i l]methyl]propyl]benzamide, cyclopropyl N-[4,5-difluoro-2-[[(1S)-3-(methylamino) -2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]pro pyl]carbamoyl]phenyl]carbamate, isopropyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3- dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]ca rbamoyl]phenyl]carbamate, ethyl N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S ,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-diox o-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-p ropyl]carbamoyl]phenyl]oxetane-3-carboxamide, Cyclopropylmethyl N-[4-chloro-2-[[(1S)-3-(methylamino)- 2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]pro pyl]carbamoyl]phenyl]carbamate, Cyclobutyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3- dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]ca Rubamoyl]phenyl]carbamate, (1-Methylcyclopropyl) N-[4-chloro-2-[[(1S)-3-(methylami no)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]meth yl]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]ami no]-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-(cyclo propylamino)-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]pro pyl]carbamoyl]phenyl]carbamate, 5-Chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-pro pyl]-2-(2-methylpropanoylamino)benzamide, 5-Chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-pro pyl]-2-(dimethylcarbamoylamino)benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-pro pyl]carbamoyl]phenyl]-1-methyl-azetidine-3-carboxamide, Cyclopropyl N-[2-[[(1S)-3-(cyclopropylamino)-2,3-di oxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]car bamoyl]-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-(methylami no)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]meth yl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, Cyclopropyl N-[5-chloro-4-fluoro-2-[[(1S)-3-(methylami no)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]meth yl]-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-i l]methyl]propyl]carbamoyl]phenyl]carbamate, (2,2-Difluorocyclopropyl)N-[4-chloro-2-[[(1S)-3-( methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-i l]methyl]propyl]carbamoyl]phenyl]carbamate, N-[(1S)-3-amino-1-[[(3S,5R)-5-methyl-2-oxo-pyr rolidin-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-tr ifluorobutanoylamino)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]pro pyl]carbamoyl]phenyl]carbamate, cyclopropylmethyl N-[4-chloro-2-[[(1S)-3-(cyclopropyl a mino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]meth yl]propyl]carbamoyl]phenyl]carbamate, 2,2,2-trifluoroethyl N-[4-chloro-2-[[(1S)-3-(methyl amino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]me thyl]propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-p Ropilyl]-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-p ropilyl]-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-p ropilyl]-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-[[(1 R)-2,2-difluorocyclopropanecarbonyl]amino]benzamide, Cyclopropyl N-[2-[[(1S)-3-(methylamino)-1-[[(3S,5 R)-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-(me (thylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl (]methyl]propyl]carbamoyl]phenyl]carbamate, Benzyl N-[4-chloro-2-[[(1S)-3-(methylamino)-2,3-dio xo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]carb amoyl]phenyl]carbamate, 5-Chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[( (3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[2-(trif luoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-Chloro-N-[(1S)-3-(methylamino)-2,3-dioxo-1-[[( (3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-2-[[2-(trif luoromethyl)cyclopropanecarbonyl]amino]benzamide, 5-Chloro-N-[(1S)-3-(cyclopropylamino)-1-[[(3S,5R )-[5-Methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]-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-[[(1 S)-3-(methylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrol idin-3-yl]methyl]propyl]carbamoyl]phenyl]carbamate, 2,2,2-Trifluoroethyl N-[4-chloro-2-[[(1S)-3-(methyl amino)-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-di oxo-propyl]carbamoyl]phenyl]-3-methyl-2-oxo-oxazolid ine-5-carboxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop [[Ropilyl]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-pyrrolidine -3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carb mart, (2,2-difluorocyclopropyl)methyl N-[4-chloro-2-[[(1S)- 3-(methylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidine -3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carb mart, (3,3-difluorocyclobutyl) N-[4-chloro-2-[[(1S)-3-(m thylamino)-1-[[(3S,5R)-5-methyl-2-oxo-pyrrolidine-3-yl methyl]-2,3-dioxo-propyl]carbamoyl]phenyl]carbamate, 5-chloro-N-[(1S)-3-(methylamino)-1-[[(3S,5R)-5- methyl-2-oxo-pyrrolidine-3-yl]methyl]-2,3-dioxo-propyl] -2-[[2-(Trifluoromethyl)cyclopropanecarbonyl]amino]benzamide do 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 do 2,2,2-trifluoroethyl N-[4-chloro-2-[[(1S)-3-(cyclo propylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3- yl]methyl]propyl]carbamoyl]phenyl]carbamate, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 S,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-[[(3 S,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-diox o-propyl]-2-[[1-(trifluoromethyl)cyclopropanecarbonyl]ami no]benzamide, (5S)-N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1 -[[(3S,5R)-5-methyl-2-oxopyrrolidin-3-yl]methyl]-2 ,3-dioxo-propyl]carbamoyl]phenyl]-3-methyl-2-oxo-ox azolidine-5-carboxamide, (5R)-N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1 -[[(3S,5R)-5-methyl-2-oxopyrrolidin-3-yl]methyl]-2 ,3-dioxo-propyl]carbamoyl]phenyl]-3-methyl-2-oxo-ox azolidine-5-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-1-[[(3 S,5R)-5-methyl-2-oxopyrrolidin-3-yl]methyl]-2,3-dio xo-propyl]carbamoyl]-6-fluoro-phenyl]-3-fluoro-bicyclo [1.1.1]pentane-1-carboxamide, N-[4-fluoro-2-[[(1S)-3-(methylamino)-1-[[(3S,5 R)-5-Methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo- propyl]carbamoyl]phenyl]-2-(trifluoromethyl)pyridine-4-car boxamide, 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-prop yl]-2-[[(2R)-4,4,4-trifluoro-2-methyl-butanoyl]a mino]benzamide, (2,2,2-Trifluoro-1-methyl-ethyl)N-[4-chloro-2-[[(1 S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]f enyl]carbamate, (2,2,2-Trifluoro-1-methyl-ethyl)N-[4-chloro-2-[[(1 S)-3-(cyclopropylamino)-1-[[(3S,5R)-5-methyl-2-oxo pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]carbamoyl]f enyl]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-prop yl]-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)cyclopropanecar bonyl]amino]benzamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]carbamoyl]phenyl]-2-(trifluoromethyl)pyrimidine-5-car boxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]carbamoyl]phenyl]-4-(trifluoromethyl)pyrimidine-2-car boxamide, N-[4-chloro-2-[[(1S)-3-(methylamino)-1-[[(3S,5R )-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-prop yl]carbamoyl]phenyl]-5-(trifluoromethyl)pyrimidine-2-car boxamide, (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]carb mart, (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]carb mart, N-[(1S)-3-(Cyclopropylamino)-1-[[(3S,5R)-5-meth yl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-dioxo-propyl]-5 -(Difluoromethyl)-2-[[1-(trifluoromethyl)cyclopropanecarbony l]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)pyrid ine-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-[[(3 S,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-[[(3 S,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]benz amide, 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]benz amide, 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]ben zamide, 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]ben zamide, N-[2,4-dichloro-6-[[(1S)-3-(methylamino)-1-[[(3S ,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]-2,3-diox o-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-prop yl]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-prop yl]carbamoyl]-3,4,5-trifluoro-phenyl]-2-(trifluoromethyl yl)pyridine-4-carboxamide, N-[4-chloro-2-[[(1S)-3-(cyclopropylamino)-2,3-diox o-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] TIFF2025097322000006.tif146158

[0027] The compound of formula I above or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier Pharmaceutical compositions comprising the bodies are also included within the scope of the present invention. The present invention also provides a pharmaceutical composition that is pharmacopoeial and / or pharmacopoeial. Any of the compounds specifically disclosed in this application, including carriers and pharma- ceutically acceptable salts thereof. These and other aspects of the invention are intended to encompass pharmaceutical compositions comprising the same. , as will become apparent from the teachings contained herein.

[0028] The present invention also provides a method for administering to a mammal a compound of the present invention in a pharma- ceutically acceptable carrier. Inhibition of coronavirus proteases, and prevention of coronavirus-induced Compositions for the treatment of diseases caused by coronaviruses, for the treatment of coronavirus infections and for the prevention of coronavirus infections These compositions may optionally contain other antiviral agents. adding the composition to blood, a blood product, or a mammalian organ to achieve inhibition of can be done.

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

[0030] The compounds 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 bases or organic bases and inorganic acids or organic acids. Salts of basic compounds included in the term "pharmaceutically acceptable salts" generally refer to non-toxic salts of the compounds of the present invention prepared by reacting the free base with a suitable organic acid or inorganic acid. Representative salts of the basic compounds of the present invention include, but are not limited to: acetate, ascorbate, adipate, alginate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, caprylate, carbonate, chloride, cyclopentanepropionate, diethylacetate, digluconate, dihydrochloride, dodecylsulfate, edetate, ectylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, Hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthoate Iodide, isonicotinic acid, isothionate, lactate, lactobionate, lauric acid Salt, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate Methyl sulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, naphthyl Salt, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, si Urate, pamoate (embonate), palmitate, pantothenate, pectinate Persulfate, phosphate / diphosphate, pimelic acid, phenylpropionic acid, polygalactu Ronate, propionate, salicylate, stearate, sulfate, basic acetate, co Succinate, tannate, tartrate, theocurate, thiocyanate, tosylate, tri Ethiodide, trifluoroacetate, undecenoate, valerate and the like. Further, when the compound of the present invention has an acidic moiety, suitable pharmaceutically acceptable salts thereof include salts derived from inorganic bases containing aluminum, ammonium, calcium, copper, ferric, ferrous, li Thium, magnesium, manganese, mangamous, potassium, sodium Lithium, zinc and the like, but are not limited thereto. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts Are also included. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, Secondary and tertiary amines, cyclic amines, dicyclohexylamine and basic ion exchange Resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylene And basic ion exchange resins, for example, arginine, betaine, caffeine, choline, N,N-dibenzylethylene Secondary and tertiary amines, cyclic amines, dicyclohexylamine and basic ion exchange Resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylene Methylamine, diethylamine, 2 - diethylaminoethanol, 2 - dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N - ethylmorpholine, N - ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, poly amine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Salts of agents such as lower halo alkylated alkyls such as methyl, ethyl, propyl and butyl chlorides, bromides, iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl; and diamyl sulfate , long - chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides and the like, and basic nitrogen - containing groups that can be quaternized are included. These salts can be obtained by known methods, for example, by mixing the compound of the present invention with an equivalent amount of a solution containing the desired acid, base, etc., and then collecting the desired salt by filtration of the salt or distillation of the solvent. The compounds of the present invention and their salts can form solvates with solvents such as water, ethanol or glycerol. The compounds of the present invention may simultaneously form salts of acid addition salts and bases depending on the type of substituents in the side chain. When the compound of formula I contains both an acidic group and a basic group in the molecule, the present invention includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned.

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

[0032] When the compound of formula I contains both an acidic group and a basic group in the molecule, the present invention includes inner salts or betaines (zwitterions) in addition to the salt forms mentioned.

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

[0034] Unless a specific enantiomer or diastereomer is indicated, the present invention encompasses all possible enantiomers and diastereomers as well as mixtures of two or more stereoisomers, for example mixtures of enantiomers and / or diastereomers in all ratios. Thus, enantiomers include enantiomerically pure forms as both the levorotatory and dextrorotatory enantiomers, racemic forms, and mixtures of the two enantiomers in all ratios. is the subject of the present invention in the form. In the case of cis / trans isomerism, the present invention includes both the cis form and the trans form, as well as mixtures of all ratios of these forms. The preparation of the individual stereoisomers can, if desired, be carried out by conventional methods, such as chromatography or crystallization, by separation of the mixture, by use of a stereochemically homogeneous starting material for the synthesis, or by stereoselective synthesis. Optionally, derivatization can be carried out prior to the separation of the stereoisomers. The separation of the mixture of stereoisomers can be carried out at an intermediate stage during the synthesis of the compound of formula I or on the final racemic product. The absolute stereochemistry can be determined, if necessary, by X-ray crystallography of crystalline products or crystalline intermediates derivatized with reagents containing stereocenters of known configuration. If the compounds of the present invention are capable of tautomerization, all individual tautomers as well as 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 solvate salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof. In the compounds of the present invention, the atoms may assume their natural isotope abundances, or one or more of the atoms may be artificially enriched with a specific isotope having the same atomic number but a different atomic mass or mass number than that predominantly found in nature. The present invention is meant to include all suitable isotope variants of the specifically and generally described compounds. For example, different isotopic forms of hydrogen (H) include protium ( H) and deuterium ( (including hydrates) and solvate salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0035] In the compounds of the present invention, the atoms may assume their natural isotope abundances, or one or more of the atoms may be artificially enriched with a specific isotope having the same atomic number but a different atomic mass or mass number than that predominantly found in nature. The present invention is meant to include all suitable isotope variants of the specifically and generally described compounds. For example, different isotopic forms of hydrogen (H) include protium ( H) and deuterium ( H) 1 H) and deuterium ( 2It contains protium. Protium is the major hydrogen isotope found in nature. By enriching deuterium, certain therapeutic advantages (e.g., increased in vivo half-life or reduced required dose) may be obtained, or compounds useful as standards for characterizing biological samples may be obtained. Isotope-enriched compounds can be prepared 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 of this specification using appropriate isotope-enriched

[0036] reagents and / or intermediates, without undue experimentation. If any variable occurs more than once in any component, its definition at each occurrence is independent every other time. Also, combinations of substituents and variables are permitted only if such combinations result in stable compounds. A line drawn from a substituent to a ring system represents that the indicated bond may be attached to any of the ring atoms that are

[0037] substitutable. When the ring system is bicyclic, the bond is intended to be attached to any of the suitable atoms on either ring of the bicyclic moiety. It is understood that one or more silicon (Si) atoms can be incorporated into the compounds of the present invention by those skilled in the art in place of one or more carbon atoms to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art from etc. Those skilled in the art will understand that differences in size and shape can result in subtle or dramatic changes in efficacy, solubility, lack of off-target activity , packaging properties, etc. . (Diass, J.O. et al. Organometallics (2006) 5 :1188 - 1198; Showell, G.A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555 -2558).

[0038] The substituents and substitution patterns on the compounds of the present invention are chemically stable and can be easily synthesized by techniques known in the art, and the following methods can be selected by those skilled in the art to provide compounds that can be easily obtained starting materials. It is understood that when the substituent itself is substituted with two or more groups, 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) is to be understood to mean that the group in question may be unsubstituted or may be substituted with one or more substituents. It is understood that it can be selected by those skilled in the art. When the 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. It should be understood that the phrase "optionally substituted" (with one or more substituents) means that the group in question may be unsubstituted or may be 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 thus all amorphous and crystalline forms of the compounds of formula I and mixtures thereof are intended to be included within the scope of the present invention. Additionally, some of the compounds of the present invention may form hydrates (i.e., with water) or solvates with common organic solvents. Such solvates and hydrates of the present compounds, particularly pharmaceutically acceptable solvates and hydrates of the compounds are intended to be included within the scope of the present invention. Likewise, the solvate-free and anhydrous forms are included within the scope of the present invention.

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

[0041] Any pharmaceutically acceptable prodrug modification of the compounds of the present invention that results in an 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 be made, optionally, by esterification of available carboxylic acid groups or by formation of esters on available hydroxy groups in the compound. Similarly, labile amides can be made. Pharmaceutically acceptable esters or amides of the compounds of the present invention can be prepared to act as prodrugs that are hydrolyzed in vivo, particularly, to an acid (or -COO- depending on the pH of the fluid or tissue where the conversion occurs) or a hydroxy form and thus are included 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 with phenyl esters.

[0042] Accordingly, the general structural formulas, embodiments and specific Compounds within the compound include salts, all possible stereoisomers and tautomers, their physical forms (e.g., amorphous and crystalline forms), solvates and hydrates, and any combination of these forms, as well as salts thereof, prodrug forms thereof, and salts of such prodrug forms, such forms being possible unless otherwise specified.

[0043] The terms used herein have their ordinary meanings, and the meanings of such terms are independent at each occurrence thereof. 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 whether the 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 "alkyl" moieties such as "hydroxyalkyl", "haloalkyl", "-O-alkyl", etc.

[0044] As used herein and throughout the present disclosure, the following terms are understood to have the following meanings, unless otherwise indicated

[0045] "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 "treat" and "treating" can refer to any process that can slow, interrupt, prevent, control, or stop the progression of a disease or disorder described herein. These terms do not necessarily indicate complete elimination of all disease or disorder symptoms. As used herein, the terms "prevent" or "prevention" refer to reducing the likelihood of developing a disease or disorder described herein, or reducing the severity of a disease or disorder described herein. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "fluoroalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atoms of the alkyl group are replaced by fluorine. In one embodiment

[0047] As used herein, the terms "prevent" or "prevention" refer to reducing the likelihood of developing a disease or disorder described herein, or reducing the severity of a disease or disorder described herein. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "fluoroalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atoms of the alkyl group are replaced by fluorine. In one embodiment

[0048] As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted. As used herein, the term "alkyl" refers to an aliphatic hydrocarbon group in which one of its hydrogen atoms is optionally replaced by any bond. The alkyl group can be straight-chain or branched-chain and can contain from about 1 to about 20 carbon atoms. In one embodiment, the alkyl group contains from about 1 to about 12 carbon atoms. In different embodiments, the alkyl group contains 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, the alkyl group is straight-chain. In another embodiment, the alkyl group is branched-chain. Unless otherwise indicated, the alkyl group is unsubstituted.

[0049] As used herein, the term "fluoroalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atoms of the alkyl group are replaced by fluorine. In one embodiment As used herein, the term "fluoroalkyl" refers to an alkyl group as defined above in which one or more of the hydrogen atoms of the alkyl group are replaced by fluorine. In one embodiment In one form, the fluoroalkyl group has 1 to 6 carbon atoms. In another embodiment, the haloalkyl group is substituted with 1 to 3 F atoms. Non-limiting examples of the fluoroalkyl group include -CH2F, -CHF2, -CF3, and -CH2CF3. The term "C1-C6 fluoroalkyl" refers to a fluoroalkyl group having 1 to 6 carbon atoms.

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

[0051] The term "cycloalkyl" means 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 cyclo alkyl 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" includes stable bicyclic or tricyclic ring systems containing up to 10 atoms in each ring, with at least one ring being aromatic and all of the ring atoms being carbon. Bicyclic and tricyclic systems include fused ring systems in which two rings share two atoms, and spiro ring systems in which two rings share one atom.

[0053] As used herein, the term "heteroaryl" includes at least one aromatic ring, with at least one ring having 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Represents a stable monocyclic or bicyclic ring system of up to 10 atoms in each ring, containing an O atom. Bicyclic The fused heteroaryl ring systems include those in which two rings share two atoms, and spiro ring systems in which two rings share one atom. Heteroaryl groups within the scope of this definition include, but are not limited to: azaindolyl, benzimidazolyl benzisoxazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carb olinyl, cinnolinyl, dihydroindenyl, furanyl, indolinyl, indolyl, i ndolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, i sothiazolyl, isoxazolyl, naphthalenyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrazolopyrimidinyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, p puryl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl dihydroindolyl, dihydroquinolinyl, dihydrobenzodioxinyl, dihydropy razolooxazinyl, dihydropyrazolothiadiazinedioxidyl, methylenedioxybenzene benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, tetrahydroquinoline and 3-oxo-3,4-dihydro-2H-benzo[b][1,4 thiazine. When the heteroaryl contains a nitrogen atom, the corresponding N-oxide is also within this definition ​ It is understood to be included in the meaning.

[0054] As used herein, the terms "heterocycloalkyl", "heterocycle" or "heterocyclyl" ", unless otherwise specified, refer to a stable non-aromatic monocyclic ring or bicyclic ring system having up to 10 atoms in each ring, containing 1 to 4 heteroatoms selected from the group consisting of O, N, S, SO or SO2. In some embodiments, the heterocycloalkyl is 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, examples of "heterocycloalkyl" include, but are not limited to: azaspirononyl, azaspirooctanyl, azetidinyl, dioxanyl, oxazazaspirodecenyl, oxaspirooctanyl, oxazolidinonyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl, etc. When the heterocycle contains nitrogen, it is understood that the corresponding N-oxide

[0055] is also included in this definition. "Celite®" (Fluka) is diatomaceous earth and can be referred to as "celite".

[0056] The term "substituted" means that one or more hydrogens on the specified atom are replaced with a selected group from the indicated groups, provided that the substitution does not exceed the normal valence of the specified atom and results And / or combinations of variables are permitted only where such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to withstand isolation from a reaction mixture to a useful degree of purity and formulation into an effective therapeutic agent. The term "in a substantially purified form" as used herein 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 a substantially purified form" also refers to a compound in a physical state that can be characterized by standard analytical techniques described herein or known to those of skill in the art to a sufficient degree of purity after the compound 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. It should also be noted that in the text, schemes, examples and tables herein, any carbon and heteroatoms with unsatisfied valences are assumed to have a sufficient number of hydrogen atoms to satisfy the valences. When a functional group in a compound is referred to as "protected", this means that the group is in a modified form that prevents unwanted side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those of skill in the art, as well as by reference to standard textbooks such as T.W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0057] Combinations of variables are permitted only where such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to withstand isolation from a reaction mixture to a useful degree of purity and formulation into an effective therapeutic agent. The term "in a substantially purified form" as used herein 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 a substantially purified form" also refers to a compound in a physical state that can be characterized by standard analytical techniques described herein or known to those of skill in the art to a sufficient degree of purity after the compound 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. In the text, schemes, examples and tables herein, any carbon and heteroatoms with unsatisfied valences are assumed to have a sufficient number of hydrogen atoms to satisfy the valences. When a functional group in a compound is referred to as "protected", this means that the group is in a modified form that prevents unwanted side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those of skill in the art, as well as by reference to standard textbooks such as T.W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0058] In the text, schemes, examples and tables herein, any carbon and heteroatoms with unsatisfied valences are assumed to have a sufficient number of hydrogen atoms to satisfy the valences. It should also be noted that in the text, schemes, examples and tables herein, any carbon and heteroatoms with unsatisfied valences are assumed to have a sufficient number of hydrogen atoms to satisfy the valences. When a functional group in a compound is referred to as "protected", this means that the group is in a modified form that prevents unwanted side reactions at the protected site when the compound is subjected to a reaction.

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

[0060] If any substituent or variable (e.g., R2) occurs two or more times in any component or Formula I, unless otherwise indicated, its definition at each occurrence is independent of its definition at every other occurrence. As used herein, the term "composition" is intended to encompass a product containing the specified amount of the specified ingredients, as well as any product resulting from the combination of the specified ingredients in the specified amounts.

[0061] The present invention also relates to a pharmaceutical product comprising at least one compound of Formula I and / or a pharmaceutically acceptable salt of a compound of Formula I and / or an optionally 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 a pharmaceutically acceptable vehicle, additives and / or other active substances and adjuvants that are pharmaceutically elegant.

[0062] The term "patient" as used herein is to be interpreted as meaning mammals such as primates, humans, sheep, horses, cows, pigs, dogs, cats, rats, and mice. 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. The pharmaceutical product according to the present invention can be administered orally, by inhalation, rectally or transdermally, or subcutaneously, intramuscularly, intravenously, intranasally or by any other appropriate route.

[0063]

[0064]

[0065] intramuscularly, intravenously, intranasally or by any other suitable route. It can be administered by intrasegmental, intraperitoneal or intravenous injection. Oral administration is preferred. Coating of stents with the compounds of formula (I) and other surfaces in contact with the blood in the body is possible.

[0066] The present invention also uses pharmaceutically suitable and pharmaceutically acceptable carriers and optionally further suitable active substances, additives or adjuvants to convert at least one compound of formula (I) into a suitable dosage form, and relates to a process for manufacturing a pharmaceutical product.

[0067] Suitable solid or galenical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops, or injection solutions and preparations with long-term release of the active substance, and in the preparations thereof, customary excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, flow promoters or lubricants, flavorings, sweeteners and solubilizers are used. 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, cod liver oil, sunflower oil, peanut oil or sesame oil and other animal and vegetable oils, polyethylene glycol and solvents such as sterile water and monohydric or polyhydric alcohols such as glycerol.

[0068] The dosing regimen using the protease inhibitor of the present invention depends on the patient type, species, age, body weight, gender and medical condition, the severity of the condition being treated, the route of administration, the patient's renal and hepatic functions, It is selected according to various factors, such as the specific compound used or its salt. A physician or veterinarian skilled in the art can readily determine and prescribe an effective amount of the drug necessary to prevent, counteract, or arrest the progression of the condition.

[0069] When used for the indicated effect, the oral dosage of the protease inhibitor is in the range of about 0.01 mg / kg body weight / day (mg / kg / day) to about 30 mg / kg / day, such as 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 (unless otherwise specified, the amount of the active ingredient is on a free base basis). For example, an 80 kg patient will receive from about 0.8 mg / day to 2.4 g / day, such as 0.8 - 1600 mg / day, 0.8 - 1200 mg / day, 0.8 - 800 mg / kg / day or 0.8 - 400 mg / day. Thus, a pharmaceutically suitable preparation for once-daily administration will contain 0.8 mg - 2.4 g, 0.8 mg - 1600 mg, 0.8 mg - 1 200 mg, 0.8 mg - 800 mg, or 0.8 mg - 400 mg, such as 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 can be administered in divided doses 2, 3 or 4 times a day. In the case of twice-daily administration, a pharmaceutically suitable preparation will contain 0.4 mg - 1.2 g, 0.4 mg - 800 mg, 0.4 mg - 600 mg, 0. 4 mg - 400 mg, or 0.4 mg - 200 mg, such as 0.5 mg, 2 mg, 4 m g, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 150 mg, or 200 mg.

[0070] Intravenously, the patient receives an amount of the active ingredient sufficient to deliver from 0.01 to 15 mg / kg / day, for example from 0.01 to 7.5 mg / k g / day or from 0.1 to 5 mg / kg / day. Such amounts can be administered in a plurality of suitable ways, for example, during a single long period or in several large doses of low concentration of the active ingredient per day, or during a short period, for example once a day, in a small amount of high concentration of the active ingredient. Glucuronic acid, L -lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid / conjugate base having a reasonable buffering capacity within the pH range acceptable for intravenous administration can be used as a buffer. The selection of the appropriate buffer and the pH of the formulation according to the solubility of the drug to be administered can be readily determined by those skilled in the art. The compounds of formula I can be administered as monotherapy and in combination with additional therapeutic agents (also referred to herein as "second therapeutic agents"), such as other antiviral drugs or the treatment of coronavirus infection etc. The protease inhibitors of the present invention can also be used in combination with agents that inhibit viral replication, such as nucleoside polymerase inhibitors, agents that induce viral error catastrophe proteases, eEF1A inhibitors, androgen receptor antagonists, dihydroorotate dehydrogenase (DHODH) inhibitors, sphingosine kinase inhibitors, MEK inhibitors,

[0071] suitable antiviral drugs including, but not limited to, antimalarial drugs, CCR5 inhibitors, PIKfyve kinase inhibitors, serine protease inhibitors and glycosylation inhibitors. In the class of the present invention, the protease inhibitors of the present invention are nucleo side

[0072] The protease inhibitors 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 proteases, eEF1A inhibitors, androgen receptor antagonists, dihydroorotate dehydrogenase (DHODH) inhibitors, sphingosine kinase inhibitors, MEK inhibitors, antimalarial drugs, CCR5 inhibitors, PIKfyve kinase inhibitors, serine protease inhibitors and glycosylation inhibitors. In the class of the present invention, the protease inhibitors of the present invention are nucleo side side ​​​It can be co-administered with a sid polymerase inhibitor, a protease inhibitor, or a combination thereof. One of ordinary skill in the art will recognize that such antiviral drugs may in some cases be co-administered as prodrugs.

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

[0074] Protease inhibitors that can be co-administered with the protease inhibitor of the present invention include, but are not limited to, camostat mesylate, upamostat, SLV213, PF-00 83523, CDI-45205, ALG-097111, GC-376, and TJC- 0642.

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

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

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

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

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

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

[0081] Examples of antimalarial drugs that can be co-administered with the protease inhibitor of the present invention include, but are not limited to, tafenoquine (ARAKODA).

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

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

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

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

[0086] Alternatively or additionally, one or more further pharmacologically active agents may be co-formulated with the compounds of the present invention The combination may be administered. One or more additional active agents may be converted to a pharma- ceutical active form after administration. It is intended to mean one or more pharmacologic active agents that are active in the body, such as prodrugs that , which are different from the compounds of the present invention, and such forms are either commercially available or or, where chemically possible, the free acid, free base and pharma- ceutically acceptable salts of the additional active agent. In general, the present invention includes, but is not limited to, polymerase nucleoside inhibitors, Protease inhibitors, agents that induce viral error catastrophe, eEF1A inhibition Agents, androgen receptor antagonists, dihydroorotate dehydrogenase (DHODH) inhibitors agents, sphingosine kinase inhibitors, MEK inhibitors, antimalarials, CCR5 inhibitors, P IKfyve kinase inhibitors, serine protease inhibitors and glycosylation inhibitors, etc. Any suitable one or more additional active agents may be administered in a single dosage formulation (fixed dose drug combination). Any combination of the compounds of the present invention may be used or the active agent may be administered simultaneously. or one or more separate dosage formulations that allow for sequential administration (simultaneous administration of separate active agents) It can be administered to a patient.

[0087] Other suitable polymerase nucleoside inhibitors, protease inhibitors, viral error inhibitors Agents that induce tastrophe, eEF1A inhibitors, androgen receptor antagonists, dihydrones Orotic acid dehydrogenase (DHODH) inhibitors, sphingosine kinase inhibitors, M EK inhibitors, antimalarials, CCR5 inhibitors, PIKfyve kinase inhibitors, serine protease inhibitors Protease Inhibitors of the Invention in Combination with Protease Inhibitors and Glycosylation Inhibitors Typical doses of 100 mg / kg / day may include additional polymerase nucleoside inhibitors depending on the therapeutic needs of the patient. A pesticidal agent, a protease inhibitor, an agent that induces viral error catastrophe, eEF1 A inhibitor, an androgen receptor antagonist, dihydroorotate dehydrogenase (DHODH ) inhibitor, a sphingosine kinase inhibitor, a MEK inhibitor, an antimalarial agent, a CCR5 inhibitor An agent, a PIKfyve kinase inhibitor, a serine protease inhibitor, and a glycosylation inhibitor Can be the same as the dose administered without co-administration of the agent, or a polymerase nucleoside Inhibitor, a protease inhibitor, an agent that induces viral catastrophe, an eEF1A inhibitor An agent, an androgen receptor antagonist, dihydroorotate dehydrogenase (DHODH) inhibitor An agent, a sphingosine kinase inhibitor, a MEK inhibitor, an antimalarial agent, a CCR5 inhibitor, A PIKfyve kinase inhibitor, a serine protease inhibitor, and a glycosylation inhibitor Can be a dose substantially less than the dose of the protease inhibitor administered without co-administration.

[0088] The compound is administered to a mammal in a therapeutically effective amount. "Therapeutically effective amount" means an amount of the compound of the present 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 the progression of a disease in the host.

[0089] The compound of the present invention is preferably administered to a mammal alone in a therapeutically effective amount. However, the compound of the present invention can also be administered to a mammal 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 administered in combination ​​​​​​The effect of the compound when administered (in this case, inhibition of the desired target) is greater than the additive effect of each of the compounds, and a synergistic effect occurs when administered individually as a single agent, for example, as described in Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55. Generally, the synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compound. The synergistic effect can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of this combination compared to the individual components. When the effect of the compound when administered (in this case, inhibition of the desired target) is greater than the additive effect of each of the compounds, and a synergistic effect occurs when administered individually as a single agent, for example, as described in Chou and Talalay, Adv. Enzyme Regul. 1984, 22, 27-55. described in a synergistic effect occurs. Generally, the synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compound. The synergistic effect can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of this combination compared to the individual components. The synergistic effect can be in terms of lower cytotoxicity, increased anticoagulant effect, or some other beneficial effect of this combination compared to the individual components.

[0090] "Administered in combination" or "combination therapy" means that the compounds 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 can be administered sufficiently close in time to provide the desired therapeutic effect. 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 can be administered sufficiently close in time to provide the desired therapeutic effect. The present invention is not limited in scope by the specific embodiments disclosed in the examples which were intended as illustrations of some aspects of the invention, and any embodiments which are functionally equivalent are within the scope of the present 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.

[0091] The present invention is not limited in scope by the specific embodiments disclosed in the examples which were intended as illustrations of some aspects of the invention, and any embodiments which are functionally equivalent are within the scope of the present 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. 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. 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 Procedures Starting materials and intermediates were purchased or prepared using known procedures described in the chemical synthesis literature or otherwise described. The various procedures used herein The preparation of the starting materials is well within the skill of those in the art. The routes applicable to the synthesis of the compounds of Formula I are described in the following scheme. Optionally, the order of the reaction steps may be changed to facilitate the reaction or to avoid unwanted reaction products. Optionally, the final product may be further modified, for example, by manipulation of the substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions commonly known to those in the art. Since the scheme is illustrative, the present invention should not be construed as being limited by the chemical reactions and conditions shown. The examples described below are provided so that the present invention may be more fully understood. These examples are merely illustrative and should in no way be construed as limiting the present invention. The chiral centers in the compounds can be present in the S or R absolute configuration, or as a mixture of both. It is understood that within the molecule, each bond drawn as a straight line from the chiral center includes both the R and S stereoisomers and mixtures thereof. The asterisk indicates a stereocenter in either the R or S configuration. The absolute stereochemistry of the individual stereoisomers in the examples and intermediates is not determined unless otherwise specified in the examples or explicitly described in the nomenclature. The numbering of the substituents shown in the scheme does not necessarily correlate with that used in the claims, and in many cases, for clarity, only one substituent attached to the compound is shown, and multiple substituents are possible under the above definitions. The compounds of the present invention are produced

[0093]

[0094] ​​​​​​​​​​​​​​​The reactions used for this purpose are those known in the literature or as exemplified by experimental procedures. In addition to other standard operations such as ester hydrolysis, cleavage of protecting groups, etc., the reactions shown in the schemes and examples of this specification are carried out by using them.

[0095] Using anhydrous solvents and reagents, under nitrogen or argon, reactions highly sensitive to moisture or air were carried out. The progress of the reaction was determined by either liquid chromatography mass spectrometry (LCMS) or analytical thin-layer chromatography (TLC) commonly performed using Merck KGaA glass-backed TLC plates, silica gel 60F 254 used for this purpose.

[0096] Analytical LCMS generally involves electrospray ionization in positive ion detection mode using a Waters SQD single quadrupole mass spectrometer (set mass range 150 - 900 daltons, data collected in centroid mode, and set scan time 0.2 seconds) and a Waters Acquity UPLC system (binary solvent manager, sample manager , and TUV). The column used was a Waters Acquity BEH C18 1×50 mm, 1.7 μm heated to 50 °C. The mobile phase used was modified with acidic or basic additives. The acidic mobile phase consisted of 0.1% trifluoroacetic acid aqueous solution for solvent A and 100% acetonitrile for solvent B. The initial condition was 95% solvent A, and solvent B was increased to 99% in 1.60 minutes, and the implementation was established for 2 minutes at a flow rate of 0.3 ml / min while holding 99% of solvent B for 0.40 minutes. Using the partial loop needle overfill injection mode, the injection volume was 0.5 μL. TUV ​​​​In V, a sampling rate of 20 points / second, normal filter constants and absorbance data were monitored at wavelengths of 215 or 254 nm in absorbance mode. The basic mobile phase consisted of 0.1% aqueous ammonium hydroxide solution for solvent A and 100% acetonitrile for solvent B. The initial condition was 99% solvent A, which was increased to 99% solvent B in 1.90 minutes, held at 99% solvent B for 0.10 minutes, and then carried out for 2 minutes at a flow rate of 0.3 ml / min. The initial condition was set to 95% solvent A, solvent B was increased to 99% in 4.90 minutes, held at 99% solvent B for 0.10 minutes, and then carried out for 5 minutes at a flow rate of 0.3 ml / min. For both methods, the partial loop needle overfill injection mode was used, and the injection volume was 5.0 μL. In TUV, a sampling rate of 20 points / second, normal filter constants and absorbance data were monitored at a wavelength of 215 nm in absorbance mode. Alternatively, the system generally used was composed of a Waters ZQ (trademark) platform with electrospray ionization in positive ion detection mode using an Agilent 1100 series HPLC equipped with an autosampler. The column was generally Waters Xterra MS C18, 3.0×50 mm, 5 μm or Waters Acquity UPLC (registered trademark) BEH C18 1.0×50 mm, 1.7 μm. The flow rate was 1 mL / min and the injection volume was 10 μL. UV detection was in the range of 210 - 400 nm. The mobile phase was composed of solvent A (water + 0.05% TFA) and solvent B (MeCN + 0.05% TFA), with a gradient of 100% solvent A for 0.7 minutes, changed to 100% solvent B over 3.75 minutes, maintained for 1.1 minutes, and then changed back to solvent A over 0.2 minutes. were monitored. The basic mobile phase consisted of 0.1% aqueous ammonium hydroxide solution for solvent A and 100% acetonitrile for solvent B. The initial condition was 99% solvent A, which was increased to 99% solvent B in 1.90 minutes, held at 99% solvent B for 0.10 minutes, and then carried out for 2 minutes at a flow rate of 0.3 ml / min. The initial condition was set to 95% solvent A, solvent B was increased to 99% in 4.90 minutes, held at 99% solvent B for 0.10 minutes, and then carried out for 5 minutes at a flow rate of 0.3 ml / min. For both methods, the partial loop needle overfill injection mode was used, and the injection volume was 5.0 μL. In TUV, a sampling rate of 20 points / second, normal filter constants and absorbance data were monitored at a wavelength of 215 nm in absorbance mode. Alternatively, the system generally used was composed of a Waters ZQ (trademark) platform with electrospray ionization in positive ion detection mode using an Agilent 1100 series HPLC equipped with an autosampler. The column was generally Waters Xterra MS C18, 3.0×50 mm, 5 μm or Waters Acquity UPLC (registered trademark) BEH C18 1.0×50 mm, 1.7 μm. The flow rate was 1 mL / min and the injection volume was 10 μL. UV detection was in the range of 210 - 400 nm. The mobile phase was composed of solvent A (water + 0.05% TFA) and solvent B (MeCN + 0.05% TFA), with a gradient of 100% solvent A for 0.7 minutes, changed to 100% solvent B over 3.75 minutes, maintained for 1.1 minutes, and then changed back to solvent A over 0.2 minutes. ​​​​​​ Returned to 100%.

[0097] Preparative reverse-phase chromatography was generally performed on a Tele dyne ISCO ACCQPrep HP125 or HP150 apparatus equipped with UV and ELSD detectors. The UV detector typically monitored wavelengths of 215 nm and 254 nm. The column was generally one of the following: Waters XBridge Prep C18 OBD 5μm 30×150mm, Waters XBridge Prep C18 OBD 5μm 30×250mm, Waters XBridge Prep C18 OBD 5μm 50×250mm, Waters SunFire Prep C1 8 OBD 5μm 30×150mm, Waters SunFire Prep C 18 OBD 10μm 30×150mm, Waters SunFire Prep C18 OBD 5μm 50×250mm, Waters SunFire Pre p C18 OBD 10μm 50×250mm, or Phenomenex Luna Prep C18 5μm 50×250mm. The mobile phase consisted of a mixture of acetonitrile containing 0.1% TFA and water containing 0.1% TFA, or a mixture of 100% acetonitrile and 5 mM (NH4)HCO3. Alternatively, a commonly used system consisted of a Waters Chromatography Workstation composed of a Waters ZQ (trademark) single quadrupole MS system equipped with electrospray ionization, a Waters 2525 gradient pump, a Waters 2767 injector / collector, and a Waters 996 PDA detector. p C18 OBD 10μm 50×250mm, or a Phenomenex Luna Prep C18 5μm 50×250mm. The mobile phase was composed of a mixture of acetonitrile containing 0.1% TFA and water containing 0.1% TFA, or a mixture of 100% acetonitrile and 5 mM (NH4)HCO3. Alternatively, a commonly used system was a Waters Chromatography Workstation composed of a Waters ZQ (trademark) single quadrupole MS system equipped with electrospray ionization, a Waters 2525 gradient pump, a Waters 2767 injector / collector, and a Waters 996 PDA detector. 5 mM (NH4)HCO3. Alternatively, a commonly used system generally consisted of a Waters ZQ (trademark) single quadrupole MS system equipped with electrospray ionization, a Waters 2525 gradient pump, a Waters 2767 injector / collector, and a Waters 996 PDA detector, which formed an LCMS system. The Waters Chromatography Workstation consisted of a Waters ZQ (trademark) single quadrupole MS system equipped with electrospray ionization, a Waters 2525 gradient pump, a Waters 2767 injector / collector, and a Waters 996 PDA detector. The Waters Chromatography Workstation It was. The MS conditions were 150 - 750 amu, positive charge electrospray, and collection caused by MS. The columns used were generally Waters SunFi re C18 5μm 30×150mm, Boston Green ODS 5μm 150×30mm, or YMC - Actus Triart C18 5μm 15 0×30mm columns. The mobile phase was composed 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 Gi lson GX - 281 injector / collector, Gilson UV / VIS - 155 detector, Gilson 333 and 334 pumps, and a Gilson W orkstation consisting of either a Phenomenex G emini - NX C18 5μm 50×250mm column, Waters XBri dge Prep C18 OBD 5μm 30×250mm, or Welch X timate C18 5μm 150×25mm. The mobile phase was composed of a mixture of acetonitrile containing 5 mM (NH4)HCO3 (0 - 75%) and water. For the Waters XBridge column, the flow rate was maintained at 50 mL / min, for the Phenomenex Gemini column it was maintained at 90 mL / min, and for the Welch Xtimate column it was maintained at 25 m L / min. The UV detection range was 210 - 400 nm. The mobile phase gradient was optimized for each individual compound. For the Welch Xtimate column, the flow rate was maintained at 25 mL / min. The UV detection range was 210 - 400 nm. The mobile phase gradient was optimized for each individual compound. For each individual compound, the mobile phase gradient was optimized. The mobile phase gradient was optimized for each individual compound.

[0098] Flash chromatography was usually performed using an ISCO CombiFlash Rf apparatus. Biotage (registered trademark) flash chromatography apparatus (Dyax Corp. ), or an ISCO CombiFlash (registered trademark) Companion XL apparatus was used, and it was carried out using a silica gel (60 Å pore size)-packed RediSep Rf, RediSep Rf Gold, or SepaFlash column. The mobile phase generally consisted of hexane or dichloromethane and a mixture with EtOAc, 3:1 EtOAc:EtOH or MeOH . The mobile phase gradient was optimized for each individual compound.

[0099] Chiral chromatography was generally carried out by supercritical fluid chromatography using a column selected from one of Daicel CHIRALPAK AD-H 2×25 cm, Daicel CHIRALPAK AD-H 3×25 cm, YMC Chiral ART Cellulose-SC, Lux Cellulose-2 5 μm 30×250 mm, or Exsil Chiral-NR 8 μm 30× 250 mm. The mobile phase consisted of a mixture of CO2 and 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 individual compound. The pressure was typically maintained at 100 bar , and the flow rate was in the range of 50 - 200 mL / min. UV monitoring was generally carried out at 220 or 205 nM.

[0100] 1 1H NMR data was typically obtained using a Br with a 5 mm BBF iProbe at room temperature ​Uker NEO 500 MHz NMR spectrometer, Bruker PI HR-BBO4 Bruker Avan equipped with a 00S1-BBF / H / D-5.0-Z SP probe ce NEO 400 MHz NMR spectrometer, or Bruker Avance III 500 MHz NMR spectrometer equipped with a 5 mm PABBO probe was used. Chemical shift values are reported in delta (δ) units, parts per million (ppm). 1 The chemical shifts of the 1H NMR spectra are referenced to the signals of the 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). The multiplicity is reported by the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet or overlap of non-equivalent resonances. The coupling constant (J) is reported in hertz (Hz). When a compound appears as a mixture of rotational isomers by NMR, the spectral data corresponding to the major species observed in solution are reported. of doublets, m = multiplet or overlap of non-equivalent resonances. The coupling constant (J) is reported in hertz ( Hz). When a compound appears as a mixture of rotational isomers 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)phosphine hexafluorophosphate. aq. is an aqueous solution. Bn is benzyl. Boc is tert -butoxycarbonyl. The Dess-Martin reagent is methyl N-(triethylammonium sulfonyl)carbamate. Cbz is benzyloxycarbonyl. CD I is 1,1'-carbonyldiimidazole. DCM is dichloromethane. ​​​​​​DIBAL or DIBAL-H is diisobutylaluminum hydride. DIEA or DIPEA is N,N-diisopropylethylamine. DMA is dimethyl acetamide. DMF is N,N-dimethylformamide. DMP is Dess ·Martin's periodinane. DMSO is dimethyl sulfoxide. EDC or EDCI is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. ELSD is an 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 performance 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 It is an oil ether. Ph is phenyl. POCl3 is phosphorus oxychloride. Potassium sodium tartrate is Rochelle salt. RP HPLC is reverse-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, generally, the compounds of the present invention can be prepared by acylating a suitably functionalized amine A-1 to provide a compound of formula A-2. Hydrolysis of ester A-2 can give an acid of formula A-3, which can be coupled with an amine of formula INT-1 to give a product of formula A-4. Oxidation of hydroxyamide A-4 can give a ketoamide of formula A-5. In some embodiments, stereoisomers can be separated during the synthesis process. The A-1 type amine, acylating agent, and INT-1 type amine are commercially available or can be synthesized from suitable intermediates.

[0103] Scheme A

Chemical formula

[0104] As illustrated in Scheme B, generally, the compounds of the present invention are suitably functionalized amines It can be prepared by acylating B-1 to obtain a compound of formula B-2, and coupling this with an amine of formula INT-1 to obtain a product of formula B-3. The hydroxyamide B-3 can be oxidized to obtain a ketoamide of formula B-4. In some embodiments, stereoisomers can be separated during the course of the synthesis. The B-1 type amine, acylating agent and INT-1 type amine are commercially available or can be synthesized from suitable intermediates.

[0105] Scheme B

Chemical formula

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

[0107] Scheme C

Chemical formula

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

Chemical Structure

[0109] Step 1: Dimethyl (2S,4S)-2-(((benzyloxy)carbonyl)amino) -4-((R)-2-((tert-butoxycarbonyl)amino)propyl)pentane di-oate A mixture of dimethyl ((benzyloxy)carbonyl)-L-glutamate (4 g, 12.93 m mol) in THF (26 mL) was added with 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 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 (2×60 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified using silica gel chromatography eluting with 2 0% EtOAc / PE. The desired fractions were concentrated to afford the title compound.

[0110] Step 2: Dimethyl (2S,4S)-2-((R)-2-aminopropyl)-4-((( (benzyloxy)carbonyl)amino)pentanedioate Dimethyl (2S,4S)-2-(((benzyloxy)carbonyl)amino)-4-( (R)-2-((tert-butoxycarbonyl)amino)propyl)pentanedioate To a solution of the diester (3 g, 6.43 mmol) in EtOAc (10 mL) was added EtOAc (20 mL) containing 4 M HCl. The reaction mixture was stirred at 25 °C for 1 h. LC / MS indicated consumption of the starting material. The reaction mixture was then concentrated to afford the HCl salt of the title compound, which was used without further purification. LRMS m / z:( M+H) Calculated 367.1; Found 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 CHCl3 (2 mL) was added sodium acetate (2.342 g, 28.5 mmol). The reaction mixture was stirred at 75 °C for 12 h. TLC indicated consumption of the starting material. The reaction was then quenched with water (50 mL) and ​​​ It was quenched. The resulting suspension was extracted with EtOAc (2 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The resulting residue was purified using silica gel chromatography eluting with 75% EtOA c / PE. The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) Calculated 335.1; Found + 335.2.

[0112] 1 H NMR (400 MHz, CDCl3) δ = 7.37 - 7.31 (m, 5H), 5 .96 - 5.95 (br d, J = 7.80 Hz, 1H), 5.83 (br d, J = 7 .80 Hz, 1H), 5.12 (s, 2H), 4.41 - 4.35 (m, 1H), 3.7 6 (s, 4H), 2.59 - 2.56 (dq, J = 5.00, 8.80 Hz, 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 = 6.40 Hz, 3H).

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

[0114] Step 1: Benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidin -3-yl)-3-oxopropan-2-yl)carbamate Methyl (S)-2-(((benzyloxy)carbonyl)amino)-3-((3S,5 (R)-5-methyl-2-oxopyrrolidin-3-yl)propanoate (2 g, 5.98 mmol) in THF (30 mL) was added dropwise with 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 indicated that the starting material was consumed and the desired product was formed . MeOH (10 mL) was added to the mixture at -78 °C, 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 salt (20 mL), then EtOAc (20 mL) was added. The mixture was stirred at room temperature for 30 min , then the mixture was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (2 × 20 mL). The organic layer was then dried over Na2SO4, filtered , and concentrated to give the title compound, which was used in the next step without further purification. LRMS m / z: (M + H) + Calcd 305.1; Found 305.1.

[0115] 1 H NMR (400 MHz, chloroform-d) δ 9.55 (s, 1H), 7.4 0 - 7.28 (m, 5H), 6.60 (br d, J = 6.2 Hz, 1H), 6.16( br s, 1H), 5.13 (s, 2H), 4.24 (br d, J = 5.6 Hz, 1H ), 3.86 - 3.67 (m, 1H), 2.66 - 2.51 (m, 1H), 2.04 - 1 .90 (m, 4H), 1.19 (br d, J = 6.3 Hz, 3H).

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

Chem.

Chem.

[0117] Step 1: Benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrolidi n-3-yl)-3-oxopropan-2-yl)carbamate To a solution of benzyl ((S)-1,1-dimethoxy-3-((3S,5R)-5-methyl-2-oxo pyrrolidin-3-yl)propan-2-yl)carbamate (2 g, 5.71 mmol) in acetone (20 mL) and water (20 mL) was added DOWEX(R) 50W X8(H) resin (20 g, 5.71 mmol). The resulting mixture was stirred at 40 °C for 1 6 h. LC / MS indicated that the starting material was consumed and the desired product was 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 then the aqueous layer was lyophilized to give the title compound, which was used in the next step without further purification. LRMS m / z: (M + H) Calculated 305.1; Found 305.1. +

[0118] 1 H NMR (400 MHz, chloroform-d) δ 9.55 (s, 1H), 7.4 0 - 7.28 (m, 5H), 6.60 (br d, J = 6.2 Hz, 1H), 6.16( br s, 1H), 5.13 (s, 2H), 4.24 (br d, J = 5.6 Hz, 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 h. LC / MS indicated consumption of the starting material and observation of the desired MS. 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 (registered trademark); 20 g SepaFlash (registered trademark) silica flash column, eluent 10% MeOH / DCM gradient @ 24 mL / min). The desired fractions were concentrated , then re-purified by preparative HPLC (column: Boston Green ODS 150*30 m m*5 μm, conditions_ (water (TFA)-ACN start B60 end B80 gradient time (min) 10 100%B hold time (min) 2, flow rate (mL / min) 25). The desired fractions were concentrated to give the title compound. LRMS m / z: (M + H) + calculated 364.1; found Measured value 364.2.

[0120] 1 H NMR (500 MHz, 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 = 8.1 Hz, 2H), 3.83 - 3.61 (m, 1H ), 2.79 (br d, J = 4.4 Hz, 3H), 2.70 - 2.50 (m, 1H), 2.03 - 1.79 (m, 4H), 1.19 (br d, J = 5.3 Hz, 3H).

[0121] Step 3: (3S)-3-Amino-2-hydroxy-N-methyl-4-((3R,5R) -5-methyl-2-oxopyrrolidin-3-yl)butanamide Benzyl ((2S)-3-hydroxy-1-((3S,5R)-5-methyl-2-ox opyrrolidin-3-yl)-4-(methylamino)-4-oxobutan-2-yl)car To a solution of bamat (800 mg, 2.201 mmol) in EtOAc (15 mL) was added 1 0% Pd on carbon (234 mg, 0.220 mmol). The mixture was degassed and backfilled with nitrogen three times. Then, the reaction mixture was stirred at 25 °C for 16 hours under a hydrogen atmosphere. LC / MS indicated 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; Observed value 230.1.

[0122] 1 H NMR (500 MHz, 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 = 4.4 Hz, 3H), 2.03 (br dd, J = 1.4, 2.4 Hz, 3 H), 1.91 - 1.52 (m, 2H), 1.22 (s, 3H).

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

Chemical Structure

Chemical Structure

[0124] Step 1: Benzyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamate Benzyl ((S)-1,1-dimethoxy-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamate (5 g, 14.86 mmol) in acetone (2 5 mL) and water (25 mL) was added DOWEX(R) 50WX8(H) resin (5 0 g). The reaction mixture was then stirred at 40 °C for 16 h. 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 Na2SO4, filtered, and concentrated under reduced pressure to give the title compound, which was used without further purification. LRMS m / z: (M + H) Calculated 291.1; Found 291.1. was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound, which was used without further purification. LRMS m / z: (M + H) Calculated 291.1; Found 291.1. Calculated value 291.1; Observed value 291.1. + Calculated value 291.1; Observed value 291.1.

[0125] Step 2: Benzyl ((2S)-3-hydroxy-4-(methylamino)-4-oxo- 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate Benzyl ((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)pro pane-2-yl)carbamate (3 g, 10.33 mmol) in DCM (40 mL) was added to a mixture of 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 hours . LC / MS indicated 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 to pH = 10 with saturated Na2CO3, and then stirred for 16 hours. The mixture was extracted with EtOAc (3 × 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*5 μm, conditions: water (0.01% TFA)-ACN starting B 17 ending B 37 gradient time (min) 10 , 100% B hold 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; found 350.2.

[0126] 1 1H NMR (400 MHz, 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-oxo pyrrolidin-3-yl)butanamide 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 (1.37 1 g). The reaction mixture was degassed and backfilled with hydrogen (3 times). The resulting mixture was stirred at 25 °C for 16 h under a hydrogen atmosphere. LC / MS indicated 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 216.1; Found 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

Chem.

Chem.

[0130] 1 H NMR (400 MHz, DMSO-d6) δ: 7.65 (s, 1H), 7.34 (s, 5H), 7.07 (d, J = 8.9 Hz, 1H), 5.18 - 4.90 (m, 2H ), 4.67 (t, J = 5.7 Hz, 1H), 3.63 - 3.42 (m, 2H), 3.4 0 - 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 = 6.3 Hz, 3H).

[0131] Step 2a: Benzyl ((S)-1-((3S,5R)-5-methyl-2-oxopyrrol idin-3-yl)-3-oxopropan-2-yl)carbamate In a 500 mL three-necked flask, under a nitrogen atmosphere, using a magnetic stirrer, at 25 °C, benzyl ((S)-1-hydroxy-3-((3S,5R)-5-methyl-2-oxo pyrrolidin-3-yl)propan-2-yl)carbamate (20 g, 65 mmol) was added. Then, DCM (200 mL) was added to the flask and stirred for 10 minutes until solubilized . Then, the reaction mixture was cooled to 0 °C. Then, while maintaining the temperature between 0 - 10 °C , DMP (42 g, 98 mmol) was added dropwise to the solution over 20 minutes. Then, the reaction mixture was warmed to 25 °C with stirring, and then LC / MS was performed. After 3 hours , the reaction product was filtered, and then the filter cake was washed with DCM (50 mL) to obtain the title compound , which was used without purification. LRMS m / z: (M + H) + Calculated value 3 05.1; Measured value 305.1.

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

[0133] Step 3: Benzyl ((2S)-4-(cyclopropylamino)-3-hydroxy-1- ((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutane -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 by dropping it into the organic layer at 25 °C. Next, a crude solution of isocyanocyclopropane (122 mmol theoretical yield) was added dropwise to the above solution from Step 2b over 20 minutes while maintaining the temperature at 25 - 3 0 °C, and then LC / MS was performed. After 1 hour at 25 °C, the reaction mixture was quenched to pH = 7 with 10 wt% aqueous Na2CO3. Then, the organic layer was separated, and the aqueous layer was extracted with DCM (3 × 80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Then, the obtained residue was purified by preparative HPLC (water (NH4HCO3)-ACN). Then, the desired fraction was concentrated to obtain the title compound. LRMS m / z: (M+H) Calculated value 390.2; + Observed value 390.2.

[0134] 1 1H NMR (400 MHz, 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-necked 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 CF3CH2O H (55 mL). The reaction mixture was then purged with hydrogen / vacuum and purged with hydrogen three times, then stirred at 25 °C under a hydrogen atmosphere (hydrogen balloon), and then LC / MS was performed. After 16 hours, the reaction mixture was filtered. The filter cake was then washed with MeOH (5 0 mL). The combined organic layers were concentrated. The resulting residue was purified by preparative HPLC (eluting with water (NH4HCO3)-ACN)). The desired fraction was concentrated to give the title compound . LRMS m / z: (M + H) + Calculated 256.1; Found 256.3.

[0136] 11H NMR (400 MHz, MeOD) δ: 4.08 (d, J = 3.7 Hz, 1H) , 3.95 (d, J = 3.4 Hz, 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-oxo pyrrolidin-3-yl)butanamide [Chemical Structure] [Chemical Structure]

[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 (2 5 mL) and water (25 mL) was added DOWEX(R) 50WX8(H) resin (5 0 g, 14.86 mmol). The resulting reaction mixture was stirred at 40 °C and then LC / MS was performed. After 16 h, the reaction mixture was filtered and the resin was washed with EtOAc (3 × 30 m L). 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 Na2SO4, filtered, and concentrated to give the title compound A compound was obtained and used directly for the next step. LRMS m / z: (M+H)+ calculated value 291.1; measured value 291.1. Calculated value 291.1; measured value 291.1.

[0139] 1 1H NMR (400 MHz, chloroform-d) δ 9.57 (s, 1H), 7.4 5 - 7.28 (m, 5H), 6.64 (br d, J = 6.0 Hz, 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)pro pane-2-yl)carbamate (2 g, 6.89 mmol) in DCM (30 mL), TFA (0.614 mL, 8.27 mmol) and isocyanocyclopropane (0.761 mL, 10.33 mmol) were added. The reaction mixture was stirred at 25 °C and then LC / MS was performed. After 3 hours, the reaction mixture was concentrated and the resulting residue was treated with NaHCO 3 (1.157 g, 13.78 mmol), MeOH (18 mL) and water (12 mL) . The resulting mixture was stirred for 2 hours. LC / MS indicated that the reaction was complete. Then, the mixture was concentrated and the residue was dissolved in water (10 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid. 3 (1.157 g, 13.78 mmol), MeOH (18 mL) and water (12 mL) showed that the reaction was complete. Then, the mixture was concentrated and the residue was dissolved in water (10 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (3 × 10 mL), and the combined organic layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid. layers were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow solid. The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. . The resulting residue was purified by flash silica gel chromatography (ISCO (registered trademark) , 20 g SepaFlash (registered trademark) silica flash column, 25% ethyl acetate / pet. eluent, ether gradient @ 50 mL / min). The desired fraction was concentrated to obtain the title compound. LRMS m / z: (M+H)+ calculated value 376.1; measured value 3 76.1.

[0141] Step 3: (3S)-3-Amino-N-cyclopropyl-2-hydroxy-4-((S) -2-oxopyrrolidin-3-yl)butanamide Benzyl ((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo- 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate (6 00 mg, 1.598 mmol) in EtOAc (20 mL) was added with 10% Pd on carbon (170 mg) under a nitrogen atmosphere . The reaction mixture was degassed and backfilled with hydrogen / vacuum (3 times). The resulting mixture was stirred at 25 °C under hydrogen (balloon), and then LC / MS was performed. After 1 hour, the reaction mixture was filtered, and then the filtrate was concentrated to obtain the title compound. LRMS m / z: (M+H)+ calculated value 242.1; measured value 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-carboxamide)benzamide Do [Chemistry]

[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 the hood, and then LC / MS was performed. After overnight at 85 °C, the reaction mixture was diluted with 200 μL of MeOH and then purified by reverse-phase chromatography (10 - 100% MeCN / H2O, 0.1% TFA modifier, 30-minute gradient, Waters 50×250 mm Sunfire 5 micron C 18 column, flow rate = 118.1 mL / min) (without post-treatment). The desired fraction was the free base. It was suspended in EtOAc and washed with saturated NaHCO3, then water, and then brine . The organic layer was then dried over Na2SO4, filtered, concentrated, and 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] [Chemistry]

[0145] Step 2: 5-Chloro-2-(1-(trifluoromethyl)cyclopropane-1-carbox amide)benzoic acid To a flask containing methyl 5-chloro-2-(1-(trifluoromethyl)cyclopropane-1-carbox amide)benzoate (150 mg, 0.466 mmol) was added MeOH (4 mL), then water (2 mL), and finally 5N sodium hydroxide (350 μL, 1.7 50 mmol). The reaction mixture was then capped and stirred at room temperature, after which LC / MS was performed. After about 30 minutes at room temperature, the reaction mixture was diluted / acidified with 1N HCl and then suspended in EtOAc and washed with 1N HCl and then brine. The organic layer was then dried over Na 2SO4, filtered, and concentrated to give the title compound, which was used without further purification . LRMS m / z: (M+H) Calculated 308.6; Found 308. + 1.

[0146]

Chemical Structure

[0147]

Chemical Structure

[0148] 1 H NMR (500 MHz, DMSO-d6) δ 9.65 (d, J = 6.6 Hz, 1H), 8.81 (d, J = 5.1 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H ), 7.97 - 7.89 (m, 2H), 7.63 (dd, J = 9.0, 2.5 Hz, 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 = 6.4 Hz , 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 [Chemical formula]

[0150] Step 1: Methyl 5-chloro-2-(2-(trifluoromethyl)isonicotinamide) 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-yl oxytris(dimethylamino)phosphonium hexafluorophosphate (2.13 g, 4.81 mmol) was added, followed by NMP (6 mL), and finally DIPEA (850 μL, 4.87 mmol). Next, the reaction mixture was capped and immediately heated to 85 °C in the hood, and then LC / MS was performed. 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 / H2O; 0.1% TFA modifier, 30-minute gradient, Waters 50×250 mm Sunfire 5 micron C18 column, flow rate = 118.1 mL / min) (without post-treatment). The desired fraction was concentrated, then dissolved in DCM / MeOH and concentrated to obtain the title compound. LRMS m / z: (M + H )+ Calculated value: 359.7; Measured value: 359.1.

[0151]

Chem.

[0152] Step 2: 5-Chloro-2-(2-(trifluoromethyl)isonicotinamido)benzoic acid Methyl 5-chloro-2-(2-(trifluoromethyl)isonicotinamido)benzoate (432 mg, 1.204 mmol) was placed in a flask, and MeOH (10 mL), then water (4 mL), and finally 5N sodium hydroxide (650 μL, 3.25 mmol) were added. Then, the reaction mixture was capped and stirred at room temperature. After the addition of NaOH, the reaction mixture was still a suspension, so DCM (3 mL) was added, by which the mixture was immediately solubilized, and then LC / MS was performed. After 1.75 hours at room temperature, the reaction mixture was diluted / acidified with 1N HCl, then suspended in EtOAc, washed with 1N HCl, and then brine . Then, the organic layer was dried over Na2SO4, filtered, and concentrated to obtain the title compound, which was used without further purification. LRMS m / z: (M+H ) + Calculated value: 345.6; Measured value: 345.0.

[0153]

Chem.

[0154]

Chemical Structure

[0155] Step 4: N-(4-chloro-2-(((S)-4-(cyclopropylamino)-1-( (3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-3,4-dioxobut 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 amide N-(4-chloro-2-(((2S)-4-(cyclopropylamino)-3-hydroxy -1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxo butan-2-yl)carbamoyl)phenyl)-2-(trifluoromethyl)isonico tinamide (140 mg, 0.241 mmol) in a vial, Dess-Martin pe riodinan (168 mg, 0.396 mmol) and sodium bicarbonate (42 mg, 0.500 mmol) were added, and finally DCM (5 mL) was added. Then, the reaction mi xture was capped and stirred at room temperature, and then LC / MS was performed. After 60 minutes, the reaction mixture was quenched / diluted with 4 mL of saturated sodium thiosulfate, then 1 mL of water, and then diluted with 10 mL of E tOAc. Stirred for 10 minutes, then suspended in EtOAc and washed with saturated sodium thio sulfate, then water, and then brine. Then, the organic layer was dried over Na2SO4 and filtered and concentrated. The resulting residue was purified by silica gel chromatography (10 - 1 00% EtOAc / Hex, 14 CV, 40 g ISCO). The desired fra ction was concentrated to give the title compound. LRMS m / z: (M+H) + calculated 580.9; found 580.1.

[0156] 1 1H NMR (500 MHz, DMSO-d6) δ 9.67 (d, J = 6.6 Hz, 1H), 9.04 (d, J = 5.0 Hz, 1H), 8.80 (d, J = 5.0 Hz, 1H ), 8.38 (d, J = 8.9 Hz, 1H), 8.21 (s, 1H), 8.09 (d, J =4.9 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.89 (s, 1H) , 7.72 (dd, J = 8.9, 2.4 Hz, 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 = 6.3 Hz, 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 - trifluorobutanamide) benz amide [Chemical formula]

[0158] Step 1: 5 - Chloro - 2 - (4,4,4 - trifluorobutanamide) benzoic acid To a solution of 2 - amino - 5 - chloro - benzoic acid (150 mg, 0.874 mmol) in DCM (5 m L) 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 and then LC / MS was performed. Then, 0 .5 M aqueous HCl solution (10 mL) was added to quench the reaction. The mixture was extracted with DCM( 2 × 10 mL). The separated organic matter was dried over Na2SO4, filtered, and concentrated was obtained. The resulting residue was purified by RP-HPLC (column: Boston Green ODS 15 0*30mm*5μm, conditions: water (TFA)-ACN starting B45 ending B65, gradient time( min): 10 100%B, retention time (min): 2, flow rate (mL / min): 25). The desired fraction was concentrated to obtain the title compound. LRMS m / z: (M+H) + Calculated value 296.0; found 296.0.

[0159]

Chemical Structure

[0160] Step 2: 5-Chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy -1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxo butan-2-yl)-2-(4,4,4-trifluorobutanamide)benzamide A mixture of 5-chloro-2-(4,4,4-trifluorobutanamide)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 with AOP( 104 mg, 0.235 mmol) and DIPEA (0.103 mL, 0.588 mmol ol) at 25 °C. The resulting mixture was stirred at 25 °C for 12 h and then LC / M S was performed. Then, the reaction mixture was subjected to RP-HPLC (column: Boston Green ODS 150*30mm*5μm, conditions: water (TFA)-ACN starting B33 ending B5 3, gradient time (min): 10 100%B, retention time (min): 2, flow rate (mL / min) 25). It was directly purified by [the method]. The desired fraction was concentrated to obtain the title compound. LRMS m / z: (M+H)+ calculated value 533.1; measured value 533.2.

[0161]

Chemical formula

[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-trifluorobutanamide)benzamide 5-Chloro-N-((2S)-4-(cyclopropylamino)-3-hydroxy-1- ((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-oxobutane -2-yl)-2-(4,4,4-trifluorobutanamide)benzamide (55 mg , 0.103 mmol) and NaHCO3 (26.0 mg, 0.310 mmol) in D CM (1.5 mL), DMP (65.7 mg, 0.155 mmol) was added at 25 °C. The resulting mixture was stirred at 25 °C for 2 hours and then LC / MS was performed. Next the reaction mixture was filtered and the filtrate was concentrated. The obtained residue was purified by RP-HPLC (column: Welch Xtimate C18 150*25mm*5μm, conditions: water (NH4H CO3)-ACN start B33 end B63, gradient time (min): 11 100%B, retention time (min): 2, flow rate (mL / min): 25). The desired fraction was concentrated to obtain the title compound. LRMS m / z: (M+H)+ calculated value 531.1; measured value 531.0.

[0163] 11H 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)benzamide)-5-cyano-N-((S )-1-((3S,5R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(meth ylamino)-3,4-dioxobutan-2-yl)nicotinamide [Chemical formula]

[0165] Step 1: 2-(3,5-Bis(trifluoromethyl)benzamide)-5-bromo nic otinic acid To a mixture of 2-amino-5-bromonicotinic acid (1 g, 4.61 mmol) and TEA (1.2 85 mL, 9.22 mmol) in DCM (25 mL), 3,5-bis(trifluoro romethyl)benzoyl chloride (1.274 g, 4.61 mmol) was slowly added at 0 °C. The resulting mixture was warmed to room temperature and stirred for a total of 16 hours, then LC / MS The reaction mixture was then diluted with DCM (20 mL) and filtered. The filtrate was concentrated under reduced pressure. Concentration at 4° C. gave 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-cyanonic acid Tinic acid Methyl 2-(3,5-bis(trifluoromethyl)benzamido)-5-bromonicothionate ferrate (470 mg, 0.998 mmol) and potassium ferricyanide (II) tribasic of hydrate (527 mg, 1.247 mmol) in DMA (8 mL) and water (1 mL) The mixture contains dicyclohexyl (2',4',6'-triisopropyl-[1,1'-biphenyl] (phenyl)-2-yl)phosphane (95 mg, 0.200 mmol) and allylpalladium Umium(II) chloride (36.5 mg, 0.100 mmol) was added at 25°C. The reaction mixture was degassed and backfilled with nitrogen three times. The resulting mixture was heated to 100°C. The mixture was stirred at rt for 48 h, after which LC / MS was performed. The reaction mixture was then filtered and the solids were filtered off. The extract was collected by filtration and then analyzed by RP-HPLC (column: Boston Green OD S 150*30mm*5μm, Conditions: Water (0.01% TFA)-ACN start B42 end Purified by 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)+ calc. Value 404.0.;Actual value 404.0.

[0167] [ka] Step 3: 2-(3,5-Bis(trifluoromethyl)benzamide)-5-cyano-N -((2S)-3-hydroxy-1-((3S,5R)-5-methyl-2-oxopyrrol idin-3-yl)-4-(methylamino)-4-oxobutan-2-yl)nicotinamide 2-(3,5-Bis(trifluoromethyl)benzamide)-5-cyanonicotinic acid( 65 mg, 0.161 mmol) and (3S)-3-amino-2-hydroxy-N-me thyl-4-((3R,5R)-5-methyl-2-oxopyrrolidin-3-yl)butanam ide (44.4 mg, 0.193 mmol) in DMF (2 mL) were added with DIPE A (0.084 mL, 0.484 mmol) and AOP (86 mg, 0.193 mmo l) at 25 °C. The resulting mixture was stirred for 16 h and then LC / MS was performed . Then, the reaction mixture was purified by RP-HPLC (column: Boston Green ODS 150*30 mm*5 μm, conditions: water (0.01% TFA)-ACN starting B 33 ending B 5 3 gradient time (min) 5 100% B hold time 2 flow rate (mL / min) 25). The desired fraction was concentrated to give the title compound. LRMS m / z: (M+H)+ calculated value 61 5.1; measured value 615.2.

[0168]

Chemical Structure

[0169] 1 H NMR (400 MHz, methanol-d4) δ 9.01-8.41 (m, 4H ), 8.21 (m, J = 16.0 Hz, 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-carboxy Mid Nicotinamide

Chem.

[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 (5 70 mg, 3.18 mmol), cesium carbonate (2.65 g, 8.1 3 mmol) was added, 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 and then the mixture was heated to 85 °C in the hood and then LC / MS was performed. After 20 minutes, the reaction mixture was suspended in EtOAc diluted with water and then washed with saturated NaHCO3 and then brine. The organic layer was then dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel column 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]

Chem.

[0173]

Chemical Structure

[0174] [Chemical Structure] 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- carboxamide)nicotinamide (114 mg, 0.199 mmol) was added Dess-Martin periodinane (168 mg, 0.396 mmol), then heavy Sodium carbonate (73 mg, 0.869 mmol) was added last, followed by DCM (5 mL). . The reaction mixture was then capped and stirred at room temperature, and then LC / MS was performed. After 30 minutes, 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 10 minutes, then suspended in EtOAc and washed with saturated sodium thiosulfate, then water, and then brine. Then, the organic layer was dried over Na2SO4, filtered, and concentrated. The resulting residue was then subjected to silica gel column chromatography (30 - 100% EtOAc / Hex, 14 CV, 40 g ISCO) for purification. The desired fractions were concentrated to obtain the title compound. LRMS m / z: (M +H)+ calculated 570.9; found 570.1.

[0175] 1 H NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.2 9 (d, J = 7.1 Hz, 1H), 8.80 (d, J = 5.0 Hz, 1H), 8.58( d, J = 2.5 Hz, 1H), 8.10 (d, J = 2.5 Hz, 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 = 6.3 Hz, 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-dioxobut (2-Tan-2-yl)carbamoyl)phenyl carbamate [Chemical formula]

[0177] Step 1: Methyl 5-chloro-2-((isopropoxycarbonyl)amino)benzoate to 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) was added. Then , the reaction mixture was capped and stirred at room temperature, and then LC / MS was performed. Then, the reaction mixture was diluted / quenched with 400 μL MeOH, and then partially concentrated. The resulting residue was purified by reverse-phase chromatography (25 - 100% MeCN / H2O, 0.1% TFA modifier, 30-minute gradient, Waters 50×250 mm Sunfire 5 micron C18 column , flow rate = 118.1 mL / min). The desired fraction was diluted with MeOH, concentrated , then dissolved in MeOH / DCM and concentrated to obtain the title compound. LRMS m / z: (M+H)+ calculated value 272.0; measured value 272.0.

[0178] [Chemical formula] Step 2: 5-Chloro-2-((isopropoxycarbonyl)amino)benzoic acid To a flask containing methyl 5-chloro-2-((isopropoxycarbonyl)amino)benzoate (45 5 mg, 1.675 mmol), MeOH (8 mL) was added, followed by water( 4 mL), and finally 5N sodium hydroxide (0.7 mL, 3.50 mmol) was added. ​Next, the reaction mixture was capped and stirred at room temperature. After adding NaOH, the reaction mixture was still a suspension, so DCM (3 mL) was added, which immediately solubilized the mixture, and then LC / MS was performed. After 3.5 hours at room temperature, the reaction mixture was diluted / acidified with 1N HCl and then suspended in EtOAc and washed with 1N HCl and 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]

Chemical Structure

[0180]

Chemical Structure

[0181] 1 H NMR (500 MHz, DMSO - d6) δ 10.56 (s, 1H), 9.6 6 (d, J = 5.9 Hz, 1H), 8.82 (d, J = 4.8 Hz, 1H), 8.25( d, J = 9.0 Hz, 1H), 8.01 - 7.88 (m, 2H), 7.60 (d, J = 9 .0 Hz, 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 = 6.2 Hz, 6H), 1.10 (d, J = 6.2 Hz, 3H), 0.69 - 0.63 - (m, 2H), 0.60 - 0.5 4 (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 - phenylpropanamide)benzamide [Chemical Formula]

[0183] Project 1: Ethyl 2,2-difluoro-3-phenylpropanoate (Bromomethyl)benzene (6.92 mL, 58.5 mmol) and ethyl 2-bro mo-2,2-difluoroacetate (8.31 g, 40.9 mmol) in DMSO (10 mL) were added copper (8.55 g, 134 mmol), copper(I) bromide (0.419 g, 2.92 mmol) and 1,10-phenanthroline (2.107 g, 11.69 mmo l) under a nitrogen atmosphere. The reaction mixture was then degassed and backfilled with nitrogen (3 times). The resulting mixture was stirred at 50 °C for 16 h under nitrogen, and then LC / MS was performed. 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 0 - 10% ethyl acetate / pet., ether gradient @ 100 mL / min) to give the title compound.

[0184] 1 1H NMR (400 MHz, MeOD) δ 7.32 - 7.27 (m, 5H), 4. 22 (q, J = 7.2 Hz, 2H), 3.40 (t, J = 16.8 Hz, 2H), 1.2 2 (t, J = 7.2 Hz, 3H).. 19 19F NMR (376 MHz, MeOD) δ 106.1.

[0185] [Chemical formula] Project 2: Benzyl 2,2-difluoro-3-phenylpropanoic acid Ethyl 2,2-difluoro-3-phenylpropanoate (4.5 g, 21.01 mm To a solution of 1,2-dichlorophenyl ether in THF (30 mL) and water (15 mL), (5.29 g, 126 mmol) was added. The reaction mixture was stirred at 25° C. for 24 h. This was followed by LC / MS. The reaction mixture was then diluted with water (30 mL) and 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 washed with anhydrous Na2SO4 Dry at 40° C., filter and concentrate to give the title compound which is used without further purification. did.

[0186] 1 H NMR(400MHz,MeOD)δ 7.32-7.27(m,5H),3. 38(t,J=16.8Hz,2H). 19 F NMR(376MHz,MeOD) δ 106.1.

[0187] [ka] Step 3: 5-chloro-2-(2,2-difluoro-3-phenylpropanamide)benzoate Aromatic acid 2,2-Difluoro-3-phenylpropanoic acid (150 mg, 0.806 mmol) To a solution of CDI (392 mg, 2.417 mmol) and TEA in THF (2 mL) (0.337 mL, 2.417 mmol) was added at 25° C. The reaction mixture was stirred at 25° C. for 2 The mixture was stirred for 1 hour, and then 2-amino-5-chlorobenzoic acid (152 mg, 0.886 mmol) was added. l) was added to the reaction. The mixture was then stirred at 25° C. for 16 hours, followed by LC / MS was carried out. Then, 1 M HCl (0.5 mL) was 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 starting B50 ending B70, gradient: time (min) 10 100% B hold time (min) 2 flow rate (mL / min) 25). The desired fraction was concentrated to obtain the title compound. LRMS m / z: (M+H)+ calculated value 340.0; found 340.0.

[0188]

Chemical Structure

[0189]

Chemical Structure

[0190] 1 1H NMR (400 MHz, 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, 16.9 Hz, 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 - carboxamide)benzamide amide [Chemical Structure] Step 1: Methyl (R) - 5 - chloro - 2 - (2,2 - difluorocyclopropane - 1 - carboxamide)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, 2.5 6 mmol), pyridine (6 mL) was added, and finally, POCl3 (0.29 7 mL, 3.18 mmol) was added. Then, the reaction mixture was capped and stirred at room temperature, and then LC / MS was performed. After 20 minutes at room temperature, the Reverse-phase chromatography (10 - 100% MeCN / H2O, 0.1% TFA modifier, 30-minute gradient, Waters 50×250mm Sunfire 5 micron C18 column with a flow rate of 118.1 mL / min) was used for purification. The desired fraction was concentrated to obtain the title compound with LRMS m / z: (M+H)+ calculated value 290.0; measured value 290.1.

[0192]

Chemical Structure

[0193]

Chemical Structure

[0194]

Chemical Structure

[0195] 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.5 7 (d, J = 6.4 Hz, 1H), 8.83 (d, J = 5.0 Hz, 1H), 8.25( d, J = 8.9 Hz, 1H), 7.91 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.60 (dd, J = 8.9, 2.4 Hz, 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 = 6.3 Hz, 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 - oxo soprolidin - 3 - yl) - 4 - (methylamino) - 3,4 - dioxobutan - 2 - yl ) carbamoyl) phenyl) carbamate [Chemical formula] TIFF2025097322000055.tif 37165 Step 1: 5 - chloro - 2 - ((methoxycarbonyl) amino) benzoic acid 2,5 - dioxopyrrolidin - 1 - ylmethyl carbonate (133 mg, 0.769 mmol) and TEA (0.268 mL, 1.923 mmol) in DCM (3 mL) solution, 2,5 - dioxopyrrolidin - 1 - ylmethyl carbonate (133 mg, 0 .769 mmol) was added at 20 °C, then the reaction mixture was heated to 40 °C and stirred for 10 hours, and then LC / MS was performed. Then the reaction mixture was concentrated, and the residue was subjected to RP - H PLC (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 hold Purified by a retention time of 2. Flow rate (mL / min): 60) to obtain the title compound. LRMS m / z: Calculated value of (M+H)+ 230.0; Measured value 230.0 1 H NMR (400 MHz, DMSO-d6) δ 14.07 (br s, 1H), 10.70 (br s, 1H), 8.29 (d, J = 9.1 Hz, 1H), 7.92 (d , J = 2.6 Hz, 1H), 7.69 (dd, J = 2.6, 9.1 Hz, 1H), 3.7 2 (s, 3H).

[0197]

Chemical Structure

[0198] [Chemical formula] 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 Methyl (4-chloro-2-(((2S)-3-hydroxy-1-((3S,5R)-5 -methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-4-oxobuta n-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 a mixture of DCM / DMSO = 3:1 (4 mL) was stirred at 20 °C for 1 hour and then LC / MS was performed. Subsequently, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure The obtained residue was purified by RP-HPLC (column: Waters Xbridge BEH C18 100*40mm*10μm. Conditions: water (10 mM HCOONH4)-AC N start B22 end B 52 gradient time (min) 11 100%B hold time 3. Flow rate (mL / min ): 50) to obtain the title compound. LRMS m / z: Calculated value of (M+H)+ 439.1; Measured value is 439.2 1 1H NMR (400 MHz, 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 [Chemical formula] 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). Then, the reaction mixture was capped and stirred at 65 °C, and then LC / MS was performed. After overnight at 65 °C, the reaction mixture was diluted / quenched with about 200 mL of water, then suspended in EtOAc and washed with 1N HCl and then brine. Then, the organic layer was 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 obtain the title compound. LRMS m / z: (M + H) Calculated value 256.0; Measured value 256.1

[0200] + [Chemical formula] 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 5-Chloro-2-((cyclopropoxycarbonyl)amino)benzoic acid (75 mg, 0 .293mmol) and (3S)-3-amino-2-hydroxy-N-methyl-4-( (3R,5R)-5-Methyl-2-oxopyrrolidin-3-yl)butanamide (77m g, 0.336 mmol) was added to a vial containing 7-azabenzotriazol-1-yl Oxytris(dimethylamino)phosphonium hexafluorophosphate (204mg , 0.460 mmol), then NMP (1.5 mL), and finally DIPEA (135 μL , 0.773 mmol) was added. The reaction mixture was then capped and heated to 85° C. After overnight at 85° C., the reaction mixture was diluted with 200 μL MeOH. The filtrate was then purified by reverse phase chromatography (5-60 %MeCN / H2O, 0.1% TFA modifier, 20 min gradient, Waters 30×150 1 mm Sunfire 5 micron C18 column, flow rate = 42.5 mL / min The desired fraction was concentrated, then dissolved in DCM / MeOH and concentrated. To obtain the title compound. LRMS m / z: (M+H) + Calculated value 467.1; measured value 4 67.4

[0201] [ka] Step 3: Cyclopropyl (4-chloro-2-(((S)-1-((3S,5R)-5- Methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-3,4-dioxo (butan-2-yl)carbamoyl)phenyl carbamate Cyclopropyl (4-chloro-2-(((2S)-3-hydroxy-1-((3S,5 R)-5-methyl-2-oxopyrrolidin-3-yl)-4-(methylamino)-4-oxo butan-2-yl)carbamoyl)phenyl carbamate (103 mg, 0.22 1 mmol) in a vial was added Dess-Martin periodinane (172 mg, 0.4 06 mmol) and sodium bicarbonate (41 mg, 0.488 mmol), and finally DCM (5 mL) was added. Then the reaction mixture was capped and stirred at room temperature, and then LC / MS was performed. After 1.5 hours, the reaction mixture was quenched / diluted with 4 mL of saturated sodium thiosulfate, then diluted with 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, and then brine. Then the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in DCM and purified by silica gel chromatography (30 - 100% EtOAc / hexane, 14 CV, 40 g ISCO). The desired fractions were concentrated to give the title compound. LRMS m / z: (M+H) calculated value 465.1; found value 465.4 + calculated value 465.1; found value 465.4

[0202] 1 H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 9.6 7 (d, J = 5.9 Hz, 1H), 8.74 - 8.69 (m, 1H), 8.23 (d, J = 9.0 Hz, 1H), 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,1 H),3.67-3.56(m,1H),2.70-2.64(m,4H),2.03- 1.92(m,2H),1.91-1.84(m,1H),1.80-1.72(m,1 H),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-diamine 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl (phenyl)carbamate [ka] Step 1: 5-Chloro-2-((cyclopropoxycarbonyl)amino)benzoic acid Vial containing 2-amino-5-chlorobenzoic acid (2.21 g, 12.88 mmol) Into the flask, 2-MeTHF (40 mL) was added, followed by cyclopropyl chloroformate (1.92 g, 15.93 mmol) was added. The reaction mixture was then capped and stirred at 65° C. After overnight at 65° C., the reaction mixture was diluted with approximately 200 mL of water / quenched. The mixture was cooled, then suspended in EtOAc and washed with 1N HCl and then with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was dissolved in DCM and The mixture was dissolved and then subjected to silica gel chromatography (0-30% IPA / DCM, 14 CV 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-(me thylamino)-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan- 2-yl)carbamoyl)phenyl)carbamate 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, 0.3 76 mmol) were placed in a vial, followed by 7-azabenzotriazol-1-yloxytri (dimethylamino)phosphonium hexafluorophosphate (206 mg, 0.46 5 mmol), then NMP (1 mL), and finally DIPEA (135 μL, 0.773 m mol). The reaction mixture was then capped and stirred at room temperature in the hood. Then LC / MS was performed. After overnight at room temperature, the reaction mixture was diluted with 200 μL of MeOH and filtered (syringe filter), and then the filtrate was purified by reverse-phase chromatography (1×4.2 mL injection ) (5 - 50% MeCN / H2O, 0.1% TFA modifier, 20-minute gradient , Waters 30×150 mm Sunfire 5 micron C18 column, flow rate = 42.5 mL / min) (without workup). The desired fraction was concentrated to give the title compound. LRM S m / z: (M+H)+ calculated 453.1; found 453.4

[0205]

Chemical Structure

[0206] 1 1H NMR (500 MHz, DMSO-d6) δ 10.61 (s, 1H), 9.6 6 (d, J = 6.0 Hz, 1H), 8.76 - 8.69 (m, 1H), 8.23 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.85 (s, 1H) , 7.62 (dd, J = 9.0, 2.4 Hz, 1H), 5.18 - 5.11 (m, 1H) , 4.11 - 4.04 (m, 1H), 3.24 - 3.12 (m, 2H), 2.67 (d, J = 4.8 Hz, 3H), 2.61 - 2.52 (m, 1H), 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 [Chemical Structure] Step 1: Methyl 5 - chloro - 2 - (3 - ((4,4 - difluorocyclohexyl)methyl yl) - 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 one overnight at room temperature, DIPEA (775 μL, 4.44 mmol) was added, and then ((4,4 - difluorocyclohexyl)methyl)(methyl)amine hydrochloride (259 m g, 1.297 mmol) was added. The mixture was stirred continuously at room temperature. After 1.5 hours at room temperature, the reaction mixture was diluted / quenched with water, then suspended in EtOAc, and saturated sodium bicarbonate was added. It was washed with um, then water, and then brine. Then, the organic layer was 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 fraction was concentrated to obtain the title compound. LRMS m / z: (M + H)+ calculated value 375.1; measured value 375.2.

[0208]

Chemical Structure

[0209]

Chemical Structure

[0210]

Chemical Structure

[0211] 1 1H NMR (500 MHz, DMSO) δ 10.75 (s, 1H), 9.64 (d , J = 6.1 Hz, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.42 (d, J = 9.1 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J = 2.5 Hz, 1H) , 7.52 (dd, J = 9.1, 2.5 Hz, 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 = 6.3 Hz, 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 - oxo pyrrolidin - 3 - yl) - 3,4 - dioxobutan - 2 - yl) - 5 - chloro - 2 - (4,4,4 - trifluorobutanamide)benzamide [Chemical formula] Step 1: Benzyl ((S) - 1 - ((3S,5R) - 5 - methyl - 2 - oxopyrrolid in - 3 - yl) - 3 - oxopropan - 2 - yl)carbamate Methyl (S) - 2 - ((((benzyloxy)carbonyl)amino) - 3 - ((3S,5 R) - 5 - methyl - 2 - oxopyrrolidin - 3 - yl)propanoate (3 g, 8.97 mmol) in THF (40 mL) was added with 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 hour and then LC / MS was performed. And quenched with saturated Rochelle 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 Na2SO4, 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), 7.3 9 - 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 - 3.6 5 (m, 1H), 2.58 (t, J = 8.0 Hz, 1H), 2.05 - 1.83 (m, 4 H), 1.20 - 1.06 (m, 3H).

[0214]

Chemical Structure

[0215]

Chemical Structure

[0216] 1 H NMR (400 MHz, 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]

Chemical Structure

[0218]

Chemical Structure

[0219]

Chemical Structure

[0220]

Chemical Structure

[0221] 1 H NMR (400 MHz, 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, 2H), 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 - 1.1 4 (m, 3H).

[0222] The following examples were prepared according to the same method as described above.

Table 1

[0223] SARS-CoV-2 3CL Protease Assay The enzymatic activity of SARS-CoV-2 3CL protease was determined by an assay based on FRET (Fluorescence Resonance Energy Transfer) that measures the cleavage of a peptide substrate by recombinantly expressed and purified enzyme The cleavage of the peptide of SEQ ID NO: 1 (CPC Scientific) by SARS-CoV-2 3CL protease was measured in reaction buffer (50 mM Hepes pH 7.5, 0.01% Triton X-100, 0.01% BSA, 2 mM DTT ) Prior to the start of the reaction with the peptide substrate (final concentration 15 μM), SARS-CoV-2 3 CL protease (final concentration 5 nM) was pre-incubated with the compound for 30 minutes. Room temperature The reaction (4 hours) was 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). The data was analyzed by standard four-parameter meter fit to determine the IC value 50 value was determined

[0224] The compounds of the present invention were tested in the above assay and the results are shown in the following table [Table 2] TIFF2025097322000119.tif234153TIFF2025097322000120.tif233153TIFF2025097322000121.tif233152TIFF2025097322000122.tif233153TIFF2025097322000123.tif234151TIFF2025097322000124.tif148156

Claims

1. Compounds of Formula I 【Chemical 1】 or a pharmaceutically acceptable salt thereof; During the ceremony, R １ is H; (C ３ -C ６ ) cycloalkyl; (C １ -C ６ ) alkyl; (C １ -C ６ ) alkyl-OH; phenyl; (C １ -C ６ ) alkyl-phenyl; containing 1 to 3 heteroatoms independently selected from N, O, or S (C ４ -C ６ ) heterocycloalkyl; containing 1 to 3 heteroatoms independently selected from N, O, or S (C １ -C ６ ) alkyl-(C ４ -C ６ ) heterocycloalkyl; containing 1 to 3 heteroatoms independently selected from N, O, or S (C １ -C ６ ) alkyl-(C ５ -C ６ ) heteroaryl; containing 1 to 3 heteroatoms independently selected from N, O, or S (C ５ -C ６ ) heteroaryl; R ２ is H; (C １ -C ６ ) alkyl; (C ３ -C ６ ) cycloalkyl; or CF ３ is; R ３ is (C １ -C ６ ) alkyl; (C １ -C ６ ) alkyl-CF ３ ; (C １ -C ６ ) Alkyl-OH; (C １ -C ６ ) alkyl-O-CH ３ ; (C １ -C ６ ) alkyl-O-CF ３ ; OH, -(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or may be substituted with up to three halogens (C １ -C ６ ) alkyl-O—(C ３ -C １０ ) cycloalkyl; (CF ２ )-phenyl; (C １ -C ６ ) alkyl-phenyl; OH, —(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or may be substituted with up to three halogens (C ３ -C １０ ) cycloalkyl; OH, —(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or may be substituted with up to three halogens (C １ -C ６ ) alkyl-(C ３ -C １０ ) cycloalkyl; containing up to three heteroatoms independently selected from N, O, and S, and including carbonyl, OH, —(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or optionally substituted with up to three halogens, (C ４ -C １０ ) heterocycle; containing up to three heteroatoms independently selected from N, O, and S, and including carbonyl, OH, —(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or optionally substituted with up to three halogens, (C １ -C ６ ) alkyl-(C ４ -C １０ ) heterocycle; OH, —(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or may be substituted with up to three halogens (C ６ -C １０ ) aryl; OH, —(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or may be substituted with up to three halogens (C １ -C ６ ) alkyl-(C ６ -C １０ ) aryl; Contains up to four heteroatoms independently selected from N, O, and S, and is OH, CN, CHF ２ , -(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ , -(C ３ -C ６ ) cycloalkyl, O—(C １ -C ６ ) alkyl, O—CF ３ , O-(C ３ -C ６ ) cycloalkyl, or optionally substituted with up to three halogens; (C ５ -C １０ ) heteroaryl; containing up to four heteroatoms independently selected from N, O, and S; OH, CN, CHF ２ , (C ３ -C ６ ) cycloalkyl, O—(C ３ -C ６ ) cycloalkyl, -(C １ -C ６ ) alkyl, O—(C １ -C ６ ) alkyl, CF ３ , O-CF ３ , -(C １ -C ６ ) alkyl-CF ３ or optionally substituted with up to three halogens, (C １ -C ６ ) alkyl-(C ５ -C １０ ) heteroaryl; —O—(C １ -C ６ ) alkyl; OH, CF ３ , -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-CF ３ or —O—(C １ -C ６ ) alkyl-(C ３ -C ６ ) cycloalkyl; OH, CF ３ , -(C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-CF ３ or —O—(C ３－ C ６ ) cycloalkyl; CHF ２ ;CF ３ ; (C １ -C ６ ) alkyl-N(CH ３ )-C(O)-O-CH ３ or N(R ８ ) ２ is; R ４ is H; F; Cl; or (C １ -C ６ ) alkyl; R ５ is H; F; Cl; or (C １ -C ６ ) alkyl; R ６ は、H;F;Cl;CN;CF ３ ;O-CHF ２ ;O-CF ３ ;-(C １ -C ６ ) Alkyl-CF ３ ; CHF ２ ;CF ３ ; (C １ -C ６ ) alkyl; (C ３ -C ６ ) Cyclo Alkyl; —O—(C ３ -C ６ ) cycloalkyl; or O—(C １ -C ６ ) alkyl; R ７ is H; F; Cl; or (C １ -C ６ ) alkyl; R ８ are independently H; (C １ -C ６ ) alkyl; OH, —(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or may be substituted with up to three halogens (C ３ -C １０ ) cycloalkyl; OH, —(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or may be substituted with up to three halogens (C １ -C ６ ) alkyl-(C ３ -C １０ ) cycloalkyl; containing up to three heteroatoms selected from N, O and S, and １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or optionally substituted with up to three halogens, (C ４ -C １０ ) heterocycle; containing up to three heteroatoms selected from N, O and S, and １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or optionally substituted with up to three halogens, (C １ -C ６ ) alkyl-(C ４ -C １０ ) heterocycle; OH, —(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or may be substituted with up to three halogens (C ６ -C １０ ) aryl; OH, —(C １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or may be substituted with up to three halogens (C １ -C ６ ) alkyl-(C ６ -C １０ ) aryl; Contains up to three heteroatoms selected from N, O and S, and １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or optionally substituted with up to three halogens, (C ５ -C １０ ) heteroaryl; containing up to three heteroatoms selected from N, O and S, and １ -C ６ ) alkyl, CF ３ , -(C １ -C ６ ) alkyl-CF ３ or optionally substituted with up to three halogens, (C １ -C ６ ) alkyl-(C ５ -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, each R ４ , R ５ , or R ７ is not present; and x is 1 or 2, However, the following compounds are excluded: 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, 5-chloro-N-[(1S)-3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxo-3-piperidyl]methyl]propyl]-2-(4,4,4-trifluorobutanoylamino)benzamide, and 【Chemistry 3】 【change】

2. R １ But, H, (C ３ ~C ６ ) cycloalkyl or (C １ ~C ６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. R １ But H, CH ３ or cyclopropyl, or a pharmaceutically acceptable salt thereof.

4. R ２ But CF ３ , C.H. ３ or H, or a pharmaceutically acceptable salt thereof.

5. R ３ is the group consisting of: 【Chemistry 2】 【change】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

6. R ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is H, F, or Cl.

7. R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is H, F, or Cl.

8. R ６ F, Cl, CHF ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

9. R ７ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is H, F, or Cl.

10. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein one of A, B, or D is N.

11. 2. The compound of claim 1, wherein A, B, and D are all C, or a pharmaceutically acceptable salt thereof.

12. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein x is 1.

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

14. 14. The pharmaceutical composition of claim 13 in the form of an orally administered tablet or capsule.

15. 14. The pharmaceutical composition of claim 13, further comprising one or more additional therapeutic agents.

16. 16. The pharmaceutical composition of claim 15, wherein the one or more additional therapeutic agents are selected from molnupiravir, pomotrervir, ensitrervir, nilmatrervir, and ritonavir.

17. The pharmaceutical composition according to claim 13 for preventing or treating coronavirus infections.

18. 18. The pharmaceutical composition of claim 17, wherein the coronavirus infection is SARS-CoV, SARS-CoV-2 or MERS-CoV infection.

19. The pharmaceutical composition of claim 18, wherein the coronavirus infection is SARS-CoV-2 infection.

20. 18. The pharmaceutical composition of claim 17, further comprising one or more additional therapeutic agents for the patient.

21. 21. The pharmaceutical composition of claim 20, wherein the one or more additional therapeutic agents are selected from molnupiravir, pomotrervir, ensitrervir, nilmatrervir, and ritonavir.

22. 10. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament.

23. 23. The use according to claim 22, wherein the medicament is for the prevention or treatment of a coronavirus infection.

24. 24. The use according to claim 23, wherein the coronavirus infection is a SARS-CoV, SARS-CoV-2 or MERS-CoV infection.

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