Inhibitors against coronaviruses

Abstract

Provided are compounds of Formula (I), (Ia), (Ib), and their uses in methods of inhibiting replication of Norovirus and Coronavirus in a biological sample or a patient, methods of reducing the amount of Norovirus or Coronavirus in a biological sample or a patient, and methods of treating Norovirus and Coronavirus in a patient comprising administering to the biological sample or patient a safe and effective amount of a compound of Formula (I), (Ia), (Ib), or a pharma- ceutically acceptable salt thereof. [ka] JPEG2024530920000142.jpg90149

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates generally to inhibitors of norovirus and coronavirus replication and methods of treating or preventing norovirus and coronavirus infections by administering the inhibitors to a patient in need of treatment thereof. [Background technology]

[0002] Norovirus is an important enteric pathogen implicated in outbreaks of nonbacterial gastroenteritis worldwide. Norovirus is primarily transmitted from person to person via the fecal-oral route, but can also be transmitted through contaminated food or water. Indirect contamination is also possible due to viral persistence in the environment. Human noroviruses belong to the genus Norovirus in the family Caliciviridae and are non-enveloped viruses with a single-stranded, positive-sense RNA genome. Norovirus strains are classified into seven groups. Viruses belonging to groups GI, GII, and GIV infect humans, while NoVs of groups GII, GIII, GIV, GV, GVI, and GVII have been reported in animals.

[0003] Coronaviruses are a common type of virus that cause a variety of illnesses in humans, ranging from the common cold to severe acute respiratory syndrome (SARS). Coronaviruses can also cause a variety of diseases in animals. Coronaviruses are enveloped, positive-strand RNA viruses, named for their crown-like appearance in electron micrographs. Coronaviruses are classified as a family in the order Nidovirales and replicate using nested mRNA. The Coronavirinae subfamily is further divided into four genera: alphacoronaviruses (including HCoV-229E and HCoV-NL63) and betacoronaviruses (including HCoV-HKU1, HCoV-OC43, Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2). Human coronaviruses (HCoVs) belong to two of these genera: alphacoronaviruses (including HCoV-229E and HCoV-NL63) and betacoronaviruses (including HCoV-HKU1, HCoV-OC43, Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2).

[0004] In 2012, a novel coronavirus emerged in Saudi Arabia, becoming known as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Approximately half of reported cases of MERS-CoV infection have been fatal, with the majority of reported cases occurring in elderly to middle-aged men. Only a small number of reported cases involved subjects with mild respiratory illness. Human-to-human transmission of MERS-CoV has been found to be possible but very limited. Another novel coronavirus emerged in Wuhan, China, in late 2019. This virus, known as SARS-CoV-2, 2019-nCoV, or Wuhan coronavirus, was responsible for the global pandemic that began in late 2019 and continued into 2020.

[0005] Given the widespread transmission and potential health impact of these viruses, drugs are needed to treat norovirus and coronavirus infections. Summary of the Invention

[0006] The present disclosure relates generally to methods of treating norovirus and coronavirus, inhibiting the replication of norovirus and coronavirus, and reducing the amount of norovirus and coronavirus, as well as compounds and compositions that may be used in such methods.

[0007] The present disclosure provides compounds and pharmaceutically acceptable salts thereof, wherein the compounds have the structure of formula (I): [ka] , In the formula, each R N are independently H or C 1-6 alkyl, and each R 1a are independently hydrogen, halo, C 1-6 Alkyl or C 1-6 haloalkyl, or both R 1a together with the carbon to which they are attached, optionally C(O)ORN Substituted with spiro C 3-6 carbocyclyl or spiro 4-8 membered heterocyclyl having 1-3 ring heteroatoms selected from N, O, and S; R 1b But hydrogen, halo, hydroxyl, C 1-6 Alkyl, or C 1-6 haloalkyl, n is 0, 1, or 2, and each R x But independently, Halo, C 1-6 Alkyl, C 3-6 Carbocyclyl, or C 6-10 aryl, wherein the aryl is optionally selected from OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; m is 0, 1, or 2; and each R y and independently halo or C 1-6 alkyl, and R 2 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-C 3-8 Carbocyclyl, or C 1-6 Alkylene-C 6-10 aryl, wherein the aryl is optionally selected from OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 substituted with 1 or 2 substituents independently selected from alkoxy; R 3 C replaced by CN, SO3H 1-6 Alkylene-O(O)CC 1-6 Alkyl, C 1-6 Alkenylene-C(O)OC 1-6 C substituted with alkyl, PO(OCH2CH2)2 1-6 Alkylene -OH, CHO, or -[C(O)]2-NR N -B, and B is C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8carbocyclyl or a 4- to 12-membered heterocyclyl having 1 to 3 ring heteroatoms selected from N, O, and S, wherein the carbocyclyl or heterocyclyl is optionally selected from C 1-6 monosubstituted with alkyl, R 3a But H or C 1-6 alkyl, and ring A is C 6-10 Cycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl containing one nitrogen heteroatom, provided that each R 1a is hydrogen, or each R 1a is methyl, ring A is phenyl, m is 0 or 1, and R y is a halo and n is 1, then R xis other than chloro, with the proviso that the compound is 1,2-diphenylethyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (2-(2-(((1,2-diphenylethoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, 2-(3-chlorophenyl)-1-phenylethyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl (3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)-2-methylpropyl (3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-phenylethyl(3-cyclohexyl-1 -oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-Dioxo-1-(2-oxopyrrolidin-3)-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(2-(((2-(3-chlorophenyl)-1-phenylethoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, 2-(2-(((2-(3-chlorophenyl)-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropan amide)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, 2-(3-chlorophenyl)-1-phenylethyl (1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl (1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidine-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate 2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propyl (1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(m-tolyl)propyl (1-((4-amino-3,4-dioxo-1- (2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propyl (3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl (1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(m-tolyl)propyl(3-cyclohexyl-1-oxo 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3- (2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino) amino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-phenylethyl (1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl (3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl (1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate, 2-(3-chlorophenyl)-1-phenylethyl (3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 1-(2-chlorophenyl)-2-(3-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propane-2 -yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3)-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3, 4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2 -yl)amino)-1-oxopropan-2-yl)carbamate, 1-(2-chlorophenyl)-2-(3-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo so-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl (1-((4-(cyclopropylamino) 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(3-cyclohexyl-1-((4-(ethylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, (3-chlorophenyl)-2-methyl-1-phenylpropyl(3-cyclohexyl-1-((4-(ethylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate 2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propyl(3-cyclohexyl-1-((4-(diethylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propyl(3-cyclohexyl-1-((4-(diethylamino)-3 ,4-dioxo)-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, ethyl(E)-4-(2-(((1,2-diphenylethoxy)carbonyl)amino)-4-methylpentanamido)-5-(2-oxopyrrolidin-3-yl)pent-2-enoate, 3-(2-(((2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propoxy)carbonyl)amino)-3-cyclohexylpropanamido)-2-oxo-4-(2-oxopyrrolidin-3-yl)butanoic acid, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate phenyl)ethyl (1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2 -methylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate), 2-(3-chlorophenyl)-2,2-difluoro-1 -phenylethyl (1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl (1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-phenylpropan-2-yl)carbamate, 2-(3-chlorophenyl)-2,2-difluoro-1-phenyl ethyl (1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)-2,2-difluoroethyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3- 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate , 1,2-bis(3-chlorophenyl)ethyl (3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclobutyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopentyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl(4-methyl-1- Oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(1-((4-(cyclopropyl 1,2-bis(3-chlorophenyl)-2,2-difluoroethyl (1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl (1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (1-(3-chlorophenyl)cyclohexyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopropyl)(4-fluorophenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxoheptan-2-yl)carbamate4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclobutyl)(phenyl)methyl( 1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-ethyl-1-phenylbutyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-fluorophenyl)-2-methyl methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (1-(3-chlorobenzyl)cyclopentyl)(phenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate 4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(4-methyl-1-((4-((1-methylazetidin-3-yl)amino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-ethyl-1-(4-fluorophenyl)butyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin)-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(4-methyl-1-oxo-1-((1- Oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 1,2-(3-chlorophenyl)-2-methylpropyl(1-((4-(cyclopropylamino)-3,4 -dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopropyl)(phenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopropyl)(4-fluorophenyl)methyl(4 -methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-fluorophenyl)cyclopropyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1-(3-fluorophenyl)cyclopropyl(phenyl)methyl(1-((4-(cyclopropylamino)-3,Provided is a compound, or a pharmaceutically acceptable salt thereof, which is not 4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclobutyl)methyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, or (4-chlorophenyl)(1-(3-chlorophenyl)cyclobutyl)methyl (1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate.

[0008] Also provided are compounds having the structure of formula (Ia), and pharmaceutically acceptable salts thereof: [ka] , Each R N are independently H or C 1-6 alkyl, and each R 1a are independently hydrogen, halo, C 1-6 Alkyl or C 1-6 haloalkyl, or both R 1a However, along with the carbon to which they are attached, spiro C 3-6 Form a carbocyclyl, R 1b But hydrogen, halo, C 1-6 Alkyl, or C 1-6 haloalkyl, n is 0, 1, or 2, and each R x and independently halo or C 1-6 alkyl, m is 0, 1, or 2, and each R y and independently halo or C 1-6 alkyl, and R 2 But C 1-6 Alkyl or C 1-6 Alkylene-C 5-8 carbocyclyl, and R 3 is CHO or -[C(O)]2-NR N-B, and B is C 1-6 Alkyl, C 3-8 carbocyclyl or a 4- to 12-membered heterocyclyl having 1 to 3 ring heteroatoms selected from N, O, and S, wherein the carbocyclyl or heterocyclyl is optionally selected from C 1-6 Also provided are compounds, and pharmaceutically acceptable salts thereof, that are mono-substituted with alkyl.

[0009] Also provided are compounds having the structure of formula (Ib), and pharmaceutically acceptable salts thereof: [ka] , In the formula, R x is Cl, F, cyclopropyl, or phenyl, and R y is F, m is 0 or 1, and R 2 But C 4-5 Alkyl, C 3-5 Haloalkyl, CH2C 3-6 carbocyclyl, or benzyl, wherein the carbocyclyl is optionally substituted with methyl or ethyl; R 3 is CHO, C(O)C(O)NH, C(O)C(O)NHcyclopropyl, or C(O)C(O)NHethyl, with the proviso that R x is Cl, m is 0, and R 3 is CHO, C(O)C(O)NH, or C(O)C(O)NH cyclopropyl, R 2 is not 2-methyl-propyl, and pharmaceutically acceptable salts thereof.

[0010] Further provided are methods of administering to a biological sample or to a patient a safe and effective amount of a compound disclosed herein, e.g., a compound of Formula (I), (Ia), (Ib), or a pharmaceutically acceptable salt thereof.

[0011] Also provided herein are methods for reducing the amount of norovirus or coronavirus in a biological sample or a patient by administering to the biological sample or the patient a safe and effective amount of a compound disclosed herein, e.g., a compound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt thereof.

[0012] Further provided is a method for treating or preventing a norovirus or coronavirus infection in a patient, comprising administering to the patient a safe and effective amount of a compound disclosed herein, e.g., a compound of Formula (I), (Ia), (Ib), or a pharmaceutically acceptable salt thereof.

[0013] Also provided are pharmaceutical compositions comprising a compound disclosed herein, e.g., a compound of Formula (I), (Ia), (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.

[0014] Also provided is the use of a compound described herein for inhibiting or reducing replication of a Norovirus or coronavirus in a biological sample or a patient, for reducing the amount of a Norovirus or coronavirus in a biological sample or a patient, or for treating a Norovirus or coronavirus in a patient.

[0015] Further provided herein is the use of a compound described herein for the manufacture of a medicament for treating a Norovirus or coronavirus infection in a patient, for reducing the amount of Norovirus or coronavirus in a biological sample or a patient, or for inhibiting the replication of Norovirus or coronavirus in a biological sample or a patient. DETAILED DESCRIPTION OF THE INVENTION

[0016] Provided herein are compounds and their uses in treating or preventing viral infections (e.g., norovirus or coronavirus infections). Also provided are uses of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising such a compound or a pharmaceutically acceptable salt thereof, for inhibiting viral replication in a biological sample or a patient, for reducing the amount of virus (reducing viral titer) in a biological sample or a patient, and for treating a viral infection in a patient.

[0017] Unless otherwise specified, structures depicted herein are meant to encompass all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational, and rotational) forms of the structure. For example, R and S configurations at each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers are included in the disclosure unless only one of the isomers is specifically indicated. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, cis / trans, conformational, and rotational mixtures of the present compounds are within the scope of the disclosure. In some cases, the compounds disclosed herein are stereoisomers. "Stereoisomer" refers to a compound that differs in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers. The compounds disclosed herein can exist as single stereoisomers or as a mixture of stereoisomers. The stereochemistry of the compounds depicted herein denotes relative, rather than absolute, stereochemistry, unless otherwise discussed. As used herein, a single stereoisomer, diastereomer, or enantiomer refers to a compound that is at least 50% or more of the shown stereoisomer, diastereomer, or enantiomer, and in some cases at least 90% or 95% of the shown stereoisomer, diastereomer, or enantiomer.

[0018] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0019] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon by a C-enriched carbon, are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, particularly deuterium analogs, may also be therapeutically useful.

[0020] The compounds of the present disclosure are defined herein by their chemical structure and / or chemical name. If a compound is referred to by both its chemical structure and chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0021] compound Provided herein are compounds of formula (I), and pharmaceutically acceptable salts thereof: [ka] , During the ceremony, Each R N are independently H or C 1-6 is alkyl, Each R 1a are independently hydrogen, halo, C 1-6 Alkyl, or C 1-6 is haloalkyl, Or both R 1a together with the carbon to which they are attached, optionally C(O)OR N Substituted with spiro C 3-6 forming a carbocyclyl or a spiro 4-8 membered heterocyclyl having 1-3 ring heteroatoms selected from N, O, and S; R 1b But hydrogen, halo, hydroxyl, C 1-6 Alkyl, or C 1-6 is haloalkyl, n is 0, 1, or 2; Each R x But independently, Halo, C 1-6 Alkyl, C 3-6 Carbocyclyl, or C 6-10 aryl, wherein the aryl is optionally selected from OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 substituted with 1 or 2 substituents independently selected from alkoxy; m is 0, 1, or 2; Each R y and independently halo or C 1-6 is alkyl, R 2 But C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-C 3-8 Carbocyclyl, or C 1-6 Alkylene-C 6-10 aryl, wherein the aryl is optionally selected from OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 substituted with 1 or 2 substituents independently selected from alkoxy; R 3 C replaced by CN, SO3H 1-6 Alkylene-O(O)CC 1-6 Alkyl, C 1-6 Alkenylene-C(O)OC 1-6 C substituted with alkyl, PO(OCH2CH2)2 1-6 Alkylene -OH, CHO, or -[C(O)]2-NR N -B, and B is C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 carbocyclyl or a 4- to 12-membered heterocyclyl having 1 to 3 ring heteroatoms selected from N, O, and S, wherein the carbocyclyl or heterocyclyl is optionally selected from C 1-6 is monosubstituted with alkyl, R 3a But H or C 1-6is alkyl, Ring A is C 6-10 Cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl containing one nitrogen heteroatom; However, each R 1a is hydrogen, or each R 1a is methyl, ring A is phenyl, m is 0 or 1, and R y is a halo and n is 1, then R x But other than Chloro, However, the compound is 1,2-diphenylethyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (2-(2-(((1,2-diphenylethoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, 2-(3-chlorophenyl)-1-phenylethyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-phenylethyl (3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3)-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(2-(((2-(3-chlorophenyl)-1-phenylethoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, 2-(2-(((2-(3-chlorophenyl)-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, 2-(3-chlorophenyl)-1-phenylethyl (1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(m-tolyl)propyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(m-tolyl)propyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-phenylethyl (1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate, 2-(3-chlorophenyl)-1-phenylethyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 1-(2-chlorophenyl)-2-(3-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3)-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 1-(2-chlorophenyl)-2-(3-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(3-cyclohexyl-1-((4-(ethylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propyl(3-cyclohexyl-1-((4-(diethylamino)-3,4-dioxo)-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, ethyl (E)-4-(2-(((1,2-diphenylethoxy)carbonyl)amino)-4-methylpentanamido)-5-(2-oxopyrrolidin-3-yl)pent-2-enoate, 3-(2-(((2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propoxy)carbonyl)amino)-3-cyclohexylpropanamido)-2-oxo-4-(2-oxopyrrolidin-3-yl)butanoic acid, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl (3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl (1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate), 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl (1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-phenylpropan-2-yl)carbamate, 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl (1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)-2,2-difluoroethyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)heptan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl (3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclobutyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopentyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)-2,2-difluoroethyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxoheptan-2-yl)carbamate, (1-(3-chlorophenyl)cyclohexyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopropyl)(4-fluorophenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclobutyl)(phenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-ethyl-1-phenylbutyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-fluorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (1-(3-chlorobenzyl)cyclopentyl)(phenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(4-methyl-1-((4-((1-methylazetidin-3-yl)amino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-ethyl-1-(4-fluorophenyl)butyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin)-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 1,2-(3-chlorophenyl)-2-methylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopropyl)(phenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin)-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopropyl)(4-fluorophenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-fluorophenyl)cyclopropyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1-(3-fluorophenyl)cyclopropyl(phenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin)-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclobutyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, or Not (4-chlorophenyl)(1-(3-chlorophenyl)cyclobutyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate.

[0022] In some embodiments, the compound and pharmaceutically acceptable salts thereof have the structure of Formula (Ia): [ka] During the ceremony, Each R N are independently H or C 1-6 is alkyl, Each R 1a are independently hydrogen, halo, C 1-6 Alkyl or C 1-6 Is it a haloalkyl? Or both R 1a However, along with the carbon to which they are attached, spiro C 3-6 forming a carbocyclyl, R 1b But hydrogen, halo, C 1-6 Alkyl, or C 1-6 is haloalkyl, n is 0, 1, or 2; Each R x and independently halo or C 1-6 is alkyl, m is 0, 1, or 2; Each R y and independently halo or C 1-6 is alkyl, R 2 But C 1-6 Alkyl or C 1-6 Alkylene-C 5-8 is a carbocyclyl, R 3 is CHO or -[C(O)]2-NR N -B, and B is C 1-6 Alkyl, C 3-8 carbocyclyl or a 4- to 12-membered heterocyclyl having 1 to 3 ring heteroatoms selected from N, O, and S, wherein the carbocyclyl or heterocyclyl is optionally selected from C 1-6 It is monosubstituted with alkyl.

[0023] As used herein, the term "alkyl" or "alkylene" means a saturated straight or branched chain hydrocarbon. n The term "alkyl" means that the alkyl group has "n" carbon atoms. For example, C4 alkyl refers to an alkyl group having 4 carbon atoms.1-6 Alkyl refers to alkyl groups having numbers of carbon atoms throughout the entire range (i.e., 1 to 6 carbon atoms) and all subgroups (e.g., 1 to 6, 2 to 6, 1 to 5, 2 to 6, 1 to 4, 2 to 5, 1, 2, 3, 4, 5, and 6 carbon atoms). Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, and t-butyl.

[0024] As used herein, the terms "halogen" and "halo" mean F, Cl, Br, or I.

[0025] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms have been replaced with a halogen. Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoroethyl, 2-fluoroethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl. Haloalkyl can be further substituted or unsubstituted, and some embodiments include, for example, C 1-6 It relates to haloalkyl having 1 to 6 carbon atoms, such as haloalkyl.

[0026] The term "carbocycle" (or "carbocyclyl") refers to a non-aromatic monocyclic, fused, bridged, or spiro ring system in which the ring atoms are carbon and which can be saturated or have one or more units of unsaturation. A carbocycle can have 3 to 8 ring carbon atoms, such as 3 to 6 ring carbon atoms. In some embodiments, the number of carbon atoms is 3 to 6, or 5 to 8. In some embodiments, the number of carbon atoms is 6. A "fused" bicyclic ring system contains two rings that share two adjacent ring atoms. A bridged bicyclic group contains two rings that share three or four adjacent ring atoms. A spiro bicyclic ring system shares one ring atom. Specific examples include, but are not limited to, cyclohexyl, cyclopentyl, cyclopropyl, and cyclobutyl. A carbocycle is unsubstituted or substituted as described herein.

[0027] The term "heterocycle" (or "heterocyclyl"), as used herein, refers to a non-aromatic monocyclic, fused, spiro, or bridged ring system having 4 to 12 ring atoms, which can be saturated or can contain one or more units of unsaturation, where one or more (e.g., 1 to 3, or 1, 2, or 3) ring atoms are heteroatoms selected from N, S, and O. In some embodiments, the heterocycle contains 5 to 6 ring members. In some embodiments, the heterocycle contains 5 ring members. In some embodiments, the heterocycle contains 6 ring members. In some embodiments, the heterocycle is piperidinyl. Examples of heterocycles include quinuclidinyl, piperidinyl, piperidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholino (including, for example, 3-morpholino, 4-morpholino), 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, pyraz ... thiazocanyl, thiazocanyl, thiazocanyl, thiazocanyl, thiazocanyl, thiazocanyl, thiazocanyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, thiazolinyl, Roridin-2-one, 1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl , 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolanyl, benzodithianyl, 3-(1-alkyl)-benzimidazol-2-onyl, and 1,3-dihydro-imidazol-2-onyl. Heterocycles are unsubstituted or substituted as described herein.

[0028] As described herein, the compounds of the present disclosure can be optionally substituted with one or more substituents, such as those generally indicated, or as exemplified by the particular classes, subclasses, and species of the present disclosure. The phrase "optionally substituted" is understood to be used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of one or more hydrogen radicals in a given structure with a specified substituent. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position.

[0029] In some cases, at least one R N is H. In some cases, at least one R N is C 1-6 In some cases, each R N is H. In some cases, at least one R N is C 1-6 alkyl, e.g., methyl. In some cases, each R N is C 1-6 Alkyl, for example methyl.

[0030] In some cases, at least one R 1a is hydrogen. In some cases, each R 1a is hydrogen.

[0031] In some cases, at least one R 1a is a halo. In some cases, each R 1a is halo. Optionally, halo is chloro or fluoro. Optionally, halo is fluoro. Optionally, at least one R 1a is fluoro. In some cases, each R 1ais fluoro. In some cases, at least one R 1a is chloro. In some cases, each R 1a is chloro.

[0032] In some cases, at least one R 1a is C 1-6 In some cases, each R 1a is C 1-6 In some cases, C 1-6 Alkyl is methyl or ethyl. Optionally, at least one R 1a is methyl or ethyl. In some cases, each R 1a is methyl or ethyl. In some cases, R 1a is methyl.

[0033] In some cases, each R 1a However, together with the carbon to which they are attached, they form a spiro C 3-6 Forms a carbocyclyl. In some cases, C 3-6 Carbocyclyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-6 Carbocyclyl is cyclopropyl. 3-6 Carbocyclyl is cyclobutyl. 3-6 Carbocyclyl is cyclopentyl. 3-6 Carbocyclyl is cyclohexyl. Optionally, each R 1a together with the carbons to which they are attached form a spiro 4-8 membered heterocyclyl having 1-3 ring heteroatoms selected from N, O, and S, and optionally C(O)OR N In some cases, each R 1a together with the carbons to which they are attached to form a spiropiperidinyl. 1a together with the carbons to which they are attached form an unsubstituted piperidinyl. 1atogether with the carbon to which they are attached, form C(O)OR N Optionally, each R 1a together with the carbon to which they are attached to form a C(O)Ot-butyl substituted spiropiperidinyl.

[0034] In some cases, n is 0 or 1. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2.

[0035] In some cases, R x is in the meta or para position. In some cases, R x is in the meta position. In some cases, R x In some cases, one R x is in the meta position. In some cases, one R x In some cases, one R x is in the meta position and is x In some cases, at least one R x is a halo. In some cases, each R x is a halo. In some cases, at least one R x is chloro. In some cases, at least one R x is fluoro. In some cases, R x is chloro. In some cases, R x is fluoro. In some cases, each R x is fluoro. In some cases, at least one R x is C 1-6 In some cases, two R x is C 1-6 In some cases, at least one R x is C 3-6 Carbocyclyl or C 6-10 Aryl, where aryl is OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6Optionally, at least one R is optionally substituted with 1 or 2 substituents independently selected from alkoxy. x is C 3-6 carbocyclyl. In some cases, at least one R x is cyclopropyl. In some cases, at least one R x C 6-10 aryl, wherein the aryl is selected from the group consisting of OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally, at least one R is optionally substituted with 1 or 2 substituents independently selected from alkoxy. x is C 6-10 aryl. In some cases, at least one R x is phenyl. In some cases, at least one R x OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C substituted with 1 or 2 substituents independently selected from alkoxy 6-10 It is aryl.

[0036] In some cases, m is 0 or 1. In some cases, m is 0. In some cases, m is 1. In some cases, m is 2.

[0037] In some cases, R y is in the meta or para position. In some cases, R y is in the meta position. In some cases, R y In some cases, one R y is in the meta position. In some cases, one R y In some cases, one R y is in the meta position and is y In some cases, at least one R y is a halo. In some cases, each R y is a halo. In some cases, at least one Ry is chloro. In some cases, at least one R y is fluoro. In some cases, R y is chloro. In some cases, R y is fluoro. In some cases, each R y is fluoro. In some cases, at least one R y is C 1-6 In some cases, two R y is C 1-6 It is alkyl.

[0038] In some cases, R 2 is C 1-6 In some cases, R 2 teeth, [ka] In some cases, R 2 teeth, C 1-6 Alkylene-C 3-8 carbocyclyl. In some cases, R 2 is C 1-6 Alkylene-C 5-8 carbocyclyl. In some cases, R 2 is C1 alkylene-C 5-8 carbocyclyl. In some cases, R 2 teeth, [ka] In some cases, R 2 is C 1-6 Haloalkyl, C 1-6 Alkylene-C 3-8 Carbocyclyl, or C 1-6 Alkylene-C 6-10 aryl, wherein the aryl is optionally selected from OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 Optionally, R is substituted with one or two substituents independently selected from alkoxy.2 is C 1-6 haloalkyl. In some cases, R 2 is C 1-6 Alkylene-C 6-10 aryl. In some cases, R 2 is benzyl.

[0039] In some cases, R 3 is CHO. In some cases, R 3 is -[C(O)]2-NR N -B. In some cases, B is C 1-6 Alkyl or C 1-6 Optionally, B is C 1-6 Optionally, B is C 1-6 In some cases, B is optionally C 1-6 Alkyl monosubstituted C 3-8 Optionally, B is unsubstituted C 3-8 Optionally, B is C 1-6 Alkyl monosubstituted C 3-8 In some cases, B is optionally C 1-6 Optionally, B is an unsubstituted C3 carbocyclyl. Optionally, B is a C3 carbocyclyl monosubstituted with alkyl. 1-6 Optionally, B is an unsubstituted C6 carbocyclyl. Optionally, B is a C 1-6 In some cases, B is optionally C6 carbocyclyl monosubstituted with alkyl. 1-6 Optionally, B is an unsubstituted 4-12 membered heterocyclyl having 1-3 ring heteroatoms selected from N, O, and S. Optionally, B is an unsubstituted 4-12 membered heterocyclyl having 1-3 ring heteroatoms selected from N, O, and S. Optionally, B is an unsubstituted 4-12 membered heterocyclyl having 1-3 ring heteroatoms selected from C 1-6and C. In some cases, B is optionally selected from C. 1-6 Optionally, B includes piperidinyl monosubstituted with alkyl. Optionally, B includes unsubstituted piperidinyl. Optionally, B includes C 1-6 Optionally, B includes piperidinyl monosubstituted with alkyl. Optionally, B includes piperidinyl monosubstituted with methyl. Optionally, B includes piperidinyl monosubstituted with ethyl. Optionally, R 3 is C substituted with CN, SO3H 1-6 Alkylene-O(O)CC 1-6 Alkyl, C 1-6 Alkenylene-C(O)OC 1-6 C substituted with alkyl or PO(OCH2CH2)2 1-6 It is alkylene-OH.

[0040] In some cases, R 3a is H. In some cases, R 3a is C 1-6 In some cases, R 3a is methyl.

[0041] In some cases, ring A is C 6-10 Optionally, Ring A is cycloalkyl. Optionally, Ring A is cyclohexyl. Optionally, Ring A is C 1 containing one nitrogen heteroatom. 6-10 aryl or 5-10 membered heteroaryl. 6-10 Optionally, Ring A is aryl. Optionally, Ring A is phenyl. Optionally, Ring A is a 5-10 membered heteroaryl containing one nitrogen heteroatom. Optionally, Ring A is pyridinyl.

[0042] In various cases, ring A comprises a phenyl and each R 1a is F and R 1b is H, and each R N is H, n is 1, and R x is a halo, R2 But C 1-6 Haloalkyl, C 1-6 Alkylene-C 3-8 Carbocyclyl, or C 1-6 Alkylene-C 6-10 aryl, wherein the aryl is optionally selected from OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 substituted with 1 or 2 substituents independently selected from alkoxy; 3 C replaced by CN, SO3H 1-6 Alkylene-O(O)CC 1-6 Alkyl, C 1-6 Alkenylene-C(O)OC 1-6 C substituted with alkyl, PO(OCH2CH2)2 1-6 Alkylene -OH, CHO, or -[C(O)]2-NR N -B.

[0043] In some cases, the compound and its pharmaceutically acceptable salts have the structure of Formula (Ib): [ka] , During the ceremony, R x is Cl, F, cyclopropyl, or phenyl; R y But F, m is 0 or 1, R 2 But C 4-5 Alkyl, C 3-5 Haloalkyl, CH2C 3-6 carbocyclyl, or benzyl, wherein the carbocyclyl is optionally substituted by methyl or ethyl; R 3 is CHO, C(O)C(O)NH, C(O)C(O)NHcyclopropyl, or C(O)C(O)NHethyl; However, R x is Cl, m is 0, and R 3is CHO, C(O)C(O)NH, or C(O)C(O)NH cyclopropyl, R 2 But not 2-methyl-propyl.

[0044] In some cases, for a compound or salt of formula (Ib), R x is Cl. In some cases, m is 0. In some cases, m is 1 and R y is F (e.g., meta-F).

[0045] In some cases, for a compound or salt of formula (Ib), R 2 is 2-methyl-propyl, butyl, pentyl, 2-methyl-butyl, 3,3-difluoropropyl, CH2-cyclopropyl, CH2-cyclobutyl, CH2-cyclopentyl, CH2-cyclohexyl, CH2-(1-ethylcyclopropyl), CH2-(1-methylcyclobutyl), CH2-(1-ethylcyclobutyl), CH2-(1-ethylcyclopentyl), or benzyl. 2 is butyl, pentyl, 2-methyl-butyl, 3,3-difluoropropyl, CH2-cyclopropyl, CH2-cyclobutyl, CH2-cyclopentyl, CH2-cyclohexyl, CH2-(1-ethylcyclopropyl), CH2-(1-methylcyclobutyl), CH2-(1-ethylcyclopentyl), CH2-(1-ethylcyclopentyl), or benzyl. 2 is CH2cyclohexyl. In some cases, R 2 is butyl or 2-methyl-butyl. Optionally, for a compound or salt of formula (Ib), R 3 is CHO. In some cases, R 3 is C(O)C(O)NH cyclopropyl.

[0046] Specific compounds contemplated include those in the table below. Compounds exhibiting a specific stereocenter exhibit at least relative stereoisomerism. Compounds with a chiral center that do not exhibit specific stereoisomerism exhibit a mixture of stereogenicity at that chiral center.

[0047] The compound can be a compound listed in Table A or Table B, or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16]

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

[0048] In some cases, the compound is selected from compounds A20 and A25-A29, or a pharmaceutically acceptable salt thereof. In some cases, the compound is selected from A20, A20-1, A20-2, A25-1, A48, A72, A119, A126, A164, A165, A167, A187, A196, A206, A209, A210, A228, A235, A239, A258, A265, A268, A270, A273, A289, A290, A295, A296, A297, A298, A299, A300, A302, A308, A309, A310, A316, A321, and A325, or a pharmaceutically acceptable salt thereof.

[0049] The compounds disclosed herein may be useful as inhibitors of norovirus or coronavirus replication in biological samples or patients. These compounds may also be useful for reducing the amount of norovirus or coronavirus (viral titer) in biological samples or patients. They may also be useful for therapeutic and prophylactic treatment of infections caused by norovirus or coronavirus in biological samples or patients.

[0050] pharmaceutically acceptable salts The compounds described herein can exist in free form or, where appropriate, as salts.These pharmaceutically acceptable salts are particularly interesting because they are useful for administering the compounds described below for medical purposes.Pharmaceutically unacceptable salts are useful in the manufacturing process for isolation and purification purposes, and in some cases, are useful for separating stereoisomers of the compounds of the present disclosure or their intermediates.

[0051] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is suitable for use in contact with the tissues of humans and lower animals without undue adverse side effects, such as toxicity, irritation, allergic response, and the like, within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio.

[0052] Pharmaceutically acceptable salts are well known in the art.For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases.These salts can be prepared in situ during the final isolation and purification of the compounds.

[0053] If the compounds described herein contain a basic group or a sufficiently basic bioisostere, an acid addition salt can be prepared by 1) reacting the purified compound in its free base form with a suitable organic or inorganic acid, and 2) isolating the salt so formed. In practice, the acid addition salt may be a more convenient form for use, and use of the salt amounts to use of the free base form.

[0054] Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydrochloride, and the like. These include hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0055] When the compounds described herein contain a carboxy group or a sufficiently acidic bioisostere, a base addition salt can be prepared by 1) reacting the purified compound in its acidic form with a suitable organic or inorganic base, and 2) isolating the salt thus formed. In practice, the use of a base addition salt may be more convenient, and use of the salt form is essentially equivalent to use of the free acid form. Salts derived from appropriate bases include alkali metals (e.g., sodium, lithium, and potassium), alkaline earth metals (e.g., magnesium, calcium), ammonium, and N +(Ci-4 alkyl) salts are included. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

[0056] Base addition salts include pharmaceutically acceptable metal salts and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium, and aluminum. Sodium and potassium salts are usually preferred. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed with counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, and the like. Suitable amine base addition salts are prepared from amines, which are frequently used in medicinal chemistry due to their low toxicity and acceptability for medical use. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine, etc.

[0057] Other acids and bases may be used in the preparation of salts which, while not themselves pharmaceutically acceptable, are useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

[0058] It is understood that the compounds disclosed herein may exist as mixtures / combinations of different pharmaceutically acceptable salts. Mixtures / combinations of the free form of the compound with pharmaceutically acceptable salts are also contemplated.

[0059] Pharmaceutical Compositions The compounds described herein can be formulated into pharmaceutical compositions further comprising a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In embodiments, the present disclosure relates to pharmaceutical compositions comprising the above-described compounds or salts thereof and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In embodiments, the pharmaceutical composition comprises a safe and effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients, or carriers that are suitably selected with respect to the intended form of administration and consistent with conventional pharmaceutical practice.

[0060] "Effective amount" includes "therapeutically effective amount" and "prophylactically effective amount." The term "therapeutically effective amount" refers to an amount effective to treat and / or ameliorate a Norovirus or coronavirus infection in a patient. The term "prophylactically effective amount" refers to an amount effective to prevent and / or substantially reduce the chance or size of developing a Norovirus or coronavirus infection.

[0061] Pharmaceutically acceptable carriers can contain inactive ingredients that do not excessively inhibit the biological activity of compound.Pharmaceutically acceptable carriers must be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or have no other undesirable reactions or side effects when administered to a subject.Standard pharmaceutical formulation techniques can be used.

[0062] As used herein, pharmaceutically acceptable carriers, adjuvants, or vehicles include any solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, that are suitable for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds described herein, for example, by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition, its use is contemplated within the scope of the present disclosure. As used herein, the phrase "side effects" encompasses undesired and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (eg, prophylactic or therapeutic agent) might be harmful or uncomfortable or risky.

[0063] Examples of materials that can function as pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as Twin 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropylmethylcellulose, wool fat, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, for example, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; cocoa butter and suppository waxes. waxes); oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, phosphate buffer solution, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulation manufacturer.

[0064] Formulations for pulmonary delivery In some embodiments, the pharmaceutical compositions disclosed herein are adapted for administration directly to the lower respiratory tract (e.g., lungs) via inhalation through the respiratory tract. Compositions for administration by inhalation can take the form of inhalable powder compositions or liquid or powder sprays and can be administered in standard forms using powder inhalers or aerosol dispensing devices. Such devices are well known. For administration by inhalation, powder formulations typically contain the active compound together with an inert solid powder diluent such as lactose or starch. Inhalable dry powder compositions can be presented in capsules and cartridges of gelatin or similar material, or in blisters of laminated aluminum foil for use in an inhaler or insufflator. Each capsule or cartridge may generally contain, for example, about 10 mg to about 100 g of each active compound. Alternatively, the compositions may be presented without excipients.

[0065] Inhalable composition can be packaged for unit dose or multiple dose delivery.For example, composition can be packaged for multiple doses in a similar manner as described in GB2242134, United States Patent No. 6,632,666, United States Patent No. 5,860,419, United States Patent No. 5,873,360 and United States Patent No. 5,590,645 (all referring to "Diskus" device), or GB2i78965, GB2129691, GB2169265, United States Patent No. 4,778,054, United States Patent No. 4,811,731 and United States Patent No. 5,035,237 (referring to "Diskhaler" device), or EP69715 ("Turbuhaler" device), or GB2064336 and United States Patent No. 4,353,656 ("Rotahaler" device).

[0066] Spray compositions for local delivery to the lungs by inhalation can be formulated as aqueous solutions or suspensions, or as aerosols delivered from pressurized packs such as metered dose inhalers (MDIs), using suitable liquefied propellants, including hydrofluoroalkanes such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, particularly 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane, and mixtures thereof. Aerosol compositions suitable for inhalation can be provided as either suspensions or solutions.

[0067] Medicaments for administration by inhalation typically have a controlled particle size. The optimal particle size for inhalation into the bronchial system is usually about 1 to about 10 μm, and in some embodiments, about 2 to about 5 μm. Particles having a size greater than about 20 μm are generally too large to reach the small airways upon inhalation. To achieve these particle sizes, particles of the active ingredient may be subjected to a size reduction process such as micronization. The desired size fraction may be separated by air classification or sieving. Preferably, the particles are crystalline.

[0068] Nasal sprays may be formulated using aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acids or alkalis to adjust the pH, tonicity adjusting agents, or antioxidants.

[0069] Solutions for inhalation by nebulization can be formulated using an aqueous vehicle to which agents such as acids or alkalis, buffer salts, isotonicity adjusting agents, or antibacterial agents have been added. They can be sterilized by filtration or heating in an autoclave, or can be provided as non-sterile products. Nebulizers deliver the aerosol as a mist generated from the aqueous formulation.

[0070] In some embodiments, the pharmaceutical compositions disclosed herein may be formulated with supplementary active ingredients.

[0071] In some embodiments, the pharmaceutical compositions disclosed herein are administered from a dry powder inhaler. In other embodiments, the pharmaceutical compositions disclosed herein are administered by an aerosol dispensing device, optionally in combination with an inhalation chamber, such as a "Volumatic"® inhalation chamber.

[0072] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and / or vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms in the compositions disclosed herein can be achieved by the addition of antibacterial and / or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is desirable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0073] In some embodiments, the pharmaceutical composition may be within a matrix that controls the release of the composition. In some embodiments, the matrix may be a lipid, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, poly(glycolic) acid, poly(lactic) acid, polycaprolactone, polylactic acid, polyanhydride, polylactide-co-glycolide, polyamino acids, polyethylene oxide, acrylic-terminated The matrix may comprise polymers such as polyethylene oxide (polyethylene oxide), polyamide, polyethylene, polyacrylonitrile, polyphosphazene, poly(orthoester), sucrose acetate isobutyrate (SAIB), and combinations thereof, as well as other polymers such as those disclosed in U.S. Patent Nos. 6,667,371, 6,613,355, 6,596,296, 6,413,536, 5,968,543, 4,079,038, 4,093,709, 4,131,648, 4,138,344, 4,180,646, 4,304,767, and 4,946,931, each of which is expressly incorporated herein by reference in its entirety. In these embodiments, the matrix provides sustained drug release.

[0074] Pharmaceutically acceptable carriers and / or diluents may include any solvents, dispersion media, coatings, antibacterial and / or antifungal agents, isotonic and absorption delaying agents, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated.

[0075] Pharmaceutical compositions can be formulated for administration according to conventional techniques. See, e.g., Remington, The Science and Practice of Pharmacy (20th Ed. 2000). For example, the intranasal pharmaceutical compositions of the present disclosure can be formulated as aerosols (which term includes both liquid aerosols and dry powder aerosols). Liquid particle aerosols can be generated by any suitable means, such as pressure-driven aerosol nebulizers or ultrasonic nebulizers, as known to those skilled in the art. See, e.g., U.S. Pat. No. 4,501,729. Similarly, solid particle aerosols (e.g., lyophilized, freeze-dried, etc.) can be generated in any solid particle pharmaceutical aerosol generating device according to techniques known in the pharmaceutical industry. As another example, pharmaceutical compositions can be formulated as on-demand dissolvable forms that provide a lyophilized portion of the pharmaceutical composition and a dissolved solution portion of the pharmaceutical composition.

[0076] In some embodiments, the pharmaceutical composition is in the form of an aqueous suspension, which can be prepared from a solution or suspension. With respect to a solution or suspension, the dosage form can be composed of lipophilic substances, liposomes (phospholipid vesicles / membranes), and / or micelles of fatty acids (e.g., palmitic acid). In certain embodiments, the pharmaceutical composition is a solution or suspension that can dissolve in the fluid secreted by the epithelial mucosa of the tissue to which the pharmaceutical composition is administered, applied, and / or delivered, which can advantageously enhance absorption.

[0077] The pharmaceutical composition can be an aqueous solution, a non-aqueous solution, or a combination of an aqueous solution and a non-aqueous solution. Suitable aqueous solutions include, but are not limited to, aqueous gels, aqueous suspensions, aqueous microsphere suspensions, aqueous microsphere dispersions, aqueous liposome dispersions, aqueous micelles of liposomes, aqueous microemulsions, and any combinations thereof, or any other aqueous solution that can be dissolved in the fluid secreted by the mucous membranes of the nasal cavity. Exemplary non-aqueous solutions include, but are not limited to, non-aqueous gels, non-aqueous suspensions, non-aqueous microsphere suspensions, non-aqueous microsphere dispersions, non-aqueous liposome dispersions, non-aqueous emulsions, non-aqueous microemulsions, and any combinations thereof, or any other non-aqueous solution that can be mixed with or dissolved in the fluid secreted by the mucous membranes.

[0078] Examples of powder formulations include, but are not limited to, simple powder mixtures, micronized powders, freeze-dried powders, lyophilized powders, powder microspheres, coated powder microspheres, liposomal dispersions, and any combination of the foregoing. Powder microspheres can be formed from a variety of polysaccharides and celluloses, including, but not limited to, starch, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, carbomer, polyvinyl alcohol alginate, acacia, chitosan, and any combination thereof.

[0079] In certain embodiments, the composition is at least partially, or even substantially (e.g., at least 80%, 90%, 95% or more) soluble in fluids secreted by mucous membranes to facilitate absorption. Alternatively or additionally, the composition may be formulated with carriers and / or other substances that promote the solubility of the agent in the secretions, including, but not limited to, fatty acids (e.g., palmitic acid), gangliosides (e.g., GM-1), phospholipids (e.g., phosphatidylserine), and emulsifiers (e.g., polysorbate 80).

[0080] Those skilled in the art will appreciate that for intranasal administration or delivery, the volume of pharmaceutical composition administered is generally small, and the pH range within the nasal cavity can be as broad as 5-8, so nasal secretions can alter the pH of the administered dose. Such alterations can affect the concentration of non-ionized drug available for absorption. Therefore, in exemplary embodiments, the pharmaceutical composition further comprises a buffer to maintain or adjust the pH in situ. Exemplary buffers include, but are not limited to, ascorbate, acetate, citrate, prolamin, carbonate, and phosphate buffers.

[0081] In embodiments, the pH of the pharmaceutical composition is selected to result in an acidic to neutral internal environment of the mucosal tissue after administration, which (1) provides the active compound in a non-ionized form for absorption, (2) prevents the growth of pathogenic bacteria that are more likely to occur in an alkaline environment, and (3) reduces the potential for mucosal irritation.

[0082] For liquid and powder sprays or aerosols, the pharmaceutical compositions can be formulated to have any suitable and desired particle or droplet size. In exemplary embodiments, the majority and / or average size of the particles or droplets is in the range of about 1, 2.5, 5, 10, 15, or 20 microns or more, and / or about 25, 30, 40, 45, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, or 425 microns or less (including all combinations of the foregoing). Representative examples of suitable ranges of bulk and / or average particle or droplet size include, but are not limited to, about 5-100 microns, about 10-60 microns, about 175-325 microns, and about 220-300 microns, which promote deposition of a safe and effective amount of active compound, for example, within the nasal cavity (e.g., the upper third of the nasal cavity, the superior nasal meatus, the olfactory region, and / or the sinus region to target the olfactory nerve pathway). Generally, particles or droplets smaller than about 5 microns will deposit in the trachea or even the lungs, while particles or droplets greater than about 50 microns will generally not reach the nasal cavity and will deposit in the anterior nose.

[0083] International Patent Publication No. 2005 / 023335 (Kurve Technology, Inc.) describes particles and droplets having diameter sizes suitable for practicing exemplary embodiments of the pharmaceutical compositions disclosed herein. In certain embodiments, the particles or droplets have an average diameter of about 5-30 microns, about 10-20 microns, about 10-17 microns, about 10-15 microns, about 12-17 microns, about 10-15 microns, or about 10-12 microns. Particles may have "substantially" the average diameters or sizes described herein, i.e., at least about 50%, 60%, 70%, 80%, 90%, or 95% or more of the particles are within the indicated diameter or size range.

[0084] The pharmaceutical composition may be delivered as a mist or atomized liquid having droplet sizes as described above.

[0085] According to certain embodiments of the present disclosure, including intranasal delivery methods, it may be desirable to extend the residence time of a pharmaceutical composition in the nasal cavity (e.g., in the upper third of the nasal cavity, the superior nasal meatus, the olfactory region, and / or the paranasal sinus region), e.g., to enhance absorption. Thus, the pharmaceutical composition may optionally be formulated with agents that extend residence time in the nasal cavity, such as bioadhesive polymers, gums (e.g., xanthan gum), chitosan (e.g., highly purified cationic polysaccharides), pectin (or any carbohydrate that thickens like a gel or emulsifier when applied to the nasal mucosa), microspheres (e.g., starch, albumin, dextran, cyclodextrin), gelatin, liposomes, carbamer, polyvinyl alcohol, alginate, acacia, chitosan, and / or cellulose (e.g., methyl or propyl, hydroxyl or carboxy, carboxymethyl or hydroxylpropyl). As a further approach, increasing the viscosity of the formulation may also provide a means of extending contact of the agent with the nasal epithelium. Pharmaceutical compositions can be formulated as nasal emulsions, ointments, or gels, which offer advantages for topical application due to their viscosity.

[0086] A moist, highly vascular membrane can promote rapid absorption; therefore, the pharmaceutical composition may optionally contain a humectant, particularly in the case of a gel-based composition, to ensure sufficient intranasal moisture content. Examples of suitable humectants include, but are not limited to, glycerin or glycerol, mineral oil, vegetable oil, membrane conditioners, soothing agents, and / or sugar alcohols (e.g., xylitol, sorbitol, and / or mannitol). The concentration of the humectant in the pharmaceutical composition will vary depending on the drug and formulation selected.

[0087] Pharmaceutical compositions can also optionally include absorption enhancers, such as agents that inhibit enzymatic activity, reduce mucus viscosity or elasticity, reduce mucociliary clearance, open tight junctions, and / or solubilize the active compound. Chemical enhancers are known in the art and include chelating agents (e.g., EDTA), fatty acids, bile salts, surfactants, and / or preservatives. Penetration enhancers can be particularly useful when formulating compounds that exhibit low membrane permeability, lack lipophilicity, and / or are degraded by aminopeptidases. The concentration of absorption enhancers in the pharmaceutical composition will vary depending on the drug and formulation selected.

[0088] Preservatives can optionally be added to pharmaceutical compositions to extend shelf life.Suitable preservatives include, but are not limited to, benzyl alcohol, parabens, thimerosal, chlorobutanol, and benzalkonium chloride, and combinations thereof.The concentration of the preservative varies depending on the preservative used, the compound to be formulated, the formulation, etc.In a typical embodiment, the preservative is present in an amount of about 2% by weight or less.

[0089] The pharmaceutical compositions described herein may optionally contain an odorant, e.g., as described in EP 0 504 263 B1, to provide an odor to aid in inhalation of the composition to facilitate delivery to the olfactory region and / or to induce transport by olfactory neurons.

[0090] Alternatively, the composition may include a flavoring agent, for example to enhance the taste and / or acceptability of the composition to a subject.

[0091] Porous particles for pulmonary administration In some embodiments, the particles are porous such that they have an appropriate density to avoid deposition in the back of the throat when administered via an inhaler. The combination of a relatively large particle size and a relatively low density avoids phagocytosis in the lungs, providing well-targeted delivery, avoiding systemic delivery of the component, and providing a high concentration of the component in the lung.

[0092] Representative methods for preparing and delivering such particles are described, for example, in U.S. Pat. No. 7,384,649 entitled "Particulate compositions for pulmonary delivery," U.S. Pat. No. 7,182,961 entitled "Particulate compositions for pulmonary delivery," U.S. Pat. No. 7,146,978 entitled "Inhalation device and method," U.S. Pat. No. 7,048,908 entitled "Particles for inhalation having sustained release properties," U.S. Pat. No. 6,956,021 entitled "Stable spray-dried protein formulations," U.S. Pat. No. 6,766,799 entitled "Inhalation device," and U.S. Pat. No. 6,732,732 entitled "Inhalation device and method."

[0093] Additional patents disclosing such particles include U.S. Pat. No. 7,279,182, entitled "Formulation for spray-drying large porous particles," U.S. Pat. No. 7,252,840, entitled "Use of simple amino acids to form porous particles," and U.S. Pat. No. 7,032,593, entitled "Inhalation device and method," U.S. Pat. No. 7,008,644, entitled "Method and apparatus for producing dry particles," U.S. Pat. No. 6,848,197, entitled "Control of process humidity to produce large, porous particles," and U.S. Pat. No. 6,749,835, entitled "Formulation for spray-drying large porous particles."

[0094] U.S. Patent No. 7,678,364, entitled "Particles for inhalation having sustained release properties," describes a method for administering to the airways of a patient in need of treatment, prevention, or diagnosis a polyvalent metal cation complexed with a therapeutic, prophylactic, or diagnostic agent, b) a pharmaceutically acceptable carrier, and c) a dry powder that is spray dried and contains a total amount of polyvalent metal cation that is about 10% w / w or more of the total weight of the agent, and 0.4 g / cm 3 Disclosed is a method for delivering particles to the pulmonary system comprising administering a safe and effective amount of a dry powder comprising a polyvalent metal cation-containing component having a tap density of about 1000 to about 15000 sq ft or less, a median geometric diameter of about 5 micrometers to about 30 micrometers, and an aerodynamic diameter of about 1 to about 5 microns.

[0095] The amount of a compound described herein or a salt thereof present in the particles can range from about 0.1% to about 95% by weight, but in some cases can be as high as 100% (e.g., from about 1% to about 50%, e.g., from about 5% to about 30%). Particles in which the compound is distributed throughout the particle can be preferred.

[0096] In some embodiments, the particles contain surfactants other than the above-mentioned phospholipids. As used herein, the term "surfactant" refers to any agent that preferentially absorbs at the interface between two immiscible phases, such as the interface between water and an organic polymer solution, the water / air interface, or the organic solvent / air interface. Surfactants generally have hydrophilic and lipophilic portions, so when absorbed into particles, they tend to present a portion to the external environment that is not attractive to similarly coated particles, thereby reducing particle aggregation. Surfactants can also facilitate the absorption of therapeutic or diagnostic agents and increase the bioavailability of the agent.

[0097] Suitable surfactants that can be used in producing the particles disclosed herein include, but are not limited to, hexadecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; surface-active fatty acids such as palmitic acid or oleic acid; glycocholate; surfactin; poloxamer; sorbitan fatty acid esters such as sorbitan trioleate (Span 85); Tween® 80 and tyloxapol.

[0098] The surfactant may be present in the particles in an amount ranging from about 0 to about 5% by weight, preferably from about 0.1 to about 1.0% by weight.

[0099] Approximately 0.4g / cm 3Particles with a tap density of less than about 5 μm, a median diameter of at least about 5 μm, and an aerodynamic diameter of about 1 μm to about 5 μm or about 1 μm to about 3 μm are better able to avoid inertial and gravitational deposition in the oropharyngeal region and are targeted to the airways or deep lung. The use of larger, more porous particles is advantageous because they can be aerosolized more efficiently than smaller, denser aerosol particles, such as those currently used for inhalation therapy.

[0100] Liposomal delivery The compositions described herein are advantageously delivered to the lungs to provide the compounds at the site of actual or potential norovirus or coronavirus infection, which can be achieved by pulmonary delivery via a metered dose inhaler or other pulmonary delivery device, or by capturing particles in the capillary bed surrounding the alveoli of the lungs.

[0101] Nanocarriers, such as liposomes, which comprise small unilamellar vesicles, offer several advantages over other conventional approaches for delivering drugs to the lung, such as extended drug release and cell-specific targeted drug delivery. Nanosized drug carriers may also be advantageous for the delivery of poorly water-soluble drugs, and certain compounds described herein are poorly water-soluble. Additional advantages include the ability to provide controlled release, protection from metabolism and degradation, reduced drug toxicity, and targeting capabilities.

[0102] The liposomes (preferably unilamellar vesicles) have a size of less than 200 nm as measured by dynamic light scattering, sufficient to preferentially deliver (i.e., target) the amount of compound to the capillary bed surrounding the alveoli, are composed of chemically pure synthetic phospholipids, and are most preferably characterized by an aliphatic side chain of at least 16 carbons in length, and contain one or more compounds described herein or pharmaceutically acceptable salts thereof. The diameter of the vesicles can be measured, for example, by dynamic light scattering using a helium-neon 100 mW NEC gas laser and a Malvern K7027 correlator, and ideally, at least two or three measurements are taken for each size determination.

[0103] The term "chemically pure phospholipid" is intended to define phospholipids that are essentially free of harmful surfactant moieties and impurities (which cause aggregation of small unilamellar vesicles (SUVs) formed therefrom) and are greater than 97% pure. Preferably, the liposomes incorporate primarily phospholipids with diameters of about 50 to about 160 nm, are essentially neutral in charge, and have side chain lengths of 16 to 18 carbon atoms. More preferably, the liposomes are prepared from distearoylphosphatidylcholine (DSPC) and contain cholesterol as a vesicle stabilizer (most preferably in an amount of 10 to 50% of the total lipid).

[0104] It may also be advantageous for the liposomes to have a melting point above body temperature (i.e., above 37°C). For this reason, it may be advantageous to use pure phospholipids, preferably saturated, with a carbon chain length of at least 16 carbons, preferably 16-18 carbons. Distearoylphosphatidylcholine (DSPC) is a preferred phospholipid.

[0105] Cholesterol is useful for stabilizing liposomes, and is preferably added in an amount sufficient to provide liposome stability.Most preferably, liposomes further comprise PEGylated phospholipids, such as DSPEPEG.The method comprises introducing into the bloodstream of a patient an amount of liposomes (preferably unilamellar vesicles), which are less than 200 nm in size, preferably comprise chemically pure synthetic phospholipids, and most preferably comprise an aliphatic side chain of at least 16 carbons in length, sufficient to preferentially deliver (i.e., target) an amount of compound to the pulmonary capillary bed surrounding the alveoli, and which contain the compound described herein or its pharmaceutically acceptable salt or prodrug.

[0106] The compounds described herein can be combined with other anti-norovirus or anti-coronavirus agents. Such additional agents can be present in the liposome, in different liposomes, or co-administered via different routes.

[0107] Liposomes contain one or more of the compounds described herein or pharmaceutically acceptable salts thereof, and may optionally contain other anti-norovirus or anti-coronavirus agents. Liposomes can be prepared by dissolving phospholipids and cholesterol in a suitable organic solvent, such as chloroform, and evaporating the solvent to form a lipid film. If an ionophore is used to load the compounds described herein into the liposomes, the ionophore can be added to the lipid solution before evaporation. The dried lipid film is then rehydrated with an appropriate aqueous phase, such as phosphate-buffered saline or other physiologically appropriate solution. Water-soluble drugs or therapeutic agents can be contained in the hydration solution, but if remote loading is desired, a loading agent, such as the chelating agents described above, can be added to the hydration solution to encapsulate them within the internal aqueous space of the liposomes.

[0108] Upon addition of the hydration solution, liposomes of various sizes spontaneously form and encapsulate a portion of the aqueous phase. The liposomes and aqueous suspension are then subjected to shear forces, such as extrusion, sonication, or treatment with a homogenizer, according to the methods described in U.S. Pat. No. 4,753,788, to generate vesicles of specific sizes.

[0109] The liposomes can then be treated to remove undesired compounds, such as unencapsulated drug, from the suspension, which can be accomplished by processes such as gel chromatography or ultrafiltration.

[0110] The use of liposomes in dry powder aerosols for targeted pulmonary delivery is described, for example, in Willis et al., Lung, June 2012, 190(3):251-262. One advantage is that the phospholipids used to prepare liposomes are similar to endogenous pulmonary surfactants.

[0111] Route of administration and dosage The compounds and pharmaceutically acceptable compositions described above can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powder, ointment, or drops), buccally, or as an oral or nasal spray to the pulmonary system, such as by use of an inhaler such as a metered dose inhaler (MDI), depending on the severity of the infection being treated. In some embodiments, the compounds or compositions disclosed herein are administered orally, by inhalation, or intravenously.

[0112] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain auxiliary agents such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0113] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be injectable sterile solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid are used in the preparation of injectables.

[0114] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other injectable sterile medium before use.

[0115] To prolong the effect of the compounds provided herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the drug-to-polymer ratio and the nature of the particular polymer used, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0116] Compositions for rectal or vaginal administration are specifically suppositories, which can be prepared by mixing a compound described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound.

[0117] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.

[0118] Solid compositions of a similar type may be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0119] The active compound may also be in microencapsulated form with one or more excipients, as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared using coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may be of a composition that releases the active ingredient only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0120] Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, this disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0121] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose, or similar dispersants commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0122] The pharmaceutical compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include, but are not limited to, lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If desired, certain sweeteners, flavorings, or coloring agents can also be added.

[0123] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0124] The pharmaceutical compositions described herein may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0125] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical application may also involve the use of a transdermal patch.

[0126] For topical application, pharmaceutical compositions can be formulated into a suitable ointment, containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, pharmaceutical compositions can be formulated into a suitable lotion or cream, containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol, and water.

[0127] For ophthalmic use, the pharmaceutical composition may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or specifically as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated into an ointment such as petrolatum.

[0128] Pharmaceutical compositions may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline employing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0129] The compounds used in the methods of the present disclosure may be formulated in unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable as a unit and dosage for the subject to be treated, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect, optionally with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0130] Treatment methods The use of the compounds described herein as therapeutic agents is provided herein. The compounds described herein or pharmaceutically acceptable salts thereof can be used to reduce viral titers in biological samples (e.g., infected cell cultures) or humans (e.g., lung viral titers in patients). The compounds described herein or pharmaceutically acceptable salts thereof can be used in methods for treating viral infections. Non-limiting examples of viral infections that can be treated with the compounds described herein or pharmaceutically acceptable salts thereof include coronavirus infections, calicivirus infections, and picornavirus infections.

[0131] Non-limiting examples of calicivirus infections include norovirus-mediated conditions and norovirus infection. As used herein, the terms "norovirus-mediated conditions," "norovirus infection," and "norovirus" are used interchangeably to mean illness caused by infection with norovirus.

[0132] Noroviruses are infectious viruses that cause gastroenteritis in mammals. Noroviruses are RNA viruses of the Caliciviridae family and include seven genogroups: GI, GII, GIII, GIV, GV, GVI, and GVII. Genogroup II, the most common human genogroup, currently contains 19 genotypes. Genogroups I, II, and IV infect humans, while genogroup III infects bovine species, and genogroup V has recently been isolated in mice. The two groups most associated with human gastroenteritis include genogroup I (GI), which includes Norwalk virus, Desert Shield virus, and Southampton virus, and genogroup II (GII), which includes Bristol virus, Rosedale virus, Toronto virus, Mexico virus, Hawaii virus, and Snow Mountain virus.

[0133] In some embodiments, the compounds used herein are for treating norovirus associated with gastroenteritis. In some embodiments, the norovirus is associated with Norwalk virus. In some embodiments, the norovirus is associated with HuNV GGII.4.

[0134] In some embodiments, the compounds disclosed herein can be used to treat Norovirus, where the compounds bind to free virus or inhibit Norovirus protease. In some cases, the compounds can target both (free virus and protease).

[0135] In humans, common symptoms of norovirus are nausea, vomiting, watery diarrhea, abdominal pain, and possibly loss of taste. Norovirus can cause long-term infection in immunocompromised humans. In severe cases, persistent infection can lead to norovirus-associated enteropathy, intestinal villous atrophy, and malabsorption. Norovirus-associated gastroenteritis is also known as the "winter vomiting bug."

[0136] People usually develop symptoms of gastroenteritis 12 to 48 hours after being infected with norovirus, which can include general malaise, weakness, muscle aches, headache, and a slight fever.

[0137] As used herein, the term "coronavirus infection" refers to a disease caused by infection with a coronavirus. Non-limiting examples of coronaviruses include severe acute respiratory syndrome-associated coronavirus (SARS), Middle East respiratory syndrome-associated coronavirus (MERS), and SARS-CoV-2 virus (also known as 2019-nCoV or Wuhan coronavirus). Non-limiting examples of coronavirus infections include SARS, MERS, and COVID-19 (i.e., SARS-CoV infection, MERS-CoV infection, and SARS-CoV-2 infection, respectively).

[0138] Coronaviruses are a family of viruses that cause disease in mammals and birds. They belong to the subfamily Orthocoronavirinae within the family Coronaviridae in the order Nidovirales. There are four main genera of coronaviruses, designated alpha, beta, gamma, and delta. Coronaviruses that affect humans include human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), human coronavirus NL63 (HCoV-NL63, New Haven coronavirus), human coronavirus HKU1, Middle East respiratory syndrome-associated coronavirus (MERS-CoV, formerly known as novel coronavirus 2012 and HCoV-EMC), and SARS-CoV-2 (also known as 2019-nCoV and Wuhan coronavirus).

[0139] In humans, coronaviruses cause respiratory infections similar to the common cold, generally with mild illness, although rare forms such as SARS, MERS, and SARS-CoV-2 (the cause of the 2019-20 COVID-19 outbreak) can be fatal. Symptoms vary in other species, such as upper respiratory tract inflammation in chickens and diarrhea in cattle and pigs. There are no vaccines or antiviral medications to prevent or treat human coronavirus infections. Coronaviruses HCoV-229E, -NL63, -OC43, and -HKU1 continually circulate in human populations, causing respiratory infections in adults and children worldwide.

[0140] In some embodiments, the compounds used herein are for the treatment of an alphacoronavirus or a betacoronavirus. In some embodiments, the compounds used herein are for the treatment of an alphacoronavirus. Non-limiting examples of alphacoronaviruses include HCoV-229E and HCoV-NL63. In some embodiments, the compounds used herein are for the treatment of a betacoronavirus. Non-limiting examples of betacoronaviruses are HCoV-HKU1, HCoV-OC43, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), and SARS-CoV-2. In some embodiments, the compounds used herein are for the treatment of noroviruses associated with SARS, MERS, and COVID-19. In some embodiments, the coronavirus is associated with SARS. In some embodiments, the coronavirus is associated with MERS. In some embodiments, the coronavirus is associated with COVID-19.

[0141] In some embodiments, the compounds disclosed herein can be used to treat coronavirus, where the compounds bind to free virus or inhibit coronavirus protease. In some cases, the compounds can target both (free virus and protease).

[0142] In humans, common symptoms of coronavirus are fever, cough, shortness of breath, and muscle aches.

[0143] Non-limiting examples of picornavirus infections include rhinovirus-mediated conditions and rhinovirus infections. As used herein, the terms "rhinovirus-mediated conditions" and "rhinovirus infections" are used interchangeably to mean diseases caused by infection with a rhinovirus.

[0144] Picornus infects both humans and animals, causing severe paralysis (paralytic poliomyelitis), aseptic meningitis, hepatitis, pleuritis, myocarditis, skin rash, and the common cold, although asymptomatic infection is common. Several medically important genera are members of this family, such as enteroviruses (including poliovirus (PV), rhinoviruses, and human enteroviruses (e.g., coxsackieviruses)), hepatoviruses, including hepatitis A virus (HAV), and aphthoviruses, including foot-and-mouth disease virus (FMDV). Rhinoviruses are recognized as the primary cause of the common cold in humans and include three distinct species: A, B, and C. Transmission is primarily via the aerosol route, with the virus replicating in the nose.

[0145] In some embodiments, the compounds disclosed herein can be used to treat picornavirus infections. In some embodiments, the compounds disclosed herein can be used to treat rhinovirus infections. In some embodiments, the compounds disclosed herein can be used to treat rhinovirus infections, where the compounds bind to free virus or inhibit rhinovirus protease. In some cases, the compounds can target both (free virus and protease).

[0146] As used herein, the term "disease" refers to a medical or pathological condition associated with a coronavirus infection.

[0147] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quails, or turkeys, or mammals), specifically "mammals," including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), more specifically humans. In one embodiment, the subject is a non-human animal, such as a livestock animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In a preferred embodiment, the subject is a "human."

[0148] As used herein, the term "biological sample" includes, but is not limited to, a cell culture or an extract thereof; a biopsy obtained from a subject or an extract thereof; blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0149] As used herein, "multiplicity of infection" or "MOI" refers to the ratio of infectious agent (e.g., phage or virus) to infected target (e.g., cell). For example, when referring to a group of cells inoculated with infectious viral particles, the multiplicity of infection or MOI is the ratio defined by dividing the number of infectious viral particles deposited in a well by the number of target cells present in that well.

[0150] As used herein, the terms "inhibition of Norovirus replication" and "inhibition of coronavirus replication" include a reduction in the amount of viral replication (e.g., at least a 10% reduction), which may be sufficient to result in a complete cessation of viral replication (i.e., a 100% reduction). In some embodiments, Norovirus or coronavirus viral replication is inhibited by at least 20%, at least 30%, at least 40%, at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.

[0151] Norovirus or coronavirus viral replication can be measured by any suitable method known in the art. For example, norovirus or coronavirus viral titers can be measured in biological samples (e.g., infected cell cultures) or in humans (e.g., lung viral titers in patients). More specifically, for cell-based assays, in each case, cells are cultured in vitro, virus is added to the culture in the presence or absence of a test agent, and a virus-dependent endpoint is evaluated after a suitable time. Such assays are known in the art. A first type of cellular assay that can be used in the present disclosure relies on the death of infected target cells, a process called cytopathic effect (CPE), in which viral infection causes the depletion of cellular resources and eventual cell lysis. In this type of cellular assay, a low percentage of cells (typically 1 / 10 to 1 / 1000) in a microtiter plate well is infected, the virus is allowed to replicate several times over 48 to 72 hours, and the amount of cell death is then measured using a decrease in cellular ATP content compared to uninfected controls. A second type of cellular assay that can be used in this disclosure relies on the amplification of virus-specific RNA molecules in infected cells, with RNA levels measured directly using branched-chain DNA hybridization (bDNA). In this second type of cellular assay, a small number of cells are first infected in the wells of a microtiter plate, the virus replicates in the infected cells, and then spreads to additional rounds of cells. The cells are then lysed and the viral RNA content is measured. The assay is stopped early, usually after 18-36 hours, while all target cells are still viable. Viral RNA is quantified by hybridization to specific oligonucleotide probes immobilized on the wells of the assay plate, followed by signal amplification via hybridization with an additional probe conjugated to a reporter enzyme.

[0152] As used herein, "virus titer (or titer)" is a measure of virus concentration. Titer testing can obtain approximate quantitative information from an analytical procedure that essentially evaluates only as positive or negative using serial dilutions. The titer corresponds to the highest dilution factor that still results in a positive reading. For example, a positive reading in the first eight serial two-fold dilutions converts to a titer of 1:256. To determine the titer, several dilutions are performed at 10 -1 , 10 -2 , 10 -3 , 10 -8 It will be prepared as follows:

[0153] As used herein, the terms "treat," "treatment," and "treating" refer to both therapeutic and prophylactic treatment. For example, therapeutic treatment includes a reduction or amelioration of the progression, severity, and / or duration of a Norovirus or coronavirus infection, or an improvement in one or more symptoms (e.g., one or more discernible symptoms) of a Norovirus or coronavirus infection, resulting from the administration of one or more therapies (e.g., one or more therapeutic agents, such as compounds or compositions of the present disclosure). In certain embodiments, therapeutic treatment includes an improvement in at least one measurable physical parameter of a Norovirus or coronavirus infection. In other embodiments, therapeutic treatment includes inhibiting the progression of a Norovirus or coronavirus infection, either physically, e.g., by stabilization of discernible symptoms, physiologically, e.g., by stabilization of physical parameters, or both. In other embodiments, therapeutic treatment includes a reduction or stabilization of a Norovirus or coronavirus-mediated infection. Antiviral medications can be used in community settings to treat people who already have norovirus or coronavirus to reduce the severity of symptoms and the number of days people are sick.

[0154] The term "chemotherapy" refers to the use of drugs, such as small molecule drugs (as opposed to "vaccines"), to treat a disorder or disease.

[0155] As used herein, the terms "prophylaxis" or "prophylactic use" and "prophylactic treatment" refer to any medical or public health procedure aimed at preventing, rather than treating or curing, a disease. As used herein, the terms "prevent," "prevention," and "preventing" refer to reducing the risk of acquiring or developing a given condition, or inhibiting the alleviation or recurrence of said condition, in a subject who is not ill but who is or has been near a person who has the disease. The term "chemoprevention" refers to the use of pharmaceutical agents, e.g., small molecule drugs (as opposed to "vaccines"), for the prevention of a disorder or disease.

[0156] As used herein, prophylactic use includes use in situations where an outbreak has been detected to prevent the transmission or spread of infection in settings where many people at high risk for severe norovirus or coronavirus complications live in close proximity to one another (e.g., hospital wards, daycare centers, prisons, nursing homes, etc.). Prophylactic use also includes use in populations in need of protection from norovirus or coronavirus but who are not protected after vaccination (e.g., due to a weakened immune system), or where a vaccine is not available for that population, or where side effects prevent them from receiving the vaccine. Prophylactic use also includes use two weeks after vaccination, because the vaccine is still ineffective during that period. Prophylactic use also includes treating people who have norovirus or coronavirus but are not sick or not considered at high risk for complications, to reduce the likelihood that they will become infected with norovirus or coronavirus and pass it on to high-risk individuals with whom they have close contact (e.g., healthcare workers, nursing home workers, etc.).

[0157] In some embodiments, the methods of the present disclosure are preventative or prophylactic measures for patients, particularly humans, who are predisposed to complications resulting from infection with a Norovirus or Coronavirus virus. Prophylactic use includes use in situations where an "index case" or "outbreak" has been confirmed, to prevent the spread of infection in the rest of the community or population.

[0158] In embodiments, the methods of the present disclosure are applied as a "prophylactic" measure to members of a community or population, particularly humans, to prevent the spread of infection.

[0159] As used herein, an "effective amount" refers to an amount sufficient to elicit a desired biological response. In this disclosure, the desired biological response is inhibiting the replication of norovirus or coronavirus, reducing the amount of norovirus or coronavirus, or reducing or ameliorating the severity, duration, progression, or onset of a norovirus or coronavirus infection; preventing the progression of a norovirus or coronavirus infection; preventing the recurrence, occurrence, onset, or progression of symptoms associated with a norovirus or coronavirus infection; or enhancing or improving the prophylactic or therapeutic effects of another therapy used against a norovirus or coronavirus infection. The amount of the compound administered to a subject depends on the mode of administration, the type and severity of the infection, and the subject's characteristics, such as general health, age, sex, weight, and tolerance to drugs. One of skill in the art would be able to determine the appropriate dosage depending on these and other factors. When co-administered with other antiviral agents, e.g., when co-administered with an anti-norovirus or anti-coronavirus drug, the "effective amount" of the second agent depends on the type of agent used. Suitable dosages are known for approved drugs and can be adjusted by those skilled in the art depending on the subject's condition, the type of disease being treated, and the amount of compound described herein used. If no amount is specified, a safe and effective amount should be assumed. For example, the compounds described herein can be administered to a subject in a dosage range of about 0.01 to 100 mg / kg body weight / day for therapeutic or prophylactic treatment.

[0160] In general, the administration regimen can be selected according to various factors, including the disorder to be treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the administration time, route of administration, and excretion rate of the specific compound used; the subject's renal and hepatic function; and the specific compound or salt thereof used, the duration of treatment; drugs used in combination with or simultaneously with the specific compound used, and similar factors well known in the medical field. Those skilled in the art can easily determine and prescribe the effective amount of the compound described herein required to treat, prevent, inhibit (completely or partially), or stop the progression of the disease.

[0161] The dosage of a compound (e.g., a compound of Formula (I), Formula (Ia), Formula (Ib), or a salt thereof) for use in the methods and compositions described herein can range from about 0.01 to about 100 mg / kg body weight / day, about 0.01 to about 50 mg / kg body weight / day, about 0.1 to about 50 mg / kg body weight / day, or about 1 to about 25 mg / kg body weight / day. In some cases, the method or composition includes a compound of Formula (I), Formula (Ia), Formula (Ib), or a salt thereof at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg. In some cases, the method or composition includes a compound of Formula (I), Formula (Ia), Formula (Ib), or a salt thereof at a dose of about 5 mg / kg. In some cases, the method or composition comprises a compound of Formula (I), Formula (Ia), Formula (Ib), or a salt thereof, at a dose of about 10 mg / kg.

[0162] For therapeutic treatment, the compounds described herein can be administered to a patient, for example, within 48 hours (or within 40 hours, or within less than 2 days, or within less than 1.5 days, or within 24 hours) of the onset of symptoms (e.g., stuffy nose, sore throat, cough, aches, fatigue, headache, and chills / sweats). Therapeutic treatment can be continued for any suitable period, such as, for example, 5 days, 7 days, 10 days, 14 days, etc. For prophylactic treatment during community outbreaks, the compounds described herein can be administered to a patient, for example, within 2 days of the onset of symptoms in index cases, and can be continued for any suitable period, such as, for example, 7 days, 10 days, 14 days, 20 days, 28 days, 35 days, 42 days, etc.

[0163] Combination therapy The compounds described herein can be used in combination therapy, i.e., in combination with other anti-norovirus or anti-coronavirus compounds, or in combination with a vaccine. Combination therapy can be particularly advantageous when a patient may be exposed to more than one form of norovirus or coronavirus virus.

[0164] A safe and effective amount can be achieved in the methods or pharmaceutical compositions of the disclosure using a compound described herein, or a pharmaceutically acceptable salt thereof, alone or in combination with an additional suitable therapeutic agent, such as an antiviral agent or a vaccine. When "combination therapy" is used, a safe and effective amount can be achieved using a first amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and a second amount of an additional suitable therapeutic agent (e.g., an antiviral agent or a vaccine).

[0165] In embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are each administered in a safe and effective amount (i.e., each in an amount that would be therapeutically effective if administered alone). In other embodiments, the compound described herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are each administered in an amount that does not provide a therapeutic effect alone (a sub-therapeutic dose). In yet other embodiments, the compound described herein, or a pharmaceutically acceptable salt thereof, may be administered in a safe and effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In yet other embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be administered in a sub-therapeutic dose, while the additional therapeutic agent, e.g., a suitable antiviral therapeutic agent, is administered in a safe and effective amount.

[0166] As used herein, the terms "in combination" or "co-administration" can be used interchangeably to refer to the use of two or more therapies (e.g., one or more prophylactic and / or therapeutic agents). The use of the terms does not restrict the order in which the therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject.

[0167] Co-administration encompasses administration of a first amount and a second amount of the compounds in an essentially simultaneous manner, for example, in a single pharmaceutical composition, e.g., a capsule or tablet having a fixed ratio of the first amount and the second amount, or in multiple, separate capsules or tablets for each. Additionally, such co-administration also includes use of each compound in a sequential manner, in any order.

[0168] In embodiments, the present disclosure relates to methods of combination therapy for inhibiting viral replication in a biological sample or a patient, or for treating or preventing Norovirus or Coronavirus infection in a patient, using a compound or pharmaceutical composition described herein, e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof. Accordingly, pharmaceutical compositions also include those comprising a compound disclosed herein (e.g., an inhibitor of viral replication) in combination with an antiviral compound that exhibits anti-Norovirus or Coronavirus viral activity.

[0169] Methods of using the compounds and compositions disclosed herein also include combining chemotherapy with a compound or composition disclosed herein, or a pharmaceutically acceptable salt thereof, or combining a compound or composition of the present disclosure with another antiviral agent.

[0170] When simultaneous administration involves separate administration of a first amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and a second amount of an additional therapeutic agent, the compounds are administered sufficiently closely in time to achieve the desired therapeutic effect. For example, the period between administrations that can produce the desired therapeutic effect can range from several minutes to several hours and can be determined taking into account the properties of each compound, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile. For example, the compound disclosed herein or a pharmaceutically acceptable salt thereof and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other, or within about 30 minutes of each other.

[0171] More specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound of the present disclosure) can be administered to a subject prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapeutic agent (e.g., a prophylactic or therapeutic agent such as an antiviral agent).

[0172] It is understood that the method of co-administration of a first amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a second amount of an additional therapeutic agent may result in an enhanced or synergistic therapeutic effect, wherein the effect of the combination is greater than the additive effect that may result from separate administration of the first amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and the second amount of an additional therapeutic agent.

[0173] As used herein, the term "synergistic" refers to a combination of a compound disclosed herein and another therapy (e.g., a prophylactic or therapeutic agent) that is more effective than the putative additive effect of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may allow for the use of lower dosages of one or more therapies and / or for the therapy to be administered less frequently to a subject. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and / or administer the therapy less frequently may reduce the toxicity associated with the administration of the therapy to a patient without reducing the efficacy of the therapy in preventing, managing, or treating a disorder. Furthermore, a synergistic effect may improve the efficacy of agents in preventing, managing, or treating a disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

[0174] When combination therapy using the compounds disclosed herein is combined with a viral vaccine, both therapeutic agents can be administered such that there can be longer periods of time between each administration (e.g., days, weeks, or months).

[0175] The presence of synergy can be determined using any suitable method for evaluating drug interactions. Suitable methods include, for example, the Sigmoid-Emax equation (Holford, NHG, and Scheiner, LB, Clin. Pharmacokinet. 6:429-453 (1981)), the Loewe additivity equation (Loewe, S, and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114:313-326 (1926)), and the median-effect equation (Chou, TC, and Talalay, P., Adv. Enzyme Regul. 22:27-55 (1984)). Each of the above-mentioned equations can be applied to experimental data to generate corresponding graphs that can be used to evaluate the effects of drug combinations. The corresponding graphs associated with the above-mentioned equations are the concentration-effect curve, the isobologram curve, and the combination index curve, respectively.

[0176] Chiral Separation The compounds described herein have asymmetric centers and can occur as racemates, racemic mixtures, individual diastereomers, or enantiomers; all isomers are included in the present disclosure. Compounds of the present disclosure that have chiral centers can exist and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. The present disclosure encompasses racemic, optically active, polymorphic, or stereoisomer forms of the disclosed compounds, or mixtures thereof, that possess the useful properties described herein. Optically active forms can be prepared, for example, by resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases, or enzymatic resolution. Each compound can be purified, and then the compound can be derivatized to form a compound described herein, or the compound itself can be purified.

[0177] Optically active forms of compounds can be prepared using any method known in the art, including, but not limited to, resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases.

[0178] Examples of methods for obtaining optically active materials include at least the following: i) Physical Separation of Crystals: A technique for manually separating macroscopic crystals of individual enantiomers. This technique can be used when crystals of the separate enantiomers are present, i.e., when the material is a conglomerate and the crystals are visually distinct. ii) Simultaneous crystallization: A technique in which the individual enantiomers are crystallized separately from a solution of the racemate, which is only possible if the latter is a conglomerate in the solid state. iii) Enzymatic resolution: A technique in which the racemate is partially or completely separated by virtue of different reaction rates between the enantiomers and an enzyme. iv) Enzymatic asymmetric synthesis: a synthetic technique that uses an enzymatic reaction in at least one step of the synthesis to obtain an enantiomerically pure or enriched synthetic precursor of a desired enantiomer. v) Chemical asymmetric synthesis: a synthetic technique in which a desired enantiomer is synthesized from an achiral precursor under conditions that result in asymmetry (chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries. vi) Diastereomeric separation: a technique in which a racemate is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their now more distinct structural differences, and the chiral auxiliary is later removed to obtain the desired enantiomer. vii) First and second order asymmetric conversion: techniques in which the diastereomers from the racemate equilibrate to give rise to a predominance in solution of the diastereomer from the desired enantiomer, or preferential crystallization of the diastereomer from the desired enantiomer disrupts the equilibrium so that ultimately, essentially, all material is converted from the desired enantiomer to the crystalline diastereomer, which is then released from the diastereomer. viii) Kinetic resolution: This technique refers to achieving partial or complete resolution of a racemic compound (or further resolution of a partially resolved compound) by the unequal reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions. ix) Enantiospecific synthesis from non-racemic precursors: A synthetic technique in which the desired enantiomer is obtained from non-chiral starting materials and in which the stereochemical integrity is not or only minimally compromised during the synthesis. x) Chiral liquid chromatography: a technique (including but not limited to chiral HPLC) in which enantiomers of a racemate are separated in a liquid mobile phase due to their different interactions with the stationary phase. The stationary phase may be made of chiral material, or the mobile phase may contain additional chiral material to cause the different interactions. xi) Chiral gas chromatography: A technique in which a racemic compound is volatilized and enantiomers are separated by their differential interaction in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase. xii) Extraction with chiral solvent: A technique in which enantiomers are separated by preferential dissolution of one enantiomer in a particular chiral solvent. xiii) Transport through chiral membranes: a technique in which a racemate is placed in contact with a thin film barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as a concentration or pressure difference causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[0179] In one embodiment, chiral chromatography is used, including but not limited to simulated moving bed chromatography. A wide variety of chiral stationary phases are commercially available.

[0180] The present disclosure will be better understood with reference to the following non-limiting examples.

[0181] Compound synthesis Example 1: Synthesis of Int-7 Preparation of Int-7 [ka] Ethyl 2-(3-chlorophenyl)-2,2-difluoroacetate (3) Ethyl 2-bromo-2,2-difluoroacetate (2) (16.9 g, 84.03 mmol) was added to a suspension of copper powder (10.58 g, 168.06 mmol) in DMSO (100 mL) under N2, and the reaction was stirred at room temperature for 1 h. 1-Chloro-3-iodobenzene (10 g, 42.016 mmol) was then added, and the reaction was stirred at 60 °C for 16 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with aqueous NH4Cl (200 mL), extracted with diethyl ether (2 × 150 mL), and the combined organic layers were washed with water (250 mL) and brine solution (300 mL), dried over sodium sulfate, and evaporated. The crude residue was purified by normal phase chromatography to give ethyl 2-(3-chlorophenyl)-2,2-difluoroacetate (3). TLC system: 5% ethyl acetate / petroleum ether R f :0.2

[0182] 2-(3-chlorophenyl)-2,2-difluoro-N-methoxy-N-methylacetamide (4) To a stirred solution of ethyl 2-(3-chlorophenyl)-2,2-difluoroacetate (3) (1 g, 4.273 mmol) in THF (20 mL) was added N,O-dimethylhydroxylamine hydrochloride (0.62 g, 6.41 mmol). The reaction was cooled to -10 °C, and then 1.0 M isopropylmagnesium chloride in THF (12.8 mL, 12.82 mmol) was slowly added and stirred at the same temperature for 2 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (120 mL), followed by brine solution (150 mL), then dried over sodium sulfate and evaporated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-N-methoxy-N-methylacetamide (4). TLC system: 20% ethyl acetate / petroleum ether R f :0.2. LCMS[ESI):m / z 250.10[M+Na] +

[0183] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-one (6) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-N-methoxy-N-methylacetamide (4) (5.5 g, 22.08 mmol) in THF (50 mL) was added phenylmagnesium bromide (5) (44 mL, 44.17 mmol) at -30 °C, and the mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (2 × 100 mL). The organic layers were combined, washed with water (150 mL) and brine solution (150 mL), then dried over sodium sulfate and evaporated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-one (6). TLC system: 20% ethyl acetate in hexanes R f :0.5

[0184] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (Int-7) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-one (6) (6 g, 22.55 mmol) in MeOH (60 mL) was added sodium borohydride (2.57 g, 67.66 mmol) at 0° C., which was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice water, and excess methanol was evaporated under reduced pressure. To this was added 1N HCl (150 mL), and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (150 mL) and brine solution (150 mL), dried over sodium sulfate, and then evaporated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (6). TLC system: 20% ethyl acetate in hexanes R f :0.45

[0185] Example 2: Synthesis of Compound A20 Diastereomers 1 and 2 A20 diastereomer 1 (A20-1) [ka] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol Compound (Int-7) was purified by SFC to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (Int-PK-1) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (Int-PK-2). TLC system: 10% ethyl acetate in petroleum ether Rf: 0.5; LCMS [ESI]: m / z 558.57 [M+H]. +

[0186] Methyl (S)-2-((((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoate (3) To a stirred solution of (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (1) (3.5 g, 13.059 mmol) in ACN (35 mL) was added N,N'-disuccinamidyl carbonate (8.35 g, 32.64 mmol), followed by triethylamine (5.4 mL, 39.177 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. The reaction mass was used directly in the next reaction.

[0187] In a separate RB flask, methyl (S)-2-amino-3-cyclohexylpropanoate hydrochloride (2) (5.77 g, 26.118 mmol) was taken up in ACN (35 mL) and treated with triethylamine (5.4 mL, 39.177 mmol). The resulting reaction mixture was stirred for 5 minutes and then added dropwise to the reaction mass prepared above, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice-water (150 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by reverse phase chromatography to give methyl (S)-2-((((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoate (3). TLC system: 10% ethyl acetate in hexane Rf: 0.55; LCMS [ESI]: m / z 502.47 [M+Na] +

[0188] (S)-2-((((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoic acid (4) To a stirred solution of methyl (S)-2-((((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoate (3) (4 g, 8.35 mmol) in THF (40 mL), water (20 mL), lithium hydroxide (0.7 g, 16.701 mmol) was added at room temperature, and the mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was completely distilled under reduced pressure, and the residue was acidified with 1N aqueous HCl to pH 2, then extracted with dichloromethane (2 × 100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-2-((((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoic acid (4). TLC system: 50% ethyl acetate in hexane Rf: 0.1; LCMS [ESI]: m / z = 953.64 [2M+Na] +

[0189] Methyl (S)-2-((S)-2-((((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5) To a stirred solution of (S)-2-((((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoic acid (4) (1.5 g, 3.225 mmol) in DMF (15 mL), EDC·HCl (0.923 g, 4.8375 mmol), HOBt (0.65 g, 4.8375 mmol), DIPEA (1.65 mL, 35.481 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (0.85 g, 3.87 mmol) were added simultaneously at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice-water (100 mL), extracted with ethyl acetate (2 × 50 mL), and washed with ice-cold water (2 × 50 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with 100% ethyl acetate to give methyl (S)-2-((S)-2-((((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5). TLC system: 5% methanol in dichloromethane Rf: 0.3; LCMS [ESI]: m / z 634.56 [M+H] +

[0190] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) To a stirred solution of methyl (S)-2-((S)-2-((((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5) (1.1 g, 1.7377 mmol) in dichloromethane (15 mL) was added 2 M LiBH in THF (0.86 mL, 1.7377 mmol) at 0 °C, and the mixture was stirred for 3 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with saturated NH Cl solution, extracted with dichloromethane (2 × 50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The resulting compound was purified by normal phase chromatography and triturated with ether to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6). TLC system: 5% methanol in dichloromethane Rf: 0.4; LCMS [ESI]: m / z = 606652 [M+H]. +

[0191] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (A20-1) To a stirred solution of (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) (800 mg, 1.322 mmol) in ethyl acetate (20 mL), Dess-Martin periodinane (840 mg, 1.983 mmol) was added at 0° C., and the solution was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mass was filtered through a Celite® pad, which was washed with ethyl acetate (100 mL). The organic layer was then washed with 10% sodium thiosulfate solution (2 x 100 mL), followed by saturated sodium bicarbonate solution (2 x 100 mL), water (1 x 100 mL), and brine (1 x 100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue, which was purified by normal phase chromatography to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (A20-1). TLC system: 10% methanol in DCM. f :0.55;LCMS[ESI):m / z 604.3[M+H] +

[0192] A20 diastereomer 2 (A20-2) [ka] Methyl (S)-2-((((R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoate (3) To a stirred solution of (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (1) (3.2 g, 11.94 mmol) in ACN (35 mL) was added N,N'-disuccinamidyl carbonate (4.6 g, 17.910 mmol), followed by triethylamine (4 mL, 35.82 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. The reaction mass was used directly in the next reaction.

[0193] In a separate flask, methyl (S)-2-amino-3-cyclohexylpropanoate hydrochloride (2) (2.65 g, 14.328 mmol) was taken up in ACN (35 mL) and treated with triethylamine (4 mL, 35.82 mmol). The resulting reaction mixture was stirred for 5 minutes and then added dropwise to the reaction mass prepared above. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water (150 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate, and evaporated under reduced pressure to give a residue that was purified by reverse-phase chromatography to give methyl (S)-2-((((R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoate (3). TLC system: 10% ethyl acetate in hexane Rf: 0.55; LCMS [ESI]: m / z 480.2 [M+H] +

[0194] (S)-2-((((R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoic acid (4) To a stirred solution of methyl (S)-2-((((R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoate (3) (2.5 g, 5.219 mmol) in THF (25 mL), water (12.5 mL), lithium hydroxide (0.394 g, 10.7438 mmol) was added at room temperature and stirred for 3 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was completely distilled under reduced pressure, and the compound was acidified to pH ∼2 with 1N aqueous HCl, extracted with dichloromethane (2 × 100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-2-((((R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoic acid (4). TLC system: 50% ethyl acetate in hexane Rf: 0.1; LCMS [ESI]: m / z = 466.14 [M+H] +

[0195] Methyl (S)-2-((S)-2-((((R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5) To a stirred solution of (S)-2-((((R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanoic acid (4) (0.5 g, 1.075 mmol) in DMF (5 mL), EDC.HCl (0.3 g, 1.612 mmol), HOBt (0.21 g, 1.612 mmol), DIPEA (0.46 mL, 3.225 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (0.23 g, 1.29 mmol) were added simultaneously at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice-water (100 mL), extracted with ethyl acetate (2 × 50 mL), and washed with ice-cold water (2 × 50 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with 100% ethyl acetate to give methyl (S)-2-((S)-2-((((R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5). TLC system: 5% methanol in dichloromethane Rf: 0.3; LCMS [ESI]: m / z 634.3 [M+H] +

[0196] (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) To a stirred solution of methyl (S)-2-((S)-2-((((R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5) (0.35 g, 0.552 mmol) in dichloromethane (5 mL) was added 2 M LiBH in THF (0.5 mL, 1.1058 mmol) at 0 °C, and the mixture was stirred for 3 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with saturated NH Cl solution, extracted with dichloromethane (2 × 50 mL), and dried over sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by normal phase chromatography and triturated with ether to give (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6). TLC system: 5% methanol in dichloromethane Rf: 0.4; LCMS [ESI]: m / z = 606.3 [M+H]. +

[0197] (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (A20-2) To a stirred solution of (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) (0.300 g, 0.49 mmol) in EtOAc (60 mL) was added Dess-Martin periodinane (0.63 g, 1.40 mmol) at 0° C., and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated hypochlorous acid solution (3 × 20 mL), followed by saturated NaHCO solution (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue, which was purified by reverse-phase column chromatography to give (1-(3-chlorophenyl)cyclopropyl)(4-fluorophenyl)methyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A20-2). TLC system: 10% methanol in dichloromethane Rf: 0.5; LCMS [ESI]: m / z 603.23 [M+H] +

[0198] Example 3: Synthesis of Compound A25 Diastereomers 1 and 2 [ka] [ka] Methyl((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)-L-leucine acid (8) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (Int-7) (3.8 g, 14.179 mmol) in ACN (40 mL) was added N,N'-disuccinamidyl carbonate (5.4 g, 21.268 mmol), followed by triethylamine (5.9 mL, 42.537 mmol) at 0 °C, and the mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. The reaction mass was used directly in the next reaction.

[0199] In a separate flask, methyl L-leucine hydrochloride (7) (3.89 g, 21.268 mmol) was taken up in ACN (40 mL) and treated with triethylamine (5.9 mL, 42.537 mmol). The resulting reaction mixture was stirred for 5 minutes, then the reaction mass prepared above was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water (150 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine solution (150 mL), dried over sodium sulfate, evaporated under reduced pressure, and the residue was purified by normal phase chromatography using petroleum ether and ethyl acetate as the mobile phase to give methyl ((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)-L-leucine acid (8). TLC system: 20% ethyl acetate / petroleum ether R f :0.4;LCMS[ESI):m / z 440.39[M+H] +

[0200] ((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)-L-leucine (9) To a stirred solution of methyl ((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)-L-leucine acid (8) (2.5 g, 5.694 mmol) in THF (25 mL) and water (25 mL) was added lithium hydroxide (717 mg, 17.084 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. Excess THF was removed under reduced pressure, and the resulting residue was acidified to pH ∼2 with 1N aqueous HCl. The mixture was extracted with DCM (2 × 100 mL), and the combined organic layers were washed with water (100 mL) and brine solution (150 mL), dried over sodium sulfate, and concentrated under reduced pressure to give ((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)-L-leucine (9). TLC system: 10% methanol in dichloromethane Rf: 0.1; LCMS [ESI]: m / z 448.30 [M+Na] +

[0201] Methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (10) To a stirred solution of ((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)-L-leucine (9) (2 g, 4.70 mmol) in DMF (20 mL), EDC·HCl (1.34 g, 7.058 mmol), HOBt (0.952 g, 7.058 mmol), DIPEA (2.5 mL, 14.61176 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (1.567 g, 7.058 mmol) were added simultaneously at 0° C., and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (100 mL) and extracted with ethyl acetate (2 x 100 mL), then the organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue which was purified by normal phase chromatography to give methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (10). TLC system: 10% MeOH / DCM Rf: 0.45; LCMS [ESI]: m / z = 594.62 [M+H] +

[0202] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (11) To a stirred solution of methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (10) (1 g, 1.686 mmol) in dichloromethane (10 mL) was added 2 M LiBH in THF (1.68 mL, 3.372 mmol) at 0 °C, and the mixture was stirred for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with saturated NH4Cl solution and extracted with dichloromethane (2 x 50 mL), then dried over sodium sulfate and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (11). TLC system: 10% methanol in dichloromethane Rf: 0.35; LCMS [ESI]: m / z 566.49 [M+H] +

[0203] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (11-PK-1) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (11-PK-2) 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (1) (7 g, 12.38 mmol) was purified by SFC purification to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (11-PK-1) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (11-PK-2) were obtained. LCMS [ESI] m / z 566.52 [M+H] +

[0204] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (11-PK-1-A) To a stirred solution of (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (11-PK-1) (1.8 g, 3.185 mmol) in ethyl acetate (15 mL) was added Dess-Martin periodinane (4.5 g, 10.83 mmol) at 0 °C, and the mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated NaHCO solution (3 × 20 mL), followed by saturated hypo solution (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue, which was purified by normal phase purification to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (11-PK-1-A). TLC system: 10% methanol in DCM f :0.55;LCMS[ESI):m / z 564.2[M+H] +

[0205] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (12-PK-1) To a stirred solution of (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (11-PK-1-A) (800 mg, 1.42 mmol) in DCM (6 mL) was added pyridine (0.7 mL, 7.1 mmol), isocyanocyclopropane (114 mg, 1.7 mmol), and TFA (80 mg, 0.71 mmol) at 0° C., and the mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl (2×30 mL), followed by water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (12-PK-1). TLC system: 10% MeOH in DCM Rf: 0.25; LCMS [ESI]: m / z 649.62 [M+H] +

[0206] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (compound A25-1) To a stirred solution of (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (12-PK-1) (900 mg, 1.388 mmol) in ethyl acetate (8 mL) was added Dess-Martin periodinane (1.4 g, 3.47 mmol) at 0° C., and the mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a Celite® pad, washed with ethyl acetate (25 mL), and the filtrate was washed with hypo solution (3×40 mL), followed by saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue, which was purified by preparative HPLC to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (compound A25-1). TLC system: 10% MeOH in DCM Rf: 0.3; LCMS [ESI]: m / z 647.3 [M+H] +

[0207] (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (11-PK-2-A) To a stirred solution of (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (11-PK-2) (1.9 g, 3.36 mmol) in ethyl acetate (15 mL), Dess-Martin periodinane (5.25 g, 11.76 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated NaHCO solution (3 × 20 mL), followed by saturated hypo solution (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue, which was purified by normal phase purification to give (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (11-PK-2-A). TLC system: 10% methanol in DCM f :0.55;LCMS[ESI):m / z 564.3[M+H] +

[0208] (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (12-PK-2) To a stirred solution of (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (11-PK-2-A) (1.1 g, 1.95 mmol) in DCM (8 mL) was added pyridine (0.8 mL, 9.75 mmol), isocyanocyclopropane (214 mg, 3.19 mmol), and TFA (111 mg, 0.95 mmol) at 0° C., and the mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with dichloromethane and washed with 1N HCl (2×30 mL), followed by water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (12-PK-2). TLC system: 10% MeOH in DCM Rf: 0.25; LCMS [ESI]: m / z 649.62 [M+H] +

[0209] (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (compound A25-2) To a stirred solution of (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (12-PK-2) (1.1 g (crude), 1.69 mmol) in ethyl acetate (12 mL) was added Dess-Martin periodinane (2.4 g, 5.94 mmol) at 0° C., and the mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a Celite® pad and washed with ethyl acetate (25 mL), and the filtrate was then washed with hypo solution (3×40 mL), followed by saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue, which was purified by preparative HPLC to give (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (compound A25-2). TLC system: 10% MeOH in DCM Rf: 0.3; LCMS [ESI]: m / z 647.3 [M+H] +

[0210] Example 4: Synthesis of Compounds A26P and A26 [ka] 2-(3-chlorophenyl)-2-methyl-1-phenylpropan-1-ol (2) To a stirred solution of 2-(3-chlorophenyl)-2-methylpropanal (Int-3) (10 g, 54.94 mmol) in THF (100 mL) was added 4-chlorophenylmagnesium bromide (1) (109.89 mL, 109.89 mmol) at -30 °C, and the reaction mixture was stirred at 0 °C for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NH4Cl (150 mL), filtered through a Celite® bed, washed with ethyl acetate (2 × 150 mL), dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give 2-(3-chlorophenyl)-2-methyl-1-phenylpropan-1-ol (2). TLC system: 10% ethyl acetate in hexane Rf: 0.3; LCMS [ESI]: m / z = 243.18 [M-OH]. +

[0211] Methyl (2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoate (4) To a stirred solution of 2-(3-chlorophenyl)-2-methyl-1-phenylpropan-1-ol (2) (10 g, 38.46 mmol) (2) in DCM (100 mL) was added pyridine (7.6 mL, 96.15 mmol). Methyl (S)-2-aminohexanoate (3) (16.25 g, 57.69 mmol) and triphosgene (5.6 g, 19.23 mmol) were then added at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was acidified with 1N HCl (25 mL) and extracted with ethyl acetate (2×25 mL). The organic layer was then dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by Combiflash eluting with 10% ethyl acetate in petroleum ether to give (2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoate (4). TLC system: 10% ethyl acetate in hexane Rf: 0.3; LCMS [ESI]: m / z = 431.12 [M+H] +

[0212] (2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoic acid (5) To a stirred solution of methyl (2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoate (4) (12 g, 27.84 mmol) in THF (80 mL), water (30 mL) was added lithium hydroxide (2.28 g, 55.68 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was completely evaporated under reduced pressure, and the residue was acidified to pH ∼2 with 1N aqueous HCl. The solution was extracted with ethyl acetate (2 × 60 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoic acid (5). TLC system: 5% methanol in dichloromethane Rf: 0.1; LCMS [ESI]: m / z 440.38 [M+Na] +

[0213] Methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (6) To a stirred solution of (2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoic acid (5) (8 g, 25.23 mmol) in DMF (100 mL), EDC.HCl (7.23 g, 37.85 mmol), HOBt (5.1 g, 37.85 mmol), DIPEA (19.79 mL, 113.55 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (8.36 g, 37.85 mmol) were added simultaneously at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice-water (100 mL), extracted with ethyl acetate (2 × 50 mL), and washed with ice-cold water (2 × 50 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with 100% ethyl acetate to give methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (6). TLC system: 5% methanol in dichloromethane Rf: 0.4; LCMS [ESI]: m / z = 586.55 [M+H] +

[0214] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (7-PK-1) and (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (7-PK-2) To a stirred solution of methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (6) (8 g, 13.67 mmol) in THF (100 mL) was added 2 M LiBH in THF (13.67 mL, 27.35 mmol) at 0 °C, and the mixture was stirred for 3 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc (2 x 50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography by eluting with 100% ethyl acetate to give 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (7).

[0215] Compound (7) was purified by SFC to give (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (7-PK-1) and (R)-(4-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (7-PK-2). TLC system: 5% methanol in dichloromethane Rf: 0.3; LCMS [ESI]: m / z 558.57 [M+H] +

[0216] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A26 precursor) To a stirred solution of (4-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (7-PK-1) (1 g, 1.79 mmol) in ethyl acetate (10 mL) was added Dess-Martin periodinane (1.14 g, 2.69 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated hypochlorite solution (3 × 20 mL), saturated NaHCO solution (3 × 20 mL), and brine (1 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue that was purified by preparative HPLC to give (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A26 precursor). TLC system: 5% methanol in dichloromethane Rf: 0.3; LCMS [ESI]: m / z 556.3 [M+H] +

[0217] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (10-PK-1) To a stirred solution of (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A26 precursor) (450 mg, 0.81 mmol), pyridine (0.5 mL, 5 vol), isocyanocyclopropane 9 (86.83 mg, 1.29 mmol), and TFA (184 mg, 1.62 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl (2 × 20 mL), followed by brine (1 × 20 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give crude (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (10-PK-1). TLC system: 10% methanol in dichloromethane Rf: 0.5; LCMS [ESI]: m / z 641.66 [M+H] +

[0218] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (Compound A26) To a stirred solution of (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (10PK-1) (450 mg, 0.70 mmol) in ethyl acetate (10 mL) was added Dess-Martin periodinane (744 mg, 1.75 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a Celite® pad, washed with ethyl acetate (20 mL), and the filtrate was washed with hypo solution (3×20 mL), followed by saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue, which was purified by preparative HPLC to give (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (compound A26). TLC system: 10% methanol in dichloromethane Rf: 0.4; LCMS [ESI]: m / z 639.3 [M+H] +

[0219] Example 5: Synthesis of Compound A27 [ka] Methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoate (3) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (Int-7) (10 g, 37.313 mmol) in ACN (100 mL) was added N,N' disuccinamidyl carbonate (23.9 g, 93.283 mmol), followed by triethylamine (15.8 mL, 111.939 mmol) at 0°C, and the mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. The reaction mass was used directly in the next reaction.

[0220] In a separate flask, methyl (S)-2-aminohexanoate HCl (2) (16.9 g, 93.283 mmol) was taken up in ACN (60 mL) and treated with triethylamine (15.8 mL, 111.939 mmol). The resulting reaction mixture was stirred for 5 minutes, then the reaction mass prepared above was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were then washed with brine solution (100 mL), dried over sodium sulfate, and evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoate (3). TLC system: 20% ethyl acetate in hexane Rf: 0.3; LCMS [ESI]: m / z 440.2 [M+H] +

[0221] (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoic acid (4) To a stirred solution of methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoate (3) (10 g, 22.727 mmol) in THF (80 mL) and water (20 mL) was added lithium hydroxide (1.9 g, 45.454 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was completely evaporated under reduced pressure, and the residue was then acidified with 1N aqueous HCl to pH ∼2, extracted with ethyl acetate (2 × 200 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoic acid (4). TLC system: 60% ethyl acetate in hexane Rf: 0.1; LCMS [ESI]: m / z = 448.2 [M+Na] +

[0222] Methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5) To a stirred solution of (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoic acid (4) (9 g, 21.176 mmol) in DMF (30 mL), EDC·HCl (6.06 g, 31.764 mmol), HOBt (4.3 g, 31.764 mmol), DIPEA (11.3 mL, 65.148 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (7 g, 31.764 mmol) were added simultaneously at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice-water (200 mL), extracted with ethyl acetate (2 × 200 mL), and washed with ice-cold water (2 × 100 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with 100% ethyl acetate to give methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5). TLC system: 80% ethyl acetate in hexane Rf: 0.3; LCMS [ESI]: m / z 594.3 [M+H] +

[0223] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6) To a stirred solution of methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5) (8 g, 13.468 mmol) in THF (80 mL) was added 2 M LiBH in THF (14 mL, 26.93 mmol) at 0 °C and stirred for 3 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with saturated NH4Cl solution, extracted with ethyl acetate (2 x 200 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6). TLC system: 5% methanol in dichloromethane Rf: 0.4; LCMS [ESI]: m / z = 566.3 [M+H] +

[0224] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6-PK-1) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6-PK-2) Compound (6) was purified by SFC to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6-PK-1) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6-PK-2). TLC system: 5% methanol in dichloromethane Rf: 0.3; LCMS [ESI]: m / z 566.3 [M+H]. +

[0225] 2-(3-Chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (Compound A27) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6) (300 mg, 0.50 mmol) dissolved in ethyl acetate (3 mL) was added Dess-Martin periodinane (674 mg, 1.59 mmol) at 0° C., and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated hypochlorite solution (3 × 20 mL), saturated NaHCO solution (3 × 20 mL), and brine (1 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue that was purified by preparative HPLC to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (compound A27). TLC system: 5% methanol in dichloromethane Rf: 0.3; LCMS [ESI]: m / z 564.3 [M+H] +

[0226] Example 6: Synthesis of Compound A28 Diastereomers 1 and 2 [ka] [ka] Methyl((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)-L-leucine acid (3) To a stirred solution of 2-(3-chlorophenyl)-2-methyl-1-phenylpropan-1-ol (1) (12.5 g, 48.07 mmol), methyl (S)-2-amino-3,3-dimethylbutanoate HCl (10.47 g, 57.69 mmol) in DCM (50 mL), pyridine (38 mL, 3 volumes) was added, followed by triphosgene (7.1 g, 24.03 mmol) at 0 °C, and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with 2 N HCl (50 mL) and extracted with DCM (2 × 40 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) (10% ABC:ACN) to give methyl ((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)-L-leucinate (3). TLC system: 20% ethyl acetate in hexane Rf: 0.3; LCMS [ESI]: m / z 454.48 [M+Na] + Chiral HPLC data: PK-1 39% & PK-2 56%

[0227] ((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)-L-leucine (4) To a stirred solution of methyl ((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)-L-leucine acid (3) (7.2 g, 16.70 mmol) in THF (40 mL) and water (40 mL) was added lithium hydroxide (1.4 g, 33.41 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was completely evaporated under reduced pressure, and the residue was acidified to pH ∼3 with 1N aqueous HCl. The solution was extracted with ethyl acetate (2 × 40 mL), dried over sodium sulfate, and concentrated under reduced pressure to give ((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)-L-leucine (4). TLC system: 100% EtOAc Rf: 0.1; LCMS [ESI]: m / z 440.47 [M+Na] +Chiral HPLC data: PK-1 39% & PK-2 60%

[0228] Methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5) To a stirred solution of ((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)-L-leucine (4) (7.2 g, 16.78 mmol) in DMF (30 mL), EDC·HCl (4.8 g, 25.17 mmol), HOBt (3.3 g, 25.17 mmol), DIPEA (8.7 mL, 50.35 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (amine fragment-2) (3.7 g, 20.14 mmol) were added simultaneously at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (80 mL), extracted with ethyl acetate (2 × 50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by RP-HPLC (10% ABC:ACN) to give methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5). TLC system: 10% methanol in dichloromethane Rf: 0.3; LCMS [ESI]: m / z 586.62 [M+H] + Chiral HPLC data: PK-1 45% & PK-2 54%

[0229] 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (6) To a stirred solution of methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5) (4.4 g, 7.52 mmol) in DCM (20 mL) was added 2 M LiBH in THF (7.5 mL, 15.04 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with saturated ammonium chloride solution (30 mL) and extracted with DCM (2 × 30 mL). The organic layer was washed with brine solution (30 mL), dried over NaSO, and concentrated to give 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (6). TLC system: 10% methanol in dichloromethane Rf: 0.2; LCMS [ESI]: m / z 558.9 [M+Na] + Chiral HPLC data: PK-1 46% & PK-2 49%

[0230] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (PK-1) and (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (PK-2) 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (6) (4 g, 7.16 mmol) was separated by SFC to give (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3 -((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (PK-1) and (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (PK-2) were obtained. TLC system: 5% methanol in dichloromethane Rf: 0.3; LCMS [ESI]: m / z 558.27 [M-OH] - Chiral HPLC data: PK-1 99% Chiral HPLC data: PK-2 99%

[0231] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (7) To a stirred solution of (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (PK-1) (700 mg, 1.25 mmol) in dichloromethane (15 mL) was added Dess-Martin periodinane (1 g, 2.51 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through a Celite® pad, washed with ethyl acetate (25 mL), then with hypo solution (3×20 mL), followed by saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue that was purified by normal phase chromatography to give (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (7). TLC system: 5% methanol in dichloromethane Rf: 0.3; LCMS [ESI]: m / z 556.45 [M+H] + Chiral HPLC data: PK-1 82%

[0232] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (9) To a stirred solution of (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (7) (550 mg, 0.98 mmol) dissolved in DCM (15 mL) were added pyridine (0.54 mL, 3 volumes) and isocyanocyclopropane (8) (0.13 mL, 1.98 mmol) sequentially at 0° C., and the mixture was stirred for 10 minutes. To this solution was added TFA (0.07 mL, 0.99 mmol) at 0° C., and the mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with dichloromethane (2 × 15 mL). The organic layer was washed with 1N HCl (3 × 15 mL) and brine solution (3 × 10 mL). The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (9). TLC system: 5% methanol in dichloromethane Rf: 0.5; LCMS [ESI]: m / z 641.5 [M+H] + Chiral HPLC data: PK-1 49% & PK-2 33%

[0233] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (Compound A28 diastereomer 1) To a stirred solution of (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (9) (350 mg, 0.54 mmol) in EtOAc (10 mL) was added Dess-Martin periodinane (463 mg, 1.09 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a Celite® pad and washed with ethyl acetate (25 mL), followed by hypo solution (3×20 mL), and saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue that was purified by RP-HPLC (10% ABC:ACN) to give (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (compound A28 diastereomer 1). TLC system: 10% methanol / dichloromethane Rf: 0.4; LCMS [ESI]: m / z 639.2 [M+H] + Chiral HPLC data: PK-1 96%

[0234] (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (7a) To a stirred solution of (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (PK-2) (700 mg, 1.25 mmol) in dichloromethane (15 mL) was added Dess-Martin periodinane (1 g, 2.51 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through a Celite® pad and washed with ethyl acetate (25 mL), hypo solution (3×20 mL), and saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue that was purified by normal phase chromatography to give (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (7a). TLC system: 10% methanol in dichloromethane Rf: 0.5; LCMS [ESI]: m / z 556.45 [M+H] + Chiral HPLC data: PK-1 93%

[0235] (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (9a) To a stirred solution of (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (7a) (520 mg, 0.98 mmol) in DCM (15 mL) were added pyridine (0.75 mL, 3 volumes) and isocyanocyclopropane (8) (0.13 mL, 1.98 mmol) sequentially at 0° C., and the mixture was stirred for 10 minutes. To this mixture was added TFA (0.07 mL, 0.99 mmol) at 0° C., and the mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (20 mL) and extracted with dichloromethane (2 × 15 mL). The organic layer was washed with 1N HCl (3 × 15 mL) and brine solution (3 × 10 mL), then dried over anhydrous NaSO and evaporated under reduced pressure to give (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (9a). TLC system: 5% methanol in dichloromethane Rf: 0.5; LCMS [ESI]: m / z 641.5 [M+H] + Chiral HPLC data: PK-1 27% & PK-1 60%

[0236] (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (Compound A28 diastereomer 2) To a stirred solution of (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (9a) (350 mg, 0.54 mmol) in EtOAc (15 mL) was added Dess-Martin periodinane (463 mg, 1.09 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a Celite® pad and washed with ethyl acetate (25 mL), hypo solution (3×20 mL), and saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue that was purified by RP-HPLC (10% ABC:ACN) to give (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (compound A28 diastereomer 2). TLC system: 10% methanol / dichloromethane Rf: 0.4; LCMS [ESI]: m / z 639.2 [M+H] + Chiral HPLC data: PK-1 97%

[0237] Example 7: Synthesis of Compound A29 [ka] (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid (2) To a stirred solution of methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (1) (1.8 mg, 2.838 mmol) in THF (30 mL) and water (15 mL) was added lithium hydroxide (357.6 mg, 8.516 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was completely evaporated under reduced pressure, and the residue was acidified to pH ∼2 with 1N aqueous HCl. The mixture was then extracted with ethyl acetate (2 x 20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid (2). TLC system: 5% methanol in dichloromethane Rf: 0.4; LCMS [ESI]: m / z = 620.60 [M+H] +

[0238] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-cyano-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)-4-(tetrahydro-114-thiophen-1-ylidene)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (8) To a stirred solution of (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid (2) (1.0 g, 1.612 mmol) in DCM (30 mL), HATU (903.09 mg, 3.225 mmol), DIPEA (0.89 mL, 4.838 mmol), and 1-(cyanomethyl)tetrahydro-1H-thiophen-1-ium bromide (3) (503.4 mg, 2.419 mmol) were added simultaneously at 0° C., and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ice water (50 mL), extracted with dichloromethane (2×50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by Combiflash NP and then eluted with 5% methanol in dichloromethane to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-cyano-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)-4-(tetrahydro-114-thiophen-1-ylidene)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (4). TLC system: 5% methanol in dichloromethane Rf: 0.3; LCMS [ESI]: m / z 729.61 [M+H]. +

[0239] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-(((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-cyano-3-oxo-1-((S)-2-oxopyrrolidin-3-yl)-4-(tetrahydro-114-thiophen-1-ylidene)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (4) (400 mg, 0.548 mmol) in methanol (30 mL) was added m-CPBA (189.13 mg, 1.096 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 hours. To this was added ethylamine HCl (5) (1.34 g, 16.454 mL) and DIPEA (3.03 mL, 16.454 mmol), and the mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO3 solution (2 x 20 mL). The organic layer was washed with brine solution (30 mL), dried over Na2SO4, and concentrated to give a residue, which was purified by preparative HPLC to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclohexyl-1-(((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound A29). TLC system: 10% methanol in dichloromethane Rf: 0.3; LCMS (ESI): m / z 675.4 [M+H] +

[0240] Example 8: Synthesis of Compounds A107 and A110 [ka] Methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoate (3) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (1) (50 g, 186.56 mmol) in ACN (500 mL) was added N,N'-disuccinamidyl carbonate (119.4 g, 466.41 mmol) followed by EtN (80.7 mL, 559.74 mmol) at 0 °C and stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. The reaction mass was used directly in the next reaction.

[0241] In a separate RB flask, methyl (S)-2-aminohexanoate (2) (70 g, 171.96 mmol) was dissolved in ACN (350 mL) and EtN (46 mL, 318.21 mmol) was added. The reaction mixture was stirred for 5 minutes, then the reaction mass prepared above was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water (200 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and evaporated under reduced pressure to give a material that was purified by silica gel (200-300 mesh) column chromatography eluting with 10% ethyl acetate in petroleum ether to give methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoate (3). TLC system: 10% ethyl acetate in hexane Rf: 0.3 LCMS [ESI]: m / z 440.13 [M+H] +

[0242] (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoic acid (4) To a stirred solution of methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoate (3) (40 g, 90.1 mmol) in THF (200 mL):water (200 mL) was added lithium hydroxide (9.56 g, 227.71 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was concentrated, acidified with 1N aqueous HCl to pH ∼2, extracted with ethyl acetate (2 x 200 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a material which was purified by silica gel (230-300 mesh) column chromatography eluting with 30% ethyl acetate in petroleum ether to give (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoic acid (4). TLC system: 5% MeOH:DCM Rf: 0.3 LCMS [ESI]: m / z = 448.26 [M+Na] +

[0243] Methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5) To a stirred solution of (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanoic acid (4) (20 g, 47.05 mmol) in DMF (100 mL) was added EDC.HCl (13.72 g, 70.4 mmol), HOBt (9.5 g, 70.4 mmol), DIPEA (25 mL, 56.446 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (amine fragment-2) (15.67 g, 70.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. Ice water (200 mL) was added to the reaction mixture, which was extracted with ethyl acetate (2 × 150 mL) and washed with ice-cold water (2 × 100 mL). The combined organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the compound. The residue was purified by silica gel column chromatography eluting with 100% ethyl acetate to give methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5). TLC system: 5% methanol in dichloromethane Rf: 0.3 LCMS [ESI]: m / z 594.3 [M+H] +

[0244] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6) To a stirred solution of methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (5) (19 g, 32.04 mmol) in THF (190 mL) was added 2 M LiBH in THF (32 mL, 64.08 mmol) at 0 °C and stirred for 2 h. The progress of the reaction was monitored by TLC and LC-MS. The reaction mixture was quenched with saturated NH Cl (250 mL), extracted with ethyl acetate (2 × 200 mL), dried over sodium sulfate, and concentrated under reduced pressure to give compound (III). This compound was purified by reverse-phase column chromatography to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6). TLC system: 5% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z = 566.2 [M+H] +

[0245] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6-PK-1) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6-PK-2) 15 g of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6) was purified by chiral SFC to give ((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidine (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6-PK-1) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6-PK-2) were obtained. TLC system: 5% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z = 566.2 [M+H] +

[0246] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A107) To a stirred solution of (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6-PK-1) (4 g, 7.064 mmol) in ethyl acetate (80 mL) was added Dess-Martin periodinane (6 g, 14.132 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated Hypo solution (3 × 100 mL), saturated NaHCO solution (3 × 100 mL), and brine (2 × 50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give compound. This compound was purified by reverse phase column chromatography to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A107). TLC system: 5% methanol in dichloromethane Rf: 0.3 LCMS [ESI]: m / z 564.3 [M+H] +

[0247] (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A110) To a stirred solution of (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (6-PK-2) (6 g, 10.64 mmol) dissolved in ethyl acetate (40 mL) was added Dess-Martin periodinane (6 g, 14.132 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with saturated Hypo solution (3 × 100 mL), saturated NaHCO solution (3 × 100 mL), and brine (2 × 50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give compound. This compound was purified by reverse phase column chromatography to give (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A110). TLC system: 5% methanol in dichloromethane Rf: 0.3 LCMS [ESI]: m / z 564.2 [M+H] +

[0248] Example 9: Synthesis of Compound A122 [ka] (S)-2-((((S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoic acid (1-PK-1) and (S)-2-((((R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoic acid (1-PK-2) 10 g of (2S)-2-(((2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoic acid (1) was purified by chiral SFC to give (S)-2-((((S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoic acid (1-PK-1) (4.2 g, 5.99 mmol) and (S)-2-((((R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoic acid (1-PK-2). TLC system: 10% MeOH in DCM Rf: 0.5 LCMS [ESI]: m / z 440.2 [M+Na] +

[0249] Methyl (S)-2-((S)-2-((((S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanamido)-3-((R)-2-oxopyrrolidin-3-yl)propanoate (2) To a stirred solution of (S)-2-((((S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanoic acid (1-PK-1) (4 g, 9.6 mmol) in DMF (20 mL) was added EDC.HCl (2.7 g, 13.8 mmol), HOBt (1.86 g, 13.8 mmol), DIPEA (5 mL, 27.6 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (amine fragment-2′) (2.56 g, 13.8 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was quenched with ice water (80 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The material was purified by Combiflash (normal phase) and the compound was eluted with 5% methanol in dichloromethane to give methyl (S)-2-((S)-2-((((S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanamido)-3-((R)-2-oxopyrrolidin-3-yl)propanoate (2). TLC system: 100% EtOAc Rf: 0.4 LCMS [ESI]: m / z 602.6 [M+H] +

[0250] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((R)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (3) To a stirred solution of methyl (S)-2-((S)-2-((((S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropoxy)carbonyl)amino)hexanamido)-3-((R)-2-oxopyrrolidin-3-yl)propanoate (2) (4 g, 6.83 mmol) in DCM (20 mL) was added 2 M LiBH4 in THF (6.8 mL, 13.6 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated to give (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-(((S)-1-hydroxy-3-((R)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (3). TLC system: 5% MeOH in DCM Rf: 0.4 LCMS [ESI]: m / z 558.3 ​​[M+H] +

[0251] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-oxo-1-(((S)-1-oxo-3-((R)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A122) To a stirred solution of (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-oxo-1-(((S)-1-oxo-3-((R)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (1-PK-1) (3.5 g, 6.3 mmol) in ethyl acetate (50 mL) was added Dess-Martin periodinane (5.3 g, 12.5 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated Hypo solution (3 × 50 mL), saturated NaHCO solution (3 × 50 mL), and brine (1 × 50 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give compound. This compound was purified by reverse-phase Combiflash chromatography to give (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-oxo-1-(((S)-1-oxo-3-((R)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A122). TLC system: 5% methanol in dichloromethane Rf: 0.5 LCMS [ESI]: m / z 556.3 [M+H] +

[0252] Example 10: Synthesis of Compounds A164 and A165 [ka] 2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethan-1-one (2) To a freshly prepared stirred solution of (3-fluorophenyl)magnesium bromide (1) (Mg (4.3 g, 258.49 mmol), 1-bromo-3-fluorobenzene (15 g, 86.16 mmol), and 1,2-dibromoethane (3 mL) in diethyl ether at 0 °C, a solution of 2-(3-chlorophenyl)-2,2-difluoro-N-methoxy-N-methylacetamide (15 g, 60.24 mmol) in THF (45 mL) was slowly added dropwise at 0 °C and stirred at room temperature for 3 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (500 mL) and extracted with ethyl acetate (2 x 700 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give 2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethan-1-one (2). TLC system: 10% ethyl acetate in hexane Rf: 0.3

[0253] 2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethan-1-ol (3) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethan-1-one (2) (9 g, 31.69 mmol) in THF (100 mL) was slowly added dropwise sodium borohydride (3.59 g, 95.07 mmol) at 0 °C and stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the starting material, the reaction mixture was quenched with ice water and evaporated under reduced pressure to remove THF. 1N HCl (150 mL) was then added and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (150 mL), brine solution (150 mL), dried over sodium sulfate, and evaporated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethan-1-ol (3). TLC system: 10% ethyl acetate in hexane Rf: 0.3

[0254] Methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethoxy)carbonyl)amino)hexanoate (5): To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethan-1-ol (3) (6.4 g, 22.37 mmol) in toluene (30 mL), methyl (S)-2-isocyanatohexanoate (9.2 g, 44.75 mmol) was added, followed by triethylamine (9.4 mL, 67.13 mmol) at room temperature and heated to 100 °C for 16 h. The reaction progress was monitored by TLC. The reaction mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with 6–7% ethyl acetate in hexane to give methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethoxy)carbonyl)amino)hexanoate (5). TLC system: 10% ethyl acetate in hexane Rf: 0.5 LCMS [ESI]: m / z 458.4 [M+H] +

[0255] (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethoxy)carbonyl)amino)hexanoic acid (6) To a stirred solution of methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethoxy)carbonyl)amino)hexanoate (5) (9.7 g, 21.22 mmol) in THF (50 mL) and water (15 mL), LiOH.HO (1.7 g, 42.45 mmol) was added at room temperature and stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove THF. The resulting residue was acidified to pH ∼2 with 1N aqueous HCl and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethoxy)carbonyl)amino)hexanoic acid (6). TLC system: 50% ethyl acetate in hexane Rf: 0.1 LCMS [ESI]: m / z = 424.2 [M-19] +

[0256] Methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (7) To a stirred solution of (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethoxy)carbonyl)amino)hexanoic acid (6) (4.0 g, 9.02 mmol) in DMF (20 mL), EDC.HCl (2.58 g, 13.54 mmol), HOBt (1.82 g, 13.54 mmol), DIPEA (4.85 mL, 27.08 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate (amine fragment-2) (2.0 g, 10.83 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. After completion of the reaction by TLC, the reaction mixture was diluted with ice water (100 mL) and extracted with ethyl acetate (2 × 150 mL). The combined organic layers were washed with ice-cold water (2 x 50 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with 100% ethyl acetate to give methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (7). TLC system: 10% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z 612.14 [M+H] +

[0257] 2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (8) To a stirred solution of methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethoxy)carbonyl)amino)hexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (7) (2.2 g, 3.60 mmol) in dichloromethane (20 mL) was slowly added dropwise 2 M LiBH in THF (3.6 mL, 7.20 mmol) at 0 °C and stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction by TLC, the reaction mixture was quenched with saturated aqueous NH Cl and extracted with dichloromethane (2 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (8). TLC system: 10% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z = 584.8 [M+H] +

[0258] (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((R)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (8-PK-1) and (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl((S)-1-(((S)-1-hydroxy-3-((R)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (8-PK-2) 2 g of 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-(((S)-1-hydroxy-3-((R)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (3) was purified by chiral SFC to give (S)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-oxo-1-(((S)-1-oxo-3-((R (R)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (3-PK-1) (1 g, 2.71 mmol) and (R)-2-(3-chlorophenyl)-2-methyl-1-phenylpropyl ((S)-1-oxo-1-(((S)-1-oxo-3-((R)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (3-PK-2) were obtained. TLC system: 10% methanol in DCM Rf: 0.4 LCMS [ESI]: m / z 584.57 [M+H] +

[0259] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A164) To a stirred solution of (S)-2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (8) (450 mg, 0.77 mmol) in ethyl acetate (20 mL) was added Dess-Martin periodinane (981 mg, 2.31 mmol) at 0 °C and stirred at room temperature for 3 h. After completion of the reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth and washed with ethyl acetate (20 mL). The resulting filtrate was washed with saturated Hypo solution (3 × 20 mL), saturated NaHCO solution (3 × 20 mL), and brine (1 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting compound was purified by trituration with DEE / n-pentane to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A164). TLC system: 5% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z 582.76 [M+H] +

[0260] (R)-2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A165) To a stirred solution of (R)-2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (8) (450 mg, 0.77 mmol) in ethyl acetate (20 mL) was added Dess-Martin periodinane (981 mg, 2.31 mmol) at 0 °C and stirred at room temperature for 3 h. After completion of the reaction by TLC, the reaction mixture was filtered through a pad of diatomaceous earth and washed with ethyl acetate (20 mL). The resulting filtrate was washed with saturated Hypo solution (3 × 20 mL), saturated NaHCO solution (3 × 20 mL), and brine (1 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting compound was purified by trituration with DEE / n-pentane to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-(3-fluorophenyl)ethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A165). TLC system: 5% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z 582.7 [M+H] +

[0261] Example 11: Synthesis of Compound A173 [ka] 2,2-Difluoro-2-(3-fluorophenyl)-1-phenylethyl ((2S)-1-(((2S)-4-(ethylamino)-3-hydroxy-4-oxo-1-((R)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (2): To a stirred solution of 2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A77) (700 mg, 1.27 mmol) in DCM was added isocyanoethane (1) (1.5 ml, 2 volumes) followed by acetic acid (0.2 mL, 3.56 mmol) at 0° C. and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl (2×20 mL) followed by brine (1×20 mL). The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure. The resulting material was purified by column chromatography using silica gel and 3% MeOH in DCM as the eluent to give 2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((2S)-1-(((2S)-4-(ethylamino)-3-acetate-4-oxo-1-((R)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (360 mg, 542.98 mmol), which was dissolved in THF (10 mL), water (5 mL), and lithium hydroxide (71 mg, 1.62 mmol) was added at 0° C. and stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (2 x 100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((2S)-1-(((2S)-4-(ethylamino)-3-hydroxy-4-oxo-1-((R)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (2). TLC system: 10% methanol in dichloromethane Rf: 0.1 LCMS [ESI]: m / z 621.70 [M+H] +

[0262] 2,2-Difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-1-(((S)-4-(ethylamino)-3,4-dioxo-1-((R)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (A173): To a stirred solution of 2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((2S)-1-(((2S)-4-(ethylamino)-3-hydroxy-4-oxo-1-((R)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (2) (0.25 g, 0.40 mmol) in ethyl acetate (10 mL) was added Dess-Martin periodinane (381 mg, 0.80 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was filtered through a pad of diatomaceous earth, washed with ethyl acetate (20 mL), and the filtrate was washed with hypo solution (3 × 20 mL) followed by saturated NaHCO solution (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a residue which was purified by reverse phase purification and 50% ACN in 0.1% aqueous formic acid to give 2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-1-(((S)-4-(ethylamino)-3,4-dioxo-1-((R)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (A173). TLC system: 10% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z 619.3 [M+H] +

[0263] Example 12: Synthesis of Compounds A220 and A221 [ka] Cyclopent-1-en-1-yl trifluoromethanesulfonate (3) To a stirred solution of cyclopent-1-en-1-ol (1) (40 g, 476.19 mmol) in THF (200 mL), 1 M LiHMDS in THF (153 mL, 428 mmol) was added dropwise at −78° C. and maintained at the same temperature for 30 minutes. N-phenyl-O-((trifluoromethyl)sulfonyl)-N-(((trifluoromethyl)sulfonyl)oxy)hydroxylamine (152.9 g, 428.57 mmol) dissolved in THF (200 mL) was then added dropwise at −78° C. and maintained at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (2×300 mL). The organic layer was washed with water (2×100 mL) and brine solution (50 mL), dried over anhydrous NaSO, and evaporated under reduced pressure. The resulting product was purified on a 100-200 silica column eluted with 2% ethyl acetate / petroleum ether to give cyclopent-1-en-1-yl trifluoromethanesulfonate (3). TLC system: 2% ethyl acetate / petroleum ether Rf: 0.6. Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(cyclopent-1-en-1-yl)propanoate (5).

[0264] To a stirred solution of zinc dust (15.6 g, 182.37 mmol) and a catalytic amount of iodine in DMF (200 mL) was slowly added dropwise methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (4) (20 g, 60.79 mmol) at room temperature and stirred for 30 min. Cyclopent-1-en-1-yl trifluoromethanesulfonate (3) (13.1 g, 60.79 mmol) was then added at room temperature and degassed with argon for 10 min. Sphos (496 mg, 1.21 mmol) and Pd(dppf)Cl (888 mg, 1.21 mmol) were then added, and the mixture was again degassed with argon for 10 min and stirred at 50 °C for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with ice water (500 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with brine solution (100 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting product was purified on a silica (100-200 mesh) column and eluted with 5% ethyl acetate / petroleum ether to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(cyclopent-1-en-1-yl)propanoate (5). TLC system: 2% ethyl acetate / petroleum ether Rf: 0.4 Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoate (6).

[0265] To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(cyclopent-1-en-1-yl)propanoate (5) (10 g, 37.17 mmol) in methanol (100 mL) was added 10% Pd-C (20% w / w) at room temperature and stirred under nitrogen balloon pressure for 16 hours. The reaction progress was monitored by TLC. The reaction mixture was filtered through a bed of diatomaceous earth, the bed was washed with methanol (50 mL), and the filtrate was evaporated under reduced pressure to give methyl (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoate (6). TLC system: 4% ethyl acetate / petroleum ether Rf: 0.5 Methyl (S)-2-amino-3-cyclopentylpropanoate hydrochloride (7):

[0266] To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoate (6) (19.1 g, 70.47 mmol) in DCM (40 mL) was added 4 M 1,4-dioxane.HCl (76 mL, 4 volumes) at 0° C. and stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was evaporated under reduced pressure to give material that was triturated with diethyl ether (2×50 mL) to give methyl (S)-2-amino-3-cyclopentylpropanoate hydrochloride (7). TLC system: 10% MeOH in DCM Rf: 0.2

[0267] Methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclopentylpropanoate (8) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (Int-7) (22 g, 82.089 mmol) in 100 mL of acetonitrile was added DSC (42 g, 164.17 mmol) followed by triethylamine (28.5 mL, 205.22 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 2 h.

[0268] In a separate RB flask, methyl (S)-2-amino-3-cyclopentylpropanoate hydrochloride (7) (13 g, 62.8 mmol) was taken up in acetonitrile (120 mL) and treated with triethylamine (21.8 mL, 75.36 mmol). The reaction mass prepared above was then added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water (150 mL), extracted with ethyl acetate (2 x 100 mL), and the combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate, and evaporated under reduced pressure to give compound. The material was purified by normal phase chromatography to give methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclopentylpropanoate (8). TLC system: 10% ethyl acetate / petroleum ether R f:0.4 LCMS[ESI):m / z 466.27[M+H] +

[0269] (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclopentylpropanoic acid (9) To a stirred solution of methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclopentylpropanoate (8) (23 g, 49.67 mmol) in THF (150 mL), water (10 mL), lithium hydroxide (5.2 g, 124.17 mmol) was added at room temperature and stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. Excess THF was distilled under reduced pressure, the compound was acidified with 1N aqueous HCl to pH 2, extracted with DCM (2 x 500 mL), and the combined organic layers were washed with water (200 mL), brine solution (150 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclopentylpropanoic acid (9). TLC system: 10% methanol in dichloromethane Rf: 0.2 LCMS [ESI]: m / z 452.25 [M+H] +

[0270] Methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclopentylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (10) To a stirred solution of (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclopentylpropanoic acid (9) (17 g, 37.69 mmol) in DMF (170 mL), HATU (21.4 g, 56.53 mmol), DIPEA (20 mL, 113.07 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (amine fragment-2) (10 g, 45.23 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (400 mL) and extracted with ethyl acetate (2 × 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by normal phase Combiflash column to give methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclopentylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (10). TLC system: 5% MeOH / DCM Rf: 0.45 LCMS [ESI]: m / z = 620.34 [M+H] +

[0271] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (11) To a stirred solution of methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclopentylpropanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (10) (1.5 g, 2.42 mmol) in dichloromethane (20 mL) was added 2 M LiBH in THF (2.4 mL, 4.84 mmol) slowly dropwise at 0 °C and stirred at 0 °C for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with saturated NH4Cl solution, extracted with dichloromethane (2 x 100 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (11). TLC system: 10% methanol in dichloromethane Rf: 0.55 LCMS [ESI]: m / z 592.27 [M+H] +

[0272] 2-(3-Chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (A93) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (11) (2.1 g, 3.55 mmol) in ethyl acetate (25 mL) was added Dess-Martin periodinane (2.2 g, 5.32 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated NaHCO solution (3 × 30 mL), followed by saturated Hypo solution (3 × 30 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (A93). TLC system: 10% methanol in DCM. f :0.55 LCMS[ESI):m / z 590.3[M+H] +

[0273] 2-(3-Chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-3-cyclopentyl-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (13) Then, to a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (A93) (4 g, 6.78 mmol) dissolved in DCM (40 mL) was added a solution of ethyl isocyanide (14.24 mmol) in DCM (10 mL) at 0° C. and stirred to room temperature for 6 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl (2×15 mL), followed by water (2×20 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the material, which was purified by reverse-phase column (C18) and eluted with 1% ammonium bicarbonate / acetonitrile to give (6S,9S)-1-(3-chlorophenyl)-6-(cyclopentylmethyl)-1,1-difluoro-4,7,11-trioxo-9-(((S)-2-oxopyrrolidin-3-yl)methyl)-2-phenyl-3-oxa-5,8,12-triazatetradecan-10-yl acetate (13). TLC system: 5% MeOH in DCM Rf: 0.4 LCMS [ESI]: m / z 705.33 [M+H] +

[0274] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-3-cyclopentyl-1-(((2S)-4-(ethylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (14) To a stirred solution of (6S,9S)-1-(3-chlorophenyl)-6-(cyclopentylmethyl)-1,1-difluoro-4,7,11-trioxo-9-(((S)-2-oxopyrrolidin-3-yl)methyl)-2-phenyl-3-oxa-5,8,12-triazatetradecan-10-yl acetate (13) (4 g, 14.9 mmol) in THF:HO (30 mL) (4:1) was added LiOH.HO (939 mg, 22.35 mmol) at 0 °C and stirred at the same temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with water, extracted with ethyl acetate (2 × 100 mL), and washed with brine solution (20 mL). The organic layer was dried over anhydrous NaSO, filtered, and evaporated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-3-cyclopentyl-1-(((2S)-4-(ethylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (14). LCMS [ESI]: m / z 663.50 [M+H] +

[0275] 2-(3-Chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-(((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (A117) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-3-cyclopentyl-1-(((2S)-4-(ethylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (14) (5 g, 7.55 mmol) in ethyl acetate (50 mL) was added Dess-Martin periodinane (6.4 g, 15.1 mmol) at 0 °C and stirred at room temperature for 6 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was filtered through a pad of diatomaceous earth, washed with ethyl acetate (50 mL), and the filtrate was washed with hypo solution (3 × 50 mL), followed by saturated NaHCO solution (3 × 50 mL) and brine solution (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting material was purified by trituration with n-pentane / DEE to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-(((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (A117). TLC system: 10% MeOH in DCM Rf: 0.6 LCMS [ESI]: m / z 661.29 [M+H] +

[0276] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-(((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (A220) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-(((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (A221). 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-(((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (A117) (4 g, 60.4 mmol) was purified by SFC chiral purification to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-3-cyclopentyl-1-(((S)-4- (Ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (A220) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl((S)-3-cyclopentyl-1-(((S)-4-(ethylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate (A221) were obtained.

[0277] Example 13: Synthesis of Compound A223 [ka] (S)-2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (5-PK-1) and (R)-2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (5-PK-2): 2,2-Difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (Int-5) (2.3 g) was isolated by chiral SFC purification to give (S)-2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-(( (S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (5-PK-1) (800 mg) and (R)-2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (5-PK-2) were obtained. LCMS [ESI]: m / z 550.3 [M+H] +

[0278] (S)-2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (A223): To a stirred solution of (S)-2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (5-PK-1) (260 mg, 0.47 mmol) in EtOAc (10 mL) was added Dess-Martin periodinane (602 mg, 1.42 mmol) at 0 °C and stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc (20 mL) and filtered through a diatomaceous earth pad. The resulting filtrate was washed with saturated Hypo solution (3 × 30 mL) followed by saturated NaHCO solution (3 × 20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting compound was purified using a reversed-phase Combiflash column (C18) and 45% ACN in 1% aqueous NH4CO3 solution as the eluent to give (S)-2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate A223. TLC system: 5% methanol in dichloromethane. LCMS (ESI): m / z = 548.3 (M+H). + Rf: 0.5

[0279] Example 14: Synthesis of Compound A224 [ka] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-1-cyano-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (1) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A48) (600 mg, 1.063 mmol) in DCM (10 mL) was added acetone cyanohydrin (0.6 mL, 1 vol), EtN (0.6 mL, 1 vol) at 0° C. and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with DCM (15 mL), washed with water (2×15 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the product. This material was triturated with n-pentane (25 mL) to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-1-cyano-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (1). TLC system: 10% methanol in dichloromethane Rf: 0.5 LCMS [ESI]: m / z 591.35 [M+H] +

[0280] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (2) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-1-cyano-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxohexan-2-yl)carbamate (1) (450 mg, 0.762 mmol) in DMSO (5 mL) was added potassium carbonate (210 mg, 1.525 mmol), followed by 30% HO (0.8 mL, 2 volumes) at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with water (2 x 15 mL), followed by brine (1 x 15 mL), dried over sodium sulfate, and evaporated under reduced pressure to give material that was triturated with n-pentane (15 mL) to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (2). TLC system: 10% methanol in dichloromethane Rf: 0.3 LCMS [ESI]: m / z 609.39 [M+H] +

[0281] 2-(3-Chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-amino-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (A224) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-amino-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (2) (300 mg, 0.492 mmol) in ethyl acetate (10 mL) was added Dess-Martin periodinane (417 mg, 0.985 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate (20 mL). The filtrate was washed with saturated Hypo solution (3 × 20 mL), saturated NaHCO solution (3 × 20 mL), followed by brine (1 × 15 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a material that was purified by reverse-phase chromatography using 0.1% ammonium carbonate in water / acetonitrile as a buffer to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-amino-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (A224). TLC system: 10% methanol in dichloromethane Rf: Rf: 0.4 LCMS (ESI): m / z 607.2 [M+H] +

[0282] Example 15: Synthesis of Compounds A222 and A226 [ka] Ethyl 2-([1,1'-biphenyl]-3-yl)-2,2-difluoroacetate (3) Ethyl 2-bromo-2,2-difluoroacetate (2) (28.97 g, 142.857 mmol) was added to a suspension of copper powder (18.52 g, 285.612 mmol) in DMSO (100 mL) under N2. The suspension was stirred at room temperature for 1 h, then 3-iodo-1,1'-biphenyl (20 g, 71.4030 mmol) was added and stirred at 60 °C for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with aqueous NH4Cl (200 mL) and extracted with diethyl ether (2 × 150 mL). The combined organic layers were washed with water (2 x 200 mL), brine (1 x 100 mL), dried over sodium sulfate, and evaporated to give material that was purified by normal phase chromatography to give ethyl 2-([1,1'-biphenyl]-3-yl)-2,2-difluoroacetate (3). TLC system: 10% ethyl acetate / petroleum ether Rf: 0.4 LCMS [ESI]: m / z 257.06 [MF] +

[0283] 2-([1,1'-biphenyl]-3-yl)-2,2-difluoro-N-methoxy-N-methylacetamide (4) To a stirred solution of ethyl 2-([1,1'-biphenyl]-3-yl)-2,2-difluoroacetate (3) (12 g, 43.478 mmol) in THF (100 mL), N,O-dimethylhydroxylamine hydrochloride (6.32 g, 65.217 mmol) was added, the reaction was cooled to -10 °C, and then 1.0 M isopropylmagnesium chloride in THF (130.434 mL, 130.434 mmol) was slowly added and stirred at the same temperature for 1 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (1 × 100 mL), followed by brine (1 × 100 mL), dried over sodium sulfate, and evaporated under reduced pressure to give 2-([1,1'-biphenyl]-3-yl)-2,2-difluoro-N-methoxy-N-methylacetamide (4). TLC system: 20% ethyl acetate in petroleum ether. f:0.5 LCMS[ESI):m / z 292.10[M+H] +

[0284] 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-one (6) To a stirred solution of 2-([1,1'-biphenyl]-3-yl)-2,2-difluoro-N-methoxy-N-methylacetamide (4) (10 g, 34.364 mmol) in THF (100 mL) was added isopropylmagnesium chloride (86 mL, 171.821 mmol) at -10 °C and stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (50 mL), brine (150 mL), dried over sodium sulfate, and evaporated under reduced pressure to give 2-([1,1'-biphenyl]-3-yl)-2,2-difluoro-1-phenylethan-1-one (6), which was used directly in the next step. TLC system: 10% ethyl acetate in hexanes R f :0.4 LCMS[ESI]:m / z 255.06[MF] +

[0285] 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-ol (7) To a stirred solution of 2-([1,1'-biphenyl]-3-yl)-2,2-difluoro-1-phenylethan-1-one (6) (7.4 g, 27.007 mmol) in THF (130 mL) was added sodium borohydride (3.062 g, 81.021 mmol) at 0 °C and stirred at room temperature for 2 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with ammonium chloride (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over sodium sulfate, and evaporated under reduced pressure to give the product, which was purified using Combiflash (normal phase) by eluting with 15% ethyl acetate in petroleum ether to give 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-ol. TLC system: 30% ethyl acetate in hexane f :0.5 LCMS[ESI]:m / z 257.09[MF] +

[0286] Methyl(((1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl)oxy)carbonyl)-L-leucine acid (9) To a stirred solution of 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-ol (7) (3.2 g, 11.594 mmol) in ACN (30 mL) was added N,N'-disuccinimidyl carbonate (7.42 g, 28.985 mmol) followed by EtN (9.6 mL, 3 volumes) at 0 °C and stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. The reaction mass was used directly in the next reaction.

[0287] In a separate RB flask, methyl L-leucine hydrochloride (8) (5.24 g, 28.985 mmol) was taken up in ACN (20 mL) and treated with EtN (9.6 mL, 3 volumes). The reaction mixture was stirred for 5 minutes, then the reaction mass prepared above was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction by TLC and LC-MS, the reaction mixture was quenched with ice water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, and evaporated under reduced pressure to give material, which was purified by Combiflash (normal phase) eluting with 5% ethyl acetate in petroleum ether to give methyl (((1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl)oxy)carbonyl)-L-leucine acid (9). TLC system: 30% ethyl acetate / petroleum ether R f :0.4 LCMS[ESI]:m / z 428.35[MF] +

[0288] (((1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl)oxy)carbonyl)-L-leucine (10) To a stirred solution of methyl(((1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl)oxy)carbonyl)-L-leucine acid (9) (1.2 g, 2.684 mmol) in THF (12 mL), water (12 mL), lithium hydroxide (128.5 mg, 5.369 mmol) was added at room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC and LC-MS. Excess THF was distilled under reduced pressure, and the compound was acidified to pH ∼2 with 1N aqueous HCl and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give ((2-([1,1'-biphenyl]-3-yl)-2,2-difluoro-1-phenylethoxy)carbonyl)-L-leucine (10). TLC system: 10% MeOH / DCM Rf: 0.5 LCMS [ESI]: m / z 456.31 [M+Na] +

[0289] Methyl (2S)-2-((2S)-2-((((1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl)oxy)carbonyl)amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (11) To a stirred solution of ((2-([1,1'-biphenyl]-3-yl)-2,2-difluoro-1-phenylethoxy)carbonyl)-L-leucine (10) (800 mg, 1.845 mmol) in DMF (20 mL) was added EDC.HCl (528.7 mg, 2.768 mmol), HOBt (373.7 mg, 2.768 mmol), DIPEA (1.02 mL, 5.536 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (amine fragment-2) (411.9 mg, 2.214 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. Water (100 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give the compound. The material was purified by normal phase chromatography to give methyl (2S)-2-((2S)-2-((((1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl)oxy)carbonyl)amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (11). TLC system: 10% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z = 602.31 [M+H] +

[0290] 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (12) To a stirred solution of methyl (2S)-2-((2S)-2-((((1-([1,1′-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl)oxy)carbonyl)amino)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (11) (500 mg, 0.830 mmol) in THF (10 mL) was added 2M HCl in THF. LiBH (0.83 mL, 1.661 mmol) was added at 0 °C and stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC and LC-MS. The reaction mixture was quenched with saturated NH Cl solution (10 mL), extracted with ethyl acetate (2 × 25 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (12). TLC system: 10% methanol in dichloromethane Rf: 0.3 LCMS [ESI]: m / z 574.48 [M+H] +

[0291] 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (A222) To a stirred solution of 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (12) (100 mg, 0.174 mmol) in ethyl acetate (3 mL) was added Dess-Martin periodinane (110.8 mg, 0.2614 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction progress was monitored by TLC and LC-MS. The suspension was filtered through a pad of diatomaceous earth, washed with ethyl acetate, and the filtrate was washed with saturated NaHCO solution (3 × 30 mL) followed by saturated Hypo solution (3 × 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give a material that was triturated with n-pentane / diethyl ether to give 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (A222). TLC system: 10% methanol in DCM f :0.4 LCMS[ESI]:m / z 572.3[M+H] +

[0292] 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (14) To a stirred solution of 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (A222) (180 mg, 0.314 mmol) in DCM (5 mL) was added isocyanocyclopropane (0.06 mL, 0.944 mmol) and pyridine (0.5 mL, 3 vol) followed by TFA (0.006 mL, 0.062 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was diluted with dichloromethane and washed with saturated NaHCO solution (50 mL) and water (50 mL), followed by brine (50 mL). The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (14). TLC system: 10% MeOH in DCM Rf: 0.5 LCMS [ESI]: m / z 657.4 [M+H] +

[0293] 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (A226) To a stirred solution of 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (14) (170 mg, 0.258 mmol) in ethyl acetate (10 mL) was added Dess-Martin periodinane (164.67 mg, 0.388 mmol) at 0°C and stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LC-MS. The suspension was filtered through a pad of diatomaceous earth and washed with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution (3 x 20 mL), followed by saturated Hypo solution (3 x 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the material. This compound was purified using reverse phase (buffer: 0.1% ABC / CAN) to give 1-([1,1'-biphenyl]-3-yl)-1,1-difluoro-3-methylbutan-2-yl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate (A226) (15). TLC system: 10% MeOH in DCM Rf: 0.5 LCMS [ESI]: m / z 655.4 [M+H] +

[0294] Example 16: Synthesis of Compounds A227 and A228 [ka] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-5,5-difluoro-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (A163): To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-5,5-difluoro-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxopentan-2-yl)carbamate (1) (2 g, 3.40 mmol) in ethyl acetate (30 mL), Dess-Martin periodinane (2.9 g, 6.81 mmol) was slowly added dropwise at 0 °C and stirred at room temperature for 2 h. After completion of the reaction by TLC, the reaction mixture was diluted with ethyl acetate (40 mL), filtered through a pad of diatomaceous earth, and washed with ethyl acetate (20 mL). The resulting filtrate was washed with saturated Hypo solution (3 × 50 mL), followed by saturated NaHCO solution (3 × 50 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting compound was purified by trituration with diethyl ether / n-pentane to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-5,5-difluoro-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (A163). TLC system: 5% methanol in DCM Rf: 0.5 LCMS [ESI]: m / z 586.2 [M+H] +

[0295] (3S)-3-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-5,5-difluoropentanamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (3): To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-5,5-difluoro-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate (A163) (1.2 g, 2.05 mmol) in dichloromethane (20 mL) was added acetic acid (1 ml) and cyclopropyl isocyanide (2) (687 mg, 10.25 mmol) at 0° C. and stirred at room temperature for 16 hours. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DCM (20 mL) and washed with water (3×40 mL) and brine solution. The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by Combiflash with 3% methanol in dichloromethane used as the eluent to give (3S)-3-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-5,5-difluoropentanamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (3). TLC system: 10% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z 713.3 [M+H] +

[0296] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-5,5-difluoro-1-oxopentan-2-yl)carbamate (4): To a stirred solution of (3S)-3-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-5,5-difluoropentanamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (3) (1 g, 1.4 mmol) in THF (8 mL), water (4 mL) was added LiOH.HO (0.11 g, 2.8 mmol) at 0 °C and stirred at room temperature for 1 hour. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove THF. The compound was acidified to pH ∼2 with 1 N aqueous HCl and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-5,5-difluoro-1-oxopentan-2-yl)carbamate (4). TLC system: 10% methanol in dichloromethane Rf: 0.3 LCMS [ESI]: m / z 671.28 [M+H] +

[0297] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-5,5-difluoro-1-oxopentan-2-yl)carbamate (A179): To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-5,5-difluoro-1-oxopentan-2-yl)carbamate (8) (1 g, 1.49 mmol) in ethyl acetate (20 mL) was added Dess-Martin periodinane (1.2 g, 2.98 mmol) at 0 °C and stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20 mL) and filtered through a calcite pad. The resulting filtrate was washed with saturated Hypo solution (3 × 50 mL) followed by saturated NaHCO solution (3 × 50 mL). The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting compound was purified by trituration with n-pentane / DEE to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-5,5-difluoro-1-oxopentan-2-yl)carbamate (A179). TLC system: 5% methanol in DCM Rf: 0.5 LCMS [ESI]: m / z 669.2 [M+H] +

[0298] (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-5,5-difluoro-1-oxopentan-2-yl)carbamate (A227) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-5,5-difluoro-1-oxopentan-2-yl)carbamate (A228). The compound 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo 1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-5,5-difluoro-1-oxopentan-2-yl)carbamate (A179) (800 mg) was purified by chiral SFC to give (S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3 ,4-Dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-5,5-difluoro-1-oxopentan-2-yl)carbamate (A227) and (R)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-5,5-difluoro-1-oxopentan-2-yl)carbamate (A228). TLC system: 10% methanol in DCM Rf: 0.3 LCMS [ESI]: m / z 647.3 [M+H] +

[0299] Example 17: Synthesis of Compound A229 [ka] Sodium (2S,6S,9S)-1-(3-chlorophenyl)-6-(cyclohexylmethyl)-1,1-difluoro-4,7,12-trioxo-9-(((S)-2-oxopyrrolidin-3-yl)methyl)-2-phenyl-3,11-dioxa-5,8-diazatetradecane-10-sulfonate (A229) To a stirred solution of sodium (2S)-2-((S)-2-((((S)-2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonate (A141) (200 mg, 0.282 mmol) in ACN (4 mL) was added propionic anhydride (0.06 g, 0.424 mmol) at room temperature and stirred at 50° C. for 16 h. The reaction progress was monitored by LC-MS. The reaction mixture was concentrated and triturated with pentane (10 mL) and diethyl ether (10 mL), followed by preparative HPLC / lyophilization to give sodium (2R,6S,9S)-1-(3-chlorophenyl)-6-(cyclohexylmethyl)-1,1-difluoro-4,7,12-trioxo-9-(((S)-2-oxopyrrolidin-3-yl)methyl)-2-phenyl-3,11-dioxa-5,8-diazatetradecane-10-sulfonate (A229). TLC system: 10% methanol in dichloromethane Rf: 0.2 LCMS [ESI]: m / z 742.2 [M-Na] +

[0300] Preparative HPLC conditions: Column / dimensions: BIRDGE C18 (19*250, 5um); Mobile phase A: MILI-Q water; Mobile phase B: acetonitrile; Gradient (time / %B): 0 / 10, 1 / 10, 9 / 40, 14.9 / 40, 15 / 98, 19.9 / 98, 20 / 10, 22 / 10; Flow rate: 18mL / min; Solubility: acetonitrile.

[0301] Example 18: Synthesis of Compound A230 [ka] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4,4-difluoro-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)butan-2-yl)carbamate (A232): To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4,4-difluoro-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxobutan-2-yl)carbamate (11) (700 mg, 1.2 mmol) in ethyl acetate (10 mL) was added Dess-Martin periodinane (1.29 g, 3.05 mmol) slowly dropwise at 0 °C and stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate (20 mL), filtered through a pad of diatomaceous earth, and the filtrate was washed with saturated sodium thiosulfate solution (3 × 30 mL), followed by saturated NaHCO solution (3 × 30 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4,4-difluoro-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)butan-2-yl)carbamate. TLC system: 10% methanol in DCM. f :0.55 LCMS[ESI):m / z 572.3[M+H] +

[0302] (3S)-3-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (13): Then, to a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4,4-difluoro-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)butan-2-yl)carbamate (A232) (550 mg, 0.96 mmol) dissolved in DCM (8 mL) was added isocyanocyclopropane (13) (200 mg, 2.88 mmol), followed by acetic acid (0.17 mL, 2.88 mmol) at 0° C. and stirred at room temperature for 6 hours. The reaction progress was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was diluted with dichloromethane and washed with saturated ammonium chloride solution (2×30 mL), followed by brine (1×20 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The resulting compound was purified by reverse-phase (C18) column chromatography using 55% CAN in 0.1% aqueous formic acid as the eluent to give (3S)-3-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (13). TLC system: 10% MeOH in DCM Rf: 0.5 LCMS [ESI]: m / z 699 [M+H] +

[0303] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4,4-difluoro-1-oxobutan-2-yl)carbamate (14): To a stirred solution of (3S)-3-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (13) (150 mg, 0.107 mmol) in THF (2 mL), water (0.4 mL) was added LiOH.HO (9.9 mg, 0.236 mmol) at 0 °C and stirred at 0 °C for 30 min. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4,4-difluoro-1-oxobutan-2-yl)carbamate (14). TLC system: 10% MeOH in DCM Rf: 0.65 LCMS [ESI]: m / z 657.41 [M+H]+

[0304] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4,4-difluoro-1-oxobutan-2-yl)carbamate (A230): To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4,4-difluoro-1-oxobutan-2-yl)carbamate (14) (90 mg, 0.132 mmol) in ethyl acetate (2 mL) was added Dess-Martin periodinane (87.2 mg, 0.205 mmol) at 0 °C and stirred at room temperature for 1 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate (10 mL). The filtrate was washed with saturated sodium thiosulfate solution (3 × 20 mL) followed by saturated NaHCO solution (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by trituration with n-pentane / DEE to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4,4-difluoro-1-oxobutan-2-yl)carbamate (A230). TLC system: 10% MeOH in DCM Rf: 0.65 LCMS [ESI]: m / z 655.2 [M+H]+

[0305] Example 19: Synthesis of Compound A231 [ka] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-((2-(benzyloxy)ethyl)amino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (2) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A48) (200 mg, 0.3552 mmol) in DCM (6 mL) was added ((2-isocyanoethoxy)methyl)benzene (1) (6 mL, 3 vol), pyridine (6 mL, 3 vol), and TFA (0.01 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LC-MS. The reaction mixture was diluted with dichloromethane (10 mL) and washed with 1 N aqueous HCl (3×20 mL), followed by brine (1×20 mL). The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-((2-(benzyloxy)ethyl)amino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (2). TLC system: 10% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z 743.34 [M+H] +

[0306] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-((2-(benzyloxy)ethyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (3) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-((2-(benzyloxy)ethyl)amino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (2) (190 mg, 0.2560 mmol) in ethyl acetate (5 mL) was added Dess-Martin periodinane (217 mg, 0.5121 mmol) at 0° C. and stirred at room temperature for 3 hours. The reaction progress was monitored by TLC. The suspension was filtered through a pad of diatomaceous earth, washed with ethyl acetate (20 mL), and the filtrate was washed with saturated Hypo solution (3×25 mL), followed by saturated NaHCO solution (3×25 mL), and brine (25 mL). The organic layer was dried over anhydrous NaSO and concentrated to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-((2-(benzyloxy)ethyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (3). TLC system: 10% methanol in dichloromethane Rf: 0.4 LCMS [ESI]: m / z 741.2 [M+H] +

[0307] 2-(3-Chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-((2-hydroxyethyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (A231) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-((2-(benzyloxy)ethyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (3) (170 mg, 0.2297 mmol) in MeOH (6 mL) was added 10% Pd / C (34 mg, 20% w / w) and triethylsilane (80 mg, 0.6891 mmol) at room temperature. The reaction mixture was stirred at 60° C. for 3 hours. After completion, the reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was dried over Na2SO4 and concentrated to give compound (III). The material was purified by preparative HPLC to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-1-(((S)-4-((2-hydroxyethyl)amino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate (A231). TLC system: 10% methanol in dichloromethane Rf: 0.4

[0308] Preparative HPLC conditions: Column / dimensions: KROMOSIL (25*150) 10µm. Mobile phase A: 10mM ABC in water (aqueous). Mobile phase B: 10mM ABC (1:1) ACN and MeOH. Gradient (time / %B): 0 / 40, 1 / 40, 18 / 98, 22 / 98, 22.1 / 40, 25 / 40. Flow rate: 25mL / min. Solubility: ACN + THF + water. LCMS (ESI): m / z 651.2 (M+H). +

[0309] Int-1 - Synthesis: N-(2-(benzyloxy)ethyl)formamide To a mixture of 2-(benzyloxy)ethan-1-amine hydrochloride (1A) in triethyl orthoformate (2 g, 10.689 mmol) at room temperature. The reaction mixture was stirred at 120° C. for 12 hours. After completion, the reaction mixture was concentrated in vacuo to give N-(2-(benzyloxy)ethyl)formamide (2A). TLC system: 5% methanol in dichloromethane Rf: 0.3 LCMS [ESI]: m / z 180.2 [M+H]+

[0310] ((2-isocyanoethoxy)methyl)benzene To a stirred solution of N-(2-(benzyloxy)ethyl)formamide (2A) (1.5 g, 8.379 mmol) in DCM (4.5 mL) was added POCl (0.5 mL, 6.284 mmol), EtN (2.1 mL, 20.93 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 3 h. After completion, the reaction mixture was quenched with saturated NaHCO solution (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were washed with water (2×15 mL), followed by brine (1×15 mL), and dried over sodium sulfate to give ((2-isocyanoethoxy)methyl)benzene (Int-1) (10 mL). TLC system: 5% methanol in dichloromethane Rf: 0.3 LCMS [ESI]: m / z 161.99 [M+H] +

[0311] Example 20: Synthesis of Compound A232 [ka] Diethyl 2-acetamido-2-(2,2-difluoroethyl)malonate (2): To a stirred solution of diethyl 2-acetamidomalonate (1) (50 g, 230 mmol) in THF (1000 mL), KOtBu (25.8 g, 230 mmol) was added and refluxed for 2 h. Then, 2,2-difluoroethyl trifluoromethanesulfonate (74 g, 345 mmol) was slowly added dropwise at 70 °C and stirred at the same temperature for 3 h. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was concentrated, and the resulting residue was diluted with EtOAc (500 mL) and washed with 0.5 N HCl (2 × 500 mL), 1 N aqueous NaOH (2 × 500 mL), and brine solution (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by recrystallization using DEE at −20° C., and the solid was filtered to give diethyl 2-acetamido-2-(2,2-difluoroethyl)malonate (2). TLC system: 50% ethyl acetate in hexanes Rf: 0.6 LCMS [ESI]: m / z 282.3 [M+H] +

[0312] 2-Amino-4,4-difluorobutanoic acid hydrochloride (3): To diethyl 2-acetamido-2-(2,2-difluoroethyl)malonate (2) (25 g, 88.9 mmol), 6N HCl (250 mL) was added at room temperature, and the mixture was refluxed at 100° C. for 16 hours. The progress of the reaction was monitored by TLC. After the completion of the starting material, the reaction mass was washed with DEE, and the aqueous layer was concentrated under reduced pressure to give 2-amino-4,4-difluorobutanoic acid hydrochloride (3). TLC system: 50% ethyl acetate in hexane Rf: 0.1 LCMS [ESI]: m / z 140.15 [M+H] +

[0313] Methyl 2-amino-4,4-difluorobutanoate hydrochloride (4): To a stirred solution of 2-amino-4,4-difluorobutanoate hydrochloride (3) (11 g, 63.2 mmol) in methanol (110 mL), SOCl (55 mL) was slowly added dropwise at 0 °C and stirred at room temperature for 12 hours. The reaction progress was monitored by LCMS. After completion of the starting material, the reaction mixture was directly concentrated under reduced pressure to give methyl 2-amino-4,4-difluorobutanoate hydrochloride (4). LCMS [ESI]: m / z 154.13 [M+H] +

[0314] Methyl 2-(((benzyloxy)carbonyl)amino)-4,4-difluorobutanoate (5): To a stirred solution of 2-amino-4,4-difluorobutanoate hydrochloride (4) (11 g, 58.02 mmol) in THF (66 mL) and water (33 mL), NaHCO (14.8 g, 175.5 mmol) was added at room temperature, followed by the slow dropwise addition of Cbz-Cl (15 g, 87.7 mmol) at 0 °C and stirring at room temperature for 6 h. The reaction progress was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was diluted with ice-cold water (300 mL) and extracted with EtOAc (500 mL). The organic layer was separated, washed with brine solution (300 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by CombiFlash column with 15% ethyl acetate in petroleum ether as the eluent to give methyl 2-(((benzyloxy)carbonyl)amino)-4,4-difluorobutanoate (5). LCMS [ESI]: m / z 288.1 [M+H] +

[0315] Methyl (S)-2-(((benzyloxy)carbonyl)amino)-4,4-difluorobutanoate (5-PK-1): 15 g of methyl 2-(((benzyloxy)carbonyl)amino)-4,4-difluorobutanoate (5) was purified by chiral SFC to give methyl (S)-2-(((benzyloxy)carbonyl)amino)-4,4-difluorobutanoate.

[0316] Methyl (S)-2-amino-4,4-difluorobutanoate (Int-1C): To a nitrogen-degassed solution of methyl (S)-2-(((benzyloxy)carbonyl)amino)-4,4-difluorobutanoate (5-PK-1) (3.5 g, 12.1 mmol) in methanol (35 mL), Pd / C (350 mg) was added at room temperature and stirred under balloon H pressure for 3 hours. The reaction progress was monitored by TLC and LCMS. After completion of the starting material, the reaction mass was filtered through a pad of diatomaceous earth, the bed was washed with methanol, and the resulting filtrate was concentrated under reduced pressure to give methyl (S)-2-amino-4,4-difluorobutanoate (Int-1C).

[0317] Methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanoate (8) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (Int-7) (5 g, 18.6 mmol) in DCM (50 mL), pyridine (15 ml) was added, followed by the slow dropwise addition of triphosgene (3.3 g, 11.19 mmol) at 0 °C and stirring at the same temperature for 30 minutes. Methyl (S)-2-amino-4,4-difluorobutanoate (Int-1C) (3.4 g, 22.3 mmol) was then added at the same temperature and stirred at room temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the starting material, the reaction mixture was quenched with 1 N HCl (10 ml) and extracted with DCM (200 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (200 ml), followed by brine solution (200 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by normal phase silica gel column chromatography using 5% ethyl acetate in petroleum ether as eluent to give methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanoate (8). TLC system: 20% ethyl acetate / petroleum ether Rf: 0.3 LCMS (ESI): m / z 448.07 [M+H]+

[0318] (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanoic acid (9): To a stirred solution of methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanoate (8) (2.9 g, 6.4 mmol) in THF (15 mL) and water (15 mL), LiOH.HO (0.8 g, 19.4 mmol) was added at room temperature and stirred for 2 hours. The progress of the reaction was monitored by TLC and LCMS. The THF solvent was distilled under reduced pressure, the compound was acidified with 1N aqueous HCl to pH 2, extracted with DCM (2 x 100 mL), and the combined organic layers were washed with water (100 mL), aqueous brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanoic acid (9). TLC system: 10% methanol in dichloromethane Rf: 0.1 LCMS [ESI]: m / z 414.22 [MF] +

[0319] Methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (10): To (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanoic acid (9) (2.6 g, 6.0 mmol) in DMF (26 mL) were added EDC.HCl (1.72 g, 9 mmol), HOBt (1.37 g, 9 mmol), DIPEA (3.1 mL, 18 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (amine fragment-2) (1.6 g, 7.2 mmol) at 0 °C and stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography using silica gel (100-200 mesh) and 95% ethyl acetate in petroleum ether to give methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (10). TLC system: 5% MeOH / DCM Rf: 0.45 LCMS [ESI]: m / z = 602.3 [M+H] +

[0320] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4,4-difluoro-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxobutan-2-yl)carbamate (11): To (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4,4-difluorobutanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (10) (2.4 g, 3.9 mmol) in DCM (30 mL) was added LiBH (2 M in THF, 3.98 mL, 7.9 mmol) slowly dropwise at 0 °C and stirred for 2 h. The reaction progress was monitored by TLC. After completion of the starting material, the reaction mixture was quenched with saturated NH Cl solution and extracted with dichloromethane (2 × 100 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting material was purified using a reverse-phase Combiflash column (C18) with 50% ACN in 0.1% aqueous TFA as the eluent to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4,4-difluoro-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxobutan-2-yl)carbamate (11). TLC system: 5% methanol in dichloromethane Rf: 0.35 LCMS [ESI]: m / z 574.15 [M+H] +

[0321] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4,4-difluoro-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)butan-2-yl)carbamate (A232): To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4,4-difluoro-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-1-oxobutan-2-yl)carbamate (11) (360 mg, 0.62 mmol) in ethyl acetate (10 mL) was added Dess-Martin periodinane (399 mg, 0.94 mmol) slowly dropwise at 0 °C and stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate (20 mL), filtered through a pad of diatomaceous earth, and the filtrate was washed with saturated sodium thiosulfate solution (3 × 30 mL), followed by saturated NaHCO solution (3 × 30 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting material was purified by reverse-phase column (C18) chromatography and 45% CAN in 0.1% NH4CO3 aqueous solution to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((S)-4,4-difluoro-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)butan-2-yl)carbamate (A232). TLC system: 10% methanol in DCM f :0.55 LCMS[ESI):m / z 572.3[M+H] +

[0322] Example 21: Synthesis of Compound A233 [ka] Sodium (2S)-2-((S)-3-cyclohexyl-2-((((R)-2,2-difluoro-2-(3-fluorophenyl)-1-phenylethoxy)carbonyl)amino)propanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonate (A233) To a stirred solution of (R)-2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-3-cyclohexyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (A119, 150 mg, 0.255 mmol) in ethyl acetate (1.2 mL), ethanol (1.35 mL), and water (0.45 mL), sodium bisulfate (53 mg, 0.51 mmol) was added at room temperature and stirred at a temperature of 45° C. for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate. The resulting filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting solid compound was triturated with acetonitrile and diethyl ether to give sodium (2S)-2-((S)-3-cyclohexyl-2-((((R)-2,2-difluoro-2-(3-fluorophenyl)-1-phenylethoxy)carbonyl)amino)propanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonate (A233). TLC system: 10% methanol in dichloromethane Rf: 0.2 LCMS [ESI]: m / z = 667.97 [M-Na] -

[0323] Example 22: Synthesis of Compound A234 [ka] Methyl (S)-2-((tert-butoxycarbonyl)amino)-4-methylenehexanoate (3): To a suspension of activated zinc (7.75 g, 91.1 mmol) in DMF (50 mL), a catalytic amount of iodine was added at room temperature and stirred for 10 minutes. Then, methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (1) (10 g, 30.3 mmol) was added dropwise at the same temperature, followed by the addition of a catalytic amount of iodine and stirring at the same temperature for 60 minutes. The reaction mass was degassed with an argon balloon for 15 minutes, and 2-bromobut-1-ene (2) (4.46 g, 33.3 mmol), Pd(dppf)Cl (442.9 mg, 0.60 mmol), and SPHOS (246 mg, 0.60 mmol) were added at room temperature and heated to 50 °C for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After the completion of the starting material, the reaction mixture was filtered through a diatomaceous earth bed, and the bed was washed with ethyl acetate. The resulting filtrate was diluted with water (250 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography using silica gel (100-200 mesh) and 0% EtOAc:petroleum ether as eluent to give methyl (S)-2-((tert-butoxycarbonyl)amino)-4-methylenehexanoate (3). TLC system: 10% ethyl acetate in hexane Rf: 0.6 LCMS [ESI]: m / z 280.22 [M+Na] +

[0324] Methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-methylhexanoate (4): To a degassed solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-4-methylenehexanoate (3) (5.0 g, 19.3 mmol) in EtOH (50 mL), Pd / C (1 g, 20% w / w) was added at room temperature and stirred under H balloon pressure for 3 hours. The reaction progress was monitored by TLC. After completion of the starting material, the reaction mass was filtered through a pad of diatomaceous earth and the bed was washed with EtOH (30 mL). The resulting filtrate was concentrated under reduced pressure to give methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-methylhexanoate (4). TLC system: 30% ethyl acetate in hexanes Rf: 0.5 LCMS [ESI]: m / z 282.23 [M+Na] +

[0325] Methyl (2S)-2-amino-4-methylhexanoate hydrochloride (int-5): To a stirred solution of methyl (2S)-2-((tert-butoxycarbonyl)amino)-4-methylhexanoate (4) (4.0 g, 18.9 mmol) in DCM (24.5 mL) was added 4 M HCl in dioxane (24.5 mL) at 0° C. and stirred at room temperature for 4 hours. The reaction progress was monitored by TLC. After completion of the starting material, the reaction mixture was concentrated under reduced pressure to give methyl (2S)-2-amino-4-methylhexanoate hydrochloride (int-5). LCMS [ESI]: m / z 160.42 [M+H] +

[0326] Methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanoate (6) To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethan-1-ol (Int-7) (8.0 g, 29.8 mmol) in ACN (40 mL) was added N,N'-disuccinamidyl carbonate (19 g, 74.5 mmol), followed by triethylamine (19.4 mL, 150.66 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC. The reaction mass was used directly in the next reaction.

[0327] In a separate RB flask, methyl (2S)-2-amino-4-methylhexanoate hydrochloride (int-5)ACN (40 mL) was obtained and treated with triethylamine (19.4 mL, 150.66 mmol). The resulting reaction mixture was stirred for 5 minutes, then the reaction mass prepared above was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water (200 mL) and extracted with ethyl acetate (2 × 250 mL). The combined organic layers were washed with brine solution (200 mL), dried over anhydrous NaSO, and evaporated under reduced pressure. This was purified by silica gel (100-200 mesh) column chromatography to give methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanoate (6). TLC system: 30% ethyl acetate in hexane Rf: 0.55 LCMS [ESI]: m / z [M+H] +

[0328] (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanoic acid (7): To a stirred solution of methyl (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanoate (6) (6.8 g, 15.0 mmol) in THF (34 mL) and water (34 mL), LiOH.HO (1.88 g, 45 mmol) was added at room temperature and stirred for 2 hours at room temperature. The progress of the reaction was monitored by TLC. THF was distilled under reduced pressure, and the compound was acidified to pH ∼2 with 1N aqueous HCl and extracted with DCM (2 × 100 mL). The combined organic layers were washed with water (100 mL) brine solution (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanoic acid (7). TLC system: 10% methanol in dichloromethane Rf: 0.1 LCMS [ESI]: m / z 440.28 [M+H]+

[0329] Methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (8): To a stirred solution of (2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanoic acid (7) (5.0 g, 11.3 mmol) in DMF (25 mL) was added EDC.HCl (3.2 g, 17.0 mmol), HOBt (2.56 g, 17.0 mmol), DIPEA (4.88 mL, 28 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (amine fragment-2) (3.28 g, 14.8 mmol) at 0 °C and stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography using silica gel (100-200 mesh) to give methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (8). TLC system: 5% MeOH / DCM Rf: 0.45 LCMS [ESI]: m / z = 608.41 [M+H] +

[0330] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxohexan-2-yl)carbamate (9): To a stirred solution of methyl (2S)-2-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (8) (4.0 g, 6.58 mmol) in DCM (40 mL) was added LiBH (2 M in THF, 6.58 mL, 13.1 mmol) slowly dropwise at 0 °C and stirred at 0 °C for 2 h. The reaction progress was monitored by TLC. After completion of the starting material, the reaction mixture was quenched with saturated NH Cl solution and extracted with dichloromethane (2 × 100 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reverse-phase column (C18) eluting with 50% ACN in 0.1% FA in water to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxohexan-2-yl)carbamate (9). TLC system: 5% methanol in dichloromethane Rf: 0.35 LCMS [ESI]: m / z 580.27 [M+H] +

[0331] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A234): To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxohexan-2-yl)carbamate (9) (400 mg, 0.69 mmol) in ethyl acetate (4 mL) was added Dess-Martin periodinane (585 mg, 1.39 mmol) slowly dropwise at 0 °C and stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate (50 mL), filtered through a pad of diatomaceous earth, and the filtrate was washed with saturated sodium thiosulfate solution (3 × 30 mL), followed by saturated NaHCO solution (3 × 30 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting material was purified by reverse-phase Combiflash column (C18) using 50% ACN in 0.1% aqueous NH4CO3 as eluent to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A234). TLC system: 10% methanol in DCM f :0.55 LCMS[ESI):m / z 578.3[M+H] +

[0332] Example 23: Synthesis of Compound A235 [ka] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A234): To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxohexan-2-yl)carbamate (9) (0.7 g, 1.20 mmol) in ethyl acetate (7 mL) was added Dess-Martin periodinane (1.02 g, 2.41 mmol) slowly dropwise at 0 °C and stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with ethyl acetate (50 mL), filtered through a pad of diatomaceous earth, and the filtrate was washed with saturated sodium thiosulfate solution (3 × 30 mL), followed by saturated NaHCO solution (3 × 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A234), which was used directly in the next step. TLC system: 10% methanol in DCM f :0.55 LCMS[ESI):m / z 578.3[M+H] +

[0333] (3S)-3-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (11): To a stirred solution of 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate (A234) (0.48 g, 0.83 mmol) in DCM (4.8 mL) was added isocyanocyclopropane (10) (160 mg, 2.49 mmol), followed by acetic acid (0.15 mL, 2.49 mmol) at 0 °C and stirred at room temperature for 6 h. The reaction progress was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was diluted with dichloromethane and washed with saturated ammonium chloride solution (2 × 30 mL), followed by brine (1 × 20 mL). The organic layer was dried over anhydrous NaSO and evaporated under reduced pressure. The resulting material was purified by reverse-phase Combiflash column (C18) using 50% ACN in 0.1% FA in water as eluent to give (3S)-3-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (11). TLC system: 10% MeOH in DCM Rf: 0.5 LCMS [ESI]: m / z 705.33 [M+H]+

[0334] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxohexan-2-yl)carbamate (12): To a stirred solution of (3S)-3-((2S)-2-(((2-(3-chlorophenyl)-2,2-difluoro-1-phenylethoxy)carbonyl)amino)-4-methylhexanamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (11) (350 mg, 0.49 mmol) in THF (3.1 mL) and water (1.05 mL) was added LiOH.HO (31.2 mg, 0.74 mmol) at 0 °C and stirred at room temperature for 1 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxohexan-2-yl)carbamate (12). TLC system: 10% MeOH in DCM Rf: 0.4 LCMS [ESI]: m / z 663.4 [M+H]+

[0335] 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxohexan-2-yl)carbamate (A235): To a stirred solution of the resulting 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxohexan-2-yl)carbamate (12) (250 mg, 0.37 mmol) in ethyl acetate (2.5 mL) was added Dess-Martin periodinane (320.2 mg, 0.75 mmol) at 0° C. and stirred at room temperature for 1 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was filtered through a bed of diatomaceous earth and washed with ethyl acetate (10 mL). The resulting filtrate was washed with saturated sodium thiosulfate solution (3×20 mL), followed by saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by trituration with n-pentane / DEE to give 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl ((2S)-1-(((S)-4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxohexan-2-yl)carbamate (A235). TLC system: 10% MeOH in DCM Rf: 0.65 LCMS [ESI]: m / z 661.3 [M+H]+

[0336] Example 24: Synthesis of compounds A236 and A237 [ka] (3S)-3-((2S)-3-cyclohexyl-2-(((2,2-difluoro-2-(3-fluorophenyl)-1-phenylethoxy)carbonyl)amino)propanamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (2): To a stirred solution of 2,2-difluoro-2-(3-fluorophenyl)-1-phenylethyl ((S)-3-cyclohexyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (A67) (600 mg, 1.02 mmol) in dichloromethane (6 mL) was added acetic acid (0.18 ml, 3.06 mmol) and cyclopropyl isocyanide (1) (200 mg, 3.06 mmol) at 0° C. and stirred at room temperature for 2 hours. The reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DCM (20 mL) and washed with water (3×40 mL) and brine solution. The organic layer was separated, dried over anhydrous NaSO, filt...

Claims

1. A compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof: 【Chemical 1】 During the ceremony, Each R Ｎ are independently H or C １－６ is alkyl, Each R １ａ are independently hydrogen, halo, C １－６ Alkyl, or C １－６ Is it a haloalkyl? Or both R １ａ together with the carbon to which they are attached are unsubstituted or C(O)OR Ｎ Spiro C substituted with ３－６ forming a carbocyclyl or a spiro 4-8 membered heterocyclyl having 1-3 ring heteroatoms selected from N, O, and S; R １ｂ is hydrogen, halo, hydroxyl, C １－６ Alkyl, or C １－６ is haloalkyl, n is 0, 1, or 2; Each R ｘ But independently, Halo, C １－６ Alkyl, C ３－６ Carbocyclyl, or C ６－１０ aryl, wherein the aryl is unsubstituted or is selected from the group consisting of OH, halo, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ substituted with 1 or 2 substituents independently selected from alkoxy; m is 0, 1, or 2; Each R ｙ are independently halo or C １－６ is alkyl, R ２ But C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkylene-C ３－８ Carbocyclyl, or C １－６ Alkylene-C ６－１０ aryl, wherein the aryl is optionally selected from OH, halo, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ substituted with 1 or 2 substituents independently selected from alkoxy; R ３ But CN, SO ３ C substituted with H １－６ Alkylene-O(O)C-C １－６ Alkyl, C １－６ Alkenylene-C(O)O-C １－６ Alkyl, PO(OCH ２ CH ２ ) ２ C substituted with １－６ Alkylene -OH, CHO, or -[C(O)] ２ -NR Ｎ -B, and B is C １－６ Alkyl, C １－６ Hydroxyalkyl, C ３－８ carbocyclyl or a 4- to 12-membered heterocyclyl having 1 to 3 ring heteroatoms selected from N, O, and S, wherein said carbocyclyl or heterocyclyl is unsubstituted or １－６ is monosubstituted with alkyl, R ３ａ is H or C １－６ is alkyl, Ring A is C ６－１０ Cycloalkyl, C ６－１０ aryl or a 5-10 membered heteroaryl containing one nitrogen heteroatom; However, each R １ａ is hydrogen, or each R １ａ is methyl, ring A is phenyl, m is 0 or 1, and R ｙ is halo and n is 1, then R ｘ But other than Chloro, However, the compound is 1,2-diphenylethyl (4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (2-(2-(((1,2-diphenylethoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, 2-(3-chlorophenyl)-1-phenylethyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-phenylethyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3)-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(2-(((2-(3-chlorophenyl)-1-phenylethoxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, 2-(2-(((2-(3-chlorophenyl)-1-phenylethoxy)carbonyl)amino)-3-cyclohexylpropanamido)-1-hydroxy-3-(2-oxopyrrolidin-3-yl)propane-1-sulfonic acid, 2-(3-chlorophenyl)-1-phenylethyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(m-tolyl)propyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(m-tolyl)propyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-phenylethyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)hexan-2-yl)carbamate, 2-(3-chlorophenyl)-1-phenylethyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 1-(2-chlorophenyl)-2-(3-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3)-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxohexan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 1-(2-chlorophenyl)-2-(3-chlorophenyl)-2-methylpropyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(3-cyclohexyl-1-((4-(ethylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propyl(3-cyclohexyl-1-((4-(diethylamino)-3,4-dioxo)-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, ethyl (E)-4-(2-(((1,2-diphenylethoxy)carbonyl)amino)-4-methylpentanamido)-5-(2-oxopyrrolidin-3-yl)pent-2-enoate, 3-(2-(((2-(3-chlorophenyl)-2-methyl-1-(naphthalen-2-yl)propoxy)carbonyl)amino)-3-cyclohexylpropanamido)-2-oxo-4-(2-oxopyrrolidin-3-yl)butanoic acid, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl(3-cyclohexyl-1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopropan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-chlorophenyl)-2-methylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(4-fluorophenyl)-2-methylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopropyl)methyl(3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-amino-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-phenylpropan-2-yl)carbamate, 2-(3-chlorophenyl)-2,2-difluoro-1-phenylethyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)-2,2-difluoroethyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)heptan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl (3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclobutyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopentyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)ethyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamate, 2-(3-chlorophenyl)-1-(3-fluorophenyl)-2-methylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 1,2-bis(3-chlorophenyl)-2,2-difluoroethyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxoheptan-2-yl)carbamate, (1-(3-chlorophenyl)cyclohexyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopropyl)(4-fluorophenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclobutyl)(phenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-ethyl-1-phenylbutyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 2-(3-fluorophenyl)-2-methyl-1-phenylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (1-(3-chlorobenzyl)cyclopentyl)(phenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-methyl-1-phenylpropyl(4-methyl-1-((4-((1-methylazetidin-3-yl)amino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-1-oxopentan-2-yl)carbamate, 2-(3-chlorophenyl)-2-ethyl-1-(4-fluorophenyl)butyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin)-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (3-chlorophenyl)(1-(3-chlorophenyl)cyclopentyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, 1,2-(3-chlorophenyl)-2-methylpropyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopropyl)(phenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin)-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (1-(3-chlorophenyl)cyclopropyl)(4-fluorophenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, (1-(3-fluorophenyl)cyclopropyl)(phenyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, 1-(3-fluorophenyl)cyclopropyl(phenyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin)-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, (4-chlorophenyl)(1-(3-chlorophenyl)cyclobutyl)methyl(4-methyl-1-oxo-1-((1-oxo-3-(2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamate, or A compound which is not (4-chlorophenyl)(1-(3-chlorophenyl)cyclobutyl)methyl(1-((4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamate, or a pharmaceutically acceptable salt thereof.

2. Each R Ｎ The compound or salt of claim 1 , wherein is H.

3. At least one R １ａ is hydrogen or C １－６ alkyl, or each R １ａ However, along with the carbon to which they are attached, spiro C ３－６ 2. The compound or salt of claim 1 which forms a carbocyclyl.

4. At least one R １ａ The compound or salt of claim 1 , wherein is halo.

5. 5. The compound or salt of claim 4, wherein halo is fluoro.

6. 2. The compound or salt of claim 1, wherein n is 1.

7. R ｘ The compound or salt of claim 6, wherein is in the meta position.

8. R ｘ The compound or salt of claim 6, wherein is halo.

9. R ｘ 9. The compound or salt of claim 8, wherein is chloro.

10. 2. The compound or salt of claim 1, wherein m is 0.

11. R ２ But C １－６ Alkyl or C １－６ Alkylene-C ５－８ 2. The compound or salt of claim 1, which is carbocyclyl.

12. R ２ but, 【Chemistry 2】 or 【Chemistry 3】 2. The compound or salt of claim 1, wherein:

13. R ３ The compound or salt of claim 1 , wherein is CHO.

14. Ring A contains phenyl, and each R １ａ is F and R １ｂ is H, and each R Ｎ is H, n is 1, and R ｘ is a halo, and R ２ But C １－６ Haloalkyl, C １－６ Alkylene-C ３－８ Carbocyclyl, or C １－６ Alkylene-C ６－１０ aryl, wherein the aryl is unsubstituted or is selected from the group consisting of OH, halo, C １－６ Alkyl, C １－６ Haloalkyl, and C １－６ substituted with 1 or 2 substituents independently selected from alkoxy; R ３ But CN, SO ３ C substituted with H １－６ Alkylene-O(O)C-C １－６ Alkyl, C １－６ Alkenylene-C(O)O-C １－６ Alkyl, PO(OCH ２ CH ２ ) ２ C substituted with １－６ Alkylene -OH, CHO, or -[C(O)] ２ -NR Ｎ The compound or salt according to claim 1, wherein:

15. having the structure of formula (Ia): 【Chemistry 4】 During the ceremony, Each R Ｎ are independently H or C １－６ is alkyl, Each R １ａ are independently hydrogen, halo, C １－６ Alkyl, or C １－６ haloalkyl, or both R １ａ However, along with the carbon to which they are attached, spiro C ３－６ forming a carbocyclyl, R １ｂ But hydrogen, halo, C １－６ Alkyl, or C １－６ is haloalkyl, n is 0, 1, or 2; Each R ｘ are independently halo or C １－６ is alkyl, m is 0, 1, or 2; Each R ｙ are independently halo or C １－６ is alkyl, R ２ But C １－６ Alkyl or C １－６ Alkylene-C ５－８ is a carbocyclyl, R ３ is CHO or -[C(O)] ２ -NR Ｎ -B, and B is C １－６ Alkyl, C ３－８ carbocyclyl or a 4- to 12-membered heterocyclyl having 1 to 3 ring heteroatoms selected from N, O, and S, wherein said carbocyclyl or heterocyclyl is unsubstituted or １－６ 2. The compound or salt of claim 1, which is monosubstituted with alkyl.

16. A compound having the structure of formula (Ib), or a pharmaceutically acceptable salt thereof: 【Chemistry 5】 During the ceremony, R ｘ is Cl, F, cyclopropyl, or phenyl; R ｙ is F, m is 0 or 1; R ２ But C ４－５ Alkyl, C ３－５ Haloalkyl, CH ２ C ３－６ carbocyclyl or benzyl, wherein the carbocyclyl is unsubstituted or substituted by methyl or ethyl; R ３ is CHO, C(O)C(O)NH ２ , C(O)C(O)NHcyclopropyl, or C(O)C(O)NHethyl; However, R ｘ is Cl, m is 0, and R ３ is CHO, C(O)C(O)NH ２ or C(O)C(O)NH cyclopropyl, when R ２ is not 2-methyl-propyl, or a pharmaceutically acceptable salt thereof.

17. (a) R ２ 2-methyl-propyl, butyl, pentyl, 2-methyl-butyl, 3,3-difluoropropyl, CH ２ -cyclopropyl, CH ２ Cyclobutyl, CH ２ Cyclopentyl, CH ２ -cyclohexyl, CH ２ -(1-ethylcyclopropyl), CH ２ -(1-methylcyclobutyl), CH ２ -(1-ethylcyclobutyl), CH ２ -(1-ethylcyclopentyl), or benzyl; (b) R ｘ is Cl; (c) m is 0; (d) R ｙ is meta-F, and / or (e) R ３ 17. The compound or salt of claim 16, wherein is CHO or C(O)C(O)NH cyclopropyl.

18. A compound listed in Table A or Table B, or a pharmaceutically acceptable salt thereof. 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 【Table 1-29】 【Table 1-30】 【Table 1-31】 【Table 1-32】 【Table 1-33】 【Table 1-34】 【Table 1-35】 【Table 1-36】 【Table 1-37】 【Table 1-38】 【Table 1-39】 【Table 1-40】 【Table 1-41】 【Table 1-42】 【Table 1-43】 【Table 1-44】 【Table 1-45】 【Table 1-46】 【Table 1-47】 【Table 1-48】 【Table 1-49】 【Table 1-50】 【Table 1-51】 【Table 1-52】 【Table 1-53】 【Table 1-54】 【Table 2-1】 【Table 2-2】

19. 19. The compound or salt of claim 18, selected from A20, A20-1, A20-2, A25-1, A48, A72, A119, A126, A164, A165, A167, A187, A196, A206, A209, A210, A228, A235, A239, A258, A265, A268, A270, A273, A289, A290, A295, A296, A297, A298, A299, A300, A302, A308, A309, A310, A316, A321, and A325.

20. A pharmaceutical composition for treating or preventing a viral infection, comprising a compound or salt according to any one of claims 1 to 19.

21. 21. The pharmaceutical composition of claim 20, wherein the viral infection is a norovirus infection.

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