Inhibitors of norovirus and coronavirus replication

Abstract

Compounds of formula (I) and methods of inhibiting viral replication in a biological sample or a patient, methods of reducing the amount of virus in a biological sample or a patient, and methods of treating a viral infection in a patient, comprising administering to the biological sample or the patient an effective amount of a compound represented by formula (I), a compound of Table A or B, or a pharmaceutically acceptable salt thereof. [Formula 1] JPEG2023521116000242.jpg18138

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 illnesses 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Z is O, NR 1 , or a bond, and each R N are independently H or C 1-6 alkyl, and R 1 But C 1-6 Alkylene-C 6-10 C optionally substituted with aryl 5-8 carbocyclyl or 5-8 membered N-heterocycle, the ring nitrogen is COO-C 1-6 optionally substituted with alkyl, R 2 But C 1-6 Alkyl, C 1-6 Alkylene-C 5-8 carbocyclyl, 4- to 10-membered heterocyclyl having 1 to 3 ring heteroatoms selected from N, O, and S; C 1-6 Alkylene-C 6-10 Aryl, or C 0-6 alkylene-5-10 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; C 1-6 Alkylene is 1 to 3 R 7 and carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with halo, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-C 6-10 Aryl, OC 1-6 Alkylene-C 6-10 Aryl, and CO2C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl;3 But C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylene-C 5-8 Carbocyclyl, C optionally substituted with 1-2 halo 0-6 Alkylene-C 6-10 aryl, or amino acid side chain, and each R 4 However, independently, halo, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Alkyloxyalkyl, oxo(=O), NR A SO2R B , SO2NR A R B , COOR A , C 0-4 Alkylene-C 6-10 Aryl, C 0-4 alkylene-(5-12 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S), or C 0-4 alkylene-(a 4-12 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), wherein the aryl, heteroaryl, and heterocycle are selected from halo, C 1-6 Alkyl, and COO-C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl, or two R 4 are combined with the one or more carbons to which they are attached to form a spiro or fused 3- to 12-membered carbocyclic or heterocyclic ring having 1 to 3 ring heteroatoms selected from N, O, and S; halo, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C(O)-C 1-6 Alkyl, SO2-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, and COO-C 1-6optionally substituted with 1 to 2 substituents independently selected from alkyl; 5 But C 1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6 Alkylene -OH, -[C(O)] 1-2 -(4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), -[C(O)] 1-2 -NR N R N , C(O)-YH, or -[C(O)] 1-2 -NR N -YXA, where A is H, C 3-8 carbocyclyl, a 4- to 12-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S; C 6-10 aryl, or 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; and the carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from halo, C 1-6 Alkyl, and COO-C 1-6 and Y is optionally substituted with 1 to 2 substituents independently selected from alkyl, a bond, C 1-6 Alkylene, C 1-6 Alkylene-OC 1-6 Alkylene, or C 1-6 alkenylene, C 1-6 Alkylene and C 1-6 Alkenylene may be halo, OH, NR N R N , and C 1-6 alkoxy; and X is a bond, NR N R N , C(O), SO2, or OC(O), and each R 6 However, independently, H, C 1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6alkylene -OH, CHO, or C(O)- (a 4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), and each R 7 But independently, Halo, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 3-5 Carbocycyl, or C 0-6 Alkylene-C 6-10 aryl, C 6-10 The aryl is optionally substituted with 1 to 2 halo or two R 7 may be combined with one or more carbons to which they are attached to form a spiro or fused C 3-6 forms a carbocyclyl ring, R A and R B However, independently, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 0-6 Alkylene-C 6-10 Aryl, C 0-6 alkylene-5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S, where n is 0-3, m is 0-5, and o is 0-5. In some embodiments, Z is O or NR 1 and each R N are independently H or C 1-6 alkyl, and R 1 But C 1-6 Alkylene-C 6-10 C optionally substituted with aryl 5-8 carbocyclyl or 5-8 membered N-heterocycle, the ring nitrogen is COO-C 1-6 optionally substituted with alkyl, R 2 But C 1-6 Alkyl, C 1-6 Alkylene-C 5-8 Carbocyclyl, C 1-6 Alkylene-C 6-10 Aryl, or C 1-6alkylene-5-10 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; C 1-6 Alkylene is C 1-6 Haloalkyl and C 2-6 and optionally substituted with 1 to 2 substituents independently selected from alkenyl, carbocyclyl, aryl, and heteroaryl, and halo, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl and CO2C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl; 3 But C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylene-C 5-8 Carbocyclyl, C 0-6 Alkylene-C 6-10 aryl, or amino acid side chain, and each R 4 However, independently, halo, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Alkyloxyalkyl, oxo(=O), NR A SO2R B , SO2NR A R B , COOR A , C 0-4 Alkylene-C 6-10 Aryl, C 0-4 alkylene-(5-12 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S), wherein the aryl, heteroaryl, and heterocycle are selected from halo, C 1-6 Alkyl, and COO-C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl, or two R 4are combined with the one or more carbons to which they are attached to form a spiro or fused 5-12 membered carbocyclic or heterocyclic ring having 1-3 ring heteroatoms selected from N, O, and S; halo, C 1-6 Alkyl, C(O)-C 1-6 Alkyl, and COO-C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl; 5 But C 1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6 alkylene-OH, CHO, C(O)-(a 4- to 8-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S), CONR N R N , or C(O)-C(O)NR N -YXA, where A is C 5-8 carbocyclyl, a 4- to 12-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S; C 6-10 aryl, or 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; and the carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from halo, C 1-6 Alkyl, and COO-C 1-6 and optionally substituted with 1 to 2 substituents independently selected from alkyl, halo, OH, NR N R N , and C 1-6 C optionally substituted with 1 to 3 substituents independently selected from alkoxy 1-6 alkylene, and X is null, NR N R N , C(O), SO2, or OC(O), and each R 6 However, independently, H, C 1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6 alkylene -OH, CHO, or C(O)- (a 4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), and RA and R B However, independently, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 0-6 Alkylene-C 6-10 Aryl, C 0-6 alkylene-5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S, wherein n is 0-3, m is 0-5, and o is 0-5.

[0008] Further provided are methods of administering to a biological sample or to a patient a safe and effective amount of a compound disclosed herein, for example, represented by Formula I, or a compound of Table A, B, or C.

[0009] Also provided herein are methods of reducing the amount of virus in a biological sample or a patient by administering to the biological sample or patient an effective amount of a compound disclosed herein, e.g., represented by Formula I, or a compound of Table A, B, or C.

[0010] Also provided is a method of treating or preventing a viral infection in a patient, comprising administering to the patient an effective amount of a compound disclosed herein, e.g., represented by Formula I, or a compound of Table A, B, or C.

[0011] Also provided are pharmaceutical compositions comprising a compound disclosed herein, for example represented by Formula I, or a compound of Table A, B, or C, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.

[0012] Use of the compounds described herein to inhibit or reduce viral replication in a biological sample or a patient, to reduce the amount of virus in a biological sample or a patient, or to treat a viral infection in a patient, is also provided.

[0013] Further provided herein is the use of a compound described herein for the manufacture of a medicament for treating a viral infection in a patient, reducing the amount of virus in a biological sample or a patient, or inhibiting viral replication in a biological sample or a patient. DETAILED DESCRIPTION OF THE INVENTION

[0014] Provided herein are compounds and their uses in treating or preventing viral infections (e.g., norovirus or coronavirus infections). Also provided are uses of the compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions comprising such compounds or pharmaceutically acceptable salts thereof, for inhibiting viral replication in a biological sample or a patient, for reducing the amount of virus (virulence reduction) in a biological sample or a patient, and for treating viral infections in a patient.

[0015] 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.

[0016] Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0017] 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.

[0018] 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.

[0019] compound Provided herein are compounds of formula (I), and pharmaceutically acceptable salts thereof: [ka] During the ceremony, Z is O, NR 1 , or a bond, Each R N are independently H or C 1-6 is alkyl, R 1 But C 1-6 Alkylene-C 6-10 C optionally substituted with aryl 5-8 carbocyclyl or 5-8 membered N-heterocycle, the ring nitrogen is COO-C 1-6 optionally substituted with alkyl; R 2 But C 1-6 Alkyl, C 1-6 Alkylene-C 5-8 carbocyclyl, 4- to 10-membered heterocyclyl having 1 to 3 ring heteroatoms selected from N, O, and S; C 1-6 Alkylene-C 6-10 Aryl, or C 0-6 alkylene-5-10 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; C 1-6 Alkylene is 1 to 3 R 7 and carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with halo, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-C 6-10 Aryl, OC 1-6 Alkylene-C 6-10Aryl, and CO2C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl; R 3 But C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylene-C 5-8 Carbocyclyl, C optionally substituted with 1-2 halo 0-6 Alkylene-C 6-10 aryl, or an amino acid side chain; Each R 4 However, independently, halo, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Alkyloxyalkyl, oxo(=O), NR A SO2R B , SO2NR A R B , COOR A , C 0-4 Alkylene-C 6-10 Aryl, C 0-4 alkylene-(5-12 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S), or C 0-4 alkylene-(a 4-12 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), wherein the aryl, heteroaryl, and heterocycle are selected from halo, C 1-6 Alkyl, and COO-C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl; The Two R's 4 are combined with the one or more carbons to which they are attached to form a spiro or fused 3- to 12-membered carbocyclic or heterocyclic ring having 1 to 3 ring heteroatoms selected from N, O, and S; halo, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C(O)-C1-6 Alkyl, SO2-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, and COO-C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl; R 5 But C 1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6 Alkylene -OH, -[C(O)] 1-2 -(4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), -[C(O)] 1-2 -NR N R N , C(O)-YH, or -[C(O)] 1-2 -NR N -YXA, where A is H, C 3-8 carbocyclyl, a 4- to 12-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S; C 6-10 aryl, or 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; and the carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from halo, C 1-6 Alkyl, and COO-C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl; Y is a bond, C 1-6 Alkylene, C 1-6 Alkylene-OC 1-6 Alkylene, or C 1-6 alkenylene, C 1-6 Alkylene and C 1-6 Alkenylene may be halo, OH, NR N R N , and C 1-6 optionally substituted with 1 to 3 substituents independently selected from alkoxy; X is a bond, NR N R N , C(O), SO2, or OC(O), Each R 6 However, independently, H, C1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6 alkylene -OH, CHO, or C(O)- (a 4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S); Each R 7 But independently, Halo, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 3-5 Carbocycyl, or C 0-6 Alkylene-C 6-10 aryl, C 6-10 aryl is optionally substituted with 1 to 2 halo; The Two R's 7 may be combined with one or more carbons to which they are attached to form a spiro or fused C 3-6 forming a carbocyclyl ring, R A and R B However, independently, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 0-6 Alkylene-C 6-10 Aryl, C 0-6 alkylene-5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; n is an integer of 0 to 3, m is an integer of 0 to 5, and o is an integer of 0 to 5.

[0020] In some embodiments, Z is O or NR 1 and Each R N are independently H or C 1-6 is alkyl, R 1 But C 1-6 Alkylene-C 6-10 C optionally substituted with aryl 5-8carbocyclyl or 5-8 membered N-heterocycle, the ring nitrogen is COO-C 1-6 optionally substituted with alkyl; R 2 But C 1-6 Alkyl, C 1-6 Alkylene-C 5-8 Carbocyclyl, C 1-6 Alkylene-C 6-10 Aryl, or C 1-6 alkylene-5-10 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; C 1-6 Alkylene is C 1-6 Haloalkyl and C 2-6 and optionally substituted with 1 to 2 substituents independently selected from alkenyl, carbocyclyl, aryl, and heteroaryl, and halo, C 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl and CO2C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl; R 3 But C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylene-C 5-8 Carbocyclyl, C 0-6 Alkylene-C 6-10 aryl, or an amino acid side chain; Each R 4 However, independently, halo, OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Alkyloxyalkyl, oxo(=O), NR A SO2R B , SO2NR A R B , COOR A , C 0-4 Alkylene-C 6-10 Aryl, C0-4 alkylene-(5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S), or C 0-4 alkylene-(a 4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), wherein the aryl, heteroaryl, and heterocycle are selected from halo, C 1-6 Alkyl, and COO-C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl; The Two R's 4 are combined with the one or more carbons to which they are attached to form a spiro or fused 5-12 membered carbocyclic or heterocyclic ring having 1-3 ring heteroatoms selected from N, O, and S; halo, C 1-6 Alkyl, C(O)-C 1-6 Alkyl, and COO-C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl; R 5 But C 1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6 alkylene-OH, CHO, C(O)-(a 4- to 8-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S), CONR N R N , or C(O)-C(O)NR N -YXA, where A is C 5-8 carbocyclyl, a 4- to 12-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S; C 6-10 aryl, or 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; and the carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from halo, C 1-6 Alkyl, and COO-C 1-6 optionally substituted with 1 to 2 substituents independently selected from alkyl; Y, Halo, OH, NR N R N , and C 1-6C optionally substituted with 1 to 3 substituents independently selected from alkoxy 1-6 is alkylene, X is null, NR N R N , C(O), SO2, or OC(O), Each R 6 However, independently, H, C 1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6 alkylene -OH, CHO, or C(O)- (a 4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S); R A and R B However, independently, H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 0-6 Alkylene-C 6-10 Aryl, C 0-6 alkylene-5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; n is an integer of 0 to 3, m is an integer of 0 to 5, and o is an integer of 0 to 5.

[0021] 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 any number of carbon atoms within the full range (i.e., 1 to 8 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.

[0022] As used herein, the terms "halogen" and "halo" mean F, Cl, Br, or I.

[0023] 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 can be saturated or have one or more units of unsaturation. A carbocycle can have 5 to 8 ring carbon atoms. In some embodiments, the number of carbon atoms is 5 to 6. 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. Cycloalkyl groups can include cycloalkenyl groups. Specific examples include, but are not limited to, cyclohexyl, cyclopentyl, cyclopropyl, and cyclobutyl. A carbocycle can be unsubstituted or substituted as described herein.

[0024] The term "heterocycle," as used herein, refers to a non-aromatic monocyclic, fused, spiro, or bridged ring system having 5 to 8 ring atoms, which may be saturated or may contain one or more units of unsaturation, wherein one or more (e.g., 1 to 3, or 1, 2, or 3) ring atoms are heteroatoms selected from N, S, and O. An "N-heterocyle" indicates that at least one of the ring heteroatoms is a nitrogen atom. 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.The heterocycle is unsubstituted or substituted as described herein.

[0025] The term "aryl" includes monocyclic aromatic rings having only carbon ring atoms (typically 6-10), such as phenyl, and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings are fused together. In some embodiments, an aryl is phenyl. Aryl rings are unsubstituted or substituted as described herein.

[0026] The term "heteroaryl" refers to a heterocycle having 5 to 8 members (e.g., 5 to 6 members), including monocyclic aromatic heterocycles and polycyclic aromatic rings in which a monocyclic aromatic ring is fused to one or more other aromatic rings. Heteroaryl groups have one or more (e.g., 1 to 4, 1 to 3, 1, 2, 3, or 4) ring heteroatoms selected from N, O, and S. Also included within the scope of the term "heteroaryl" as used herein are groups in which an aromatic ring is "fused" to one or more non-aromatic rings (carbocyclic or heterocyclic), where the radical or point of attachment is on the aromatic ring. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl, such as 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, Examples include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, and 1,3,5-triazinyl. The heteroaryl ring is unsubstituted or substituted as described herein.

[0027] As used herein, the term "amino acid side chain" refers to the side chain of an amino acid, e.g., methyl in alanine, isopropyl in valine, isobutyl in leucine, and sec-butyl in isoleucine. Amino acids contemplated by side chain include alanine, arginine, asparagine, aspartic acid, glutamine, glutamic acid, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, and valine.

[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 exemplified by the specific classes, subclasses, and species of the present disclosure. It will be understood that the phrase "optionally substituted" is 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] Optionally, Z is O or NR 1In some cases, Z is O or a bond. In some cases, Z is O. In some cases, Z is a bond. In various cases, Z is NR 1 In some cases, R 1 is C 1-6 Alkylene-C 6-10 C optionally substituted with aryl 5-8 carbocyclyl. In some cases, R 1 is the unsubstituted C 5-8 carbocyclyl. In some cases, R 1 is the unsubstituted C 5-6 carbocyclyl. In some cases, R 1 is cyclopentyl. In some cases, R 1 is cyclohexyl. In some cases, R 1 is C 1-6 Alkylene-C 6-10 Aryl-substituted C 5-8 carbocyclyl. In some cases, R 1 is C 1-6 Alkylene-C 6-10 Aryl-substituted C 5-6 carbocyclyl. In some cases, R 1 is C 1-6 Alkylene-C 6-10 aryl-substituted C5 carbocyclyl. 1 is C 1-6 Alkylene-C 6-10 aryl-substituted C6 carbocyclyl. 1 is C1 alkylene-C 6-10 aryl-substituted C5 carbocyclyl. 1 is C1 alkylene-C 6-10 aryl-substituted C6 carbocyclyl. 1 is a benzyl-substituted C 5-6 carbocyclyl. In some cases, R 1 is a C5 carbocyclyl substituted with benzyl. 1 is a benzyl-substituted C6 carbocyclyl.

[0031] In some cases, R 1 is a 5-8 membered N-heterocycle, the ring nitrogen is COO-C 1-6 In some cases, R 1 is a 5-6 membered N-heterocycle, the ring nitrogen is COO-C 1-6 In some cases, R 1 is a 6-membered N-heterocycle, the ring nitrogen is COO-C 1-6 In some cases, R 1 is a six-membered N-heterocycle, the ring nitrogen of which is substituted with COO-t-butyl.

[0032] In some cases, R 2 is C 1-6 Alkyl, C 1-6 Alkylene-C 5-8 carbocyclyl, 4- to 10-membered heterocyclyl having 1 to 3 ring heteroatoms selected from N, O, and S; C 1-6 Alkylene-C 6-10 aryl, 5-10 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S, or C 1-6 alkylene-5-10 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; C 1-6 Alkylene is a group consisting of 1 to 3 R 7 In some cases, R 2 is C 1-6 In some cases, R 2 is methyl. In some cases, R 2 is C 1-6 Alkylene-C 6-10 aryl. In some cases, R 2 is C 1-6 alkylene-C6 aryl. In some cases, R 2 is benzyl. In some cases, R 2 is C 1-6 Alkylene-C 5-8 carbocyclyl. In some cases, R2 is a 4-10 membered heterocyclyl having 1-3 ring heteroatoms selected from N, O, and S. In some cases, R 2 is C 1-6 alkylene- is a 5-10 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S. In some cases, R 2 C 1-6 Alkylene is a group consisting of 1 to 3 R 7 In some cases, R 2 C 1-6 Alkylene is an alkylene group with one R 7 In some cases, R 2 C 1-6 Alkylene is a group consisting of two R 7 In some cases, R 2 C 1-6 Alkylene is a group consisting of three R 7 In some cases, R 2 C 1-6 The alkylene is unsubstituted. 2 The carbocyclyl, heterocyclyl, aryl, or heteroaryl of 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylene-C 6-10 Aryl, OC 1-6 Alkylene-C 6-10 Aryl, and CO2C 1-6 Optionally, R is substituted with 1 to 2 substituents independently selected from alkyl. 2 The carbocyclyl, heterocyclyl, aryl, or heteroaryl of 1-6 Alkoxy, C 1-6 Alkyl, C 1-6 Haloalkyl and CO2C 1-6 Optionally, R is substituted with 1 to 2 substituents independently selected from alkyl. 2 The carbocyclyl, heterocyclyl, aryl, or heteroaryl in is unsubstituted.

[0033] In some cases, R 3 is C 1-6 In some cases, R 3 is a C4 alkyl. In some cases, R 2 teeth, [ka] In some cases, R 3 is C 1-6 Alkylene-C 5-8 carbocyclyl. In some cases, R 3 is C 1-6 alkylene-C6 carbocyclyl. In some cases, R 3 teeth, [ka] In some cases, R 3 is C 2-6 Alkenyl or C 2-6 alkynyl. In some cases, R 3 is C 0-6 Alkylene-C 6-10 aryl. In some cases, R 3 is an amino acid side chain. In various cases, the amino acid side chain is methyl, isopropyl, isobutyl, sec-butyl, CH2CH2SCH3, CH2-indolyl, benzyl, CH2OH, CH(OH)CH3, CH2SH, CH2-(4-OH-phenyl), CH2C(O)NH2, CH2CH2C(O)NH2, CH2COOH, CH2CH2COOH, CH2CH2CH2NH2, CH2CH2CH2NHC(NH)NH2, or imidazolyl.

[0034] In the compounds disclosed herein, m is 0 to 5. In various cases, m is 0. In some cases, m is 1. In some cases, m is 2. In some cases, m is 3 to 5.

[0035] In some cases, n is 0. In some cases, n is 1, 2, or 3, or 1 or 2. In some cases, each R4 independently, C 1-6 Alkyl, oxo (=O), C 0-4 Alkylene-C 6-10 Aryl, C 0-4 alkylene-(5-12 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S), or C 0-4 alkylene-(a 4-12 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), wherein the aryl, heteroaryl, and heterocycle are selected from halo, C 1-6 Alkyl, and COO-C 1-6 Optionally, at least one R is substituted with 1 to 2 substituents independently selected from alkyl. 4 Halo, OH, CN, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-6 Alkyloxyalkyl, NR A SO2R B , SO2NR A R B , or COOR A In some cases, two R 4 may be combined to form a spiro or fused 5-8 membered carbocyclic or heterocyclic ring having 1-3 ring heteroatoms selected from N, O, and S; halo, C 1-6 Alkyl, C 1-6 Alkylene-OC 1-6 Alkyl, C(O)-C 1-6 Alkyl, SO2-C 1-6 Alkyl, C(O)-C 1-6 Alkyl, and COO-C 1-6 Optionally, two R 4 may be combined to form a spiro or fused 5-8 membered carbocyclic or heterocyclic ring having 1-3 ring heteroatoms selected from N, O, and S; halo, C 1-6 Alkyl, C(O)-C 1-6 Alkyl, and COO-C 1-6In some embodiments, n is 1 and R 4 is C 1-6 Alkyl, oxo (=O), C 0-4 Alkylene-C 6-10 Aryl, C 0-4 alkylene-(5-12 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S), or C 0-4 alkylene-(a 4-12 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), and the aryl, heteroaryl, and heterocycle are each independently selected from halo, C 1-6 Alkyl, and COO-C 1-6 Optionally, n is 2 and each R 4 independently, C 1-6 Alkyl, oxo (=O), C 0-4 Alkylene-C 6-10 Aryl, C 0-4 alkylene-(5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S), or C 0-4 alkylene-(a 4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), and the aryl, heteroaryl, and heterocycle are each independently selected from halo, C 1-6 Alkyl, and COO-C 1-6 Optionally, n is 2 and two R 4 may combine with the one or more carbons to which they are attached to form a spiro or fused 5-12 membered carbocyclic or heterocyclic ring having 1-3 ring heteroatoms selected from N, O, and S; halo, C 1-6 Alkyl, C(O)-C 1-6 Alkyl, and COO-C 1-6 Optionally, two R groups having carbon atoms to which they are attached may be substituted with one to two substituents independently selected from alkyl. 4forms a spiro 5-12 membered carbocyclic or heterocyclic ring having 1-3 ring heteroatoms selected from N, O, and S; halo, C 1-6 Alkyl, C(O)-C 1-6 Alkyl, and COO-C 1-6 Optionally, two R groups having carbon atoms to which they are attached may be substituted with one to two substituents independently selected from alkyl. 4 form a fused 5-12 membered carbocyclic or heterocyclic ring having 1-3 ring heteroatoms selected from N, O, and S; halo, C 1-6 Alkyl, C(O)-C 1-6 Alkyl, and COO-C 1-6 It is optionally substituted with 1 to 2 substituents independently selected from alkyl.

[0036] In the compounds disclosed herein, o is 0 to 5. In some cases, o is 0. In some cases, o is 1 or 2. In various embodiments, each R 6 is H. In some cases, at least one R 6 is C 1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6 alkylene -OH, CHO, or C(O)- (a 4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S);

[0037] In some cases, R 5 is C 1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6 Alkylene -OH, -[C(O)] 1-2 -(4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), -[C(O)] 1-2 -NR N R N , C(O)-YH, or C(O)-C(O)NR N -YXA, where A is H, C 3-8carbocyclyl, a 4- to 12-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S; C 6-10 aryl, or 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from halo, C 1-6 Alkyl, and COO-C 1-6 Optionally, R is substituted with 1 to 2 substituents independently selected from alkyl. 5 is C 1-6 C substituted with alkylene-OH, PO(OCH2CH2)2 1-6 C substituted with alkylene-OH, SO3H 1-6 alkylene -OH, CHO, or C(O)- (a 4- to 8-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S), or CONR N R N In some cases, R 5 is C 1-6 alkylene-OH. In some cases, R 5 is C substituted with PO(OCH2CH2)2 1-6 alkylene-OH. In some cases, R 5 is C substituted with SO3H 1-6 alkylene-OH. In some cases, R 5 is C1 alkylene -OH substituted with SO3H. In some cases, R 5 is C(O)-YH. In some cases, R 5 is CHO. In some cases, R 5 is C(O)—(a 4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S). 5 is C(O)—C(O) (a 4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S). 5 CONR N R N In some cases, R 5 is C(O)-C(O)NR N R N is.

[0038] In some cases, R 5 is C(O)-C(O)NR N -YXA, where A is H, C 3-8 carbocyclyl, a 4- to 12-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S; C 6-10 aryl, or 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from halo, C 1-6 Alkyl, and COO-C 1-6 and Y is optionally substituted with 1 to 2 substituents independently selected from alkyl, halo, OH, NR N R N , and C 1-6 C optionally substituted with 1 to 3 substituents independently selected from alkoxy 1-6 alkylene, and X is null, NR N R N , C(O), SO2, or OC(O). In some cases, A is C 5-8 carbocyclyl, a 4- to 12-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S; C 6-10 aryl, or 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; carbocyclyl, heterocyclyl, aryl, or heteroaryl may be selected from halo, C 1-6 Alkyl, and COO-C 1-6 and Y is optionally substituted with 1 to 2 substituents independently selected from alkyl, halo, OH, NR N R N , and C 1-6 C optionally substituted with 1 to 3 substituents independently selected from alkoxy 1-6 alkylene, and X is null, NR N R N , C(O), SO2, or OC(O). In various cases, R N is H. In various cases, Y is C 1-6 Optionally, Y is a bond, C1-6 Alkylene, or C 1-6 alkenylene, C 1-6 Alkylene and C 1-6 Alkenylene is a group consisting of halo, OH, NR N R N , and C 1-6 Optionally, Y is substituted with 1 to 3 substituents independently selected from halo, OH, NR N R N , and C 1-6 C substituted with 1 to 3 (or 1) substituents independently selected from alkoxy 1-6 In some cases, X is an alkylene. In some cases, X is a bond. In some cases, X is NR N R N , C(O), SO2, or OC(O). In various cases, A is C 5-8 Carbocyclyl or C 6-10 Aryl, halo, C 1-6 Alkyl, and COO-C 1-6 Optionally, A is a 4-12 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S, or a 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S, and is optionally substituted with 1-2 substituents independently selected from halo, C 1-6 Alkyl, and COO-C 1-6 Optionally substituted with 1 to 2 substituents independently selected from alkyl. Optionally, A comprises pyridyl (e.g., 2-pyridyl).

[0039] In some cases, each R 7 independently, halo, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 3-5 Carbocycyl, or C 0-6 Alkylene-C 6-10 aryl, C 6-10 The aryl is optionally substituted with 1 to 2 halo. 7 is a halo. In some cases, at least one R 7is C 1-6 haloalkyl. In some cases, at least one R 7 is C 2-6 alkenyl. In some cases, at least one R 7 is C 3-5 In some cases, at least one R 7 is C 0-6 Alkylene-C 6-10 aryl, C 6-10 The aryl is optionally substituted with 1 to 2 halo. 7 is C 0-6 Alkylene-C 6-10 aryl, C 6-10 The aryl is substituted with 1 to 2 halo. Optionally, at least one R 7 is C 0-6 Alkylene-C 6-10 aryl, C 6-10 The aryl is unsubstituted. Optionally, at least one R 7 is phenyl optionally substituted with 1 to 2 halo. 7 is phenyl optionally substituted with one halo. 7 is chlorophenyl. In some cases, at least one R 7 is phenyl. In some cases, two R 7 may be combined with one or more carbons to which they are attached to form a spiro or fused C 3-6 Forms a carbocyclyl ring. In some cases, two R 7 However, they combine with the carbon to which they are attached to form spiro C 3-6 Forms a carbocyclyl ring. In some cases, two R 7 are combined with the carbon to which they are attached to form condensed C 3-6 Forms a carbocyclyl ring.

[0040] In some cases, R A and R B are each independently H, C1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 0-6 Alkylene-C 6-10 Aryl, C 0-6 alkylene- is a 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S. In some cases, R A and R B At least one of R is H. A and R B Each of R is H. A and R B At least one of the 1-6 In some cases, R A is C 1-6 In some cases, R A is methyl. In some cases, R B is C 1-6 In some cases, R B is methyl.

[0041] 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.

[0042] The compound can be a compound listed in Table A or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2]

[0043] The compound can be a compound listed in Table B or a pharmaceutically acceptable salt thereof. [Table 2]

[0044] The compound can be a compound listed in Table C or a pharmaceutically acceptable salt thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15]

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

Table 3-45

Table 3-46

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] "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.

[0057] Pharmaceutically acceptable carriers may contain inert ingredients that do not excessively inhibit the biological activity of compounds.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 subjects.Standard pharmaceutical formulation techniques can be used.

[0058] 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. Adverse effects from a therapy (e.g., a prophylactic or therapeutic agent) can be harmful, uncomfortable, or dangerous. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicity (including gastric and intestinal ulcers and erosions), nausea, vomiting, neurotoxicity, nephrotoxicities, renal toxicities (including conditions such as papillary necrosis and chronic interstitial nephritis), hepatotoxicity (including elevated serum liver enzyme levels), bone marrow toxicity (including leukopenia, bone marrow suppression, thrombocytopenia, and anemia), xerostomia, metallic taste, prolonged gestation, weakness, somnolence, pain (including myalgia, bone pain, and headache), hair loss, asthenia, dizziness, extrapyramidal symptoms, akathisia, cardiovascular disorders, and sexual dysfunction.

[0059] 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.

[0060] 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 may take the form of inhalable powder compositions or liquid or powder sprays, and may 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 may 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.

[0061] 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).

[0062] Spray compositions for localized delivery to the lungs by inhalation may 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] In some embodiments, the pharmaceutical compositions disclosed herein may be formulated with supplementary active ingredients.

[0067] 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.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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 can 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.

[0074] 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.

[0075] 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).

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] The pharmaceutical composition may be delivered as a mist or atomized liquid having droplet sizes as described above.

[0081] 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 an agent that extends residence time in the nasal cavity: a bioadhesive polymer, a gum (e.g., xanthan gum), a chitosan (e.g., a highly purified cationic polysaccharide), a pectin (or any carbohydrate that thickens like a gel or emulsifier when applied to the nasal mucosa), a microsphere (e.g., starch, albumin, dextran, cyclodextrin), a gelatin, a liposome, a carbamer, a polyvinyl alcohol, an alginate, acacia, a chitosan, and / or a 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.

[0082] 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.

[0083] The pharmaceutical composition can also optionally include an absorption enhancer, such as an agent that inhibits enzymatic activity, reduces mucus viscosity or elasticity, reduces mucociliary clearance, opens tight junctions, and / or solubilizes 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 enhancer in the pharmaceutical composition will vary depending on the drug and formulation selected.

[0084] 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.

[0085] The pharmaceutical compositions described herein may optionally include 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.

[0086] Alternatively, the composition may include a flavoring agent, for example to enhance the taste and / or acceptability of the composition to a subject.

[0087] 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.

[0088] 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."

[0089] 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."

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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 compound amount to the capillary bed surrounding the alveoli, are composed of chemically pure synthetic phospholipids, most preferably characterized by an aliphatic side chain of at least 16 carbons in length, and contain one or more compounds described herein or their pharmaceutically acceptable salts. 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.

[0099] 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).

[0100] 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.

[0101] 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 comprise a compound as described herein or its pharmaceutically acceptable salt or prodrug.

[0102] 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.

[0103] 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 included 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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 may 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 may 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 may 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 a long-chain alcohol diluent or dispersant, 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] Noroviruses are infectious viruses that cause gastroenteritis in mammals. They 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, whereas genogroup III infects bovine species. 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.

[0129] 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.

[0130] 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).

[0131] 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."

[0132] 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.

[0133] As used herein, the terms "coronavirus-mediated condition" and "coronavirus infection" are used interchangeably to mean 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-mediated conditions or coronavirus infections include SARS, MERS, and COVID-19.

[0134] Coronaviruses are a family of viruses that cause disease in mammals and birds. They belong to the Orthocoronavirinae subfamily of the Coronaviridae family in the Nidovirales order. There are four main genera of coronaviruses: 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).

[0135] 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.

[0136] 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.

[0137] 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).

[0138] In humans, common symptoms of coronavirus are fever, cough, shortness of breath, and muscle aches.

[0139] 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.

[0140] Picornus infects both humans and animals, causing severe paralysis (paralytic poliomyelitis), aseptic meningitis, hepatitis, pleuritis, myocarditis, skin rash, and the common cold, although asymptomatic infections are common. Several medically important genera are members of this family, such as enteroviruses (including polioviruses (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 consist of three distinct species: A, B, and C. Transmission is primarily via the aerosol route, with the virus replicating in the nose.

[0141] 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).

[0142] The terms "disease," "disorder," and "condition" may be used interchangeably herein to refer to a Norovirus- or coronavirus-mediated medical or pathological condition.

[0143] 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."

[0144] As used herein, the term "biological sample" includes, but is not limited to, a cell culture or extract thereof; a biopsy obtained from a mammal or an extract thereof; blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0145] 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.

[0146] As used herein, the terms "inhibition of Norovirus replication" and "inhibition of coronavirus replication" include both a reduction in viral replication (e.g., a reduction of at least 10%) and a complete cessation of viral replication (i.e., a 100% reduction in viral replication). In some embodiments, viral replication of Norovirus or coronavirus is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.

[0147] 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.

[0148] 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:

[0149] As used herein, the terms "treat," "treatment," and "treating" refer to both therapeutic and prophylactic treatments. For example, therapeutic treatment includes the reduction or amelioration of the progression, severity, and / or duration of a Norovirus- or coronavirus-mediated condition, or the amelioration of one or more symptoms (e.g., one or more discernible symptoms) of a Norovirus- or coronavirus-mediated condition, 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 the improvement of at least one measurable physical parameter of a Norovirus- or coronavirus-mediated condition. In other embodiments, therapeutic treatment includes inhibiting the progression of a Norovirus- or coronavirus-mediated condition, 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 the 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.

[0150] The term "chemotherapy" refers to the use of drugs, such as small molecule drugs (as opposed to "vaccines"), to treat a disorder or disease.

[0151] 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.

[0152] 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.).

[0153] 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.

[0154] 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.

[0155] 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 norovirus or coronavirus replication, 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 exact amount of a 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 will 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 coronavirus drug, the "effective amount" of the second agent will depend on the type of drug 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 condition 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.

[0156] In general, the administration regimen can be selected according to various factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; 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. One 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.

[0157] Dosages of compounds for use as 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. It is understood that the total daily amount can be administered in a single dose or in multiple doses, such as twice daily (e.g., every 12 hours), three times daily (e.g., every 8 hours), or four times daily (e.g., every 6 hours).

[0158] 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.

[0159] 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.

[0160] A safe and effective amount may be achieved in the methods or pharmaceutical compositions of the disclosure using a compound of Formula I, Table A, Table B, or Table C, 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 may be achieved using a first amount of a compound of Formula I, Table A, Table B, or Table C, or a pharmaceutically acceptable salt thereof, and a second amount of an additional suitable therapeutic agent (e.g., an antiviral agent or a vaccine).

[0161] In embodiments, the compound of Formula I, Table A, Table B, or Table C, 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 of Formula I, Table A, Table B, or Table C, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are each administered in an amount that would not provide a therapeutic effect alone (a sub-therapeutic dose). In still other embodiments, the compound of Formula I, Table A, Table B, or Table C, or a pharmaceutically acceptable salt thereof, can be administered in a safe and effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still other embodiments, the compound of Formula I, Table A, Table B, or Table C, or a pharmaceutically acceptable salt thereof, can 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.

[0162] 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.

[0163] 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.

[0164] 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 of Formula I, Table A, Table B, or Table C, 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.

[0165] Methods of using the compounds and compositions disclosed herein also include combining chemotherapy with a compound of Formula I, Table A, Table B, or Table C or a pharmaceutical composition or a pharmaceutically acceptable salt thereof, or combining a compound or composition of the disclosure with another antiviral agent.

[0166] When simultaneous administration involves separate administration of a first amount of a compound of Formula I, Table A, Table B, or Table C, 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 provide 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 of Formula I, Table A, Table B, or Table C, 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.

[0167] 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).

[0168] It is understood that the method of co-administration of a first amount of a compound of Formula I, Table A, Table B, or Table C, 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 combined effect is greater than the additive effect that may result from separate administration of a first amount of a compound of Formula I, Table A, Table B, or Table C, or a pharmaceutically acceptable salt thereof, and a second amount of an additional therapeutic agent.

[0169] 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.

[0170] 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).

[0171] 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 addition 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.

[0172] 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 compounds of the present disclosure, 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.

[0173] 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.

[0174] 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 a chiral material, or the mobile phase may contain additional chiral material to cause the different interactions. xi) Chiral gas chromatography: A technique in which the racemate is volatilized and the enantiomers are separated by their different interactions 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.

[0175] 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.

[0176] The present disclosure will be better understood with reference to the following non-limiting examples.

[0177] Compound synthesis Example 1: Synthesis of Compounds C12, C20, and C1 [ka] tert-Butyl 4-((S)-4-(((benzyloxy)carbonyl)amino)-5-methoxy-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (3) A mixture of (S)-4-(((benzyloxy)carbonyl)amino)-5-methoxy-5-oxopentanoic acid (1) (1 g, 3.389 mmol), tert-butyl 2-phenylpiperazine-1-carboxylate (2) (888 mg, 3.389 mmol), and pyridine (2 mL, 1 vol) in EtOAc (40 mL) was treated with T3P (4.31 mL, 50 wt% in EtOAc, 16.129 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with 1 N HCl (20 mL), water (50 mL) was added, extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 50% ethyl acetate in petroleum ether to give tert-butyl 4-((S)-4-(((benzyloxy)carbonyl)amino)-5-methoxy-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (3). TLC system: 50% ethyl acetate in petroleum ether, R f :0.3 LCMS(ESI):m / z 540.40(M+H) +

[0178] tert-Butyl 4-((S)-4-amino-5-methoxy-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (4) To a stirred solution of tert-butyl 4-((S)-4-(((benzyloxy)carbonyl)amino)-5-methoxy-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (3) (1 g, 1.855 mmol) in MeOH (40 mL) was added 10% Pd / C (500 mg, 50% wet) at room temperature, and the reaction mixture was stirred under H atmosphere (balloon pressure) at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was filtered through Celite, washed with MeOH (2 x 10 mL), and evaporated under reduced pressure to give tert-butyl 4-((S)-4-amino-5-methoxy-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (4). TLC system: 5% methanol in DCM R f :0.2 LCMS(ESI):m / z 406.35(M+H) +

[0179] tert-Butyl 4-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-methoxy-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (5) To a stirred solution of (S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (acid fragment) (1 g, 2.949 mmol) in DMF (20 mL) at 0 °C, EDC.HCl (845 mg, 4.424 mmol), HOBT (597 mg, 4.424 mmol), DIPEA (1.5 mL, 8.849 mmol), and tert-butyl 4-((S)-4-amino-5-methoxy)-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (4) (1.38 g, 3.539 mmol) were added and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ice water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 40% ethyl acetate in petroleum ether to give tert-butyl 4-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-methoxy-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (5). TLC system: 5% methanol in DCM R f :0.4 LCMS(ESI):m / z 727.67(M+H) +

[0180] tert-Butyl 4-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-hydroxypentanoyl)-2-phenylpiperazine-1-carboxylate (6) To a stirred solution of tert-butyl 4-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-methoxy-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (5) (900 mg, 1.241 mmol) in DCM (10 mL) was added 2 M LiBH4 in THF (1.24 mL, 2.48 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After 2 h, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 30 mL). The organic layer was washed with brine solution (30 mL) and the combined organic layers were dried over NaSO and concentrated to give crude tert-butyl 4-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-hydroxypentanoyl)-2-phenylpiperazine-1-carboxylate (6). TLC system: 5% MeOH R in DCM f 0.3 LCMS(ESI):m / z 699.2(M+H) +

[0181] tert-Butyl 4-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (C20) To a stirred solution of tert-butyl 4-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-hydroxypentanoyl)-2-phenylpiperazine-1-carboxylate (6) (150 mg, 0.2148 mmol) in DCM (10 mL) was added Dess-Martin periodinane (273 mg, 0.6446 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 DCM (50 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 crude compound tert-butyl 4-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (C20). TLC system: 10% methanol in DCM R f :0.3 LCMS(ESI):m / z 697.27(M+H) +

[0182] tert-Butyl 4-((4S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-(diethoxyphosphoryl)-5-hydroxypentanoyl)-2-phenylpiperazine-1-carboxylate (C1) To a stirred solution of tert-butyl 4-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-oxopentanoyl)-2-phenylpiperazine-1-carboxylate (C20) (200 mg crude, 0.2873 mmol) in DCM (10 mL) was added DIPEA (0.16 mL, 0.8620 mmol), followed by diethyl phosphite (0.12 mL, 0.8620 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give a crude residue. It was purified by preparative HPLC to give tert-butyl 4-((4S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-(diethoxyphosphoryl)-5-hydroxypentanoyl)-2-phenylpiperazine-1-carboxylate (C1). TLC system: 5% MeOH R in DCM f :0.4 LCMS(ESI):m / z 835.58(M+H) +

[0183] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-1-hydroxy-5-oxo-5-(3-phenylpiperazin-1-yl)pentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C12) To a stirred solution of tert-butyl 4-((4S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-(diethoxyphosphoryl)-5-hydroxypentanoyl)-2-phenylpiperazine-1-carboxylate (C1) (220 mg, 0.2637 mmol) in 1,4-dioxane (2 mL) was added 4N HCl in dioxane (2 mL) dropwise at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give a crude residue. It was purified by preparative HPLC to give 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-1-hydroxy-5-oxo-5-(3-phenylpiperazin-1-yl)pentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C12). TLC system: 10% MeOH R in DCM f :0.3 LCMS(ESI):m / z 735.53(M+H) +

[0184] Example 2: Synthesis of Compounds C22 and C2 [ka] Methyl N2-(tert-butoxycarbonyl)-N5,N5-dimethyl-L-glutamate (C) To a stirred solution of (S)-4-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (A) (3 g, 11.4942 mmol) in DCM (30 mL) was added TEA (3.2 mL, 22.988 mmol), BOP reagent (7.62 g, 17.241 mmol) and 2 M dimethylamine in THF (7.4 mL, 14.942 mmol) (B) were added at 0 °C, and the reaction mixture was then stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with ice water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 40% methanol in DCM to give methyl N2-(tert-butoxycarbonyl)-N5,N5-dimethyl-L-glutamate (C). TLC system: 5% MeOH / DCM R f :0.3 LCMS(ESI):m / z 289.30[M+H] +

[0185] Methyl N5,N5-dimethyl-L-glutamate hydrochloride (amine fragment) To a stirred solution of methyl N2-(tert-butoxycarbonyl)-N5-(3-chlorophenethyl)-N5-methyl-L-glutamate (C) (1.5 g, 5.208 mmol) in 1,4-dioxane (20 mL) was added 4N HCl in dioxane (15 mL) dropwise at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give methyl N5,N5-dimethyl-L-glutamate hydrochloride (amine fragment). TLC system: 5% MeOH / DCM R f :0.1 LCMS(ESI):m / z 189.17[M+H] +

[0186] Methyl 2-amino-4,4-dimethylpentanoic acid hydrochloride (2) To a stirred solution of 2-amino-4,4-dimethylpentanoic acid (1) (4 g, 27.586 mmol) in MeOH (40 mL) at room temperature, SOCl (12 mL, 3 volumes) was added dropwise at 0° C. and stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude residue as a solid. This was triturated with petroleum ether, and the solid was filtered and then dried under vacuum to give methyl 2-amino-4,4-dimethylpentanoic acid hydrochloride (2). TLC system: 5% MeOH / DCM R f :0.3

[0187] Methyl 2-((((3-chlorobenzyl)oxy)carbonyl)amino)-4,4-dimethylpentanoate (4) To a stirred solution of (3-chlorophenyl)methanol (3) (2 g, 14.084 mmol) in ACN (20 mL) was added N,N'-disuccinamidyl carbonate (5.4 g, 21.126 mmol), followed by triethylamine (6 mL, 42.25 mmol) at room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. The reaction mass was used directly in the next reaction.

[0188] In a separate RB flask, methyl 2-amino-4,4-dimethylpentanoate hydrochloride (2) (3.27 g, 16.901 mmol) was taken up in ACN (20 mL) and treated with triethylamine (6 mL, 42.252 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. After 16 hours, the reaction mixture was quenched with ice water (15 mL), extracted with ethyl acetate (2 x 15 mL), and the combined organic layers were washed with brine solution (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give methyl 2-((((3-chlorobenzyl)oxy)carbonyl)amino)-4,4-dimethylpentanoate (4). TLC system: 20% ethyl acetate in petroleum ether Rf: 0.6 LCMS (ESI): m / z: 328.41 [M+H] -

[0189] 2-((((3-chlorobenzyl)oxy)carbonyl)amino)-4,4-dimethylpentanoic acid (5) To a stirred solution of methyl 2-((((3-chlorobenzyl)oxy)carbonyl)amino)-4,4-dimethylpentanoate (4) (1.5 g, 4.587 mmol) in THF (20 mL) and water (10 mL), lithium hydroxide (330 mg, 13.761 mmol) was added at room temperature and stirred for 3 hours at room temperature. The progress of the reaction was monitored by TLC and LCMS. After 3 hours, the reaction mixture was completely distilled under reduced pressure, and the crude compound was acidified with 2N HCl solution to pH 4, extracted with ethyl acetate (2 × 10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude compound 2-((((3-chlorobenzyl)oxy)carbonyl)amino)-4,4-dimethylpentanoic acid (5). TLC system: 20% ethyl acetate in petroleum ether, Rf: 0.2 LCMS (ESI): m / z 620.1 (M+H) +

[0190] Methyl N2-(2-((((3-chlorobenzyl)oxy)carbonyl)amino)-4,4-dimethylpentanoyl)-N5,N5-dimethyl-L-glutamate (6) To a stirred solution of 2-((((3-chlorobenzyl)oxy)carbonyl)amino)-4,4-dimethylpentanoic acid (5) (1.6 g, 5.1118 mmol) in DMF (20 mL) were added EDC.HCl (1.46 g, 7.667 mmol), HOBT (1.03 g, 7.667 mmol), DIPEA (1.96 mL, 10.6508 mmol), and methyl N5-(3-chlorophenethyl)-N5-methyl-L-glutamic acid hydrochloride (amine fragment) (2.7 mL, 15.335 mmol) simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with ice water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 80% ethyl acetate in petroleum ether to give methyl N2-(2-((((3-chlorobenzyl)oxy)carbonyl)amino)-4,4-dimethylpentanoyl)-N5,N5-dimethyl-L-glutamate (6). TLC system: 5% methanol in DCM Rf: 0.3 LCMS (ESI): m / z 484.90 [M+H] +

[0191] 3-Chlorobenzyl (1-(((S)-5-(dimethylamino)-1-hydroxy-5-oxopentan-2-yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamate (7) To a stirred solution of methyl N2-(2-((((3-chlorobenzyl)oxy)carbonyl)amino)-4,4-dimethylpentanoyl)-N5,N5-dimethyl-L-glutamate (6) (600 mg, 1.2422 mmol) in DCM (10 mL) was added 2 M LiBH4 in THF (1.3 mL, 2.484 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was then quenched with water (30 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, and concentrated to give a crude residue. It was purified by silica gel column chromatography to give 3-chlorobenzyl (1-(((S)-5-(dimethylamino)-1-hydroxy-5-oxopentan-2-yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamate (7). TLC system: 10% methanol in DCM Rf: 0.1 LCMS (ESI): m / z 456.47 (M+H) +

[0192] 3-Chlorobenzyl (1-(((S)-5-(dimethylamino)-1,5-dioxopentan-2-yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamate (C22) To a stirred solution of 3-chlorobenzyl (1-(((S)-5-(dimethylamino)-1-hydroxy-5-oxopentan-2-yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamate (7) (150 mg, 0.329 mmol) in DCM (5 mL) was added PIDA (127 mg, 0.395 mmol) at 0 °C, followed by TEMPO (10 mg, 0.065 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 DCM (10 mL) and washed with saturated Hypo solution (3 × 20 mL), followed by saturated NaHCO solution (3 × 20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give a crude residue. It was purified by preparative HPLC to give 3-chlorobenzyl (1-(((S)-5-(dimethylamino)-1,5-dioxopentan-2-yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamate (C22). TLC system: 10% MeOH in DCM Rf: 0.4 LCMS (ESI): m / z 454.25 (M+H) +

[0193] 3-Chlorobenzyl (1-(((2S)-1-(diethoxyphosphoryl)-5-(dimethylamino)-1-hydroxy-5-oxopentan-2-yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamate (C2) To a stirred solution of 3-chlorobenzyl (1-(((S)-5-(dimethylamino)-1,5-dioxopentan-2-yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamate (C22) (200 mg, 0.4415 mmol) in DCM (10 mL) was added DIPEA (0.2 mL, 1.324 mmol), followed by diethyl phosphite (0.2 mL, 1.324 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give 3-chlorobenzyl (1-(((2S)-1-(diethoxyphosphoryl)-5-(dimethylamino)-1-hydroxy-5-oxopentan-2-yl)amino)-4,4-dimethyl-1-oxopentan-2-yl)carbamate (C2). TLC system: 5% methanol in DCM Rf: 0.3 LCMS (ESI): m / z 592.51 (M+H) +

[0194] Example 3: Synthesis of Compounds C16 and C6 [ka] Methyl (S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoate (3) To a stirred solution of (S)-2-amino-3-cyclohexylpropanoic acid hydrochloride (2) (3 g, 13.531 mmol) in THF (20 mL) and DIPEA (7 mL, 40.59 mmol) was added pentyl carbonochloridate (1) (2.34 mL, 16.2 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After 2 hours, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 50% ethyl acetate in petroleum ether to give methyl (S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoate. TLC system: 30% ethyl acetate in petroleum ether, R f :0.55 LCMS(ESI):m / z 330.2(M+NH) +

[0195] (S)-3-Cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoic acid (4) To a stirred solution of methyl (S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoate (3) (2.5 g, 8.3 mmol) in THF (20 mL) and water (5 mL), lithium hydroxide (600 mg, 25 mmol) was added at room temperature and stirred for 3 hours. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was completely distilled under reduced pressure, and the crude compound was acidified with 1N aqueous HCl to pH 4, extracted with dichloromethane (2 x 30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoic acid (4). TLC system: 5% methanol in DCM R f :0.2

[0196] Methyl (S)-2-((S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) To a stirred solution of (S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoic acid (4) (1 g, 3.5 mmol) in DMF (20 mL), EDC.HCl (1 g, 5.2 mmol), HOBT (700 mg, 5.23 mmol), DIPEA (1.7 mL, 10.46 mmol), and methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (amine fragment) (1.38 g, 4.2 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ice-water (30 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 40% ethyl acetate in petroleum ether to give methyl (S)-2-((S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5). TLC system: 5% methanol in DCM. f :0.6 LCMS(ESI):m / z 560.63(M+H) +

[0197] Pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) To a stirred solution of methyl (S)-2-((S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) (900 mg, 1.6 mmol) in DCM (10 mL) was added 2 M LiBH in THF (1.2 mL, 1.53 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After 2 h, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 30 mL). The organic layer was washed with brine solution (30 mL) and the combined organic layers were dried over NaSO and concentrated to give crude pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6). TLC system: 5% MeOH in DCM. f 0.3 LCMS(ESI):m / z 532.5(M+H) +

[0198] Pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C16) To a stirred solution of pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) (200 mg, 0.376 mmol) in DCM (5 mL) was added Dess-Martin periodinane (479 mg, 1.13 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 DCM (50 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 crude compound pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C16). TLC system: 5% methanol in DCM R f :0.4 LCMS(ESI):m / z 530.56(M+H) +

[0199] Pentyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C6) To a stirred solution of pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C16) (248 mg, 0.47 mmol) in DCM (5 mL) was added DIPEA (0.24 mL, 1.41 mmol), followed by diethyl phosphite (0.19 mL, 1.41 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give pentyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C6). TLC system: 5% MeOH R in DCM f :0.45LCMS(ESI):m / z 668.68(M+H) +

[0200] Example 4: Synthesis of compounds C26 and C7 [ka] Methyl (S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoate (3) To a stirred solution of (S)-2-amino-3-cyclohexylpropanoic acid hydrochloride (2) (4.8 g, 2.1 mmol) in THF (20 mL) and DIPEA (9.7 mL, 5.4 mmol) was added hexyl carbonochloridate (1) (3 g, 1.8 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After 2 hours, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified on a silica gel column eluting with 50% ethyl acetate in petroleum ether to give methyl (S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoate (3). TLC system: 5% MeOH R in DCM. f :0.55 LCMS(ESI):m / z 314.42(M+H) +

[0201] (S)-3-Cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoic acid (4) To a stirred solution of methyl (S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoate (3) (2 g, 6.36 mmol) in THF (20 mL) and water (5 mL), lithium hydroxide (450 mg, 19 mmol) was added at room temperature and stirred for 3 hours. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was completely distilled under reduced pressure, and the crude compound was acidified with 1N aqueous HCl to pH 4, extracted with dichloromethane (2 x 30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoic acid (4). TLC system: 5% methanol in DCM R f :0.2 LCMS(ESI):m / z 300.2(M+H) +

[0202] tert-Butyl 1-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-methoxy-5-oxopentanoyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate (5) To a stirred solution of (S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoic acid (1.2 g, 4 mmol) in DMF (20 mL) at 0 °C, EDC.HCl (1.14 g, 6 mmol), HOBT (834 mg, 6 mmol), DIPEA (2 mL, 12 mmol), and methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (amine fragment) (1.57 g, 4.8 mmol) were added and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ice-water (500 mL), extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 40% ethyl acetate in petroleum ether to give tert-butyl 1-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-methoxy-5-oxopentanoyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate (5). TLC system: 5% methanol in DCM. f :0.4 LCMS(ESI):m / z 574.53(M+H) +

[0203] Hexyl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) To a stirred solution of methyl (S)-2-((S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) (960 mg, 1.67 mmol) in DCM (10 mL) was added 2 M LiBH in THF (1.25 mL, 1.5 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After 2 h, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 30 mL). The organic layer was washed with brine solution (30 mL) and the combined organic layers were dried over NaSO and concentrated to give crude hexyl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6). TLC system: 5% MeOH in DCM. f 0.3 LCMS(ESI):m / z 546.51(M+H) +

[0204] Hexyl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C26) To a stirred solution of hexyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) (250 mg, 0.45 mmol) in DCM (5 mL) was added Dess-Martin periodinane (583 mg, 1.37 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 DCM (50 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 crude hexyl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C26). TLC system: 5% methanol in DCM. f :0.5 LCMS(ESI):m / z 544.55(M+H) +

[0205] Hexyl((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C7) To a stirred solution of hexyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (248 mg, 0.45 mmol) in DCM (5 mL) was added DIPEA (0.23 mL, 1.37 mmol), followed by diethyl phosphite (0.18 mL, 1.37 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give hexyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C7). TLC system: 5% MeOH R in DCM f :0.5 LCMS(ESI):m / z 682.6(M+H) +

[0206] Example 5: Synthesis of Compounds C15 and C9 [ka] tert-Butyl (5-chloro-2-hydroxybenzyl)(2-hydroxyethyl)carbamate (3) To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (1) (5 g, 32.05 mmol) in methanol (50 mL), 2-aminoethan-1-ol (2) (1.95 mL, 32.05 mmol) was added at room temperature and stirred for 6 hours. NaBH (605 mg, 16.02 mmol) was then added at 0 °C and stirred for 6 hours. The reaction mixture was cooled to 0 °C, and triethylamine (2.8 mL, 19.93 mmol) and (Boc)O (3.98 g, 18.27 mmol) were added. The mixture was left at room temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was evaporated under reduced pressure and acidified with 2 N HCl to pH 4. The solid was filtered, washed with water (100 mL), and dried under vacuum to give tert-butyl (5-chloro-2-hydroxybenzyl)(2-hydroxyethyl)carbamate (3). TLC system: 50% ethyl acetate in petroleum ether, Rf: 0.4 LCMS (ESI): m / z 300.35 [MH]

[0207] 7-Chloro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (4) To a stirred solution of DIAD (3.25 g, 16.12 mmol) and triphenylphosphine (4.22 g, 13.12 mmol) in THF (50 mL) was slowly added tert-butyl (5-chloro-2-hydroxybenzyl)(2-hydroxyethyl)carbamate (3) (5 g, 16.61 mmol) in THF (20 mL) at −10° C. and allowed to stand at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, dissolved in dichloromethane (50 mL), and TFA (17 mL) was added at 0° C. and stirred at room temperature for 5 hours. The progress of the reaction was monitored by TLC. The reaction mixture was basified to pH 12 with 10% NaOH, extracted with DCM (2×50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 7-chloro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (4). TLC system: 100% ethyl acetate; Rf: 0.25 LCMS (ESI): m / z = 184.33 [M+H] +

[0208] Methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) To a stirred solution of methyl (S)-4-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentanoate (5) (1.5 g, 57.47 mmol) in DMF (20 mL), EDC.HCl (1.64 g, 86.20 mmol), HOBT (1.16 g, 86.20 mmol), DIPEA (3.17 mL, 172.3 mmol), and 7-chloro-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (4) (2.1 g, 68.96 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with ice water (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 50% ethyl acetate in petroleum ether to give methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(7-chloro-2,3-dihydrobenzo)[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (6). TLC system: 70% ethyl acetate in petroleum ether, R f :0.5 LCMS(ESI):m / z 427.36[M+H] +

[0209] Methyl (S)-2-amino-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (7) To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (6) (2 g, 4.69 mmol) in 1,4-dioxane (20 mL) was added 4N HCl in dioxane (20 mL) dropwise at 0° C., and the reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give methyl (S)-2-amino-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (7). TLC system: 5% methanol in DCM Rf: 0.1 LCMS (ESI): m / z 327.25 [M+H] +

[0210] Methyl (S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-oxopentanoate (7) To a stirred solution of (S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (acid fragment) (0.7 g, 2.064 mmol) in DMF (10 mL), EDC.HCl (0.59 g, 3.097 mmol), HOBT (0.418 g, 3.097 mmol), DIPEA (0.5 mL, 6.19 mmol), and methyl (S)-2-amino-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (7) (0.896 g, 2.477 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was diluted with ice water (25 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash column eluting with 45% ethyl acetate in petroleum ether to give methyl (S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-oxopentanoate (8). TLC system: 50% ethyl acetate in petroleum ether, Rf: 0.5 LCMS (ESI): m / z 647.22 [M+H] +

[0211] 3-Chlorobenzyl ((S)-1-(((S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (8) To a stirred solution of methyl (S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-oxopentanoate (8) (0.3 g, 0.463 mmol) in DCM (5 mL) was added 2 M LiBH in THF (0.7 mL, 0.46 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 then quenched with aqueous NH Cl (10 mL) and extracted with ethyl acetate (2 × 15 mL). The organic layer was washed with brine solution (20 mL), dried over NaSO, and concentrated to give 3-chlorobenzyl ((S)-1-(((S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (9). TLC system: 5% methanol in DCM Rf: 0.3 LCMS (ESI): m / z 620.26 (M+H) +

[0212] 3-Chlorobenzyl ((S)-1-(((S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (C15) To a stirred solution of 3-chlorobenzyl ((S)-1-(((S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (9) (200 mg, 0.33 mmol) dissolved in ethyl acetate (10 mL) was added Dess-Martin periodinane (426 mg, 1.005 mmol) at 0° C. and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated 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 the crude material, which was purified by Combiflash chromatography by eluting with 3% methanol in dichloromethane to give 3-chlorobenzyl ((S)-1-(((S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (C15). TLC system: 5% methanol in DCM Rf: 0.5 LCMS (ESI): m / z 618.33 (M+H) +

[0213] 3-Chlorobenzyl ((2S)-1-(((2S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-(diethoxyphosphoryl)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (C9) To a stirred solution of 3-chlorobenzyl ((S)-1-(((S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (C15) (250 mg crude, 0.405 mmol) in DCM (10 mL), DIPEA (0.2 mL, 1.215 mmol) was added, followed by diethyl phosphite (0.12 mL, 1.215 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC purification to give 3-chlorobenzyl ((2S)-1-(((2S)-5-(7-chloro-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-(diethoxyphosphoryl)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (C9). TLC system: 5% methanol in DCM R f :0.3 LCMS(ESI):m / z 756.10[M+H] +

[0214] Example 6: Synthesis of Compounds C29 and C11 [ka] Methyl (2S)-2-((tert-butoxycarbonyl)amino)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-5-oxopentanoate (2) To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (1) (2.0 g, 5.08 mmol) in THF (30 mL) was added 1 M LHMDS (10.7 mL, 10.01 mmol) at −78° C. and stirred for 1 h, followed by methyl iodide (1.2 mL, 20.32 mmol) in THF and stirring for 2 h at −78° C. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (2×40 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by NP and the compound was eluted with 30% ethyl acetate in petroleum ether to give methyl (2S)-2-((tert-butoxycarbonyl)amino)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-5-oxopentanoate (2). TLC system: 50% ethyl acetate in hexane, Rf: 0.4 LCMS (ESI): m / z 407.41 [M+H] +

[0215] Methyl(2S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-5-oxopentanoic acid hydrochloride (3) To a stirred solution of methyl (2S)-2-((tert-butoxycarbonyl)amino)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-5-oxopentanoate (4) (2.2 g, 7.18 mmol) in 1,4-dioxane (20 mL) was added 4N HCl in dioxane (20 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give methyl (2S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-5-oxopentanoic acid hydrochloride (3). TLC system: 10% methanol in DCM Rf: 0.1 LCMS (ESI): m / z 307.36 [M+H] +

[0216] Methyl (2S)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-5-oxopentanoate (4) To a stirred solution of (S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (acid fragment) (1.0 g, 2.98 mmol) in DMF (15 mL), EDC.HCl (0.84 g, 4.47 mmol), HOBt (0.59 g, 4.47 mmol), DIPEA (1.6 mL, 8.94 mmol), and methyl (2S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-5-oxopentanoic acid hydrochloride (3) (1 g, 3.27 mmol) were added simultaneously 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 ice water (40 mL), extracted with ethyl acetate (2 × 40 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by grace NP, and the compound was eluted with 2% methanol in dichloromethane to give methyl (2S)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-5-oxopentanoate (4). TLC system: 5% methanol in dichloromethane - Rf: 0.3 LCMS (ESI): m / z 628.59 [M+H] +

[0217] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-4-methyl-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (5) To a stirred solution of methyl (2S)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-5-oxopentanoate (4) (1.2 g, 1.91 mmol) in DCM (15 mL) was added 2 M LiBH in THF (1.4 mL, 2.86 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 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-4-methyl-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (5). TLC system: 5% methanol in dichloromethane - Rf: 0.2 LCMS (ESI): m / z 600.56 [M+H] +

[0218] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C29) To a stirred solution of 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-4-methyl-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (5) (150 mg, 0.25 mmol) dissolved in dichloromethane (5 mL) was added Dess-Martin periodinane (318 mg, 0.751 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (10 mL), followed by saturated Hypo solution (3 × 15 mL), followed by saturated NaHCO solution (3 × 15 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give the crude compound. The crude compound was purified by preparative HPLC to give 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C29). TLC system: 5% methanol in dichloromethane Rf: 0.5 LCMS (ESI): m / z 598.28 (M+H) +

[0219] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-4-methyl-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C11) To a stirred solution of 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-4-methyl-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C29) (250 mg crude, 0.41 mmol) in DCM (10 mL) was added DIPEA (0.22 mL, 1.23 mmol), followed by diethyl phosphite (0.17 mL, 1.23 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepine)-4(5H)-yl)-1-hydroxy-4-methyl-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C11). TLC system: 5% methanol in dichloromethane - Rf: 0.4 LCMS (ESI): m / z 736.54 (M+H) +

[0220] Example 7: Synthesis of Compounds C23 and C13 [ka] tert-Butyl (S)-4-(((3-cyclohexyl-1-methoxy-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (3) To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1) (300 mg, 1.49 mmol) in ACN (5 mL) was added N,N'-disuccinamidyl carbonate (572 mg, 2.23 mmol), followed by triethylamine (0.62 mL, 4.47 mmol) at room temperature and stirred for 16 hours. The reaction progress was monitored by TLC. The reaction mass was used directly in the next reaction.

[0221] In a separate RB flask, methyl (S)-2-amino-3-cyclohexylpropanoate (2) (250 mg, 1.12 mmol) was taken up in ACN (5 mL) and treated with triethylamine (0.3 mL, 2.25 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. After 16 hours, the reaction mixture was quenched with ice water (15 mL), extracted with ethyl acetate (2 × 15 mL), and the combined organic layers were washed with brine solution (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give tert-butyl (S)-4-(((3-cyclohexyl-1-methoxy-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (3). TLC system: 50% ethyl acetate in petroleum ether Rf: 0.3 LCMS (ESI): m / z: 435.2 [M+Na] -

[0222] (S)-2-((((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (4) To a stirred solution of tert-butyl (S)-4-(((3-cyclohexyl-1-methoxy-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (3) (0.35 g, 0.84 mmol) in THF (10 mL), water (10 mL), lithium hydroxide (106 mg, 2.54 mmol) was added at room temperature and stirred for 3 hours at room temperature. The reaction progress was monitored by TLC and LCMS. The reaction mixture was distilled completely under reduced pressure, and the crude compound was acidified to pH 3 with 1N aqueous HCl, extracted with ethyl acetate (2×20 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-2-((((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (4). TLC system: 20% ethyl acetate in petroleum ether Rf: 0.1 LCMS (ESI): m / z = 421.39 [M+Na] +

[0223] tert-Butyl 4-((((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-methoxy-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (5) To a stirred solution of (S)-2-((((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (4) (1.5 g, 3.64 mmol) in DMF (20 mL), EDC.HCl (1.04 g, 5.46 mmol), HOBT (0.73 g, 5.46 mmol), DIPEA (1.9 mL, 10.92 mmol), and methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (amine fragment) (1.27 g, 4.36 mmol) were added simultaneously at 0° C. and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ice water (50 mL) and the resulting solid was filtered, washed with excess water, and then dried under vacuum to give tert-butyl 4-((((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-methoxy-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (5). TLC system: 5% methanol in DCM R f :0.3 LCMS(ESI):m / z 673.46[M+H] +

[0224] tert-Butyl 4-((((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (6) To a stirred solution of tert-butyl 4-((((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-methoxy-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (5) (1.5 g, 2.23 mmol) in DCM (15 mL) was added 2 M LiBH in THF (2.2 mL, 4.46 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 and LCMS. The reaction mixture was then quenched with saturated NH Cl solution (30 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with brine solution (30 mL), dried over Na SO , and concentrated to give the crude compound. It was triturated with diethyl ether to give tert-butyl 4-((((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (6). TLC system: 5% methanol in DCM. f :0.2 LCMS(ESI):m / z 645.67[M+H] +

[0225] tert-Butyl 4-((((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (C23) To a stirred solution of tert-butyl 4-((((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (6) (200 mg, 0.31 mmol) dissolved in ethyl acetate (5 mL) was added Dess-Martin periodinane (395 mg, 0.93 mmol) at 0° C. and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated Hypo solution (3×20 mL), saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which residue was purified by normal phase chromatography eluting with 3% methanol in dichloromethane to give tert-butyl 4-((((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (C23). TLC system: 5% methanol in DCM Rf: 0.4 LCMS (ESI): m / z 643.68 (M+H) +

[0226] tert-Butyl 4-((((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (C13) To a stirred solution of tert-butyl 4-((((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (C23) (200 mg crude, 0.31 mmol) in DCM (10 mL) was added DIPEA (0.16 mL, 0.93 mmol), followed by diethyl phosphite (0.13 mL, 0.93 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4 and evaporated to give a crude residue, which was purified by preparative HPLC to give tert-butyl 4-((((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f])[1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (C13). TLC system: 5% methanol in DCM R f :0.4 LCMS(ESI):m / z 781.71[M+H] +

[0227] Example 8: Synthesis of Compounds C24 and C14 [ka] Methyl (S)-3-cyclohexyl-2-(((heptyloxy)carbonyl)amino)propanoate (3) To a stirred solution of (S)-2-amino-3-cyclohexylpropanoic acid hydrochloride (2) (2.97 g, 13.48 mmol) in THF (20 mL) and DIPEA (5.8 mL, 33.70 mmol) was added heptyl carbonochloridate (1) (2 g, 11.235 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After 2 hours, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified on a silica gel column eluting with 50% ethyl acetate in petroleum ether to give methyl (S)-3-cyclohexyl-2-(((heptyloxy)carbonyl)amino)propanoate (3). TLC system: 20% EtOAc in petroleum ether R f :0.55 LCMS(ESI):m / z 328.49(M+H) +

[0228] (S)-3-Cyclohexyl-2-(((heptyloxy)carbonyl)amino)propanoic acid (4) To a stirred solution of methyl (S)-3-cyclohexyl-2-(((heptyloxy)carbonyl)amino)propanoate (3) (1.2 g, 3.66 mmol) in THF (12 mL) and water (6 mL), lithium hydroxide (264 mg, 11.009 mmol) was added at room temperature and stirred for 3 hours. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was completely distilled under reduced pressure, and the crude compound was acidified with 1N aqueous HCl to pH 4, extracted with dichloromethane (2 x 30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-3-cyclohexyl-2-(((heptyloxy)carbonyl)amino)propanoic acid (4). TLC system: 5% methanol in DCM R f :0.2 LCMS(ESI):m / z 314.2(M+H) +

[0229] Methyl (S)-2-((S)-3-cyclohexyl-2-(((heptyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) To a stirred solution of (S)-3-cyclohexyl-2-(((heptyloxy)carbonyl)amino)propanoic acid (1 g, 3.18 mmol) in DMF (20 mL) at 0 °C, EDC.HCl (0.91 g, 4.7 mmol), HOBT (660 mg, 4.7 mmol), DIPEA (1.2 mL, 9.5 mmol), and methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (amine fragment) (1.26 g, 3.8 mmol) were added and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ice-water (500 mL), extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 40% ethyl acetate in petroleum ether to give methyl (S)-2-((S)-3-cyclohexyl-2-(((heptyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5). TLC system: 5% methanol in DCM. f :0.4 LCMS(ESI):m / z 588.68(M+H) +

[0230] Heptyl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) To a stirred solution of methyl (S)-2-((S)-3-cyclohexyl-2-(((heptyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) (600 mg, 1.01 mmol) in DCM (12 mL) was added 2 M LiBH in THF (0.76 mL, 1.52 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After 2 h, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 30 mL). The organic layer was washed with brine solution (30 mL) and the combined organic layers were dried over NaSO and concentrated to give crude hexylheptyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6). TLC system: 5% MeOH in DCM. f 0.3 LCMS(ESI):m / z 560.3(M+H) +

[0231] Heptyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C24) To a stirred solution of heptyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) (180 mg, 0.32 mmol) in DCM (5 mL) was added Dess-Martin periodinane (410 mg, 0.96 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 DCM (50 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 crude heptyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C24). TLC system: 5% methanol in DCM R f :0.5 LCMS(ESI):m / z 558.52(M+H) +

[0232] Heptyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C14) To a stirred solution of hexylheptyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (249 mg, 0.446 mmol) in DCM (5 mL) was added DIPEA (0.177 mL, 1.33 mmol), followed by diethyl phosphite (0.18 mL, 1.33 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give heptyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C14). TLC system: 5% MeOH R in DCM f :0.5 LCMS(ESI):m / z 696.70(M+H) +

[0233] Example 9: Synthesis of Compounds C17 and C5 [ka] 1-Benzylcyclopropan-1-amine (2) To a stirred solution of 2-phenylacetonitrile (1) (2 g, 17.094 mmol) in EtO:THF (1:1) (20 mL) was added titanium isopropoxide (5.14 g, 18.119 mmol), followed by the slow dropwise addition of 2 M ethylmagnesium chloride in THF (17 mL, 34.188 mmol) at 0 °C over 10 min. The reaction mixture was then stirred at room temperature for 1 h, followed by the slow addition of BF-EtO (4.8 mL, 34.188 mmol) over 15 min at 0 °C (an exotherm occurred) and stirring at room temperature for 1 h. The reaction progress was monitored by TLC and LCMS. After 1 h, the reaction mixture was poured into 10% NaOH solution (100 mL), resulting in the formation of a white precipitate. The reaction mixture was filtered through a bed of Celite, washed with ethyl acetate (50 mL), and the filtrate was washed with brine solution (100 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 70% ethyl acetate in petroleum ether to give 1-benzylcyclopropan-1-amine (2). TLC system: 80% ethyl acetate in petroleum ether Rf: 0.3 LCMS (ESI): m / z 148.11 [M+H] +

[0234] tert-Butyl(1-benzylcyclopropyl)carbamate (3) To a stirred solution of 1-benzylcyclopropan-1-amine (2) (4.2 g, 28.5714 mmol) in DCM (50 mL) was added TEA (4.1 mL, 57.142 mmol), followed by the slow dropwise addition of Boc anhydride (6.8 mL, 31.428 mmol) over 10 minutes at 0 °C. The reaction mixture was then stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was diluted with ice water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 5% ethyl acetate in petroleum ether to give tert-butyl (1-benzylcyclopropyl)carbamate (3). TLC system: 30% ethyl acetate in petroleum ether, Rf: 0.8 LCMS (ESI): m / z 148.11 [M-Boc] +

[0235] tert-Butyl (1-benzylcyclopropyl)(methyl)carbamate (4) To a stirred solution of tert-butyl(1-benzylcyclopropyl)carbamate (3) (2 × 2.5 g, 10.121 mmol) in DMF (25 mL) in a sealed vessel, 60% NaH (607 mg, 15.182 mmol) was added at 0 °C and stirred for 15 minutes at 0 °C. After that, methyl iodide (2.6 mL, 40.485 mmol) was added dropwise slowly over 10 minutes at 0 °C. The reaction mixture was then heated to 40 °C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After 16 hours, the reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to give tert-butyl(1-benzylcyclopropyl)(methyl)carbamate (4). TLC system: 5% ethyl acetate in petroleum ether, Rf: 0.6 LCMS (ESI): m / z 162.11 [M-Boc] +

[0236] 1-Benzyl-N-methylcyclopropan-1-amine hydrochloride (5) To a stirred solution of tert-butyl(1-benzylcyclopropyl)(methyl)carbamate (4) (1.3 g, 4.9808 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in dioxane (20 mL) dropwise 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. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give 1-benzyl-N-methylcyclopropan-1-amine hydrochloride (5). TLC system: 5% methanol in DCM Rf: 0.2 LCMS (ESI): m / z 162.32 [M+H] +

[0237] Methyl N5-(1-benzylcyclopropyl)-N2-(tert-butoxycarbonyl)-N5-methyl-L-glutamate (7) To a stirred solution of (S)-4-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (6) (1 g, 3.831 mmol) in DMF (10 mL), EDC.HCl (1.1 g, 5.747 mmol), HOBT (775 mg, 5.747 mmol), DIPEA (2.11 mL, 11.494 mmol), and 1-benzyl-N-methylcyclopropan-1-amine hydrochloride (5) (678 mg, 4.214 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 40% ethyl acetate in petroleum ether to give methyl N5-(1-benzylcyclopropyl)-N2-(tert-butoxycarbonyl)-N5-methyl-L-glutamate (7). TLC system: 50% ethyl acetate in petroleum ether, Rf: 0.5 LCMS (ESI): m / z 305.19 [M-Boc] +

[0238] Methyl N5-(1-benzylcyclopropyl)-N5-methyl-L-glutamate hydrochloride (8) To a stirred solution of methyl N5-(1-benzylcyclopropyl)-N2-(tert-butoxycarbonyl)-N5-methyl-L-glutamate (7) (1.0 g, 2.475 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in dioxane (20 mL) dropwise 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. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give methyl N5-(1-benzylcyclopropyl)-N5-methyl-L-glutamate hydrochloride (8). TLC system: 5% methanol in DCM. Rf: 0.2. LCMS (ESI): m / z 305.26 [M+H]. +

[0239] Methyl N5-(1-benzylcyclopropyl)-N2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoyl)-N5-methyl-L-glutamate (9) To a stirred solution of (S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (acid fragment) (1.0 g, 2.949 mmol) in DMF (10 mL), EDC.HCl (845 mg, 4.424 mmol), HOBT (597 mg, 5.899 mmol), DIPEA (1.63 mL, 8.849 mmol), and methyl N5-(1-benzylcyclopropyl)-N5-methyl-L-glutamate hydrochloride (8) (986 mg, 3.244 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with ice-water (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 60% ethyl acetate in petroleum ether to give methyl N5-(1-benzylcyclopropyl)-N2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoyl)-N5-methyl-L-glutamate (9). TLC system: 50% ethyl acetate in petroleum ether, Rf: 0.5 LCMS (ESI): m / z 626.58 [M+H] +

[0240] 3-Chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (10) To a stirred solution of methyl N5-(1-benzylcyclopropyl)-N2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoyl)-N5-methyl-L-glutamate (9) (1 g, 1.6 mmol) in THF (10 mL) was added 2 M LiBH4 in THF (1.6 mL, 3.2 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 and LCMS. The reaction mixture was then quenched with water (10 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with brine solution (10 mL), dried over Na2SO4, and concentrated to give the crude compound. It was purified by combi-flash and the compound was eluted with 80% ethyl acetate in petroleum ether to give 3-chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (10). TLC system: 100% ethyl acetate Rf: 0.2 LCMS (ESI): m / z 598.98 (M+H) +

[0241] 3-Chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1,5-dioxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C17) To a stirred solution of 3-chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (10) (150 mg, 0.2508 mmol) dissolved in ethyl acetate (10 mL), Dess-Martin periodinane (320 mg, 0.752 mmol) was added at 0° C. and stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed with saturated Hypo solution (3×10 mL), and washed with saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give the crude compound. It was purified by Combiflash chromatography eluting with 20% MeOH in DCM to give 3-chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1,5-dioxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C17). TLC system: 80% ethyl acetate in petroleum ether, Rf: 0.4 LCMS (ESI): m / z 596.44 (M+H) +

[0242] 3-Chlorobenzyl ((2S)-1-(((2S)-5-((1-benzylcyclopropyl)(methyl)amino)-1-(diethoxyphosphoryl)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C5) To a stirred solution of 3-chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1,5-dioxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C17) (200 mg, 0.033 mmol) in DCM (10 mL) was added DIPEA (0.2 mL, 1.032 mmol), followed by diethyl phosphite (0.14 mL, 1.032 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give 3-chlorobenzyl ((2S)-1-(((2S)-5-((1-benzylcyclopropyl)(methyl)amino)-1-(diethoxyphosphoryl)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C5). TLC system: 100% ethyl acetate Rf: 0.3 LCMS (ESI): m / z 734.51 (M+H) +

[0243] Example 10: Synthesis of Compounds C18 and C19 [ka] Methyl (S)-3-cyclohexyl-2-((propoxycarbonyl)amino)propanoate (3) To a stirred solution of (S)-2-amino-3-cyclohexylpropanoic acid hydrochloride (2) (4 g, 22.13 mmol) in THF (20 mL) and DIPEA (8.7 mL, 49.18 mmol) was added propyl carbonochloridate (1) (3 g, 24.59 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After 2 hours, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 20% ethyl acetate in petroleum ether to give methyl (S)-3-cyclohexyl-2-((propoxycarbonyl)amino)propanoate (3). TLC system: 50% ethyl acetate in petroleum ether, R f :0.55 LCMS(ESI):m / z 272.2(M+H) +

[0244] (S)-3-Cyclohexyl-2-((propoxycarbonyl)amino)propanoic acid (4) To a stirred solution of methyl (S)-3-cyclohexyl-2-((propoxycarbonyl)amino)propanoate (3) (3 g, 11.07 mmol) in THF (20 mL) and water (5 mL), lithium hydroxide (1.06 g, 44.28 mmol) was added at room temperature and stirred for 3 hours. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was completely distilled under reduced pressure, and the crude compound was acidified with 1N aqueous HCl to pH 4, extracted with dichloromethane (2 × 30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-3-cyclohexyl-2-((propoxycarbonyl)amino)propanoic acid (4). TLC system: 5% methanol in DCM R f :0.2 LCMS(ESI):m / z 256.26(MH) +

[0245] Methyl (S)-2-((S)-3-cyclohexyl-2-((propoxycarbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) To a stirred solution of (S)-3-cyclohexyl-2-((propoxycarbonyl)amino)propanoic acid (4) (0.6 g, 2.33 mmol) in DMF (10 mL), EDC.HCl (0.66 g, 3.501 mmol), HOBT (0.47 g, 3.5 mmol), DIPEA (1.2 mL, 6.99 mmol), and methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (amine fragment) (0.8 g, 2.33 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ice-water (30 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 40% ethyl acetate in petroleum ether to give ethyl (S)-2-((S)-3-cyclohexyl-2-((propoxycarbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5). TLC system: 5% methanol in DCM. f :0.6 LCMS(ESI):m / z 532.61(M+H) +

[0246] Propyl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) To a stirred solution of ethyl (S)-2-((S)-3-cyclohexyl-2-((propoxycarbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) (400 mg, 0.753 mmol) in DCM (10 mL) was added 2 M LiBH in THF (0.7 mL, 1.506 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After 2 h, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 30 mL). The organic layer was washed with brine solution (30 mL) and the combined organic layers were dried over NaSO and concentrated to give propyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6). TLC system: 5% MeOH in DCM. f 0.3 LCMS(ESI):m / z 504.64.5(M+H) +

[0247] Propyl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C18) To a stirred solution of propyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) (230 mg, 0.45 mmol) in EA (5 mL) was added Dess-Martin periodinane (581 mg, 1.37 mmol) at 0 °C and stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was diluted with DCM (50 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 NaSO, filtered, and concentrated to give the crude product. It was purified by preparative HPLC to give propyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C18). TLC system: 5% methanol in DCM R f :0.4 LCMS(ESI):m / z 502.46(M+H) +

[0248] Propyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C19) To a stirred solution of propyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C18) (crude) (200 mg, 0.199 mmol) in DCM (2 mL) was added DIPEA (0.2 mL, 0.59 mmol), followed by diethyl phosphite (0.2 mL, 0.59 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give propyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C19). TLC system: 5% MeOH R in DCM f :0.45 LCMS(ESI):m / z 640.59(M+H) +

[0249] Example 11: Synthesis of Compound C21 [ka] Methyl (S)-3-cyclohexyl-2-(indoline-1-carboxamido)propanoate (3) To a stirred solution of indoline (1) (3 g, 25.21 mmol) in ACN (30 mL) was added N,N'-disuccinamidyl carbonate (12.9 g, 50.42 mmol), followed by triethylamine (4.7 mL, 0.327 mmol) at room temperature and stirred for 3 h. The reaction progress was monitored by TLC. The reaction mass was used directly in the next reaction.

[0250] In a separate RB flask, methyl (S)-2-amino-3-cyclohexylpropanoate (2) (4 g, 21.73 mmol) was taken up in ACN (20 mL) and treated with triethylamine (9.1 mL, 65.21 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. After 16 hours, the reaction mixture was quenched with ice water (100 mL), extracted with ethyl acetate (2 x 100 mL), and the combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give methyl (S)-3-cyclohexyl-2-(indoline-1-carboxamido)propanoate (3). TLC system: 50% ethyl acetate / petroleum ether, R f :0.45 LCMS(ESI):m / z 331.34[M+H] +

[0251] (S)-3-Cyclohexyl-2-(indoline-1-carboxamido)propanoic acid (4) To a stirred solution of methyl (S)-3-cyclohexyl-2-(indoline-1-carboxamido)propanoate (3) (2 g, 6.06 mmol) in THF (20 mL) and water (10 mL), lithium hydroxide (436 mg, 18.18 mmol) was added at room temperature and stirred for 3 hours. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was completely distilled under reduced pressure, and the crude compound was acidified with 1N aqueous HCl to pH 4, extracted with dichloromethane (2 × 30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude (S)-3-cyclohexyl-2-(indoline-1-carboxamido)propanoic acid (4). TLC system: 5% MeOH / DCM R f :0.1 LCMS(ESI):m / z 317.49[M+H] +

[0252] Methyl (S)-2-((S)-3-cyclohexyl-2-(indoline-1-carboxamido)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) To a stirred solution of (S)-3-cyclohexyl-2-(indoline-1-carboxamido)propanoic acid (4) (600 mg, 1.89 mmol) in DMF (20 mL) at 0 °C, EDC·HCl (543 mg, 2.84 mmol), HOBT (384 mg, 2.84 mmol), and DIPEA (1.1 mL, 5.67 mmol) were added and the reaction mass was stirred for 15 min. After 15 min, methyl N 5 -methyl-N 5 -phenethyl-L-glutamate hydrochloride (amine fragment) (622 mg, 1.89 mmol) was added and stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ice water (150 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layers were washed with brine solution (80 mL), and the organic layer was dried over sodium sulfate and evaporated under reduced pressure to give the crude product. The crude residue was purified by normal phase chromatography, eluting with 60% EtOAc in petroleum ether, to give methyl (S)-2-((S)-3-cyclohexyl-2-(indoline-1-carboxamido)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5). TLC system: 5% MeOH / DCM R f :0.6 LCMS(ESI):m / z 591.17[M+H] +

[0253] N-((S)-3-Cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)indoline-1-carboxamide (6) To a stirred solution of N-((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)indoline-1-carboxamide (5) (100 mg, 0.16 mmol) in DCM (5 mL) at 0 °C, 2 M LiBH in THF (0.14 mL, 0.34 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine solution (20 mL), and the organic layer was dried over NaSO and concentrated to give the crude compound. The crude compound was purified by normal phase chromatography to give N-((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)indoline-1-carboxamide (6). TLC system: 5% MeOH / DCM R f :0.45 LCMS(ESI):m / z 563.48(M+H) +

[0254] N-((S)-3-Cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)indoline-1-carboxamide (7) To a stirred solution of N-((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)indoline-1-carboxamide (6) (150 mg, 0.266 mmol) in ethyl acetate (5 mL) was added Dess-Martin periodinane (334 mg, 0.8 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 (50 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 NaSO, filtered, and concentrated to give N-((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)indoline-1-carboxamide (7). TLC system: 5% methanol in DCM. f :0.5 LCMS(ESI):m / z 561.45(M+H) +

[0255] Diethyl ((2S)-2-((S)-3-cyclohexyl-2-(indoline-1-carboxamido)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentyl)phosphonate (Compound C21) To a stirred solution of N-((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)indoline-1-carboxamide (7) (150 mg, 0.26 mmol) dissolved in DCM (2 mL) was added DIPEA (0.14 mL, 0.8 mmol) and diethyl phosphite (0.11 mL, 0.8 mmol) at 0 °C and stirred at room temperature for 16 h. The reaction mixture was quenched with ice water (10 mL) and extracted with DCM (3 × 20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give the crude compound. The crude compound was purified by preparative HPLC to give pure diethyl ((2S)-2-((S)-3-cyclohexyl-2-(indoline-1-carboxamido)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentyl)phosphonate (compound C21). TLC system: 80% EtOAc in petroleum ether Rf: 0.3 LCMS (ESI): m / z 699.58 (M+H) +

[0256] Example 13: Synthesis of Compounds C27 and C8 [ka] 1-phenethylpyrrolidin-2-one (3) To a stirred solution of pyrrolidin-2-one 1 (10 g, 117.64 mmol) in toluene (150 mL), 60% NaH (7.0 g, 176.47 mmol), TBAI (8.68 g, 23.52 mmol), followed by (2-bromoethyl)benzene 2 (21.64 mL, 152.94 mmol) were added and refluxed for 6 hours. The reaction mixture was quenched with ice water (150 mL), extracted with ethyl acetate (2 x 150 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified on a silica gel column eluting with 70% ethyl acetate in hexane to give 1-phenethylpyrrolidin-2-one 3. TLC system: 80% ethyl acetate in hexane Rf: 0.2 LCMS (ESI): m / z 190.29 [M+H] +

[0257] 2-Oxo-1-phenethylpyrrolidine-3-carbaldehyde (4) To a stirred solution of 1-phenethylpyrrolidin-2-one 3 (4.0 g, 21.141 mmol) in THF (60 mL) was added dropwise 2 M LDA in THF (16 mL, 31.71 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, then DMF (2.3 mL, 31.712 mmol) in THF (10 mL) was added and stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was quenched with saturated NH4Cl solution, extracted with ethyl acetate (2 × 50 mL), dried over sodium sulfate, and evaporated under reduced pressure to give 2-oxo-1-phenethylpyrrolidine-3-carbaldehyde 4, which was used in the next step without any purification. TLC system: 80% ethyl acetate in hexane Rf: 0.4 LCMS (ESI): m / z 218.20 [M+H] +

[0258] Methyl (E)-2-(((benzyloxy)carbonyl)amino)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)acrylate (6) To a stirred solution of 2-oxo-1-phenethylpyrrolidine-3-carbaldehyde (4) (4.5 g, crude) in THF (60 mL) was added methyl 2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl)acetate (8.2 g, 24.86 mmol), followed by DBU (4.72 g, 31.07 mmol) at 0° C. and stirred for 2 h. The reaction mixture was diluted with ice water (50 mL), extracted with ethyl acetate (2×40 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified on a silica gel column eluting with 25% ethyl acetate in hexane to give methyl (E)-2-(((benzyloxy)carbonyl)amino)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)acrylate (6). TLC system: 50% ethyl acetate in hexane Rf: 0.5 LCMS (ESI): m / z 218.20 [M+H] +

[0259] Methyl 2-amino-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (7) To a stirred solution of methyl (E)-2-(((benzyloxy)carbonyl)amino)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)acrylate (6) (2.2 g, 5.213 mmol) in methanol (15 mL) and ethyl acetate (15 mL), 10% Pd / C (500 mg) was added and stirred under H balloon pressure (15 Psi) for 6 hours. The reaction progress was monitored by TLC and LCMS. After 6 hours, the reaction mixture was filtered through a bed of Celite, washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure to give methyl 2-amino-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (7). TLC system: 50% ethyl acetate in hexanes Rf: 0.4 LCMS (ESI): m / z 291.28 [M+H] +

[0260] Methyl 2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (8) To a stirred solution of (S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (acid fragment) (1.0 g, 2.948 mmol) in DMF (15 mL), EDC.HCl (0.84 g, 4.42 mmol), HOBT (0.59 g, 4.42 mmol), DIPEA (1.14 mL, 8.84 mmol), and methyl 2-amino-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (7) (0.5 g, 1.74 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (50 mL), extracted with ethyl acetate (2 × 40 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 2% methanol in dichloromethane to give methyl 2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (8). TLC system: 5% methanol in dichloromethane Rf: 0.4 LCMS (ESI): m / z 612.47 (M+H) +

[0261] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-((1-hydroxy-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (9) To a stirred solution of methyl 2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (8) (400 mg, 0.65 mmol) in DCM (4 mL) was added 2 M LiBH in THF (0.65 mL, 1.30 mmol) at 0 °C, and the reaction mixture was stirred at the same temperature for 2 h. The reaction progress was monitored by TLC and LCMS. Then, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine solution (20 mL), dried over NaSO, and concentrated to give the crude product. The crude residue was purified on a silica gel column by eluting with 2% methanol in dichloromethane to give 3-chlorobenzyl ((2S)-3-cyclohexyl-1-((1-hydroxy-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (9). TLC system: 5% methanol in dichloromethane Rf: 0.2 LCMS (ESI): m / z 584.45 (M+H) +

[0262] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (Compound C27) To a stirred solution of 3-chlorobenzyl ((2S)-3-cyclohexyl-1-((1-hydroxy-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (9) (130 mg, 0.22 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (188 mg, 0.44 mmol) at 0 °C and stirred at room temperature for 5 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with dichloromethane (15 mL) and washed with saturated Hypo solution (3 × 20 mL), saturated NaHCO solution (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by preparative HPLC to give 3-chlorobenzyl ((2S)-3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (compound C27). TLC system: 10% methanol in DCM Rf: 0.3 LCMS (ESI): m / z 582.29 (M+H) +

[0263] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-((1-(diethoxyphosphanyl)-1-hydroxy-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (Compound C8) To a stirred solution of crude 3-chlorobenzyl ((2S)-3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (compound C27) (220 mg, 0.378 mmol) in DCM (5 mL) was added DIPEA (0.2 mL, 1.13 mmol) and diethyl phosphite (0.2 mL, 1.13 mmol) at 0° C. and stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (15 mL) and extracted with DCM (3×15 mL). The organic layer was dried over anhydrous NaSO, filtered, and purified by preparative HPLC to give 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-1-hydroxy-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C8). TLC system: 10% methanol in DCM Rf: 0.5 LCMS (ESI): m / z 720.58 (M+H) +

[0264] Example 14: Synthesis of Compounds C30 and C28 [ka] tert-Butyl (2-hydroxybenzyl) (2-hydroxyethyl) carbamate (C) To a stirred solution of 2-hydroxybenzaldehyde (A) (25 g, 204.91 mmol) in methanol (50 mL), 2-aminoethan-1-ol (12.49 mL, 204.91 mmol) was added at room temperature and stirred for 6 hours. NaBH (3.89 g, 102.45 mmol) was then added at 0 °C and stirred for 6 hours. The reaction mixture was cooled to 0 °C, and triethylamine (33.2 mL, 245.89 mmol) and (Boc)O (49.13 g, 225.40 mmol) were added. The mixture was left at room temperature for 24 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was evaporated under reduced pressure and acidified with 2 N HCl to pH 4. The solid was filtered, washed with water (200 mL), and dried under vacuum to give tert-butyl (2-hydroxybenzyl)(2-hydroxyethyl)carbamate (C). TLC system: 30% ethyl acetate in petroleum ether Rf: 0.2 LCMS (ESI): m / z = 290.27 [M+Na] +

[0265] 2,3,4,5-Tetrahydrobenzo[f][1,4]oxazepine (C) To a stirred solution of DIAD (36.72 mL, 187.26 mmol), triphenylphosphine (49.1 g, 187.26 mmol) in THF (250 mL) was slowly added tert-butyl (2-hydroxybenzyl) (2-hydroxyethyl) carbamate (C) (25 g, 93.63 mmol) in THF (100 mL) at -10 °C and left at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, dissolved in dichloromethane (200 mL), and TFA (175 mL) was added at 0 °C and stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC, and the reaction mixture was evaporated under reduced pressure to give a crude product, which was diluted with water and washed with diethyl ether (2×100 mL). The aqueous layer was then basified with 10% NaOH to pH 12, extracted with DCM (2×150 mL), dried over sodium sulfate, and concentrated under reduced pressure to give 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (D). TLC system: 80% ethyl acetate in petroleum ether Rf: 0.1 LCMS (ESI): m / z=150.12 [M+H] +

[0266] Methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (F) To a stirred solution of (S)-4-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (E) (10.0 g, 38.31 mmol) in DMF (100 mL), EDC.HCl (10.9 g, 57.47 mmol), HOBT (7.7 g, 57.47 mmol), DIPEA (20.0 mL, 114.93 mmol), and 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (D) (6.2 g, 42.14 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ice water (200 mL), extracted with ethyl acetate (2 x 100 mL), dried over Na2SO4, and concentrated to give the crude compound, which was purified by normal phase chromatography eluting with 40% ethyl acetate in hexane to give methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (F). TLC system: 50% ethyl acetate in petroleum ether Rf: 0.3 LCMS (ESI): m / z = 393.38 [M+H] +

[0267] Methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (amine fragment) To a stirred solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (F) (5.0 g, 12.75 mmol) in 1,4-dioxane (20 mL) was added 4 N HCl in dioxane (20 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give pure methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate hydrochloride (amine fragment). TLC system: 5% methanol in dichloromethane Rf: 0.1 LCMS (ESI): m / z = 293.1 [M+H] +

[0268] Methyl (S)-3-cyclohexyl-2-(((piperidin-4-yloxy)carbonyl)amino)propanoic acid hydrochloride (2) To a stirred solution of tert-butyl (S)-4-(((3-cyclohexyl-1-methoxy-1-oxopropan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (1) (4 g, 9.70 mmol) in 1,4-dioxane (40 mL) was added 4N HCl in dioxane (40 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give methyl (S)-3-cyclohexyl-2-(((piperidin-4-yloxy)carbonyl)amino)propanoic acid hydrochloride (2). TLC system: 50% ethyl acetate in petroleum ether Rf: 0.1 LCMS (ESI): m / z 313.33 [M+H] +

[0269] Methyl (S)-3-cyclohexyl-2-((((1-(methylsulfonyl)piperidin-4-yl)oxy)carbonyl)amino)propanoate (3) To a stirred solution of methyl (S)-3-cyclohexyl-2-(((piperidin-4-yloxy)carbonyl)amino)propanoate (2) (3.3 g, 10.57 mmol) in DCM (40 mL) was added triethylamine (4.5 mL) followed by mesyl chloride (1 mL, 12.69 mmol) at 0° C. and stirred for 2 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with DCM, washed with water (2×30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give methyl (S)-3-cyclohexyl-2-((((1-(methylsulfonyl)piperidin-4-yl)oxy)carbonyl)amino)propanoate (3). TLC system: 70% ethyl acetate in petroleum ether Rf: 0.3 LCMS (ESI): m / z=391.2 [M+H] +

[0270] (S)-3-Cyclohexyl-2-((((1-(methylsulfonyl)piperidin-4-yl)oxy)carbonyl)amino)propanoic acid (4) To a stirred solution of methyl (S)-3-cyclohexyl-2-((((1-(methylsulfonyl)piperidin-4-yl)oxy)carbonyl)amino)propanoic acid (3) (2.0 g, 5.12 mmol) in THF (15 mL), water (15 mL) was added lithium hydroxide (644 mg, 15.38 mmol) at 0° C. and stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was distilled completely under reduced pressure, and the crude compound was acidified to pH ∼3 with 1N aqueous HCl, extracted with ethyl acetate (2 × 30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-3-cyclohexyl-2-((((1-(methylsulfonyl)piperidin-4-yl)oxy)carbonyl)amino)propanoic acid (4). TLC system: 5% methanol in DCM R f :0.2 LCMS(ESI):m / z 377.52[M+H] +

[0271] Methyl (S)-2-((S)-3-cyclohexyl-2-((((1-(methylsulfonyl)piperidin-4-yl)oxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) To a stirred solution of (S)-3-cyclohexyl-2-((((1-(methylsulfonyl)piperidin-4-yl)oxy)carbonyl)amino)propanoic acid (4) (1.0 g, 2.65 mmol) in DMF (15 mL), EDC.HCl (764 mg, 3.98 mmol), HOBT (538 mg, 3.98 mmol), DIPEA (1.4 mL, 7.97 mmol), and methyl (S)-2-amino-5-(2,3-dihydrobenzo)[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (amine fragment) (0.93 g, 3.19 mmol) were added simultaneously at 0° C. and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ice water (50 mL) and the resulting solid was filtered, washed with excess water, and dried under vacuum to give methyl (S)-2-((S)-3-cyclohexyl-2-((((1-(methylsulfonyl)piperidin-4-yl)oxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5). TLC system: 5% methanol in DCM R f :0.4 LCMS(ESI):m / z 651.25[M+H] +

[0272] 1-(Methylsulfonyl)piperidin-4-yl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) To a stirred solution of methyl (S)-2-((S)-3-cyclohexyl-2-((((1-(methylsulfonyl)piperidin-4-yl)oxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) (0.5 g, 0.76 mmol) in DCM (15 mL) was added 2 M LiBH in THF (0.76 mL, 1.53 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 and LCMS. The reaction mixture was then quenched with saturated NH Cl solution (30 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with brine solution (30 mL), dried over Na SO , and concentrated to give the crude compound. It was triturated with diethyl ether to give 1-(methylsulfonyl)piperidin-4-yl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f])[1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6). TLC system: 5% methanol in DCM Rf: 0.2 LCMS (ESI): m / z 623.40 (M+H) +

[0273] 1-(Methylsulfonyl)piperidin-4-yl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (Compound C30) To a stirred solution of 1-(methylsulfonyl)piperidin-4-yl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) (220 mg, 0.35 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (449 mg, 1.06 mmol) at 0° C. and stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated 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 the crude product, and the residue was purified by preparative HPLC to give 1-(methylsulfonyl)piperidin-4-yl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate Compound C30). TLC system: 5% methanol in DCM R f :0.4 LCMS(ESI):m / z 621.44[M+H] +

[0274] 1-(Methylsulfonyl)piperidin-4-yl((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepine)-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (Compound C28) To a stirred solution of 1-(methylsulfonyl)piperidin-4-yl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C30) (crude 220 mg, 0.35 mmol) in DCM (10 mL), DIPEA (0.19 mL, 1.06 mmol) was added, followed by diethyl phosphite (0.15 mL, 1.06 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give 1-(methylsulfonyl)piperidin-4-yl((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C28). TLC system: 5% methanol in DCM R f :0.4 LCMS(ESI):m / z 759.50[M+H] +

[0275] Example 23: Synthesis of Compound C10 [ka] 1-(3-chlorophenyl)cyclopropan-1-ol (2) To a stirred solution of 2-phenylacetonitrile (1) (5 g, 29.41 mmol) in THF (60 mL) was added titanium isopropoxide (11.69 g, 41.17 mmol), followed by the slow dropwise addition of 2 M ethylmagnesium chloride in THF (37 mL, 73.52 mmol) at 0 °C over 30 min. The reaction mixture was then stirred at room temperature for 36 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (3 × 40 mL), washed with brine solution (100 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 15% ethyl acetate in petroleum ether to give 1-(3-chlorophenyl)cyclopropan-1-ol (2). TLC system: 20% ethyl acetate in petroleum ether, Rf: 0.3 LCMS (ESI): m / z 151.18 [M-OH] +

[0276] Methyl (S)-2-(((1-(3-chlorophenyl)cyclopropoxy)carbonyl)amino)-3-cyclohexylpropanoate (4) To a stirred solution of 1-(3-chlorophenyl)cyclopropan-1-ol (2) (1.4 g, 8.33 mmol) in ACN (20 mL) was added N,N'-disuccinamidyl carbonate (3.19 g, 12.49 mmol), followed by triethylamine (2.8 mL, 24.99 mmol) at room temperature and stirred for 6 hours. The reaction progress was monitored by TLC. The reaction mass was used directly in the next reaction.

[0277] In a separate RB flask, methyl (S)-2-amino-3-cyclohexylpropanoate (3) (2.70 g, 12.82 mmol) was taken up in ACN (20 mL) and treated with triethylamine (3.5 mL, 24.27 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. After 16 hours, the reaction mixture was quenched with ice water (100 mL), extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give methyl (S)-2-(((1-(3-chlorophenyl)cyclopropoxy)carbonyl)amino)-3-cyclohexylpropanoate (4). TLC system: 20% ethyl acetate in petroleum ether Rf: 0.6 LCMS (ESI): m / z = 380.44 [M+H] +

[0278] (S)-2-(((1-(3-chlorophenyl)cyclopropoxy)carbonyl)amino)-3-cyclohexylpropanoic acid (5) To a stirred solution of methyl (S)-2-(((1-(3-chlorophenyl)cyclopropoxy)carbonyl)amino)-3-cyclohexylpropanoate (4) (1.3 g, 3.43 mmol) in THF (20 mL) and water (10 mL), lithium hydroxide (246 mg, 10.29 mmol) was added at room temperature and stirred for 3 hours at room temperature. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was completely distilled under reduced pressure, and the crude compound was acidified to pH 3 with 1N aqueous HCl, extracted with ethyl acetate (2×30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-2-(((1-(3-chlorophenyl)cyclopropoxy)carbonyl)amino)-3-cyclohexylpropanoic acid (5). TLC system: 5% methanol in DCM R f :0.1 LCMS(ESI):m / z 366.43[M+H] +

[0279] Methyl N2-((S)-2-(((1-(3-chlorophenyl)cyclopropoxy)carbonyl)amino)-3-cyclohexylpropanoyl)-N5-methyl-N5-phenethyl-L-glutamate (7) To a stirred solution of (S)-2-(((1-(3-chlorophenyl)cyclopropoxy)carbonyl)amino)-3-cyclohexylpropanoic acid (5) (1.0 g, 2.73 mmol) in DMF (10 mL), EDC.HCl (0.78 g, 4.10 mmol), HOBT (0.55 g, 4.10 mmol), DIPEA (1.5 mL, 8.21 mmol), and methyl N5-methyl-N5-phenethyl-L-glutamate hydrochloride (6) (1.03 g, 3.28 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with ice water (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash eluting with 60% ethyl acetate in petroleum ether to give methyl N2-((S)-2-(((1-(3-chlorophenyl)cyclopropoxy)carbonyl)amino)-3-cyclohexylpropanoyl)-N5-methyl-N5-phenethyl-L-glutamate (7). TLC system: 80% ethyl acetate in petroleum ether, Rf: 0.5 LCMS (ESI): m / z 627.47 [M+H] +

[0280] 1-(3-chlorophenyl)cyclopropyl((S)-3-cyclohexyl-1-(((S)-1-hydroxy-5-(methyl(phenethyl)amino)-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (8) To a stirred solution of methyl N2-((S)-2-(((1-(3-chlorophenyl)cyclopropoxy)carbonyl)amino)-3-cyclohexylpropanoyl)-N5-methyl-N5-phenethyl-L-glutamate (7) (1 g, 1.60 mmol) in THF (10 mL) was added 2 M LiBH4 in THF (2.4 mL, 4.80 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 and LCMS. The reaction mixture was then quenched with water (10 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with brine solution (20 mL), dried over Na2SO4, and concentrated to give the crude compound. It was triturated with diethyl ether to give 1-(3-chlorophenyl)cyclopropyl((S)-3-cyclohexyl-1-(((S)-1-hydroxy-5-(methyl(phenethyl)amino)-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (8). TLC system: 100% ethyl acetate Rf: 0.2 LCMS (ESI): m / z 598.60 (M+H) +

[0281] 1-(3-Chlorophenyl)cyclopropyl((S)-3-cyclohexyl-1-(((S)-5-(methyl(phenethyl)amino)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (Compound C10) To a stirred solution of 1-(3-chlorophenyl)cyclopropyl((S)-3-cyclohexyl-1-(((S)-1-hydroxy-5-(methyl(phenethyl)amino)-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (8) (150 mg, 0.25 mmol) dissolved in ethyl acetate (10 mL) was added Dess-Martin periodinane (319 mg, 0.75 mmol) at 0° C. and stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated Hypo solution (3 × 10 mL) and saturated NaHCO solution (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which residue was purified by normal phase chromatography eluting with 3% methanol in dichloromethane to give 1-(3-chlorophenyl)cyclopropyl((S)-3-cyclohexyl-1-(((S)-5-methyl(phenethyl)amino)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C10). TLC system: 5% methanol in DCM Rf: 0.4 LCMS (ESI): m / z 596.43 (M+H) +

[0282] Example 27: Synthesis of Compound C4 [ka] 1-(tert-butyl) 2-ethyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (1) To a stirred solution of ethyl (S)-5-oxopyrrolidine-2-carboxylate (1) (20.0 g, 127.38 mmol) in DCM (200 mL) were added triethylamine (22.02 mL, 152.86 mmol), Boc anhydride (30.54 mL, 140.12 mmol), and DMAP (1.5 g, 12.73 mmol) at 0° C., and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC, and the reaction mixture was quenched with ice-water (500 mL), extracted with dichloromethane (3×400 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by Grace NP compound eluting with 30% ethyl acetate and petroleum ether to give 1-(tert-butyl) 2-ethyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (2) (29.0 g, 112.71 mmol, 88% yield) as an off-white solid. TLC system: 30% ethyl acetate in petroleum ether, Rf: 0.3 LCMS (ESI): m / z 258.23 (M+H). +

[0283] 1-(tert-butyl) 2-ethyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (2) To a stirred solution of 1-(tert-butyl) 2-ethyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (2) (6.0 g, 23.34 mmol) in dry THF (600 mL) was added 1 M LiHMDS (28 mL, 28.01 mmol) at −78 °C and stirred for 3 h. The reaction progress was monitored by TLC, and the reaction mixture was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (2 × 200 mL), and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by Grace NP compound eluting with 20% ethyl acetate and petroleum ether to give 1-(tert-butyl) 2-ethyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (3) (1.4 g, 5.16 mmol, 22% yield) as a clear, gummy liquid. TLC system: 20% ethyl acetate in petroleum ether, Rf: 0.4 LCMS (ESI): m / z 272.28 (M+H) +

[0284] Ethyl (2S)-2-((tert-butoxycarbonyl)amino)-4-methyl-5-oxo-5-(phenethylamino)pentanoate (5) To a stirred solution of 1-(tert-butyl) 2-ethyl (2S)-4-methyl-5-oxopyrrolidine-1,2-dicarboxylate (3) (1.4 g, 5.16 mmol) in toluene (50 mL), 2-phenylethylamine (4) (625 mg, 5.16 mmol) was added and heated at 90 °C in a sealed tube for 6 h. The reaction progress was monitored by TLC, and the reaction mixture was concentrated. The crude residue was purified by Grace NP compound eluting with 50% ethyl acetate and petroleum ether to give ethyl (2S)-2-((tert-butoxycarbonyl)amino)-4-methyl-5-oxo-5-(phenethylamino)pentanoate (5) (1.0 g, 2.549 mmol, 49% yield) as a clear, gummy liquid. TLC system: 50% ethyl acetate in petroleum ether Rf: 0.5 LCMS (ESI): m / z 393.4 (M+H) +

[0285] Ethyl (2S)-2-amino-4-methyl-5-oxo-5-(phenethylamino)pentanoate (6) To a stirred solution of ethyl (2S)-2-((tert-butoxycarbonyl)amino)-4-methyl-5-oxo-5-(phenethylamino)pentanoate (5) (1.0 g, 2.98 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in dioxane (10 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give ethyl (2S)-2-amino-4-methyl-5-oxo-5-(phenethylamino)pentanoate (6) (0.720 g, 2.462 mmol, 96% yield) as an off-white solid. TLC system: 70% ethyl acetate in petroleum ether R f :0.9 LCMS(ESI):m / z 293.28(M+H) +

[0286] Ethyl (2S)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-4-methyl-5-oxo-5-(phenethylamino)pentanoate (7) To a stirred solution of (S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (acid fragment) (0.830 g, 2.448 mmol) in DMF (10 mL) was added EDC.HCl (0.71 g, 3.672 mmol), HOBt (0.49 g, 3.67 mmol), DIPEA (1.35 mL, 7.345 mmol), and ethyl (2S)-2-amino-4-methyl-5-oxo-5-(phenethylamino)pentanoate (6) (0.714 g, 2.448 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified by grace NP compound eluting with 50% methanol in dichloromethane to give ethyl (2S)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-4-methyl-5-oxo-5-(phenethylamino)pentanoate (7) (1.3 g, 2.116 mmol, 86% yield) as an off-white solid. TLC system: 50% ethyl acetate in petroleum ether, R f :0.4 LCMS(ESI):m / z 614.47(M+H) +

[0287] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-1-hydroxy-4-methyl-5-oxo-5-(phenethylamino)pentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (8) To a stirred solution of ethyl (2S)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-4-methyl-5-oxo-5-((phenethylamino)pentanoate (7) (0.250 g, 0.407 mmol) in DCM (20 mL) was added 2M HCl in THF. LiBH (0.407 mL, 0.814 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was then quenched with saturated NH Cl solution (20 mL) and extracted with DCM (2 × 20 mL). The organic layer was washed with brine solution (20 mL), dried over Na SO , and concentrated to give 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-1-hydroxy-4-methyl-5-oxo-5-(phenethylamino)pentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (8) (0.200 g, 0.349 mmol, 86% yield) as an off-white solid. TLC system: 100% ethyl acetate R f :0.6 LCMS(ESI):m / z 572.49(M+H) +

[0288] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-(((3S)-2-hydroxy-5-methyl-6-oxo-1-(phenethylpiperidin-3-yl)amino)-1-oxopropan-2-yl)carbamate (compound C4) To a stirred solution of 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-1-hydroxy-4-methyl-5-oxo-5-(phenethylamino)pentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (8) (200 mg, 0.349 mmol) in DCM (10 mL) was added Dess-Martin periodinane (296.6 mg, 0.699 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 DCM (15 mL) and washed with saturated Hypo solution (3 × 20 mL) and saturated NaHCO solution (3 × 20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give the crude compound. The crude residue was purified by preparative HPLC to give 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((3S)-2-hydroxy-5-methyl-6-oxo-1-(phenethylpiperidin-3-yl)amino)-1-oxopropan-2-yl)carbamate (compound C4) (40 mg, 0.0877 mmol, 25% yield) as an off-white solid. TLC system: 100% ethyl acetate R f :0.5 LCMS(ESI):m / z 552.89(M-OH) +

[0289] Example 28: Synthesis of Compounds C17 and C5 [ka] 1-Benzylcyclopropan-1-amine (2) To a stirred solution of 2-phenylacetonitrile (1) (2 g, 17.094 mmol) in EtO:THF (1:1) (20 mL) was added titanium isopropoxide (5.14 g, 18.119 mmol), followed by the slow dropwise addition of 2 M ethylmagnesium chloride in THF (17 mL, 34.188 mmol) at 0 °C over 10 min. The reaction mixture was then stirred at room temperature for 1 h, followed by the slow addition of BF-EtO (4.8 mL, 34.188 mmol) over 15 min at 0 °C (an exotherm occurred) and stirring at room temperature for 1 h. The reaction progress was monitored by TLC and LCMS. After 1 h, the reaction mixture was poured into 10% NaOH solution (100 mL), resulting in the formation of a white precipitate. The reaction mixture was filtered through a bed of Celite, washed with ethyl acetate (50 mL), and the filtrate was washed with brine solution (100 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 70% ethyl acetate in petroleum ether to give 1-benzylcyclopropan-1-amine (2). TLC system: 80% ethyl acetate in petroleum ether Rf: 0.3 LCMS (ESI): m / z 148.11 [M+H] +

[0290] tert-Butyl(1-benzylcyclopropyl)carbamate (3) To a stirred solution of 1-benzylcyclopropan-1-amine (2) (4.2 g, 28.5714 mmol) in DCM (50 mL) was added TEA (4.1 mL, 57.142 mmol), followed by the slow dropwise addition of Boc anhydride (6.8 mL, 31.428 mmol) over 10 minutes at 0 °C. The reaction mixture was then stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was diluted with ice water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 5% ethyl acetate in petroleum ether to give tert-butyl (1-benzylcyclopropyl)carbamate (3). TLC system: 30% ethyl acetate in petroleum ether, Rf: 0.8 LCMS (ESI): m / z 148.11 [M-Boc] +

[0291] tert-Butyl (1-benzylcyclopropyl)(methyl)carbamate (4) To a stirred solution of tert-butyl(1-benzylcyclopropyl)carbamate (3) (2 × 2.5 g, 10.121 mmol) in DMF (25 mL) in a sealed vessel, 60% NaH (607 mg, 15.182 mmol) was added at 0 °C and stirred for 15 minutes. After that, methyl iodide (2.6 mL, 40.485 mmol) was added dropwise slowly over 10 minutes at 0 °C. The reaction mixture was then heated to 40 °C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After 16 hours, the reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to give tert-butyl(1-benzylcyclopropyl)(methyl)carbamate (4). TLC system: 5% ethyl acetate in petroleum ether, Rf: 0.6 LCMS (ESI): m / z 162.11 [M-Boc] +

[0292] 1-Benzyl-N-methylcyclopropan-1-amine hydrochloride (5) To a stirred solution of tert-butyl(1-benzylcyclopropyl)(methyl)carbamate (4) (1.3 g, 4.9808 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in dioxane (20 mL) dropwise 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. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give 1-benzyl-N-methylcyclopropan-1-amine hydrochloride (5). TLC system: 5% methanol in DCM Rf: 0.2 LCMS (ESI): m / z 162.32 [M+H] +

[0293] Methyl N5-(1-benzylcyclopropyl)-N2-(tert-butoxycarbonyl)-N5-methyl-L-glutamate (7) To a stirred solution of (S)-4-((tert-butoxycarbonyl)amino)-5-methoxy-5-oxopentanoic acid (6) (1 g, 3.831 mmol) in DMF (10 mL), EDC.HCl (1.1 g, 5.747 mmol), HOBT (775 mg, 5.747 mmol), DIPEA (2.11 mL, 11.494 mmol), and 1-benzyl-N-methylcyclopropan-1-amine hydrochloride (5) (678 mg, 4.214 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 40% ethyl acetate in petroleum ether to give methyl N5-(1-benzylcyclopropyl)-N2-(tert-butoxycarbonyl)-N5-methyl-L-glutamate (7). TLC system: 50% ethyl acetate in petroleum ether, Rf: 0.5 LCMS (ESI): m / z 305.19 [M-Boc] +

[0294] Methyl N5-(1-benzylcyclopropyl)-N5-methyl-L-glutamate hydrochloride (8) To a stirred solution of methyl N5-(1-benzylcyclopropyl)-N2-(tert-butoxycarbonyl)-N5-methyl-L-glutamate (7) (1.0 g, 2.475 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in dioxane (20 mL) dropwise 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. After consumption of the starting material, the reaction mixture was evaporated under reduced pressure to give the crude compound, which was triturated with diethyl ether to give methyl N5-(1-benzylcyclopropyl)-N5-methyl-L-glutamate hydrochloride (8). TLC system: 5% methanol in DCM. Rf: 0.2. LCMS (ESI): m / z 305.26 [M+H]. +

[0295] Methyl N5-(1-benzylcyclopropyl)-N2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoyl)-N5-methyl-L-glutamate (9) To a stirred solution of (S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (acid fragment) (1.0 g, 2.949 mmol) in DMF (10 mL), EDC.HCl (845 mg, 4.424 mmol), HOBT (597 mg, 5.899 mmol), DIPEA (1.63 mL, 8.849 mmol), and methyl N5-(1-benzylcyclopropyl)-N5-methyl-L-glutamate hydrochloride (8) (986 mg, 3.244 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was diluted with ice-water (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified by Combiflash chromatography eluting with 60% ethyl acetate in petroleum ether to give methyl N5-(1-benzylcyclopropyl)-N2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoyl)-N5-methyl-L-glutamate (9). TLC system: 50% ethyl acetate in petroleum ether, Rf: 0.5 LCMS (ESI): m / z 626.58 [M+H] +

[0296] 3-Chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (10) To a stirred solution of methyl N5-(1-benzylcyclopropyl)-N2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoyl)-N5-methyl-L-glutamate (9) (1 g, 1.6 mmol) in THF (10 mL) was added 2 M LiBH4 in THF (1.6 mL, 3.2 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 and LCMS. The reaction mixture was then quenched with water (10 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with brine solution (10 mL), dried over Na2SO4, and concentrated to give the crude compound. It was purified by Combiflash column eluting with 80% ethyl acetate in petroleum ether to give 3-chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (10). TLC system: 100% ethyl acetate Rf: 0.2 LCMS (ESI): m / z 598.98 (M+H) +

[0297] 3-Chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1,5-dioxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C17) To a stirred solution of 3-chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (10) (150 mg, 0.2508 mmol) dissolved in ethyl acetate (10 mL), Dess-Martin periodinane (320 mg, 0.752 mmol) was added at 0° C. and stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed with saturated Hypo solution (3×10 mL), and washed with saturated NaHCO solution (3×20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give the crude compound. It was purified by Combiflash chromatography eluting with 20% MeOH in DCM to give 3-chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1,5-dioxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C17). TLC system: 80% ethyl acetate in petroleum ether, Rf: 0.4 LCMS (ESI): m / z 598.98 (M+H) +

[0298] 3-Chlorobenzyl ((2S)-1-(((2S)-5-((1-benzylcyclopropyl)(methyl)amino)-1-(diethoxyphosphoryl)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C5) To a stirred solution of 3-chlorobenzyl ((S)-1-(((S)-5-((1-benzylcyclopropyl)(methyl)amino)-1,5-dioxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C17) (200 mg, 0.033 mmol) in DCM (10 mL) was added DIPEA (0.2 mL, 1.032 mmol), followed by diethyl phosphite (0.14 mL, 1.032 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2 × 20 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give 3-chlorobenzyl ((2S)-1-(((2S)-5-((1-benzylcyclopropyl)(methyl)amino)-1-(diethoxyphosphoryl)-1-hydroxy-5-oxopentan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C5). TLC system: 100% ethyl acetate Rf: 0.3 LCMS (ESI): m / z 734.51 (M+H) +

[0299] Example 29: Synthesis of Compounds C16 and C6 [ka] Methyl (S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoate (3) To a stirred solution of (S)-2-amino-3-cyclohexylpropanoic acid hydrochloride (2) (3 g, 13.531 mmol) in THF (20 mL) and DIPEA (7 mL, 40.59 mmol) was added pentyl carbonochloridate (1) (2.34 mL, 16.2 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After 2 hours, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 50% ethyl acetate in petroleum ether to give methyl (S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoate (3). TLC system: 30% ethyl acetate in petroleum ether, R f :0.55 LCMS(ESI):m / z 330.2(M+NH) +

[0300] (S)-3-Cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoic acid (4) To a stirred solution of methyl (S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoate (3) (2.5 g, 8.3 mmol) in THF (20 mL) and water (5 mL), lithium hydroxide (600 mg, 25 mmol) was added at room temperature and stirred for 3 hours. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was completely distilled under reduced pressure, and the crude compound was acidified with 1N aqueous HCl to pH 4, extracted with dichloromethane (2 x 30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoic acid (4). TLC system: 5% methanol in DCM R f :0.2

[0301] Methyl (S)-2-((S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) To a stirred solution of (S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanoic acid (4) (1 g, 3.5 mmol) in DMF (20 mL), EDC.HCl (1 g, 5.2 mmol), HOBT (700 mg, 5.23 mmol), DIPEA (1.7 mL, 10.46 mmol), and methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate hydrochloride (amine fragment) (1.38 g, 4.2 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ice-water (30 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 40% ethyl acetate in petroleum ether to give methyl (S)-2-((S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5). TLC system: 5% methanol in DCM. f :0.6 LCMS(ESI):m / z 560.63(M+H) +

[0302] Pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) To a stirred solution of methyl (S)-2-((S)-3-cyclohexyl-2-(((pentyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) (900 mg, 1.6 mmol) in DCM (10 mL) was added 2 M LiBH in THF (1.2 mL, 1.53 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After 2 h, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 30 mL). The organic layer was washed with brine solution (30 mL) and the combined organic layers were dried over NaSO and concentrated to give crude pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6). TLC system: 5% MeOH in DCM. f 0.3 LCMS(ESI):m / z 532.5(M+H) +

[0303] Pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C16) To a stirred solution of pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) (250 mg, 0.45 mmol) in DCM (5 mL) was added Dess-Martin periodinane (583 mg, 1.37 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 DCM (50 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 crude compound pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (C16), which was used directly in the next step. TLC system: 5% methanol in DCM R f :0.4 LCMS(ESI):m / z 530.56(M+H) +

[0304] Pentyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C6) To a stirred solution of pentyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C16) (248 mg, 0.47 mmol) in DCM (5 mL) was added DIPEA (0.24 mL, 1.41 mmol), followed by diethyl phosphite (0.19 mL, 1.41 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2×15 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give pentyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C6). TLC system: 5% MeOH R in DCM f :0.45 LCMS(ESI):m / z 668.68(M+H) +

[0305] Example 30: Synthesis of compounds C26 and C7 [ka] Methyl (S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoate (3) To a stirred solution of (S)-2-amino-3-cyclohexylpropanoic acid hydrochloride (2) (4.8 g, 2.1 mmol) in THF (20 mL) and DIPEA (9.7 mL, 5.4 mmol) was added hexyl carbonochloridate (1) (3 g, 1.8 mmol) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC and LCMS. After 2 hours, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue was purified on a silica gel column eluting with 50% ethyl acetate in petroleum ether to give methyl (S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoate (3). TLC system: 5% MeOH R in DCM. f :0.55 LCMS(ESI):m / z 314.42(M+H) +

[0306] (S)-3-Cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoic acid (4) To a stirred solution of methyl (S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoate (3) (2 g, 6.36 mmol) in THF (20 mL) and water (5 mL), lithium hydroxide (450 mg, 19 mmol) was added at room temperature and stirred for 3 hours. The reaction progress was monitored by TLC and LCMS. After 3 hours, the reaction mixture was completely distilled under reduced pressure, and the crude compound was acidified with 1N aqueous HCl to pH 4, extracted with dichloromethane (2 x 30 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoic acid (4). TLC system: 5% methanol in DCM R f :0.2 LCMS(ESI):m / z 300.2(M+H) +

[0307] tert-Butyl 1-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-methoxy-5-oxopentanoyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate (5) To a stirred solution of (S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanoic acid (1.2 g, 4 mmol) in DMF (20 mL) at 0 °C, EDC.HCl (1.14 g, 6 mmol), HOBT (834 mg, 6 mmol), DIPEA (2 mL, 12 mmol), and methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate hydrochloride (amine fragment) (1.57 g, 4.8 mmol) were added and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ice-water (500 mL), extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 40% ethyl acetate in petroleum ether to give tert-butyl 1-((S)-4-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-5-methoxy-5-oxopentanoyl)-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4-carboxylate (5). TLC system: 5% methanol in DCM. f :0.4 LCMS(ESI):m / z 574.53(M+H) +

[0308] Hexyl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) To a stirred solution of methyl (S)-2-((S)-3-cyclohexyl-2-(((hexyloxy)carbonyl)amino)propanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) (960 mg, 1.67 mmol) in DCM (10 mL) was added 2 M LiBH in THF (1.25 mL, 1.5 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After 2 h, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 30 mL). The organic layer was washed with brine solution (30 mL) and the combined organic layers were dried over NaSO and concentrated to give crude hexyl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6). TLC system: 5% MeOH in DCM. f 0.3 LCMS(ESI):m / z 546.51(M+H) +

[0309] Hexyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C26) To a stirred solution of hexyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (6) (250 mg, 0.45 mmol) in DCM (5 mL) was added Dess-Martin periodinane (583 mg, 1.37 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 DCM (50 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 crude hexyl((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C26), which was used directly in the next step. TLC system: 5% methanol in DCM R f :0.5 LCMS(ESI):m / z 544.55(M+H) +

[0310] Hexyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (Compound C7) To a stirred solution of hexyl ((S)-3-cyclohexyl-1-(((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (248 mg, 0.45 mmol) in DCM (5 mL) was added DIPEA (0.23 mL, 1.37 mmol), followed by diethyl phosphite (0.18 mL, 1.37 mmol), and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ammonium chloride (15 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give hexyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C7). TLC system: 5% MeOH R in DCM f :0.5 LCMS(ESI):m / z 682.6(M+H) +

[0311] Example 31: Synthesis of Compounds C27 and C8 [ka] 1-phenethylpyrrolidin-2-one (3) To a stirred solution of pyrrolidin-2-one 1 (10 g, 117.64 mmol) in toluene (150 mL), 60% NaH (7.0 g, 176.47 mmol), TBAI (8.68 g, 23.52 mmol), followed by (2-bromoethyl)benzene 2 (21.64 mL, 152.94 mmol) were added and refluxed for 6 hours. The reaction mixture was quenched with ice water (150 mL), extracted with ethyl acetate (2 x 150 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified on a silica gel column eluting with 70% ethyl acetate in hexane to give 1-phenethylpyrrolidin-2-one 3. TLC system: 80% ethyl acetate in hexane Rf: 0.2 LCMS (ESI): m / z 190.29 [M+H] +

[0312] 2-Oxo-1-phenethylpyrrolidine-3-carbaldehyde (4) To a stirred solution of 1-phenethylpyrrolidin-2-one (3) (4.0 g, 21.141 mmol) in THF (60 mL) was added dropwise 2 M LDA in THF (16 mL, 31.71 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, then DMF (2.3 mL, 31.712 mmol) in THF (10 mL) was added and stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. After consumption of the starting material, the reaction mixture was quenched with saturated NH4Cl solution, extracted with ethyl acetate (2 × 50 mL), dried over sodium sulfate, and evaporated under reduced pressure to give 2-oxo-1-phenethylpyrrolidine-3-carbaldehyde (4), which was used directly in the next step. TLC system: 80% ethyl acetate in hexanes Rf: 0.4 LCMS (ESI): m / z 218.20 [M+H] +

[0313] Methyl (E)-2-(((benzyloxy)carbonyl)amino)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)acrylate (6) To a stirred solution of 2-oxo-1-phenethylpyrrolidine-3-carbaldehyde (4) (4.5 g, crude) in THF (60 mL) was added methyl 2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl)acetate (8.2 g, 24.86 mmol), followed by DBU (4.72 g, 31.07 mmol) at 0° C. and stirred for 2 h. The reaction mixture was diluted with ice water (50 mL), extracted with ethyl acetate (2×40 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified on a silica gel column eluting with 25% ethyl acetate in hexane to give methyl (E)-2-(((benzyloxy)carbonyl)amino)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)acrylate (6). TLC system: 50% ethyl acetate in hexane Rf: 0.5 LCMS (ESI): m / z 218.20 [M+H] +

[0314] Methyl 2-amino-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (7) To a stirred solution of methyl (E)-2-(((benzyloxy)carbonyl)amino)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)acrylate (6) (2.2 g, 5.213 mmol) in methanol (15 mL) and ethyl acetate (15 mL), 10% Pd / C (500 mg) was added and stirred under H balloon pressure (15 Psi) for 6 hours. The reaction progress was monitored by TLC and LCMS. After 6 hours, the reaction mixture was filtered through a bed of Celite, washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure to give methyl 2-amino-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (7). TLC system: 50% ethyl acetate in hexanes Rf: 0.4 LCMS (ESI): m / z 291.28 [M+H] +

[0315] Methyl 2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (8) To a stirred solution of (S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (acid fragment) (1.0 g, 2.948 mmol) in DMF (15 mL), EDC.HCl (0.84 g, 4.42 mmol), HOBT (0.59 g, 4.42 mmol), DIPEA (1.14 mL, 8.84 mmol), and methyl 2-amino-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (7) (0.5 g, 1.74 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (50 mL), extracted with ethyl acetate (2 × 40 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 2% methanol in dichloromethane to give methyl 2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (8). TLC system: 5% methanol in dichloromethane Rf: 0.4 LCMS (ESI): m / z 612.47 (M+H) +

[0316] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-((1-hydroxy-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (9) To a stirred solution of methyl 2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propanoate (8) (400 mg, 0.65 mmol) in DCM (4 mL) was added 2 M LiBH in THF (0.65 mL, 1.30 mmol) at 0 °C, and the reaction mixture was stirred at the same temperature for 2 h. The reaction progress was monitored by TLC and LCMS. Then, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine solution (20 mL), dried over NaSO, and concentrated to give the crude product. The crude residue was purified on a silica gel column by eluting with 2% methanol in dichloromethane to give 3-chlorobenzyl ((2S)-3-cyclohexyl-1-((1-hydroxy-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (9). TLC system: 5% methanol in dichloromethane Rf: 0.2 LCMS (ESI): m / z 584.45 (M+H) +

[0317] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (Compound C27) To a stirred solution of 3-chlorobenzyl ((2S)-3-cyclohexyl-1-((1-hydroxy-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (9) (200 mg, 0.34 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (436 mg, 1.02 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 dichloromethane (15 mL) and washed with saturated Hypo solution (3 × 10 mL) and saturated NaHCO solution (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to give crude 3-chlorobenzyl ((2S)-3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (compound C27), which was used directly in the next step. TLC system: 10% methanol in DCM Rf: 0.4 LCMS (ESI): m / z 582.52 (M+H) +

[0318] 3-Chlorobenzyl ((2S)-3-cyclohexyl-1-((1-(diethoxyphosphanyl)-1-hydroxy-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (Compound C8) To a stirred solution of crude 3-chlorobenzyl ((2S)-3-cyclohexyl-1-oxo-1-((1-oxo-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)propan-2-yl)carbamate (compound C27) (220 mg, 0.378 mmol) in DCM (5 mL) was added DIPEA (0.2 mL, 1.13 mmol) and diethyl phosphite (0.2 mL, 1.13 mmol) at 0° C. and stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with ice water (15 mL) and extracted with DCM (3×15 mL). The organic layer was dried over anhydrous NaSO, filtered, and purified by preparative HPLC to give 3-chlorobenzyl ((2S)-3-cyclohexyl-1-(((2S)-1-(diethoxyphosphoryl)-1-hydroxy-3-(2-oxo-1-phenethylpyrrolidin-3-yl)propan-2-yl)amino)-1-oxopropan-2-yl)carbamate (compound C8). TLC system: 10% methanol in DCM Rf: 0.5 LCMS (ESI): m / z 720.58 (M+H) +

[0319] Example 32: Synthesis of Compounds C35 and C31 [ka] Methyl (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanoate (3) To a stirred solution of methyl (S)-2-amino-3-cyclohexylpropanoate hydrochloride (2) (500 mg, 2.26 mmol) in 1,4-dioxane (10 mL) was added diphosgene (0.4 mL, 3.39 mmol) at room temperature and heated to reflux for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure to give a crude residue, which was used directly in the next reaction.

[0320] In a separate RB flask, 1-(3-chlorophenyl)-N-methylmethanamine (1) (350 mg, 2.26 mmol) was taken up in ACN (10 mL) and treated with triethylamine (0.95 mL, 6.78 mmol). The resulting reaction mixture was stirred for 5 minutes, then the reaction mass prepared above was added dropwise. The reaction mixture was stirred at room temperature and heated to 80 °C for 3 hours. The reaction mixture was quenched with ice water (20 mL), extracted with ethyl acetate (2 × 20 mL), and the combined organic layers were washed with brine solution (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give methyl (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanoate (3). TLC system: 50% ethyl acetate in hexane, Rf: 0.3 LCMS (ESI): m / z 367.32 [M+H] +

[0321] (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanoic acid (4) To a stirred solution of (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanoic acid (3) (600 mg, 1.63 mmol) in THF (4 mL) and water (2 mL), lithium hydroxide (117 mg, 4.89 mmol) was added at room temperature and stirred for 3 hours at room temperature. The reaction progress was monitored by TLC and LCMS. The reaction mixture was completely distilled under reduced pressure, and the crude compound was acidified to pH 3 with 1N aqueous HCl, extracted with ethyl acetate (2×15 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanoic acid (4). TLC system: 100% EtOAc Rf: 0.1 LCMS (ESI): m / z 353.47 [M+H] +

[0322] Methyl (S)-2-((S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) To a stirred solution of (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanoic acid (500 mg, 1.42 mmol) in DMF (10 mL), EDC.HCl (406 mg, 2.13 mmol), HOBt (287 mg, 2.13 mmol), DIPEA (0.7 mL, 4.26 mmol), and methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (amine fragment) (559 mg, 1.70 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (20 mL), extracted with ethyl acetate (2 × 20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by Combiflash NP compound eluting with 2% methanol in dichloromethane to give methyl (S)-2-((S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5). TLC system: 5% methanol in dichloromethane - Rf: 0.4 LCMS (ESI): m / z 627.89 [M+H] +

[0323] (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexyl-N-((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)propanamide (6) To a stirred solution of methyl (S)-2-((S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoate (5) (480 mg, 0.95 mmol) in DCM (10 mL) was added 2 M LiBH in THF (0.95 mL, 1.91 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 (20 mL) and extracted with DCM (2 × 20 mL). The organic layer was washed with brine solution (20 mL), dried over NaSO, and concentrated to give (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexyl-N-((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)propanamide (6). TLC system: 5% methanol in dichloromethane Rf: 0.2 LCMS (ESI): m / z 599.53 [M+H] +

[0324] (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexyl-N-((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)propanamide (compound C35) To a stirred solution of (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexyl-N-((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentan-2-yl)propanamide (6) (200 mg, 0.33 mmol) dissolved in dichloromethane (5 mL) was added Dess-Martin periodinane (425 mg, 1.00 mmol) at 0 °C and stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (15 mL), followed by saturated Hypo solution (3 × 15 mL), followed by saturated NaHCO solution (3 × 15 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to give the crude compound. The crude compound was purified by preparative HPLC to give (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexyl-N-((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)propanamide (compound C35). TLC system: 10% methanol in dichloromethane Rf: 0.5 LCMS (ESI): m / z 597.44 (M+H) +

[0325] Diethyl ((2S)-2-((S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanamido)-5-(2,3-dihydrobenzo[f][1,4])oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentyl)phosphonate (Compound C31) To a stirred solution of (S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexyl-N-((S)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1,5-dioxopentan-2-yl)propanamide (compound C35) (110 mg, crude 0.18 mmol) in DCM (4 mL) was added DIPEA (0.1 mL, 0.55 mmol), followed by diethyl phosphite (76 mg, 0.55 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ammonium chloride (10 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous NaSO and evaporated to give a crude residue. It was purified by preparative HPLC to give diethyl ((2S)-2-((S)-2-(3-(3-chlorobenzyl)-3-methylureido)-3-cyclohexylpropanamido)-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-1-hydroxy-5-oxopentyl)phosphonate (compound C31). TLC system: 10% methanol in dichloromethane Rf: 0.4 LCMS (ESI): m / z 735.44 (M+H) +

[0326] Example 33: Synthesis of Compound C32 [ka] [ka] tert-Butyl 4-nitropiperidine-1-carboxylate (B) To a stirred solution of tert-butyl 4-iodopiperidine-1-carboxylate (A) (20 g, 64.308 mmol) in DMSO (100 mL) was added phloroglucinol (12.9 g, 102.89 mmol), followed by sodium nitrite (8.8 g, 128.6 mmol) at room temperature and stirred at 45 °C for 16 h. The reaction progress was monitored by TLC. The reaction mixture was quenched with water (250 mL) and extracted with diethyl ether (3 × 100 mL). The combined organic layers were washed with water (2 × 50 mL), brine solution (50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give tert-butyl 4-nitropiperidine-1-carboxylate (B). TLC system: 50% EtOAc / petroleum ether R f :0.45

[0327] 4-Nitropiperidine hydrochloride (C) To a stirred solution of tert-butyl 4-nitropiperidine-1-carboxylate (B) (3 g, 13.043 mmol) in 1,4-dioxane (5 mL) was added 4N HCl (5 mL) at 0° C. and stirred at room temperature for 4 hours. The reaction progress was monitored by TLC and LCMS. After 4 hours, the reaction mixture was completely distilled under reduced pressure and the crude compound was triturated with diethyl ether (2×10 mL) to give 4-nitropiperidine hydrochloride (C). TLC system: 5% MeOH / DCM R f :0.1 LCMS(ESI):m / z 131.10[M+H] +

[0328] 1-(4-Nitropiperidin-1-yl)ethan-1-one (Int-4) To a stirred solution of 4-nitropiperidine hydrochloride (C) (2.2 g, 13.25 mmol) dissolved in DCM (20 mL), acetic anhydride (1.25 mL, 13.25 mmol) and triethylamine (2.7 mL, 19.87 mmol) were added simultaneously at 0 °C and stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with ice-water (20 mL) and extracted with DCM (2 × 20 mL). The organic layer was washed with water (2 × 10 mL), brine solution (10 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give the title compound. TLC system: 30% EtOAc in petroleum ether. Rf: 0.3. LCMS (ESI): m / z 173.33 [M+H]. +

[0329] 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (2) To a stirred solution of ethyl (S)-5-oxopyrrolidine-2-carboxylate (1) (20.0 g, 127.38 mmol) in DCM (200 mL) was added triethylamine (22.02 mL, 152.86 mmol), Boc anhydride (30.54 mL, 140.12 mmol), and DMAP (1.5 g, 12.73 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC, and the reaction mixture was quenched with ice-water (500 mL), extracted with dichloromethane (3 × 400 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by Grace NP compound eluting with 30% ethyl acetate and petroleum ether to give 1-(tert-butyl) 2-ethyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (2). TLC system: 30% ethyl acetate in petroleum ether, Rf: 0.3 LCMS (ESI): m / z 258.23 (M+H) +

[0330] 1-(tert-butyl) 2-methyl(S,Z)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (3) To a stirred solution of 1-(tert-butyl) 2-methyl (S)-5-oxopyrrolidine-1,2-dicarboxylate (2) (10 g, 41.15 mmol) in dimethoxymethane (100 mL) was added Bredereck's reagent (13 mL, 61.72 mmol) at 0 °C and stirred at 80 °C for 3 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was completely distilled under reduced pressure, and the crude compound was triturated with diethyl ether (2 × 20 mL) to give 1-(tert-butyl) 2-methyl (S,Z)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (3). TLC system: 60% EtOAc in petroleum ether Rf: 0.2

[0331] 1-(tert-butyl) 2-methyl (S)-4-methylene-5-oxopyrrolidine-1,2-dicarboxylate (4) To a stirred solution of 1-(tert-butyl) 2-methyl(S,Z)-4-((dimethylamino)methylene)-5-oxopyrrolidine-1,2-dicarboxylate (3) (500 mg, 1.666 mmol) in THF (4 mL) was added 1 N HCl (1.75 mL) at room temperature and stirred for 3 h. The reaction progress was monitored by TLC. The layers were separated and the organic layer was used directly in the next reaction.

[0332] In a separate RB flask, 33% formaldehyde (3V) and potassium carbonate (344 mg, 2.49 mmol) were added to the above organic layer at 0° C. and stirred at room temperature for 4 hours. The reaction progress was monitored by TLC and LCMS. The layers were separated, the aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with saturated sodium bicarbonate (100 mL), brine solution (50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give 1-(tert-butyl) 2-methyl (S)-4-methylene-5-oxopyrrolidine-1,2-dicarboxylate. TLC system: 30% EtOAc / petroleum ether R f :0.2

[0333] Dimethyl (S)-2-((tert-butoxycarbonyl)amino)-4-methylenepentanedioate (5) To a stirred solution of 1-(tert-butyl) 2-methyl (S)-4-methylene-5-oxopyrrolidine-1,2-dicarboxylate (4) (400 mg, 1.56 mmol) in dry THF (10 mL) was added lithium methoxide (1 M in methanol) (1.88 mL, 1.88 mmol) at −40° C. and stirred at the same temperature for 20 minutes. The reaction progress was monitored by TLC. The reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine solution (10 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give dimethyl (S)-2-((tert-butoxycarbonyl)amino)-4-methylenepentanedioate (5). TLC system: 30% EtOAc in petroleum ether Rf: 0.3 LCMS (ESI): m / z 310.3 (M+Na+H) +

[0334] Dimethyl 2-((1-acetyl-4-nitropiperidin-4-yl)methyl)-4-((tert-butoxycarbonyl)amino)pentanedioate (6) To a stirred solution of dimethyl (S)-2-((tert-butoxycarbonyl)amino)-4-methylenepentanedioate (5) (500 mg, 1.74 mmol) in ACN (5 mL) was added 1-(4-nitropiperidin-1-yl)ethan-1-one (Int-4) (300 mg, 1.74 mmol) and DBU (0.55 mL, 3.48 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 evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give dimethyl 2-((1-acetyl-4-nitropiperidin-4-yl)methyl)-4-((tert-butoxycarbonyl)amino)pentanedioate (6). TLC system: 5% MeOH / DCMR f :0.35 LCMS(ESI):m / z 482.4(M+H) +

[0335] Methyl 3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (7) To a stirred solution of dimethyl 2-((1-acetyl-4-nitropiperidin-4-yl)methyl)-4-((tert-butoxycarbonyl)pentanedioate (6) (100 mg, 0.217 mmol) in methanol (4 mL) was added nickel chloride (31 mg, 0.23 mmol) followed by sodium borohydride (42 mg, 1.08 mmol) at −10° C. and stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. The reaction mixture was diluted with water. (5 mL), extracted with ethyl acetate (3 × 10 mL), and the combined organic layers were washed with water (2 × 10 mL), brine solution (10 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give methyl 3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (7). TLC system: 10% MeOH / DCM R f :0.2 LCMS(ESI):m / z 420.35(M+Na+H) +

[0336] Methyl 3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-2-aminopropanoic acid hydrochloride (8) To a stirred solution of methyl 3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-2-((tert-butoxycarbonyl)amino)propanoate (7) (80 mg, 0.2 mmol) in dioxane (2 mL) was added 4 M HCl in dioxane (2 mL) 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. The crude residue was triturated with n-pentane to give methyl 3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-2-aminopropanoate hydrochloride (8). TLC system: 15% MeOH / DCM R f :0.1

[0337] Methyl 3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)propanoate (9) To a stirred solution of (S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanoic acid (acid fragment) (54 mg, 0.16 mmol) in DMF (5 mL), EDC.HCl (42 mg, 0.22 mmol), HOBT (30 mg, 0.22 mmol), DIPEA (0.1 mL, 0.44 mmol), and methyl 3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-2-aminopropanoic acid hydrochloride (8) (50 mg, 0.14 mmol) were added simultaneously and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 h, the reaction mixture was quenched with ice-water (20 mL), extracted with ethyl acetate (2 × 30 mL), and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude residue was purified on a silica gel column by eluting with 50% ethyl acetate in petroleum ether to give methyl 3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)propanoate (9). TLC system: 5% methanol in DCM.f :0.6 LCMS(ESI):m / z 619.57(M+H) +

[0338] 3-Chlorobenzyl ((2S)-1-((1-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-3-hydroxypropan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (10) To a stirred solution of methyl 3-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-2-((S)-2-((((3-chlorobenzyl)oxy)carbonyl)amino)-3-cyclohexylpropanamido)propanoate (9) (90 mg, 0.14 mmol) in DCM (10 mL) was added 2 M LiBH in THF (0.2 mL, 0.24 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by TLC and LCMS. After 2 h, the reaction mixture was quenched with water (20 mL) and extracted with DCM (2 × 30 mL). The organic layer was washed with brine solution (30 mL) and the combined organic layers were dried over NaSO and concentrated to give 3-chlorobenzyl ((2S)-1-((1-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-3-hydroxypropan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (10). TLC system: 5% MeOH in DCM. f 0.3 LCMS(ESI):m / z 591.43(M+H) +

[0339] 3-Chlorobenzyl ((2S)-1-((1-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-3-oxopropan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C32) To a stirred solution of 3-chlorobenzyl ((2S)-1-((1-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-3-hydroxypropan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (10) (80 mg, 0.13 mmol) in ethyl acetate (5 mL) was added Dess-Martin periodinane (230 mg, 0.54 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 (10 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 NaSO, filtered, and concentrated to give the crude product. It was purified by preparative HPLC to give 3-chlorobenzyl ((2S)-1-((1-(8-acetyl-2-oxo-1,8-diazaspiro[4.5]decan-3-yl)-3-oxopropan-2-yl)amino)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (compound C32). TLC system: 5% methanol in DCM R f :0.4 LCMS(ESI):m / z 589.46(M+H) +

[0340] Example 34: Synthesis of Compounds C51 and C34 [ka] tert-Butyl (S)-4-(((1-methoxy-4-methyl-1-oxopentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (3) To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1) (10 g, 49.67 mmol) in ACN (80 mL) was added N,N'-disuccinamidyl carbonate (19.7 g, 74.51 mmol), followed by triethylamine (20.9 mL, 149.1 mmol) at 0°C and stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. The reaction mass was used directly in the next reaction.

[0341] In a separate RB flask, methyl L-leucinate hydrochloride (2) (13.5 g, 74.58 mmol) was taken up in ACN (50 mL) and treated with triethylamine (20.9 mL, 149.1 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. After 16 hours, the reaction mixture was quenched with ice-water (150 mL), extracted with ethyl acetate (2 × 150 mL), and the combined organic layers were washed with brine solution (100 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give tert-butyl (S)-4-(((1-methoxy-4-methyl-1-oxopentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (3). TLC system: 30% ethyl acetate in petroleum ether, Rf: 0.5 LCMS (ESI): m / z 395.29 [M+Na] -

[0342] (((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)carbonyl)-L-leucine (4) To a stirred solution of tert-butyl (S)-4-(((1-methoxy-4-methyl-1-oxopentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (3) (3.5 g, 9.40 mmol) in THF (20 mL), water (5 mL), lithium hydroxide (1.18 g, 28.2 mmol) was added at room temperature and stirred at room temperature for 3 hours. The reaction progress was monitored by TLC and LCMS. The reaction mixture was distilled completely under reduced pressure, and the crude compound was acidified to pH 3 with 1N aqueous HCl, extracted with ethyl acetate (2×50 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)carbonyl)-L-leucine (4). TLC system: 10% methanol in dichloromethane Rf: 0.1 LCMS (ESI): m / z = 381.53 [M+Na] +

[0343] tert-Butyl 4-((((S)-1-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (5) To a stirred solution of (((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)carbonyl)-L-leucine (4) (2.0 g, 5.58 mmol) in DMF (20 mL), EDC.HCl (1.6 g, 8.37 mmol), HOBT (1.13 g, 8.37 mmol), DIPEA (2.8 mL, 16.75 mmol), and methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid hydrochloride (amine fragment-2) (1.2 g, 6.70 mmol) were added simultaneously at 0° C. and stirred at room temperature for 16 h. The reaction progress was monitored by TLC and LCMS. After 16 hours, the reaction mixture was quenched with ice water (100 mL), extracted with ethyl acetate (2 x 50 mL), and the combined organic layers were washed with brine solution (50 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography eluting with 5% methanol in dichloromethane to give tert-butyl 4-((((S)-1-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (5). TLC system: 10% methanol in DCM R f :0.4 LCMS(ESI):m / z 527.74[M+H] +

[0344] tert-Butyl 4-((((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (6) To a stirred solution of tert-butyl 4-((((S)-1-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (5) (620 mg, 1.17 mmol) in DCM (10 mL) was added 2 M LiBH in THF (1.2 mL, 2.35 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 and LCMS. The reaction mixture was then quenched with saturated NH Cl solution (30 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layer was washed with brine solution (30 mL), dried over Na SO and concentrated to give the crude compound. It was purified by SFC preparative purification to give pure tert-butyl 4-((((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (6). TLC system: 10% methanol in DCM R f :0.2 LCMS(ESI):m / z 499.70[M+H] +

[0345] tert-Butyl 4-((((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl))propan-2-yl)amino)pentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (Compound C34) To a stirred solution of tert-butyl 4-((((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (6) (100 mg, 0.20 mmol) dissolved in dichloromethane (3 mL) was added Dess-Martin periodinane (255 mg, 0.60 mmol) at 0° C. and stirred at room temperature for 3 h. The reaction mixture was diluted with dichloromethane (10 mL), washed with saturated Hypo solution (3×15 mL), and diluted with saturated NaHCO solution (3×15 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which residue was purified by preparative HPLC chromatography to give tert-butyl 4-((((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (compound C34). TLC system: 10% methanol in DCM Rf: 0.3 LCMS (ESI): m / z 497.44 (M+H) +

[0346] (2S)-2-((S)-2-((((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonate (compound C51) To a stirred solution of tert-butyl 4-((((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)carbamoyl)oxy)piperidine-1-carboxylate (compound C34) (90 mg, 0.18 mmol) in ethanol (2 mL), EtOAc (1 mL), water (1 mL) was added NaHSO (38 mg, 0.36 mmol) at room temperature and heated to 50° C. for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After 16 hours, the reaction mixture was cooled to room temperature and filtered through a pad of Celite, which was then washed with ethanol (5 mL). The filtrate was evaporated under reduced pressure to give a crude residue. The residue was triturated with diethyl ether (2 x 5 mL), EtOAc (2 x 5 mL), the solvent was decanted, and the solid was thoroughly dried to give (2S)-2-((S)-2-((((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)carbonyl)amino)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonate (compound C51). TLC system: 10% methanol in DCM R f :0.1 LCMS(ESI): m / z 577.2[MH]- M=free base

[0347] Example 35: Synthesis of Compounds C37 and C40 [ka] tert-Butyl 4-(benzylamino)piperidine-1-carboxylate (3) To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (1) (3 g, 15.0753 mmol) and phenylmethanamine (2) (2.2 mL, 18.0904 mmol) in methanol (30 mL) was added 8 M borane pyridine complex (2.8 mL, 3.39 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. The reaction mixture was evaporated under reduced pressure to give a crude residue, which was quenched with ice-water (20 mL), extracted with ethyl acetate (2 × 20 mL), and the combined organic layers were washed with brine solution (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give tert-butyl 4-(benzylamino)piperidine-1-carboxylate (3). TLC system: 50% ethyl acetate in hexane, Rf: 0.3 LCMS (ESI): m / z 291.52 [M+H] +

[0348] tert-Butyl (S)-4-(1-benzyl-3-(1-methoxy-4-methyl-1-oxopentan-2-yl)ureido)piperidine-1-carboxylate (2) To a stirred solution of methyl L-leucine hydrochloride (4) (3 g, 13.574 mmol) in 1,4-dioxane (30 mL) was added diphosgene (2.4 mL, 20.361 mmol) at room temperature and heated to reflux for 5 hours. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure to give a crude residue, which was used directly in the next reaction.

[0349] In a separate RB flask, tert-butyl 4-(benzylamino)piperidine-1-carboxylate (3) (3 g, 10.344 mmol) was taken up in ACN (30 mL) and treated with triethylamine (4.47 mL, 31.034 mmol). The resulting reaction mixture was stirred for 5 minutes, then the reaction mass prepared above was added dropwise. The reaction mixture was stirred at room temperature and heated to 80 °C for 16 hours. The reaction mixture was quenched with ice water (20 mL), extracted with ethyl acetate (2 × 20 mL), and the combined organic layers were washed with brine solution (20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by normal phase chromatography to give tert-butyl (S)-4-(1-benzyl-3-(1-methoxy-4-methyl-1-oxopentan-2-yl)ureido)piperidine-1-carboxylate (5). TLC system: 50% ethyl acetate in hexane Rf: 0.5 LCMS (ESI): m / z 484.50 [M+Na] +

[0350] (benzyl(1-(tert-butoxycarbonyl)piperidin-4-yl)carbamoyl)-L-leucine (6) To a stirred solution of tert-butyl (S)-4-(1-benzyl-3-(1-methoxy-4-methyl-1-oxopentan-2-yl)ureido)piperidine-1-carboxylate (5) (3.4 g, 7.375 mmol) in THF (30 mL), water (15 mL), lithium hydroxide (531 mg, 22.125 mmol) was added at room temperature and stirred for 3 hours at room temperature. The reaction progress was monitored by TLC and LCMS. The reaction mixture was distilled completely under reduced pressure, and the crude compound was acidified to pH 3 with 1N aqueous HCl, extracted with ethyl acetate (2×15 mL), dried over sodium sulfate, and concentrated under reduced pressure to give (benzyl(1-(tert-butoxycarbonyl)piperidin-4-yl)carbamoyl)-L-leucine (6). TLC system: 50% ethyl acetate in hexane, Rf: 0.1 LCMS (ESI): m / z 448.39 [M+H] +

[0351] tert-Butyl 4-(1-benzyl-3-((S)-1-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)ureido)piperidine-1-carboxylate (7) To a stirred solution of (benzyl(1-(tert-butoxycarbonyl)piperidin-4-yl)carbamoyl)-L-leucine (6) (2.3 g, 5.145 mmol) in DMF (30 mL), EDC.HCl (1.47 g, 7.718 mmol), HOBt (1.04 g, 7.718 mmol), DIPEA (2.8 mL, 15.436 mmol), and methyl (S)-2-amino-5-(2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)-5-oxopentanoic acid hydrochloride (amine fragment-2) (1.14 g, 6.171 mmol) were added simultaneously at 0 °C and stirred at room temperature for 16 h. The reaction mixture was diluted with ice water (20 mL), extracted with ethyl acetate (2 × 20 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by Combiflash NP compound eluting with 2% methanol in dichloromethane to give tert-butyl 4-(1-benzyl-3-((S)-1-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)ureido)piperidine-1-carboxylate (7). TLC system: 10% methanol in dichloromethane Rf: 0.4 LCMS (ESI): m / z 616.88 [M+H] +

[0352] tert-Butyl 4-(1-benzyl-3-((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl))amino)-4-methyl-1-oxopentan-2-yl)ureido)piperidine-1-carboxylate (8) To a stirred solution of tert-butyl 4-(1-benzyl-3-((S)-1-(((S)-1-methoxy-1-oxo-3-((S)-2-oxopyrrolidin-3)-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)ureido)piperidine-1-carboxylate (7) (1.3 g, 2.524 mmol) in THF (20 mL) was added 2 M LiBH in THF (2.5 mL, 5.048 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 (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with brine solution (30 mL), dried over NaSO, and concentrate...

Claims

1. A compound having the structure of formula (I) below, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 During the ceremony, Z is O or NR 1; Each R Ｎ are independently H or C １－６ is alkyl, R １ But C １－６ Alkylene-C ６－１０ C optionally substituted with aryl ５－８ carbocyclyl, or a 5-8 membered N-heterocycle, wherein the ring nitrogen is COO—C １－６ optionally substituted with alkyl; R ２ But C １－６ Alkylene-C ６－１０ aryl, C １－６ The alkylene is one to three R ７ wherein the aryl is substituted with halo, C １－６ Alkoxy, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkylene-C ６－１０ Aryl, O-C １－６ Alkylene-C ６－１０ Aryl, and CO ２ C １－６ optionally substituted with 1 to 2 substituents independently selected from alkyl; (a) R ３ But C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkylene-C ５－８ Carbocyclyl, C optionally substituted with 1 to 2 halo ０－６ Alkylene-C ６－１０ aryl, or (b) R 3 is methyl, isopropyl, isobutyl, sec-butyl, CH 2 CH 2 SCH 3 , CH 2 -indolyl, benzyl, CH 2 OH, CH(OH)CH 3 , CH 2 SH, CH 2 -(4-OH-phenyl), CH 2 C(O)NH 2 , CH 2 CH 2 C(O)NH 2 , CH 2 COOH, CH 2 CH 2 COOH, CH 2 CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHC(NH)NH 2 , or imidazolyl; Each R ４ However, independently, halo, OH, CN, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkyl-OH, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ Alkoxy, C ３－６ Alkyloxyalkyl, oxo (=O), NR Ａ SO ２ R Ｂ , S.O. ２ NR Ａ R Ｂ , COOR Ａ , C ０－４ Alkylene-C ６－１０ Aryl, C ０－４ alkylene-(5-12 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S), or C ０－４ alkylene-(a 4- to 12-membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), wherein the aryl, heteroaryl, and heterocycle are selected from halo, C １－６ Alkyl, and COO-C １－６ optionally substituted with 1 to 2 substituents independently selected from alkyl; Two R's ４ are combined with the one or more carbons to which they are attached to form a spiro or fused 3- to 12-membered carbocyclic or heterocyclic ring having 1 to 3 ring heteroatoms selected from N, O, and S; halo, C １－６ Alkyl, C １－６ Alkylene -O-C １－６ Alkyl, C(O)-C １－６ Alkyl, SO ２ -C １－６ Alkyl, C(O)-C １－６ Alkyl, and COO-C １－６ optionally substituted with 1 to 2 substituents independently selected from alkyl; R ５ But C １－６ Alkylene-OH, PO(OCH ２ CH ２ ) ２ C substituted with １－６ Alkylene -OH, SO ３ C substituted with H １－６ Alkylene -OH, -[C(O)] １－２ -(4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S), -[C(O)] １－２ -NR Ｎ R Ｎ , C(O)-Y-H, or -[C(O)] １－２ -NR Ｎ -Y-X-A, where A is H, C ３－８ carbocyclyl, a 4- to 12-membered heterocycle having 1 to 3 ring heteroatoms selected from N, O, and S; C ６－１０ aryl, or 5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S, wherein said carbocyclyl, heterocyclyl, aryl, or heteroaryl is selected from halo, C １－６ Alkyl, and COO-C １－６ optionally substituted with 1 to 2 substituents independently selected from alkyl; Y is a bond, C １－６ Alkylene, C １－６ Alkylene -O-C １－６ Alkylene, or C １－６ alkenylene, C １－６ Alkylene and C １－６ Alkenylene may be selected from halo, OH, NR Ｎ R Ｎ , and C １－６ optionally substituted with 1 to 3 substituents independently selected from alkoxy; X is a bond, NR Ｎ R Ｎ , C(O), SO ２ or OC(O), Each R ６ However, independently, H, C １－６ Alkylene-OH, PO(OCH ２ CH ２ ) ２ C substituted with １－６ Alkylene -OH, SO ３ C substituted with H １－６ alkylene-OH, CHO, or C(O)-(a 4-8 membered heterocycle having 1-3 ring heteroatoms selected from N, O, and S); Each R ７ But independently, Halo, C １－６ Haloalkyl, C ２－６ Alkenyl, C ３－５ Carbocyclyl, or C ０－６ Alkylene-C ６－１０ aryl, C ６－１０ aryl is optionally substituted with 1 to 2 halo; Two R on the same or adjacent carbon atoms ７ are combined with one or more carbons to which they are attached to form C ３－６ forming a carbocyclyl ring, R Ａ and R Ｂ are each independently H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl, C ０－６ Alkylene-C ６－１０ Aryl, C ０－６ alkylene-5-8 membered heteroaryl having 1-3 ring heteroatoms selected from N, O, and S; n is 0 to 3; m is 1, A compound or a pharmaceutically acceptable salt thereof, wherein o is 0 to 5.

2. Each R Ｎ The compound or salt thereof according to claim 1, wherein is H.

3. 2. The compound or salt thereof according to claim 1, wherein Z is O.

4. R ２ The compound or salt thereof according to claim 1, wherein is benzyl.

5. R ３ But C １－６ The compound or salt thereof according to claim 1, wherein the aryl group is alkyl.

6. R ３ but, 【Chemistry 2】 The compound or salt thereof according to claim 5, wherein:

7. R ３ But C １－６ Alkylene-C ５－８ Carbocyclyl, C ２－６ Alkenyl, C ２－６ Alkynyl, or C0-6 alkylene-C ６－１０ The compound or salt thereof according to claim 1, wherein the compound is aryl.

8. The compound or salt thereof according to claim 1, wherein R 3 is methyl, isopropyl, isobutyl, sec-butyl, CH 2 CH 2 SCH 3 , CH 2 -indolyl, benzyl, CH 2 OH, CH(OH)CH 3 , CH 2 SH, CH 2 -(4-OH-phenyl), CH 2 C(O)NH 2 , CH 2 CH 2 C(O)NH 2 , CH 2 COOH, CH 2 CH 2 COOH, CH 2 CH 2 CH 2 CH 2 NH 2 , CH 2 CH 2 CH 2 NHC(NH)NH 2 , or imidazolyl.

9. The compound or salt thereof according to claim 1, wherein n is 0.

10. R ２ But C １－６ Alkylene-C ６－１０ aryl, C １－６ The alkylene is one to three R ７ 2. The compound of claim 1, or a salt thereof, substituted with:

11. C １－６ Alkylene is a group consisting of three R ７ 11. The compound or salt thereof according to claim 10, substituted with:

12. At least one R ７ is unsubstituted or substituted with 1 to 2 halo groups; ０－６ Alkylene-C ６－１０ The compound or salt thereof according to claim 10, wherein the compound is aryl.

13. The compound or salt thereof according to claim 1, wherein o is 1 or 2.

14. Each R ６ The compound or salt thereof according to claim 13, wherein is H.

15. R ５ is C(O)-C(O)NR Ｎ The compound or salt thereof according to claim 1, wherein the compound is -Y-X-A.

16. 16. The compound or salt thereof according to claim 15, wherein X is a bond.

17. The compound or salt thereof according to claim 1, which is a compound having the structure shown in Table C or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition for treating or preventing a viral infection, comprising the compound according to any one of claims 1 to 17 or a salt thereof.

19. 19. The pharmaceutical composition of claim 18, wherein the viral infection is a coronavirus infection, a calicivirus infection, or a picornavirus infection.

20. 20. The pharmaceutical composition of claim 19, wherein the calicivirus infection is a norovirus infection.

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