SARS-COV-2 Mpro inhibitor compound

Abstract

The invention described herein relates to a compound of formula (1b): JPEG2024511881000068.jpg64100 or a salt thereof, 1 , R 1a , R 2 , R 3 and R 5 are defined herein and relate to SARS-CoV-2 and related viruses and their use in the treatment of disorders associated with SARS-CoV-2.

Description

[Technical field]

[0001] This application relates to novel compounds and their use as inhibitors of the main protease (Mpro) of SARS-CoV-2. The compounds described herein are useful in the treatment of disorders associated with SARS-CoV-2 and related viruses and SARS-CoV-2:Mpro. This application is also directed to pharmaceutical compositions comprising these compounds and the manufacture and use of these compounds and compositions in the treatment of disorders associated with SARS-CoV-2 and related viruses and SARS-CoV-2:Mpro. The compounds and compositions can help prevent death or complications arising due to chronic underlying or comorbid conditions in patients infected with SARS-CoV-2 and related viruses. [Background technology]

[0002] Coronaviruses have long existed in nature and have been known to infect humans as zoonotic diseases. However, in the last two decades, the emergence of novel human coronavirus infections causing severe respiratory disease has become a major global health concern. These include severe acute respiratory syndrome coronavirus (SARS-CoV) from 2002 to 2004, Middle East respiratory syndrome coronavirus (MERS-CoV) from 2012 to 2015, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the most recently emerged strain of coronavirus identified in Wuhan, China in 2019, and the etiological agent of the coronavirus disease 2019 (COVID-19) viral pneumonia that occurred in 2019–2020. Despite the tragic and widespread impact of such outbreaks and the increasing likelihood of future outbreaks due to the periodic emergence of novel human coronaviruses, there are still no effective antiviral treatments targeting coronavirus infections.

[0003] SARS-CoV-2 has a large RNA genome of ~30 kb, two-thirds of which encodes two polyproteins, pp1a and pp1b (Hegyi et al.: 595-99). These polyproteins are processed into 16 nonstructural proteins (nsps) and released from the long polypeptide chain by two viral cysteine ​​proteases, papain-like protease (nsp3) and 3C-like protease (nsp5). The latter, also called main protease (Mpro), cleaves the viral polyprotein at 11 sites to generate 12 nonstructural proteins (nsp5-16). Among these nsps are those involved in the replication and transcription machinery, such as RNA-dependent RNA polymerase (nsp12) and helicase (nsp13). The critical role that Mpro plays in viral replication has been demonstrated by mutagenesis experiments (Kim et al., Virology 208(1):1-8; Stobart et al., Journal of Virology 86(9):4801-10), making it an attractive target for designing inhibitors to treat coronavirus infections. Furthermore, since there are no human proteases with similar cleavage specificity, selective inhibitors of Mpro are likely to be non-toxic (Anand et al., Science 300(5626):1763-67).

[0004] There is precedent for the use of protease inhibitors in the treatment of viral diseases (Bacon et al., The New England Journal of Medicine 364(13):1207-17), and because the active site of SARS-CoV-2 Mpro is similar to other viral proteases, efforts are ongoing to identify clinically approved drugs that can be repurposed to treat COVID-19 (Riva et al., Nature,586:113-119). A screen of 18 viral protease inhibitors designed to treat human immunodeficiency virus (HIV) and hepatitis C virus (HCV) identified the anti-HCV drug boceprevir and the preclinical inhibitor GC376 against feline infectious peritonitis virus (FIPV) as inhibitors of SARS-CoV-2 Mpro (Fu et al., Nature Communications 11(1): 4417). GC376 showed a more potent inhibitory effect on recombinant protease activity (IC50=0.15 μM) than boceprevir (IC50=8 μM), but GC376 showed side effects in studies conducted in cats, raising potential safety concerns (Pedersen et al., Journal of Feline Medicine and Surgery 20(4):378-92). Boceprevir was also identified as an inhibitor of SARS-CoV-2 Mpro alongside telaprevir in a separate study, although both drugs inhibited SARS-CoV-2 Mpro with IC50 values ​​above 1 μM (Anson et al., 2020.doi:10.21203 / rs.3.rs-26344 / v1). In addition to SARS-CoV-2 Mpro, the inhibitory effects of boceprevir and telaprevir against Mpro proteases of eight other coronaviruses, including SARS, MERS, HKU1, HKU4, HKU5, NL63, FIPV, and IBV, were also evaluated. Boceprevir inhibited the proteases of all coronaviruses except NL63, and telaprevir similarly showed inhibitory activity against SARS, HKU4, HKU5, NL63, and IBV, demonstrating a broad spectrum of activity.Although the antiviral activity of these agents against SARS-CoV-2 Mpro is not sufficient for clinical development, their ability to inhibit a wide range of proteases highlights the possibility of designing broad-spectrum antivirals that can treat not only SARS-CoV-2 infections but also other human coronaviruses and potential future novel coronaviruses.

[0005] The sequence similarity of the Mpro active site between SARS-CoV and SARS-CoV-2 was also exploited in the identification of the SARS-CoV-2 Mpro inhibitor PF-07304814, a phosphate prodrug of PF 00835231 originally designed for the treatment of SARS-CoV (Boras et al., BioRxiv, 2020.09.12.293498). PF00835231 inhibited SARS-CoV-2 Mpro with a Ki value of 0.27 nM and further demonstrated broad inhibitory activity against 10 coronavirus strains with Ki values ​​of 0.03–4 nM. This corresponded to an activity of ~1 μM in cell-based live virus assays. The activity of PF-00835231 in combination with the nucleoside RNA-dependent RNA polymerase inhibitor remdesivir was also evaluated. Indeed, PF-00835231 and remdesivir showed synergistic or additive effects in cell-based antiviral assays, suggesting that combinations of Mpro inhibitors with antivirals with other mechanisms of action may be of clinical utility.

[0006] In 2020, the crystal structure of SARS-CoV-2 Mpro in complex with N3 (a Michael receptor inhibitor) was published (Jin et al.: 289-93), enabling virtual screening and structure-based drug design (SBDD) of inhibitors of SARS-CoV-2 Mpro. Such SBDD efforts included the design of peptidomimetic α-ketoamides as broad-spectrum inhibitors of coronaviruses and enteric viruses, with the two most promising inhibitors exhibiting IC50 values ​​of 0.71-12.27 μM in recombinant inhibition assays against the proteases of enteric viruses EV-A71 and CVB3, and coronaviruses SARS-CoV and NL63 (Zhang et al., Journal of Medicinal Chemistry 63(9): 4562-4578). The activity observed in the recombinant protease assays was largely consistent with the antiviral activity in cell-based live virus assays, with IC50 values ​​within 10-fold in both systems. This suggests that good activity in the protease inhibition assay is a good indicator of antiviral activity.

[0007] Currently, there are no targeted therapeutics for the treatment of COVID-19, and effective treatment options are very limited. Despite much ongoing research activity and numerous clinical trials, only remdesivir and favipiravir have been approved in some countries for the treatment of SARS-CoV-2 infections, but their efficacy is modest (Zhou et al., ACS Pharmacology & Translational Science 3(5):813-834). There is a need for targeted therapeutics for the treatment of SARS-CoV-2 infections, and for the above reasons, SARS-CoV-2 Mpro is an attractive drug target for SARS-CoV-2. The compounds disclosed herein have been shown to be inhibitors of SARS-CoV-2 Mpro, and thus are potential candidates for the treatment of coronavirus infections and related disorders, including but not limited to COVID-19. Summary of the Invention

[0008] The present invention provides compounds that have activity as SARS-CoV-2:Mpro inhibitors.

[0009] The present invention relates to a compound represented by formula (1b): [ka] or a salt thereof, R 1 and R 1a are independently H, C optionally substituted with 1 to 6 fluorine or chlorine atoms, 1-6 a saturated hydrocarbon group or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms, or 1 and R 1a are joined to form a saturated ring optionally containing additional heteroatoms; R 2 C includes a cycloalkyl group optionally substituted with one or more substituents selected from fluorine or hydroxyl. 3-5 is a saturated hydrocarbon group; R 3 is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group, or optionally containing a saturated ring containing an oxygen heteroatom, optionally substituted with one or more substituents selected from fluorine or hydroxyl, or 3 is CH2aryl, CH(CH3)aryl or C(CH3)2aryl; R 5 is C 2-8 It is a hydrocarbon group, optionally containing one or more rings or double bonds, and is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0010] The compounds of the present invention can be used as SARS-CoV-2:Mpro inhibitors. The compounds of the present invention can be used to treat SARS-CoV-2 and related viruses or diseases or disorders associated with SARS-CoV-2. The compounds of the present invention can help prevent death or complications arising from chronic underlying diseases or comorbidities in patients infected with SARS-CoV-2 and related viruses. Such chronic underlying diseases or comorbidities can include, for example, hypertension, obesity, chronic lung disease (TB, asthma and cystic fibrosis), diabetes and cardiovascular disease (coronary heart disease, congenital heart disease and heart failure). The compounds of the present invention can be used to manufacture medicaments. The compounds or medicaments of the present invention can be used to treat, prevent, ameliorate, control or reduce the risk of diseases or disorders involving SARS-CoV-2 and related viruses and SARS-CoV-2:Mpro. The compounds or medicaments can be used to treat, prevent, ameliorate, control or reduce the risk of chronic underlying diseases or comorbidities in patients infected with SARS-CoV-2 and related viruses.

[0011] The compounds of the invention can be used as single agents or in combination with one or more additional pharmaceutical agents. The compounds of the invention can be useful in the treatment of SARS-CoV-2 and related viruses or symptoms associated therewith. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Detailed Description of the Invention The present invention relates to novel compounds. The present invention also relates to the use of the novel compounds as inhibitors of SARS-CoV-2:Mpro. The present invention further relates to the use of the novel compounds in the manufacture of a medicament for use as a SARS-CoV-2:Mpro inhibitor. The present invention further relates to compounds, compositions and medicaments that can be useful in the treatment of SARS-CoV-2 and related viruses or symptoms or indications associated therewith.

[0013] The present invention relates to a compound represented by formula (1b): [ka] or a salt thereof, R 1 and R 1a are independently H, C optionally substituted with 1 to 6 fluorine or chlorine atoms, 1-6 a saturated hydrocarbon group or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms, or 1 and R 1a are joined to form a saturated ring optionally containing additional heteroatoms; R 2 C includes a cycloalkyl group optionally substituted with one or more substituents selected from fluorine or hydroxyl. 3-5 is a saturated hydrocarbon group; R 3 is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group, or optionally containing a saturated ring containing an oxygen heteroatom, optionally substituted with one or more substituents selected from fluorine or hydroxyl, or 3 is CH2aryl, CH(CH3)aryl or C(CH3)2aryl; R 5 is C 2-8 It is a hydrocarbon group, optionally containing one or more rings or double bonds, and is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0014] Furthermore, formula (1a): [ka] or a salt thereof; The Q is CN or a group of the formula: [ka] Based on R 1 and R1a are independently H, C optionally substituted with 1 to 6 fluorine or chlorine atoms, 1-6 a saturated hydrocarbon group or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms, or 1 and R 1a are joined to form a saturated ring optionally containing additional heteroatoms; R 2 C includes a cycloalkyl group optionally substituted with one or more substituents selected from fluorine or hydroxyl. 3-5 A saturated hydrocarbon group or the R 2 is a saturated ring containing an oxygen heteroatom optionally substituted with one or more substituents selected from fluorine, methyl or hydroxyl; R 3 is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group, or optionally containing a saturated ring containing an oxygen heteroatom, optionally substituted with one or more substituents selected from fluorine or hydroxyl, or 3 is CH2aryl, CH(CH3)aryl or C(CH3)2aryl; and R 4 is H or CO-R 5 and R 5 is C 2-8 It is a hydrocarbon group, optionally containing one or more rings or double bonds, and is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0015] Furthermore, equation (1): [ka] or a salt thereof; R 1 and R 1a are independently H, C optionally substituted with 1 to 6 fluorine or chlorine atoms, 1-6a saturated hydrocarbon group or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms, or 1 and R 1a are joined to form a saturated ring optionally containing additional heteroatoms; R 2 C includes a cycloalkyl group optionally substituted with one or more substituents selected from fluorine or hydroxyl. 3-5 A saturated hydrocarbon group or the R 2 is a saturated ring containing an oxygen heteroatom optionally substituted with one or more substituents selected from fluorine, methyl or hydroxyl; R 3 is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group, or optionally containing a saturated ring containing an oxygen heteroatom, optionally substituted with one or more substituents selected from fluorine or hydroxyl, or 3 is CH2aryl, CH(CH3)aryl or C(CH3)2aryl; and R 4 is H or CO-R 5 and R 5 is C 2-8 It is a hydrocarbon group, optionally containing one or more rings or double bonds, and is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0016] What is provided is formula (2): [ka] or a salt thereof; R 1 is H, C optionally substituted with 1 to 6 fluorine or chlorine atoms 1-6 a saturated hydrocarbon group or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms; R 2C includes a cycloalkyl group optionally substituted with one or more substituents selected from fluorine or hydroxyl. 3-5 A saturated hydrocarbon group or the R 2 is a saturated ring containing an oxygen heteroatom optionally substituted with one or more substituents selected from fluorine, methyl or hydroxyl; R 3 is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group, or optionally containing a saturated ring containing an oxygen heteroatom, optionally substituted with one or more substituents selected from fluorine or hydroxyl, or 3 is CH2aryl, CH(CH3)aryl or C(CH3)2aryl; R 5 is C 2-8 It is a hydrocarbon group, optionally containing one or more rings or double bonds, and is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0017] What is provided is formula (2): [ka] or a salt thereof; R 1 is H, C optionally substituted with 1 to 6 fluorine or chlorine atoms 1-6 a saturated hydrocarbon group or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms; R 2 is a C containing cycloalkyl group. 3-5 is a saturated hydrocarbon group; R 3 is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group or a saturated ring optionally containing an oxygen heteroatom; R 4 is C 2-8It is a hydrocarbon group, optionally substituted with 1 to 6 fluorine or chlorine atoms, and optionally containing one or more rings or double bonds.

[0018] What is provided is formula (3): [ka] or a salt thereof; R 1 and R 1a are independently H, C optionally substituted with 1 to 6 fluorine or chlorine atoms, 1-6 a saturated hydrocarbon group or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms, or 1 and R 1a are joined to form a saturated ring optionally containing additional heteroatoms; R 2 C includes a cycloalkyl group optionally substituted with one or more substituents selected from fluorine or hydroxyl. 3-5 A saturated hydrocarbon group or the R 2 is a saturated ring containing an oxygen heteroatom optionally substituted with one or more substituents selected from fluorine, methyl or hydroxyl; R 3 is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group, or optionally containing a saturated ring containing an oxygen heteroatom, optionally substituted with one or more substituents selected from fluorine or hydroxyl, or 3 is CH2aryl, CH(CH3)aryl or C(CH3)2aryl; and R 4 is H or CO-R 5 and R 5 is C 2-8 It is a hydrocarbon group, optionally containing one or more rings or double bonds, and is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0019] Provided is a compound of formula (2b): [ka] or a salt thereof; R 1 is H, C optionally substituted with 1 to 6 fluorine or chlorine atoms 1-6 a saturated hydrocarbon group or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms; R 2 C includes a cycloalkyl group optionally substituted with one or more substituents selected from fluorine or hydroxyl. 3-5 A saturated hydrocarbon group or the R 2 is a saturated ring containing an oxygen heteroatom optionally substituted with one or more substituents selected from fluorine, methyl or hydroxyl; R 3 is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group, or optionally containing a saturated ring containing an oxygen heteroatom, optionally substituted with one or more substituents selected from fluorine or hydroxyl, or 3 is CH2aryl, CH(CH3)aryl or C(CH3)2aryl; and R 5 is C 2-8 It is a hydrocarbon group, optionally substituted with 1 to 6 fluorine or chlorine atoms, optionally containing one or more rings or double bonds, and optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or with a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0020] Provided is a compound of formula (2b): [ka] or a salt thereof; R 1 is H, C optionally substituted with 1 to 6 fluorine or chlorine atoms 1-6a saturated hydrocarbon group or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms; R 2 is a C containing cycloalkyl group. 3-5 is a saturated hydrocarbon group; R 3 is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group or a saturated ring optionally containing an oxygen heteroatom; R 5 is C 2-8 It is a hydrocarbon group, optionally substituted with 1 to 6 fluorine or chlorine atoms, and optionally containing one or more rings or double bonds.

[0021] In the compounds herein, Q can be CN. Q has the formula: [ka] It can be a group of the formula:

[0022] Q: [ka] may be selected from the group consisting of:

[0023] In the compounds herein, R 1a can be H. R 1a is C optionally substituted with 1 to 6 fluorine or chlorine atoms 1-6 R may be a saturated hydrocarbon group. 1a R can be methyl. 1a R can be cyclopropyl. 1a R may be a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms. 1a may be selected from the group consisting of -CH2-cyclopropyl, -CH2-chlorophenyl, -CH2-phenyl, methylcyclopropyl, 1,1-dimethylcyclopropyl, 1,2-dimethylcyclopropyl, difluorocyclopropyl.

[0024] In the compounds herein, R1 can be H. R 1 is C optionally substituted with 1 to 6 fluorine or chlorine atoms 1-6 R may be a saturated hydrocarbon group. 1 R can be methyl. 1 R can be cyclopropyl. 1 R may be a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms. 1 may be selected from the group consisting of -CH2-cyclopropyl, -CH2-chlorophenyl, -CH2-phenyl, methylcyclopropyl, 1,1-dimethylcyclopropyl, 1,2-dimethylcyclopropyl, difluorocyclopropyl.

[0025] R 1 below: [ka] may be selected from the group consisting of:

[0026] R 1 is H, CH3, benzyl, cyclopropyl or [ka] It could be.

[0027] R 1a R may be selected from the group consisting of H and methyl. 1a can be H. R 1 and R 1a Both can be H. 1 and R 1a may both be -CH3.

[0028] R 1 and R 1a can be linked to form a saturated ring, optionally containing additional heteroatoms. The ring can contain 3 to 6 atoms. The heteroatom can be O or N. The ring can be an alkyl chain (CH2)n, where n is 2 to 5. n can be 2, 3, 4 or 5. R 1 and R1a can be bonded to form a 3- to 6-membered ring. 1 and R 1a can be linked to form an aziridine ring, an azetidine ring, a pyrrolidine ring, a piperidine ring, or a morpholine ring. 1 and R 1a may be bonded to form an azetidine ring. 1 and R 1a may be linked to form an azetidine or aziridine ring.

[0029] In the compounds herein, R 2 C includes a cycloalkyl group optionally substituted with one or more substituents selected from fluorine or hydroxyl. 3-5 may be a saturated hydrocarbon group, or R 2 R may be a saturated ring containing an oxygen heteroatom optionally substituted with one or more substituents selected from fluorine, methyl, or hydroxyl. 2 C includes a cycloalkyl group optionally substituted with one or more substituents selected from fluorine or hydroxyl. 3-5 R may be a saturated hydrocarbon group. 2 is a C containing cycloalkyl group. 3-5 R may be a saturated hydrocarbon group. 2 R may be a saturated ring containing an oxygen heteroatom. The ring may contain 3 to 6 atoms, one of which is O. The ring may be optionally substituted with one or more substituents selected from fluorine, methyl or hydroxyl groups. 2 may be selected from the group consisting of cyclobutyl, cyclopropyl, methylcyclopropyl.

[0030] R 2 below: [ka] may be selected from the group consisting of:

[0031] R 2 below: [ka] may be selected from the group consisting of:

[0032] R2: [ka] It could be.

[0033] In the compounds herein, R 3 is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group, or optionally containing a saturated ring containing an oxygen heteroatom, which may be optionally substituted with one or more substituents selected from fluorine or hydroxyl, or R 3 R can be CHaryl, CH(CH)aryl, or C(CH)aryl. 3 R is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group or optionally containing a saturated ring containing an oxygen heteroatom, and may be optionally substituted with one or more substituents selected from fluorine or hydroxyl. 3 R is a saturated group, contains 3 to 5 carbon atoms, and may contain a cycloalkyl group. 3 R may be a saturated group, including a saturated ring containing an oxygen heteroatom. The ring may contain 3 to 6 atoms, one of which is O. The ring may contain one or more substituents selected from fluorine, methyl groups, or hydroxyl groups. 3 R can be CHaryl, CH(CH)aryl or C(CH)aryl. The aryl group can be phenyl. 3 may be selected from the group consisting of -CH2-cyclopropyl, -CH(CH3)2, -C(CH3)3, cyclopropyl, oxolane, oxetane, -CH(CH3)CH2CH3, cyclobutyl, C(CH3)2Ph, CH2Ph.

[0034] R 3 below: [ka] may be selected from the group consisting of:

[0035] In the compounds herein, R 4 can be H or CO-R5, 5 is C 2-8 It is a hydrocarbon group, optionally containing one or more rings or double bonds, and is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.

[0036] In the compounds herein, R 5 is C 2-8 R is a hydrocarbon group, optionally substituted with 1 to 6 fluorine or chlorine atoms, which may optionally contain one or more rings or double bonds, and which is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl group, heterocycloalkyl group, aryl group, or heteroaryl group. 5 is C 2-8 R is a hydrocarbon group, which may optionally contain one or more rings or double bonds. 5 may be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, ethyl, -CH(CH3)2, -CH2(CH3)2-CH(CH3)CH2CH3, -CH2CF3, CH(CF3)2, methylcyclopropyl, vinyl (-CH=CH2), bicyclo(1,1,1)pentane, and cubane.

[0037] R 5 below: [ka] may be selected from the group consisting of:

[0038] R 5 below: [ka] may be selected from the group consisting of:

[0039] What is provided is formula (1): [ka] or a salt thereof; R 1a is H or methyl; R 1 is H, methyl, benzyl or cyclopropyl; Or the above R 1 and R 1a combine to form a saturated ring of 3 to 6 atoms; R 2 below: [ka] Selected from the group consisting of: R 3 below: [ka] is selected from the group consisting of: R 4 CO-R 5 and R 5 below: [ka] is selected from the group consisting of:

[0040] The compound has the formula (1a), (1b), (1) or (1i): [ka] or a salt thereof, 1 , R 1a , R 2 , R 3 , R 4 and R 5 is as defined herein.

[0041] The compound has formula (2), (2a), (2i), (2b), (2ba) or (2bi): [ka] or a salt thereof, 1 , R 1a , R 2 , R 3 and R 5 is as defined herein.

[0042] The compound has the formula (3), (3a), (3b) or (3i): [ka] or a salt thereof, 1 , R 1a , R 2 , R 3 , R 4 and R 5 is as defined herein.

[0043] The compound may be selected from any one of Examples 1 to 35 shown in Table 1, or an isomer or salt thereof.

[0044] The compounds are as follows: (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxo-propyl]-3-[(2S)-2-(cyclopropanecarbonylamino)-3-methylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-alloisoleucyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-(acryloyl-L-valyl)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-((1R,2S)-2-methylcyclopropyl)-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3-cyclopropyl-2-isobutyramidopropanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-(((S)-2-methylbutanoyl)-L-valyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-(cyclopropanecarboxamido)-2-cyclopropylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-cyclopropyl-2-isobutyramidoacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(benzylamino)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(2-isobutyramido-2-(oxetan-3-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-(cyclopropanecarboxamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-((S)-2-acrylamido-3,3-dimethylbutanoyl)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-((S)-2-acrylamido-3,3-dimethylbutanoyl)-N-(4-(benzylamino)-1-cyclopropyl-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(benzylamino)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(benzylamino)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-(cyclopropanecarboxamido)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-((S)-2-(cyclopropanecarboxamido)-3,3-dimethylbutanoyl)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-((S)-2-acrylamido-3,3-dimethylbutanoyl)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(1-cyclopropyl-4-(methylamino)-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(1-cyclopropyl-4-(dimethylamino)-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(aziridin-1-yl)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-cyclobutyl-2-isobutyramidoacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3-methyl-3-phenylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-((cyclopropanecarbonyl)-L-valyl)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(2-isobutyramido-2-(tetrahydrofuran-3-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(1-cyclopropyl-4-(((S)-2,2-dimethylcyclopropyl)amino)-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-phenylalanyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(3,3,3-trifluoro-2-(trifluoromethyl)propanamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; or a salt thereof, may be selected from the group consisting of:

[0045] Further embodiments include the use of the compounds of the present invention or salts thereof or pharmaceutical compositions comprising the compounds of the present invention as SARS-CoV-2:Mpro inhibitors. The compounds of the present invention can be used as SARS-CoV-2:Mpro inhibitors. The compounds of the present invention can be used to treat SARS-CoV-2 or diseases or disorders associated with SARS-CoV-2. The compounds of the present invention can help prevent death or complications arising due to chronic underlying diseases or comorbidities in patients infected with SARS-CoV-2. Such chronic underlying diseases or comorbidities can include, for example, hypertension, obesity, chronic lung disease (TB, asthma and cystic fibrosis), diabetes and cardiovascular disease (coronary heart disease, congenital heart disease and heart failure). The compounds of the present invention can be used for the manufacture of medicaments. The compounds or medicaments of the present invention can be used for the treatment, prevention, amelioration, control or reduction of risk of diseases or disorders involving SARS-CoV-2 and SARS-CoV-2:Mpro. The compounds or agents can be used to treat, prevent, ameliorate, control or reduce the risk of chronic underlying or co-morbid conditions in patients infected with SARS-CoV-2.

[0046] The compounds of the invention can be used as single agents or in combination with one or more additional pharmaceutical agents. The compounds of the invention can be useful in the treatment of SARS-CoV-2 or symptoms or indications associated therewith.

[0047] As provided herein, the compounds described herein or their salts and the compositions described herein can be administered with an agent for treating any of the diseases and disorders disclosed herein.

[0048] The compounds of the present invention can be presented in the form of prodrugs. By "prodrug" is meant, for example, any compound that is converted in vivo to the biologically active compound of the present invention. For example, some prodrugs are esters or phosphate esters (e.g., physiologically acceptable metabolically labile esters) of the active compound. During metabolism, the ester group (-C(=O)OR) or phosphate ester group (P(=O)(OH)2-OR) is cleaved to give the active drug. Such esters can be formed, for example, by esterifying a hydroxyl group present in the parent compound and, if appropriate, prior protecting any other reactive groups present in the parent compound, followed by deprotection, if necessary. Other functional groups present in the active compound, such as amide or amino groups, can be used to form prodrugs. Some prodrugs are also enzymatically activated to give the active compound or a compound that, upon further chemical reaction, gives the active compound (e.g., ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or an amino acid ester derivative.

[0049] As a result, provided are prodrugs of compounds as defined herein, which contain functional groups that are convertible under physiological conditions to form hydroxyl, amide or amino groups.

[0050] definition For the purposes of this application, the following definitions apply unless otherwise indicated.

[0051] As used herein, the term "SARS-CoV-2:Mpro inhibitor" refers to any compound that binds to and modulates the function of SARS-CoV-2:Mpro.

[0052] The term "treatment" in relation to any of the uses of the compounds described herein, including those of formula (1b), is used to refer to any form of intervention in which a compound is administered to a subject suffering from, at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question. Thus, the term "treatment" includes both prophylactic (preventative) treatment and treatment in the event of measurable or detectable symptoms of the disease or disorder.

[0053] The term "therapeutically effective amount" (e.g., in the context of a method for treating a disease or condition) refers to an amount of a compound effective to produce a desired therapeutic effect. For example, when the condition is pain, a therapeutically effective amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief can be, for example, complete elimination of pain or a reduction in the severity of pain.

[0054] Terms such as "benzyl," "bicyclic," "hydrocarbon," "heterocyclic," "carbocyclic," "alkyl," "aryl," "amino," "heteroaryl," "cycloalkyl," and "halo" are all used in their conventional sense (e.g., as defined in the IUPAC Gold Book) unless otherwise indicated. "Optionally substituted," as applied to any group, means that the group may be optionally substituted with one or more substituents, which may be the same or different.

[0055] The term "saturated hydrocarbon group", such as "C1-4 saturated hydrocarbon group", means a hydrocarbon group that does not contain a carbon-carbon double or triple bond. Thus, the saturated hydrocarbon group can be an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkylcycloalkyl group or an alkylcycloalkylalkyl group. Examples of C1-4 saturated hydrocarbon groups include C1-4 alkyl groups, cyclopropyl groups, cyclobutyl groups and cyclopropylmethyl groups.

[0056] As used herein, the term "cycloalkyl," where the specified number of carbon atoms permits, includes both monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, as well as bicyclic and tricyclic groups. Bicyclic cycloalkyl groups include bridged ring systems such as bicycloheptane, bicyclooctane, adamantane, and the like.

[0057] Insofar as any of the compounds described have chiral centers, the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers. The invention described herein relates to all crystal forms, solvates and hydrates of the compounds disclosed. Insofar as any of the compounds disclosed herein have acid or basic centers, such as carboxylates or amino groups, all salt forms of said compounds are included herein. For pharmaceutical applications, the salts should be considered as pharmaceutically acceptable salts.

[0058] The salt or pharma-ceutically acceptable salt that can be mentioned includes acid addition salt and base addition salt.Such salt can be formed by conventional means, for example, by reacting the free acid or free base form of the compound with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing said solvent or said medium using standard techniques (for example, in vacuum, lyophilization or filtration).Salt can also be prepared by exchanging the counterion of the compound in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0059] Examples of pharma- ceutically acceptable salts include acid addition salts derived from mineral and organic acids, as well as salts derived from metals such as sodium, magnesium, potassium and calcium.

[0060] Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+) camphor, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamine, dodecylsulfuric acid, ethane-1,2-disulfone, ethanesulfone, 2-hydroxyethanesulfone, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid, and the like. Acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), L-malic acid, malonic acid, (±)-DL-mandelic acid, mesylate, malonic acid ... Acids that may be used include, for example, thalilic acid, methanesulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., thiocyanic acid, undecylenic acid, and valeric acid.

[0061] Also included are solvates of the compounds and their salts. Preferred solvates are those formed by incorporating molecules of a non-toxic pharma- ceutically acceptable solvent (hereinafter referred to as a solvating solvent) into the solid structure (e.g., crystalline structure) of the compounds of the present invention. Examples of such solvents include water, alcohol (such as ethanol, isopropanol, and butanol) and dimethylsulfoxide. Solvates can be prepared by recrystallizing the compounds of the present invention using a solvent or a mixture of solvents containing a solvating solvent. Whether a solvate is formed can be determined by subjecting the crystals of the compounds to analysis using well-known standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray crystallography.

[0062] Solvates may be stoichiometric or non-stoichiometric solvates. Particular solvates may be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates. For a more detailed discussion of solvates and the methods used to prepare and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0063] The term "pharmaceutical composition" in the context of the present invention means a composition that contains an active agent and further comprises one or more pharma- ceutically acceptable carriers. Depending on the mode of administration and the nature of the dosage form, the composition may further contain components selected from, for example, diluents, adjuvants, excipients, vehicles, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, flavorings, antibacterial agents, antifungal agents, lubricants and dispersing agents. The composition may take the form of, for example, tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, troches, emulsions, solutions, cachets, granules, capsules and suppositories, as well as injectable liquid preparations including liposomal preparations.

[0064] The compounds of the present invention may include one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of that element. For example, a reference to hydrogen includes within its scope 1H, 2H (D), and 3H (T). Similarly, a reference to carbon and oxygen includes within its scope 12C, 13C, and 14C, and 16O and 18O, respectively. In a similar manner, a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, a reference to an alkyl group, such as an ethyl group, or an alkoxy group, such as a methoxy group, also includes variations in which one or more of the hydrogen atoms in the group are in the form of a deuterium or tritium isotope, such as an ethyl group (perdeuteroethyl group) in which all five hydrogen atoms are in the form of a deuterium isotope, or a methoxy group (trideuteromethoxy group) in which all three hydrogen atoms are in the form of a deuterium isotope. Isotopes may be radioactive or non-radioactive.

[0065] Treatment dosages can vary depending on the needs of the patient, the severity of the condition being treated, and the compound being used. Determining the appropriate dosage for a particular situation is within the skill of one of ordinary skill in the art. Generally, treatment is initiated with a dosage that is less than the optimal dosage of the compound. Thereafter, the dosage is gradually increased until the optimum effect is achieved under the circumstances. For convenience, the total daily dosage can be divided and administered during the day.

[0066] The magnitude of the effective dose of the compound will, of course, vary depending on the nature of the severity of the condition to be treated, the particular compound and its route of administration. The selection of the appropriate dose is within the skill of the art without undue burden. In general, the daily dose range can be about 10 μg to about 30 mg per kg of human and non-human animal body weight, preferably about 50 μg to about 30 mg per kg of human and non-human animal body weight, for example about 50 μg to about 10 mg per kg of human and non-human animal body weight, for example about 100 μg to about 30 mg per kg of human and non-human animal body weight, for example about 100 μg to about 10 mg per kg of human and non-human animal body weight, most preferably about 100 μg to about 1 mg per kg of human and non-human animal body weight.

[0067] Pharmaceutical Formulation While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (eg, formulation).

[0068] As a result, in some embodiments of the present invention, there are provided pharmaceutical compositions comprising at least one compound of the present invention, together with at least one pharma- ceutically acceptable excipient.

[0069] The pharma- ceutically acceptable excipients may be selected, for example, from carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and cosolvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g., release retarding or delaying polymers or waxes), binding agents, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, isotonicity agents, thickeners, flavoring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilizers, or other excipients conventionally used in pharmaceutical compositions.

[0070] As used herein, the term "pharmacologically acceptable" means a compound, material, composition, and / or dosage form that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0071] Pharmaceutical compositions containing the compounds of the present invention may be formulated according to known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, U.S.A. The pharmaceutical compositions may be in any form suitable for oral, parenteral, intravenous, intramuscular, intrathecal, subcutaneous, topical, intranasal, intrabronchial, sublingual, buccal, ophthalmic, otic, rectal, vaginal or transdermal administration.

[0072] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, troches, syrups, liquids, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0073] The composition may be a tablet composition or a capsule composition. A tablet composition may contain a unit dosage of the active compound together with an inert diluent or carrier, such as a sugar or sugar alcohol, for example; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent, for example, sodium carbonate, calcium phosphate, calcium carbonate or cellulose or its derivatives, for example, microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropylmethylcellulose and starch, for example, corn starch. Tablets may also contain common ingredients, such as binders and granulating agents, for example, polyvinylpyrrolidone, disintegrants (e.g., swellable cross-linked polymers such as cross-linked carboxymethylcellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers) and effervescent agents, for example, citrate / bicarbonate mixtures. Such excipients are well known and need not be described in detail here.

[0074] Tablets are designed to release the drug on contact with gastric fluids (immediate release tablets) or to release in a controlled manner over an extended period of time or at specific parts of the digestive tract (controlled release tablets).

[0075] A pharmaceutical composition typically comprises about 1% (w / w) to about 95%, preferably % (w / w) of an active ingredient and 99% (w / w) to 5% (w / w) of a pharma- ceutically acceptable excipient (e.g., as defined above) or a combination of such excipients. Preferably, the composition comprises about 20% (w / w) to about 90% (w / w) of an active ingredient and 80% (w / w) to 10% of a pharma- ceutically acceptable excipient or a combination of excipients. A pharmaceutical composition comprises about 1% to about 95%, preferably about 20% to about 90%, of an active ingredient. A pharmaceutical composition according to the present invention may be in unit dosage form, such as, for example, ampoules, vials, suppositories, prefilled syringes, dragees, powders, tablets or capsules.

[0076] Tablets and capsules may contain, for example, 0-20% disintegrant, 0-5% lubricant, 0-5% flow aid, and / or 0-99% (w / w) filler / bulking agent (depending on the drug dose). They may also contain 0-10% (w / w) polymer binder, 0-5% (w / w) antioxidant, 0-5% (w / w) pigment. Extended release tablets will also typically contain 0-99% (w / w) release-controlling (e.g. retarding) polymer (depending on the dose). The film coat of the tablet or capsule typically contains 0-10% (w / w) polymer, 0-3% (w / w) pigment, and / or 0-2% (w / w) plasticizer.

[0077] The composition may be a parenteral composition. Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) co-solvent and / or 0-99% (w / w) water for injection (WFI) (depending on the dose and whether lyophilized). Formulations for intramuscular injections (depots) can also contain 0-99% (w / w) oil.

[0078] Pharmaceutical formulations may be presented to the patient in a "patient pack" that contains the entire course of treatment in one package, usually a blister pack.

[0079] The compounds of the present invention are generally presented in unit dosage form, and as such will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, e.g., 1 nanogram to 2 milligrams of active ingredient. Within these ranges, specific subranges of compound are 0.1 milligrams to 2 grams of active ingredient (more usually, 10 milligrams to 1 gram, e.g., 50 milligrams to 500 milligrams) or 1 microgram to 20 milligrams (e.g., 1 microgram to 10 milligrams, e.g., 0.1 milligram to 2 milligrams of active ingredient).

[0080] For oral compositions, a unit dosage form may contain from 1 milligram to 2 grams, more typically from 10 milligrams to 1 gram, for example, 50 milligrams to 1 gram, for example, 100 milligrams to 1 gram of active compound.

[0081] The active compound is administered to a patient (e.g., a human or animal patient) in need thereof in an amount sufficient to achieve the desired therapeutic effect (an effective amount). The exact amount of compound to be administered can be determined by the supervising physician according to standard procedures.

[0082] The compounds can be administered with other drugs, for example, other drugs used to treat patients with SARS-CoV-2. The compounds can be combined with HIV drugs known to inhibit cypP450-mediated metabolism, such as ritonavir or the combination of lopinavir / ritonavir. EXAMPLES

[0083] The invention will now be illustrated by reference to the following non-limiting examples shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3]

[0084] Preparation of the Compounds of the Invention The compounds of the present invention are prepared by routes such as, but not limited to, those detailed in Scheme 1. Details of many of the standard transformations, such as the following routes, and other transformations that can be used to perform the same transformations, can be obtained from standard reference texts such as "Organic Synthesis", M.B. Smith, McGraw-Hill (1994), "Advanced Organic Chemistry", 4th Edition, J. March, John Wiley & Sons (1992) or "Protective Groups in Organic Synthesis", 3rd Edition, T.W. Greene, John Wiley & Sons (1999).

[0085] Nitrogen protected derivatives of α-amino acids, such as Boc or Fmoc derivatives, are either commercially available or can be prepared by standard transformations known to those skilled in the art, including those detailed in the Synthesis of Intermediates and Synthesis of Examples sections below. Similarly, ester derivatives of α-amino acids, such as methyl or ethyl esters, are either commercially available or can be prepared by standard transformations known to those skilled in the art, including those detailed in the Synthesis of Intermediates and Synthesis of Examples sections below.

[0086] Acid functions in nitrogen-protected derivatives of α-amino acids can be coupled with amines to give the corresponding amide derivatives (e.g., Route 1, step vi; Routes 2 and 3, step ix; Route 4, step iv), as well as other carboxylic acids (e.g., Route 3, step xi; Route 4, step vii). Amide functions can also be introduced by other means, such as reacting an amine with ethyl 2,2,2-trifluoroacetate in the presence of a base such as Et3N, in a solvent such as MeOH, usually at room temperature (e.g., Route 4, step vii). Derivatives of α-amino acids can be coupled with carboxylic acids to give the corresponding amide derivatives (e.g., Route 1, steps viii, x; Route 2, steps v, vii; Route 3, steps v, vii; Route 4, step ii). Ester functions present in α-amino acid derivatives or, for example, in the product of amide coupling with α-amino acid derivatives, can be hydrolyzed under acidic or basic conditions, for example with lithium hydroxide monohydrate in solvents such as THF, MeOH, HO or mixtures thereof, typically at 0° C. or rt (e.g., Route 2, step viii; Route 4, steps iii, vi). Hydrolysis produces carboxylic acids which can then be reacted with amines or derivatives of α-amino acids under amide coupling conditions as detailed above (e.g., Route 1, step vi; Route 2 or 3, step ix; Route 3, step xi; Route 4, step viii).

[0087] Nitrogen protection present in the α-amino acid derivative or in the product of amide coupling with the α-amino acid derivative can be removed under conditions known to those skilled in the art. Boc groups can be removed under acidic conditions, for example with a solution of HCl in EtOAc (rt), TFA in a solvent such as DCM (rt), HCl in a solvent mixture such as 1,4-dioxane / DCM (rt) or in the presence of TMSCl in MeOH at elevated temperatures such as 60° C., simultaneously with another transformation such as hydrolysis of the nitrile group to a methyl ester. Fmoc groups can be removed under basic conditions, for example with 20% piperidine in DMF at rt. The deprotection reaction gives rise to an amine functionality which can be used in a subsequent amide coupling reaction.

[0088] Amide coupling reaction conditions will typically employ a combination of coupling agents or reagents, such as T3P, HATU, or EDCI (often as hydrochlorides) and agents such as HOBt, with or without a suitable base, such as DIPEA, NMM, or Et3N, in a solvent such as DCM or DMF, typically at room temperature. Alternatively, a derivative of an α-amino acid may be coupled with an acid chloride, such as cyclopropanecarbonyl chloride, using a suitable base, such as DIPEA, in a solvent such as DCM, typically at room temperature, to form an amide derivative.

[0089] The acid functionality present in the α-amino acid derivatives can be converted to aldehydes by a process that involves the formation of N-methoxy-N-methylamide derivatives (commonly known as Weinreb amides) followed by reduction to the aldehyde using conditions such as the use of lithium aluminum hydride in a solvent such as THF, typically at 0° C. (e.g., Routes 1, 2 and 3, steps i and ii). The aldehydes can then be used in a series of steps to form substituted or unsubstituted ketoamide functionalities. For example, in one such reaction, reaction with acetone cyanohydrin in the presence of a base such as Et3N in a solvent such as DCM, typically at 0° C. or rt (e.g., Route 1, step iii) leads to the 1-cyano, 1-hydroxy derivative. The cyano (also known as nitrile) functionality in the 1-cyano, 1-hydroxy derivatives can be hydrolyzed to the primary amide using, for example, hydrogen peroxide in the presence of a base such as potassium carbonate in a solvent such as DMSO, typically at 0° C. or rt (e.g., Route 1, step iv). Alternatively, the cyano functionality can be converted to a methyl ester by reaction with methanol under acidic conditions, for example in the presence of TMSCl at elevated temperatures such as 60° C. (e.g., Route 3, step iv). A similar conversion to an ethyl ester can be achieved by reaction of the primary amide group with ethanol and thionyl chloride at elevated temperatures such as 65° C. (e.g., Route 4, step i). In a second transformation of the aldehyde, reaction with an isocyanide, for example an alkyl or benzyl isocyanide, in the presence of AcOH in a solvent such as DCM, usually at rt, leads to an alkylamino or benzylamino substituted 1-oxo-2-yl acetic acid derivative (e.g., Route 2, step iii). The acetic acid substituent can be removed under conditions such as Et3N in MeOH at rt to give a substituted hydroxyketoamide derivative (e.g., Route 2, step iv).The hydroxy group derived from the aldehyde by the above methods can be oxidized to the ketone either at this stage or after further transformation using an oxidizing agent such as IBX or DMP in a suitable solvent such as DMSO, typically at 0° C. or rt (e.g. Routes 1, 2 and 3, steps xi, x, xii, respectively).

[0090] [ka] [ka]

[0091] Scheme 1 General Procedure Where preparative routes are not described, the relevant intermediates are commercially available. Commercially available reagents were used without purification. Room temperature (rt) refers to approximately 20-27 °C. 1 H NMR spectra were recorded on a Bruker instrument at 300 MHz or 400 MHz. Chemical shift values ​​were expressed in parts per million (ppm), i.e. (δ)-values. For the multiplicity of NMR signals the following abbreviations were used: s=singlet, br=broad, d=doublet, t=triplet, q=quartet, quin=quintet, h=heptet, dd=doublet of doublets, dt=double of triplets, m=multiplet. Coupling constants are listed as J values ​​and measured in Hz. NMR and mass spectrometry results were corrected taking into account background peaks. TLC for reaction monitoring refers to TLC grade with silica gel as stationary phase.

[0092] LCMS experiments were performed under the following conditions and LCMS data were given in the following format: mass ion, retention time.

[0093] Method A.Instrument: Shimadzu LCMS-2020; Column: Chromolith@Flash RP-18E 25-2 MM or Kinetex EVO C18 2.1×30 mm, 5 μm; Gradient [time (min) / solvent B (%) in A]: 0.0 / 5, 0.8 / 95, 1.2 / 95, 1.21 / 5, 1.55 / 5 (solvent A = 0.0375% TFA (v / v) in water, B = 0.01875% TFA (v / v) in MeCN); UV detection at 220 and 254 nm; Column temperature 50 °C; Flow rate 1.5 mL / min

[0094] Method A2. Instrument: Agilent 1200 LC with Agilent 6110 MSD; Column: Agilent ZORBAX SB-Aq, 2.1 * 50 mm, 5 μm; gradient [time (min) / solvent B (%) in A]: 0.0 / 1, 0.4 / 1, 3.4 / 90, 3.91 / 1, 4.5 / 1 (solvent A = 0.0375% TFA (v / v) in water, B = 0.01875% TFA (v / v) in MeCN); UV detection at 220 and 254 nm; column temperature 50 °C; flow rate 0.8 mL / min

[0095] Method B. Instrument: Shimadzu LCMS-2020; Column: Kinetex EVO C18 2.1×30 mm, 5 μm; Method B gradient [time (min) / solvent B in A (%)]: 0.0 / 0, 0.8 / 60, 1.2 / 60, 1.21 / 0, 1.55 / 0 (solvent A = 0.025% NH3·H2O (25%, w / w) in water (v / v), B = MeCN); UV detection 210-254 nm; Column temperature 40 °C or 50 °C; Flow rate 0.8 or 1.5 mL / min

[0096] Method C.Instrument: Shimadzu LCMS-2020; Column: Chromolith Flash RP-18e 25×2.0 mm or Kinetex EVO C18 2.1×30 mm, 5 μm; Gradient [time (min) / solvent B (%) in A]: 0.0 / 0, 0.8 / 60, 1.2 / 60, 1.21 / 0, 1.55 / 0 (solvent A = 0.0375% TFA (v / v) in water, B = 0.01875% TFA (v / v) in MeCN); UV detection 210-254 nm; Column temperature 50 °C; Flow rate 0.8 mL / min

[0097] Methods D and D2. Instrument: Agilent G1956A; Column: XBridge C18, 2.1 * 50 mm, 5 μm; Method D gradient [time (min) / solvent B (%) in A]: 0.0 / 5, 0.4 / 5, 3.4 / 90, 3.90 / 100, 3.91 / 5 (solvent A = 0.05% NH3·H2O (25%, w / w) in water (v / v), B = MeCN); Method D2 gradient [time (min) / solvent B (%) in A]: 0.0 / 5, 0.4 / 5, 3.4 / 90, 4.00 / 100, 4.01 / 5 (solvent A = 0.05% NH3·H2O (25%, w / w) in water (v / v), B = MeCN); UV detection 220, 254 nm; column temperature 40 °C; flow rate 0.8 mL / min

[0098] Method E. Instrument: Agilent G1956A; Column: XBridge C18, 2.1 * 50 mm, 5 μm; gradient [time (min) / solvent B (%) in A]: 0.0 / 1, 0.4 / 1, 3.4 / 90, 4.00 / 100, 4.01 / 1 (solvent A = 0.05% NH3·H2O (25%, w / w) in water (v / v), B = MeCN); UV detection 220, 254 nm; column temperature 40 °C; flow rate 0.8 mL / min

[0099] Methods F and F2. Instrumentation: Method F, Acquity UPLC with PDA and QDA detectors; Method F2; Acquity H-Class with PDA and QDA detectors; Column: C18, 50 *2.1 mm, 1.6 μm; gradient [time (min) / solvent B (%) in A]: 0.0 / 3, 0.2 / 3, 2.7 / 98, 3.00 / 100, 3.50 / 100, 3.51 / 3 (solvent A = 0.1% HCO2H in water, B = 0.1% HCO2H in water:acetonitrile (10:90)); column temperature 35 °C; flow rate 0.8 mL / min

[0100] Method F3. Instrument: Acquity UPLC with PDA and QDA detectors; Column: C18, 50 * 2.1 mm, 2.5 μm; gradient [time (min) / solvent B (%) in A]: 0.0 / 3, 0.2 / 3, 2.7 / 98, 3.00 / 100, 3.50 / 100, 3.51 / 3 (solvent A = 0.1% HCO2H in water, B = 0.1% HCO2H in water:acetonitrile (10:90)); column temperature 30 °C; flow rate 0.8 mL / min

[0101] Method G. Instrument: Acquity UPLC with PDA and QDA detectors; Column: C18, 50 * 2.1 mm, 2.5 μm; gradient [time (min) / solvent B (%) in A]: 0.0 / 3, 0.2 / 3, 2.7 / 98, 3.0 / 100, 3.5 / 100, 3.51 / 3 (solvent A = 5 mM (NH4)HCO3 in water, B = MeCN); column temperature 35 °C; flow rate 1.0 mL / min

[0102] Method H. Instrument: Waters Alliance 2690 and 996 PDA with Micromass ZQ detector; Column: C18, 150 * 4.6 mm, 3.5 μm; gradient [time (min) / solvent B (%) in A]: 0.0 / 10, 7.0 / 90, 9.0 / 100, 14.0 / 100, 14.01 / 10 (solvent A = 0.1% TFA in water, B = MeCN); column temperature room temperature; flow rate 1.0 mL / min

[0103] Method I. Instrument: Acquity UPLC with PDA and QDA detectors; Column: C18, 50 *2.1 mm, 2.5 μm; gradient [time (min) / solvent B (%) in A]: 0.0 / 3, 0.2 / 3, 2.7 / 98, 3 / 100, 3.5 / 100, 3.51 / 3 (solvent A = 0.1% HCO2H in water, B = 0.1% HCO2H in water:acetonitrile (10:90)); column temperature 30 °C; flow rate 0.8 mL / min

[0104] Method J. Instrument: Agilent 1100 LC with Agilent G1956A; Column: Waters XBridge C18 2.1 * 50 mm, 5 μm; gradient [time (min) / solvent B (%) in A]: 0.0 / 1, 0.4 / 1, 3.4 / 90, 4.0 / 100, 4.01 / 1, 4.5 / 1 (solvent A = 0.05% NH3·H2O (25%, w / w) in water (v / v), B = MeCN); UV detection at 220 and 254 nm; column temperature 40 °C; flow rate 0.8 mL / min

[0105] Method K. Instrument: Agilent Infinity II G6125C; Column: C18, 150 * 4.6 mm, 3.5 μm; gradient [time (min) / solvent B (%) in A]: 0.0 / 10, 7.0 / 90, 9.0 / 100, 14.0 / 100, 14.01 / 10, 17.0 / 10 (solvent A = 0.1% NH3 (v / v) in water, B = MeCN); column temperature 25 °C; flow rate 1.0 mL / min

[0106] Method L. Instrument: Agilent 1290 Infinity II Series LC / 6125 Quadrupole MSD SL; Column: Waters XBridge C8 50 * 4.6 mm, 3.5 μm; gradient [time (min) / solvent B (%) in A]: 0.0 / 5, 2.5 / 95, 4.0 / 95, 4.5 / 5, 6.0 / 5 (solvent A = 0.1% TFA:MeCN (95:5) in HO, B = 0.1% TFA in MeCN); UV detection 210-400 nm; column temperature 25 °C; flow rate 1.5 mL / min.

[0107] Abbreviation AcOH = acetic acid Boc = tert-butyloxycarbonyl CDI=N,N-carbonyldiimidazole DCM = dichloromethane DMF = N,N-dimethylformamide DMP = Dess-Martin Periodont DIPEA = N,N-diisopropylethylamine DMSO = dimethyl sulfoxide EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOAc = ethyl acetate Fmoc = fluorenylmethoxycarbonyl or ((9H-fluoren-9-yl)methoxy)carbonyl) h=hour(s) HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate HOBt = 1-hydroxybenzotriazole HPLC = High Performance Liquid Chromatography IBX = -Iodoxybenzoic acid L = liters LC = Liquid Chromatography MeCN = acetonitrile min=minute(s) MS=mass spectrometry NMM = N-methylmorpholine NMR=nuclear magnetic resonance MTBE = Methyl tert-butyl ether rt=room temperature T3P = propylphosphonic anhydride TFA = trifluoroacetic acid TFAA = Trifluoroacetic anhydride THF = tetrahydrofuran TLC = Thin Layer Chromatography TMSCl = trimethylsilyl chloride UPLC = Ultra Performance Liquid Chromatography

[0108] The prefixes n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, tertiary.

[0109] Synthesis of intermediates Intermediate 1 (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0110] Process 1 : To a mixture of methyl 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl acetate (551 g, 1.85 mol) in DCM (2.5 L) was slowly added 1,1,3,3-tetramethylguanidine (214 g, 1.85 mol, 233 mL) at 0° C. After stirring for 30 min at 0° C., cyclopropanecarbaldehyde (100 g, 1.43 mol, 107 mL) was added to the reaction mixture at 0° C., and the resulting mixture was stirred at 25° C. for 12 h under N2. H2O (2 L) was added, and the resulting mixture was extracted with DCM (800 mL×3), and the combined organic layers were washed with brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by gradient silica gel column chromatography (petroleum ether:EtOAc 1:0 to 10:1) afforded methyl (E)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-prop-2-enoate (374 g, 1.55 mol) as a white solid. LCMS (Method A): m / z 142.2 at 0.79 min (M-100+H). 1H NMR: (400MHz,DMSO-d6)δ0.59~0.64(2H,m), 0.87~0.93(2H,m), 1.38(9H,br s), 1.59~1.71(1H,m), 3.62(3H,s), 5.61~5.98(1H,m), 8.37(1H,br s).

[0111] Process 2 To a solution of methyl (E)-2-(tert-butoxycarbonylamino)-3-cyclopropyl-prop-2-enoate (374 g, 1.55 mol) in THF (2.5 L) was slowly added dropwise BH3-Me2S (10 M in Me2S, 620 mL) under N2 at 0 °C. The reaction mixture was stirred under N2 at 25 °C for 24 h. The reaction mixture was quenched by dropwise addition of MeOH (2 L) at 0 °C, and the resulting mixture was stirred at 25 °C under N2 for 1 h, then concentrated in vacuo. Purification by gradient silica gel column chromatography (petroleum ether: EtOAc 1:0 to 10:1) afforded methyl 2-(tert-butoxycarbonylamino)-3-cyclopropyl-propionate (213 g, crude) as a colorless oil. LCMS (Method A): m / z 144.2 at 0.83 min (M-100+H). 1 HNMR:(400MHz,DMSO-d6)δ-0.05~0.01(1H,m), 0.07~0.13(1H,m), 0.35~0.41(2H,m), 0.73~0.79(1H,m), 1.33(1H,br s), 1.38(9H,s), 1.57~1.64(1H,m), 3.61(3H,s), 3.96~4.05(1H,m), 7.26(1H,br d,J=7.6Hz).

[0112] Process 3To a mixture of methyl 2-(tert-butoxycarbonylamino)-3-cyclopropyl-propionate (213 g, 875 mmol) in MeOH (600 mL), THF (600 mL) and HO (600 mL) was added LiOH·HO (73.5 g, 1.75 mol) at 25 °C. The resulting mixture was stirred at 25 °C for 2 h under N2 and then concentrated in vacuum. Aqueous hydrochloric acid (1 N) was added to adjust the pH to about 7, and the resulting mixture was extracted with ethyl acetate (600 mL × 3). The combined organic layers were washed with brine (800 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to afford 2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (197 g, crude) as a colorless oil. LCMS (Method A): m / z 130.2 at 0.73 min (M-100+H). 1 HNMR:(400MHz,DMSO-d6)δ-0.01(1H,br s), 0.07(1H,br s), 0.35(2H,br s), 0.73(1H,br s), 1.37(9H,br s), 1.42~1.46(1H,m), 1.54(1H,br s), 3.81(1H,brs), 6.64(1H,brs).

[0113] Process 4To a mixture of 2-(tert-butoxycarbonylamino)-3-cyclopropyl-propanoic acid (197 g, 859 mmol) in DMF (800 mL) was slowly added HOBt (139 g, 1.03 mol) and EDCI-HCl (198 g, 1.03 mol) at 25° C. After stirring for about 12 min at 25° C., N-methoxymethanamine hydrochloride (101 g, 1.03 mol) and Et3N (104 g, 1.03 mol, 144 mL) were added and the resulting mixture was stirred at 25° C. under N2 for 2 h. H2O (1.5 L) was added and the resulting mixture was extracted with EtOAc (800 mL×3). The combined organic layers were washed with brine (500 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by gradient silica gel column chromatography (petroleum ether:EtOAc 1:0 to 10:1) afforded tert-butyl-N-[1-(cyclopropylmethyl)-2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (209 g, 0.77 mol) as a white solid. LCMS (Method A): m / z 173.2 at 0.81 min (M-100+H). 1 HNMR:(400MHz,DMSO-d6)δ-0.06~0.01(1H,m), 0.07~0.13(1H,m), 0.35~0.41(2H,m), 0.74~0.78( 1H,m), 1.14~1.22(1H,m), 1.37(9H,s), 1.58~1.66(1H,m), 3.09(3H,s), 3.73(3H,s), 4.44(1H,br d,J=3.2Hz), 7.01(1H,br d,J=8.4Hz).

[0114] Process 5: To a mixture of tert-butyl N-[1-(cyclopropylmethyl)-2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (189 g, 659 mmol) in THF (1.5 L) was added LiAlH4 (25.0 g, 659 mmol) slowly at 0 °C, and the reaction mixture was stirred at 25 °C under N2 for 1 h. H2O (25 mL) was added dropwise at 0 °C, the resulting mixture was filtered, and the residue was washed with THF (1 L). The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by gradient silica gel column chromatography (petroleum ether: EtOAc 1:0 to 5:1) to give tert-butyl N-[1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (105 g, crude) as a pale yellow oil. LCMS (Method A): m / z 114.2 at 0.75 min (M-100+H). 1 HNMR: (400MHz,DMSO-d6)δ0.06~0.08(2H,m), 0.38~0.40(2H,m), 0.76~0.78(1H,m), 1.40(9H,s), 1.44~1.48(2H,m), 3.86~3.92(1H,m), 7.31(1H,br d,J=7.2Hz), 9.45(1H,s).

[0115] Process 6To a mixture of tert-butyl N-[1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (121 g, 567 mmol) in DCM (1 L) was slowly added Et3N (86.1 g, 851 mmol, 118 mL) and 2-hydroxy-2-methyl-propanenitrile (74.7 g, 878 mmol, 80.2 mL) at 0° C. The reaction mixture was stirred at 25° C. for 12 h under N2. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (500 mL) at 0° C., and the resulting mixture was extracted with DCM (300 mL×3). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by gradient silica gel column chromatography (petroleum ether:EtOAc 1:0 to 5:1) afforded tert-butyl N-[2-cyano-1-(cyclopropylmethyl)-2-hydroxy-ethyl]carbamate (69.2 g, crude) as a pale yellow oil. 1 H NMR:(400MHz,DMSO-d6)δ-0.06~0.01(1H,m), 0.09~0.15(1H,m), 0.35~0.41(2H,m), 0.66~0.75(1H,m), 1. 33~1.35(1H,m), 1.39(9H,s), 1.48~1.56(1H,m), 3.60~3.71(1H,m), 6.49~6.60(1H,m), 6.93~7.07(1H,m).

[0116] Process 7To a mixture of tert-butyl N-[2-cyano-1-(cyclopropylmethyl)-2-hydroxy-ethyl]carbamate (71.0 g, 295 mmol) and K2CO3 (81.7 g, 591 mmol) in DMSO (500 mL) was slowly added dropwise H2O2 (449 g, 3.96 mol, 380 mL, 30% purity, w / w) at 0 °C. The reaction mixture was stirred at 0-25 °C for 12 h under nitrogen atmosphere. The reaction mixture was diluted with H2O (1 L), added with saturated aqueous Na2S2O3 (1 L) at 0 °C, and cooled slowly. The resulting mixture was acidified to pH 8 with 1N aqueous hydrochloric acid and extracted with DCM (500 mL × 3). The combined organic layers were washed with brine (500 mL), saturated aqueous Na2S2O3 (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by gradient silica gel column chromatography (petroleum ether:EtOAc 10:1 to 0:1) afforded tert-butyl N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]carbamate (35.6 g, 0.14 mol). LCMS (Method A): m / z 159.2 at 0.70 min (M-100+H). 1 HNMR:(400MHz,DMSO-d6)δ0.01-0.05(2H,m), 0.37(2H,br d,J=7.6Hz), 0.63~0.67(1H,m), 1.36(9H,s), 1.39(2H,s), 3.77~3.82(1H,m), 3.88~3.91(1H,m), 5.44(1H,d,J=6.4Hz), 5.95(1H,br d,J=9.2Hz), 7.20(2H,br d,J=10.8Hz).

[0117] Process 8To a mixture of tert-butyl N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]carbamate (5.60 g, 21.7 mmol) in EtOAc (30 mL) was added HCl / EtOAc (4N, 34 mL) at 25° C. The resulting mixture was stirred at 25° C. for 1 h under nitrogen. After concentration in vacuum, purification by preparative HPLC (HCl as additive) afforded 3-amino-4-cyclopropyl-2-hydroxybutanamide hydrochloride (3.30 g, 20.9 mmol) as a white solid. LCMS (Method B): m / z 158.9 (M+H) at 0.38 min. 1 H NMR:(400MHz,DMSO-d6)δ-0.06~0.13(2H,m), 0.37~0.46(2H,m), 0.74~0.85(1H,m), 1.21~1.51( 2H,m), 3.45~3.47(1H,m), 4.11~4.28(1H,m), 6.18~6.57(1H,m), 7.42~7.55(2H,m), 7.95(1H,br s), 8.25(1H,br s)

[0118] Preparative HPLC (HCl) method for purification of step 8. Instrument: Shimadzu LC-20AP; Column: Phenomenex luna C18 250 x 80 mm x 10 μm; Mobile phase: A = 0.05% HCl (v / v) in water, B = MeCN; Gradient: 0-10% B in A over 15 min; Flow rate 150 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0119] Process 93-Amino-4-cyclopropyl-2-hydroxy-butanamide (2.00 g, 12.6 mmol) and (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.97 g, 11.6 mmol) were dissolved in DMF (30 mL) and EtN (2.56 g, 25.3 mmol, 3.52 mL) and T3P (12.1 g, 19.0 mmol, 11.3 mL, 50% purity in EtOAc) were added slowly at 25 °C. The resulting mixture was stirred under N2 at 25 °C for 2 h before H2O (50 mL) was added and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by gradient silica gel column chromatography (petroleum ether:EtOAc 10:11:1) followed by preparative HPLC (NHHCO as additive) afforded tert-butyl (1R,2S,5S)-2-[[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.43 g, 3.62 mmol) as a white solid. LCMS (Method C): m / z 396.2 (M+H) at 0.99 min. 1 H NMR:(400MHz,DMSO-d6)δ-0.15~0.11(2H,m), 0.23~0.41(2H,m), 0.62~0.76(1 H,m), 0.83~0.87(1H,m), 0.87~1.03(6H,m), 1.27~1.36(9H,m), 1.36~1.40(2H, m), 1.42~1.62(1H,m), 3.23~3.31(1H,m), 3.43~3.58(1H,m), 3.83~4.02(2H,m ), 4.03~4.23(1H,m), 5.43~5.88(1H,m), 7.12~7.29(2H,m), 7.39~8.06(1H,m).

[0120] Preparative HPLC (NH4HCO3) method for purification of step 9. Instrument: Shimadzu LC-20AP; Column: Kromasil Eternity XT 250 x 80 mm x 10 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 37-67% B in A over 20 min; Flow rate: 140 mL / min; Column temperature 40 °C; Wavelength: 220 nm, 254 nm.

[0121] Step 10 tert-Butyl (1R,2S,5S)-2-[[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.40 g, 3.24 mmol) in EtOAc (5 mL) at 25° C. was added HCl / EtOAc (4N, 15.3 mL) and the resulting mixture was stirred at 25° C. under N2 for 1 h. Concentration in vacuo afforded (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Intermediate 1, 1.15 g, 3.89 mmol) as a pale yellow solid. LCMS (Method C): m / z 296.1 (M+H) at 0.66 min. 1 H NMR:(400MHz,DMSO-d6)δ-0.16~0.17(2H,m), 0.27~0.44(2H,m), 0.60~0.72(1H,m), 1. 02~1.09(6H,m), 1.29~1.64(2H,m), 1.65~1.89(2H,m), 3.02~3.07(1H,m), 3.60(2H,br s), 3.89~3.98(1H,m), 4.18~4.29(1H,m), 7.08~7.38(2H,m), 8.35~8.72(1H,m), 8.72~8.94(1H,m), 9.87~10.23(1H,m).

[0122] Intermediate 2(1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0123] Process 1 : (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide intermediate 1 (280 mg, 0.95 mmol) and (tert-butoxycarbonyl)-L-valine (309 mg, 1.42 mmol) in DMF (3 mL) were slowly added with EtN (192 mg, 1.90 mmol, 0.26 mL) and T3P (905 mg, 1.42 mmol, 0.85 mL, 50% purity, w / w) at 25° C. The resulting mixture was stirred at 25° C. for 12 h under nitrogen atmosphere. H2O (50 mL) was added and the resulting mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (formic acid as additive) to give tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-propyl]carbamate (183 mg, 0.37 mmol) as a white solid. LCMS (Method C): m / z 495.2 (M+H) at 1.04 min. 1H NMR: (400MHz, DMSO-d6)δ-0.15~0.08(2H,m), 0.26~0.41(2H,m), 0.63~0.72(1H,m), 0.76~0.99(12H,m), 1.00(2H,br s), 1.14~1.30(1H,m), 1.30~1.39(9H,m), 1.40~1.45(1H,m), 1.77~1.95(1H,m), 3.70~3.84(2H,m), 3.85~3 .97(2H,m), 4.04~4.29(2H,m), 4.98~5.96(1H,m), 6.88~7.00(1H,m), 7.12~7.28(2H,m), 7.37~7.81(1H,m).

[0124] Preparative HPLC (formic acid) method for purification of step 1. Instrument: Shimadzu LC-20AP; Column: Phenomenex luna C18 150 x 40 mm x 15 μm; Mobile phase: A = 0.225% formic acid (v / v) in water, B = MeCN; Gradient: 33-63% B in A over 10 min; Flow rate: 60 mL / min; Column temperature 40 °C; Wavelength: 220 nm, 254 nm.

[0125] Process 2 HCl / EtOAc (4N, 3 mL) was dissolved with tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-propyl]carbamate (150 mg, 0.30 mmol) in EtOAc (3 mL) at 25° C. and the resulting mixture was stirred at 25° C. under N2 for 1 h. The reaction mixture was concentrated in vacuo to afford (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (125 mg, crude) as a pale yellow solid. LCMS (Method C): m / z 395.2 (M+H) at 0.73 min.

[0126] Intermediate 3 (1R,2S,5S)-N-(4-amino-3-hydroxy-1-((1R,2S)-2-methylcyclopropyl)-4-oxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0127] Process 1 : n-BuLi (2.5M in n-hexane, 344 mL) was added dropwise to a solution of ethyl 2-diethoxyphosphorylacetate (193 g, 861 mmol, 171 mL) in 2-methyltetrahydrofuran (1 L) under N2 at 25° C. The resulting mixture was stirred at 25° C. for 30 min, followed by the addition of (2R)-2-methyloxirane (50.0 g, 861 mmol, 60.3 mL) at 25° C. The resulting mixture was stirred at 150° C. for 12 h in a 5 L autoclave at a pressure of 15 Psi. The reaction mixture was cooled to 25° C. and distilled under reduced pressure (approximately 0.03 bar) at 100° C. to yield the step 1 product (2S)-2-methylcyclopropanecarboxylate (91.0 g, 710 mmol) as a colorless oil. 1 H NMR: (400MHz, CDCl3) δ0.63~0.69(1H,m), 1.11(3H,d,J=6.0Hz), 1.13~1.18(1H,m), 1.24~1.28(3H,m), 1.34~1.44(2H,m), 4.07~4.15(2H,m).

[0128] Process 2:AlMe3 (2M in PhMe, 78.0 mL, 156.0 mmol) was added dropwise to a mixture of N-methoxymethanamine hydrochloride (15.2 g, 156 mmol) in PhMe (100 mL) under N2 at 0 °C. The resulting mixture was stirred at 25 °C for 30 min, then a solution of (2S)-ethyl 2-methylcyclopropanecarboxylate (10.0 g, 78.0 mmol) in PhMe (150 mL) was added at 0 °C. The resulting mixture was stirred at 25 °C for 12 h, then H2O (100 mL) was added. The aqueous phase was extracted with ethyl acetate (100 mL x 3) and the combined organic phase was washed with brine (100 mL x 3), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by gradient silica gel column chromatography eluting with petroleum ether:ethyl acetate 20:1 to 5:1 to afford (1S,2S)-N-methoxy-N,2-dimethyl-cyclopropanecarboxamide (3.00 g, 21.0 mmol) as a yellow oil. LCMS (Method A): m / z 144.2 at 0.60 min (M+H). 1 H NMR: (400MHz, CDCl3) δ0.61~0.68(1H,m), 1.13(3H,d,J=6.0Hz), 1.16~1.21(1H,m), 1.31~1.41(1H,m), 1.78~1.90(1H,m), 3.20(3H,s), 3.75(3H,s).

[0129] Step 3:To a mixture of (1S,2S)-N-methoxy-N,2-dimethyl-cyclopropanecarboxamide (3.00 g, 21.0 mmol) in THF (30 mL) was added DIBAL-H (1 M in PhMe, 23.1 mL, 23.1 mmol) dropwise at -70 °C under N2. The resulting mixture was stirred at -70 °C for 30 min. Separately, n-BuLi (2.5 M in n-hexane, 17.6 mL, 35.2 mmol) was added dropwise to a solution of methyl 2-(tert-butoxycarbonylamino)-2-dimethoxyphosphoryl acetate (6.85 g, 23.1 mmol) in THF (70 mL) at -70 °C under N2, and the resulting mixture was stirred at -70 °C for 30 min before being added to the initial reaction mixture at -70 °C. After stirring at 25° C. for 12 h, water (100 mL) was added at 0° C., and the resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by gradient silica gel column chromatography eluting with petroleum ether / ethyl acetate 10:1 to 5:1 afforded methyl (E)-2-(tert-butoxycarbonylamino)-3-[(1S,2S)-2-methylcyclopropyl]prop-2-enoate (3.40 g, 13.3 mmol) as a yellow oil. LCMS (Method A): m / z 200.1 at 0.85 min (M-56+H). 1 H NMR:(400MHz,CDCl3)δ0.77~0.85(2H,m), 1.04~1.11(1H,m), 1.12~1.17(3H,m), 1.3 5~1.42(1H,m), 1.48(9H,s), 3.75(3H,s), 5.74~5.96(1H,m), 6.06(1H,d,J=10.8Hz).

[0130] Process 4-12: (1R,2S,5S)-N-(4-amino-3-hydroxy-1-((1R,2S)-2-methylcyclopropyl)-4-oxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (Intermediate 3, 0.39 g, 1.26 mmol, pale yellow solid) was prepared from methyl (E)-2-(tert-butoxycarbonylamino)-3-[(1S,2S)-2-methylcyclopropyl]prop-2-enoate (23.5 g, 92.1 mmol) using a procedure similar to that detailed for Intermediate 1 (Steps 2-10). LCMS (Method B): m / z 310.2 at 1.00 min (M+H). 1 H NMR:(400MHz,CD3OD)δ0.10~0.61(4H,m), 0.94~1.05(3H,m), 1.11~1.19(6H,m), 1.21~1.49(2H,m), 1.52~1 .70(1H,m), 1.78~1.85(1H,m), 3.21~3.30(1H,m), 3.71~3.79(1H,m), 4.08~4.20(2H,m), 4.29~4.48(1H,m).

[0131] Intermediate 4 : Isobutyryl-L-valine [ka]

[0132] Process 1 To a mixture of (2S)-2-amino-3-methyl-butanoic acid methyl hydrochloride (5.00 g, 29.8 mmol) in DCM (50 mL) was added DIPEA (11.6 g, 89.5 mmol, 15.6 mL) and 2-methylpropanoyl chloride (3.81 g, 35.8 mmol) at 0° C. The resulting mixture was stirred at 25° C. for 12 h, after which DCM (100 mL) and water (80 mL) were added. The organic phase was washed with water (2×80 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield methyl (2S)-3-methyl-2-(2-methylpropanoylamino)butanoate (6.00 g, 29.8 mmol) as a yellow oil. LCMS (Method A): m / z 202.2 (M+H) at 0.35 min.

[0133] Process 2 : LiOH-HO (2.50 g, 59.6 mmol) was added to THF (4.00 g, 19.9 mmol) in THF (20 mL), MeOH (6 mL) and HO (6 mL) at 0° C., the resulting mixture was stirred at 25° C. for 1 h, and adjusted to about pH 7 by adding 2N aqueous hydrochloric acid, followed by the addition of EtOAc (100 mL). The phases were separated and the organic phase was washed with water (80 mL×3), dried over anhydrous NaSO, filtered and concentrated in vacuo. Purification by preparative HPLC (formic acid as additive) afforded (2S)-3-methyl-2-(2-methylpropanoylamino)butanoic acid (intermediate 4, 1.60 g, 8.55 mmol) as a white solid. LCMS (Method A): m / z 188.2 at 0.37 min (M+H). 1 H NMR:(400MHz,DMSO-d6)δ0.96~0.99(6H,m), 1.11~1.14(6H,m), 2.12~2.20(1H,m), 2.56~2.64(1H,m), 4.00(1H,d,J=6.0Hz)

[0134] Preparative HPLC (formic acid) method for purification of intermediate 4. Instrument: Shimadzu LC-20AP; Column: Phenomenex Synergi Max-RP C18 250k x 50 mm x 10 μm; Mobile phase: A = 0.225% formic acid in water (v / v), B = MeCN; Gradient: 1 to 30% B in A over 20 min; Flow rate: 150 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0135] Intermediate 5 (1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka]

[0136] Process 1 HATU (10.5 g, 27.7 mmol) was added to a solution of (tert-butoxycarbonyl)-L-valine (5.00 g, 23.0 mmol) in DMF (30 mL) and the mixture was stirred at rt for 10 min. Methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (5.66 g, 27.7 mmol) and DIPEA (11.9 mL, 69.1 mmol) were added and the reaction mixture was stirred at rt for 2 h. The reaction mixture was partitioned between cold water (250 mL) and EtOAc (100 mL), the aqueous phase was extracted with EtOAc (2×70 mL) and the combined organic phases were dried (Na2SO4). After concentration in vacuo, purification by reverse-phase gradient flash column chromatography on C18 silica, eluting with 0–50% MeCN in water, afforded methyl (1R,2S,5S)-3-((tert-butoxycarbonyl)-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (5.90 g, 16.0 mmol) as a yellow sticky solid. LCMS (Method F): m / z 269.3 (M-100) at 2.24 min.

[0137] Process 2 To a solution of methyl (1R,2S,5S)-3-((tert-butoxycarbonyl)-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (5.90 g, 16.0 mmol) in DCM (50 mL) was added TFA (6 mL) dropwise at 0° C. After stirring at rt for 2 h, concentration in vacuo afforded methyl (1R,2S,5S)-3-(L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid trifluoroacetate (6.50 g) as a yellow sticky solid. LCMS (Method F): m / z 269.3 (M+H) at 0.93 min.

[0138] Process 3Et3N (7.17 mL, 51.0 mmol) was added dropwise to a solution of methyl (1R,2S,5S)-3-(L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate trifluoroacetate (6.50 g, 17.0 mmol) in THF (100 mL) at 0° C. and the reaction mixture was stirred at 0° C. for 10 min. Isobutyryl chloride (1.80 mL, 17.0 mmol) was added and after stirring at rt for 1 h, water (250 mL) and EtOAc (100 mL) were added and the phases were separated. The aqueous layer was extracted with EtOAc (2×100 mL) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by reverse-phase gradient flash column chromatography on C18 silica eluting with 0–40% MeCN in water afforded methyl (1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.10 g, 12.1 mmol) as a white solid. LCMS (Method F): m / z 339.3 (M+H) at 1.79 min.

[0139] Process 4 LiOH·H2O (2.48 g, 60.6 mmol) was added to a solution of methyl (1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.10 g, 12.1 mmol) in THF (20 mL), water (10 mL) and the mixture was stirred at rt for 2 h. Water (50 mL) was added and the mixture was acidified to pH approx. 5 with glacial acetic acid (20 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford (1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (intermediate 5, 3.30 g, 10.2 mmol) as a white solid, which was used without further purification. LCMS (Method F): m / z 325.3 (M+H) at 1.49 min.

[0140] Intermediate 6: 3-Amino-N-benzyl-4-cyclopropyl-2-hydroxybutanamide [ka]

[0141] Process 1 (S)-2-(((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-cyclopropylpropanoic acid (12.0 g, 34.2 mmol), EDCI-HCl (7.20 g, 37.5 mmol) and HOBt (5.06 g, 37.5 mmol) were dissolved in DMF (20 mL) at rt and stirred for 20 min. N,O-Dimethylhydroxylamine hydrochloride (3.65 g, 37.5 mmol) and Et3N (5.26 mL, 37.5 mmol) were added and the reaction mixture was stirred at rt for 2 h. After partitioning between water (200 mL) and EtOAc (100 mL), the aqueous layer was extracted with EtOAc (2 x 70 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Trituration with n-hexane afforded (9H-fluoren-9-yl)methyl (S)-(3-cyclopropyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (12.0 g, 30.4 mmol) as a light brown oil. LCMS (Method F): m / z 417.1 (M+Na) at 2.28 min.

[0142] Process 2To a solution of (9H-fluoren-9-yl)methyl (S)-(3-cyclopropyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (12.0 g, 30.5 mmol) in dry THF (50 mL) was added lithium aluminum hydride (2 M in THF, 15.0 mL, 30.0 mmol) dropwise at −78° C. under nitrogen atmosphere. After stirring at −78° C. for 2 h under nitrogen atmosphere, saturated aqueous NH4Cl (70 mL) was added. The mixture was filtered through Celite and the residue was washed with EtOAc (100 mL). The filtrate was concentrated in vacuo to give crude (9H-fluoren-9-yl)methyl (S)-(1-cyclopropyl-3-oxopropan-2-yl)carbamate (9.20 g) as a pale yellow solid, which was used in the next step without purification. LCMS (Method G): m / z 336.6 (M+H) at 2.33 and 2.70 min.

[0143] Process 3 : To a solution of (9H-fluoren-9-yl)methyl (S)-(1-cyclopropyl-3-oxopropan-2-yl)carbamate (9.20 g, 27.5 mmol) in DCM (30 mL) was added benzyl isocyanide (3.56 g, 30.2 mmol) and ice-cold AcOH (4.71 mL, 82.4 mmol) at 0° C. After stirring at rt for 2 h, 1N aqueous hydrochloric acid (20 mL), water (70 mL) and DCM (100 mL) were added. The phases were separated and the aqueous phase was extracted with DCM (2×100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (100 mL) and dried (Na2SO4). Filtration and concentration under vacuum followed by trituration with n-hexane afforded (3S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(benzylamino)-4-cyclopropyl-1-oxobutan-2-yl acetate (14.0 g, 2.73 mmol) as a white solid. LCMS (Method F): m / z 513.0 (M+H) at 2.50 and 2.53 min.

[0144] Process 4: Et3N (8.00 mL, 54.6 mmol) and (3S)-3-(((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(benzylamino)-4-cyclopropyl-1-oxobutan-2-yl acetate (14.0 g, 27.3 mmol) were dissolved in MeOH (200 mL) and the reaction mixture was stirred at rt for 2 h. After concentration in vacuo, the resulting solid was suspended in water (100 mL) and filtered. After drying, trituration with n-hexane afforded (9H-fluoren-9-yl)methyl ((2S)-4-(benzylamino)-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)carbamate (10.0 g, 21.3 mmol) as a white solid. LCMS (Method F): m / z 471.3 (M+H) at 2.43 and 2.46 min.

[0145] Process 5 : (9H-fluoren-9-yl)methyl ((2S)-4-(benzylamino)-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)carbamate (10.0 g, 21.3 mmol) was dissolved in 20% piperidine in DMF (100 mL) and stirred at rt for 40 min. After dilution with cold water (500 mL), the resulting suspension was filtered through Celite. The filtrate was concentrated in vacuo and triturated with MeCN (70 mL) to yield (3S)-3-amino-N-benzyl-4-cyclopropyl-2-hydroxybutanamide (intermediate 6, 3.00 g, 7.01 mmol) as a white solid. LCMS (Method F): m / z 249.3 (M+H) at 0.83 and 0.91 min. 1HNMR: (400MHz,DMSO-d6)δ-0.14~-0.19(m,1H), -0.03~0.06(m,1H), 0.28~0.3 3(m,1H), 0.35~0.39(m,1H), 0.77~0.81(q,1H,J=5.2Hz), 0.91~0.97(m,1H), 1 .24~1.31(m,1H), 1.53(brs,2H), 2.93~2.95(t,1H,J=4.4Hz), 3.83(s,1H), 4. 21~4.32(m,2H), 5.56(s,1H), 7.22~7.319(m,5H), 8.29~8.32(t,1H,J=6.0Hz).

[0146] Intermediate 7 : 3-Amino-4-cyclopropyl-2-hydroxybutanoic acid methyl hydrochloride [ka]

[0147] Process 1 : (S)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid (2.42 g, 10.6 mmol) was dissolved in PhMe (25 mL) under N2 at 0 °C. CDI (1.75 g, 10.8 mmol) was added at 0 °C and the reaction mixture was stirred at 0 °C for 2 h. N,O-Dimethylhydroxylamine hydrochloride (1.34 g, 13.7 mmol) and DIPEA (1.86 mL, 10.8 mmol) were added at 0 °C and the reaction mixture was stirred at rt for 16 h. After partitioning between water (50 mL) and EtOAc (50 mL), the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to afford tert-butyl (S)-(3-cyclopropyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (2.00 g, 7.35 mmol) as an off-white solid. LCMS (Method F2): m / z 273.1 (M+H) at 2.04 min.

[0148] Process 2: LiAlH4 (2.5 M in THF, 2.95 mL, 7.35 mmol) was added dropwise to tert-butyl (S)-(3-cyclopropyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (2.00 g, 7.35 mmol) in THF (20 mL) under N2 at 0 °C and the reaction mixture was stirred at rt for 1 h. After partitioning between saturated aqueous NH4Cl (50 mL) and EtOAc (60 mL), the aqueous phase was extracted with EtOAc (2 x 60 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to afford tert-butyl (1-cyclopropyl-3-oxopropan-2-yl)carbamate (1.30 g, 6.10 mmol) as a yellow sticky material, which was used without further purification. TLC:Rf 0.6 (EtOAc / Hexane, 3:7).

[0149] Process 3 : Sodium carbonate (1.94 g, 18.3 mmol) was added to a solution of tert-butyl (1-cyclopropyl-3-oxopropan-2-yl)carbamate (1.30 g, 6.09 mmol) in PhMe (5 mL) and water (2 mL) and the reaction mixture was stirred at rt for 15 min. Acetone cyanohydrin (0.84 mL, 9.14 mmol) was added and the reaction mixture was stirred at rt for 1 h. After dilution with water (20 mL) and acidification with 2N HCl (8 mL) to pH approx. 5, the mixture was extracted with EtOAc (3×60 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. Purification by normal phase gradient flash column chromatography on silica eluting with 0-20% EtOAc in n-hexane afforded tert-butyl (1-cyano-3-cyclopropyl-1-hydroxypropan-2-yl)carbamate (1.00 g, 4.16 mmol) as a brown sticky material. LCMS (Method F2): m / z 185.2 (M-56) at 1.68 min.

[0150] Process 4: Trimethylsilyl chloride (2 mL, 15.7 mmol) was added to a solution of tert-butyl (1-cyano-3-cyclopropyl-1-hydroxypropan-2-yl)carbamate (1.00 g, 4.16 mmol) in MeOH (15 mL) and the mixture was stirred at 60 °C for 3 h. After concentration in vacuo, purification by reverse-phase gradient flash column chromatography (silica C18) eluting with 0-12% MeCN in water afforded methyl 3-amino-4-cyclopropyl-2-hydroxybutanoate hydrochloride (0.80 g, 3.81 mmol) as a yellow sticky material. LCMS (Method F2): 0.36 min, m / z 174.0 (M+H) with approximately 69% purity.

[0151] Intermediate 8 4-Cyclopropyl-2-hydroxy-3-((1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)butanoic acid [ka]

[0152] Process 1: A solution of EDCI-HCl (0.35 g, 1.85 mmol) and HOBt (0.21 g, 1.54 mmol), (1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Intermediate 5, 0.50 g, 1.54 mmol) and methyl 3-amino-4-cyclopropyl-2-hydroxybutanoate hydrochloride (Intermediate 7, 0.35 g, 1.70 mmol) was dissolved in EtOAc (5 mL) and water (0.5 mL). After stirring at rt for 16 h, the reaction mixture was partitioned between water (30 mL) and EtOAc (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse-phase gradient flash column chromatography (silica C18) eluting with 0–40% MeCN in water afforded methyl 4-cyclopropyl-2-hydroxy-3-((1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)butanoate (0.40 g, 0.83 mmol) as an off-white solid. LCMS (Method F): m / z 480.3 (M+H) at 1.56 min.

[0153] Process 2To a solution of methyl 4-cyclopropyl-2-hydroxy-3-((1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)butanoate (0.21 g, 0.43 mmol) in 1,4-dioxane (1 mL) and water (1 mL) was added LiOH monohydrate (89 mg, 2.18 mmol). After stirring at rt for 3 h, water (50 mL) was added and the reaction mixture was extracted with EtOAc (2×30 mL). The aqueous phase was acidified to around pH 2 with 1N HCl (1.5 mL) and extracted with EtOAc (3×30 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to afford 4-cyclopropyl-2-hydroxy-3-((1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)butanoic acid (0.18 g, 0.39 mmol) as a brown gum. LCMS (Method F2): m / z 466.1 (M+H) at 1.69, 1.77 and 1.83 min.

[0154] Intermediate 9: tert-Butyl N-((1S)-1-((1R,2S,5S)-2-((3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methyl-2-phenyl-propyl)carbamate [ka]

[0155] Process 1To a mixture of 3-methyl-3-phenyl-butanoic acid (4.50 g, 25.3 mmol) in THF (60 mL) was added EtN (3.83 g, 37.9 mmol, 5.27 mL) and 2,2-dimethylpropanoyl chloride (3.35 g, 27.8 mmol, 3.42 mL) dropwise at -78 °C under N2. The reaction mixture was stirred at -78 °C until a white solid formed. The reaction mixture was warmed to 0 °C and stirred for 1 h before being cooled to -78 °C (mixture A). To a solution of (4S)-4-isopropyloxazolidin-2-one (6.52 g, 50.5 mmol) in THF (80 mL) was added n-BuLi (2.5 M in n-hexane, 20.2 mL) dropwise at -78 °C under N2 (mixture B). Mixture B was added to mixture A at -78°C, and the reaction mixture was stirred at -78°C for 2 h, then at 25°C for 12 h. The reaction mixture was slowly quenched in saturated aqueous NH4Cl solution (100 mL) at 0°C, then stirred at 25°C for 1 h. The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by gradient flash column chromatography on silica gel eluting with petroleum ether to petroleum ether / ethyl acetate 5 / 1, followed by preparative reverse-phase HPLC (formic acid as additive) to give (4S)-4-isopropyl-3-(3-methyl-3-phenyl-butanoyl)oxazolidin-2-one (6.15 g, 21.3 mmol) as a yellow oil. LCMS (Method A): m / z 290.2 (M+H) at 0.91 min. 1H NMR: (400MHz, CDCl3) δ 0.74 (3H, d, J=6.8 Hz), 0.81 (3H, d, J=6.8 Hz), 1.50 (6H, d, J=1.6 Hz), 2.12-2.20 (1H, m), 3. 36 (2H, d, J=4.0 Hz), 4.01-4.09 (2H, m), 4.20-4.24 (1H, m), 7.15-7.21 (1H, m), 7.27-7.33 (2H, m), 7.37-7.42 (2H, m). 1H NMR:(400MHz,CDCl3)δ0.74(3H,d,J=6.8Hz), 0.81(3H,d,J=6.8Hz), 1.50(6H,d,J=1.6Hz), 2.12~2.20(1H,m), 3.3 6(2H,d,J=4.0Hz), 4.01~4.09(2H,m), 4.20~4.24(1H,m), 7.15~7.21(1H,m), 7.27~7.33(2H,m), 7.37~7.42(2H,m).

[0156] Preparative reversed phase HPLC (formic acid) method for purification of intermediate 9, step 1. Apparatus: Shimadzu LC-20AP; Column: Phenomenex Luna C18 250 x 80 mm x 15 μm; Mobile phase: A = 0.225% formic acid (v / v) in water, B = MeCN; Gradient: 55 to 85% B in A over 35 min; Flow rate: 140 mL / min; Column temperature 40 °C; Wavelength: 220 nm, 254 nm.

[0157] Process 2To a mixture of (4S)-4-isopropyl-3-(3-methyl-3-phenyl-butanoyl)oxazolidin-2-one (6.00 g, 20.7 mmol) in THF (50 mL) was added dropwise KHMDS (1 M in THF, 22.8 mL) at -78 °C under N2. A solution of N-diazo-2,4,6-triisopropyl-benzenesulfonamide (8.02 g, 25.9 mmol) in THF (30 mL) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h, then HOAc (5.73 g, 95.4 mmol, 5.46 mL) was added at -78 °C. The reaction mixture was stirred at 40 °C for 2 h, then quenched in saturated aqueous NH4Cl solution (100 mL) at 0 °C and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), saturated aqueous NaHCO3 (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by gradient flash column chromatography on silica gel eluting with petroleum ether to petroleum ether / ethyl acetate 20 / 1 afforded (4S)-3-[(2S)-2-azido-3-methyl-3-phenyl-butanoyl]-4-isopropyl-oxazolidin-2-one (5.92 g, 17.9 mmol) as a pale yellow oil. LCMS (Method A): m / z 303.2 (M+H-28) at 0.94 min + . 1 H NMR:(400MHz,CDCl3)δ0.83(6H,dd,J=15.6,7.2Hz), 1.54~1.56(6H,m), 2.28~2.34(1H,m), 3.57(1H,t,J=8.4Hz), 3. 87~3.91(1H,m), 3.97(1H,dd,J=8.8,2.0Hz), 5.66(1H,s), 7.25~7.28(1H,m), 7.30~7.36(2H,m), 7.38~7.43(2H,m).

[0158] Process 3A mixture of (4S)-3-[(2S)-2-azido-3-methyl-3-phenyl-butanoyl]-4-isopropyl-oxazolidin-2-one (5.70 g, 17.3 mmol), Boc2O (8.28 g, 38.0 mmol, 8.72 mL) and Pd / C (500 mg, 10% purity, w / w) in EtOAc (50 mL) was stirred under H2 (15 PSI) at 25° C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by gradient flash column chromatography on silica gel eluting with petroleum ether to petroleum ether / ethyl acetate 10 / 1, followed by preparative HPLC (formic acid as additive) and then normal phase preparative HPLC (NH3-H2O as additive) to yield tert-butyl N-[(1S)-1-[(4S)-4-isopropyl-2-oxo-oxazolidine-3-carbonyl]-2-methyl-2-phenyl-propyl]carbamate (6.50 g, 16.1 mmol) as a pale yellow oil. LCMS (Method A): m / z 405.2 at 0.95 min (M+H). 1 H NMR:(400MHz,CDCl3)δ0.76~0.83(6H,m), 1.41(3H,s), 1.43(9H,s), 1.48(3H,s), 2.21~2.29(1H,m), 3.45(1H,t,J=8.4Hz), 3.79~3.83(1H ,m), 3.90(1H,dd,J=8.8,2.0Hz), 4.86~5.32(1H,m), 6.13(1H,d,J=10.0Hz), 7.20~7.26(1H,m), 7.28~7.34(2H,m), 7.41(2H,d,J=7.6Hz).

[0159] Preparative reversed phase HPLC (formic acid) method for purification of intermediate 9, step 3. Instrument: Shimadzu LC-20AP; column Phenomenex Luna C18 250 x 80 mm x 10 μm; mobile phase: A = 0.225% formic acid (v / v) in water, B = MeCN, gradient: 48 to 78% B in A over 20 min; flow rate: 100 mL / min; column temperature: 40 °C; wavelength: 220 nm, 254 nm.

[0160] Preparative normal phase HPLC (NH3-H2O) method for purification of intermediate 9, step 3. Apparatus: Shimadzu LC-20AP; Column: Welch Ultimate XB-SiOH 250 x 50 mm x 10 μm; Mobile phase: A = Hexane, B = 0.1% NH3-H2O (v / v) in EtOH, 2% B in A over 15 min; Flow rate: 100 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0161] Process 4 To a mixture of tert-butyl N-[(1S)-1-[(4S)-4-isopropyl-2-oxo-oxazolidine-3-carbonyl]-2-methyl-2-phenyl-propyl]carbamate (3.00 g, 7.42 mmol) and 1N aqueous LiOH solution (22.3 mL) in THF (80 mL) and H2O (20 mL), 30% aqueous H2O2 solution (10.1 g, 89.0 mmol, 8.60 mL) was added dropwise at 0° C. under N2. The reaction mixture was stirred at 25° C. for 12 h, and then H2O (100 mL) and saturated aqueous Na2SO3 solution (300 mL) were added at 0° C. The mixture was stirred at 25° C. for 1 h, and then the pH was adjusted to about 7 by adding 1N aqueous hydrochloric acid solution, and the mixture was extracted with CHCl2 (50 mL×3). The combined organic phase was washed with brine (100 mL) and saturated aqueous Na2SO3 (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by gradient flash column chromatography on silica gel eluting with petroleum ether / ethyl acetate (10 / 1 to 1 / 1), followed by preparative HPLC (formic acid as additive) and preparative HPLC (NH4HCO3 as additive) afforded (2S)-2-(tert-butoxycarbonylamino)-3-methyl-3-phenyl-butanoic acid (1.53 g, 5.22 mmol) as a pale yellow solid. LCMS (Method A2): m / z 194.1 (M+H-100) at 2.87min + . 1H NMR:(400MHz,DMSO-d6)δ1.28(9H,s), 1.30(6H,d,J=5.6Hz), 4.01(1H,d,J=8.8Hz), 5 .86(1H,d,J=9.2Hz), 7.07~7.13(1H,m), 7.22(2H,t,J=7.6Hz),7.32(2H,d,J=7.6Hz).

[0162] Preparative reversed phase HPLC (formic acid) method for purification of intermediate 9, step 4. Apparatus: Shimadzu LC-20AP; Column: Phenomenex Luna C18 250 x 70 mm x 10 μm; Mobile phase: A = 0.225% formic acid (v / v) in water, B = MeCN; Gradient: 30-60% B in A over 20 min; Flow rate: 140 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0163] Preparative reversed phase HPLC (NH4HCO3) method for purification of intermediate 9, step 4. Apparatus: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 14 to 44% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0164] Process 5: (2S)-2-(tert-butoxycarbonylamino)-3-methyl-3-phenyl-butanoic acid (Intermediate 9, Step 4 product, 669 mg, 2.28 mmol), HOBt (308 mg, 2.28 mmol) and EDCI (437 mg, 2.28 mmol) were stirred in DMF (5 mL) for 0.2 h at 25° C. (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Intermediate 1, 450 mg, 1.52 mmol) and Et3N (308 mg, 3.04 mmol, 0.42 mL) were added and the reaction mixture was stirred at 25° C. for 2 h. The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (formic acid as additive) and then by preparative HPLC (NH4HCO3 as additive) to give tert-butyl N-((1S)-1-((1R,2S,5S)-2-((3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl)-2-methyl-2-phenyl-propyl)carbamate (intermediate 9, 42.0 mg, 0.07 mmol) as a pale yellow solid. LCMS (Method A): m / z 571.2 (M+H) at 0.90 min + . 1 H NMR:(400MHz,CDCl3)δ0.06~0.22(2H,m),0.40~0.58(2H,m),0.66~0.76( 1H,m),0.76~0.89(3H,m),0.96~0.99(3H,m),1.22~1.37(2H,m),1.38~1. 43(15H,m),1.44~1.48(2H,m),3.69~3.86(1H,m),4.20~4.33(2H,m),4.6 1~4.76(1H,m),4.92~5.28(1H,m),5.46~5.71(1H,m),7.29~7.43(5H,m).

[0165] Preparative reversed phase HPLC (formic acid) method for purification of intermediate 9, step 5. Instrument: Shimadzu LC-20AP; Column: Phenomenex Luna C18 75×30 mm×3 μm; Mobile phase: A=0.225% formic acid (v / v) in water, B=MeCN; Gradient: 45-75% B in A over 20 min; Flow rate: 25 mL / min; Column temperature: 40° C.; Wavelength: 220 nm, 254 nm.

[0166] Preparative reversed phase HPLC (NH4HCO3) method for purification of intermediate 9, step 5. Apparatus: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 32-62% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0167] Intermediate 10 4-Cyclopropyl-2-hydroxy-3-((1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)butanoic acid [ka]

[0168] Process 1: (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (5.00 g, 21.6 mmol) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (5.34 g, 26.0 mmol) were dissolved in DMF (30 mL) at rt. 34 g, 26.0 mmol) was dissolved in DMF (30 mL) at rt. HATU (9.89 g, 26.0 mmol) was added and the reaction mixture was stirred at rt for 30 min, then DIPEA (11.3 mL, 64.9 mmol) was added and the reaction mixture was stirred at rt for 3 h. Cold water (100 mL) was added and the resulting precipitate was collected by filtration to give crude methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (9.30 g) as a brown sticky solid. LCMS (Method F3): m / z 327.4 (M-56) at 2.35 and 2.37 min.

[0169] Process 2 4N HCl in 1,4-dioxane (90 mL) was added to a solution of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (9.30 g) in DCM (30 mL) under N2. After stirring at rt for 2 h, the reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether (3 x 10 mL) to give methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (6.70 g, 21.0 mmol) as a white solid. LCMS (Method F3): m / z 283.5 (M+H) at 1.14 and 1.28 min.

[0170] Process 3Et3N (8.80 mL, 63.2 mmol) was added dropwise to a solution of methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (6.70 g, 21.0 mmol) in THF (40 mL) at 0° C. and the reaction mixture was stirred for 15 min. Isobutyryl chloride (2.23 g, 21.1 mmol) was added and the reaction mixture was stirred at rt for 30 min, after which water (200 mL) was added and extracted with EtOAc (3×100 mL). The combined organic phases were dried (Na2SO4), concentrated in vacuo and purified by reverse-phase gradient flash column chromatography (silica C18) eluting with 0% to 42% MeCN in water to give methyl (1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.90 g, 13.9 mmol) as a brown sticky solid. LCMS (Method F3): m / z 353.5 (M+H) at 1.88 and 1.96 min.

[0171] Process 4 LiOH monohydrate (2.92 g, 69.6 mmol) and methyl (1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.90 g, 13.9 mmol) were dissolved in 1,4-dioxane (20 mL) and water (15 mL). The reaction mixture was stirred at rt for 4 h, after which water (200 mL) and EtOAc (100 mL) were added. The phases were separated and the aqueous phase was acidified to around pH 2 with 1N HCl (15 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give crude (1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (4.80 g) as a white solid. LCMS (Method F3): m / z 339.5 (M+H) at 1.59 and 1.74 min.

[0172] Process 5 HATU (3.37 g, 8.86 mmol), (1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.50 g, 4.43 mmol) and methyl 3-amino-4-cyclopropyl-2-hydroxybutanoate hydrochloride (1.11 g, 5.32 mmol) were dissolved in DMF (15 mL) and the reaction mixture was stirred at rt for 15 min. N-Methylmorpholine (1.95 mL, 17.7 mmol) was added and the reaction mixture was stirred at rt for 30 min and then concentrated under vacuum. Purification by reverse-phase gradient flash column chromatography (silica C18) eluting with 0% to 46% MeCN in water gave methyl 4-cyclopropyl-2-hydroxy-3-((1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)butanoate (1.70 g, 3.44 mmol) as a white solid. LCMS (Method F3): m / z 494.5 (M+H) at 1.69 and 1.75 min.

[0173] Process 6To a solution of methyl 4-cyclopropyl-2-hydroxy-3-((1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)butanoate (0.25 g, 0.51 mmol) in 1,4-dioxane (2 mL) and water (2 mL) was added LiOH monohydrate (0.11 g, 2.53 mmol) and the reaction mixture was stirred at rt for 2 h. Water (70 mL) and EtOAc (50 mL) were added and the aqueous layer was acidified to around pH 2 with 1N HCl (3 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give 4-cyclopropyl-2-hydroxy-3-((1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)butanoic acid (Intermediate 10, 0.20 g, 0.39 mmol) as a white solid. LCMS (Method F3): m / z 480.5 (M+H) at 1.55 and 1.58 min.

[0174] Synthesis of Examples Example 1 (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0175] Process 1To a mixture of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (305 mg, 1.32 mmol) in DMF (5 mL) was added HOBt (178 mg, 1.32 mmol) and EDCI.HCl (253 mg, 1.32 mmol) at 25° C., the mixture was stirred for about 12 minutes, and then (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Intermediate 1, 300 mg, 1.02 mmol) and Et3N (206 mg, 2.03 mmol, 0.28 mL) were added. The reaction mixture was stirred at 25° C. under N2 for 2 hours. H2O (50 mL) was added and the mixture was extracted with EtOAc (20 mLx3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (formic acid as additive) to give tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (251 mg, 0.49 mmol) as a white solid. LCMS (Method A): m / z 509.2 (M+H) at 1.08 min. 1 H NMR:(400MHz,CDCl3)δ0.05~0.27(2H,m),0.41~0.53(2H,m),0.68~0.81( 1H,m),0.86~0.88(3H,m),0.97(3H,d,J=3.6Hz),0.98~1.06(9H,m),1.39( 9H,s),1.43(2H,brd,J=6.8Hz),1.52~1.57(1H,m),1.66~1.89(1H,m),3. 78~4.19(3H,m),4.19~4.34(2H,m),4.34~4.48(1H,m),6.78~7.20(1H,m).

[0176] Preparative HPLC (formic acid) method for purification of step 1. Instrument: Shimadzu LC-20AP; Column: Phenomenex Luna C18 150 x 40 mm x 15 μm; Mobile phase: A = 0.225% formic acid (v / v) in water, B = MeCN; Gradient: 40-70% B in A over 10 min; Flow rate: 60 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0177] Process 2 HCl in EtOAc (4N, 5 mL) was dissolved tert-butyl N-[(1S)-1-[(1R,2S,5S)-2-[[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]carbamate (220 mg, 0.43 mmol) in EtOAc (5 mL) at 25° C. and the resulting mixture was stirred at 25° C. under N2 for 1 h. The reaction mixture was concentrated in vacuo to afford (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (185 mg) as a white solid which was used crude without purification. LCMS (Method A): m / z 409.2 (M+H) at 0.68 min.

[0178] Process 3To a mixture of (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-3-[(2S)-2-amino-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.0]hexane-2-carboxamide (180 mg, crude) and EtN (0.12 mL, 0.88 mmol) in DCM (5 mL) was added 2-methylpropanoyl chloride (0.06 mL, 0.57 mmol) at 0 °C and the resulting mixture was stirred at 25 °C under N for 1 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (formic acid as additive) to give the desired Step 3 product (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-3-[(2S)-3,3-dimethyl-2-(2-methylpropanoylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (121 mg, 0.25 mmol) as a white solid. LCMS (Method A): m / z 479.2 (M+H) at 0.77 min. 1 H NMR:(400MHz,CDCl3)δ0.05~0.26(2H,m),0.39~0.53(2H,m),0.68~0.81(1H,m),0.81~0 .88(3H,m),0.92~0.99(6H,m),0.99~1.07(9H,m),1.13(3H,d,J=7.2Hz),1.17~1.39(1H, m),1.41~1.60(2H,m),1.70~1.82(1H,m),2.32~2.44(1H,m),3.81~4.21(3H,m),4.25~4 .32(1H,m),4.38~4.52(1H,m),4.54~4.66(1H,m),6.10~6.27(1H,m),6.76~7.00(1H,m).

[0179] Preparative HPLC (formic acid) method for purification of step 3. Instrument: Shimadzu LC-20AP; Column: Unisil3-100C18Ultra150×25mm×3μm; Mobile phase: A=0.225% formic acid (v / v) in water, B=MeCN; Gradient: 30-60% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40° C.; Wavelength: 220 nm, 254 nm.

[0180] Process 4 (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-3-[(2S)-3,3-dimethyl-2-(2-methylpropanoylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.0]hexane-2-carboxamide (110 mg, 0.23 mmol) was dissolved in DMSO (3 mL) and 2-iodylbenzoic acid (161 mg, 0.57 mmol) was added at 0° C. and the resulting mixture was stirred at 25° C. for 12 h under N2. H2O (0.5 mL) was added and the resulting mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (NHHCO was added) to give Example 1, (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxo-propyl]-3-[(2S)-3,3-dimethyl-2-(2-methylpropanoylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (55.5 mg, 0.12 mmol) as a white solid. LCMS (Method D): m / z 477.3 (M+H) at 2.69 min. 1H NMR:(400MHz,CDCl3)δ0.00~0.16(2H,m),0.39~0.50(2H,m),0.69~0.76(1H,m),0.81(2H,d,J=2.4Hz) ,0.95~1.01(9H,m),1.03(2H,s),1.08(3H,d,J=6.8Hz),1.14(3H,d,J=6.8Hz),1.46~1.81(6H,m),2.3 3~2.40(1H,m),3.76~3.86(1H,m),4.01(1H,brd,J=10.8Hz),4.46(1H,d,J=13.6Hz),4.60~4.69(1H,m ),5.35~5.40(1H,m),5.74(1H,brs),6.08~6.16(1H,m),6.79(1H,brd,J=10.8Hz),7.27~7.53(1H,m).

[0181] Preparative HPLC (NH4HCO3) method for purification of Example 1. Instrument: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 25-55% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0182] Example 2 (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxo-propyl]-3-[(2S)-2-(cyclopropanecarbonylamino)-3-methylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0183] Steps 1 and 2The title compound (34.3 mg, 0.07 mmol, white solid) was prepared from intermediate 2 (125 mg, 0.32 mmol) and cyclopropanecarbonyl chloride (39.8 mg, 0.38 mmol, 0.03 mL) in a similar manner to that detailed for Example 1 (steps 3 and 4). Example 2 was purified by preparative HPLC (NH4HCO3 as additive). LCMS (Method D): m / z 461.3 (M+H) at 2.41 min. 1 H NMR:(400MHz,CDCl3)δ0.03~0.13(2H,m),0.45~0.49(2H,m),0.67~0.77(4H,m),0.86(3H,s),0.93~0. 96(6H,m),1.03(3H,s),1.05(1H,brd,J=3.6Hz),1.37~1.41(1H,m),1.48~1.51(1H,m),1.62~1.68(1H ,m),1.75~1.83(2H,m),2.00~2.06(1H,m),3.77~3.84(1H,m),3.97(1H,brd,J=10.4Hz),4.44~4.55(2 H,m),5.26~5.43(1H,m),5.69~5.91(1H,m),6.33~6.44(1H,m),6.75~6.85(1H,m),7.26~7.49(1H,m).

[0184] Preparative HPLC (NH4HCO3) method for purification of Example 2. Instrument: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 15-45% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0185] Example 3 (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-alloisoleucyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0186] The title compound (50.0 mg, 0.10 mmol, white solid) was prepared from Intermediate 1 (380 mg, 1.29 mmol) and (2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoic acid (372 mg, 1.61 mmol) using procedures similar to those detailed for Intermediate 1 (Step 90) and Example 1 (Steps 2-4). Example 3 was purified by preparative HPLC (NH4HCO3 as additive). LCMS (Method D): m / z 477.3 (M+H) at 2.59 min. 1 H NMR:(400MHz,CDCl3)δ0.00~0.16(2H,m),0.41~0.52(2H,m),0.66~0.77(1H,m),0.84(3H,s),0.85~0.88(3H,m ),0.89~0.96(3H,m),1.03(3H,s),1.06~1.10(3H,m),1.13(3H,m),1.45~1.56(2H,m),1.63~1.70(1H,m),1.71~ 1.90(4H,m),2.30~2.42(1H,m),3.77~3.84(1H,m),4.04(1H,d,J=10.8Hz),4.44(1H,d,J=9.6Hz),4.51~4.58(1 H,m),5.35~5.40(1H,m),5.96(1H,brs),6.15(1H,brt,J=9.8Hz),6.80(1H,brd,J=11.2Hz),7.27~7.47(1H,m).

[0187] Preparative HPLC (NH4HCO3) method for purification of Example 3. Instrument: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 22-52% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0188] Example 4(1R,2S,5S)-3-(Acryloyl-L-valyl)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0189] The title compound (32.4 mg, 0.07 mmol, white solid) was prepared from intermediate 2 (130 mg, 0.33 mmol) and prop-2-enoyl chloride (38.8 mg, 0.43 mmol, 0.03 mL) in a similar manner to Example 1 (steps 3 and 4). Example 4 was purified twice by preparative HPLC (NH4HCO3 as additive, then formic acid as additive). LCMS (Method D): m / z 447.0 (M+H) at 2.21 min. 1 H NMR:(400MHz,CDCl3)δ0.00~0.14(2H,m),0.40~0.51(2H,m),0.68~0.74(1H,m),0.84~0.89(3H,m),0.89~0.93(3H,m), 0.95~1.00(3H,m),1.02~1.07(3H,m),1.48~1.56(1H,m),1.61~1.67(1H,m),1.73~1.81(1H,m),1.86~2.09(2H,m),3.80 ~3.88(1H,m),3.96(1H,brd,J=10.4Hz),4.40~4.49(1H,m),4.56~4.66(1H,m),5.25~5.43(1H,m),5.64(1H,brd,J=10.4 Hz), 5.81~6.01(1H,m),6.08~6.17(1H,m),6.24~6.31(1H,m),6.36~6.62(1H,m),6.77~6.88(1H,m),7.26~7.45(1H,m).

[0190] Preparative HPLC (NH4HCO3) method for purification of Example 4. Instrument: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 15-45% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0191] Preparative HPLC (Formic Acid) method for purification of Example 4. Instrument: Shimadzu LC-20AP; Column: Shim-pack C18 150×25 mm×10 μm; Mobile phase: A=0.225% formic acid (v / v) in water, B=MeCN; Gradient: 12-42% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40° C.; Wavelength: 220 nm, 254 nm.

[0192] Example 5 (1R,2S,5S)-N-(4-amino-1-((1R,2S)-2-methylcyclopropyl)-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0193] (1R,2S,5S)-N-(4-amino-3-hydroxy-1-((1R,2S)-2-methylcyclopropyl)-4-oxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (Intermediate 3, 0.37 g, 1.07 mmol) and (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (232 mg, 1.07 mmol) were used in a similar procedure to that detailed for Example 1 (Steps 1-4). Example 5 was purified by preparative HPLC (formic acid as additive). LCMS (Method D2): m / z 477.3 (M+H) at 2.59 min. 1H NMR:(400MHz,CD3OD)δ0.10~0.30(2H,m),0.34~0.62(2H,m),0.88~1.14(23H,m),1.40~1 .59(2H,m),1.94~2.17(1H,m),2.43~2.57(1H,m),3.89~4.09(2H,m),4.10~4.53(3H,m).

[0194] Preparative HPLC (Formic Acid) method for purification of Example 5. Instrument: Shimadzu LC-20AP; Column: Shim-pack C18 150×25 mm×10 μm; Mobile phase: A=0.225% formic acid (v / v) in water, B=MeCN; Gradient: 25-55% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 25° C.; Wavelength: 220 nm, 254 nm.

[0195] Example 6 (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3-cyclopropyl-2-isobutyramidopropanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0196] The title compound (76.6 mg, 0.16 mmol, white solid) was prepared from (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Intermediate 1, 380 mg, 1.29 mmol). 29 mmol) and (2S)-2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoic acid (383 mg, 1.67 mmol) were used in a similar procedure to that detailed for Intermediate 1 (Step 9) and Example 1 (Steps 2-4). Example 6 was purified by preparative HPLC (NH4HCO3 as additive). LCMS (Method D): m / z 475.6 (M+H) at 2.51 min. 1 H NMR:(400MHz,CDCl3)δ-0.02~0.14(4H,m),0.39~0.50(4H,m),0.62~0.77(2H,m),0.85~0.95(3H,m),1.03(3H, s),1.06~1.10(3H,m),1.11~1.13(3H,m),1.39~1.53(2H,m),1.56~1.64(1H,m),1.64~1.77(2H,m),1.77~1.89( 1H,m),2.31~2.41(1H,m),3.80~3.86(1H,m),3.91~4.00(1H,m),4.43(1H,d,J=11.2Hz),4.70~4.80(1H,m),5.2 9~5.43(1H,m),6.27~6.42(1H,m),6.48(1H,brdd,J=18.8,8.0Hz),6.85(1H,brd,J=9.6Hz),7.19~7.38(1H,m).

[0197] Preparative HPLC (NH4HCO3) method for purification of Example 6. Instrument: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 18-48% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0198] Example 7 (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0199] The title compound (16.1 mg, 0.03 mmol, white solid) was prepared from (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Intermediate 1, 180 mg, 0.61 mmol). 61 mmol) and (2S)-3-methyl-2-(2-methylpropanoylamino)butanoic acid (Intermediate 4, 114 mg, 0.61 mmol) were used in a similar procedure to that detailed for Intermediate 1 (Step 1) and Example 1 (Step 4). Example 7 was purified twice by preparative HPLC (formic acid as additive, then NH4HCO3 as additive). LCMS (Method E): m / z 463.3 (M+H) at 2.73 min. 1 H NMR:(400MHz,CDCl3)δ0.05~0.08(1H,m),0.11~0.13(1H,m),0.47~0.50(2H,m),0.70~0.75(1H,m),0.87(3H,s ),0.92~0.96(6H,m),1.05(3H,s),1.12~1.16(6H,m),1.52(1H,brs),1.68~1.72(1H,m),1.76~1.88(2H,m),2. 01~2.08(1H,m),2.36~2.41(1H,m),3.80~3.85(1H,m),3.98(1H,brd,J=10.8Hz),4.47(1H,d,J=12.0Hz),4.50 ~4.58(1H,m),5.35~5.43(1H,m),5.45~5.53(1H,m),5.98~6.06(1H,m),6.75~6.78(1H,m),7.21~7.44(1H,m).

[0200] Preparative HPLC (Formic Acid) method for purification of Example 7. Instrument: Shimadzu LC-20AP; Column: Unisil 3-100 C18 Ultra 150×50 mm×3 μm; Mobile phase: A=0.225% formic acid (v / v) in water, B=MeCN; Gradient: 25-55% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 25° C.; Wavelength: 220 nm, 254 nm.

[0201] Preparative HPLC (NH4HCO3) method for purification of Example 7. Instrument: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 21-51% B in A over 9 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0202] Example 8 (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-(((S)-2-methylbutanoyl)-L-valyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0203] (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-3-[(2S)-2-amino-3-methyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Intermediate 2, 120 mg, 0.28 mmol)) and (2S)-2-methylbutanoic acid (28.4 mg, 0.28 mmol) were used in a similar procedure as detailed for Example 1 (Steps 1 and 4). Example 8 was purified by preparative HPLC (formic acid as additive). LCMS (Method D2): m / z 477.0 (M+H) at 2.60 min. 1H NMR:(400MHz,CDCl3)δ0.00~0.20(2H,m),0.42~0.55(2H,m),0.68~0.76(1H,m),0.82~0.88(6H,m),0.91~0. 99(6H,m),1.05(3H,s),1.14(3H,d,J=6.8Hz),1.36~1.42(1H,m),1.48~1.54(1H,m),1.56~1.72(2H,m),1.7 5~1.89(2H,m),1.95~2.09(1H,m),2.11~2.22(1H,m),3.75~3.90(1H,m),4.01~4.04(1H,m),4.41~4.65(2H, m),5.39(1H,brs),5.60~5.83(1H,m),6.04~6.25(1H,m),6.78(1H,brd,J=11.6Hz),7.42(1H,brd,J=7.2Hz).

[0204] Preparative HPLC (Formic Acid) method for purification of Example 8. Instrument: Shimadzu LC-20AP; Column: Phenomenex luna C18 150×25 mm, 10 μm; Mobile phase: A=0.225% formic acid (v / v) in water, B=MeCN; Gradient: 32-62% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 25° C.; Wavelength: 220 nm, 254 nm.

[0205] Example 9 (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-(cyclopropanecarboxamido)-2-cyclopropylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0206] The title compound (10.9 mg, 0.02 mmol, white solid) was prepared from Intermediate 1 (560 mg, 1.90 mmol) and (2S)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (612 mg, 2.84 mmol) using procedures similar to those detailed for Intermediate 1 (Step 1) and Example 1 (Steps 2-4). Example 9 was purified by preparative HPLC (NH4HCO3 as additive). LCMS (Method D2): m / z 459.3 (M+H) at 2.44 min. 1 H NMR:(400MHz,CDCl3)δ0.01~0.19(2H,m),0.40~0.61(6H,m),0.67~0.81(3H,m),0.86~ 0.94(3H,m),0.94~1.03(2H,m),1.03~1.10(3H,m),1.10~1.23(1H,m),1.36~1.42(1H,m ),1.46~1.53(1H,m),1.66~1.71(1H,m),1.72~1.89(2H,m),3.76~3.99(2H,m),4.22~4. 45(1H,m),4.45~4.66(1H,m),5.36~5.64(1H,m),6.34~6.59(1H,m),6.66~6.83(1H,m).

[0207] Preparative HPLC (NH4HCO3) method for purification of Example 9. Instrument: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 15-45% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0208] Example 10 (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-cyclopropyl-2-isobutylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0209] The title compound (20.2 mg, 0.04 mmol white solid) was prepared from Intermediate 1 (560 mg, 1.90 mmol) and (2S)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (612 mg, 2.84 mmol) using procedures similar to those detailed for Intermediate 1 (Step 1) and Example 1 (Steps 2-4). Example 10 was purified by preparative HPLC (NH4HCO3 as additive). LCMS (Method D2): m / z 461.5 (M+H) at 2.48 min. 1 H NMR:(400MHz,CDCl3)δ0.01~0.06(1H,m),0.09~0.14(1H,m),0.40~0.52(6H,m),0.68~0.73(1H,m),0.89( 3H,s),1.04(3H,s),1.13(6H,dd,J=15.6,6.8Hz),1.47~1.53(1H,m),1.68(1H,dd,J=7.6,2.0Hz),1.78~1. 83(2H,m),1.84~1.90(1H,m),2.34~2.42(1H,m),3.82~3.90(2H,m),4.36(1H,brt,J=7.8Hz),4.46(1H,d,J =16.8Hz),5.36~5.45(1H,m),5.77~5.91(1H,m),6.32~6.34(1H,m),6.75~6.87(1H,m),7.22~7.34(1H,m).

[0210] Preparative HPLC (NH4HCO3) method for purification of Example 10. Instrument: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 15-45% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0211] Example 11(1R,2S,5S)-N-(4-(benzylamino)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0212] Process 1 HATU (1.23 g, 3.23 mmol) was added to a solution of (1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Intermediate 5, 0.70 g, 2.16 mmol) in DMF (10 mL) and the reaction mixture was stirred at rt for 10 min. 3-Amino-N-benzyl-4-cyclopropyl-2-hydroxybutanamide (Intermediate 6, 0.53 g, 2.16 mmol) and DIPEA (1.11 mL, 6.47 mmol) were added and after stirring at rt for 18 h the reaction mixture was partitioned between cold water (150 mL) and EtOAc (70 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3x70 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse-phase gradient column chromatography (C18 silica) eluting with 0-60% MeCN in water gave (1R,2S,5S)-N-((2S)-4-(benzylamino)-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (0.59 g, 1.06 mmol) as a white solid. LCMS (Method G): m / z 555.9 (M+H) at 2.20, 2.25, 2.38 min.

[0213] Process 2:IBX (0.40 g, 1.44 mmol) was added to a solution of (1R,2S,5S)-N-((2S)-4-(benzylamino)-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (0.40 g, 0.72 mmol) in DMSO (5 mL) at rt and the reaction mixture was stirred at 60° C. for 2 h. Water (50 mL) and EtOAc (30 mL) were added, the phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo. Purification by reverse-phase gradient column chromatography (C18 silica) eluting with 0-60% MeCN in water gave Example 11 (0.22 g, 0.40 mmol) as a white solid. LCMS (Method H): m / z 553.3 (M+H) at 7.70 and 7.958.29 min. 1 H NMR:(400MHz,DMSO-d6)δ0.08~0.07(m,2H),0.41~0.35(m,2H),0.77~0.69(m,9H),1.01~0.83(m,1 0H),1.32(d,1H,J=7.6Hz),1.49~1.40(m,2H),1.79~1.69(m,1H),1.91~1.90(m,1H),2.45~2.41(m ,1H),3.75~3.72(m,1H),3.89(d,1H,J=10.4Hz),4.11(t,1H,J=9.2Hz),4.43~4.25(m,3H),5.10~5 .05(m,1H),7.33~7.24(m,5H),7.97(d,1H,J=8.4Hz),8.50(d,1H,J=6.4Hz),9.26(t,1H,J=6.0Hz).

[0214] Example 12 (1R,2S,5S)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0215] Process 1 EDCI-HCl (0.19 g, 1.03 mmol) and HOBt (0.11 g, 0.86 mmol) were mixed with 4-cyclopropyl-2-hydroxy-3-((1R,2S,5S)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide)butanoic acid (Intermediate 8, 0.40 g, 0.86 mmol) and cyclopropylamine (59 mg, 1.03 mmol) in EtOAc (4 mL) and HO (1 mL) at 0° C. and the reaction mixture was stirred at rt for 3 h and then concentrated in vacuo. Purification by reverse-phase gradient flash column chromatography (C18 silica) eluting with 0–46% MeCN in water gave (1R,2S,5S)-N-(1-cyclopropyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (0.25 g, 0.50 mmol) as an off-white solid. LCMS (Method I): m / z 505.6 (M+H) at 1.51, 1.57, 1.66 min.

[0216] Process 2 :DMP (0.31 g, 0.74 mmol) was added to a solution of (1R,2S,5S)-N-(1-cyclopropyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (0.25 g, 0.49 mmol) in EtOAc (3 mL) and the reaction mixture was stirred at rt for 48 h. After filtration through Celite and washing with EtOAc (50 mL), the filtrate was concentrated in vacuo. Purification by reverse-phase gradient flash column chromatography (C18 silica), eluting with 0-65% MeCN in water with 0.1% formic acid as a modifier, afforded Example 12 (31 mg, 0.06 mmol) as an off-white solid. LCMS (Method I): m / z 503.5 (M+H) at 1.48, 1.75 min. 1 H NMR:(400MHz,DMSO-d6)δ0.08~0.03(m,2H),0.42~0.37(m,2H),0.56(s,2H),0.65~0.63(d,2H,J=7.2Hz) ,0.75~0.74(m,9H),1.11~0.82(m,10H),1.48~1.23(m,3H),1.89~1.69(m,1H),1.92~1.90(m,1H),2.50~ 2.33(m,1H),2.74~2.60(m,1H),3.74~3.70(m,1H),3.91~3.88(m,1H),4.12~4.07(m,1H),4.29(s,1H),5 .05~5.01(m,1H),7.98~7.96(d,1H,J=8.4Hz),8.47~8.46(d,1H,J=6.4Hz),8.75~8.74(d,1H,J=4.8Hz).

[0217] Example 26 (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3-methyl-3-phenylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0218] The title compound (18.2 mg, 0.03 mmol, white solid) was prepared from intermediate 9 (31.0 mg, 0.05 mmol) in the same manner as in Example 1 (steps 2-4). Example 26 was purified by preparative HPLC (NH4HCO3 as additive). LCMS (Method J): m / z 539.3 (M+H) at 2.80 min. 1H NMR:(400MHz,CDCl3)δ0.03~0.22(2H,m),0.43~0.57(2H,m),0.71~0.78(3H,m),0.78~0.89(1H,m),0.94~0.98(3H, m),1.02~1.08(6H,m),1.27~1.32(1H,m),1.40~1.48(6H,m),1.52~1.62(1H,m),1.80~1.91(2H,m),2.27~2.35(1H,m ),2.83~2.89(1H,m),3.69~3.72(1H,m),4.32~4.36(1H,m),4.97~5.01(1H,m),5.27~5.43(1H,m),5.72~5.88(1H,m) ,6.09~6.20(1H,m),6.81(1H,brs),7.17~7.23(1H,m),7.26~7.34(2H,m),7.38(2H,d,J=7.6Hz),7.41~7.52(1H,m).

[0219] Preparative HPLC (NH4HCO3) method for purification of Example 26. Instrument: Shimadzu LC-20AP; Column: Waters Xbridge 150 x 25 mm x 5 μm; Mobile phase: A = 10 mM NH4HCO3 in water (v / v), B = MeCN; Gradient: 30-60% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0220] Example 28 (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0221] Process 1N-Methylmorpholine (0.17 mL, 1.59 mmol) was added to 4-cyclopropyl-2-hydroxy-3-((1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)butanoic acid (Intermediate 10, 0.19 g, 0.40 mmol) and azetidine (32 mg, 0.48 mmol) in DMF (2.8 mL) at 0° C., the reaction mixture was stirred at rt for 4 h, water (80 mL) was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by reverse-phase gradient flash column chromatography (silica C18) eluting with 0% to 60% MeCN in water gave (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (0.15 g, 0.29 mmol) as a brown solid. LCMS (Method F3): m / z 519.4 (M+H) at 1.58, 1.65 and 1.70 min.

[0222] Process 2Dess-Martin periodinane (0.17 g, 0.41 mmol) was added to a solution of (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (0.14 g, 0.27 mmol) in EtOAc (3 mL) and the reaction mixture was stirred at rt for 16 h before being filtered through a bed of Celite and washed with EtOAc (100 mL). The filtrate was concentrated in vacuo and purified by reversed-phase gradient flash column chromatography (silica C18). 1% formic acid) to give Example 28, (1R,2S,5S)—N-(4-(azetidin-1-yl)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (57 mg, 0.11 mmol) as a white solid. LCMS (Method K): m / z 517.0 (M+H) at 7.49 min. 1 H NMR:(400MHz,DMSO-d6)δ0.03~0.11(m,2H),0.35~0.43(m,2H),0.80~1.03(m,22H),1.2 9~1.31(m,1H),1.43~1.50(m,2H),1.69~1.71(m,1H),2.23~2.27(t,2H,J=7.8Hz),2.54~ 2.59(m,1H),3.77~3.85(m,2H),3.88~4.00(m,2H),4.20~4.33(m,3H),4.39~4.41(d,1H ,J=9.6Hz),4.72~4.77(m,1H),7.74~7.76(d,1H,J=9.2Hz),8.52~8.53(d,1H,J=6.4Hz).

[0223] Example 34: (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0224] Process 1 To a mixture of (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2-hydroxy-3-oxo-propyl]-3-[(2S)-2-amino-3,3-dimethylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Example 1, Step 2 product, 400 mg, 0.98 mmol) in CHCl (5 mL) was added dropwise a solution of EtN (0.20 mL, 1.47 mmol) and TFAA (0.20 mL, 1.47 mmol, 0.20 mL) in CHCl (2 mL) at 0° C. The reaction mixture was stirred at 25° C. for 2 h, after which H0 (40 mL) was added. After extraction with ethyl acetate (20 mLx3), the combined organic phase was washed with brine (30 mLx3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC (formic acid as additive) afforded (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (170 mg, 0.34 mmol) as a white solid. LCMS (Method A): m / z 505.2 (M+H) at 0.81 min. 1 H NMR:(400MHz,MeOD-d4)δ-0.08~0.21(2H,m),0.26~0.53(2H,m),0.64~1.14(16H,m),1.16~2.32(4H,m),3.60~4.73(6H,m).

[0225] Preparative HPLC (Formic Acid) method for purification of step 1. Instrument: Shimadzu LC-20AP; Column: Unisil 3-100 C18 Ultra 150 x 50 mm x 3 μm; Mobile phase: A = 0.225% formic acid (v / v) in water, B = MeCN; Gradient: 30-60% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0226] Process 2 :IBX (305 mg, 1.09 mmol) was added to a solution of (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (220 mg, 0.44 mmol) in DMSO (3 mL) and the reaction mixture was stirred at 25° C. for 2 h, after which H2O (20 mL) was added and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (30 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC (formic acid as additive) afforded (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (195 mg, 0.39 mmol) as a white solid. LCMS (Method J): m / z 503.3 (M+H) at 3.04 min. 1 H NMR:(400MHz,DMSO-d6)δ-0.14~0.16(2H,m),0.24~0.49(2H,m),0.56~1.20(16H,m),1.34~1.77(4H,m),3.47~3.99(2H ,m),4.17~4.64(2H,m),4.74~5.38(1H,m),7.66~7.85(1H,m),7.86~8.11(1H,m),8.26~8.74(1H,m),9.15~9.59(1H,m).

[0227] Preparative HPLC (Formic Acid) method for purification of step 1. Instrument: Shimadzu LC-20AP; Column: Unisil 3-100 C18 Ultra 150 x 50 mm x 3 μm; Mobile phase: A = 0.225% formic acid (v / v) in water, B = MeCN; Gradient: 33-63% B in A over 10 min; Flow rate: 25 mL / min; Column temperature: 40 °C; Wavelength: 220 nm, 254 nm.

[0228] Example 35 (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide [ka]

[0229] Process 1 LiOH (154 mg, 6.37 mmol) was added to a suspension of methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 10, step 1 product, 2.50 g, 6.37 mmol) in THF / MeOH / H2O (32 mL, 10:3:3:3) and the mixture was stirred at rt for 3 h. The aqueous layer was acidified to pH 2-3 with 1.5 N HCl and extracted with DCM (2x30 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo to afford (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.12 g, 5.60 mmol) as a white solid, which was used in the next step without further purification. LCMS (Method L): m / z 369.3 (M+H) at 2.26 min. 1 H NMR:(400MHz,DMSO-d6)δ12.53(br s,1H),6.68(d,J=9.6Hz,1H),4.13(s,1H),4.05(d,J=9.6Hz,1H),3.91(d,J=10.4Hz,1H),3.79~3.7 4(m,1H),1.51~1.47(m,1H),1.41~1.37(m,1H),1.35(s,9H),1.01(s,3H),0.94(s,9H),0.84(s,3H).

[0230] Step 2: SOCl2 (1.15 mL, 15.6 mmol) was added to a stirred solution of 3-amino-4-cyclopropyl-2-hydroxybutanamide (2.50 g, 15.6 mmol) in EtOH (20 mL) at 0 °C and the reaction mixture was stirred at 65 °C for 15 h. Concentration in vacuo and azeotropic evaporation with toluene (2x20 mL) afforded crude ethyl 3-amino-4-cyclopropyl-2-hydroxybutanoate (2.10 g) as a brown semi-solid, which was used in the next step without further purification. LCMS (Method L): m / z 188.3 (M+H) at 1.03 min.

[0231] Process 3To a suspension of (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.45 g, 6.25 mmol) and ethyl 3-amino-4-cyclopropyl-2-hydroxybutanoate (1.65 g, 7.50 mmol) in DCM (20 mL) was added DIPEA (3.37 mL, 18.8 mmol) at rt followed by T3P (50% in EtOAc) (5.58 mL, 9.38 mmol) at 0° C. The resulting reaction mixture was stirred at rt for 3 h, 10% aqueous NaHCO3 was added at rt and the mixture was extracted with DCM (2×25 mL). The combined organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by gradient flash column chromatography on silica, eluting with 0-50% EtOAc in petroleum ether, gave ethyl 3-((1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-4-cyclopropyl-2-hydroxybutanoate (2.30 g, 4.19 mmol) as a pale yellow gum. LCMS (Method L): m / z 538.4 (M+H) at 2.43-2.47 min. 1 H NMR:(400MHz,DMSO-d6)δ7.90(d,J=8.8Hz,1H),6.57(d,J=9.2Hz,1H),5.57~5. 50(m,1H),4.27(d,J=2.8Hz,1H),4.11~4.09(m,1H),4.04~4.00(m,4H),3.95~3. 85(m,1H),3.82~3.71(m,1H),1.40(s,9H),1.18~1.13(m,6H),1.05~0.95(m,4H) ,0.93~0.83(m,10H),0.72~0.61(m,1H),0.35~0.09(m,2H),0.15~0.15(m,2H).

[0232] Step 4: To a solution of 4M HCl in 1,4-dioxane (5 mL, 20 mmol) was added ethyl 3-((1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-4-cyclopropyl-2-hydroxybutanoate (2.20 g, 4.01 mmol) in DCM (10 mL) dropwise at 0° C. and the reaction mixture was stirred at rt for 3 h. The supernatant layer was decanted from the reaction mixture and the solid gummy residue was triturated with MTBE (10 mL). The MTBE layer was decanted and the residue was dried in vacuum to give crude ethyl 3-((1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-4-cyclopropyl-2-hydroxybutanoate hydrochloride (1.80 g) as an off-white solid, which was used in the next step without further purification. LCMS (Method L): m / z 438.4 (M+H) at 1.42-1.79 min.

[0233] Process 5 : LiOH (296 mg, 12.2 mmol) was added dropwise to a suspension of ethyl 3-((1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-4-cyclopropyl-2-hydroxybutanoate hydrochloride (1.45 g, 2.45 mmol) in THF / MeOH / HO (16 mL, 10:3:3) at rt. After stirring at rt for 3 h, water (5 mL) was added and the mixture was acidified with 1.5 N aqueous hydrochloric acid to pH ∼2-3, and the reaction mixture was concentrated in vacuo and azeotroped with toluene (3x20 mL) to afford crude 3-((1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-4-cyclopropyl-2-hydroxybutanoic acid hydrochloride (2.2 g) as a light brown solid, which was used in the next step without further purification. LCMS (Method L): m / z 410.3 (M+H) from 1.05 to 1.53 min.

[0234] Process 6 To a solution of trimethylamine (1.04 mL, 7.38 mmol) and ethyl 2,2,2-trifluoroacetate (0.48 mL, 4.92 mmol) was added 3-((1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-4-cyclopropyl-2-hydroxybutanoic acid hydrochloride (2.4 g, 2.46 mmol) in MeOH (20 mL) at 0° C. and the reaction mixture was stirred at rt for 16 h. The reaction mixture was then acidified with 4 M hydrochloric acid in 1,4-dioxane (3 mL, 12 mmol), water (10 mL) was added and concentrated in vacuo before being extracted with EtOAc (2×25 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and azeotroped with toluene (3x20mL) to afford crude 4-cyclopropyl-3-((1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-2-hydroxybutanoic acid (1.20g) as an off-white solid, which was used in the next step without further purification. LCMS (Method L): m / z 506.4 (M+H) from 2.03 to 2.09 min.

[0235] Process 7N-Methylmorpholine (NMM, 1.37 mL, 12.4 mmol), azetidine hydrochloride (467 mg, 4.94 mmol) and 4-cyclopropyl-3-((1R,2S,5S)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-2-hydroxybutanoic acid (1.42 g, 2.47 mmol) were dissolved in DMF (5 mL) and the reaction mixture was stirred at rt for 5 min. HATU (1.42 g, 3.71 mmol) was added at 0° C. and the reaction mixture was stirred at rt for 2 h, after which water (2 mL) was added and concentrated in vacuo. Purification by gradient reverse-phase flash column chromatography on silica C18 eluting with 0% to 70% MeCN in water gave (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (0.75 g, 1.18 mmol) as an off-white solid. LCMS (Method L): m / z 545.3 (M+H) in 2.06-2.14 min. 1 H NMR:(400MHz,DMSO-d6)δ9.43~9.31(m,1H),7.94~7.71(m,1H),5.22~5.01(m,1H),4.43~4.31(m,1H),4.30~4.17(m,3H),4.15~3.70(m,4H) ),2.28~2.18(m,2H),1.57~1.48(m,2H),1.31~1.22(m,2H),1.21~0.82(m,17H),0.76~0.65(m,1H),0.39~0.17(m,2H),0.15~0.19(m,2H).

[0236] Process 8Dess-Martin periodinane (1.17 g, 2.75 mmol) was added to a solution of (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (0.50 g, 0.92 mmol) in EtOAc (10 mL) at rt and the reaction mixture was stirred at rt for 2 h before EtOAc (10 mL) was added. The mixture was filtered through Celite and the residue was washed with EtOAc (50 mL). The filtrate was concentrated in vacuo to give 0.25 g of (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3-hydroxy-4-oxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide). Purification by gradient reverse-phase flash column chromatography on silica C18 (HO+0.1% TFA) afforded (1R,2S,5S)—N-(4-(azetidin-1-yl)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (Example 35, 185 mg, 0.33 mmol) as a white solid. LCMS (Method L): m / z 543.3 (M+H) at 2.34 min. 1 H NMR:(400MHz,DMSO-d6)δ9.40~9.35(m,1H),8.73~8.58(m,1H),4.81~4.51(m,1H),4.44~4.18(m,2H),3.97~3.69(m,4H) ),2.34~2.22(m,2H),1.73~1.34(m,3H),1,34~1.28(m,1H),1.06~0.76(m,18H),0.42~0.36(m,2H),0.18~0.05(m,2H).

[0237] biological activity SARS-CoV-2 Mpro construct design The SARS CoV-2-Mpro (main protease / 3C-like protease, UniProt ID: P0DTD1) protein sequence, up to its self-cleavage boundary and as well as the preceding N-terminal 5 amino acid residues including the P1 glutamine residue, was codon-optimized for E. coli expression and cloned into pET26b (Merck, #US169862-3) or pGEX6P1 (Fisher Scientific, #10350355) vectors using BamHI and XhoI sites. Thus, the expression constructs featured the native viral N-terminal sequence and a C-terminal modified 3C protease cleavage site (LEVLFQGK) with an alternative lysine residue at the P2' position followed by a polyhistidine (His-8) tag.

[0238] Protein expression and purification Chemically competent BL21(DE3)-RIL E. coli (Agilent, #230240) cells were transformed with the relevant coronavirus Mpro constructs and grown overnight at 37°C on LB agar plates supplemented with the appropriate antibiotics. All cultivations were performed at 37°C. Scrapings of colonies were grown in 15 mL of antibiotic-supplemented LB medium for approximately 2 hours, taking care that the optical density (OD) measured at 600 nm in a spectrophotometer did not exceed 2.0. This preculture was inoculated into 500 mL expression cultures: LB medium for IPTG-induced expression, or autoinduction Super Broth medium (Formedium, #AIMSB0210). In LB medium, expression was induced at an OD of 0.7–1.0 by adding IPTG to a final concentration of 0.5 mM. Cultures were then grown overnight at 18°C. For autoinduction expression, the temperature was reduced to 18°C ​​when an OD of 0.7–1.0 was observed, and the culture was grown overnight. Cells were harvested by centrifugation and frozen until use.

[0239] Thawed cells were resuspended in resuspension buffer: 20 mM Tris-HCl pH 8.0, 150 mM NaCl, DNase I (Merck #4716728001) and lysed by sonication. The lysate was clarified by centrifugation at 23,000 rcf for 15 min at 4°C. The supernatant was loaded onto 5 mL of NiNTA resin (Cytiva, #17-5248-02) at a flow rate of 0.5 mL / min. The resin was washed with the same buffer as above containing 20 mM imidazole. Mpro protein was eluted with the same buffer containing 250 mM imidazole. The target protein was further purified in resuspension buffer using a Superdex S75 16 / 60 pg (GE, #GE28-9893-33) column. Protein purity was assessed by SDS-PAGE and identity was confirmed by mass spectrometry. The purified protein was concentrated and stored frozen until further use.

[0240] SARS-CoV-2 Mpro enzyme assay The activity of SARS-Cov-2 Mpro was determined in a fluorescence resonance energy transfer (FRET)-based enzyme assay using the FRET substrate Dabcyl-KTSAVLQSGFRKM-E(Edans)-Amide. Briefly, 100 nL of test compound (concentrations ranging from 10 μM to 0.00051 μM) was preincubated with 5 μL of 5 nM (final concentration) Mpro enzyme for 20 min at room temperature in an assay buffer containing 20 mM Tris (pH 7.5), 100 mM NaCl, and 1 mM EDTA. The reaction was initiated by the addition of 5 μL of 25 μM (final concentration) FRET substrate (Dabcyl-KTSAVLQSGFRKM-E(Edans)-Amide). The resulting fluorescence intensity at Ex=360 nm / Em=490 nm was measured every 90 s for 60 min at room temperature using a PHERAstar plate reader (BMG Labtech). The linear portion of the reaction was selected using MARS software (BMG Labtech) and RFU per minute was calculated. pIC50 and pKi were determined using 4PL GraphPad Prism and data were expressed as mean n=2±SD. pKi values ​​of the compounds of the present invention are shown in Table 2. [Table 2-1]

Table 2-2

Claims

1. Formula (1b): 【Chemistry 1】 or a salt thereof, wherein: R １ and R １ａ are independently H, C optionally substituted with 1 to 6 fluorine or chlorine atoms, １－６ a saturated hydrocarbon group or a benzyl group optionally substituted with 1 to 6 fluorine or chlorine atoms, or R １ and R １ａ are joined to form a saturated ring optionally containing additional heteroatoms; R ２ C includes a cycloalkyl group optionally substituted with one or more substituents selected from fluorine or hydroxyl. ３－５ is a saturated hydrocarbon group; R ３ is a saturated group containing 3 to 5 carbon atoms, optionally containing a cycloalkyl group, or optionally containing a saturated ring containing an oxygen heteroatom, optionally substituted with one or more substituents selected from fluorine or hydroxyl, or R ３ is CH ２ Ariel, CH (CH ３ )aryl or C(CH ３ ) ２ is an aryl; R ５ is C ２－８ A hydrocarbon group, optionally containing one or more rings or double bonds, optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; or a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.

2. R １ is H, CH ３ , benzyl, cyclopropyl or 【Chemistry 2】 2. The compound of claim 1 ,

3. R １ａ is H. The compound of claim 1 or claim 2.

4. R １ and R １ａ and R are both H.

5. R １ and R １ａ are both -CH ３ 2. The compound of claim 1,

6. R １ and R １ａ The compound of claim 1, wherein:

7. R １ and R １ａ The compound of claim 1 , wherein:

8. R ２ Below: 【Chemistry 3】 2. The compound of claim 1 selected from the group consisting of:

9. R ３ Below: 【Chemistry 4】 2. The compound of claim 1 selected from the group consisting of:

10. R ５ Below: 【Chemistry 5】 2. The compound of claim 1 selected from the group consisting of:

11. Formula (3b): 【Chemistry 6】 or a salt thereof.

12. below: (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxo-propyl]-3-[(2S)-2-(cyclopropanecarbonylamino)-3-methylbutanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-alloisoleucyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-(acryloyl-L-valyl)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-((1R,2S)-2-methylcyclopropyl)-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3-cyclopropyl-2-isobutyramidopropanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-(((S)-2-methylbutanoyl)-L-valyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-(cyclopropanecarboxamide)-2-cyclopropylacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-cyclopropyl-2-isobutyramidoacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(benzylamino)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-valyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(2-isobutyramido-2-(oxetan-3-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-(cyclopropanecarboxamide)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-((S)-2-acrylamido-3,3-dimethylbutanoyl)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-((S)-2-acrylamido-3,3-dimethylbutanoyl)-N-(4-(benzylamino)-1-cyclopropyl-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(benzylamino)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(benzylamino)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-(cyclopropanecarboxamide)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-((S)-2-(cyclopropanecarboxamide)-3,3-dimethylbutanoyl)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-((S)-2-acrylamido-3,3-dimethylbutanoyl)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(1-cyclopropyl-4-(methylamino)-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(1-cyclopropyl-4-(dimethylamino)-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(aziridin-1-yl)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-cyclobutyl-2-isobutyramidoacetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3-methyl-3-phenylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-3-((cyclopropanecarbonyl)-L-valyl)-N-(1-cyclopropyl-4-(cyclopropylamino)-3,4-dioxobutan-2-yl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(2-isobutyramido-2-(tetrahydrofuran-3-yl)acetyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(1-cyclopropyl-4-(((S)-2,2-dimethylcyclopropyl)amino)-3,4-dioxobutan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-(isobutyryl-L-phenylalanyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(3,3,3-trifluoro-2-(trifluoromethyl)propanamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-amino-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-(4-(azetidin-1-yl)-1-cyclopropyl-3,4-dioxobutan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; or a salt thereof.

13. The compound according to claim 1, which has an inhibitory activity against SARS-CoV-2 Mpro.

14. 13. A pharmaceutical composition comprising a compound of claim 1 and a pharma- ceutically acceptable excipient.

15. 15. The pharmaceutical composition of claim 14 for use in the treatment of SARS-CoV-2 or in the treatment of a disorder associated with SARS-CoV-2.

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