SARS-COV-2 Mpro inhibitors and their uses

Abstract

This application relates to novel compounds and their use as SARS-CoV-2 main protease (Mpro) inhibitors. The compounds described herein are useful for the treatment of SARS-CoV-2 and related viruses and disorders associated with SARS-CoV-2:Mpro. This application is also directed to pharmaceutical compositions containing these compounds, as well as the manufacture and use of these compounds and compositions in the treatment of SARS-CoV-2 and SARS-CoV-2-related viruses and disorders:Mpro. The compounds and compositions are useful for preventing death or complications arising from underlying chronic or comorbid conditions in patients infected with SARS-CoV-2 and related viruses.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION This application relates to novel compounds and their use as SARS-CoV-2 main protease (Mpro) inhibitors. The compounds described herein are useful for the treatment of SARS-CoV-2 and related viruses and disorders associated with SARS-CoV-2:Mpro. This application is also directed to pharmaceutical compositions containing these compounds, as well as the manufacture and use of these compounds and compositions in the treatment of SARS-CoV-2 and SARS-CoV-2-related viruses and disorders:Mpro. The compounds and compositions are useful for preventing death or complications arising from underlying chronic or comorbid conditions in patients infected with SARS-CoV-2 and related viruses. [Background technology]

[0002] Coronaviruses have long existed in nature and have infected humans as zoonotic diseases. However, over the past two decades, novel human coronavirus infections causing severe respiratory illness have emerged and become a major global health problem. These include severe acute respiratory syndrome coronavirus (SARS-CoV), which emerged from 2002 to 2004, Middle East respiratory syndrome coronavirus (MERS-CoV), which emerged from 2012 to 2015, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a 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 from 2019 to 2020. Despite the tragic and widespread impact of these outbreaks and the increasing likelihood of future outbreaks due to the periodic emergence of novel human coronaviruses, there are currently no effective antiviral treatments targeting coronavirus infections.

[0003] SARS-CoV-2 has a large RNA genome of approximately 30 kb, two-thirds of which encodes two polyproteins, pp1a and pp1b (Hegyi et al. Journal of General Virology 83 (3): 595-99). These polyproteins are processed into 16 nonstructural proteins (nsps), which are then liberated from the long polypeptide chain by two viral cysteine ​​proteases: papain-like protease (nsp3) and 3C-like protease (nsp5). The latter, also known as main protease (Mpro), cleaves the viral polyprotein at 11 sites to generate 12 nonstructural proteins (nsp5-16). These nsp proteins include those involved in replication and transcription machinery, such as RNA-dependent RNA polymerase (nsp12) and helicase (nsp13). The critical role of Mpro 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, because there are no human proteases with similar cleavage specificity, selective inhibitors of Mpro are likely to be nontoxic (Anand et al. 2003. Science 300 (5626): 1763-67).

[0004] The use of protease inhibitors for the treatment of viral diseases is well known (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 that of other viral proteases, efforts are ongoing to identify clinically approved drugs that can be repurposed for the treatment of COVID-19 (Riva et al. Nature, 586: 113-119). A screen of 18 viral protease inhibitors designed for the treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) identified the anti-HCV drug boceprevir and the preclinical inhibitor GC376 for feline infectious peritonitis virus (FIPV) as inhibitors of SARS-CoV-2 Mpro (Fu et al. Nature Communications 11 (1): 4417). GC376 is a novel inhibitor of boceprevir (IC). 50 = 8 μM) 50 = 0.15 μM), but GC376 showed side effects in a study 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, but both drugs showed low IC 50In addition to SARS-CoV-2 M, boceprevir and telaprevir were also evaluated for their inhibitory effects against M proteases from eight other coronaviruses, including SARS, MERS, HKU1, HKU4, HKU5, NL63, FIPV, and IBV. Boceprevir inhibited all coronavirus proteases except NL63, and telaprevir similarly demonstrated inhibitory activity against SARS, HKU4, HKU5, NL63, and IBV, demonstrating broad-spectrum activity. Although the antiviral activity of these drugs 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 infection but also other human coronaviruses and novel coronaviruses that may emerge in the future.

[0005] The sequence similarity between the SARS-CoV and SARS-CoV-2 M active sites was also exploited to identify the SARS-CoV-2 M inhibitor PF-07304814. PF-07304814 is a phosphate prodrug of PF-00835231, originally designed for the treatment of SARS-CoV (Boras et al. BioRxiv, 2020.09.12.293498). PF-00835231 has a K of 0.27 nM. i inhibits SARS-CoV-2 M with a K of 0.03-4 nM i PF-00835231 demonstrated broad inhibitory activity against 10 coronavirus strains, with β-blockers (β-blockers) at 1000 ng / mL (1000 ng / mL). This corresponded to an activity of approximately 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 demonstrated synergistic or additive effects in cell-based antiviral assays. This suggests that combining Mpro inhibitors with antivirals with other mechanisms of action may be clinically useful.

[0006] In 2020, the crystal structure of SARS-CoV-2 M complexed with N3 (a Michael acceptor inhibitor) was published (Jin et al. Nature 582 (7811): 289-93), enabling virtual screening and structure-based drug design (SBDD) of inhibitors of SARS-CoV-2 M. Such SBDD efforts included the design of peptidomimetic α-ketoamides as broad-spectrum inhibitors of coronaviruses and enteroviruses, with the two most promising inhibitors exhibiting IC values ​​of 0.71–12.27 μM in recombinant inhibition assays against the proteases of enteroviruses EV-A71 and CVB3, and coronaviruses SARS-CoV and NL63. 50 The activity observed in the recombinant protease assay was in close agreement with the antiviral activity in the cell-based live virus assay, with IC 50 The values ​​were within 10-fold in both systems, suggesting 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 significant ongoing research activities and numerous clinical trials, only remdesivir and favipiravir have received limited approval in certain countries for the treatment of SARS-CoV-2 infection, with limited efficacy (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 infection, and for the above reasons, SARS-CoV-2 M is an attractive drug target for SARS-CoV-2. The compounds disclosed herein have been shown to be inhibitors of SARS-CoV-2 M and are therefore 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 having activity as SARS-CoV-2:Mpro inhibitors. Accordingly, in a first aspect of the invention, the compound has formula (I'):

[0009] [ka]

[0010] or a salt, solvate, hydrate, N-oxide or prodrug thereof, wherein: R 1 and R 1a are independently H; C optionally containing a cycloalkyl group and optionally substituted with 1 to 6 halo; 1-6 a saturated hydrocarbon group; or a benzyl group optionally substituted with 1 to 6 halo; R 1 and R 1a are joined together with the nitrogen to which they are attached to form a 3-6 membered saturated ring further containing a heteroatom and optionally substituted with 1-6 halo; R 2is a C optionally substituted with one or more oxo, hydroxy and halo groups; 3-6 is cycloalkyl; R is

[0011] [ka]

[0012] represents R 3 is selected from: (i) a saturated group containing 1 to 6 carbon atoms, optionally including a cycloalkyl group; or (ii) a saturated ring containing an oxygen or nitrogen heteroatom, said saturated group or ring being optionally substituted with one or more substituents selected from fluorine, hydroxy, or methoxy; or R 3 is -CH2aryl; -CH(CH3)aryl; or -C(CH3)2aryl; R 5 is C 1-8 a hydrocarbon group, optionally containing one or more rings or double bonds, optionally substituted with one or more groups selected from halo; cyano; hydroxy; methoxy; amino; and cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; or R represents -LA; where L is -CR 7 =CR 8 -, -CHR 9 -CHR 10 -or -O-CHR 11 - and; R 7 ~R 11 are independently H, -(CH2) m CO2R 12 or C optionally substituted with 1 to 6 fluorine atoms 1-3 alkyl; or R 9 and R 10 combines to form a cyclopropyl; A is halo, -CN, -CO2R 13 , OR13 , -SO2R 13 , -SONHR 13 , -OSO2R 13 , -PO(R 13 )2, -SF5, C 1-3 Alkyl and C 1-3 phenyl or heteroaryl optionally substituted with one or more groups selected from haloalkyl; R 12 and R 13 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; Each m independently represents 0 to 3.

[0013] R 2 C containing a cycloalkyl group unsubstituted or substituted with one or more substituents selected from fluorine or hydroxyl 3-5 When it is a saturated hydrocarbon group, it is preferred that: R is,

[0014] [ka]

[0015] where R 5 is methyl optionally substituted with one or more substituents selected from halo; cyano; hydroxy; methoxy; amino; and R 3 is as defined herein; or R represents -LA as defined herein.

[0016] It is also preferred that the compound of the present invention is not one of the following compounds: (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 or a salt thereof; or (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.

[0017] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention, including a salt, solvate, hydrate, N-oxide or prodrug thereof, and a pharmaceutically acceptable excipient.

[0018] In a third aspect of the invention, there is provided a compound of the invention, or a pharmaceutical composition comprising said compound, for use in the treatment of SARS-CoV-2 or a disorder associated with SARS-CoV-2.

[0019] In a fourth aspect of the invention, there is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of SARS-CoV-2 or a disease associated with SARS-CoV-2.

[0020] In a fifth aspect of the present invention, there is provided a method of treating a disease or disorder susceptible to SARS-CoV-2 Mpro inhibition in a subject, said method comprising administering a pharmaceutically effective amount of a compound of the present invention, or a salt, solvate, hydrate, N-oxide or prodrug thereof. A feature of this aspect is that the disease or disorder is SARS-CoV-2 or a disorder associated with SARS-CoV-2. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention relates to the use of compounds as inhibitors of SARS-CoV-2:M. The present invention further relates to the use of novel compounds in the manufacture of a medicament for use as a SARS-CoV-2:M inhibitor. The present invention further relates to compounds, compositions and medicaments useful in the treatment of SARS-CoV-2 and related viruses or conditions or symptoms associated therewith.

[0022] The compound is of formula (I') as defined herein. Also described herein is a compound of formula (I):

[0023] [ka]

[0024] or a salt, solvate, hydrate, N-oxide or prodrug thereof, wherein R 1 and R 1a are independently H; C optionally containing a cycloalkyl group and optionally substituted with 1 to 6 halo; 1-6 a saturated hydrocarbon group; or a benzyl group optionally substituted with 1 to 6 halo; R 1 and R 1a are joined together with the nitrogen to which they are attached to form a 3-6 membered saturated ring further containing a heteroatom and optionally substituted with 1-6 halo; R 2 is C 3-6 Cycloalkyl, C 1-4 alkyl and saturated 3- to 6-membered heterocycle (preferably, the saturated 3- to 6-membered heterocycle does not contain an oxygen atom in the ring), each of which is optionally substituted with one or more oxo, hydroxy, and halo groups; or R 2 -(CH2) p CONHR 6 or R 2 -(CH2) p CO2R 6 and; R 6 is H, C 1-3 Alkyl, and C 1-3 haloalkyl; R is

[0025] [ka]

[0026] represents R 3is selected from: (i) a saturated group containing 1 to 6 carbon atoms, optionally including a cycloalkyl group; or (ii) a saturated ring containing an oxygen or nitrogen heteroatom, said saturated group or ring being optionally substituted with one or more substituents selected from fluorine, hydroxy, or methoxy; or R 3 is -CH2aryl; -CH(CH3)aryl; or -C(CH3)2aryl; R 5 is C 1-8 a hydrocarbon group, optionally containing one or more rings or double bonds, optionally substituted with one or more groups selected from halo; cyano; hydroxy; methoxy; amino; and cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; or R represents -LA; In the formula, L is -CR 7 =CR 8 -, -CHR 9 -CHR 10 -or -O-CHR 11 - and; R 7 ~R 11 are independently H, -(CH2) m CO2R 12 or C optionally substituted with 1 to 6 fluorine atoms 1-3 alkyl; or R 9 and R 10 combines to form a cyclopropyl; A is halo, -CN, -CO2R 13 , -OR 13 , -SO2R 13 , -SONHR 13 , -OSO2R 13 , -PO(R 13 )2, -SF5, C 1-3 Alkyl and C 1-3 phenyl or heteroaryl optionally substituted with one or more groups selected from haloalkyl; R 12 and R 13 are independently H, C1-3 Alkyl, and C 1-3 haloalkyl; m is independently 0 to 3; where R 2 C, which contains a cycloalkyl group that is unsubstituted or substituted with one or more substituents selected from fluorine or hydroxyl 3-5 When it is a saturated hydrocarbon group, R is

[0027] [ka]

[0028] where R 5 is methyl optionally substituted with one or more substituents selected from halo; cyano; hydroxy; methoxy; amino; and R 3 is as defined herein; or R represents -LA as defined herein; wherein the compound of formula (I) is not: (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 or a salt thereof; or (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.

[0029] The compound of formula (I') or (I) may optionally be a compound according to formula (Ii):

[0030] [ka]

[0031] wherein the stereochemistry is as shown above and the substituents are as defined elsewhere herein.

[0032] The term “C 1-8 A "hydrocarbon group" is a group consisting of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms and an appropriate number of hydrogen atoms, such as an alkyl group. It may be linear or branched. It may also include cycloalkyl groups. 1-6 For portions of the range of saturated hydrocarbon groups, all subgroups thereof are contemplated, e.g., C 1-7 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C1, C 2-8 , C 2-7 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C2, C 3-8 , C 3-7 , C 3-6 , C 3-5 , C 3-4 , C3, C 4-8 , C 4-7 , C 4-6 , C 4-5 , C4, C 5-8 , C 5-7 , C 5-6 , C5, C 6-8 , C 6-7 , C6, C 7-8 C, C7, and C8 saturated hydrocarbon groups. 1-8 Non-limiting examples of "saturated hydrocarbon groups" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, straight-chain and branched pentyl, hexyl, septyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the following groups:

[0033] [ka]

[0034] "C 1-8 A "hydrocarbon group" can be saturated or unsaturated. Unsaturated means that the group contains one or more carbon-carbon double or triple bonds and / or aromatic rings. Examples of unsaturated hydrocarbon groups include ethylenyl, propylenyl, isopropylenyl, butylenyl, phenyl, and the like.

[0035] The term "optionally" or "optionally" indicates that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0036] C 1-6 The saturated hydrocarbon group is optionally substituted with 1 to 6 halo.

[0037] The term "substituted" indicates that the group to which it refers has one or more hydrogen atoms replaced with another group. For example, a "substituted hydrocarbon group" refers to a monovalent radical of a hydrocarbon group in which one or more hydrogens bonded to the hydrocarbon have been replaced with another group.

[0038] In view of the above, the term "optionally substituted" means that the group to which it refers may or may not be substituted, for example with one or more halo.

[0039] As used herein, the term "halo" refers to a halogen atom, preferably F, Cl, Br or I, more preferably F or Cl unless otherwise specified.

[0040] A "benzyl group" is:

[0041] [ka]

[0042] R 1 and R 1amay be linked together with the nitrogen to which they are attached to form a 3-6 membered saturated ring optionally containing an additional heteroatom and optionally substituted with 1-6 halo, preferably F. This is 1 and R 1a is part of a saturated heterocyclic ring containing 3 to 6 ring atoms, i.e., 3, 4, 5, or 6 ring atoms. Preferably, this forms 4 to 6 saturated heterocyclic rings. Non-limiting examples of this heterocyclic group include the monocyclic groups of the following groups:

[0043] [ka]

[0044] R 1 and R 1a are linked, they preferably form an azetidine, which is optionally substituted with 1 to 6 halo, preferably F.

[0045] As used herein, a "heteroatom" is N, O or S, preferably N or O.

[0046] R 1a is preferably H, in which case R 1 , H; C optionally containing a cycloalkyl group and optionally substituted with 1 to 6 halo 1-6 or a benzyl group optionally substituted with 1 to 6 halo. 1 C optionally containing H or a cycloalkyl group, optionally substituted with 1 to 6 halo 1-6 Preferably, R is a saturated hydrocarbon group, more preferably H, methyl, ethyl, propyl, or cyclopropyl, each of which is optionally substituted with 1 to 6 halo. Most preferably, R 1a is H and R 1 is H, methyl or cyclopropyl.

[0047] Alternatively, R 1 and R1a When they are joined together with the nitrogen to which they are attached to form a 3- to 6-membered saturated ring, the ring formed is preferably azetidine, pyrrolidine, or piperidine, each of which is optionally substituted with 1 to 6 halo.

[0048] In formula (I), R 2 is C 3-6 Cycloalkyl, C 1-4 It is selected from alkyl and saturated 3- to 6-membered heterocyclic rings, each of which is optionally substituted with one or more oxo, hydroxy, and halo groups. It is highly preferred that the saturated 3- to 6-membered heterocyclic rings do not contain oxygen atoms in the ring. Alternatively, R 2 is -(CH2) p CONHR 6 , or -(CH2) p CO2R 6 In these two cases, R 6 is H, C alkyl, and C 1-3 haloalkyl.

[0049] In formula (I'), R 2 is a C optionally substituted with one or more oxo, hydroxy and halo groups; 3-6 It is cycloalkyl.

[0050] As used herein, "C 3-6 "Cycloalkyl" refers to a monocyclic alkyl group having 3 to 6 carbon atoms. 3-6 For the moiety in the scope of "cycloalkyl," all subgroups thereof are contemplated, for example, C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , C4, C 5-6 , C5, C6 cycloalkyl. Examples of these cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0051] The term "saturated 3- to 6-membered heterocycle" refers to a ring containing a heteroatom, except that one or more carbon atoms in the ring are replaced with a heteroatom, such as N or O. 3-6 The term "saturated 3- to 6-membered heterocycle" is similar to "cycloalkyl." For the portion of the scope "saturated 3- to 6-membered heterocycle," all subgroups thereof are contemplated, including, for example, 3- to 6-membered, 3- to 5-membered, 3- to 4-membered, 4- to 6-membered, 4- to 5-membered, 4-membered, 5- to 6-membered, 5-membered, and 6-membered heterocycles. Examples of these heterocycles include aziridine, azetidine, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, piperazine, tetrahydropyran, thiane, and morpholine.

[0052] The term "oxo" is =O.

[0053] "C 1-3 The term "haloalkyl" refers to a C 1-3 A saturated hydrocarbon group, i.e., an alkyl in which one or more of the hydrogen atoms is replaced with halo, e.g., F, Cl, Br, or I, preferably F or Cl, more preferably F. 1-3 For the haloalkyl portion, C 1-3 , C 1-2 , C1, C 2-3 All subgroups thereof are contemplated, such as C, C and C haloalkyl. 1-3 Non-limiting examples of haloalkyls include -CH2F, -CF2H, -CF3, -CH2Cl, -CCl2H, -CCl3, -CHFCl, -CF2Cl, -CCl2F, -CH2CF3, -CF2CF3, -CF2CF3, and -CH2CH2CF3.

[0054] In the compounds of formula (I), R 2 is C 3-6 Cycloalkyl, C 1-4 Preferably, the C is selected from alkyl, and a saturated 5- or 6-membered heterocyclic ring (preferably a saturated 5- or 6-membered heterocyclic ring that does not contain an oxygen atom in the ring), and is optionally substituted with one or more oxo, hydroxy, and halo groups. 3-6 Cycloalkyl groups and C 1-4The alkyl group or heterocycle may optionally be substituted with 1 to 3 halo and / or 1 oxo.

[0055] In particular, R 2

[0056] [ka]

[0057] and each optionally substituted with one or more halo, preferably F.

[0058] R 2 It is more preferable that R is cyclic. 2 But C 3-6 It is more preferably selected from cycloalkyl and saturated 3- to 6-membered heterocycles (preferably saturated 3- to 6-membered heterocycles not containing an oxygen atom in the ring), for example, C 3-6 Cycloalkyl and saturated 5- or 6-membered heterocycles (preferably saturated 5- or 6-membered heterocycles that do not contain oxygen atoms in the ring), each of which is optionally substituted with one or more oxo, hydroxy, and halo groups. 3-6 The cycloalkyl groups and heterocycles may optionally be substituted with 1 to 3 halo and / or 1 oxo.

[0059] From this perspective, R 2 is most preferably

[0060] [ka]

[0061] and each optionally substituted with one or more halo, preferably F.

[0062] In formula (I'), R 2 is most preferably

[0063] [ka]

[0064] and each optionally substituted with one or more halo, preferably F.

[0065] In the compounds described herein, R represents one of two subgroups:

[0066] [ka]

[0067] When R is the first of the two groups, the compound of formula (I) or (I') has formula (IA):

[0068] [ka]

[0069] or a salt, solvate, hydrate, N-oxide or prodrug thereof, In the formula, R 1 , R 1a , R 2 , R 3 and R 5 is as defined herein.

[0070] The compound of formula (IA) above may optionally be a compound according to formula (IAi):

[0071] [ka]

[0072] wherein the stereochemistry is as shown above and the substituents are as defined elsewhere herein.

[0073] When R is -LA, the compound of formula (I) or (I') has formula (IB):

[0074] [ka]

[0075] or a salt, solvate, hydrate, N-oxide or prodrug thereof, In the formula, R 1 , R 1a , L and A are as defined herein.

[0076] In the compound of formula (IA), R 3 is selected from: (i) a saturated group containing 1 to 6 carbon atoms, optionally including a cycloalkyl group; or (ii) a saturated ring containing an oxygen or nitrogen heteroatom; The saturated group or ring is optionally substituted with one or more substituents selected from fluorine, hydroxy or methoxy.

[0077] Alternatively, R 3 is -CH2aryl; -CH(CH3)aryl; or -C(CH3)2aryl.

[0078] The term "saturated group containing 1 to 6 carbon atoms" refers to a C 1-6 It is a saturated hydrocarbon group, which may optionally contain a cycloalkyl group as part of its 1 to 6 carbon atoms.

[0079] The saturated ring containing oxygen or nitrogen is a 3- to 6-membered saturated heterocycle as defined above.

[0080] R 3 Preferred groups include methyl, ethyl, propyl, (especially iso-propyl), tert-butyl, sec-butyl, iso-butyl, and the following groups:

[0081] [ka]

[0082] R 3 More preferred groups for are as follows:

[0083] [ka]

[0084] Each is optionally substituted.

[0085] R 3 More preferred groups are methyl, isopropyl, tert-butyl and

[0086] [ka]

[0087] is.

[0088] Most preferably, R 3 is isopropyl or tert-butyl.

[0089] R 5 is (saturated or unsaturated) C 1-8 is a hydrocarbon group, optionally containing one or more rings or double bonds, and optionally substituted with one or more groups selected from halo; cyano; hydroxy; methoxy; amino; and cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. Preferably, R 5 is a saturated or unsaturated C optionally substituted with one or more halo, preferably F 1-5 It is a hydrocarbon group.

[0090] The term "aryl" as used herein refers to a C6 aromatic group, also known as phenyl.

[0091] The term "heteroaryl" refers to a 5- or 6-membered aromatic ring containing at least one heteroatom. Non-limiting examples of heteroaryl groups include pyrrole, pyrazole, imidazole, triazole, tetrazole, furan, thiophene, oxazole, isoxazole, isothiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

[0092] R 5 Preferred examples include methyl, -CF3, ethyl, propyl, (particularly isopropyl), cyclopropyl, butyl, and cyclobutyl, and more preferred are -CF3, isopropylcyclopropyl, and

[0093] [ka]

[0094] is.

[0095] More preferably, R 5 teeth

[0096] [ka]

[0097] Most preferably, R 5 is -CF3 or

[0098] [ka]

[0099] is.

[0100] As noted above, R may be -LA, in which case the compound of formula (I) or (I') is a compound of formula (IB).

[0101] In LA, the group L is a linker, i.e., bivalent, and is -CR 7 =CR8 -, -CHR (9 )-CHR (10 )- or -O-CHR (11 )- is selected from.

[0102] R 7 ~R 11 (i.e., R 7 , R 8 , R 9 , R 10 and R 11 ) are independently H, -(CH2) m CO2R 12 or C 1-3 alkyl, wherein the C 1-3 The alkyl is optionally substituted with 1 to 6 (i.e., 1, 2, 3, 4, 5, or 6) fluorine atoms, and m is independently 0 to 3. R 12 is H, C 1-3 Alkyl, and C 1-3 haloalkyl.

[0103] In certain cases, the group R 9 and R 10 are linked to form a cyclopropyl, where L is

[0104] [ka]

[0105] is.

[0106] It is preferred that L is -CH=CH-, -CH2CH2-, -CH2-CH(CH2CH3)-, -CH2-CH(CH2CO2H)-, -OCH2-, -CH2-CH(CH3)-, -CH2-CH(CF3)-, or -OCH(CH3)-.

[0107] [ka]

[0108] Most preferably, L is -CH=CH-.

[0109] The group "A" is a phenyl group or a heteroaryl group (preferably a 6-membered heteroaryl group). These two groups are substituted with halo, -CN, -COR 13 , -OR 13 , -SO2R 13 , -SONHR 13 , -OSO2R 13 , -PO(R 13 )2, -SF5 and C 1-3 Each R is optionally substituted with one or more groups selected from alkyl. 13 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl.

[0110] The group "A" is preferably selected from halo, hydroxy and C 1-3 More preferably, the group "A" is phenyl or pyridinyl optionally substituted with one or more groups selected from alkyl. More preferably, the group "A" is phenyl or pyridinyl optionally substituted with one or more groups selected from halo (especially F and Cl). "A" groups of particular interest are as follows:

[0111] [ka]

[0112] In view of the above, preferred groups for "-LA" are as follows:

[0113] [ka]

[0114] Notwithstanding the above, R 2 C containing a cycloalkyl group unsubstituted or substituted with one or more substituents selected from fluorine or hydroxyl 3-5 When it is a saturated hydrocarbon group, R represents:

[0115] [ka]

[0116] where R 5 is methyl optionally substituted with one or more substituents selected from halo; cyano; hydroxy; methoxy; amino; and R 3 is as defined herein; or R represents -LA as defined herein.

[0117] The compound of formula (I) may be a compound according to formula (IIA):

[0118] [ka]

[0119] or a salt, solvate, hydrate, N-oxide or prodrug thereof; During the ceremony, R 1a is H; R 1 is H, methyl, ethyl, propyl, or cyclopropyl, each of which is optionally substituted with 1 to 6 halo; R 1 and R 1a taken together with the nitrogen to which they are attached form an azetidine, pyrrolidine, or piperidine ring, which is optionally substituted with 1 to 6 halo, preferably F; R 2 is C 3-6 Cycloalkyl, C 1-4 alkyl, or a 5- or 6-membered heterocycle (preferably a saturated 5- or 6-membered heterocycle that does not contain an oxygen atom in the ring), optionally substituted with one or more oxo, hydroxy, and halo groups; R represents:

[0120] [ka]

[0121] In the formula, R3 is selected from methyl, ethyl, propyl, iso-propyl, tert-butyl, sec-butyl, iso-butyl, and the following groups:

[0122] [ka]

[0123] R 5 is saturated or unsaturated C 1-5 a hydrocarbon group, optionally substituted with one or more halo, preferably F; or R represents -LA, wherein L is -CH=CH-, -CH2CH2-, -CH2-CH(CH2CH3)-, -CH2-CH(CH2CO2H)-, -OCH2-, -CH2-CH(CH3)-, -CH2-CH(CF3)-, -OCH(CH3)-, or

[0124] [ka]

[0125] and A is halo (preferably fluoro), hydroxy and C 1-3 and phenyl or pyridinyl optionally substituted with one or more groups selected from alkyl.

[0126] Furthermore, the compounds of the present invention preferably do not: (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; or ●(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.

[0127] Preferably, the present invention does not include salts of said compounds. More preferably, the present invention does not include salts, solvates, hydrates, N-oxides or prodrugs of said compounds.

[0128] Preferably, the present invention does not include compounds of the following structure:

[0129] [ka]

[0130] Preferred compounds described herein are selected from the following: N-(4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)-3-(3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; • N-[1-(cyclopropylmethyl)-3-(methylamino)-2,3-dioxo-propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; • N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxo-propyl]-6,6-dimethyl-3-[3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; • N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxo-propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; • N-[3-(cyclopropylamino)-2,3-dioxo-1-[[2-oxopyrrolidin-3-yl]methyl]propyl]-3-[3,3-dimethyl-2-(2-methylpropanoylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[3-(cyclopropylamino)-2,3-dioxo-1-[[2-oxo-3-piperidyl]methyl]propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; and N-(4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)-3-(3-(2,4-difluorophenyl)acryloyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; or a salt, solvate, hydrate, N-oxide or prodrug thereof:

[0131] Further preferred compounds described herein are selected from the following: (1R,2S,5S)-N-(4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-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-[1-(cyclopropylmethyl)-3-(methylamino)-2,3-dioxo-propyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; • (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxopropyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; • (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxopropyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; ●(1R,2S,5S)-N-[3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-3-[(2S)-3,3-dimethyl-2-(2-methylpropanoylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-[3-(cyclopropylamino)-2,3-dioxo-1-[[(3R)-2-oxo-3-piperidyl]methyl]propyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; and (1R,2S,5S)—N-(4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-((E)-3-(2,4-difluorophenyl)acryloyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, or a salt, solvate, hydrate, N-oxide or prodrug thereof.

[0132] More preferred compounds described herein may be selected from the following: • N-[1-(cyclopropylmethyl)-3-(methylamino)-2,3-dioxo-propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; • N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxo-propyl]-6,6-dimethyl-3-[3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; • N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxo-propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; • N-[3-(cyclopropylamino)-2,3-dioxo-1-[[2-oxopyrrolidin-3-yl]methyl]propyl]-3-[3,3-dimethyl-2-(2-methylpropanoylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[3-(cyclopropylamino)-2,3-dioxo-1-[[2-oxo-3-piperidyl]methyl]propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; and N-(4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)-3-(3-(2,4-difluorophenyl)acryloyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, or a salt, solvate, hydrate, N-oxide or prodrug thereof.

[0133] Further preferred compounds may be selected from: ●(1R,2S,5S)-N-[1-(cyclopropylmethyl)-3-(methylamino)-2,3-dioxo-propyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; • (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxopropyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; • (1R,2S,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; ●(1R,2S,5S)-N-[3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-3-[(2S)-3,3-dimethyl-2-(2-methylpropanoylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-[3-(cyclopropylamino)-2,3-dioxo-1-[[(3R)-2-oxo-3-piperidyl]methyl]propyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; and (1R,2S,5S)—N-(4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-((E)-3-(2,4-difluorophenyl)acryloyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, or a salt, solvate, hydrate, N-oxide or prodrug thereof.

[0134] More preferred compounds can be selected from: • N-[1-(cyclopropylmethyl)-3-(methylamino)-2,3-dioxo-propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; • N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxo-propyl]-6,6-dimethyl-3-[3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; • N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxo-propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; or a salt, solvate, hydrate, N-oxide or prodrug thereof.

[0135] Further preferred compounds can be selected from: ●(1R,2S,5S)-N-[1-(cyclopropylmethyl)-3-(methylamino)-2,3-dioxo-propyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; • (1R,2S,5S)-N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxopropyl]-6,6-dimethyl-3-[(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; (1R,2S,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, or a salt, solvate, hydrate, N-oxide or prodrug thereof.

[0136] The present invention will now be described with reference to the following non-limiting examples shown in Table 1.

[0137] [Table 1-1]

[0138] [Table 1-2]

[0139] Examples outside the scope of the claims are for reference purposes only.

[0140] In this disclosure, if there is a discrepancy between a compound name and a compound structure, the compound structure takes precedence.

[0141] The compounds of the present invention can be used as they are or, if necessary, as salts thereof, particularly pharmacologically acceptable salts (acid or base addition salts). The term "pharmacologically acceptable addition salts" as used herein refers to the therapeutically active, non-toxic acid and base addition salt forms that the compounds can form. A basic compound can be converted to a pharmaceutically acceptable acid addition salt by treating the base form with an appropriate acid. Exemplary acids include inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, and phosphoric acid, and organic acids such as formic acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, and ascorbic acid. Exemplary base addition salt forms are sodium, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids such as arginine and lysine. The term addition salts as used herein also includes solvates which the compounds and their salts are able to form, such as, for example, hydrates, alcoholate salts, etc.

[0142] Throughout this disclosure, a given chemical formula or name is intended to encompass all (pharmaceutically acceptable) salts, solvates, hydrates, N-oxides, and / or prodrug forms thereof. It is understood that the compounds of the present invention include all hydrates and / or solvates of the compound formula. It is understood that certain functional groups, such as hydroxyl groups, amino groups, etc., form complexes and / or coordination compounds with water and / or various solvents in the various physical forms of the compounds. Thus, the above formulas should be understood to include and represent various hydrates and / or solvates thereof.

[0143] The compounds of the present invention also include tautomers. Tautomers occur when a single bond and an adjacent double bond swap positions, resulting in the migration of a proton. Tautomers include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and rings in which protons can occupy more than one position on a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomers may exist in equilibrium or be sterically locked into a single form by appropriate substitution.

[0144] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereoisomers, are contemplated unless otherwise specified. The terms "diastereoisomer" and "diastereomer" are used interchangeably herein. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis- and trans-geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomers.

[0145] In the case of compounds containing asymmetric carbon atoms, the present invention relates to D-forms, L-forms, and D,L mixtures, and also to diastereoisomers when two or more asymmetric carbon atoms are present. Compounds of the present invention containing asymmetric carbon atoms and occurring as a racemate in principle can be separated into optically active isomers by known methods, for example with an optically active acid. However, it is also possible to use optically active starting materials from the beginning, in which case the corresponding optically active or diastereoisomeric compounds are obtained as final products.

[0146] The compounds of the present invention may contain isotopic forms of atoms therein, for example, the compounds may be isotopically labeled and / or isotopically enriched forms. The compounds of the present invention herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 32 P, 35 S, 18 F, 36 Examples include Cl.

[0147] The term "N-oxide" refers to an N-oxide, such as the following example: + -O - A compound containing a functional group is shown.

[0148] [ka]

[0149] The term "prodrug" refers to a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvation. Prodrugs may be inactive when administered to a subject in need thereof, but are converted in vivo to an active compound of the present invention. Prodrugs are typically rapidly converted in vivo, such as by hydrolysis in blood, to yield the parent compound of the present invention. Prodrug compounds typically offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Silverman, RB, The Organic Chemistry of Drug Design and Drug Action, 2nd Ed., Elsevier Academic Press (2004), pages 498 to 549). Prodrugs of compounds of the present invention can be prepared by modifying functional groups, such as hydroxy, amino, or mercapto groups, present in the compounds of the present invention so that they are cleaved to the parent compound of the present invention either by routine manipulation or in vivo. Examples of prodrugs include, but are not limited to, acetate, formate, and succinate derivatives of hydroxy functional groups, or phenylcarbamate derivatives of amino functional groups.

[0150] For clinical use, the compounds disclosed herein are formulated into pharmaceutical compositions (or formulations) for various modes of administration. It will be understood that the compounds of the present invention can be administered with physiologically acceptable carriers, excipients, and / or diluents (i.e., one, two, or all three of these). The pharmaceutical compositions disclosed herein can be administered by any suitable route, preferably oral, rectal, nasal, topical (including buccal and sublingual), sublingual, transdermal, intrathecal, transmucosal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. Other formulations can be conveniently presented in unit dosage form, such as tablets and sustained-release capsules, and liposomes, and can be prepared by any method well known in the art of pharmacy. Pharmaceutical formulations are typically prepared by mixing the active substance or a pharmaceutically acceptable salt thereof with a conventional pharmaceutically acceptable carrier, diluent, or excipient. Examples of excipients include water, gelatin, gum arabic, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, etc. Such formulations may also contain other pharmacologically active agents and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavorings, buffers, etc. Typically, the amount of active compound is 0.1 to 95% by weight of the formulation, preferably 0.2 to 20% by weight for parenteral formulations, and more preferably 1 to 50% by weight for oral formulations. Formulations can also be prepared by known methods such as granulation, compression, microencapsulation, and spray coating. Formulations can be prepared in dosage forms such as tablets, capsules, granules, powders, syrups, suspensions, suppositories, and injections using conventional methods. Liquid formulations can be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules can be coated using conventional methods. To maintain therapeutically effective plasma concentrations for extended periods of time, the compounds disclosed herein can be incorporated into sustained release formulations.

[0151] In addition to the above, the pharmaceutically acceptable excipient may be selected from, for example, 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 retarding polymers or waxes), binders, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffering agents, binders, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffering agents, tonicity adjusters, thickeners, flavors, sweeteners, pigments, plasticizers, flavoring agents, stabilizers, or other excipients conventionally used in pharmaceutical compositions.

[0152] In view of the above, a second aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention, including a salt, solvate, hydrate, N-oxide or prodrug thereof, and a pharmaceutically acceptable excipient.

[0153] The pharmaceutical composition may further comprise one or more drugs that inhibit cypP450-mediated metabolism, which may be selected from ritonavir, lopinavir, or a combination thereof.

[0154] The dosage level and frequency of administration of a particular compound will vary depending on various factors, including the potency of the particular compound employed, the metabolic stability and duration of action of the compound, the patient's age, weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the condition being treated, and the patient being treated. The daily dosage ranges, for example, from about 0.001 mg to about 100 mg per kg of body weight, and can be administered in single or multiple doses, for example, from about 0.01 mg to about 25 mg per kg. Typically, such doses are administered orally, although parenteral administration can also be selected.

[0155] The object of the present invention relates to the compounds of the present invention for use as a pharmaceutical. The term "pharmaceutical" refers to a substance used in medical treatment or as a medicine. The compounds of the present invention are useful as inhibitors of SARS-CoV-2 Mpro, and are therefore useful for the treatment or prevention of pathologies (diseases or disorders) affected by SARS-CoV-2 Mpro.

[0156] In view of the above, a third aspect of the present invention provides a compound of the present invention, or a pharmaceutical composition comprising said compound, for use in the treatment of SARS-CoV-2 or a disorder associated with SARS-CoV-2.

[0157] In a fourth aspect of the invention, there is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of SARS-CoV-2 or a disease associated with SARS-CoV-2.

[0158] In a fifth aspect of the present invention, there is provided a method of treating a disease or disorder sensitive to SARS-CoV-2 Mpro inhibition in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of a compound of the present invention, or a salt, solvate, hydrate, N-oxide or prodrug thereof. A feature of this aspect is that the disease or disorder is SARS-CoV-2 or a disorder associated with SARS-CoV-2.

[0159] Therefore, the compounds of the present invention are believed to be useful in preventing death or complications due to chronic underlying or comorbid conditions in patients infected with SARS-CoV-2, such as hypertension, obesity, chronic lung disease (tuberculosis, asthma, and cystic fibrosis), diabetes, and cardiovascular disease (coronary heart disease, congenital heart disease, and heart failure).

[0160] In the above methods or uses, the compounds or compositions of the present invention may be administered in combination with one or more drugs that inhibit cypP450-mediated metabolism, which may be selected from ritonavir, lopinavir, or a combination thereof.

[0161] As used herein, the terms "therapy" and "treatment" can include prevention of a disease or disorder, or amelioration or elimination of a disease or disorder after it has been established.

[0162] As used herein, the term "administration" or "administering" refers to a route of administration of a compound disclosed herein. Exemplary routes of administration include, but are not limited to, oral, intravenous, intraperitoneal, intraarterial, and intramuscular. The preferred route of administration may vary depending on various factors, such as the components of a pharmaceutical composition comprising a compound disclosed herein, the site of potential or actual disease, and the severity of the disease.

[0163] As used herein, the terms "subject" and "patient" are used interchangeably. They refer to a human or other mammal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate) that can be affected by or susceptible to a disease or condition, but may or may not have the disease or condition. Preferably, the subject is a human.

[0164] A "therapeutically effective amount" refers to an amount of a compound of the invention that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject sees or feels an effect).

[0165] The methods provided herein include those in which a subject is identified as being in need of a particular treatment. Identifying a subject in need of such treatment can be at the discretion of the subject or a medical professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

[0166] In other aspects, the methods herein include methods further comprising monitoring the subject's response to the treatment administration. Such monitoring may include periodic sampling of the subject's tissues, fluids, specimens, cells, proteins, chemical markers, genetic material, etc. as markers or indicators of the treatment regimen. In other methods, subjects are pre-screened or identified as being in need of such treatment by assessment for relevant markers or indicators of suitability for such treatment.

[0167] The compounds of the present invention can be used as single agents or in combination with one or more additional pharmaceutical agents. For example, the compounds of the present invention can be co-administered with HIV treatments known to inhibit CYP450-mediated metabolism, such as ritonavir or the combination of lopinavir / ritonavir.

[0168] Preparation of Compounds of the Invention The compounds of the present invention can be prepared by conventional methods or in analogy with conventional methods. The preparation of intermediates and compounds according to embodiments of the present invention can be illustrated in particular by the following schemes. The definitions of variables in the structures in the schemes herein correspond to the definitions of the corresponding positions in the formulae defined herein.

[0169] [ka]

[0170] Intermediate 1 Synthesis 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

[0171] [ka]

[0172] Methyl (1S,2S,5R)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1 g, 5.85 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (1.36 g, 5.85 mmol) were dissolved in DCM (20 mL) at 0 °C. DIPEA (3.31 mL, 17.55 mmol) and propylphosphonic anhydride solution (≥50 wt% in ethyl acetate, 5.22 mL, 8.78 mmol) were added, and the resulting reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with water (20 mL), and the organic layer was extracted with DCM (2 × 30 mL). The combined organic layer was washed with saturated NaHCO (25 mL), brine (25 mL), and dried over anhydrous NaSO. The organic layer was concentrated under reduced pressure, and the resulting crude was purified by flash column chromatography (silica gel: 230-400 mesh, eluent: 50% EtOAc / pet ether) to give methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate, a sticky colorless gum (1 g, 44.2%). LCMS (ELSD): 383.3 [MH] + .

[0173] Intermediate 2 Synthesis 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

[0174] [ka]

[0175] Methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1 g, 2.59 mmol) was dissolved in a mixture of THF (4 mL), MeOH (4 mL), and water (2 mL). LiOH.HO (0.33 g, 7.76 mmol) was added at RT, and the resulting reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated in vacuo. The crude residue was diluted with water (5 mL), acidified with citric acid solution (2.5 mL), and the aqueous layer was extracted with DCM (2×10 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid as a yellow gum. This gum was carried on to the next step without further purification (0.9 g, crude). LCMS (ELSD): 369.3 [MH] + .δ 12.53 (bs, 1H), 6.68 (d, J = 9.6 Hz, 1H), 4.13 (s, 1H), 4.05 (d, J = 9.6 Hz, 1H), 3.91 (d, J = 10.4 Hz, 1H), 3.79-3.74 (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).

[0176] Intermediate 3 Synthesis of methyl 2-((1S,2S,5R)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate

[0177] [ka]

[0178] (1S,2S,5R)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (900 mg, 2.44 mmol), methyl (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (544 mg, 2.44 mmol) were added in DCM (20 mL) at 0°C, and DIPEA (1.44 mL, 7.82 mmol) and propylphosphonic anhydride solution (50% by weight or more in ethyl acetate, 1. 45 mL, 2.44 mmol) was slowly added, and the resulting reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated NaHCO3 solution (15 mL) and diluted with water (20 mL). The organic layer was extracted with DCM (2 x 50 mL), and the combined organic layers were washed with brine (25 mL) and dried over anhydrous Na2SO4. The organic portion was concentrated under reduced pressure, and the resulting crude was purified by flash column chromatography (silica gel: 230-400 mesh, eluent: 100% EtOAc) to give the desired product methyl 3H2O4. 2-((1S,2S,5R)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate was obtained as a white solid (0.5 g, 35.9%). LCMS (ELSD): 537.3 [MH]+. δ 8.57 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 6.62 (d, J = 9.0 Hz, 1H), 4.44-4.39 (m, 1H), 4.25 (s, 1H), 4.05-4.00 (m, 1H), 3.90-3.81 (m, 2H), 3.64 (s, 3H), 3.17-3.02 (m, 2H), 2.50-2.44 (m, 1H), 2.12-2.00 (m, 2H), 1.60-1.47 (m, 3H), 1.35 (s, 9H), 1.26-1.16 (m, 1H), 1.03 (s, 3H), 0.96-0.84 (m, 12H).

[0179] Intermediate 4 Synthesis of tert-butyl ((2S)-1-((1S,2S,5R)-2-((1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0180] [ka]

[0181] Methyl 2-((1S,2S,5R)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (500 mg, 0.93 mmol) was added in MeOH (5 mL) and THF (10 mL) at 0 °C, NaBH (211 mg, 5.59 mmol) was added slowly in portions, and the resulting reaction mixture was stirred at 0 °C for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure. The resulting residue was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL), and the combined organic layers were washed with brine (25 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (silica gel: 230-400 mesh; eluent: 0-10% MeOH / DCM) to give tert-butyl ((2S)-1-((1S,2S,5R)-2-((1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate as a white solid (0.3 g, 60.8%). LCMS (ELSD): 509.4 [MH]+. δ 7.80 (d, J = 9.6 Hz, 1H), 7.45 (s, 1H), 6.61 (d, J = 9.2 Hz, 1H), 4.66 (t, J = 5.6 Hz, 1H), 4.18 (s, 1H), 4.04-3.99 (m, 1H), 3.90-3.75 (m, 3H), 3.30-3.27 (m, 2H), 3.12-3.08 (m, 1H), 2.99-2.92 (m, 1H), 2.52-2.38 (m, 1H), 2.20-2.10 (m, 1H), 1.73-1.68 (m, 1H), 1.52-1.35 (m, 13H), 0.98-0.71 (m, 15H).

[0182] Intermediate 5 Synthesis of tert-butyl ((2S)-1-((1S,2S,5R)-6,6-dimethyl-2-((1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0183] [ka]

[0184] tert-Butyl ((2S)-1-((1S,2S,5R)-2-((1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (300 mg, 0.59 mmol) was dissolved in DCM (10 mL) at 0° C., DMP (500 mg, 1.18 mmol) was added slowly, and the resulting reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by UPLCMS and LCMS), the reaction mixture was quenched with saturated NaHCO (10 mL) and diluted with water (15 mL). The aqueous layer was extracted with DCM (2×25 mL), and the combined organic layers were washed with saturated NaHCO (20 mL), brine (20 mL), and dried over anhydrous NaSO. The organic portion was concentrated under reduced pressure, and the resulting crude material was purified by flash column chromatography (silica gel: 230-400 mesh, eluent: 10% MeOH / DCM) to give the desired compound, tert-butyl ((2S)-)1-((1S,2S,5R)-6,6-dimethyl-2-((1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate, as an off-white solid (0.3 g, 82%). LCMS: 507.4 [MH] + .

[0185] Intermediate 6 Synthesis of 3-((1S,2S,5R)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate

[0186] [ka]

[0187] tert-Butyl ((2S)-1-((1S,2S,5R)-6,6-dimethyl-2-((1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (300 mg, 0.59 mmol) in DCM (3 mL) was slowly added at 0°C, and the resulting reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by UPLCMS and LCMS), the reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with DCM (2×20 The resulting mixture was extracted with 1 mL of ethyl acetate. The combined organic layers were then washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel: 230-400 mesh, eluent: 10% MeOH / DCM) to give 3-((1S,2S,5R)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate as a yellow gum (0.3 g, 70.3%). LCMS: 634.4 [MH] + .

[0188] Intermediate 7 Synthesis of tert-butyl ((2S)-1-((1S,2S,5R)-2-((4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

[0189] [ka]

[0190] To a suspension of 3-((1S,2S,5R)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamido)-1-(cyclopropylamino)-1-oxo-4-((S)-2-oxopyrrolidin-3-yl)butan-2-yl acetate (300 mg, 0.379 mmol) in a mixture of THF (2 mL), MeOH (2 mL) and water (1 mL) was added LiOH.HO (48.2 mg, 1.13 mmol) at 0° C., and the resulting reaction mixture was stirred at 0° C. for 3 h. After completion of the reaction (monitored by UPLCMS & LCMS), the reaction mixture was diluted with water (10 mL) and the aqueous layer was extracted with DCM (2×15 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel: 230-400 mesh, eluent: 10% MeOH / DCM) to obtain the desired compound tert-butyl ((2S)-1-((1S,2S,5R)-2-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate as a brown solid (0.15 g, 64.3%). LCMS (ELSD): 592.4 [MH] + .

[0191] Example 1 Synthesis of (1R,2S,5S)-N-(4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0192] [ka]

[0193] (1S,2S,5R)-N-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (100 mg, 0.17 mmol) in DCM (5 mL) was added in portions at 0 °C, and the resulting reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (10 mL), and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with saturated NaHCO (20 mL), brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Method A). The collected fractions were concentrated under reduced pressure. The resulting residue was partitioned between 10% NaHCO3 solution (20 mL) and DCM (2 × 20 mL). The organic layer was separated, dried over anhydrous Na2SO4, concentrated under reduced pressure, and lyophilized to give the desired compound (1R,2S,5S)-N-(4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as a pale yellow solid (0.051 g, 50.8%). LCMS (ELSD): 586.3 [MH]+. δ 9.40-5.94 (m, 4H), 4.42 (d, J = 8.4 Hz, 1H), 4.29-4.25 (m, 1H), 4.10-3.84 (m, 1H), 3.69-3.53 (m, 1H), 3.20-2.95 (m, 2H), 2.80-2.52 (m, 2H), 2.31-2.14 (m, 1H), 1.90-1.36 (m, 6H), 1.03-0.92 (m, 12H), 0.90-0.68 (m, 3H), 0.68-0.41 (m, 4H).

[0194] [ka]

[0195] Intermediate 8 Synthesis 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

[0196] [ka]

[0197] To a solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2 g, 11.70 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (2.73 g, 11.70 mmol) in DCM (30 mL), DIPEA (2.1 mL, 11.70 mmol) was added at RT, followed by T3P (6.83 mL, 11.70 mmol, 50% solution in EtOAc) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by LCMS), the reaction was quenched with 10% aqueous NaHCO3 solution, and the aqueous layer was extracted with DCM (2 x 25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel: 230-400 mesh, eluent: 0-50% EtOAc / petroleum ether) to give methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate as a pale yellow gum (2.42 g, 52.7%). LCMS (ELSD): 383.4 [MH] +.δ 6.76 (d, J = 9.6 Hz, 1H), 4.21 (s, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.94 (d, J = 10.4 Hz, 1H), 3.81-3.77 (m, 1H), 3.65 (s, 3H), 1.54-1.51 (m, 1H), 1.41-1.38 (m, 1H), 1.37 (s, 9H), 1.01 (s, 3H), 0.96 (s, 9H), 0.85 (s, 3H).

[0198] Intermediate 9 Synthesis 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

[0199] [ka]

[0200] Methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (2.5 g, 6.37 mmol) in a mixture of THF (20 mL), MeOH (6 mL), and water (6 mL) was added with LiOH.HO (0.15 g, 6.37 mmol) at RT. The resulting reaction mixture was stirred at room temperature for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (10 mL) and washed with MTBE (10 mL). The aqueous layer was acidified with HCl (1.5 N, pH ∼2–3) and extracted with DCM (2 × 30 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid as a white solid, which was used in the next step without further purification (2.12 g, crude, 88%). LCMS (ELSD): 369.3 [MH]+ .δ 12.53 (br s, 1H), 6.68 (d, J = 9.6 Hz, 1H), 4.13 (s, 1H), 4.05 (d, J = 9.6 Hz, 1H), 3.91 (d, J = 10.4 Hz, 1H), 3.79-3.74 (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).

[0201] Intermediate 10 Synthesis of ethyl 3-amino-4-cyclopropyl-2-hydroxybutanoate

[0202] [ka]

[0203] To a stirred solution of 3-amino-4-cyclopropyl-2-hydroxybutanamide (2.5 g, 15.64 mmol, HEP-WUXI-A81-INT5) in EtOH (20 mL) at 0 °C, SOCl (1.15 mL, 15.64 mmol) was added dropwise, and the resulting reaction mixture was stirred at 65 °C for 15 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to remove volatiles. The residue was dried by azeotropic co-distillation with toluene (2 × 20 mL) to give ethyl 3-amino-4-cyclopropyl-2-hydroxybutanoate as a brown semi-solid, which was used in the next step without further purification (2.1 g, crude, 63.1%). LCMS (ELSD): 188.3 [M−H] + .

[0204] Intermediate 11 Synthesis of 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

[0205] [ka]

[0206] (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) were dissolved in DCM (20 mL), and DIPEA (3.37 mL, 18.75 mmol) and then T3P (50% in EtOAc) (5.58 mL, 9.38 mmol) were added at 0 °C. The resulting reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with aq. NaHCO3 (10%) at RT, and the aqueous layer was extracted with DCM (2 x 25 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude residue was purified by flash column chromatography using (silica gel: 230-400 mesh; eluent: 0-50% EtOAc / pet ether) to give 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 as a pale yellow gum (2.3 g, 67%). LCMS (ELSD): 538.4 [MH] + δ 7.90 (d, J = 8.8 Hz, 1H), 6.57 (d, J = 9.2 Hz, 1H), 5.57-5.50 (m, 1H), 4.11-3.71 (m, 8H), 1.51-1.41 (m, 2H), 1.40 (s, 9H), 1.05-0.80 (m, 18H), 0.72-0.61 (m, 1H), 0.35-0.03 (m, 5H), 0.14-0.05 (m, 1H).

[0207] Intermediate 12 Synthesis 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

[0208] [ka]

[0209] 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 (2.2 g, 4.01 mmol) was added dropwise in DCM (10 mL) at 0 °C, and hydrochloric acid in dioxane (5 mL, 4 M) was added, and the resulting reaction mixture was stirred at RT for 3 h. After completion of the reaction (monitored by LCMS), the supernatant layer was decanted from the reaction mixture, and the solid gummy residue was triturated with MTBE (10 mL). The ether layer was decanted and the residue was dried under vacuum to give 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-hydroxybutanoic acid hydrochloride as an off-white solid, which was used in the next step without further purification (1.8 g, 76%). LCMS (ELSD): 438.4 [MH] + .

[0210] Intermediate 13 Synthesis of ethyl 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-hydroxybutanoate

[0211] [ka]

[0212] 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 (0.47 g, 0.99 mmol) was dissolved in DCM (10 mL) at 0 °C, triethylamine (0.34 mL, 2.47 mmol) and trifluoroacetic anhydride (0.17 mL, 1.19 mmol) were added, and the resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (15 mL), and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaHCO (5 mL), then brine (10 mL), and dried over anhydrous NaSO. The organic portion was filtered and concentrated under reduced pressure to give the desired compound ethyl 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-hydroxybutanoate, which was carried on to the next step without further purification (0.53 g, 97%). LCMS (ELSD): 534.3 [MH] + .

[0213] Intermediate 14 Synthesis of 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

[0214] [ka]

[0215] Ethyl 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-hydroxybutanoate (530 mg, 0.99 mmol) was dissolved in a mixture of THF (5 mL), MeOH (4 mL), and water (3 mL). LiOH (71.4 mg, 2.98 mmol) was added at RT, and the resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with ice-cold water (20 mL), and the aqueous layer was washed with EtOAc (2×15 mL). The combined aqueous extracts were acidified with 1.5 N aqueous hydrochloric acid (10 mL). The resulting solid was filtered through a Büchner funnel and concentrated under reduced pressure to give 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, which was carried on directly to the next step without further purification (0.36 g, 71%). LCMS: 506.4 [M−H] + .

[0216] Intermediate 15 Synthesis of (1R,2S,5S)-N-(1-cyclopropyl-3-hydroxy-4-(methylamino)-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

[0217] [ka]

[0218] To a suspension of 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 (360 mg, 0.71 mmol) in DMF (5 mL) was added DIPEA (0.32 mL, 1.78 mmol) and HATU (406 mg, 1.07 mmol) at 0 °C. Then, MeNH2 (0.53 mL, 1.07 mmol) in THF was added, and the reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by UPLC-MS), the reaction mixture was diluted with water (15 mL), and the aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel: 230-400 mesh; eluent: 20-80% EtOAc / per ether) to give the desired product (1R,2S,5S)-N-(1-cyclopropyl-3-hydroxy-4-(methylamino)-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 as a yellowish liquid (0.31 g, 76%). LCMS (ELSD): 519.3 [MH] + .

[0219] Example 2 Synthesis of (1R,2S,5S)-N-[1-(cyclopropylmethyl)-3-(methylamino)-2,3-dioxopropyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0220] [ka]

[0221] To a solution of (1R,2S,5S)-N-(1-cyclopropyl-3-hydroxy-4-(methylamino)-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 (0.31 g, 0.59 mmol) in DCM (8 mL), DMP (0.51 g, 1.19 mmol) was added in portions at room temperature, and the resulting reaction mixture was stirred at room temperature for 1.5 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with ice-cold water (15 mL), and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with saturated aqueous NaHCO (10 mL), brine (10 mL), and dried over anhydrous NaSO. The organic portion was concentrated under reduced pressure, and the resulting crude was purified by Prep-HPLC (Method A: A-0.1% TFA in water, B-ACN, flow rate: 2.0 mL / min; column: X-Bridge C8). The fractions were concentrated and washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted with DCM (3 x 15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting compound was dried and lyophilized to give the desired product (1R,2S,5S)-N-[1-(cyclopropylmethyl)-3-(methylamino)-2,3-dioxo-propyl]-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as an off-white solid (0.056 g, 24.67%). LCMS (ELSD): 517.3 [MH] + .δ 9.47-9.30 (m, 1H), 8.65-8.47 (m, 1H), 6.22-5.90 (m, 1H), 5.10-4.90 (m, 1H), 4.43-4.29 (m, 2H), 3.90-3.70 (m, 1H), 3.73-3.67 (m, 1H), 2.78-2.50 (m, 3H), 1.70-1.40 (m, 2H), 0.90-0.63 (m, 16H), 0.45- -0.14 (m, 6H).

[0222] [ka]

[0223] Intermediate 16 Synthesis 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

[0224] [ka]

[0225] To a suspension of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (1.8 g, 7.78 mmol) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.317 g, 7.78 mmol) in DCM (20 mL) was added DIPEA (4.08 mL, 23.35 mmol) at 0 °C. Then, a 50% wt. % solution of propylphosphonic anhydride in ethyl acetate (7.01 mL, 11.67 mmol) was added, and the resulting reaction mixture was stirred at RT for 16 h. After completion of the reaction (monitored by UPLC-LCMS), the reaction mass was diluted with 10% NaHCO3 solution (20 mL), and the aqueous layer was extracted with DCM (3 × 20 mL). The combined organic layers were separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound obtained was purified on a Biotage-Isolera column using 25 g of silica snap (silica gel: 230-400 mesh; eluent: 0-30% ethyl acetate in PET-ether as a gradient) to give the target compound, methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate, as a yellow gum (1.8 g, 58.0%). LCMS (ELSD): 383.4 [MH] + .

[0226] Intermediate 17 Synthesis of methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride

[0227] [ka]

[0228] Methyl (1R,2S,5S)-3-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (500 mg, 1.30 mmol) was dissolved in 1,4-dioxane (5 mL), and HCl-dioxane (4 M, 5 mL, 20.00 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at RT for 5 h. After completion of the reaction (monitored by UPLC-LCMS), the reaction mixture was concentrated under reduced pressure to give the desired compound, methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride, as a brown gum. This compound was carried forward to the next step without further purification (0.500 g, crude). LCMS (ELSD): 283.4 [MH] + .

[0229] Intermediate 18 Synthesis of methyl (1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

[0230] [ka]

[0231] To a suspension of methyl (1R,2S,5S)-3-((S)-2-amino-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (500 mg, 1.56 mmol) in DCM (5 mL) at 0 °C, triethylamine (0.6 mL, 4.27 mmol) and isobutyryl chloride (0.2 mL, 1.91 mmol) were added, and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated under reduced pressure to give the desired compound, methyl (1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate, as a yellow gum. This compound was carried on directly to the next step without further purification (0.478 g, crude). LCMS (ELSD): 353.3 [MH] + .

[0232] Intermediate 19 Synthesis of (1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

[0233] [ka]

[0234] To a suspension of methyl (1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (470 mg, 1.33 mmol) in a mixture of THF (3 mL), water (2 mL), and methanol (1 mL), LiOH.HO (168 mg, 4.00 mmol) was added at room temperature, and the resulting reaction mixture was stirred at room temperature for 4 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated, and the resulting residue was dissolved in water (5 mL). The aqueous layer was acidified with dilute hydrochloric acid (1.5N, 10 mL), and the resulting solid was filtered and dried under vacuum to give the desired compound (1R,2S,5S)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid as an off-white solid. This compound was carried forward to the next step without further purification (0.45 g, crude). LCMS (ELSD): 339.4 [MH] + .

[0235] Intermediate 20 Synthesis of (1R,2S,5S)-N-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0236] [ka]

[0237] (1R,2S,5S)-3-((S)-2-Isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (200 mg, 0.59 mmol) in DMF (3 mL) was dissolved in DMF (3 mL) at 0 °C, and 3-amino-N-cyclopropyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide hydrochloride (164 mg, 0.59 mmol) and DIPEA (0.310 mL, 1.77 mmol) were added. HATU (337 mg, 0.88 mmol) was then added at 0 °C, and the resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction (monitored by UPLC-LCMS), the reaction mixture was diluted with water (5 mL), and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting crude compound was purified by flash column chromatography using silica gel (100-200 mesh, eluent: 0-10% MeOH in DCM gradient) to give the elimination compound (1R,2S,5S)-N-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as a pale yellow gum. This mixture was carried forward directly without further purification (0.250 g, mixture). LCMS (ELSD): 562.4 [MH]. + .

[0238] Example 5 Synthesis of (1R,2S,5S)-N-[3-(cyclopropylamino)-2,3-dioxo-1-[[(3S)-2-oxopyrrolidin-3-yl]methyl]propyl]-3-[(2S)-3,3-dimethyl-2-(2-methylpropanoylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0239] [ka]

[0240] (1R,2S,5S)-N-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide (250 mg, 0.44 mmol) was dissolved in DCM (5 mL), Dess-Martin periodinane (378 mg, 0.89 mmol) was added at RT, and the reaction mixture was stirred at RT for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with saturated aqueous NaHCO3 (5 mL), and the aqueous layer was extracted with DCM (3 x 15 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The compound was purified by prep-HPLC, and the fractions containing the desired mass peak were concentrated under reduced pressure. The resulting residue was partitioned between 10% NaHCO3 solution (20 mL) and DCM (2 x 20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure, and lyophilized to give the desired compound (1R,2S,5S)-N-(4-(cyclopropylamino)-3,4-dioxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)-3-((S)-2-isobutyramido-3,3-dimethylbutanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide as an off-white solid (3.5 mg, 1.37%). LCMS (ELSD): 560.5 [MH] +.δ 8.76 (d, J = 4.8 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.79-7.73 (m, 1H), 7.61 (s, 1H), 5.18-5.03 (m, 1H), 4.39 (d, J = 9.2 Hz, 1H), 4.25 (s, 1H), 4.14 (d, J = 9.2 Hz, 1H), 3.83-3.80 (m, 2H), 3.52-3.51 (m, 1H), 3.20-3.17 (m, 1H), 3.10-3.00 (m, 1H), 2.75-2.70 (m, 1H), 2.64-2.54 (m, 2H), 2.25-2.13 (m, 1H), 1.90-1.80 (m, 1H), 1.70-1.60 (m, 2H), 1.50-1.45 (m, 2H), 1.25 (d, J = 8.0 Hz, 4H), 1.02-0.94 (m, 13H), 0.89-0.83 (m, 2H), 0.67-0.64 (m, 2H), 0.58-0.57 (m, 2H).

[0241] Examples 3, 4, 6 and 7 were synthesized using the same procedure as above.

[0242] Biological data SARS-CoV-2 Mpro Construction Design The SARS-CoV-2-Mpro (main protease / 3C-like protease, UniProt ID: P0DTD1) protein sequence, including its self-cleavage boundary and the preceding five N-terminal amino acids 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 the BamHI and XhoI sites. Thus, expression constructs featured the native viral N-terminal sequence, a C-terminal modified 3C protease cleavage site (LEVLFQGK) with an alternative lysine residue at the P2' position, and a polyhistidine (His-8) tag.

[0243] Protein expression and purification Chemically competent BL21(DE3)-RIL E. coli (Agilent, #230240) cells were transformed with the relevant coronavirus Mpro construct and grown overnight at 37°C on LB agar plates supplemented with the appropriate antibiotic. All incubations were performed at 37°C. The cells were grown in 15 mL of antibiotic-supplemented LB medium for approximately 2 hours, ensuring that the optical density (OD) measured at 600 nm in a spectrophotometer did not exceed 2.0. This preculture was used to inoculate 500 mL of 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. The cells were then grown overnight at 18°C. For autoinduction expression, the temperature was reduced to 18°C ​​once an OD of 0.7-1.0 was observed, and the cells were then harvested by centrifugation and frozen until use.

[0244] 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 minutes 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 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.

[0245] SARS-CoV-2 Mpro enzyme assay The activity of SARS-CoV-2 Mpro was measured using a fluorescence resonance energy transfer (FRET)-based enzyme assay using the FRET substrate Dabcyl-KTSAVLQSGFRKM-E(Edans)-Amide. Briefly, 5 μL of test compound (concentrations ranging from 100 μM to 0.0017 μM) was preincubated with 5 μL of 20 nM (final concentration) Mpro enzyme in assay buffer containing 20 mM HEPES, 120 mM NaCl, 0.4 mM EDTA, 4 mM DTT, and 20% glycerol for 30 min at 30°C. The reaction was initiated by adding 10 μL of 20 μM (final concentration) FRET substrate (Dabcyl-KTSAVLQSGFRKM-E(Edans)-Amide). The reaction was incubated for 1 hour and the resulting fluorescence intensity was measured at Ex=360 nm / Em=490 nm at 30°C using a SPARK 20M plate reader (Tecan). 50 and pKi were measured using 4PL GraphPad Prism, and data are expressed as mean values ​​(n = 2) ± SD.

[0246] [Table 2]

[0247] MDCK-MDR1 permeability and P-gp substrate assays The permeability and drug efflux of certain exemplary compounds was investigated using the following assays. Test compounds were added to either the apical side of confluent monolayers of MDCK-MDR1 (Madin-Darby canine kidney cells transfected to stably express active P-glycoprotein), and permeability was measured by monitoring the appearance of the test compound on the basolateral side of the monolayer using LC-MS / MS. Experiments were performed in the absence and presence of the P-glycoprotein (P-gp) inhibitor elacridar (2 μM) to determine whether the compounds underwent P-gp-mediated efflux.

[0248] method MDCK-MDR1 cells obtained from NIH (Rockville, Maryland, USA) were used at passage numbers 6 to 30. The cells were 3.4 x 10 5 cells / cm 2 Cells were seeded onto transwell plates. Cells were cultured in DMEM, and the medium was replaced on day 3. Permeability assays were performed on days 4 or 5. Cell culture and assays were performed at 37°C in an atmosphere of 95% relative humidity and 5% CO2. On the day of the assay, both the apical and basolateral surfaces were washed twice with Hanks Balanced Salt Solution (HBSS) at the desired pH preheated to 37°C to prepare monolayers. Both the apical and basolateral compartments were then incubated in HBSS at the desired pH for 40 minutes to stabilize physiological parameters.

[0249] Test articles were diluted in assay buffer to a final test article concentration (typically 1 μM). The final DMSO concentration was 1% (v / v). Lucifer Yellow, a fluorescent integrity marker, was also included in the dosing solution. Analytical standards were prepared from DMSO dilutions of the test article and transferred to the buffer, maintaining the DMSO concentration at 1% (v / v) or less. The typical assay buffer was HBSS pH 7.4.

[0250] To assess AB permeability, HBSS was removed from the apical compartment and replaced with the test compound dosing solution or the test compound plus P-gp inhibitor dosing solution. The apical compartment insert was then placed in a companion plate containing fresh buffer (containing ≤1% (v / v) DMSO). After 60 min, the apical compartment insert and companion plate were separated, and apical and basolateral samples were diluted and analyzed. Test compound permeability was assessed in duplicate. Compounds with known permeability properties were run as controls in each assay plate.

[0251] Test and control compounds were quantified by LC-MS / MS cassette analysis using a seven-point calibration with appropriate dilutions of the samples. The starting concentration (C0) was determined from the dose solution, and experimental recoveries were calculated from C0 and the concentrations in both the apical and basolateral compartments.

[0252] The permeability coefficient (P app)は , was calculated from the following formula:

[0253]

number

[0254] where dQ / dt is the permeation rate of the drug across the cell, C0 is the donor compartment concentration at time zero, and A is the area of ​​the cell monolayer. C0 was obtained from analysis of the dosing solution.

[0255] [Table 3]

[0256] As shown by this example, "R 2 Compounds bearing a cycloalkyl, such as cyclopropyl, at the " position have been shown to provide particularly good pharmacokinetic properties. In particular, such compounds have been shown to have high permeability when tested both with and without P-gp inhibitors. These compounds have also been shown to have high in vivo activity when tested in mouse and hamster models. Without wishing to be bound by theory, it is believed that such permeability is due to the increased lipophilicity of such compounds.

[0257] Reference Example The present specification also discloses the following reference compounds synthesized by the same process as above, the details of their synthesis and activity data are described in PCT / GB2022 / 050836.

[0258] [Table 4-1]

[0259] [Table 4-2]

[0260] [Table 4-3]

[0261] The pKi data for these reference examples in the table below was obtained using the modified SARS-CoV-2 Mpro enzyme assay (disclosed below) and is described in PCT / GB2022 / 050836.

[0262] SARS-CoV-2 Mpro enzyme assay The activity of SARS-CoV-2 Mpro was measured using 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 in assay buffer containing 20 mM Tris (pH 7.5), 100 mM NaCl, and 1 mM EDTA for 20 min at room temperature. 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 and RFU per minute was calculated using MARS software (BMG Labtech). 50 and pKi were measured using 4PL GraphPad Prism, and the data are expressed as mean n=2±SD. The pKi values ​​of the compounds of the present invention are shown in the table below.

[0263] [Table 5]

[0264] These data demonstrate the efficacy of compounds with structures related to those described herein.

[0265] Numbered Embodiments 1. Formula (I):

[0266] [ka]

[0267] or a salt, solvate, hydrate, N-oxide or prodrug thereof, wherein R 1 and R 1aare independently H; C optionally containing a cycloalkyl group and optionally substituted with 1 to 6 halo; 1-6 a saturated hydrocarbon group; or a benzyl group optionally substituted with 1 to 6 halo; Or R 1 and R 1a are joined together with the nitrogen to which they are attached to form a 3-6 membered saturated ring, optionally containing an additional heteroatom and optionally substituted with 1-6 halo; R 2 is C 3-6 Cycloalkyl, C 1-4 alkyl and saturated 3- to 6-membered heterocycle, each optionally substituted with one or more oxo, hydroxy, and halo groups; or R 2 Ha-(CH2) p CONHR 6 or R 2 Ha-(CH2) p CO2R 6 and; R 6 is H, C 1-3 Alkyl, and C 1-3 haloalkyl; R is

[0268] [ka]

[0269] represents R 3 teeth, (i) a saturated group containing 1 to 6 carbon atoms and optionally containing a cycloalkyl group; or (ii) a saturated ring containing an oxygen or nitrogen heteroatom wherein the saturated group or ring is optionally substituted with one or more substituents selected from fluorine, hydroxy or methoxy; or R 3 is -CH2aryl; -CH(CH3)aryl; or -C(CH3)2aryl; R 5 is C 1-8C which is a hydrocarbon group, optionally containing one or more rings or double bonds, and optionally substituted with one or more groups selected from halo; cyano; hydroxy; methoxy; amino; and cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. 1-8 is a hydrocarbon group; or R represents -LA; where L is -CR 7 =CR 8 -, -CHR 9 -CHR 10 -or -O-CHR 11 - and; R 7 ~R 11 are independently H, -(CH2) m CO2R 12 or C optionally substituted with 1 to 6 fluorine atoms 1-3 is alkyl; or R 9 and R 10 connects to form a cyclopropyl; A is phenyl or heteroaryl, optionally halo, —CN, —COR 13 , -OR 13 , -SO2R 13 , -SONHR 13 , -OSO2R 13 , -PO(R 13 )2, -SF5, C 1-3 Alkyl and C 1-3 phenyl or heteroaryl optionally substituted with one or more groups selected from haloalkyl; R 12 and R 13 are independently H, C 1-3 Alkyl, and C 1-3 haloalkyl; m is independently 0 to 3; R 2 C includes a cycloalkyl group that is unsubstituted or substituted with one or more substituents selected from fluorine or hydroxyl. 3-5 When it is a saturated hydrocarbon group, R is

[0270] [ka]

[0271] represents R 5 is methyl, optionally substituted with one or more substituents selected from halo; cyano; hydroxy; methoxy; and amino; and R 3 is as defined herein; or R represents -LA as defined herein; However, the compound of formula (I) (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 or a salt thereof; or It is not (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.

[0272] 2. The compound of embodiment 1, wherein the compound has formula (IA):

[0273] [ka]

[0274] or a salt, solvate, hydrate, N-oxide or prodrug thereof, wherein the substituents are as defined in claim 1.

[0275] The compound of embodiment 1 or 2, wherein R 3 teeth,

[0276] [ka]

[0277] each optionally substituted with one or more halo, preferably F.

[0278] 4.R 3

[0023] The compound of any preceding embodiment, wherein is iso-propyl or tert-butyl.

[0279] 5.R 5 is saturated or unsaturated C 1-5 The compound of any of the preceding embodiments, wherein the hydrocarbon group is optionally substituted with one or more halo, preferably F.

[0280] 6. The compound of any preceding embodiment, wherein R 5 teeth,

[0281] [ka]

[0282] Preferably CF3,

[0283] [ka]

[0284] Most preferably -CF3,

[0285] [ka]

[0286] is.

[0287] 7. The compound of embodiment 1, wherein the compound has formula (IB):

[0288] [ka]

[0289] or a salt, solvate, hydrate, N-oxide or prodrug thereof, wherein the substituents are as defined in embodiment 1.

[0290] 8.L is -CH=CH-, -CH2CH2-, -CH2-CH(CH2CH3)-, -CH2-CH(CH2CO2H)-, -OCH2-, -CH2-CH(CH3)-, -CH2-CH(CF3)-, -OCH(CH3)-, or

[0291] [ka]

[0292] The compound of any one of embodiments 1 or 7, wherein

[0293] 9. The compound of any of embodiments 1, 7, or 8, wherein L is -CH=CH-.

[0294] 10. A is phenyl or pyridinyl, each optionally containing halo, hydroxy and C 1-3 The compound of any of embodiments 1, 7, 8, or 9, substituted with one or more groups selected from alkyl.

[0295] 11.A is

[0296] [ka]

[0297] 11. The compound of any of embodiments 1, 7, 8, 9, or 10, selected from:

[0298] 12. The compound of any preceding embodiment, wherein: (i)R 1is H or a C optionally containing a cycloalkyl group, optionally substituted with 1 to 6 halo, preferably F. 1-6 is a saturated hydrocarbon group; and / or (ii)R 1a is H, Preferably, R 1 is H, methyl or cyclopropyl, and R 1a is H.

[0299] 13.R 1 and R 1a and R 1 and R 2 together with the nitrogen to which they are attached join to form a 3-6 membered saturated ring, optionally containing an additional heteroatom, and optionally substituted with 1-6 halo, preferably F.

[0300] 14.R 2 is optionally substituted with one or more oxo, hydroxy and halo, C 3-6 The compound of any of the preceding embodiments, which is cycloalkyl, or a saturated 5- or 6-membered heterocycle.

[0301] 15. The compound of the preceding embodiment, wherein R 2 teeth,

[0302] [ka]

[0303] is selected from the group consisting of

[0304] Each is optionally substituted with one or more halo, preferably F.

[0305] 16. The compound of embodiment 1, wherein the compound is N-(4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)-3-(3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[1-(cyclopropylmethyl)-3-(methylamino)-2,3-dioxo-propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxo-propyl]-6,6-dimethyl-3-[3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxo-propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[3-(cyclopropylamino)-2,3-dioxo-1-[[2-oxopyrrolidin-3-yl]methyl]propyl]-3-[3,3-dimethyl-2-(2-methylpropanoylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[3-(cyclopropylamino)-2,3-dioxo-1-[[2-oxo-3-piperidyl]methyl]propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-(4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)-3-(3-(2,4-difluorophenyl)acryloyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide or a salt, solvate, hydrate, N-oxide or prodrug thereof.

[0306] 17. A pharmaceutical composition comprising a compound as defined in any of the preceding embodiments, and a pharmaceutically acceptable excipient.

[0307] 18. A compound according to any one of embodiments 1 to 16 or a pharmaceutical composition according to embodiment 17 for use as a medicament.

[0308] 19. A compound according to any one of embodiments 1 to 16 or a pharmaceutical composition according to embodiment 17 for use in the treatment of SARS-CoV-2 or a disorder associated with SARS-CoV-2.

[0309] 20. Use of a compound according to any one of embodiments 1 to 16 in the manufacture of a medicament for the treatment of SARS-CoV-2 or a disorder associated with SARS-CoV-2.

[0310] 21. A method of treating a disease or disorder sensitive to SARS-CoV-2 Mpro inhibition in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound defined in any one of embodiments 1-16.

[0311] 22. A method of treating SARS-CoV-2 or a disorder associated with SARS-CoV-2 in a subject in need thereof, said method comprising administering to said subject a pharmaceutically effective amount of a compound defined in any one of embodiments 1-16.

Claims

1. Formula (I'): 【Chemical 1】 [During the ceremony, R １ and R １ａ are independently H; C optionally containing a cycloalkyl group and optionally substituted with 1 to 6 halo; １－６ a saturated hydrocarbon group; or a benzyl group optionally substituted with 1 to 6 halo; Or R １ and R １ａ are joined together with the nitrogen to which they are attached to form a 3-6 membered saturated ring, optionally containing an additional heteroatom and optionally substituted with 1 to 6 halo; R ２ is optionally substituted with one or more oxo, hydroxy and halo groups; ３－６ is cycloalkyl; R is 【Chemistry 2】 represents R ３ teeth, (i) a saturated group containing 1 to 6 carbon atoms and optionally containing a cycloalkyl group; or (ii) a saturated ring containing an oxygen or nitrogen heteroatom wherein said saturated group or ring is optionally substituted with one or more substituents selected from fluorine, hydroxy or methoxy; or R ３ is -CH ２ Aryl; -CH(CH ３ ) aryl; or —C(CH ３ ) ２ is aryl; R ５ is C １－８ C is a hydrocarbon group, optionally containing one or more rings or double bonds, and optionally substituted with one or more groups selected from halo; cyano; hydroxy; methoxy; amino; and cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. １－８ is a hydrocarbon group; or R represents -LA; Here, L is -CR ７ =CR ８ --, --CHR ９ -CHR １０ -, or -O-CHR １１ - and; R ７ ~R １１ are independently H, -(CH ２ ) ｍ CO ２ R １２ or C optionally substituted with 1 to 6 fluorine atoms １－３ is alkyl; or R ９ and R １０ is connected to form a cyclopropyl; A is phenyl or heteroaryl, optionally halo, —CN, —CO ２ R １３ , -OR １３ , -SO ２ R １３ , -SONHR １３ , -OSO ２ R １３ , -PO(R １３ ) ２ , -SF ５ , C １－３ Alkyl and C １－３ phenyl or heteroaryl optionally substituted with one or more groups selected from haloalkyl; R １２ and R １３ are independently H, C １－３ Alkyl, and C １－３ haloalkyl; m is independently 0 to 3; R ２ is a C containing a cycloalkyl group that is unsubstituted or substituted with one or more substituents selected from fluorine or hydroxyl ３－５ When it is a saturated hydrocarbon group, R is 【Chemistry 3】 represents R ５ is methyl, optionally substituted with one or more substituents selected from halo; cyano; hydroxy; methoxy; and amino; R ３ is as defined herein; or R represents -LA as defined herein. or a salt, solvate, hydrate, N-oxide or prodrug thereof, However, the compound of formula (I') is (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 or a salt thereof; or The compound is not (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.

2. The compound has the formula (IA): 【Chemistry 4】 or a salt, solvate, hydrate, N-oxide or prodrug thereof, wherein the substituents are as defined in claim 1.

3. R ３ but, 【Chemistry 5】 3. The compound of claim 1 or 2, selected from the group consisting of: each optionally substituted with one or more halo, preferably F.

4. R ３ 10. The compound of any preceding claim, wherein is iso-propyl or tert-butyl.

5. R ５ is saturated or unsaturated C １－５ 10. A compound according to any preceding claim which is a hydrocarbon group, optionally substituted with one or more halo, preferably F.

6. R ５ but, 【Chemistry 6】 Preferably -CF ３ , 【Chemistry 7】 Most preferably -CF ３ , 【Chemistry 8】 10. The compound of any preceding claim, wherein

7. The compound has formula (IB): 【Chemistry 9】 or a salt, solvate, hydrate, N-oxide or prodrug thereof, wherein the substituents are as defined in claim 1.

8. Lが、-CH=CH-、-CH ２ CH ２ -、-CH ２ --H(H) ２ CH ３ )-、-H ２ --H(H) ２ CO ２ H)-、-OCH ２ -、-CH ２ --H(H) ３ )-、-H ２ -EH(CF) ３ )-、-OCH(CH ３ )-、or 【Chemistry 10】 8. The compound of claim 1 or 7, wherein:

9. 9. The compound of any one of claims 1, 7 or 8, wherein L is -CH=CH-.

10. A is phenyl or pyridinyl, each optionally containing halo, hydroxy and C １－３ 10. The compound of any one of claims 1, 7, 8 or 9, substituted with one or more groups selected from alkyl.

11. A is, 【Chemistry 11】 10. The compound of any one of claims 1, 7, 8, 9 or 9, selected from:

12. (i) R １ contains H or an optionally cycloalkyl group, optionally substituted with 1 to 6 halo, preferably F; １－６ is a saturated hydrocarbon group; and / or (ii) R １ａ is H, Preferably, R １ is H, methyl or cyclopropyl, and R １ａ 4. A compound according to any preceding claim, wherein is H.

13. R １ and R １ａ are joined together with the nitrogen to which they are attached to form a 3-6 membered saturated ring, optionally containing an additional heteroatom, and optionally substituted with 1 to 6 halo, preferably F.

14. R ２ but, 【Chemistry 12】 is selected from the group consisting of 10. A compound according to any preceding claim, each optionally substituted with one or more halo, preferably F.

15. N-[1-(cyclopropylmethyl)-3-(methylamino)-2,3-dioxo-propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[3-amino-1-(cyclopropylmethyl)-2,3-dioxo-propyl]-6,6-dimethyl-3-[3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxo-propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[3-(cyclopropylamino)-2,3-dioxo-1-[[2-oxopyrrolidin-3-yl]methyl]propyl]-3-[3,3-dimethyl-2-(2-methylpropanoylamino)butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; N-[3-(cyclopropylamino)-2,3-dioxo-1-[[2-oxo-3-piperidyl]methyl]propyl]-3-[3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide; and N-(4-(cyclopropylamino)-3,4-dioxo-1-(2-oxopyrrolidin-3-yl)butan-2-yl)-3-(3-(2,4-difluorophenyl)acryloyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide or a salt, solvate, hydrate, N-oxide or prodrug thereof.

16. A pharmaceutical composition comprising a compound as defined in any of the preceding claims and a pharmaceutically acceptable excipient.

17. 17. The pharmaceutical composition of claim 16, further comprising one or more drugs that inhibit metabolism via cypP450, preferably said drugs being selected from ritonavir, lopinavir or a combination thereof.

18. A compound according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 16 or 17 for use as a medicament.

19. A compound according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 16 or claim 17 for use in the treatment of SARS-CoV-2 or a disorder associated with SARS-CoV-2.

20. 20. Use of a compound according to any one of claims 1 to 15 in the manufacture of a medicament for the treatment of SARS-CoV-2 or a disorder associated with SARS-CoV-2.

21. 18. A method of treating a disease or disorder susceptible to SARS-CoV-2 Mpro inhibition in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound as defined in any one of claims 1 to 15, or a pharmaceutical composition as defined in claim 16 or claim 17.

22. 18. A method of treating SARS-CoV-2 or a disorder associated with SARS-CoV-2 in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of any one of claims 1 to 15, or a pharmaceutical composition of claim 16 or claim 17.

23. 19. A compound as defined in any one of claims 1 to 15, or a pharmaceutical composition as defined in claim 16 or claim 17, for use in accordance with claim 18 or 19, wherein said compound or composition is administered in combination with one or more agents that block CYPP450-mediated metabolism, preferably wherein said agents are selected from ritonavir, lopinavir or a combination thereof.

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