antiviral compounds

Abstract

The present invention relates to a compound represented by general formula (I) The present invention provides a viral protease inhibitor having the formula: TIFF2025533950000078.tif6491, wherein the variables are as described herein, compositions comprising the compound, methods of making the compound, and methods of using the compound.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to peptidomimetic compounds that act as viral protease inhibitors. The present invention further relates to methods for preparing and using such compounds. [Background technology]

[0002] Background of the Invention In December 2019, a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the outbreak of the novel coronavirus disease COVID-19, which has spread to more than 200 countries with over 9 million confirmed cases and 479,133 confirmed deaths worldwide as of June 26, 2020 (WHO COVID-19 Situation Report-157). The WHO has declared the coronavirus outbreak a Public Health Emergency of International Concern. Currently, there are no clinically effective vaccines or specific antiviral drugs available for the prevention and treatment of SARS-CoV-2 infection.

[0003] Coronaviruses (CoVs) are enveloped, positive-sense, single-stranded RNA viruses. Seven human coronaviruses (HCoVs) have been identified to date: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and novel coronavirus (SARS-CoV-2). While SARS-CoV, MERS-CoV, and SARS-CoV-2 are highly pathogenic, the others generally cause mild to moderate upper respiratory tract illness and contribute to 15%–30% of common cold cases in human adults.

[0004] The RNA genome of SARS-CoV-2 is approximately 30 kilobases in length and shares approximately 80% sequence identity with SARS-CoV (Zhou P. et al., "A pneumonia outbreak associated with a new coronavirus of probable bat origin." Nature 579(7798):270-273, 2020). It consists of six major open reading frames (ORFs). ORF 1a / b, which accounts for approximately two-thirds of the total genome length, directly translates two polyproteins, pp1a and pp1ab, that encode 16 nonstructural proteins (nsp), forming the replication-transcription complex. Processing of these polyproteins requires the use of papain-like proteases (PLs). pro ) and Nsp3, which encodes a 3-chymotrypsin-like cysteine ​​protease (3CL pro (Main protease, M pro nsp5, which encodes the 3CL gene, is essential. pro cleaves the polyprotein at 11 different sites to generate various nsp sequences that are important for viral replication. pro Inhibitors that block the cleavage function of 3CL can inhibit viral replication. pro 3CL is highly conserved between SARS-CoV and SARS-CoV-2 (96% sequence identity), as well as other human coronaviruses. Furthermore, no human proteases with similar cleavage specificity are known. These desirable properties make 3CL a promising candidate for the 3CL family of proteases. pro has become one of the most attractive targets for coronavirus infection. Summary of the Invention

[0005] Summary of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] where the variables are as defined herein.

[0006] In further aspects, the present invention provides methods of making, pharmaceutical compositions containing, and methods of using the compounds of formula (I) described herein. DETAILED DESCRIPTION OF THE INVENTION

[0007] Detailed Description of the Invention definition It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where inconsistent therewith. All features disclosed herein (including any accompanying claims, abstract, and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or any novel one or any novel combination of steps of any method or process so disclosed.

[0008] The term "alkyl" refers to alkyl groups containing 1 to 6 carbon atoms ("C 1-6 "-alkyl") refers to a monovalent or polyvalent, e.g., monovalent or divalent, straight-chain or branched saturated hydrocarbon group, e.g., of 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, an alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, but non-limiting, examples of alkyl are methyl, tert-butyl, and 2,2-dimethylpropyl.

[0009] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0010] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C 3-10 In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbocyclic rings having two common carbon atoms, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., a cycloalkyl moiety in which the two rings are joined through one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. A particularly preferred, but non-limiting, example of cycloalkyl is cyclopropyl.

[0011] The term "cycloalkylalkyl" refers to a cycloalkyl group that is attached to the parent molecule via an alkylene group. A particularly preferred, but non-limiting example of a cycloalkylalkyl is 1-bicyclo[1.1.1]pentanylmethyl.

[0012] The term "alkylcycloalkyl" refers to a cycloalkyl group in which at least one of the hydrogen atoms of the cycloalkyl group is replaced by an alkyl group. Preferably, "alkylcycloalkyl" refers to a cycloalkyl group in which one, two, or three hydrogen atoms of the cycloalkyl group are replaced by an alkyl group. A particularly preferred, but non-limiting, example of an alkylcycloalkyl is 1-methylcyclopropyl.

[0013] The term "aryl" refers to a group having a total of 6 to 14 ring members ("C6-C 14 Aryl) is preferably a monocyclic, bicyclic, or tricyclic carbocyclic ring system having 6 to 12 ring members, more preferably 6 to 10 ring members, in which at least one ring of the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred, but non-limiting example of aryl is phenyl.

[0014] The term "arylalkyl" refers to an aryl group attached to the parent molecule via an alkylene group. A particularly preferred, but non-limiting example of an arylalkyl is benzyl.

[0015] The term "aryloxy" refers to an aryl group attached to the parent molecule through an oxygen atom. A non-limiting example of an aryloxy is phenoxy.

[0016] The term "heteroaryl" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic, preferably bicyclic, ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5- to 10-membered, more preferably a 5- to 8-membered, and even more preferably a 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5- to 10-membered, particularly a 5- to 8-membered or 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O, S, and N. In some most preferred examples, "heteroaryl" refers to a 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O, S, and N.Some non-limiting examples of heteroaryls include spiro[cyclopropane-1,3′-indoline] (e.g., spiro[cyclopropane-1,3′-indoline]-1′-yl), 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-8-yl, 1H-indol-9-yl, 1H-indol-10-yl, 1H-indol-11-yl, 1H-indol-12-yl, 1H-indol-13-yl, 1H-indol-14-yl, 1H-indol-15-yl, 1H-indol-16-yl, 1H-indol-17-yl, 1H-indol-18-yl, 1H-indol-19 ... 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol 1H-imidazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiazol-2-yl, thiazol- 4-yl, thiazol-5-yl, pyridazin-3-yl, pyridazin-4-yl, 1,2,4-triazol-4-yl, 1,2,4-triazol-1-yl, 4H-1,2,4-triazol-3-yl, 4,5,6,7-tetrahydroindazol-2-yl, 6,7-dihydro-4H-pyrano[4,3-c]pyrazol-2-yl, thiazolyl, benzofuran-4-yl, tetrathiazolyl, isoxazolyl, and morpholinyl. Particularly preferred, but non-limiting examples of heteroaryl include pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and triazolyl.

[0017] The term heteroarylalkyl refers to a heteroaryl group that is attached to the parent molecule via an alkylene group. A particularly preferred, but non-limiting example of a heteroarylalkyl is pyridylmethyl.

[0018] The terms "heterocyclyl" or "heterocycloalkyl" refer to saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring systems of 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, and most preferably 3 to 6 ring atoms, in which 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclyl" refers to heterocyclic moieties consisting of two rings that share two ring atoms (i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms) and spirocyclic moieties (i.e., the two rings are connected through one common ring atom). Some non-limiting examples of heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, 5-azaspiro[2.5]octan-5-yl, piperidyl, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonan-2-yl, 1,2-dihydropyridinyl, piperidyl, pyrrolidinyl, and thietanyl.

[0019] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably fluoro. Some non-limiting examples of haloalkyl include trifluoromethyl, difluoromethyl, CHClF, 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. Particularly preferred examples of haloalkyl include difluoromethyl and CHClF.

[0020] The term "oxo" refers to a double-bonded oxygen (=O).

[0021] The term "carbamoyl" refers to the group H2N-C(O)-.

[0022] The term "acyl" refers to the group CH3-C(O)-.

[0023] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, and is not biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid, as well as organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, and the like.

[0024] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0025] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0026] The term "treatment" as used herein includes (1) suppressing a condition, disorder, or symptom (e.g., arresting, reducing, or delaying the onset of a disease or, in the case of maintenance treatment, the recurrence of a disease, the onset of at least one clinical or subclinical symptom of a disease); and / or (2) alleviating symptoms (i.e., causing regression of a condition, disorder, or symptom, or at least one of its clinical or subclinical symptoms). The benefit to the patient to be treated is either statistically significant or at least perceptible to the patient or physician. However, it will be understood that when a pharmaceutical agent is administered to a patient to treat a disease, the result may not necessarily be effective treatment.

[0027] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition in a mammal, particularly a human, who may be affected by or predisposed to the condition, disorder or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder or condition.

[0028] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein: L is C1-C6-alkyl, R 1 is C3~C 10 -Cycloalkyl, halo-C3~C 10 -Cycloalkyl, C6-C 14 -aryl, 3-14 membered heteroaryl, C1-C6-alkyl, and halo-C1-C6-alkyl; R 2 is hydrogen, C3 to C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C1-C6-alkyl-C3-C10 -cycloalkyl, C1-C6-alkyl, C1-C6-alkyl-S-C1-C6-alkyl, 3-14-membered heteroaryl, (3-14-membered heteroaryl)-C1-C6-alkyl, C6-C 14 -aryl, and C6-C 14 -aryl-C1-C6-alkyl, R 3a , R 3b , R 4a , and R 4b are each independently selected from hydrogen, halogen, C1-C6-alkyl, and halo-C1-C6-alkyl, or R 3a and R 3b together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 4a and R 4b are each independently selected from hydrogen and C1-C6-alkyl, and the C3-C 10 -cycloalkyl is optionally substituted with 1 to 2 C1-C6-alkyl substituents, or R 4a and R 4b together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 3a and R 3b are each independently selected from hydrogen and C1-C6-alkyl, and the C3-C 10 -cycloalkyl is optionally substituted with 1 to 2 C1-C6-alkyl substituents, or R 3a and R 4a together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 3b and R 4b are each independently selected from hydrogen and C1-C6-alkyl, and the C3-C 10 -cycloalkyl is optionally substituted with 1 to 2 C1-C6-alkyl substituents, R 5is selected from fluoro and chloro; R 6 is selected from hydrogen, chloro, and acyl; R 7a and R 7b are both C1-C6-alkyl, and R 7c and R 7d are both selected from hydrogen and C1-C6-alkyl, or R 7a , R 7b and R 7d is hydrogen and R 7c is C1-C6-alkyl, or R 7a is C1-C6-alkyl, and R 7b is hydrogen and R 7c and R 7d are both selected from hydrogen and C1-C6-alkyl, or R 7a and R 7b together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 7c and R 7d are both selected from hydrogen and C1-C6-alkyl, or R 7a and R 7d together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 7b and R 7c are both selected from hydrogen and C1-C6-alkyl.

[0029] In one embodiment, the compound of formula (I) is a compound of formula (Ia) [ka] or a pharmaceutically acceptable salt thereof, wherein: L is C1-C6-alkyl, R 1 is C3~C 10 -Cycloalkyl, halo-C3~C10 -Cycloalkyl, C6-C 14 -aryl, 3-14 membered heteroaryl, C1-C6-alkyl, and halo-C1-C6-alkyl; R 2 is hydrogen, C3 to C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C1-C6-alkyl-C3-C 10 -cycloalkyl, C1-C6-alkyl, C1-C6-alkyl-S-C1-C6-alkyl, 3-14-membered heteroaryl, (3-14-membered heteroaryl)-C1-C6-alkyl, C6-C 14 -aryl, and C6-C 14 -aryl-C1-C6-alkyl, R 3a , R 3b , R 4a , and R 4b are each independently selected from hydrogen, halogen, C1-C6-alkyl, and halo-C1-C6-alkyl, or R 3a and R 3b together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 4a and R 4b are each independently selected from hydrogen and C1-C6-alkyl, and the C3-C 10 -cycloalkyl is optionally substituted with 1 to 2 C1-C6-alkyl substituents, or R 4a and R 4b together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 3a and R 3b are each independently selected from hydrogen and C1-C6-alkyl, and the C3-C 10 -cycloalkyl is optionally substituted with 1 to 2 C1-C6-alkyl substituents, or R 3a and R 4atogether with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 3b and R 4b are each independently selected from hydrogen and C1-C6-alkyl, and the C3-C 10 -cycloalkyl is optionally substituted with 1 to 2 C1-C6-alkyl substituents, R 5 is selected from fluoro and chloro; R 6 is selected from hydrogen, chloro, and acyl; R 7a and R 7b are both C1-C6-alkyl, and R 7c is selected from hydrogen and C1-C6-alkyl, or R 7a and R 7b are both hydrogen, and R 7c is C1-C6-alkyl, or R 7a is C1-C6-alkyl, and R 7b is hydrogen and R 7c is selected from hydrogen and C1-C6-alkyl, or R 7a and R 7b together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 7c is selected from hydrogen and C1-C6-alkyl.

[0030] In one embodiment, the present invention provides a compound comprising R 1 Halo-C3~C 10 -cycloalkyl or halo-C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0031] In a preferred embodiment, the present invention provides R 1 Halo-C3~C 10 Provided are compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, which are cycloalkyl.

[0032] In one embodiment, the present invention provides a compound comprising R 1 is selected from 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, CHClF, and CHF2, or a pharmaceutically acceptable salt thereof.

[0033] In one embodiment, the present invention provides a compound comprising R 1 is selected from 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, and CHF2, or a pharmaceutically acceptable salt thereof.

[0034] In a preferred embodiment, the present invention provides R 1 is 1-fluorocyclopropyl or 2,2-difluorocyclopropyl, or a pharmaceutically acceptable salt thereof.

[0035] In a particularly preferred embodiment, the present invention provides 1 is 1-fluorocyclopropyl;

[0036] In a particularly preferred embodiment, the present invention provides 1 is 2,2-difluorocyclopropyl, or a pharmaceutically acceptable salt thereof.

[0037] In one embodiment, the present invention provides a compound comprising R 2 is hydrogen or C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0038] In a preferred embodiment, the present invention provides R 2 is selected from tert-butyl, 1-methylpropyl and 1-ethylpropyl, or a pharmaceutically acceptable salt thereof.

[0039] In a particularly preferred embodiment, the present invention provides 2 is tert-butyl or 1-methylpropyl, or a pharmaceutically acceptable salt thereof.

[0040] In a particularly preferred embodiment, the present invention provides 2 is tert-butyl, or a pharmaceutically acceptable salt thereof.

[0041] In a particularly preferred embodiment, the present invention provides 2 is 1-methylpropyl, or a pharmaceutically acceptable salt thereof.

[0042] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 3a and R 4a together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 3b and R 4b are both hydrogen atoms, and the C3 to C 10 -Cycloalkyl is optionally substituted with 1 to 2 C1-C6-alkyl substituents.

[0043] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 3a and R 4a together with the carbon atom to which they are attached form cyclopropyl or cyclopentyl, and R 3b and R 4b are both hydrogen, and the cyclopropyl or cyclopentyl is optionally substituted with 1 to 2 methyl substituents.

[0044] In a particularly preferred embodiment, the present invention provides a [ka] but [ka] and [ka] The present invention provides a compound of formula (I) as described herein, selected from:

[0045] In a particularly preferred embodiment, the present invention provides a [ka] but [ka] or a pharmaceutically acceptable salt thereof.

[0046] In a particularly preferred embodiment, the present invention provides a [ka] but [ka] or a pharmaceutically acceptable salt thereof.

[0047] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is CH2.

[0048] In a preferred embodiment, the present invention provides R 5 is fluoro and R 6 is chloro; or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 7a and R 7b are both C1-C6-alkyl, and R 7c and R 7d are both hydrogen, or R 7a and R 7d together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 7b and R 7c are both hydrogen, or R 7a is C1-C6-alkyl, and R 7b , R 7c and R 7d are all hydrogen, or R 7a and R 7b together with the carbon atoms to which they are attached, form C3-C 10 - forms a cycloalkyl, R 7c and R 7d are both hydrogen.

[0050] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 7a and R 7b are both methyl, and R 7c and R 7d are both hydrogen, or R 7a and R 7d together with the carbon atom to which they are attached to form a cyclopropyl, and R 7b and R 7c are both hydrogen, or R 7a is methyl and R 7b , R 7c and R 7d are all hydrogen, or R 7a and R7b together with the carbon atom to which they are attached to form a cyclopropyl, and R 7c and R 7d are both hydrogen.

[0051] In a preferred embodiment, the present invention provides R 7a and R 7b are both C1-C6-alkyl, and R 7c is hydrogen, or a pharmaceutically acceptable salt thereof.

[0052] In a particularly preferred embodiment, the present invention provides 7a and R 7b are both methyl and R 7c is hydrogen, or a pharmaceutically acceptable salt thereof.

[0053] In one embodiment, the present invention provides a compound comprising R 7a and R 7b are both hydrogen and R 7c is C1-C6-alkyl.

[0054] In one embodiment, the present invention provides a compound comprising R 7a and R 7b are both hydrogen and R 7c is methyl, or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment, the present invention provides a compound comprising R 7a is C1-C6-alkyl, and R 7b is hydrogen and R 7c is selected from hydrogen and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment, the present invention provides a compound comprising R 7a is C1-C6-alkyl, and R 7b and R 7cand R are both hydrogen, or a pharmaceutically acceptable salt thereof.

[0057] In one embodiment, the present invention provides a compound comprising R 7a is methyl and R 7b and R 7c and R are both hydrogen, or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the present invention provides a compound comprising R 7a and R 7b However, together with the carbon atoms to which they are attached, C3 to C 10 - forms a cycloalkyl, R 7c is selected from hydrogen and C1-C6-alkyl, or a pharmaceutically acceptable salt thereof.

[0059] In one embodiment, the present invention provides a compound comprising R 7a and R 7b However, together with the carbon atoms to which they are attached, C3 to C 10 Forms a cycloalkyl, R 7c is hydrogen, or a pharmaceutically acceptable salt thereof.

[0060] In one embodiment, the present invention provides a compound comprising R 7a and R 7b together with the carbon atom to which they are attached to form a cyclopropyl, and R 7c is hydrogen, or a pharmaceutically acceptable salt thereof.

[0061] In one embodiment, the present invention provides N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; rac-(1S)-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl-[(2R)-2-chloro-2-fluoro-acetyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; (2R)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2-chloro-2-fluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; (2S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2-chloro-2-fluoro-acetamide; (2R)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-chloro-2-fluoro-acetamide; (2S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-chloro-2-fluoro-acetamide; (2R)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-chloro-2-fluoro-acetamide; (2S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-chloro-2-fluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2R)-2-chloro-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-fluoro-acetamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (2S)-2-chloro-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-fluoro-acetamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(6S)-5-oxo-4-azaspiro[2.4]heptan-6-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S,5S)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R,5S)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R,5S)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S,5S)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,4S,5R)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1S,4S,5S)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoroacetyl]-[[(1R,4S,5R)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,4R,5R)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(1S,4S,5S)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; and (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-Chloro-2-fluoro-acetyl]-[[(1R,4R,5R)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide The present invention provides a compound of formula (I) as described herein, selected from:

[0062] In a preferred embodiment, the present invention comprises: N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; rac-(1S)-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl-[(2R)-2-chloro-2-fluoro-acetyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; and N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide The present invention provides a compound of formula (I) as described herein, selected from:

[0063] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound is N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

[0064] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound is N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

[0065] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound is (1S)—N—[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

[0066] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound is (1S)—N—[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

[0067] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound is rac-(1S)-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl-[(2R)-2-chloro-2-fluoro-acetyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

[0068] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound is N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide, or a pharmaceutically acceptable salt thereof.

[0069] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, which is N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide.

[0070] In certain embodiments, the present invention provides pharmaceutically acceptable salts of compounds according to formula (I) described herein. In further particular embodiments, the present invention provides compounds according to formula (I) described herein in their free form (i.e., as a free base or a free acid).

[0071] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms therein with atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Exemplary isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125Certain isotopically labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0072] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may result in greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring lower dosages.

[0073] 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples set forth below, by substituting an appropriate isotopically labeled reagent for a previously employed non-isotopically labeled reagent.

[0074] Manufacturing method The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following method descriptions have the meanings indicated herein unless otherwise indicated.

[0075] If one of the starting materials, intermediates, or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (e.g., those described in "Protective Groups in Organic Chemistry," 5th Ed., 2014, John Wiley & Sons, NY, by T.W. Greene and P.G.M. Hutts) can be introduced prior to a critical step by applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0076] When the starting material or intermediate contains a stereocenter, the compound of formula (I) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemates can be separated into their antipodes via diastereomeric salts, for example, by crystallization with an optically pure acid, or by separating the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. Starting materials and intermediates containing a stereocenter can also be separated to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compound of formula (I) generally results in the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0077] Those skilled in the art will recognize that in the synthesis of compounds of formula (I), (unless otherwise desired) an "orthogonal protecting group strategy" can be applied to cleave several protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been described in the literature (e.g., Barany and R.B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0078] Those skilled in the art will recognize that the reaction sequence may vary depending on the reactivity and nature of the intermediates.

[0079] More specifically, compounds of formula (I) can be prepared by the methods described below, the methods described in the Examples, or similar methods. Appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. For literature-described reaction conditions affecting the described reactions, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley & Sons, New York, NY, 1999. The reactions could be easily carried out with or without a solvent. There are no particular limitations on the nature of the solvent used, so long as it does not adversely affect the reagents involved in the reaction and is capable of dissolving the reagents to at least some extent. The described reactions can be carried out over a wide temperature range, so the exact reaction temperature is not critical to the present invention. The described reactions are conveniently carried out in a temperature range from -78°C to reflux. The reaction time required can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the described intermediates and compounds. The reaction sequence is not limited to the sequence shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0080] If the starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared analogously to existing procedures for closely related analogs or as outlined in the experimental section.

[0081] All substituents, especially R 1 ~R 6 , R 1a , R 3a , R 3b , R 4a , R 4b , R 7a , R 7b , R 7c and L are as defined above and in the claims unless otherwise indicated.

[0082] Scheme 1 [ka] In Scheme 1, PG1 and PG2 are protecting groups selected from Cbz and Boc, respectively. LG1 is Cl, OH, OEt or [ka] and LG2 is Cl or OH.

[0083] Compounds of formula III can be prepared by a protection reaction between compounds of formula II and di-tert-butyl dicarbonate in the presence of an organic base such as TEA, DIPEA, or DMAP in a solvent such as DCM, THF, dioxane, or a mixture of dioxane and water. Compounds of formula III are then reacted with benzyl bromide in the presence of a base such as Na2CO3, K2CO3, or Cs2CO3 in a solvent such as DMF or CH3CN to obtain compounds of formula IV. Compounds of formula IV can be deprotected in the presence of an acid such as HCl or TFA in a solvent such as DCM or dioxane, or in a neat reaction without a solvent, to obtain compounds of formula Va. Compounds of formula VI-a can be obtained by a coupling reaction between compounds of formula V-1, compounds of formula Va, and coupling reagents such as T3P, HATU, HOPO, PyBOP, or EDCI / HOBt in the presence of an organic base such as TEA, DIPEA, or DMAP. Compounds of Formula VII can be obtained by deprotection of compounds of Formula VI-a in a solvent such as DCM or dioxane in the presence of an acid such as HCl or TFA, or by a neat reaction without a solvent. Compounds of Formula VIII can be obtained by a coupling reaction using compounds of Formula VII-1, compounds of Formula VII, and coupling reagents such as T3P, HATU, PyBOP, HOPO, or EDCI / HOBt in a solvent such as THF, EtOAc, DMF, or DCM in the presence of an organic base such as TEA, DIPEA, or DMAP. Alternatively, compounds of Formula VIII can be obtained by reaction of compounds of Formula VII with compounds of Formula VII-1 in a solvent such as MeOH, DCM, THF, or DMF in the presence of an organic base such as TEA, DIPEA, or DMAP. Compounds of Formula IX can be obtained by hydrogenolysis of compounds of Formula VIII in the presence of Pd / C, Pd(OH)2, or a mixture of Pd / C and Pd(OH)2 in a solvent such as MeOH, EtOH, THF, or EtOAc.The compound of formula IX is reacted with the compound of formula IX-1 in the presence of a coupling reagent such as T3P, HATU, PyBOP, HOPO, or EDCI / HOBt and an organic base such as TEA, DIPEA, or DMAP in a solvent such as THF, EtOAc, DMF, or DCM to give the compound of formula X. The compound of formula XI can be obtained by deprotection of the compound of formula X in the presence of an acid such as HCl or TFA in a solvent such as DCM or dioxane, or by a neat reaction without a solvent. The compound of formula XI is then reacted with the compound of formula XI-1 in the presence (or absence) of a coupling reagent such as T3P, HATU, PyBOP, HOPO, or EDCI / HOBt and a base such as TEA, DIPEA, or DMAP in a solvent such as THF, EtOAc, DMF, or DCM to give the compound of formula I.

[0084] Scheme 2 [ka] In Scheme 2, PG1, PG2 and LG1 are as defined in Scheme 1.

[0085] Alternatively, compound X can be prepared by using compound Vb as the starting material. Compound Vb is reacted with compound V-1 in the presence of a coupling reagent such as T3P, HATU, PyBOP, HOPO, or EDCI / HOBt and an organic base such as TEA, DIPEA, or DMAP in a solvent such as DMF or DCM to give compound VI-b. Compound XII can be obtained by hydrolysis of compound VI-b in a mixture of MeOH and HO in the presence of a base such as LiOH·HO, NaOH, or KOH. Compound VIII can be obtained by coupling reaction of compound XII, compound IX-1, and a coupling reagent such as T3P, HATU, HOPO, PyBOP, or EDCI / HOBt in a solvent such as THF, EtOAc, DMF, or DCM in the presence of an organic base such as TEA, DIPEA, or DMAP. Compounds of formula XIV can be obtained by hydrogenolysis of compounds of formula XIII in the presence of Pd / C, Pd(OH) or a mixture of Pd / C and Pd(OH) in a solvent such as MeOH, EtOH, THF or EtOAc. Compounds of formula XIV can be reacted with compounds of formula VII-1 in the presence of a coupling reagent such as T3P, HATU, PyBOP, HOPO or EDCI / HOBt and an organic base such as TEA, DIPEA or DMAP in a solvent such as DMF or DCM to obtain compounds of formula X. Alternatively, compounds of formula X can be obtained by reacting compounds of formula XIV with compounds of formula VII-1 in the presence of an organic base such as TEA, DIPEA or DMAP in a solvent such as MeOH, DCM, THF or DMF. After deprotection and coupling, compounds of formula I can be prepared from compounds of formula X according to the last two steps of Scheme 1.

[0086] In one aspect, the present invention provides a method for preparing a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, the method comprising: [ka] (R1 , R 2 , R 3a , R 3b , R 4a , R 4b , R 7a , R 7b , R 7c and L is as defined herein) Compound of formula (XI-1) [ka] (R 5 and R 6 is as defined in any one of claims 1 to 16, and LG2 is a leaving group; in the presence of a coupling reagent and a base to form the compound of formula (I).

[0087] In one embodiment, the leaving group LG2 is halogen, particularly chloro.

[0088] In one embodiment, the base used in the method is selected from TEA, DIPEA, and DMAP.

[0089] In one embodiment, the solvent used in the process is DMF or DCM.

[0090] In one embodiment, the coupling reagent is selected from T3P, HATU, PyBOP, HOPO and EDCI / HOBt.

[0091] Uses of the Compounds of the Invention In one aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0092] In one aspect, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for treating or preventing a coronavirus infection.

[0093] In one aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for inhibiting the enzymatic activity of a 3C-like protease.

[0094] In one aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating or preventing a coronavirus infection.

[0095] In one aspect, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting the enzymatic activity of a 3C-like protease.

[0096] In one aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a coronavirus infection.

[0097] In one aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in inhibiting the enzymatic activity of a 3C-like protease.

[0098] In one aspect, the present invention provides a method of treating or preventing a coronavirus infection, the method comprising administering to a subject in need thereof a therapeutically active amount of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof.

[0099] In one aspect, the present invention provides a method for inhibiting the enzymatic activity of a 3C-like protease, the method comprising contacting the 3C-like protease with a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0100] In one embodiment, the coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle East respiratory syndrome coronavirus (MERS-CoV).

[0101] In one embodiment, the coronavirus is severe acute respiratory syndrome coronavirus (SARS-CoV).

[0102] In one embodiment, the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0103] In one embodiment, the coronavirus is Middle East Respiratory Syndrome coronavirus (MERS-CoV).

[0104] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein and a therapeutically inert carrier.

[0105] In one embodiment, a pharmaceutical composition according to Example 9 or Example 10 is provided.

[0106] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as pharmaceuticals (e.g., in the form of pharmaceutical preparations).The pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories).However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0107] The compound of formula (I) and its pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert inorganic or organic adjuvants for the preparation of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid, or its salts, etc., can be used as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules, for example.

[0108] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances, and liquid polyols.

[0109] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0110] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0111] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0112] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. They may also contain still other therapeutically valuable substances.

[0113] Dosage can vary widely and will of course be adapted to the individual requirements of each particular case. Generally, for oral administration, a daily dose of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (for example, about 300 mg per person), is preferably divided into 1 to 3 individual doses, which, if appropriate, can be, for example, of equal amounts. However, it is clear that the upper limit given herein can be exceeded if indicated. [Example]

[0114] The present invention will be more fully understood by reference to the following examples, which, however, should not be construed as limiting the scope of the claims to the examples.

[0115] Where preparations are obtained as mixtures of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0116] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0117] Abbreviation The abbreviations used herein are as follows: aq.water-based ACN Acetonitrile BnBr benzyl bromide CbzCl Benzyl chloroformate Cbz benzyl formate CDCl3 deuterated chloroform CD3OD deuterated methanol DIPEA N,N-Diethylpropylamine DMF Dimethylformamide DMSO dimethyl sulfoxide DBU 1,8-diazabicycloundec-7-ene EDCI N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride EDTA Ethylenediaminetetraacetic acid EtOAc or EA ethyl acetate FAM carboxyfluorescein FRET Fluorescence Resonance Energy Transfer HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid h time HPLC High-Performance Liquid Chromatography HOBt N-hydroxybenzotriazole HOPO 2-hydroxypyridine-N-oxide LiHMDS Lithium bis(trimethylsilyl)amide N mol / L MS(ESI) Mass spectrometry (electrospray ionization) min(s) minutes NMR nuclear magnetic resonance obsd. Actual measurement PE Petroleum Ether prep-HPLC Preparative High Performance Liquid Chromatography PyBOP Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate RT or rt Room temperature sat. saturation SFC Supercritical Fluid Chromatography TAMRA carboxytetramethylrhodamine TCEP Tris(2-carboxyethyl)phosphine TEA Triethylamine TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran T3P Propylphosphonic Anhydride

[0118] General experimental conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) a Biotage SP1 system and a Quad12 / 25 cartridge module; ii) an ISCO combi-flash chromatography instrument. Silica gel brand and pore size: i) KP-SIL 60Å, particle size: 40-60 μm; ii) CAS registration number: silica gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0119] Alternatively, intermediates and final compounds may be synthesized using X Bridge™ PerpC 18(5 μm, OBD (trademark) 30 x 100 mm) column, X Bridge (trademark) Perp C 18 (20-40 μm, OBD™ 30 × 100 mm) column, Welch Ultimate X Bridge™ SiOH 250 × 50 × 10 μm column, SunFire™ Perp C 18 Purification was performed by preparative HPLC on a reversed-phase column using a (5 μm, OBD™ 30×100 mm) column, a Phenomenex Luna C18 75*30 mm*3 μm column, or a Phenomenex Synergi C18 150*25 mm*10 μm column.

[0120] For SFC chiral separations, intermediates were separated on chiral columns (Daicel Chiralpak IC, 5 μm, 30 × 250 mm), (Daicel Chiralpak IC, 10 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), AD (10 μm, 30 × 250 mm), Chiralpak IG-3 (50 × 4.6 mm i.d., 3 μm), using a Mettler Toledo Multigram III SFC system, ACSWH-PREP-SFC-C, Waters 80Q preparative SFC, or Thar 80 preparative SFC, solvent systems: CO₂ and IPA (0.5% TEA in IPA), CO₂ and MeOH (0.1% NH₃·H₂O in MeOH), or CO₂ and Neu-IPA, backpressure 100 bar, UV detection at 254 or 220 nm.

[0121] LC / MS spectra were obtained using a Waters UPLC-SQD Mass or a SHIMADZU LCMS-2020. Standard LC / MS conditions were as follows (run time 3 min): Acidic conditions: A: 0.1% formic acid and 1% acetonitrile in HO; B: 0.1% formic acid in acetonitrile; Basic conditions: A: 0.05% NH3·H2O in H2O, B: acetonitrile.

[0122] Mass spectra (MS): Generally, only ions that represent the parent mass are reported; unless otherwise stated, the mass ions quoted are positive mass ions (M+H). + is.

[0123] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0124] All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents from commercial suppliers were used without further purification unless otherwise noted.

[0125] Preparation example Intermediate 1 (2R)2-Chloro-2-fluoroacetic acid [ka] Step 1: Preparation of 2-chloro-2-fluoroacetic acid [ka] To a solution of ethyl chlorofluoroacetate (1000 g, 7142 mmol) (Aldrich, CAS number 401-56-9) in ethanol (9 L) was added water (1 L) and NaOH (313 g, 7826 mmol). The reaction mixture was stirred at 25° C. for 12 hours. 1 H NMR showed that the reaction was complete. The mixture was concentrated in vacuo to remove most of the EtOH. The residue was then diluted with water (1500 mL) and acidified with 2N HCl to pH = 4-5. The mixture was extracted with MTBE (1 L x 4). The combined organic layers were dried over Na2SO4. The mixture was filtered and concentrated to give the crude product 2-chloro-2-fluoroacetic acid (718 g) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ:ppm 6.16 (d, J=50.4 Hz, 1H).

[0126] Step 2: Preparation of (2R)-2-chloro-2-fluoroacetic acid [ka]

[0127] A solution of (S)-1-phenylethanamine (386.7 g, 3191 mmol) in 3000 mL of EtOAc was added at 0° C. to a solution of 2-chloro-2-fluoroacetic acid (718.0 g, 3191 mmol). The mixture was stirred at 0° C. for 2 hours and then allowed to stand overnight. The reaction mixture was filtered, and the filter cake was dissolved in acetone (760 g in 7600 mL) at 80° C. The resulting solution was slowly cooled to 20° C. and allowed to stand overnight. The precipitate was filtered, collected, and dissolved in acetone (100 g / L) at 80° C. (The recrystallization procedure was repeated twice.) The collected solid was triturated with acetone three times (acetone, 100 g / 500 mL). The solid was collected, dissolved in water (1 L), and acidified with 1 M HCl (750 mL). The mixture was extracted with MTBE (1 L × 3). The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give (2R)-2-chloro-2-fluoro-acetic acid (121.2 g, 61% purity, Intermediate 1) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ:ppm 6.29 (d,J=50.8 Hz, 1H).

[0128] Intermediate 2 (2S)2-Chloro-2-fluoroacetic acid [ka] Preparation of (2S)-2-chloro-2-fluoroacetic acid [ka] To a solution of 2-chloro-2-fluoroacetic acid (160.0 g, 1.42 mol) in 600 mL of EtOAc was added (R)-1-phenylethanamine (186.1 g, 1.54 mol) in 600 mL of EtOAc at 0° C. The reaction was stirred at 0° C. for 2 hours. The reaction mixture was filtered, and the filter cake was triturated in acetone (720 g, 2.2 L) at 80° C. for 1 hour. The resulting solution was gradually cooled to 30° C. and stirred at 30° C. for 16 hours. The trituration was repeated four times. Optical rotation (C = 3.8 g / 100 mL in MeOH at 25° C., salt) showed a specific rotation of +10.896. The suspension was filtered, and the filter cake was dissolved in water (1 L) and then acidified with 1 N HCl (1.5 L). The mixture was extracted with MTBE (500 mL × 10). The combined organic phase was dried over Na2SO4, filtered and concentrated to give (2S)-2-chloro-2-fluoro-acetic acid (138.9 g, Intermediate 2) as a brown liquid. 1 H NMR (400 MHz, CDCl3) δ: ppm 10.12 (s, 1H), 6.26 (d, J = 50.4 Hz, 1H).

[0129] Intermediate 3 tert-Butyl N-amino-N-[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate [ka] Step 1: Preparation of tert-butyl 3,3-dimethyl-2-oxo-pyrrolidine-1-carboxylate [ka] To a solution of 3,3-dimethyl-2-pyrrolidinone (500 mg, 4.42 mmol) in ACN (5 mL) was added DMAP (54 mg, 0.44 mmol) and di-tert-butyl dicarbonate (1254 mg, 5.74 mmol). The mixture was stirred at 25° C. for 12 hours. The resulting mixture was concentrated in vacuo to give a residue. The residue was purified on a silica gel column eluted with PE / EtOAc = 4 / 1 to give tert-butyl 3,3-dimethyl-2-oxo-pyrrolidine-1-carboxylate (7.1 g) as a white solid.

[0130] Step 2: Preparation of tert-butyl 2,2-dimethyl-5-oxo-pyrrolidine-1-carboxylate [ka]

[0131] To a solution of tert-butyl 2,2-dimethyl-5-oxo-pyrrolidine-1-carboxylate (7.0 g, 32.82 mmol) in THF (20 mL) was added LiHMDS (36.1 mL, 36.1 mmol) at −78° C. under a N atmosphere. The reaction mixture was stirred at the same temperature for 15 minutes. To the mixture was added 2,2,2-trifluoroethyl trifluoroacetate (6.43 g, 32.82 mmol) at −78° C. Then, the mixture was stirred at −78° C. for 15 minutes. The reaction was quenched with saturated NH4Cl (20 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in toluene (80 mL). To the solution was added paraformaldehyde (4.93 g, 164.11 mmol) and K2CO3 (9.98 g, 72.21 mmol). The reaction mixture was stirred at 95 °C under a N2 atmosphere for 1 hour. The reaction mixture was diluted with EtOAc (100 mL) and filtered. The filtrate was concentrated in vacuo to give crude tert-butyl 2,2-dimethyl-5-oxo-pyrrolidine-1-carboxylate (7.0 g) as a yellow solid. MS measured value (ESI + ) [(2M+Na) + ]:473.4.

[0132] Step 3: Preparation of tert-butyl 4-[(2-benzyloxycarbonylhydrazino)methyl]-2,2-dimethyl-5-oxo-pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl 2,2-dimethyl-4-methylene-5-oxo-pyrrolidine-1-carboxylate (7.39 g, 32.8 mmol) in IPA (80 mL) was added benzyl carbazate (8.2 g, 49.21 mmol). The mixture was stirred at 85° C. for 12 hours. The resulting mixture was concentrated in vacuo to give tert-butyl 4-[(2-benzyloxycarbonylhydrazino)methyl]-2,2-dimethyl-5-oxo-pyrrolidine-1-carboxylate (12.84 g) as a yellow oil. MS measured value (ESI + )[(2M+H) + ]:783.4.

[0133] Step 4: Preparation of benzyl N-[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methylamino]carbamate; 2,2,2-trifluoroacetic acid [ka] A solution of tert-butyl 4-[(2-benzyloxycarbonylhydrazino)methyl]-2,2-dimethyl-5-oxo-pyrrolidine-1-carboxylate (22.2 g, 56.82 mmol) in DCM (80 mL) and TFA (20 mL) was stirred for 1 h at 25° C. The mixture was concentrated in vacuo to give benzyl N-[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methylamino]carbamate;2,2,2-trifluoroacetic acid (23.0 g) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:292.3.

[0134] Step 5: Preparation of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxo-3-piperidyl)methyl]carbamate [ka] To a solution of benzyl N-[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methylamino]carbamate; 2,2,2-trifluoroacetic acid (23.0 g, 56.74 mmol) in methanol (200 mL) was added DIPEA (73.3 g, 567.38 mmol) and di-tert-butyl dicarbonate (37.2 g, 170.21 mmol). The reaction mixture was stirred at 50° C. for 1 hour. The mixture was concentrated in vacuo to give a residue. The residue was purified by reverse flash chromatography (conditions: 120 g flash column Welch Ultimate XB_C18 20-40 μm; 120A, water (0.1% TFA)-ACN, 0-60%, 60 ml / min) to give tert-butyl N-(benzyloxycarbonylamino)-N-[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (2.5 g) as a yellow oil.

[0135] MS measured value (ESI + )[(M+H) + ]:392.2. Step 6: Preparation of tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate [ka] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (2.5 g, 6.39 mmol) in methanol (25 mL) was added Pd / C (250 mg, 10% purity). The suspension was degassed under vacuum and purged with H three times. The resulting mixture was stirred under a H balloon at 25 °C for 3 h. The suspension was filtered, and the filtrate was concentrated in vacuo to give tert-butyl N-amino-N-[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (1.25 g, Intermediate 3) as a yellow solid. MS measured value (ESI + )[(M+H) + ]:258.2.

[0136] Intermediate 4 Benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid [ka] Step 1: Preparation of O3-benzyl O2-tert-butyl (3S,3aS,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2,3-dicarboxylate [ka] To a solution of (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (500 mg, 1.96 mmol) in DMF (10 mL) was added KCO (541 mg, 3.92 mmol) and BnBr (435 mg, 3.9 mmol). The reaction mixture was stirred at 25 °C for 2 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by back-flush elution with 0 to 80% ACN in H2O (0.1% TFA) to give O3-benzyl O2-tert-butyl (3S,3aS,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2,3-dicarboxylate (645 mg) as a yellow oil. MS measured value (ESI + ) [(M+Na) + ]:368.0.

[0137] Step 2: Preparation of benzyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; trifluoroacetic acid [ka] A mixture of O3-benzyl O2-tert-butyl (3S,3aS,6aR)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2,3-dicarboxylate (645 mg, 1.87 mmol) in DCM (2 mL) and TFA (2 mL) was stirred for 1 h at 25 °C. The mixture was concentrated in vacuo to give benzyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; trifluoroacetic acid (670 mg, crude) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:246.2.

[0138] Step 3: Preparation of (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate [ka] To a mixture of (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (393 mg, 1.7 mmol) in DMF (5 mL), DIPEA (1097 mg, 8.49 mmol), HATU (479 mg, 2.04 mmol), and benzyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (610.0 mg, 1.7 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction solution was diluted with 40 mL of water and extracted with ethyl acetate (50 mL × 2). The organic layer was washed with brine (50 mL × 2), dried over Na2SO4, and concentrated in vacuo. The residue was purified by reverse flash chromatography eluting with 0 to 86% ACN in HO (0.1% TFA) to give (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (544 mg) as a pale yellow oil. MS measured value (ESI + )[(M+H) + ]:459.2.

[0139] Step 4: Preparation of benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid [ka] A solution of benzyl (3S,3aS,6aR)-2-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (544 mg, 1.19 mmol) in DCM (4 mL) and TFA (4 mL) was stirred for 1 h at 25 ° C. The resulting mixture was concentrated in vacuo to give benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethylbutanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (500 mg, Intermediate 4) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:359.3.

[0140] Examples 1a and 1b N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide and and N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide [ka] [ka] Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka]

[0141] To a solution of Z-ILe-OH (2.84 g, 10.7 mmol, TCI, CAS: 3160-59-6) in DMF (30 mL), DIPEA (5.03 g, 38.9 mmol), HATU (4.44 g, 11.67 mmol), and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (2.0 g, 9.72 mmol, WuXi AppTec, CAS: 565456-77-1) were added at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL × 3). The combined organic layer was washed with brine (100 mL), dried over Na SO , filtered, and concentrated. The residue was purified by silica gel column eluted with PE / EtOAc = 2 / 1 to give methyl (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.03 g) as a yellow solid. MS measured value (ESI + )[(M+H) + ]:417.3.

[0142] Step 2: Preparation of (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a solution of methyl (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.0 g, 7.2 mmol) in THF (20 mL) was added a solution of LiOH.HO (605 mg, 14.42 mmol) in water (20 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 150 min. The resulting mixture was diluted with 1 N HCl (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.42 g) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:403.2.

[0143] Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[rac-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methyl]carbamate [ka] To a solution of (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (800 mg, 1.99 mmol) in DMF (10 mL) was added DIPEA (771 mg, 5.96 mmol), HOPO (287 mg, 2.58 mmol), EDCI (495 mg, 2.58 mmol), and tert-butyl N-amino-N-[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (511 mg, 1.99 mmol, Intermediate 3) at 0° C. The mixture was then stirred at 25° C. for 12 h. The resulting mixture was diluted with EtOAc (200 mL), washed with 1N HCl (60 mL) and brine (60 mL), dried over NaSO, and concentrated in vacuo to give tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[rac-(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (1210 mg) as a yellow solid. MS measured value (ESI + )[(M+H) + ]:642.3.

[0144] Step 4: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[rac-(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[rac-(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (1.2 g, 1.87 mmol) in methanol (30 mL) was added 100 mg of 10% Pd on activated carbon. The suspension was degassed under vacuum and purged with hydrogen three times. The resulting mixture was stirred under a hydrogen balloon at 25 °C for 2 h. The suspension was filtered and the filtrate was concentrated in vacuo to give tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[rac-(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (953 mg) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:508.4.

[0145] Step 5: Preparation of tert-butyl N-[rac-(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]-N-[[(1R,2S,5S)-3-[(2S,3S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]carbamate [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[rac-(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (950 mg, 1.87 mmol) and 1-fluorocyclopropane-1-carboxylic acid (292 mg, 2.8 mmol) in DCM (16 mL) was added DIPEA (726 mg, 5.61 mmol). After cooling to 0 °C, T3P (1905 mg, 2.99 mmol, 50% in EtOAc) was added to the mixture. The reaction mixture was stirred at 0 °C for 1 h. The resulting mixture was diluted with DCM (150 mL), washed with brine (60 mL × 2), dried over NaSO, filtered, and concentrated in vacuo to afford tert-butyl N-[rac-(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]-N-[[(1R,2S,5S)-3-[(2S,3S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]carbamate (820 mg) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:594.3.

[0146] Step 6: Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[rac-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methylamino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; hydrochloride salt [ka] A solution of rac-tert-butyl N-[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]-N-[[(1R,2S,5S)-3-[(2S,3S)-2-[(1-fluorocyclopropanecarbonyl)amino]-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]carbamate (800.0 mg, 1.35 mmol) in DCM (10 mL) and TFA (3 mL) was stirred at 25° C. for 1 h. The resulting mixture was concentrated in vacuo, and the residue was purified by reverse flash chromatography (conditions: 40 g flash column Welch Ultimate XB_C18 20-40 μm; 120 A, water (0.1% HCl)-ACN, 45%, 70 mL / min) to give N-[(1S,2S)-1-[(1R,2S,5S)-2-[[rac-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methylamino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; hydrochloride (700 mg) as a pale yellow solid. MS measured value (ESI + )[(M+H) + ]:494.4.

[0147] Step 7: N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide and and preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide [ka]

[0148] To a solution of (2R)-2-chloro-2-fluoroacetic acid (424 mg, 2.64 mmol, Intermediate 1) in DCM (10 mL) was added POCl3 (369 mg, 2.38 mmol). The mixture was stirred at 25 °C for 1 h. The resulting solution was then added dropwise to a solution of rac-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methylamino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide hydrochloride (700 mg, 1.32 mmol) and DIPEA (1365 mg, 10.56 mmol) in DCM (10 mL) at -5 °C. The mixture was then stirred at the same temperature for 30 minutes. The reaction was quenched with MeOH (10 mL) and acidified to pH=5 with 4N HCl / dioxane at −10° C. The resulting mixture was then concentrated under vacuum at 30° C., and the residue was purified by reverse flash chromatography (conditions: 40 g flash column Welch Ultimate XB_C18 20-40 μm; 120A, water (0.1% Purification by HCl (FA)-ACN, 51%, 70 mL / min) gave N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropan-1-ol. A mixture of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide was obtained.The mixture was separated by preparative SFC (sample preparation: add 20 mL of CHOH to the sample; instrument: Waters 80Q; mobile phase: 15% MeOH (0.1% NH H O) in supercritical CO; flow rate: 50 g / min; cycle time: 5.8 min, total time: 50 min; single injection volume: 2.5 mL; back pressure: 100 bar to keep the CO supercritical flow) to give Example 1a (139 mg, retention time = 6.06 min) and Example 1b (79 mg, retention time = 8.83 min) as white solids.

[0149] Example 1a 1 H NMR(400 MHz,DMSO-d6)δ:ppm 11.09(s,1H),8.55-8.34(d,J=7.2 Hz,1H),7.90(s,1H),6.85(d,J=50.4 Hz,1H),4.26-4.19(m,1H),4.17(s,1H),3.98-3.92(m,1H),3.89-3.79(m, 2H),3.52-3.42(m,2H),2.75-2.67(m,1H),2.12-2.03(m,1H),2.01-1.90(m ,1H),1.69-1.56(m,2H),1.55-1.44(m,2H),1.34-1.25(m,2H),1.22(s,3H ),1.14(s,3H),1.10-1.05(m,2H),1.04(s,3H),0.90(s,3H),0.82(t,J=7.6 Hz,6H). MS measured value (ESI + )[(M+H) + ]:588.2.

[0150] Example 1b 1H NMR(400 MHz,DMSO-d6)δ:ppm 11.09(s,1H),8.48(d,J=7.6 Hz,1H),7.86(s,1H),6.80(d,J=50.4 Hz,1H),4.21-4.13(m,1H),4.08(s,1H),3.93-3.86(m,1H),3.84-3.74 (m,2H),3.39-3.33(m,2H),2.81-2.73(m,1H),2.05-1.85(m,2H),1.60- 1.50(m,2H),1.48-1.39(m,2H),1.29-1.18(m,2H),1.15(s,3H),1.11( s,3H),1.06-1.00(m,2H),0.98(s,3H),0.84(s,3H),0.80-0.72(m,6H). MS measured value (ESI + )[(M+H) + ]:588.2.

[0151] Examples 2a and 2b (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide and and (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide [ka] [ka] Step 1: Preparation of benzyl (3S,3aS,6aR)-2-[(2S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate [ka] To a solution of (1S)-2,2-difluorocyclopropanecarboxylic acid (274 mg, 2.24 mmol, Pharmablock, CAS: 1883301-82-3) and benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (1.06 g, 2.24 mmol, Intermediate 4) in DCM (15 mL) was added DIPEA (1450 mg, 11.22 mmol). After cooling to 0 °C, T3P (1570 mg, 2.47 mmol, 50% purity in EtOAc) was added dropwise to the mixture. The mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated in vacuo, and the residue was purified by silica gel column eluted with PE / EtOAc=3 / 1 to give benzyl (3S,3aS,6aR)-2-[(2S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (900 mg) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:463.2.

[0152] Step 2: Preparation of (3S,3aS,6aR)-2-[(2S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid [ka] To a solution of benzyl (3S,3aS,6aR)-2-[(2S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (900 mg, 1.95 mmol) in THF (20 mL) was added 90 mg of 10% Pd on activated carbon. The mixture was degassed under vacuum and purged with hydrogen three times. The resulting mixture was stirred under a hydrogen balloon at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give (3S,3aS,6aR)-2-[(2S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (600 mg) as a yellow foam.

[0153] Step 3: Preparation of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[rac-(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate [ka] To a solution of (3S,3aS,6aR)-2-[(2S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (600 mg, 1.61 mmol) in DMF (10 mL) was added DIPEA (521 mg, 4.03 mmol), EDCI (402 mg, 2.09 mmol), HOPO (233 mg, 2.09 mmol), and tert-butyl N-amino-N-[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (415 mg, 1.61 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with EtOAc (200 mL), washed with 1N HCl (50 mL), brine (60 mL, ×2), dried over NaSO, and concentrated in vacuo to give tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[rac-(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (910 mg) as a yellow foam. MS measured value (ESI + )[(M+H) + ]:612.4.

[0154] Step 4: Preparation of N-[(1S)-1-[(3S,3aS,6aR)-3-[[rac-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide [ka] A solution of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(2,2-difluorocyclopropanecarbonyl)amino]-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[rac-(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl]carbamate (900 mg, 1.47 mmol) in DCM (10 mL) and TFA (3 mL) was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse flash chromatography (120 g flash column; Welch Ultimate XB_C18 20–40 μm; 35 min; 75 mL / min, ACN-water, 0.1% HCl) to give N-[(1S)-1-[(3S,3aS,6aR)-3-[[rac-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (510 mg) as a white solid. MS measured value (ESI + )[(M+H) + ]:512.7.

[0155] Step 5: (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide and and (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide [ka] To a solution of (2S)-2-chloro-2-fluoro-acetic acid (260 mg, 1.51 mmol, Intermediate 2) in DCM (15 mL) was added POCl (210 mg, 1.37 mmol). The mixture was stirred at 25 °C for 1 h. The resulting solution was then added dropwise to a solution of N-[(1S)-1-[(3S,3aS,6aR)-3-[[rac-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide (350 mg, 0.68 mmol) and DIPEA (884 mg, 6.84 mmol) in DCM (15 mL) at −5° C. The mixture was then stirred at the same temperature for 30 minutes. The reaction was quenched with MeOH (10 mL) and acidified to pH=5 with 4N HCl / dioxane at −10° C. The resulting mixture was then concentrated under vacuum at 30°C, and the residue was purified by reverse flash chromatography (conditions: 120 g flash column Welch Ultimate XB_C18 20-40 μm; 120A, water (0.1% FA)-ACN, 0-60%, 60 mL / min) to give (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropyl A mixture of pancarboxamide and (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide was obtained.The mixture was separated by preparative SFC (method column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 μm); conditions Neu-MeOH, start B25, end B25, gradient time (min) 3.3 100%B hold time (min) flow rate (mL / min): 150), and Example 2a (retention time = 1.93 min) and Example 2b (retention time = 3.67 min) were obtained as white solids.

[0156] Example 2a 1 H NMR (400 MHz, DMSO-d6) δ: ppm 11.05 - 10.69 (m, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.92 - 7.85 (m, 1H), 7.20 - 6.38 (m, 1H), 4.85 (d, J = 8.8 Hz, 1H), 4.01 - 3.94 (m, 1H), 3.90 - 3.67 (m, 3H), 3.55 - 3.45 (m, 1H), 2.92 - 2.84 (m, 1H), 2.78 - 2.69 (m, 2H), 2.62 - 2.56 (m, 1H), 2.11 - 1.98 (m, 1H), 1.92 - 1.78 (m, 4H), 1.75 - 1.55 (m, 4H), 1.42 - 1.30 (m, 1H), 1.20 (s, 3H), 1.12 - 1.09 (m, 3H), 0.98 - 0.96 (m, 9H). MS measured value (ESI + )[(M + H) + : 606.3.

[0157] Example 2b 1 H NMR (400 MHz, DMSO-d6) δ: ppm 11.03 - 10.68 (m, 1H), 8.47 - 8.36 (m, 1H), 7.92 - 7.87 (m, 1H), 7.20 - 6.52 (m, 1H), 4.50 - 4.43 (m, 1H), 4.10 - 3.65 (m, 4H), 2.95 - 2.80 (m, 2H), 2.80 - 2.70 (m, 2H), 2.64 - 2.59 (m, 1H), 2.15 - 2.07 (m, 1H), 1.90 - 1.77 (m, 4H), 1.75 - 1.50 (m, 4H), 1.40 - 1.33 (m, 1H), 1.21 (s, 3H), 1.45 (d, J = 12.0 Hz, 3H), 0.97 (s, 9H). MS measured value (ESI+ )[(M+H) + ]:606.3.

[0158] Example 3 (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[rac-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide [ka] The title compound was prepared by using (2R)-2-chloro-2-fluoro-acetic acid (Intermediate 1) instead of (2S)-2-chloro-2-fluoro-acetic acid (Intermediate 2) in a similar manner to the procedure described for the preparation of Example 2a and Example 2b, to give the racemic product (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[rac-(5,5-dimethyl-2-oxo-pyrrolidin-3-yl)methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide as a white solid.

[0159] 1H NMR(400 MHz,DMSO-d6)δ:ppm 11.10-11.04(m,1H),8.49-8.35(m,1H),7.98-7.82(m,1H),7.00(d,J=50.4 Hz,1H),4.51-4.44(m,1H),4.00-3.84(m,2H),3.79-3.65(m,2H),3.46-3.41(m,1H),2.95-2.86(m,1H),2.78-2.70(m,1H), 2.61-2.56(m,2H),2.17-2.00(m,1H),1.93-1.72(m,6H),1.68-1.54(m,2H),1.40-1.31(m,1H),1.21(s,3H),1.15(d,J=7.2 Hz,3H),0.96(s,9H). MS measured value (ESI + )[(M+H) + ]:606.2.

[0160] The following examples can be carried out in the same manner as the previous examples. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] [Table 1-17] [Table 1-18]

[0161] Biological Examples Example 41 SARS-CoV-2 3CL pro Inhibition assay SARS-CoV-2 3CL pro The full-length gene encoding the standard SARS-CoV-2 3CL was synthesized and optimized for expression in E. coli. pro The method for cloning and producing SARS-CoV 3CL pro The protocol published for the 3C-like protease was followed (Grum-Tokars V. et al., "Evaluating the 3C-like protease activity of SARS-Coronavirus: Recommendations for standardized assays for drug discovery." Virus Res. 2008 Apr;133(1):63-73). The protein sequence is as follows: SGFRKMAFPSGKVEGCMVQVTCGTTTLNGLWLDDVVYCPRHVICTSEDMLNPNYEDLLIRKSNHNFLVQAGNVQLRVIGHSMQNCVLKLKVDTANPKTPKYKFVRIQPGQTFSVLACYNGSPSGVYQCAMRPNFTIKGSFLNGSCGSVGFNID YDCVSFCYMHHMELPTGVHAGTDLEGNFYGPFVDRQTAQAAGTDTTITVNVLAWLYAAVINGDRWFLNRFTTTLNDFNLVAMKYNYEPLTQDHVDILGPLSAQTGIAVLDMCASLKELLQNGMNGRTILGSALLEDEFTPFDVVRQCSGVTFQ

[0162] SARS-CoV-2 3CL pro For the assay, 2 μL of 0.02 μM recombinant SARS-CoV-2 3CL protease was mixed with serial dilutions of each compound in 4 μL assay buffer containing 40 mM HEPES, pH 8.0, 1 mM CHAPS, 150 mM NaCl, 1 mM EDTA, 1 mM TCEP in wells of a 384-well plate and pre-incubated for 1 hour at room temperature. The custom-synthesized fluorogenic 3CL used in the assay. pro The peptide substrate is: FAM-KTSAVLQSGFRKMEK-TAMRA. This FRET-based substrate is a canonical 3CL pro The peptide substrate contains a FAM fluorophore attached to its N-terminus. The fluorophore is internally quenched by TAMRA. The reaction was initiated by adding 10 μL of substrate at a final concentration of 15 μM, and each well was incubated at room temperature for 30 min. The final concentration of protease used in the assay was 25 nM, and each compound had a final concentration range of 100–0.0016 μM. SARS-CoV 3CL pro IC is the value that inhibits the catalytic activity of 50 The values ​​were calculated by four-parameter equation analysis.

[0163] Example 42 SARS-CoV 3CL pro Inhibition assay SARS-CoV 3CL pro teeth, SGFRKMAFPSGKVEGCMVQVTCGTTTLNGLWLDDTVYCPRHVICTAEDMLNPNYEDLLIRKSNHSFLVQAGNVQLRVIGHSMQNCLLRLKVDTSNPKTPKYKFVRIQPGQTFSVLACYNGSPSGVYQCAMRPNHTIKGSFLNGSCGSVGFNID YDCVSFCYMHHMELPTGVHAGTDLEGKFYGPFVDRQTAQAAGTDTTITLNVLAWLYAAVINGDRWFLNRFTTTNLDFNLVAMKYNYEPLTQDHVDILGPLSAQTGIAVLDMCAALKELLQNGMNGRTILGSTILEDEFTPFDVVRQCSGVTFQ The protein sequence was expressed in E. coli BL21(DE3).

[0164] SARS-CoV 3CL pro For the assay, 2 μL of 0.02 μM recombinant SARS-CoV 3CL protease was mixed with serial dilutions of each compound in 4 μL assay buffer containing 40 mM HEPES, pH 8.0, 1 mM CHAPS, 150 mM NaCl, 1 mM EDTA, 1 mM TCEP in wells of a 384-well plate and pre-incubated for 1 hour at room temperature. The custom-synthesized fluorogenic 3CL used in the assay. pro The peptide substrate is: FAM-KTSAVLQSGFRKMEK-TAMRA. This FRET-based substrate is a canonical 3CL pro The peptide substrate contains a FAM fluorophore attached to its N-terminus. The fluorophore is internally quenched by TAMRA. The reaction was initiated by adding 10 μL of substrate at a final concentration of 15 μM, and each well was incubated at room temperature for 30 min. The final concentration of protease used in the assay was 25 nM, and each compound had a final concentration range of 100–0.0016 μM. SARS-CoV 3CL pro IC is the value that inhibits the catalytic activity of 50 The values ​​were calculated by four-parameter equation analysis.

[0165] Example 43 MERS-CoV 3CL pro Inhibition assay MERS-CoV 3CL pro teeth, SGLVKMSHPSGDVEACMVQVTCGSMTLNGLWLDNTVWCPRHVMCPADQLSDPNYDALLISMTNHSFSVQKHIGAPANLRVVGHAMQGTLLKLTVDVANPSTPAYTFTTVKPGAAFSVLACYNGRPTGTFTVVMRPNYTIKGSFLCGSCGSVGY TKEGSVINFCYMHQMELANGTHTGSAFDGTMYGAFMDKQVHQVQLTDKYCSVNVVAWLYAAILNGCAWFVKPNRTSVVSFNEWALANQFTEFVGTQSVDMLAVKTGVAIEQLLYAIQQLYTGFQGKQILGSTMLEDEFTPEDVNMQIMGVVMQ The protein sequence was expressed in E. coli BL21(DE3).

[0166] MERS-CoV 3CL pro For the assay, 2 μL of 0.02 μM recombinant MERS-CoV 3CL protease was mixed with serial dilutions of each compound in 4 μL assay buffer containing 40 mM HEPES, pH 8.0, 1 mM CHAPS, 150 mM NaCl, 1 mM EDTA, 1 mM TCEP in wells of a 384-well plate and pre-incubated for 1 hour at room temperature. The custom-synthesized fluorogenic 3CL used in the assay. pro The peptide substrate is: FAM-KTSAVLQSGFRKMEK-TAMRA. This FRET-based substrate is a canonical 3CL proThe peptide substrate contains a FAM fluorophore attached to its N-terminus. The fluorophore is internally quenched by TAMRA. The reaction was initiated by adding 10 μL of substrate at a final concentration of 15 μM, and each well was incubated at room temperature for 30 minutes. The final concentration of protease used in the assay was 25 nM, and each compound had a final concentration range of 100–0.0016 μM. MERS-CoV 3CL pro IC, the value that inhibits 50% of the catalytic activity of 50 The values ​​were calculated by four-parameter equation analysis.

[0167] Example 44 HCoV-229E 3CL pro Inhibition assay HCoV-229E 3CL pro teeth, AGLRKMAQPSGFVEKCVVRVCYGNTVLNGLWLGDIVYCPRHVIASNTTSAIDYDHEYSIMRLHNFSIISGTAFLGVVGATMHGVTLKIKVSQTNMHTPRHSFRTLKSGEGFNILACYDGCAQGVFGVNMRTNWTIRGSFINGACGSPGYNL KNGEVEFVYMHQIELGSGSHVGSSFDGVMYGGFEDQPNLQVESANQMLTVNVVAFLYAAILNGCTWWLKGEKLFVEHYNEWAQANGFTAMNGEDAFSILAAKTGVCVERLLHAIQVLNNGFGGKQILGYSSLNDEFSINEVVKQMFGVNLQ The protein sequence was expressed in E. coli BL21(DE3).

[0168] HCoV-229E 3CL pro For the assay, 2 μL of 0.02 μM recombinant HCoV-229E 3CL protease was mixed with serial dilutions of each compound in 4 μL assay buffer containing 40 mM HEPES, pH 8.0, 1 mM CHAPS, 150 mM NaCl, 1 mM EDTA, 1 mM TCEP in wells of a 384-well plate and pre-incubated for 1 hour at room temperature. The custom-synthesized fluorogenic 3CL used in the assay.pro The peptide substrate is: FAM-KTSAVLQSGFRKMEK-TAMRA. This FRET-based substrate is a canonical 3CL pro The peptide substrate contains a FAM fluorophore attached to its N-terminus. The fluorophore is internally quenched by TAMRA. The reaction was initiated by adding 10 μL of substrate at a final concentration of 15 μM, and each well was incubated at room temperature for 30 minutes. The final concentration of protease used in the assay was 25 nM, and each compound had a final concentration range of 100 to 0.0016 μM. HCoV-229E 3CL pro IC, the value that inhibits 50% of the catalytic activity of 50 The values ​​were calculated by four-parameter equation analysis.

[0169] Example 45 HCoV-OC43 3CL pro Inhibition assay HCoV-OC43 3CL pro teeth, SGIVKMVNPTSKVEPCVVSVTYHNMTLNGLWLDDKVYCPRHVICSASDMTNPDYTNLLCVTSSDFTVLFDRLSLTVMSYQMRGCMLVLTVTLQNSRTPKYTFGVVKPGETFTVLAA YNGKPQGAFHVTMRSSYTIKGSFLCGGSCGSVGYVIMGDCVKFVYMHQLELSTGCHTGTDFNGDFYGPYKDAQVVQLPIQDYIQSVNFLAWLYAAILNNCNWFIQSDKCSVEDFNVMALSNGFSQVKSDLVIDALSMTGVSLETLLAAIKRLKNGFQGRQIMGSCSFEDELTPSDV YQQLAGIKLQ In E. coli BL21(DE3) with the protein sequence It was expressed.

[0170] HCoV-OC43 3CL proFor the assay, 2 μL of 0.02 μM recombinant HCoV-OC43 3CL protease was mixed with serial dilutions of each compound in 4 μL assay buffer containing 40 mM HEPES, pH 8.0, 1 mM CHAPS, 150 mM NaCl, 1 mM EDTA, 1 mM TCEP in wells of a 384-well plate and pre-incubated for 1 h at room temperature. The custom-synthesized fluorogenic 3CL used in the assay. pro The peptide substrate is: FAM-KTSAVLQSGFRKMEK-TAMRA. This FRET-based substrate is a canonical 3CL pro The peptide substrate contains a FAM fluorophore attached to its N-terminus. The fluorophore is internally quenched by TAMRA. The reaction was initiated by adding 10 μL of substrate at a final concentration of 15 μM, and each well was incubated at room temperature for 30 min. The final concentration of protease used in the assay was 25 nM, and each compound had a final concentration range of 100–0.0016 μM. HCoV-OC43 3CL pro IC is the value that inhibits the catalytic activity of 50 The values ​​were calculated by four-parameter equation analysis. [Table 2] [Table 3-1] [Table 3-2]

[0171] Example 46 The compounds of formula (I) can be used in a manner known per se as active ingredient to prepare tablets of the following composition: Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0172] Example 47 The compounds of formula (I) can be used in a manner known per se as active ingredients to prepare capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Compounds of formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, L is C １ ~C ６ - alkyl, R １ is C ３ ~C １０ -cycloalkyl, halo-C ３ ~C １０ -cycloalkyl, C ６ ~C １４ -aryl, 3- to 14-membered heteroaryl, C １ ~C ６ -alkyl, and halo-C １ ~C ６ - alkyl, R ２ is hydrogen, C ３ ~C １０ -cycloalkyl, C ３ ~C １０ -cycloalkyl-C １ ~C ６ -Alkyl, C １ ~C ６ -Alkyl-C ３ ~C １０ -cycloalkyl, C １ ~C ６ -Alkyl, C １ ~C ６ -Alkyl-S-C １ ~C ６ -alkyl, 3- to 14-membered heteroaryl, (3- to 14-membered heteroaryl)-C １ ~C ６ -Alkyl, C ６ ~C １４ -aryl, and C ６ ~C １４ -aryl-C １ ~C ６ - alkyl, R ３ａ , R ３ｂ , R ４ａ , and R ４ｂ are each independently hydrogen, halogen, or C １ ~C ６ -alkyl, and halo-C １ ~C ６ - alkyl, or R ３ａ and R ３ｂ together with the carbon atoms to which they are attached, form C ３ ~C １０ - forms a cycloalkyl, R ４ａ and R ４ｂ are each independently hydrogen and C １ ~C ６ -alkyl, wherein said C ３ ~C １０ -Cycloalkyl is 1 to 2 C １ ~C ６ - optionally substituted with alkyl substituents, or R ４ａ and R ４ｂ together with the carbon atoms to which they are attached, form C ３ ~C １０ - forms a cycloalkyl, R ３ａ and R ３ｂ are each independently hydrogen and C １ ~C ６ -alkyl, wherein said C ３ ~C １０ -Cycloalkyl is 1 to 2 C １ ~C ６ - optionally substituted with alkyl substituents, or R ３ａ and R ４ａ together with the carbon atoms to which they are attached, form C ３ ~C １０ - forms a cycloalkyl, R ３ｂ and R ４ｂ are each independently hydrogen and C １ ~C ６ -alkyl, wherein said C ３ ~C １０ -Cycloalkyl is 1 to 2 C １ ~C ６ - optionally substituted with alkyl substituents; R ５ is selected from fluoro and chloro; R ６ is selected from hydrogen, chloro, and acyl; R ７ａ and R ７ｂ are both C １ ~C ６ -alkyl, and R ７ｃ and R ７ｄ are both hydrogen and C １ ~C ６ - alkyl, or R ７ａ , R ７ｂ and R ７ｄ is hydrogen, and R ７ｃ is C １ ~C ６ - alkyl, or R ７ａ is C １ ~C ６ -alkyl, and R ７ｂ is hydrogen, and R ７ｃ and R ７ｄ are both hydrogen and C １ ~C ６ - alkyl, or R ７ａ and R ７ｂ together with the carbon atoms to which they are attached, form C ３ ~C １０ - forms a cycloalkyl, R ７ｃ and R ７ｄ are both hydrogen and C １ ~C ６ - alkyl, or R ７ａ and R ７ｄ together with the carbon atoms to which they are attached, form C ３ ~C １０ - forms a cycloalkyl, R ７ｂ and R ７ｃ are both hydrogen and C １ ~C ６ - selected from alkyl, A compound of formula (I), or a pharmaceutically acceptable salt thereof.

2. R １ But, Halo-C ３ ~C １０ -cycloalkyl or halo-C １ ~C ６ 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -alkyl.

3. R １ are 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, CHClF and CHF ２ 3. The compound of formula (I) according to claim 2, selected from: or a pharmaceutically acceptable salt thereof.

4. R １ The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein is 1-fluorocyclopropyl or 2,2-difluorocyclopropyl.

5. R ２ But C １ ~C ６ 5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: - alkyl.

6. R ２ 6. The compound of formula (I) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein is selected from tert-butyl, 1-methylpropyl, and 1-ethylpropyl.

7. R ２ 7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, wherein is tert-butyl or 1-methylpropyl.

8. R ３ａ and R ４ａ together with the carbon atoms to which they are attached, C ３ ~C １０ - forms a cycloalkyl, R ３ｂ and R ４ｂ are both hydrogen, and ３ ~C １０ -Cycloalkyl is 1 to 2 C １ ~C ６ - a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, optionally substituted with an alkyl substituent.

9. R ３ａ and R ４ａ together with the carbon atom to which they are attached form cyclopropyl or cyclopentyl, R ３ｂ and R ４ｂ are both hydrogen, and said cyclopropyl or cyclopentyl is optionally substituted with 1 to 2 methyl substituents, or a pharmaceutically acceptable salt thereof.

10. basis 【Chemistry 2】 but, 【Chemistry 3】 and 【Chemistry 4】 10. The compound of formula (I) according to claim 9, selected from: or a pharmaceutically acceptable salt thereof.

11. L is CH ２ 11. The compound of formula (I) according to any one of claims 1 to 10, wherein:

12. R ５ is fluoro and R ６ 12. A compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein is chloro.

13. R ７ａ and R ７ｂ Both are C １ ~C ６ -alkyl, and R ７ｃ and R ７ｄ are both hydrogen, or R ７ａ and R ７ｄ together with the carbon atoms to which they are attached, C ３ ~C １０ - forms a cycloalkyl, R ７ｂ and R ７ｃ are both hydrogen, or R ７ａ But C １ ~C ６ -alkyl, and R ７ｂ , R ７ｃ and R ７ｄ are all hydrogen, or R ７ａ and R ７ｂ together with the carbon atoms to which they are attached, C ３ ~C １０ - forms a cycloalkyl, R ７ｃ and R ７ｄ are both hydrogen, A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

14. R ７ａ and R ７ｂ are both methyl, and R ７ｃ and R ７ｄ are both hydrogen, or R ７ａ and R ７ｄ together with the carbon atom to which they are attached form a cyclopropyl, and R ７ｂ and R ７ｃ are both hydrogen, or R ７ａ is methyl, and R ７ｂ , R ７ｃ and R ７ｄ are all hydrogen, or R ７ａ and R ７ｂ together with the carbon atom to which they are attached form a cyclopropyl, and R ７ｃ and R ７ｄ are both hydrogen, 14. A compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof.

15. R ７ａ and R ７ｂ are both methyl, and R ７ｃ 15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

16. N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; rac-(1S)-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl-[(2R)-2-chloro-2-fluoro-acetyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; (2R)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2-chloro-2-fluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; (2S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2-chloro-2-fluoro-acetamide; (2R)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-chloro-2-fluoro-acetamide; (2S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-chloro-2-fluoro-acetamide; (2R)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-chloro-2-fluoro-acetamide; (2S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-chloro-2-fluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2R)-2-chloro-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-fluoro-acetamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (2S)-2-chloro-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-fluoro-acetamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(6S)-5-oxo-4-azaspiro[2.4]heptan-6-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(6R)-5-oxo-4-azaspiro[2.4]heptan-6-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S,5S)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R,5S)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R,5S)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S,5S)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S,5R)-5-methyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,4S,5R)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1S,4S,5S)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoroacetyl]-[[(1R,4S,5R)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,4R,5R)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(1S,4S,5S)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; and (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(1R,4R,5R)-3-oxo-2-azabicyclo[3.1.0]hexan-4-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide 2. The compound of formula (I) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

17. N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; rac-(1S)-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[(5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl-[(2R)-2-chloro-2-fluoro-acetyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; and N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-5,5-dimethyl-2-oxo-pyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide 17. A compound of formula (I) according to claim 16, selected from: or a pharmaceutically acceptable salt thereof.

18. A method for preparing a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, comprising the step of: 【Chemistry 5】 (In the formula, R １ , R ２ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ７ａ , R ７ｂ , R ７ｃ and L is as defined in any one of claims 1 to 17 Compound of formula (XI-1) 【Chemistry 6】 (In the formula, R ５ and R ６ is as defined in any one of claims 1 to 17, and LG ２ is a leaving group) and in the presence of a coupling reagent and a base to form said compound of formula (I).

19. A compound of formula (I) according to any one of claims 1 to 17 when prepared according to the process of claim 18.

20. A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

21. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

22. 20. A method for treating or preventing a coronavirus infection, comprising administering to a subject in need thereof a therapeutically active amount of a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

23. 20. A method of inhibiting the enzymatic activity of a 3C-like protease, comprising contacting the 3C-like protease with a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

24. A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use in a method according to claim 22 or 23.

25. Use of a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, in a method according to claim 22 or 23.

26. 20. Use of a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing coronavirus infection.

27. Use of a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting the enzymatic activity of a 3C-like protease.

28. The invention as hereinbefore described.

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