Antiviral Compounds

Abstract

The present invention relates to a compound represented by the general formula (I) The present invention provides a viral protease inhibitor having the formula: TIFF2024545135000558.tif3653, wherein the variables are as described herein, compositions comprising the compounds, methods of making the compounds, and methods of using the compounds.

Description

[Technical Field]

[0001] The present invention relates to peptidomimetic (or peptide-like) compounds, particularly viral protease inhibitors, for treating viral infections, and methods for preparing and using such compounds. [Background technology]

[0002] 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] In a first aspect, the present invention provides a compound of formula (I) [ka] wherein the variables are as defined herein. In one aspect, the present invention provides methods for preparing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, the methods being as depicted in Schemes 1-3 below.

[0006] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when prepared according to the process described herein.

[0007] In a further 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.

[0008] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

[0009] In a further 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.

[0010] In a further 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. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows the crystal structure of Example 165a as assessed by single crystal X-ray diffraction. DETAILED DESCRIPTION OF THE INVENTION

[0012] 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.

[0013] 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.

[0014] 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).

[0015] 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 "Cycloalkyl"). 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., 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.

[0016] 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.

[0017] 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 a cycloalkyl group in which one of the hydrogen atoms of the cycloalkyl group is replaced by an alkyl group, such as 1-methylcyclopropyl.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] 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 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 heteroaryl containing 1 to 2 heteroatoms independently selected from O, S, and N.Some non-limiting examples of heteroaryl 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 7-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.

[0022] 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.

[0023] 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, 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-dihydropyridin, piperidyl, pyrrolidinyl, and thietanyl.

[0024] 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. Particularly preferred, but non-limiting, examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0025] The term "oxo" refers to a double-bonded oxygen (=O).

[0026] The term "carbamoyl" refers to the group H2N-C(O)-.

[0027] The term "acyl" refers to the group CH3-C(O)-.

[0028] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being 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, particularly 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. Furthermore, 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, potassium, lithium, ammonium, calcium, 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.

[0029] 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.

[0030] According to the Cahn-Ingold-Prelog Convention, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0031] The term "treatment," as used herein, includes: (1) suppressing a condition, disorder, or symptom (e.g., in the case of maintenance treatment, arresting, reducing, or delaying the onset or recurrence of at least one clinical symptom or subclinical disease thereof); and / or (2) alleviating symptoms (i.e., causing regression of the condition, disorder, or symptom, or at least one of its clinical symptoms or subclinical symptoms). The benefit to the treated patient 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 outcome need not necessarily be effective treatment.

[0032] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, particularly in a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited clinical or asymptomatic symptoms of the condition, disorder or condition.

[0033] 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, L 1 is a covalent bond, O, NH, and [ka] is selected from A is C6~C 14aryl and 3- to 14-membered heteroaryl; R 1 is the base [ka] and groups [ka] is selected from 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, wherein the C3-C 10 -cycloalkyl may be optionally substituted with one C1-C6-alkyl substituent, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 14-membered heteroaryl or C6-C 14 -aryl, and the 3- to 14-membered heteroaryl or C6-C 14 -aryl may be optionally substituted with 1 to 2 substituents selected from halogen and halo-C1-C6-alkyl; R 1a is C3~C 10 -Cycloalkyl, C6-C 14 -aryl, 3- to 14-membered heteroaryl, C1-C6-alkyl and halo-C1-C6-alkyl, wherein the C3-C 10 -cycloalkyl and 3- to 14-membered heteroaryl may be optionally substituted by 1 to 2 substituents selected from halogen, C1-C6-alkyl and halo-C1-C6-alkyl; R 3a , R3b , 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 may be 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 may be 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 may be optionally substituted by 1 to 2 C1-C6-alkyl substituents, R 5 is selected from 3- to 14-membered heterocycloalkyl, 3- to 14-membered heteroaryl, carbamoyl, and C1-C6-alkyl-NH-C(O)-, wherein the 3- to 14-membered heterocycloalkyl is optionally substituted with one oxo substituent; R 6 is selected from fluoro and chloro; R 7is selected from hydrogen, chloro, and acyl; R 8 and R 9 are each independently selected from hydrogen, halogen and halo-C1-C6-alkyl.

[0034] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C1-C6-alkyl, R 1 is the base [ka] , C6~C 14 -aryloxy, and 3- to 14-membered heteroaryl, 14 -aryloxy and the 3- to 14-membered heteroaryl may be optionally substituted by 1 to 2 substituents selected from halogen 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, wherein the C3-C 10 -cycloalkyl may be optionally substituted with one C1-C6-alkyl substituent, or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 14-membered heteroaryl, which is optionally substituted with one halo-C1-C6-alkyl substituent; R 1a is C3~C 10-Cycloalkyl, C6-C 14 -aryl, 3- to 14-membered heteroaryl, C1-C6-alkyl and halo-C1-C6-alkyl, wherein the C3-C 10 -cycloalkyl and 3- to 14-membered heteroaryl may be optionally substituted by 1 to 2 substituents selected from halogen, C1-C6-alkyl and halo-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 may be 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 may be 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 may be optionally substituted by 1 to 2 C1-C6-alkyl substituents, R 5 is selected from 3- to 14-membered heterocycloalkyl, 3- to 14-membered heteroaryl, carbamoyl, and C1-C6-alkyl-NH-C(O)-, wherein the 3- to 14-membered heterocycloalkyl is optionally substituted with one oxo substituent; R 6 is selected from fluoro and chloro; R 7 is selected from hydrogen, chloro, and acyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C1-C6-alkyl, R 1 is the base [ka] , C6~C 14 -aryloxy, and 3- to 14-membered heteroaryl, 14 -aryloxy and the 3- to 14-membered heteroaryl may be optionally substituted by 1 to 2 substituents selected from halogen 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; or R 1 and R 2 together with the carbon atoms to which they are attached form a 3- to 14-membered heteroaryl, which is optionally substituted with one halo-C1-C6-alkyl substituent; R1a is C3~C 10 -C1-C6-alkyl, 3- to 14-membered heteroaryl, C1-C6-alkyl, and halo-C1-C6-alkyl, wherein the C3-C 10 -cycloalkyl and 3- to 14-membered heteroaryl are optionally substituted by one halo-C1-C6-alkyl substituent; 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 may be 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 may be 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 may be optionally substituted by 1 to 2 C1-C6-alkyl substituents, R 5is selected from 3- to 14-membered heterocycloalkyl, 3- to 14-membered heteroaryl, carbamoyl, and C1-C6-alkyl-NH-C(O)-, wherein the 3- to 14-membered heterocycloalkyl is optionally substituted with one oxo substituent; R 6 is selected from fluoro and chloro; R 7 is selected from hydrogen, chloro, and acyl.

[0035] In one embodiment, the compound of formula (I) of the present invention has formula (II) [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0036] In one embodiment, the compound of formula (I) of the present invention has formula (III) [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0037] In one embodiment, the compound of formula (I) of the present invention has formula (IV) [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0038] In one embodiment, the compound of formula (I) of the present invention has the formula (V) [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0039] In one embodiment, the compound of formula (I) of the present invention has formula (VI) [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0040] In one embodiment, the compound of formula (I) of the present invention has the formula (VII) [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0041] In one embodiment, the compound of formula (I) of the present invention has the formula (VIII) [ka] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.

[0042] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L 1 is a covalent bond, O, NH, and [ka] is selected from A is C6~C 14 aryl and 3- to 14-membered heteroaryl; R 1 is the base [ka] and groups [ka] is selected from R 2 is hydrogen, C3 to C 10 -Cycloalkyl, C3-C 10 -cycloalkyl-C1-C6-alkyl, (3-14 membered heteroaryl)-C1-C6-alkyl, C1-C6-alkyl, C6-C 14 -Aryl, C6-C 14 -aryl-C1-C6-alkyl and C1-C6-alkyl-S-C1-C6-alkyl, 10 -cycloalkyl optionally substituted with one C1-C6-alkyl substituent, or R 1 and R 2 together with the carbon atom to which they are attached, form a C6-C alkyl group substituted with two substituents selected from halogen and halo-C1-C6-alkyl. 14 -aryl, R 1a is C3~C 10 -Cycloalkyl, C6-C 14 -aryl, 3- to 14-membered heteroaryl, C1-C6-alkyl and halo-C1-C6-alkyl, wherein the C3-C 10 -cycloalkyl and 3- to 14-membered heteroaryl may be optionally substituted by 1 to 2 substituents selected from halogen, C1-C6-alkyl and halo-C1-C6-alkyl; R 8 and R 9 are each independently selected from hydrogen, halogen and halo-C1-C6-alkyl.

[0043] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L 1 is a covalent bond, O, NH, and [ka] is selected from A is selected from phenyl, pyridyl, and pyrimidinyl; R1 is the base [ka] and groups [ka] is selected from R 2 is selected from hydrogen, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-bicyclo[1.1.1]pentanylmethyl, methyl, ethyl, propyl, sec-butyl, tert-butyl, isobutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2-methylsulfanylethyl, phenyl, benzyl and pyridylmethyl; or R 1 and R 2 together with the carbon atom to which they are attached form a phenyl substituted with two substituents selected from fluoro and CF3; R 1a is selected from bicyclo[1.1.1]pentanyl, cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1-methylcyclopropyl, 1-fluorocyclobutyl, 3,3-difluorocyclobutyl, cyclobutyl, phenyl, isoxazolyl, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, CHFCl, CHCl2, CHF2, CF3, 1-fluoro-1-methyl-ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl and 1,1,2,2,2-pentachloroethyl; R 8 and R 9 are each independently selected from hydrogen, fluoro, and CF3.

[0044] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L 1 is a covalent bond, O, NH, and [ka] is selected from A is selected from phenyl, pyridyl, and pyrimidinyl; R 1 is the base [ka] and groups [ka] is selected from R 2 is selected from hydrogen, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-bicyclo[1.1.1]pentanylmethyl, methyl, ethyl, propyl, sec-butyl, tert-butyl, isobutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2-methylsulfanylethyl, phenyl, benzyl and pyridylmethyl; or R 1 and R 2 together with the carbon atom to which they are attached form a phenyl substituted with two substituents selected from fluoro and CF3; R 1a is selected from bicyclo[1.1.1]pentanyl, cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1-methylcyclopropyl, 1-fluorocyclobutyl, 3,3-difluorocyclobutyl, phenyl, isoxazolyl, methyl, ethyl, propyl, isopropyl, tert-butyl, CHFCl, CHCl2, CHF2, CF3, 1-fluoro-1-methyl-ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl and 1,1,2,2,2-pentachloroethyl; R 8 and R 9 are each independently selected from hydrogen, fluoro, and CF3.

[0045] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is the base [ka] and R 2 is C3~C 10 -cycloalkyl and C1-C6-alkyl, R 1a is C3~C 10 -cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl, wherein the C3-C 10 -Cycloalkyl may be optionally substituted with 1 to 2 halogen substituents.

[0046] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is the base [ka] and R 2 is selected from cyclopropyl, 1,1-dimethylpropyl, 1-ethylpropyl, sec-butyl and tert-butyl; R 1a is selected from cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, isopropyl, tert-butyl, 1-fluoroethyl, CHFCl, CF3 and CHF2.

[0047] In a preferred embodiment, the present invention provides R 1 Based on [ka] or a pharmaceutically acceptable salt thereof.

[0048] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is the base [ka] and C6-C substituted with 1-2 halogen substituents 14 -aryloxy; R 1a is C3~C 10 -Cycloalkyl, C6-C 14 -aryl, 3- to 14-membered heteroaryl, C1-C6-alkyl and halo-C1-C6-alkyl, wherein the C3-C 10 -cycloalkyl and 3- to 14-membered heteroaryl may be optionally substituted by 1 to 2 substituents selected from halogen, C1-C6-alkyl and halo-C1-C6-alkyl; In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is the base [ka] and R 1a is C3~C 10 -cycloalkyl, 3-14 membered heteroaryl, C1-C6-alkyl, and halo-C1-C6-alkyl, wherein the 3-14 membered heteroaryl is substituted by one halo-C1-C6-alkyl substituent.

[0049] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is the base [ka] and R 1a is C3~C10 -cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl, wherein the C3-C 10 -Cycloalkyl may be optionally substituted with 1 to 2 halogen substituents.

[0050] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is the base [ka] and R 1a is C3~C 10 -cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl, wherein the C3-C 10 The -cycloalkyl may be optionally substituted with one halogen substituent.

[0051] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is the base [ka] and R 1a is selected from C1-C6-alkyl and halo-C1-C6-alkyl.

[0052] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is the base [ka] and R 1ais selected from 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, isopropyl, tert-butyl, CF3, and CHF2.

[0053] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is the base [ka] and R 1a is selected from 1-fluorocyclopropyl, isopropyl, tert-butyl, CF3, and CHF2.

[0054] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is the base [ka] and R 1a is selected from isopropyl, tert-butyl, CF3, and CHF2.

[0055] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is the base [ka] and R 1a is halo-C1-C6 alkyl.

[0056] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is the base [ka] and R 1a is selected from CHF2 and CF3.

[0057] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is the base [ka] and R 1a is CF3.

[0058] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is the base [ka] and R 1a is CHF2.

[0059] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is the base [ka] and R 1a is C3~C 10 -cycloalkyl, and the C3-C 10 -cycloalkyl is substituted with 1 to 2 halogen substituents.

[0060] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R1 is the base [ka] and R 1a is selected from 2,2-difluorocyclopropyl and 1-fluorocyclopropyl.

[0061] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is the base [ka] and R 1a is 2,2-difluorocyclopropyl.

[0062] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is the base [ka] and R 1a is 1-fluorocyclopropyl.

[0063] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 2 But hydrogen, C3~C 10 or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 2 But hydrogen, C3~C 10 -Cycloalkyl, C3-C 10 -cycloalkyl-C1-C6-alkyl, (3- to 14-membered heteroaryl)-C1-C6-alkyl and C1-C6-alkyl, wherein the C3-C10 The present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein -cycloalkyl is optionally substituted with one C1-C6-alkyl substituent.

[0065] In a preferred embodiment, the present invention provides R 2 But C3~C 10 The present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R is selected from -cycloalkyl and C1-C6-alkyl.

[0066] In a particularly preferred embodiment, the present invention provides 2 is selected from cyclopropyl and tert-butyl, or a pharmaceutically acceptable salt thereof.

[0067] In a particularly preferred embodiment, the present invention provides 2 is selected from cyclopropyl, sec-butyl and tert-butyl, or a pharmaceutically acceptable salt thereof.

[0068] In a preferred embodiment, the present invention provides R 2 is C1-C6-alkyl; or a pharmaceutically acceptable salt thereof.

[0069] In a particularly preferred embodiment, the present invention provides a compound comprising: 2 is tert-butyl, or a pharmaceutically acceptable salt thereof.

[0070] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3a is C1-C6-alkyl, and R 3b is hydrogen or C1-C6-alkyl, and R 4a and R 4bare both hydrogen, 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 both hydrogen, 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 However, both are hydrogen, and the C3 to C 10 -Cycloalkyl may be optionally substituted with 1 to 2 C1-C6-alkyl substituents.

[0071] 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 3b are both C1-C6-alkyl, and R 4a and R 4b are both hydrogen, 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 both hydrogen, 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 Both are hydrogen, and C3 to C 10 -Cycloalkyl may be optionally substituted by two C1-C6-alkyl substituents.

[0072] 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 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 may be optionally substituted by two C1-C6-alkyl substituents. In a particularly 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 3b are both methyl, and R 4a and R 4b are both hydrogen, or R 3a and R 3b together with the carbon atom to which they are attached to form a cyclopropyl, and R 4a and R 4b are both hydrogen, or 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 is substituted with two methyl substituents.

[0073] In a particularly 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 is substituted with two methyl substituents.

[0074] In a particularly preferred embodiment, the present invention provides a compound comprising the group [ka] but [ka] and [ka] The present invention provides a compound of formula (I) as described herein, selected from:

[0075] In a particularly preferred embodiment, the present invention provides a compound comprising the group [ka] but [ka] or a pharmaceutically acceptable salt thereof.

[0076] In a particularly preferred embodiment, the present invention provides a compound comprising the group [ka] but [ka] or a pharmaceutically acceptable salt thereof.

[0077] In a particularly preferred embodiment, the present invention provides a compound comprising the group [ka] but [ka] or a pharmaceutically acceptable salt thereof.

[0078] In a particularly preferred embodiment, the present invention provides a compound comprising the group [ka] but [ka] or a pharmaceutically acceptable salt thereof.

[0079] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C1-C3-alkyl.

[0080] 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 or CH2CH2.

[0081] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is CH2.

[0082] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C1-C6-alkyl, R 5 is selected from 3- to 14-membered heterocycloalkyl and 3- to 14-membered heteroaryl, wherein the 3- to 14-membered heterocycloalkyl is substituted with one oxo substituent.

[0083] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C1-C6-alkyl, R 5is a 3- to 14-membered heterocycloalkyl substituted with one oxo substituent.

[0084] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: L is CH2, R 5 is pyrrolidinyl substituted with one oxo substituent.

[0085] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 5 is a 3- to 9-membered heterocycloalkyl substituted with one oxo substituent, or a pharmaceutically acceptable salt thereof.

[0086] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 5 is a 3-8 membered heterocycloalkyl substituted with one oxo substituent, or a pharmaceutically acceptable salt thereof.

[0087] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 5 is a 3- to 7-membered heterocycloalkyl substituted with one oxo substituent, or a pharmaceutically acceptable salt thereof.

[0088] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 5 is a 3- to 6-membered heterocycloalkyl substituted with one oxo substituent, or a pharmaceutically acceptable salt thereof.

[0089] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 5 is a 4-6 membered heterocycloalkyl substituted with one oxo substituent, or a pharmaceutically acceptable salt thereof.

[0090] In a preferred embodiment, the present invention provides R 5is a 5- to 6-membered heterocycloalkyl substituted with one oxo substituent, or a pharmaceutically acceptable salt thereof.

[0091] In a particularly preferred embodiment, the present invention provides 5 is selected from pyrrolidinyl and piperidyl, each of which is substituted with one oxo substituent, or a pharmaceutically acceptable salt thereof.

[0092] In a particularly preferred embodiment, the present invention provides 5 is pyrrolidinyl substituted with one oxo substituent, or a pharmaceutically acceptable salt thereof.

[0093] In a particularly preferred embodiment, the present invention provides 5 is piperidyl substituted with one oxo substituent, or a pharmaceutically acceptable salt thereof.

[0094] In a particularly preferred embodiment, the present invention provides 5 but, [ka] or a pharmaceutically acceptable salt thereof.

[0095] In a particularly preferred embodiment, the present invention provides 5 but, [ka] or a pharmaceutically acceptable salt thereof.

[0096] In a particularly preferred embodiment, the present invention provides 5 but, [ka] or a pharmaceutically acceptable salt thereof.

[0097] In a particularly preferred embodiment, the present invention provides 5 but, [ka] or a pharmaceutically acceptable salt thereof.

[0098] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from fluoro and chloro; R 7 is selected from hydrogen and chloro.

[0099] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is fluoro, R 7 is chloro.

[0100] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C1-C6-alkyl, R 1 is the base [ka] and C6-C substituted with 1-2 halogen substituents 14 -aryloxy; R 1a is C3~C 10 -Cycloalkyl, C6-C 14-aryl, 3- to 14-membered heteroaryl, C1-C6-alkyl, and halo-C1-C6-alkyl, wherein the C3-C 10 -cycloalkyl and 3- to 14-membered heteroaryl may be optionally substituted by 1 to 2 substituents selected from halogen, C1-C6-alkyl and halo-C1-C6-alkyl; R 2 is hydrogen, C3 to C 10 -Cycloalkyl, C3-C 10 -cycloalkyl-C1-C6-alkyl, (3- to 14-membered heteroaryl)-C1-C6-alkyl and C1-C6-alkyl, wherein the C3-C 10 -cycloalkyl may be optionally substituted by one C1-C6-alkyl substituent, R 3a is C1-C6-alkyl, and R 3b is hydrogen or C1-C6-alkyl, and R 4a and R 4b are both hydrogen, 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 both hydrogen, 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 However, both are hydrogen, and the C3 to C 10 -cycloalkyl may be optionally substituted by 1 to 2 C1-C6-alkyl substituents, R 5 is selected from 3- to 14-membered heterocycloalkyl and 3- to 14-membered heteroaryl, wherein the 3- to 14-membered heterocycloalkyl is substituted with one oxo substituent; R 6 is selected from fluoro and chloro; R7 is selected from hydrogen and chloro.

[0101] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C1-C6-alkyl, R 1 is the base [ka] and R 1a is C3~C 10 -cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl, wherein the C3-C 10 -cycloalkyl is optionally substituted with one halogen substituent; R 2 is C3~C 10 -cycloalkyl and C1-C6-alkyl, R 3a and R 3b are both C1-C6-alkyl, and R 4a and R 4b are both hydrogen, 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 both hydrogen, 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 both hydrogen atoms, and the C3 to C 10 -cycloalkyl optionally substituted by two C1-C6-alkyl substituents, R 5 is a 3- to 14-membered heterocycloalkyl substituted with one oxo substituent; R 6 is fluoro, R 7 is chloro.

[0102] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: L is CH2; R 1 is the base [ka] and R 1a is selected from 1-fluorocyclopropyl, isopropyl, tert-butyl, CF3, and CHF2; R 2 is selected from cyclopropyl, sec-butyl and tert-butyl; R 3a and R 3b are both methyl, and R 4a and R 4b are both hydrogen, or R 3a and R 3b together with the carbon atom to which they are attached to form a cyclopropyl, and R 4a and R 4b are both hydrogen, or 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 is substituted with two methyl substituents; R 5 is pyrrolidinyl substituted with one oxo substituent, R 6 is fluoro, R 7 is chloro.

[0103] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C1-C6-alkyl, R 1 is the base [ka] and R 1a is C3~C 10 - selected from cycloalkyl, 3-14 membered heteroaryl, C1-C6-alkyl, and halo-C1-C6-alkyl, wherein the 3-14 membered heteroaryl is substituted by one halo-C1-C6-alkyl substituent; R 2 is hydrogen, C3 to C 10 -cycloalkyl and C1-C6-alkyl, R 3a is C1-C6-alkyl, and R 3b is hydrogen or C1-C6-alkyl, and R 4a and R 4b are both hydrogen, 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 both hydrogen, 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 both hydrogen atoms, and the C3 to C 10 -cycloalkyl may be optionally substituted by 1 to 2 C1-C6-alkyl substituents, R 5 is selected from 3- to 14-membered heterocycloalkyl and 3- to 14-membered heteroaryl, wherein the 3- to 14-membered heterocycloalkyl is substituted with one oxo substituent; R6 is selected from fluoro and chloro; R 7 is selected from hydrogen and chloro.

[0104] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C1-C6-alkyl, R 1 is the base [ka] and R 1a is selected from C1-C6 alkyl and halo-C1-C6 alkyl; R 2 is C3~C 10 -cycloalkyl and C1-C6-alkyl, R 3a and R 3b are both C1-C6-alkyl, and R 4a and R 4b are both hydrogen, 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 both hydrogen, 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 both hydrogen atoms, and the C3 to C 10 -cycloalkyl may be optionally substituted by two C1-C6-alkyl substituents, R 5 is a 3- to 14-membered heterocycloalkyl substituted with one oxo substituent; R 6 is fluoro, R 7 is chloro.

[0105] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: L is CH2, R 1 is the base [ka] and R 1a is selected from isopropyl, tert-butyl, CF3, and CHF2; R 2 is selected from cyclopropyl and tert-butyl; R 3a and R 3b are both methyl, and R 4a and R 4b are both hydrogen, or R 3a and R 3b together with the carbon atom to which they are attached to form a cyclopropyl, and R 4a and R 4b are both hydrogen, or 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 is substituted with two methyl substituents; R 5 is pyrrolidinyl substituted with one oxo substituent, R 6 is fluoro, R 7 is chloro.

[0106] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from the following: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[but-2-ynoyl-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-phenyl-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methylsulfanyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-(4-pyridylmethyl)ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-(1-bicyclo[1.1.1]pentanylmethyl)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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; (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (3R,3aR,6aS)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3,5-difluorophenoxy)acetyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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-propanamide; N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-cyclobutyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; N-[(1S)-1-[(2S,4S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]propanamide; Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-methyl-cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; Rac-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3,3-trifluoro-propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]butanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-fluoro-2-methyl-propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-fluoro-2-methyl-propanamide; Rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-dichloro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dichloro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide; Rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[rac-(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]propanamide; N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; Rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; 2,2-Dichloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]acetamide; Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]benzamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1R)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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; (1R)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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)-2-oxopyrrolidin-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)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; (1R)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; 2,2-Difluoro-N-[rac-(1S,2S)-2-methyl-1-[rac-(1R,2S,5S)-6,6-dimethyl-2-[[[rac-(2S)-2-chloro-2-fluoro-acetyl]-[[rac-(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; 2,2-Difluoro-N-[rac-(1S,2R)-2-methyl-1-[rac-(1R,2S,5S)-6,6-dimethyl-2-[[[rac-(2R)-2-chloro-2-fluoro-acetyl]-[[rac-(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2R)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; (2S)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2S)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; (2R)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; rac-2,2-difluoro-N-[(1S,2R)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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; rac-2-fluoro-N-[(1S)-2-ethyl-1-[(2S)-4,4-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]pyrrolidine-1-carbonyl]butyl]propanamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; (2S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; (2R)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]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)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]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)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; (1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-N'-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)-3-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-N'-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[3-fluoro-5-(trifluoromethyl)benzoyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)-3-[(E)-3-[3,5-bis(trifluoromethyl)phenyl]prop-2-enoyl]-N'-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[(E)-3-(3,5-difluorophenyl)prop-2-enoyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(5-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-3,3-dimethyl-2-(2-pyridylamino)butanoyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; and (2S)-2-Chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide.

[0107] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from the following: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide; N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide; 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide; 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]-N-methyl-propanamide; 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-2-[(2,2-difluoroacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide; 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-2-[(2,2-difluoroacetyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]-N-methyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; 3-[(2-chloroacetyl)-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide; 2,2,2-trifluoro-N-[(1S)-1-[(1R,2S,5S)-2-[[(2-fluoroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]acetamide; 3-[[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-(2-fluoroacetyl)amino]propanamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-phenyl-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methylsulfanyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloro-3-oxo-butanoyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[(2-chloro-2-fluoro-acetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(4S)-4-[[(2-chloro-2-fluoro-acetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2-difluoro-acetamide; N-[(1S)-1-(1-bicyclo[1.1.1]pentanylmethyl)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-(4-pyridylmethyl)ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-difluoro-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-(1-bicyclo[1.1.1]pentanyl)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-[3-(trifluoromethyl)isoxazole-5-carbonyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; N-[(1S)-1-[(2S,3S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S,3S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; and N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0108] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from the following: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide; N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide; and N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0109] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from the following: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2S)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2R)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2S)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]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]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide.

[0110] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from the following: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1R)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2S)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; and (2S)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide.

[0111] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide.

[0112] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0113] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0114] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0115] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide.

[0116] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide.

[0117] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.

[0118] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide.

[0119] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide.

[0120] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide.

[0121] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide.

[0122] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide.

[0123] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide.

[0124] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide.

[0125] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is (2R)—N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide.

[0126] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the compound is (2S)—N—[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide.

[0127] 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).

[0128] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms therein with atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of 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 125 Certain 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 percent of a given isotope.

[0129] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may confer greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring lower dosages.

[0130] 11 C. 18 F, 15 O and 13Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (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, substituting an appropriate isotopically labeled reagent for the previously employed non-isotopically labeled reagent.

[0131] 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 given herein unless indicated to the contrary.

[0132] 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 (such as those described in "Protective Groups in Organic Chemistry," by T.W. Greene and P.G.M. Hutts, 5th Edition, 2014, John Wiley & Sons, NY) 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.

[0133] 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 well 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).

[0134] 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 some 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).

[0135] Those skilled in the art will recognize that the reaction sequence may vary depending on the reactivity and nature of the intermediates.

[0136] More specifically, compounds of formula (I) can be prepared by the methods described below, the methods described in the Examples, or similar methods. Suitable 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 restrictions on the nature of the solvent used, so long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the described reactions at temperatures ranging from -78°C to reflux. The reaction time required for the reaction 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 intermediates and compounds described. The reaction order is not limited to the order shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0137] 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 similar analogs or as outlined in the experimental section.

[0138] All substituents, especially R 1 ~R 7 , R 1a , R 3a , R 3b , R 4a , R 4b and L are as defined above and in the claims unless otherwise indicated.

[0139] Scheme 1 [ka] In Scheme 1, PG1 and PG2 are protecting groups selected from Cbz and Boc, respectively, and LG1 is Cl, OH, OEt or [ka] and LG2 is a halogen.

[0140] The compound of formula III can be prepared by a protection reaction between the compound 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. The compound of formula III is then reacted with benzyl bromide in the presence of a base such as NaCO, KCO, or CsCO in a solvent such as DMF or CHCN to obtain the compound of formula IV. The compound 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 the compound of formula Va. The compound of formula VI-a can be obtained by a coupling reaction using the compound of formula V-1, the compound of formula Va, and a coupling reagent(s) such as T3P, HATU, HOPO, PyBOP, or EDCI / HOBt in the presence of an organic base such as TEA, DIEPA, or DMAP. Compounds of formula VII can be obtained by deprotection of compounds of formula VI-a 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 any solvent. Compounds of formula VIII can be obtained by a coupling reaction using compounds of formula VII-1, compounds of formula VII, and coupling reagent(s) such as T3P, HATU, PyBOP, HOPO, or EDCI / HOBt in the presence of an organic base such as TEA, DIEPA, or DMAP in a solvent such as THF, EtOAc, DMF, or DCM. Alternatively, compounds of formula VIII can be obtained by reaction of compounds of formula VII with compounds of formula VII-1 in the presence of an organic base such as TEA, DIEPA, or DMAP in a solvent such as MeOH, DCM, THF, or DMF. 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. 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.Deprotection of the compound of formula X in the presence of an acid such as HCl or TFA and in (or without) a solvent such as DCM or dioxane can give the compound of formula XI. The compound of formula XI is then reacted with the compound of formula XI-1 in the presence of coupling reagent(s) 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 Ia.

[0141] Scheme 2 [ka] In Scheme 2, PG1 and LG1 are as defined in Scheme 1.

[0142] Alternatively, the compound of formula X can be prepared by using the compound of formula Vb as the starting material. The compound of formula Vb is reacted with the compound of formula V-1 in the presence of a coupling reagent(s) 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 the compound of formula VI-b. The compound of formula XII can be obtained by hydrolysis of the compound of formula VI-b in a mixture of MeOH and HO in the presence of a base such as LiOH·HO, NaOH, or KOH. The compound of formula VIII can be obtained by a coupling reaction using the compound of formula XII, the compound of formula IX-1-a, and a coupling reagent(s) such as T3P, HATU, HOPO, PyBOP, or EDCI / HOBt in the presence of an organic base such as TEA, DIEPA, or DMAP in a solvent such as THF, EtOAc, DMF, or DCM. Hydrogenolysis of a compound 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 can provide a compound of formula XIV. Reaction of a compound of formula XIV with a compound of formula VII-1 in the presence of coupling reagent(s) 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 provides a compound of formula X. Alternatively, a compound of formula X can be obtained by reaction of a compound of formula XIV with a compound of formula VII-1 in the presence of an organic base such as TEA, DIEPA or DMAP in a solvent such as MeOH, DCM, THF or DMF. After deprotection and coupling, a compound of formula Ia can be prepared from a compound of formula X according to the last two steps of Scheme 1.

[0143] Scheme 3 [ka] In Scheme 3, PG1 is as defined in Scheme 1.

[0144] Alternatively, compounds of formula Ia can be prepared according to Scheme 3. Compounds of formula II are reacted with benzyl carboxylate or benzyl carboxylate 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 to give compounds of formula XV. Compounds of formula XV are reacted with compounds of formula IX-1-a 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 compounds of formula XVI. Compounds of formula XVII can be obtained by hydrogenolysis of compounds of formula XVI 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. The compound of formula XVII is reacted with the compound of formula V-1 in the presence of coupling reagent(s) such as T3P, HATU, HOPO, PyBOP or EDCI / HOBt and an organic base such as TEA, DIEPA or DMAP in a solvent such as THF, EtOAc, DMF or DCM to give the compound of formula XIII. By following the last four steps of Scheme 1, the compound of formula Ia can be prepared from the compound of formula XIII.

[0145] Scheme 4 [ka] In Scheme 4, PG1 is a protecting group selected from Cbz or Boc, and LG1 is Cl, OEt or [ka] is.

[0146] Alternatively, the compound of formula IX can be prepared by using the compound of formula VI-a as the starting material. The compound of formula XII can be obtained by hydrogenolysis of the compound of formula VI-a 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. The compound of formula XII can then be hydrolyzed in a mixture of MeOH and HO in the presence of a base such as LiOH·HO, NaOH, or KOH to obtain the compound of formula XX. When PG1 is Cbz, the compound of formula XX can be obtained by hydrogenation of the compound of formula VI-a 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, or THF. The compound of formula XX is reacted with the compound of formula VII-1 in the presence of an organic base such as TEA, DIPEA, or DMAP in a solvent such as MeOH, DMF, or DCM to obtain the compound of formula IX. By following the last three steps of Scheme 1, compounds of formula Ia can be prepared from compounds of formula IX.

[0147] Scheme 5 [ka] In Scheme 5, LG2 is as defined in Scheme 1.

[0148] Compounds of formula XXI can be prepared by coupling compounds of formula II with compounds of formula II-1 in the presence of an organic base such as TEA, DIPEA, or DMAP in a solvent such as DMF or DCM. Compounds of formula IX-1-a are reacted with compounds of formula XXI in the presence of coupling reagent(s) such as T3P, HATU, PyBOP, HOPO, or EDCI / HOBt and an organic base such as TEA, DIEPA, or DMAP in a solvent such as THF, EtOAc, DMF, or DCM to give compounds of formula XXII. Deprotection of compounds of formula XXII in the presence of an acid such as HCl or TFA in a solvent such as DCM or dioxane (or no solvent) can give compounds of formula XXIII. The compound of formula XXIII is then reacted with a compound of formula XI-1 in the presence of coupling reagent(s) 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 a compound of formula Ib.

[0149] Scheme 6 [ka] In Scheme 6, PG1 and LG2 are as defined in Scheme 1.

[0150] The compound of formula XIV can be obtained by hydrogenation of the compound of formula XIII 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, or THF. The compound of formula XIV is then deprotected in the presence of an acid such as DCM, HCl in dioxane, or TFA, or without a solvent, to obtain the compound of formula XXIV. When PG1 is Boc, the compound of formula XXIV can also be obtained from the compound of formula XIII under the same acid conditions as above. The compound of formula XXIV is reacted with the compound of formula XI-2 in the presence of a coupling reagent(s) such as T3P, HATU, PyBOP, HOPO, EDCI / HOBt, or without, and a base such as TEA, DIPEA, or DMAP in a solvent such as THF, EtOAc, DMF, or DCM to obtain the compound of formula Ic.

[0151] 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, comprising: (a) Formula (XI) [ka] (In the formula, R 1a , R 2 , R 3a , R 3b , R 4a , R 4b , R 5 and L is as defined herein. The compound of formula (XI-1) [ka] (In the formula, R 6 and R 7 is as defined herein and LG2 is a leaving group). in the presence of a coupling reagent and a base, Formula (Ia) [ka] (In the formula, R 1a , R 2, R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 and L is as defined herein, or (b) Formula (XXIII) [ka] (In the formula, R 1 , R 3a , R 3b , R 4a , R 4b , R 5 and L is as defined herein. The compound of formula (XI-1) [ka] (In the formula, R 6 and R 7 is as defined herein and LG2 is a leaving group). in the presence of a coupling reagent and a base, Formula (Ib) [ka] (In the formula, R 1 , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 and L is as defined herein.

[0152] In one embodiment, the leaving group LG2 is halogen, particularly chloro.

[0153] In one embodiment, the base used in the method is selected from TEA, DIPEA and DMAP.

[0154] In one embodiment, the solvent used in the process is DMF or DCM.

[0155] In one embodiment, the coupling reagent is selected from T3P, HATU, PyBOP, HOPO and EDCI / HOBt.

[0156] In one aspect, the present invention provides a compound of formula (XI) or a salt thereof: [ka] In the formula, R 1a , R 2 , R 3a , R 3b , R 4a , R 4b , R 5 and L is as defined herein.

[0157] In one aspect, the present invention provides a compound of formula (XXIII) or a salt thereof: [ka] In the formula, R 1 , R 3a , R 3b , R 4a , R 4b , R 5 and L is as defined herein.

[0158] 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.

[0159] 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 treatment or prevention of a coronavirus infection.

[0160] 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.

[0161] 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 the treatment or prevention of a coronavirus infection.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] In one aspect, the present invention provides a method for the treatment or prevention of a coronavirus infection, 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.

[0166] In one aspect, the present invention provides a method of 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.

[0167] 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).

[0168] In one embodiment, the coronavirus is severe acute respiratory syndrome coronavirus (SARS-CoV).

[0169] In one embodiment, the coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

[0170] In one embodiment, the coronavirus is Middle East Respiratory Syndrome coronavirus (MERS-CoV).

[0171] 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.

[0172] In one embodiment, a pharmaceutical composition according to Example 193 or 194 is provided.

[0173] 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). Pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, liquids, 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).

[0174] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be treated with pharmaceutically inert inorganic or organic adjuvants for the production 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.

[0175] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances, and liquid polyols.

[0176] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0177] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0178] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0179] 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. Pharmaceutical preparations may also contain other therapeutically valuable substances.

[0180] 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 / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (for example, about 300 mg / person) will be appropriate, preferably divided into 1 to 3 individual doses, for example, of the same amount.However, it is clear that the upper limit given herein can be exceeded in indicated cases.

[0181] Example 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.

[0182] 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.

[0183] Unless otherwise noted, all reactions and intermediates were prepared under an argon atmosphere.

[0184] 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-7ene 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 NMP 1-methyl-2-pyrrolidone 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 TCFH N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate TEA Triethylamine TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran T3P Propylphosphonic Anhydride

[0185] General experimental conditions Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) a Biotage SP1 system and Quad 12 / 25 cartridge module; ii) an ISCO combi-flash chromatography instrument. The silica gel brands and pore sizes were: i) KP-SIL 60Å, particle size: 40-60 μm; ii) CAS Registry Number: Silica Gel: 63231-67-4, particle size: 47-60 micron; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd., pore size: 200-300 or 300-400.

[0186] Alternatively, intermediates and final compounds can be purified using X Bridge™ Perp C 18 (5μm, OBD(TM) 30 x 100mm) column, X Bridge(TM) Perp C 18 (20-40 μm, OBD™ 30 x 100 mm) column, Welch Ultimate X Bridge™ SiOH 250 x 50 x 10 μm column, SunFire™ Perp C 18 Purification was by preparative HPLC on reversed phase columns 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.

[0187] 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 system SFC, 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, back pressure 100 bar, UV detection 254 nm or 220 nm. 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.

[0188] 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.

[0189] NMR spectra were obtained using a Bruker Avance 400 MHz.

[0190] All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents from commercial suppliers were used without further purification unless otherwise noted.

[0191] Preparation example Preparation of intermediates Intermediate 1 Benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka]

[0192] Step 1: Preparation of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a solution of Na2CO3 (1.37 g, 12.89 mmol) and (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride (1.0 g, 6.44 mmol) (Pharmablock, CAS number: 1373205-30-1) in water (15 mL) and 1,4-dioxane (15 mL), di-tert-butyl dicarbonate (2.1 g, 9.67 mmol) was added. The reaction was stirred at 20 °C for 12 h. The reaction mixture was diluted with H2 (80 mL) and washed with EtOAc (50 mL). The aqueous layer was acidified to pH = 2-3 with 1 M HCl. The mixture was extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (40 mL), dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to give (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.4 g) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ:ppm:4.21(s,0.5H),4.12(s,0.5H),3.69-3.56(m,1H),3.48-3.04(m,1H),1.69(d,J=7.2 Hz,0.5H),1.48-1.39(m,10.5H),1.06-1.05(m,3H),0.99(d,J=16 Hz,3H).

[0193] Step 2: Preparation of O2-benzyl O3-tert-butyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate [ka] To a solution of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.4 g, 5.48 mmol) in DMF (30 mL) was added K2CO3 (1.51 g, 10.97 mmol) and BnBr (1.22 g, 7.13 mmol). The reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with EtOAc (130 mL) and washed with water (50 mL) and brine (50 mL × 3). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column eluted with PE to PE / EtOAc = 4 / 1 to give O2-benzyl O3-tert-butyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.6 g) as a colorless oil. MS measured value (ESI + )[M+Na] + :368.2

[0194] Step 3: Preparation of benzyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a solution of O2-benzyl O3-tert-butyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,3-dicarboxylate (1.1 g, 3.18 mmol) in DCM (10 mL) was added TFA (10.0 mL). The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give (1R,2S,5S)-benzyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (780 mg) as a colorless oil. MS measured value (ESI + ) [M+H] + :246.1

[0195] Step 4: Preparation of benzyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (0.74 g, 3.18 mmol) (BePharm, CAS number: 62965-35-9) in DMF (30 mL) was added HATU (1.45 g, 3.82 mmol), DIPEA (2.46 g, 19.08 mmol), and (1R,2S,5S)-benzyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (0.78 g, 3.18 mmol). The reaction mixture was stirred at 25 °C for 2 h. The mixture was diluted with EtOAc (100 mL) and washed with water (50 mL) and brine (50 mL × 3). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column eluted with PE / EtOAc=10 / 1 to give (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.25 g) as a colorless oil. MS measured value (ESI + ) [M+H] + :459.4

[0196] Step 5: Preparation of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) [ka] To a solution of benzyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.25 g, 2.73 mmol) in DCM (10 mL) was added TFA (10 mL). The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo to give benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (0.97 g, Intermediate 1) as a colorless oil. MS measured value (ESI + ) [M+H] + :359.3.

[0197] Intermediate 2 Benzyl (1R,2S,5S)-3-[(2S)-2-amino-2-cyclopropyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (2S)-2-(tert-butoxycarbonylamino)-2-cyclopropyl-acetic acid (BePharm, CAS number: 155976-13-9) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to give benzyl (1R,2S,5S)-3-[(2S)-2-amino-2-cyclopropyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 2) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:343.1.

[0198] Intermediate 3 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 [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (AstaTech, CAS number: 597569-42-1) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to give 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 (Intermediate 3) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:359.3.

[0199] Intermediate 4 Benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.2.0]heptane-2-carboxylate [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (1S,2S,5R)-3-azabicyclo[3.2.0]heptane-2-carboxylic acid (Pharmablock, CAS number: 77882-10-1) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride, to give (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.2.0]heptane-2-carboxylate (Intermediate 4) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:345.3.

[0200] Intermediate 5 Benzyl (6S)-5-[(2S)-2-amino-3,3-dimethyl-butanoyl]-5-azaspiro[2.4]heptane-6-carboxylate [ka] The title compound was prepared analogously to the procedure described for the preparation of intermediate 1, using (6S)-5-tert-butoxycarbonyl-5-azaspiro[2.4]heptane-6-carboxylic acid (Wuxiapptec, catalog) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to give benzyl (6S)-5-[(2S)-2-amino-3,3-dimethyl-butanoyl]-5-azaspiro[2.4]heptane-6-carboxylate (intermediate 5) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:345.2.

[0201] Intermediate 6 Benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate [ka] The title compound was prepared in a similar manner to the procedure described for the preparation of Intermediate 1, using (2S,4R)-4-methylpyrrolidine-2-carboxylic acid; hydrochloride (Wuxiapptec, CAS number: 365280-18-8) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride, to give benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate (Intermediate 6) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:333.2.

[0202] Intermediate 7 Benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate [ka] The title compound was prepared in a similar manner to the procedure described for the preparation of Intermediate 1, using (2S)-4,4-dimethylpyrrolidine-2-carboxylic acid; hydrochloride (Porse Fine Chemical, CAS number: 1443252-76-3) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride, to give benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate (Intermediate 7) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:347.2.

[0203] Intermediate 8 Benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] The title compound was prepared in a similar manner to the procedure described for the preparation of Intermediate 1, using (1S,2S,5R)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Pharmablock, CAS number: 400720-05-0) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to afford benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 8) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:331.1.

[0204] Intermediate 9 Tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] Step 1: Preparation of tert-butyl 3-methylene-2-oxo-pyrrolidine-1-carboxylate [ka] A solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (100.0 g, 539.9 mmol) (Accela, CAS number: 85909-08-6) in THF (1000 mL) was added to a stirred solution of LiHMDS (1133 mL, 1134 mmol) at 0 °C. The reaction mixture was warmed to 20 °C over 30 min, after which 2,2,2-trifluoroethyl trifluoroacetate (211.69 g, 1080 mmol) was added. Stirring was continued at 20 °C for an additional 20 min, after which the reaction was quenched with saturated NH Cl (500 mL). The mixture was extracted with EtOAc (600 mL × 2). The combined organic layers were dried over Na SO , filtered, and concentrated in vacuo. The residue was dissolved in toluene (1000 mL), and then formaldehyde (48.64 g, 1620 mmol) and K2CO3 (164.16 g, 1188 mmol) were added to the solution. The reaction mixture was heated at 110 °C for 2 hours. The mixture was diluted with EtOAc (800 mL), washed with brine (200 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 3-methylene-2-oxo-pyrrolidine-1-carboxylate (80 g) as a pale yellow oil. MS measured value (ESI + )[M-Bu+H] + :142.1.

[0205] Step 2: Preparation of tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl 3-methylene-2-oxo-pyrrolidine-1-carboxylate (80.0 g, 405.62 mmol) in i-PrOH (800 mL) was added benzyl N-aminocarbabate (67.41 g, 405.62 mmol). The reaction mixture was stirred at 85° C. under N for 12 hours. The mixture was concentrated in vacuo to give crude product tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-pyrrolidine-1-carboxylate (147 g) as a yellow oil. MS actual value (ESI+) [2M+H] + :727.2.

[0206] Step 3: Preparation of benzyl N-[(2-oxopyrrolidin-3-yl)methylamino]carbamate [ka] To a solution of tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-pyrrolidine-1-carboxylate (147.0 g, 404.5 mmol) in DCM (700 mL) was added TFA (500 mL). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated in vacuo to give benzyl N-[(2-oxopyrrolidin-3-yl)methylamino]carbamate (147.0 g) as a yellow oil. MS measured value (ESI + ) [M+H] + :264.0.

[0207] Step 4: Preparation of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxopyrrolidin-3-yl)methyl]carbamate [ka] To a solution of benzyl N-[(2-oxopyrrolidin-3-yl)methylamino]carbamate (150.0 g, 569.71 mmol) in EtOH (800 mL) was added DIPEA (220.9 g, 1709 mmol) and BocO (149.2 g, 683.66 mmol). The reaction mixture was stirred at 50° C. for 12 hours. The mixture was concentrated in vacuo. The residue was diluted with EtOAc (1000 mL), washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column eluted with PE / EtOAc = 1 / 1 to EtOAc to give impure product, which was further purified by reverse flash (0.1% TFA) to give tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxopyrrolidin-3-yl)methyl]carbamate (50.0 g) as a pale yellow oil. MS measured value (ESI + )[M-Boc+H] + :264.2.

[0208] Step 5: Preparation of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxopyrrolidin-3-yl)methyl]carbamate (160.0 g, 440.27 mmol) in methanol (1500 mL) was added Pd / C (15.0 g) and Pd(OH) / C (15.0 g) under N. The reaction mixture was degassed under vacuum and purged with H three times. The resulting mixture was stirred under a H balloon at 25 °C for 12 h. The mixture was filtered through a Celite pad, and the filtrate was concentrated in vacuo to give tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (100 g) as a colorless oil. The racemate was resolved by SFC prep (Column: Phenomenex-Cellulose-2 (250 mm × 50 mm, 10 μm); Conditions: Phase A to CO, Phase B to Neu-MeOH: B%: 45-45%; Flow rate (mL / min): 220; Gradient time: 3.55 min, Injection: 440) to give tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (41.4 g, Intermediate 9) as a pale yellow solid. 1 H NMR(400 MHz, CDCl3)δ:ppm 5.77(s,1H),3.75-3.55(m,2H),3.45-3.30(m,2H),2.85-2.75(m,1H),2.30-2.20(m,1H),1.99-1.89(m,1H),1.51-1.42(m,9H) MS measured value (ESI + ) [M+H] + :230.1 SFC: Retention time = 1.615 min, ee% = 98.05%

[0209] Intermediate 10 (2R)-2-chloro-2-fluoroacetyl chloride [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 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 2 M HCl to pH = 4-5. The mixture was extracted with MTBE (1 L × 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).

[0210] Step 2: Preparation of (2R)-2-chloro-2-fluoro-acetic acid [ka] To a solution of 2-chloro-2-fluoro-acetic acid (718.0 g, 3191 mmol) in EtOAc (3000 mL) was added a solution of (S)-1-phenylethanamine (386.7 g, 3191 mmol) in EtOAc (3000 mL) at 0° C. 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 three times in acetone (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 NaSO, filtered, and concentrated in vacuo to give (2R)-2-chloro-2-fluoro-acetic acid (121.15 g, 61% purity, containing MTBE) as a yellow oil. 1 H NMR(400 MHz, CDCl3)δ:ppm 6.29(d,J=50.8 Hz,1H).

[0211] Step 3: Preparation of (2R)-2-chloro-2-fluoro-acetic acid [ka] A mixture of (2R)-2-chloro-2-fluoro-acetic acid (12.0 g, 106.68 mmol) and PCl (24.5 g, 117.47 mmol) was stirred at 20 °C for 1 hour and at 70 °C for 1 hour. 1 H NMR showed that the reaction was complete, and then (2R)-2-chloro-2-fluoro-acetyl chloride (22.8 g, 40% purity using POCl and MTBE, Intermediate 10) was recovered as a colorless liquid by distillation (70 °C, 20 mmHg). 1 H NMR(400 MHz, CDCl3)δ:ppm 6.40(d,J=50.8 Hz,1H).

[0212] Intermediate 11 tert-Butyl N-amino-N-(1H-pyrazol-3-ylmethyl)carbamate [ka] Step 1: Preparation of benzyl N-(1H-pyrazol-3-ylmethylamino)carbamate: [ka] To a solution of 1H-pyrazole-3-carbaldehyde (5.0 g, 52.03 mmol) (BePharm, CAS number: 3920-50-1) and benzyl carbazate (8.68 g, 52.20 mmol) in methanol (100 mL) was added HOAc (10.0 mL, 174.85 mmol). The mixture was stirred at 25 °C for 3 h. NaBH (19.6 g, 312.21 mmol) was then added to the mixture. The mixture was stirred at 60 °C for 12 h. The reaction was concentrated in vacuo to remove methanol. The residue was diluted with H2O (50 mL) and extracted with EtOAc (50 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by reverse column chromatography (conditions: 330 g flash column Welch Ultimate XB_C 18 The crude product was purified by HPLC using a 20-40 μm column chromatography (120A, ACN (0.1% TFA) in water, 26%-26%, 100 mL / min). The fraction was basified with saturated aqueous NaHCO to pH=9 and extracted with EtOAc (100 mL×3). The organic phase was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give benzyl N-(1H-pyrazol-3-ylmethylamino)carbamate (10 g) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:246.9

[0213] Step 2: Preparation of tert-butyl N-(benzyloxycarbonylamino)-N-(1H-pyrazol-3-ylmethyl)carbamate [ka] To a solution of benzyl N-(1H-pyrazol-3-ylmethylamino)carbamate (3.0 g, 12.18 mmol) in EtOH (40 mL) was added DIPEA (6.29 g, 48.67 mmol) and BocO (5.32 g, 24.38 mmol). The mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified on a silica gel column eluted with EtOAc / PE=1 / 1 to EtOAc to give tert-butyl N-(benzyloxycarbonylamino)-N-(1H-pyrazol-3-ylmethyl)carbamate (1.2 g) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:347.0.

[0214] Step 3: Preparation of tert-butyl N-amino-N-(1H-pyrazol-3-ylmethyl)carbamate [ka] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-(1H-pyrazol-3-ylmethyl)carbamate (1.2 g, 3.46 mmol) in MeOH (15 mL) was added Pd / C (120.0 mg) and Pd(OH) (120.0 mg). The mixture was degassed in vacuo and purged with H three times. The resulting mixture was stirred at 25 °C under a hydrogen balloon (760 mmHg) for 2 hours. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column eluted with EtOAc to MeOH / EtOAc = 10 / 1 to give tert-butyl N-amino-N-(1H-pyrazol-3-ylmethyl)carbamate (600 mg, Intermediate 11) as a colorless oil. 1 H NMR(400 MHz,CD3OD)δ:ppm 7.53(d,J=2.0 Hz,1 H),6.24(d,J=1.6 Hz,1 H),4.61(s,2H),1.49(s,9H). MS measured value (ESI + ) [(2M+Na) + ]:447.3.

[0215] Intermediate 12 5-(trifluoromethyl)isoxazole-3-carboxylic acid [ka] Step 1: Preparation of ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate [ka] To a solution of ethyl (Z)-2-chloro-2-(hydroxyimino)acetate (3.0 g, 19.8 mmol) (Accela, CAS number: 14337-43-0) in EtOAc (50 mL) was added 2-bromo-3,3,3-trifluoroprop-1-ene (10.4 g, 59.39 mmol) and NaHCO (5.5 g, 65.32 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo at 30 °C to give ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate (3.75 g) as a yellow oil. 1 H NMR(400 MHz,DMSO-d6)δ:ppm 7.93(s,1H),4.44-4.39(m,2H),1.34(t,J=7.2 Hz,3H).

[0216] Step 2: Preparation of 5-(trifluoromethyl)isoxazole-3-carboxylic acid [ka] To a solution of ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate (3.75 g, 17.93 mmol) in methanol (40 mL) was added a solution of NaOH (1.58 g, 39.45 mmol) in water (40 mL) at 0 °C. The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to remove MeOH. The residue was diluted with EtOAc (80 mL) and washed with 1 M HCl (40 mL). The aqueous phase was extracted with EtOAc (80 mL × 6). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified on a silica gel column eluted with PE / EtOAc = 7 / 3 to 1 / 1 to give 5-(trifluoromethyl)isoxazole-3-carboxylic acid (2.3 g, Intermediate 12) as a white solid. 1 H NMR(400 MHz,CDCl3)δ:ppm 7.39(br.s,1H),7.18(s,1H).

[0217] Intermediate 13 2-(3,5-difluorophenoxy)acetyl chloride [ka] Step 1: Preparation of ethyl 2-(3,5-difluorophenoxy)acetate [ka] To a solution of 3,5-difluorophenol (475 mg, 3.65 mmol) in DMF (10 mL) was added K2CO3 (1008 mg, 7.3 mmol) and ethyl bromoacetate (0.4 mL, 3.65 mmol). The mixture was stirred at 25 °C for 4 h. The mixture was diluted with EtOAc (50 mL) and poured into water (50 mL). The aqueous phase was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL) and dried over Na2SO4. After filtration and concentration, the residue was purified on a silica gel column eluted with EtOAc / PE = 50 / 1 to 10 / 1 to give ethyl 2-(3,5-difluorophenoxy)acetate (650 mg) as a colorless liquid.

[0218] Step 2: Preparation of 2-(3,5-difluorophenoxy)acetic acid [ka] To a solution of ethyl 2-(3,5-difluorophenoxy)acetate (150 mg, 0.690 mmol) in MeOH (5 mL) and water (2 mL) was added LiOH·HO (73 mg, 1.73 mmol). The mixture was stirred at 20 °C for 1 h. The mixture was diluted with HO (30 mL) and washed with EtOAc (20 mL × 2). The aqueous phase was adjusted to pH = 5-6 by adding concentrated HCl and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give 2-(3,5-difluorophenoxy)acetic acid (130 mg) as a white solid.

[0219] Step 3: Preparation of 2-(3,5-difluorophenoxy)acetyl chloride [ka] To a solution of 2-(3,5-difluorophenoxy)acetic acid (110 mg, 0.580 mmol) in DCM (5 mL) was added SOCl (1 mL). The mixture was stirred at 40 °C for 2 h. The mixture was concentrated in vacuo to give 2-(3,5-difluorophenoxy)acetyl chloride (120 mg, Intermediate 13) as a colorless oil.

[0220] Intermediate 14 tert-Butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] Step 1: Preparation of (1R,2S,5S)-3-benzyloxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a solution of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride (1.5 g, 7.83 mmol) in DCM (20 mL) was added TEA (2.37 g, 23.48 mmol) and CbzOsu (2.93 g, 11.74 mmol) at 0 °C. The mixture was warmed to 25 °C and stirred at 25 °C for 16 h. The mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography eluting with ACN in HO (0.1% TFA) = 0 to 64% to give (1R,2S,5S)-3-benzyloxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.96 g) as a black oil. 1 H NMR(400 MHz,CD3OD)δ:ppm 7.37-7.27(m,5H),5.55-5.75(br.s,1H),5.17-5.11(m,2H),4.29(d,J=12.4 Hz,1H),3.74-3.65(m,1H),3.55(t,J=12.8 Hz,1H),1.67-1.53(m,1H),1.50-1.43(m,1H),1.07(d,J=2.4 Hz,3H),0.98(d,J=5.6 Hz,1H). MS measured value (ESI + ) [(M+Na) + ]:311.9

[0221] Step 2: Preparation of benzyl (1R,2S,5S)-2-[[tert-butoxycarbonyl-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate [ka] To a solution of (1R,2S,5S)-3-benzyloxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (1.4 g, 4.84 mmol) in DMF (20 mL) was added DIPEA (3.1 g, 24.19 mmol), EDCI (1113 mg, 5.81 mmol), and HOPO (645 mg, 5.81 mmol) at 0 °C. Then, tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.1 g, 4.84 mmol) was added to the reaction mixture. The resulting mixture was warmed to 25 °C and stirred for 16 h. The mixture was purified by reverse-phase flash chromatography eluting with 0-54% ACN in HO (0.1% TFA) to give benzyl (1R,2S,5S)-2-[[tert-butoxycarbonyl-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (1.9 g) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:501.3.

[0222] Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of (1R,2S,5S)-2-[[tert-butoxycarbonyl-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.53 g, 5.04 mmol) in MeOH (30 mL) was added Pd / C (100 mg, 10% purity) under a N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under a H balloon at 25 °C for 2 h. The mixture was filtered, and the filtrate was concentrated to give tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.6 g, Intermediate 14) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:367.2.

[0223] Intermediate 15 Benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (2S,4R)-1-tert-butoxycarbonyl-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (PharmaBlock, CAS number: 470482-44-1) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to give benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate (Intermediate 15) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:387.2.

[0224] Intermediate 16 (2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid [ka] Step 1: Preparation of N-methoxy-N,1-dimethyl-cyclopropanecarboxamide [ka] To a solution of 1-methylcyclopropane-1-carboxylic acid (3.1 g, 30.96 mmol) in DCM (10 mL) was added dropwise DMF (45 mg, 0.620 mmol) and SOCl (3.7 g, 30.96 mmol) at 0 °C. The mixture was heated to 40 °C for 2 h. After cooling to room temperature, the mixture was added to a solution of EtN (934 mg, 92.36 mmol) and 1-methylcyclopropanecarbonyl chloride (3.65 g, 30.79 mmol) in DCM (50 mL) at 0 °C. The mixture was then stirred at 0-25 °C for 1 h. The mixture was concentrated, and the residue was purified on a silica gel column eluted with PE / EtOAc (20 / 1 to 4 / 1) to give N-methoxy-N,1-dimethyl-cyclopropanecarboxamide (3.3 g) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ:ppm 3.72(s,3H),3.23(s,3H),1.36(s,3H),1.06-1.00(m,2H),0.59-0.53(m,2H).

[0225] Step 2: Preparation of 1-methylcyclopropanecarbaldehyde [ka] To a solution of N-methoxy-N,1-dimethyl-cyclopropanecarboxamide (6.0 g, 41.91 mmol) in THF (60 mL) was added DIBAL-H (50.29 mL, 50.29 mmol, 1N) dropwise at −70° C. The mixture was stirred at −70° C. for 2 h. The mixture was poured into 1N HCl (100 mL). The organic layer was separated and the aqueous phase was extracted with DCM (50 mL × 3). The combined organic phases were dried over NaSO, filtered, and concentrated to give a solution of 1-methylcyclopropanecarbaldehyde, which was used directly in the next step without further purification. 1 H NMR(400 MHz,CDCl3)δ:ppm 8.64(s,1H),1.25(s,3H),1.16-1.15(m,2H),0.93-0.92(m,2H).

[0226] Step 3: Preparation of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetonitrile [ka] To the solution of 1-methylcyclopropanecarbaldehyde from step 2 was added (R)-(-)-2-phenylglycinol (4.11 g, 29.96 mmol). The mixture was stirred at 25 °C for 2 hours. Then, trimethylsilyl cyanide (4.95 g, 49.90 mmol) was added dropwise to the mixture at 0 °C. The mixture was then stirred at 0 to 25 °C for 12 hours. The mixture was purified, and the residue was purified by silica gel column eluted with PE / EtOAc = 10 / 1 to 2 / 1 to give (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetonitrile (5.1 g) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:231.1.

[0227] Step 4: Preparation of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetic acid [ka] To a solution of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetonitrile (4.8 g, 20.84 mmol) in AcOH (10.0 mL) was added 12 N HCl (40.0 mL). The mixture was stirred at 80° C. for 1 h. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (Column Phenomenex Luna C 18 250 × 80 mm × 10 μm; Conditions: ACN in water (HCl: 0% to 30%; 140 mL / min) to give (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetic acid hydrochloride (2.7 g) as a white solid. 1 H NMR(400 MHz,D2O)δ:ppm 7.53-7.40(m,5H),4.20(dd,J=8.0 Hz,5.6 Hz,1H),4.07(dd,J=12.0 Hz,8.4 Hz,1H),4.00(dd,J=12.0 Hz,5.6 Hz,1H),2.57(s,1H),0.98(s,3H),0.60-0.35(m,3H),0.05-0.15(m,1H). MS measured value (ESI + )[(M+H) + ]:249.8.

[0228] Step 5: Preparation of (2S)-2-amino-2-(1-methylcyclopropyl)acetic acid [ka] To a solution of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1-methylcyclopropyl)acetic acid; hydrochloride (2.7 g, 9.48 mmol) in AcOH (30 mL) and methanol (150 mL) was added wet Pd(OH) / C (200 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 45 °C for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give crude (2S)-2-amino-2-(1-methylcyclopropyl)acetic acid; hydrochloride (4.0 g) as a yellow oil. 1 H NMR(400 MHz,D2O)δ:ppm 3.07(s,1H),1.20(s,3H),0.96-0.79(m,1H),0.57-0.53(m,2H),0.52-0.46(m,1H). MS measured value (ESI + )[(M+H) + ]:130.3.

[0229] Step 6: Preparation of (2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid [ka] To a solution of (2S)-2-amino-2-(1-methylcyclopropyl)acetic acid; hydrochloride (4.0 g, 24.15 mmol, crude) in 1,4-dioxane (50 mL) and water (50 mL) was added Na2CO3 (12.8 g, 120.76 mmol) and di-t-butyl dicarbonate (5271 mg, 24.15 mmol). The suspension was stirred at 25 °C for 12 h. The mixture was diluted with water (100 mL) and washed with EtOAc (50 mL × 2). The aqueous phase was adjusted to pH = 4 with 1 N HCl and extracted with EtOAc (100 mL × 2). The organic layer was washed with brine (60 mL), dried over Na2SO4 and concentrated in vacuo to give (2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid (1.9 g, Intermediate 16) as a yellow oil. 1H NMR(400 MHz,CDCl3)δ:ppm 5.20(d,J=3.6 Hz,1H),3.75(d,J=7.6 Hz,1H),1.46(s,9H),1.08(s,3H),0.85-0.78(m,1H),0.75-0.67(m,1H),0.51-0.45(m,1H),0.44-0.36(m,1H). MS measured value (ESI + )[(M-C4H9+H) + ]:174.1.

[0230] Intermediate 17 Benzyl (6S)-5-azaspiro[2.4]heptane-6-carboxylate hydrochloride [ka] Step 1: Preparation of O6-benzyl O5-tert-butyl (6S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate [ka] To a solution of (6S)-5-tert-butoxycarbonyl-5-azaspiro[2.4]heptane-6-carboxylic acid (2.00 g, 8.29 mmol) (Wuxiapptec, Cas number: 112963444-1) and K2CO3 (2.28 g, 16.55 mmol) in DMF (40 mL) was added BnBr (1.28 mL, 10.76 mmol). The mixture was stirred at 25 °C for 12 hours. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic phase was washed with brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with ethyl PE / EtOAc=10 / 1 to 2 / 1 to give O6-benzyl O5-tert-butyl (6S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2300 mg) as a colorless oil. MS measured value (ESI + ) [(M-Boc+H) + ]:232.2.

[0231] Step 2: Preparation of benzyl (6S)-5-azaspiro[2.4]heptane-6-carboxylate; hydrochloride salt [ka] A solution of O6-benzyl O5-tert-butyl (6S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2.3 g, 6.94 mmol) in 4 N HCl / dioxane (10.0 mL) was stirred for 1 hour at 25° C. The mixture was concentrated in vacuo to give benzyl (6S)-5-azaspiro[2.4]heptane-6-carboxylate hydrochloride (1800 mg, Intermediate 17) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:232.2.

[0232] Intermediate 18 Benzyl (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidine-2-carboxylic acid (Bide, CAS number: 364750-81-2) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid to give benzyl (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate (Intermediate 18) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:333.2.

[0233] Intermediate 19 (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoic acid [ka] Step 1: Preparation of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-iodo-1-bicyclo[1.1.1]pentanyl)propanoate [ka] To a solution of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (30 g, 101.07 mmol) in pentane (30 mL) was added dropwise methyllithium (71.73 mL, 222.36 mmol) at -45 °C. The reaction mixture was stirred at the same temperature for 15 minutes under N2 protection. The reaction flask was removed from the dry ice / ethanol bath and placed in an ice-water bath. The reaction mixture was stirred at that temperature for 2 hours. The volatiles were collected using a short-path distillation condenser under a dry ice-ethanol environment at 50 °C to give tricyclo[1.1.1.01,3]pentane (7.0 g) in diethyl ether (approximately 50 mL). Boc-3-iodo-l-alanine methyl ester (7.0 g, 21.27 mmol) was added to the solution, which was then cooled to -40 °C. Triethylborane (2.82 mL, 2.82 mmol) was added slowly. The resulting mixture was stirred at 20° C. for 1 hour and then concentrated in vacuo. The residue was purified by reverse-phase Flash (0.1% TFA in water, MeCN) to give methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-iodo-1-bicyclo[1.1.1]pentanyl)propanoate (7.0 g) as a white solid. 1 H NMR(400 MHz,CDCl3)δ:4.98(d,J=7.6 Hz,1H),4.30(q,J=4.4 Hz,1H),3.74(s,3H),2.23-2.28(m,6H),2.10-2.16(m,1H),1.84-1.90(m,1H),1.45(s,9H). MS measured value (ESI + ) [(M-Boc+H) + ]:295.9.

[0234] Step 2: Preparation of methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoate [ka] To a solution of methyl (2S)-2-(tert-butoxycarbonylamino)-3-(3-iodo-1-bicyclo[1.1.1]pentanyl)propanoate (4.0 g, 10.12 mmol) and 2,6-lutidine (813 mg, 30.36 mmol) in pentane (30 mL) was added tris(trimethylsilyl)silane (6.24 mL, 20.24 mmol). The mixture was stirred at 20 °C for 20 minutes, and then BEt (0.31 mL, 1.01 mmol) was added. The resulting mixture was stirred at 20 °C for 30 minutes. The mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by silica gel column eluted with PE / EtOAc=50 / 1 to 8 / 1 to give methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoate (2.0 g) as a colorless gum. 1 H NMR(400 MHz,CDCl3)δ:4.98(d,J=7.6 Hz,1H),4.30(q,J=4.4 Hz,1H),3.73(s,3H),2.45(s,1H),1.92-2.03(m,1H),1.76-1.83(m,1H),1.75(s,6H),1.45(s,9H). MS observed value (ESI+) [M-Boc+H]+: 169.9.

[0235] Step 3: Preparation of methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoate [ka] To a solution of methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoate (1.03 g, 3.81 mmol) in THF (10 mL) and water (5 mL) was added LiOH·HO (480 mg, 11.43 mmol). The mixture was stirred at 25 °C for 4 h. The mixture was diluted with water (100 mL) and acidified to pH = 4 with 1 N HCl (15 mL). The mixture was extracted with EtOAc (100 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to give (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert-butoxycarbonylamino)propanoic acid (802 mg, Intermediate 19) as a yellow oil. MS measured value (ESI + ) [(M-Boc+H) + ]:156.2.

[0236] Intermediate 20 (2S)-2-(benzyloxycarbonylamino)-4,4-dimethyl-pentanoic acid [ka] Preparation of (2S)-2-(benzyloxycarbonylamino)-4,4-dimethyl-pentanoic acid [ka] To a solution of (S)-2-(((benzyloxy)carbonyl)amino)-4,4-dimethylpentanoic acid (400 mg, 2.75 mmol) in an aqueous solution of NaOH (5.52 mL, 1N) was added a solution of CbzCl (0.48 mL, 3.38 mmol) in MeCN (0.80 mL) slowly over 5 min at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction was diluted with HO (15 mL) and acidified to pH = 3 with 1N HCl. The mixture was extracted with EtOAc (30 mL × 3). The organic phase was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified on a silica gel column eluted with PE / EtOAc = 2 / 1 to 1 / 1 to give (2S)-2-(benzyloxycarbonylamino)-4,4-dimethyl-pentanoic acid (700 mg, Intermediate 20) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:280.1.

[0237] Intermediate 21 Benzyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid [ka] Similar to the procedure described for the preparation of intermediate 1, (1R,2S,5S)-benzyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate, (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3 The title compound was prepared using a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (AstaTech, CAS number: 597569-42-1) to give benzyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 21) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:246.2.

[0238] Intermediate 22 Benzyl (3S,3aS,6aR)-2-[(2S,3R)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid [ka] Similar to the procedure described for the preparation of intermediate 1, (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid was used in place of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, and (2S)-2-(tert-butoxycarbonyl)- The title compound was prepared using Boc-L-isoleucine instead of (3S,3aS,6aR)-2-[(2S,3R)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 22) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:359.2.

[0239] Intermediate 23 Benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-2-cyclobutyl-acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid [ka] Similar to the procedure described for the preparation of intermediate 1, (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid was used instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, and (2S)-2-(tert-butoxycarbonylamino)-2-cyclobutyl-acetic acid (GL) was used instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid. The title compound was prepared using Benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-2-cyclobutyl-acetyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 23) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:357.2.

[0240] Intermediate 24 Benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-ethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid [ka] Similar to the procedure described for the preparation of intermediate 1, (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid was used instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, and (2S)-2-(tert-butoxycarbonylamino)-3-ethyl-pentanoic acid (KaiXin) was used instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid. The title compound was prepared using Benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3-ethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 24) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:373.2.

[0241] Intermediate 25 (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid [ka] Step 1: Preparation of N-methoxy-N,2,2-trimethyl-butanamide [ka] To a solution of 2,2-dimethylbutyric acid (15.0 g, 129.13 mmol) in DCM (50 mL) was added (COCl) (32.78 g, 258.26 mmol) at 0 °C. The mixture was stirred at 20 °C for 8 h and then concentrated in vacuo at 45 °C. The residue was dissolved in DCM (30 mL) and added to a solution of O,N-dimethylhydroxylamine HCl (12.6 g, 129.13 mmol) and EtN (65.33 g, 645.66 mmol) in DCM (300 mL) at 0 °C. The mixture was then stirred at 20 °C for 4 h. The reaction mixture was diluted with water (200 mL) and extracted with DCM (200 mL × 2). The organic phase was washed with 1 N HCl (200 mL), brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column eluted with PE to PE / EtOAc=6 / 1 to give N-methoxy-N,2,2-trimethyl-butanamide (15.5 g) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ:ppm 3.67(s,3H),3.18(s,3H),1.66(q,J=7.6 Hz,2H),1.22(s,6H),0.85(t,J=7.6 Hz,3H). MS measured value (ESI + )[(M+H) + ]:160.1.

[0242] Step 2: Preparation of 2,2-dimethylbutanal [ka] To a solution of N-methoxy-N,2,2-trimethylbutanamide (5.0 g, 31.4 mmol) in THF (50 mL) was added LiAlH4 / THF (47.1 mL, 47.1 mmol, 1N) at −78 °C and stirred at the same temperature for 1 h. The reaction was quenched dropwise with HO (1.8 mL) at −78 °C over 10 min, and then aqueous NaOH (1.8 mL, 15%) was added at −78 °C over 5 min. HO (5.5 mL) was then added at −78 °C over 5 min. The white suspension was warmed to 15 °C and stirred for 10 min. After adding Na2SO4 (10 g), the mixture was stirred at 15 °C for another 10 min. The mixture was filtered, and the filter cake was washed with THF (25 mL × 2). The filtrate was used directly in the next step.

[0243] Step 3: Preparation of 2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanenitrile [ka] To a solution of 2,2-dimethylbutanal (3.0 g, 29.95 mmol) in THF (100 mL) was added (R)-(-)-2-phenylglycinol (4.11 g, 29.95 mmol). The reaction was stirred at 15 °C for 2 h. After cooling to 0 °C, trimethylsilyl cyanide (5.94 g, 59.9 mmol) was added dropwise at 0 °C over 15 min. The resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated, and the residue was purified by silica gel column eluted with PE up to PE / EtOAc = 4 / 1 to give 2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanenitrile (5.0 g) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:247.2.

[0244] Step 4: Preparation of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanoic acid [ka] To a solution of 2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanoic acid (5.0 g, 18.84 mmol) in acetic acid (10 mL) was added concentrated HCl (20.0 mL). The reaction was stirred at 80 °C for 12 h. The reaction solution was concentrated, and the residue was purified by preparative HPLC (Phenomenex Luna C18 (250 × 70 mm, 10 μm), water (0.1% HCl)-CAN, 20–30%, 140 mL / min) to give (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanoic acid (2.5 g) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ:ppm 7.40-7.32(m,5H),5.31-5.05(m,1H),3.69-3.52(m,3H),2.77(s,1H),1.39-1.24(m,2H),0.88-0.81(m,6H),0.57(t,J=7.6 Hz,3H). MS measured value (ESI + )[(M+H) + ]:266.1.

[0245] Step 5: Preparation of (2S)-2-amino-3,3-dimethyl-pentanoic acid [ka] To a solution of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanoic acid (2.5 g, 9.42 mmol) in methanol (60 mL) and acetic acid (40 mL) was added Pd(OH) (750 mg). The suspension was degassed three times with H and stirred under a H balloon at 20 °C for 16 h. The suspension was filtered and the filtrate was concentrated in vacuo to give (2S)-2-amino-3,3-dimethyl-pentanoic acid; acetic acid (1.93 g) as a white solid. MS measured value (ESI + )[(M+H) + ]:146.2.

[0246] Step 6: Preparation of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid [ka] To a solution of (2S)-2-amino-3,3-dimethyl-pentanoic acid; acetic acid (1.78 g, 8.67 mmol) in THF (40 mL) and water (40 mL), Na2CO3 (4.59 g, 43.33 mmol) and (Boc)2O (2.84 g, 12.99 mmol) were added successively. The suspension was stirred at 20 °C for 12 h. The suspension was diluted with HO (40 mL) and extracted with EtOAc (50 mL × 3). The aqueous phase was acidified to pH = 4 with 1 N HCl and extracted with EtOAc (50 mL × 3). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (1.8 g, Intermediate 25) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ:ppm 5.05-5.04(m,1H),4.21(d,J=9.2 Hz,1 H),2.11(s,1H),1.46(s,9H),1.50(q,J=7.2 Hz,2H),0.97(s,6H),0.91(t,J=7.2 Hz,3H). MS measured value (ESI + ) [(M+Na) + ]:268.1.

[0247] Intermediate 26 Benzyl N-amino-N-(3-amino-3-oxo-propyl)carbamate [ka] Step 1: Preparation of tert-butyl N-[(3-amino-3-oxo-propyl)amino]carbamate [ka] To a solution of tert-butyl hydrazine carboxylate (10.0 g, 75.67 mmol) in iPrOH (100 mL) was added acrylamide (5.38 g, 75.67 mmol). The reaction mixture was stirred at 70 °C for 3 hours. The mixture was concentrated, and the residue was dissolved in ethyl acetate (60 mL), washed with 1 N HCl (30 mL), brine (20 mL), and dried over anhydrous Na SO . After filtration and concentration, tert-butyl 2-(3-amino-3-oxopropyl)hydrazine-1-carboxylate (8 g) was obtained as a colorless oil.

[0248] Step 2: Preparation of benzyl N-(3-amino-3-oxo-propyl)-N-(tert-butoxycarbonylamino)carbamate [ka] To a solution of tert-butyl 2-(3-amino-3-oxopropyl)hydrazine-1-carboxylate (1.2 g, 5.9 mmol) was added benzyl (2,5-dioxopyrrolidin-1-yl)carbonate (1.47 g, 5.9 mmol) in DMF (30 mL) at 25 °C. The mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with HO (100 mL) and extracted with EtOAc (100 mL × 3). The organic phase was washed with brine (80 mL × 3), dried over NaSO, and concentrated in vacuo. The residue was purified on a silica gel column eluted with DCM to DCM / MeOH = 10 / 1 to give benzyl N-(3-amino-3-oxopropyl)-N-(tert-butoxycarbonylamino)carbamate (580 mg) as a white solid. MS measured value (ESI + ) [(M+Na) + ]:360.1.

[0249] Step 3: Preparation of benzyl N-amino-N-(3-amino-3-oxo-propyl)carbamate; 2,2,2-trifluoroacetic acid [ka] To a solution of benzyl N-(3-amino-3-oxo-propyl)-N-(tert-butoxycarbonylamino)carbamate (500 mg, 1.48 mmol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at 20° C. for 1 hour. The mixture was concentrated in vacuo to give benzyl N-amino-N-(3-amino-3-oxo-propyl)carbamate 2,2,2-trifluoroacetic acid (520 mg, Intermediate 26) as a yellow oil, which was used directly for the next step.

[0250] Intermediate 27 trans-Methyl 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate [ka] Step 1: Preparation of 1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole [ka] To a stirred solution of 13% NaClO / HO (11.78 mL) and MTBE (10 mL) was added 3-azabicyclo[3.3.0]octane hydrochloride (2.0 g, 13.55 mmol) (Accela, CAS number: 112626-50-3) at 0 °C. The reaction mixture was then stirred at 0 °C for 3 h. The reaction mixture was warmed to room temperature and diluted with MTBE (20 mL). The organic phase was added to a stirred solution of 25% wt. aqueous NaOH / HO (8.64 mL) and TBAB (280.0 mg, 0.870 mmol). The mixture was stirred at room temperature for 1 h and at 50 °C for 48 h. The reaction mixture was cooled to room temperature and washed with 20% brine (10 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole (1.23 g) as a white solid. 1H NMR(400 MHz,CDCl3)δ:ppm 7.31(s,1H),4.10-4.03(m,1H),3.57-3.51(m,1H),3.29(t,J=8.0 Hz,1 H),2.71-2.63(m,1H),1.70-1.65(m,3H),1.60-1.54(m,1H),1.42-1.38(m,1H),1.30-1.26(m,1H).

[0251] Step 2: Preparation of trans-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carbonitrile [ka] To a solution of 1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole (1.23 g, 11.27 mmol) in DCM (10 mL) was slowly added methanol (1.23 mL), followed by TMSCN (2.79 g, 28.17 mmol) at 0 °C. The mixture was stirred at 10 °C for 3 h. The reaction mixture was concentrated in vacuo, and the residue was purified on a silica gel column eluted with PE up to PE / EtOAc = 1 / 1 to give trans-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carbonitrile (1.2 g) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ:ppm 3.67(d,J=2.4 Hz,1 H),3.24(dd,J=10.0 Hz,7.6 Hz,1 H),2.83-2.76(m,2H),2.72-2.64(m,1H),1.99-1.82(m,3H),1.70-1.61(m,1H),1.49-1.43(m,1H),1.41-1.33(m,2H).

[0252] Step 3: Preparation of trans-methyl 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate [ka] A solution of (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carbonitrile (1.2 g, 8.81 mmol) in HCl / MeOH (11.0 mL, 4N) was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to remove HCl / MeOH. The residue was diluted with EtOAc (80 mL) and washed with a saturated aqueous solution of Na2CO3 (40 mL). The aqueous layer was extracted with EtOAc (50 mL × 5). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give trans-methyl 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate (1.1 g, Intermediate 27) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ:ppm 3.73(s,3H),3.31-3.27(m,2H),2.62-2.57(m,2H),2.52-2.48(m,1H),2.15(br s,1H),1.78-1.74(m,1H),1.67-1.56(m,4H),1.44-1.38(m,1H).

[0253] Intermediate 28 (2S)-2-Chloro-2-fluoroacetyl chloride [ka] Step 1: Preparation of (2S)-2-chloro-2-fluoro-acetic acid [ka] To a solution of 2-chloro-2-fluoroacetic acid (160.0 g, 1.42 mol) in EtOAc (600 mL) was added a solution of (R)-1-phenylethanamine (186.1 g, 1.54 mol) in EtOAc (600 mL) 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 slowly cooled to 30 °C and stirred at 30 °C for 16 hours. The trituration was repeated four times. Optical rotation (3.8 g / 100 mL, salt in MeOH at C = 25 °C) indicated 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 phases were dried over Na2SO4, filtered and concentrated to give (2S)-2-chloro-2-fluoro-acetic acid (138.88 g) as a brown liquid. 1 H NMR(400 MHz,CDCl3)δ:ppm 10.12(s,1H),6.26(d,J=50.4 Hz,1H).

[0254] Step 2: Preparation of (2S)-2-chloro-2-fluoro-acetyl chloride [ka] To PCl5 (28.5 g, 136.65 mmol) was added (2S)-2-chloro-2-fluoro-acetic acid (21.3 g, 124.02 mmol) dropwise with stirring under N2 at 0 °C for 1 h (the internal temperature of the suspension did not exceed 5 °C). The suspension was warmed to 25 °C over 30 min and stirred at 25 °C for 1 h to obtain a clear solution. The solution was heated to 70 °C and stirred at 70 °C for 1 h. 1 H-NMR showed that the starting material was completely consumed and the desired product was formed. The mixture was purified by distillation (70 °C, 30 mmHg) to give (2S)-2-chloro-2-fluoroacetyl chloride (42.0 g, Intermediate 28) as a colorless liquid. 1H NMR(400 MHz,CDCl3)δ:ppm 6.47-6.24(m,1H).

[0255] Alternative synthesis methods: [ka] To a solution of (2S)-2-chloro-2-fluoro-acetic acid (1478 mg, 7.89 mmol, 60% purity) in DCM (15 mL) was added oxalyl chloride (841 mg, 6.62 mmol) and 5 drops of DMF at 0° C. The mixture was then stirred at 25° C. for 1 h. The crude product was used in the next step without further purification.

[0256] Intermediate 29 Methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid [ka] Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a solution of Boc-L-isoleucine (25.0 g, 108.09 mmol) in DMF (200 mL) was added DIPEA (69.88 g, 540.62 mmol). After cooling to 0 °C, HATU (51.5 g, 135.44 mmol) and methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (23.37 g, 113.65 mmol) were added to the mixture. The reaction mixture was then stirred at 15 °C for 12 hours. The reaction mixture was poured into water (300 mL) and extracted with EtOAc (300 mL × 3). The combined organic phase was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column eluted with PE / EtOAc=5 / 1 to give methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (35.0 g) as a yellow oil. MS observed value (ESI+) [(M+H) + ]:383.2.

[0257] Step 2: Preparation of methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid [ka] To a solution of methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (5.0 g, 13.07 mmol) in DCM (30 mL) was added TFA (30.0 mL). The reaction mixture was stirred at 25 °C for 30 minutes. The reaction mixture was concentrated in vacuo to give methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (5.0 g, Intermediate 29) as a yellow oil. MS observed value (ESI+) [(M+H) + ]:283.4.

[0258] Intermediate 30 Methyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 29, using (2S)-2-(tert-butoxycarbonylamino)-3-ethyl-pentanoic acid (KaiXin Biological, CAS number: 35264-04-1) instead of Boc-L-isoleucine to give methyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 30) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:297.0.

[0259] Intermediate 31 Benzyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; Hydrochloride [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (2S)-2-(tert-butoxycarbonylamino)-3-ethyl-pentanoic acid (KaiXin Biological, CAS number: 35264-04-1) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to give benzyl (1R,2S,5S)-3-[(2S)-2-amino-3-ethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (Intermediate 31) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:373.4.

[0260] Intermediate 32 Benzyl (2S)-1-[(2S)-2-amino-3-ethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; Hydrochloride [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (2S)-4,4-dimethylpyrrolidine-2-carboxylic acid; hydrochloride (Porse Fine Chemical, CAS number: 1443252-76-3) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride, and (2S)-1-tert-butoxycarbonyl-4,4-dimethyl-pyrrolidine-2-carboxylic acid instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, to give benzyl (2S)-1-[(2S)-2-amino-3-ethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride (Intermediate 32) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:361.3.

[0261] Intermediate 33 (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid [ka] Preparation of (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid [ka] To a solution of (2S)-2-amino-3,3-dimethyl-pentanoic acid; acetic acid (900 mg, 4.38 mmol, from Intermediate 25, Step 5) in water (10 mL) and THF (10 mL) was added Na2CO3 (1.4 g, 13.21 mmol). After cooling to 0 °C, CbzCl (1.13 g, 6.62 mmol) was added to the mixture. The reaction mixture was stirred at 20 °C for 12 h. The suspension was diluted with H2O (20 mL) and extracted with EtOAc (40 mL). The aqueous phase was acidified to pH = 2 with 1 N HCl and extracted with EtOAc (40 mL × 3). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by back-flash (conditions: 120 g flash column Welch Ultimate XB_C18 20-40 μm; 120A, water (0.1% TFA)-ACN, 30-60%, 65 ml / min) to give (2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-pentanoic acid (440.0 mg) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:280.1.

[0262] Intermediate 34 Benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; hydrochloride [ka] Similar to the procedure described for the preparation of intermediate 1, (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid was used in place of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, and (2S)-2-(tert-butoxycarbonylamino) The title compound was prepared using (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 25) instead of -3,3-dimethyl-butanoic acid to give benzyl (3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (Intermediate 34) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:373.2.

[0263] Intermediate 35 Benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; Hydrochloride [ka] Similar to the procedure described for the preparation of intermediate 1, (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; (2S)-4,4-dimethylpyrrolidine-2-carboxylic acid; hydrochloride (Porcelain Fine Hydrochloride) was used instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; The title compound was prepared by using (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 25) in place of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (BePharm, CAS number: 62965-35-9) and (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (BePharm, CAS number: 62965-35-9) to give benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate; hydrochloride (Intermediate 35) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:361.2.

[0264] Intermediate 36 Benzyl 1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3-dimethyl-pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid [ka] The title compound was prepared in a similar manner to the procedure described for the preparation of Intermediate 1, using 3,3-dimethylpyrrolidine-2-carboxylic acid; hydrochloride (Chengdu Asta Tech, CAS number: 61406-78-8) instead of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride to give benzyl 1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3-dimethyl-pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 36) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:347.2.

[0265] Intermediate 37 (1R,2S,5S)-3-[(2S)-2-amino-2-cyclobutyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (2S)-2-(tert-butoxycarbonylamino)-2-cyclobutyl-acetic acid (GL Biochem, CAS number: 155905-77-4) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to give (1R,2S,5S)-3-[(2S)-2-amino-2-cyclobutyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 37) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:357.2.

[0266] Intermediate 38 Benzyl (2S,4R)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetaldehyde [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (2S,4R)-1-tert-butoxycarbonyl-4-(trifluoromethyl)pyrrolidine-2-carboxylic acid (PharmaBlock, CAS number: 470482-44-1) instead of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid and Boc-Ile-OH instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to give benzyl (2S,4R)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate; 2,2,2-trifluoroacetaldehyde (Intermediate 38) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:387.1.

[0267] Intermediates 39a and 39b Tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate and tert-butyl N-amino-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate [ka] and [ka]

[0268] Step 1: Preparation of tert-butyl 3-methylene-2-oxo-piperidine-1-carboxylate [ka] To a solution of 1-Boc-2-piperidone (45.0 g, 225.85 mmol, Bidepharm, CAS number: 85908-96-9) in THF (500 mL) was added LiHMDS (474.3 mL, 474.3 mmol) at 0 °C under a N atmosphere. The reaction mixture was stirred at 20 °C for 30 minutes and then cooled to 0 °C. To the mixture was added 2,2,2-trifluoroethyl trifluoroacetate (62.75 g, 320.06 mmol) at 0 °C. The mixture was then stirred at 20 °C for 50 minutes. The reaction was quenched with saturated NH Cl (500 mL) and extracted with EtOAc (300 mL × 2). The organic layer was washed with brine (100 mL × 3), dried over Na SO , filtered, and concentrated in vacuo. The residue was dissolved in toluene (500 mL). To the solution was added paraformaldehyde (20.3 g, 677.54 mmol) and K2CO3 (68.7 g, 496.86 mmol). The reaction mixture was stirred at 110 °C under a N2 atmosphere for 2 hours. The reaction was diluted with EtOAc (250 mL) and water (250 mL). The mixture was extracted with EtOAc (200 mL x 2). The organic layer was washed with brine (150 mL x 3), dried over Na2SO4, filtered, and concentrated in vacuo to give tert-butyl 3-methylene-2-oxo-piperidine-1-carboxylate (26.5 g, crude) as a yellow oil. MS measured value (ESI + )[(M-tBu+H) + ]:156.0.

[0269] Step 2: Preparation of tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-piperidine-1-carboxylate [ka] To a solution of tert-butyl 3-methylene-2-oxo-piperidine-1-carboxylate (26.5 g, 125.4 mmol) in i-PrOH (300 mL) was added benzyl carbazate (20.85 g, 125.44 mmol). The mixture was degassed with N2 three times. The resulting mixture was stirred at 85 °C for 12 h. The mixture was concentrated in vacuo to give tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-piperidine-1-carboxylate (47.3 g, crude) as a yellow oil. MS measured value (ESI + ) [(M-Boc+H) + ]:278.4.

[0270] Step 3: Preparation of benzyl N-[(2-oxo-3-piperidyl)methylamino]carbamate; 2,2,2-trifluoroacetic acid [ka] To a solution of tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-piperidine-1-carboxylate (47.3 g, 125.3 mmol) in DCM (320 mL) was added TFA (250.0 mL). The mixture was stirred at 20° C. for 30 minutes and concentrated in vacuo to give benzyl N-[(2-oxo-3-piperidyl)methylamino]carbamate; 2,2,2-trifluoroacetic acid (49.0 g, crude) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:278.1.

[0271] Step 4: Preparation of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxo-3-piperidyl)methyl]carbamate [ka] To a solution of benzyl N-[(2-oxo-3-piperidyl)methylamino]carbamate; 2,2,2-trifluoroacetic acid (49.0 g, 125.2 mmol) in methanol (500 mL) was added DIPEA (80.9 g, 626.1 mmol) and BocO (32.9 g, 162.8 mmol) at 0° C. The mixture was then stirred at 50° C. for 12 hours and at 80° C. for another 12 hours. The resulting mixture was concentrated in vacuo, and the residue was purified by reverse flash and silica gel column chromatography to give tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxo-3-piperidyl)methyl]carbamate (3.07 g) as a pale yellow solid. Ten grams of the racemic product was resolved by preparative SFC (sample preparation: add 400 mL of MeOH to sample; instrument: Thr 80; mobile phase: 45% MeOH in supercritical CO (NEU); flow rate: 70 g / min; cycle time: 4.62 min, total time: 600 min; single injection volume: 3.5 mL; back pressure: 100 bar to keep the CO supercritical) to give tert-butyl N-(benzyloxycarbonylamino)-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate (retention time: 3.49 min) (4.1 g) and tert-butyl N-(benzyloxycarbonylamino)-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (retention time: 4.83 min) (4.2 g) as yellow oils. MS observed value (ESI+) [(M+H) + ]:378.2.

[0272] Step 5: Preparation of tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate [ka] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxo-3-piperidyl)methyl]carbamate (1.0 g, 2.65 mmol) in methanol (20 mL) was added Pd(OH) (50 mg) and Pd / C (50 mg, 10% purity) under a N atmosphere. The suspension was degassed with H three times. The resulting mixture was stirred under a H balloon at 25 °C for 12 h. The suspension was filtered, and the filtrate was concentrated in vacuo to give racemic tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate (570 mg, racemic) as a pale yellow oil. MS measured value (ESI + ) [(M-Boc+H) + ]:144.2.

[0273] Step 6: Preparation of tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate [ka] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (3.6 g, 9.54 mmol) in methanol (40 mL) were added Pd(OH) (200 mg) and Pd / C (200.0 mg, 10% purity). The mixture was degassed three times with H and stirred under a H balloon at 25 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (2.3 g, Intermediate 39a) as a colorless oil. MS observed value (ESI+) [(M+H) + ]:244.4.

[0274] Step 7: Preparation of tert-butyl N-amino-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate [ka] To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (3.6 g, 9.54 mmol) in methanol (20 mL) were added Pd(OH) (360 mg) and Pd / C (360 mg, 10% purity). The mixture was degassed three times with H and stirred under a H balloon at 25 °C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (2.3 g, Intermediate 39b) as a colorless oil. MS observed value (ESI+) [(M-Boc+H)+]: 144.2.

[0275] Intermediate 39a was used to prepare N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoroacetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide (Example 165a), which was crystallized and analyzed by single-crystal X-ray diffraction (Figure 1), confirming the absolute configuration of intermediate 39a as the (S)-configuration and the corresponding precursor tert-butyl N-(benzyloxycarbonylamino)-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate. The enantiomer of 39a was designated as the (R)-configuration (39b).

[0276] The procedure for preparing N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide was as follows:

[0277] Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a solution of Boc-Ile-OH (96.0 g, 415.06 mmol) in DMF (192 mL) and MeCN (1536 mL), methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; hydrochloride (89.64 g, 435.82 mmol) and HATU (173.6 g, 456.57 mmol) were added at 0 °C under N to give a colorless solution, followed by the dropwise addition of DIPEA (216.88 mL, 1245.19 mmol) at 0 °C under N to give a pale yellow solution. The reaction was then warmed to 20 °C, stirred under N for 16 h, and concentrated in vacuo. The residue was added to ethyl acetate (2400 mL) and water (3600 mL). The resulting suspension was filtered, the filter cake was washed with ethyl acetate (500 mL), and the filter cake was dried in vacuo to give methyl (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (75.0 g) as a white solid. MS measured value (ESI + )[(M+H) + ]:383.2.

[0278] Step 2: Preparation of (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-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-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (50.0 g, 130.72 mmol) in THF (500 mL) was added a solution of LiOH.HO (10.97 g, 261.4 mmol) in water (500 mL). The mixture was then stirred at 25 °C for 2 h. The reaction mixture was poured into ice / water (300 mL) and acidified to pH = 5 with 12 N HCl. The mixture was then extracted with EA (500 mL × 2). The combined organic phases were washed with brine (100 mL), dried over NaSO and concentrated in vacuo to give (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (48.1 g) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:369.2.

[0279] Step 3: Preparation of (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride salt [ka] To a solution of (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methylpentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (48.1 g, 130.54 mmol) in DCM (500 mL) was added HCl / dioxane (500 mL, 2000.0 mmol). The mixture was stirred at 25 °C for 2 hours and concentrated in vacuo to give (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methylpentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride salt (39.8 g) as a yellow foam.

[0280] Step 4: Preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a solution of (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (39.79 g, 130.54 mmol) in methanol (400 mL) was added dropwise triethyl ether (TEA) (79.26 g, 783.24 mmol) followed by the addition of ethyl trifluoroacetate (55.64 g, 391.62 mmol) at 0° C. The mixture was then warmed to 50° C. and stirred at 50° C. for 12 hours. The mixture was diluted with EtOAc (500 mL), washed with brine (300 ml), dried over NaSO, and concentrated to give (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (45.0 g) as a yellow foam. MS measured value (ESI + )[(M+H) + ]:365.1.

[0281] Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate [ka] To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg, 0.41 mmol) in DMF (5 mL) was added DIPEA (266 mg, 2.06 mmol). After cooling to 0 °C, the mixture was added HOPO (55 mg, 0.49 mmol), EDCI (157 mg, 0.49 mmol), and tert-butyl N-amino-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (100 mg, 0.41 mmol). The mixture was then stirred at 30 °C for 12 h. The resulting mixture was poured into water (30 mL) at 25 °C with stirring and extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine (40 mL × 2), followed by 1 N HCl (50 mL), 10% aqueous KCO (50 mL), and brine (30 mL), dried over NaSO, and concentrated in vacuo to give tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (242 mg) as a white solid. MS measured value (ESI + )[(M+H) + ]:590.5.

[0282] Step 6: Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxo-3-piperidyl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate (242 mg, 0.41 mmol) in DCM (6 mL) was added TFA (3.0 mL). The mixture was stirred at 25 °C for 1 h. The resulting mixture was concentrated in vacuo, and the residue was purified by back-flush (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,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxo-3-piperidyl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; hydrochloride salt (182 mg) as a white solid. MS measured value (ESI + )[(M+H) + ]:490.2.

[0283] Step 7: Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide [ka] To a solution of (2R)-2-chloro-2-fluoro-acetic acid (126 mg, 0.69 mmol) in DCM (2 mL), POCl (95 mg, 0.62 mmol) was added. The solution was stirred at 25 °C for 1 hour. The resulting solution was added dropwise to a solution of N-[(1S,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxo-3-piperidyl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; hydrochloride (182 mg, 0.35 mmol) and DIPEA (447 mg, 3.46 mmol) in DCM (2 mL) at -5 °C. The mixture was stirred at the same temperature for 1 hour. The reaction was quenched with methanol (2 mL) and 4 N HCl / dioxane (2 mL) at −5° C. The resulting mixture was concentrated in vacuo at room temperature. The residue was purified by back-flash (120 g flash column; Welch Ultimate XB_C18 20–40 μm; 35 min; 75 mL / min, ACN-water, 0.1% FA) to give N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide (120 mg) as a white solid.

[0284] 2 mg of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide was crystallized in a mixed solvent of MeOH and water (0.2 ml, v / v=4 / 1) at room temperature to obtain transparent crystals. 1 H NMR (400 MHz, DMSO- d6)δ ppm 11.16(s,1H),9.97(d,J=7.6 Hz,1H),7.57(s,1H),6.90-6.70(m,1H),4.21(dd,J=10.4 Hz,7.6 Hz,1H),4.15(s,1H),4.00(dd,J=14.0 Hz,9.6 Hz,1H),3.94-3.83(m,2H),3.46(dd,J=13.6 Hz,4.0 Hz,1H),3.15-3.07(m,2H),2.48-2.42(m,1H),1.99-1.88(m,1H),1.87-1.73(m,2H),1.69-1.65(m,1 H),1.63-1.54(m,1H),1.53-1.40(m,3H),1.17-1.08(m,1H),1.06(s,3H),0.92(s,3H),0.87(d,J=6.8 Hz,3H),0.82(d,J=7.2 Hz,3H). MS measured value (ESI + )[(M+H) + ]:584.2.

[0285] Intermediate 40 Benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 25) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to give benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 40) as a yellow oil.

[0286] Intermediate 41 Benzyl (3S,3aS,6aR)-2-[(2S,3S)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; hydrochloride [ka] Similar to the procedure described for the preparation of intermediate 1, (3S,3aS,6aR)-2-tert-butoxycarbonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid was used in place of (1R,2S,5S)-3-tert-butoxycarbonyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid, and (2S)-2-(t The title compound was prepared using Boc-Ile-OH instead of (3S,3aS,6aR)-2-[(2S,3S)-2-amino-3-methyl-pentanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate; hydrochloride (Intermediate 41) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:359.3.

[0287] Intermediate 42 Benzyl (1R,2S,5S)-3-[(2S)-2-amino-4,4-dimethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid [ka] The title compound was prepared by a procedure similar to that described for the preparation of Intermediate 1, using (2S)-2-(benzyloxycarbonylamino)-4,4-dimethyl-pentanoic acid (Intermediate 20) instead of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid to give benzyl (1R,2S,5S)-3-[(2S)-2-amino-4,4-dimethyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate; 2,2,2-trifluoroacetic acid (Intermediate 43) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:373.3.

[0288] Intermediate 43 (2S)-4,4-Dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid [ka] Step 1: Preparation of O1-tert-butyl O2-methyl(2S)-4,4-dimethylpyrrolidine-1,2-dicarboxylate

[0289] To a solution of 2S)-1-tert-butoxycarbonyl-4,4-dimethyl-pyrrolidine-2-carboxylic acid (500 mg, 2.06 mmol) in DMF (10 mL) was added K2CO3 (852.07 mg, 6.17 mmol) and MeI (875 mg, 6.17 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (40 mL) and acidified to pH = 4 with 1 N HCl. The resulting mixture was extracted with EtOAc (50 mL × 2). The combined organic phases were washed with brine (60 mL), dried over Na2SO4, and concentrated in vacuo to give O1-tert-butyl O2-methyl(2S)-4,4-dimethylpyrrolidine-1,2-dicarboxylate (528 mg) as a colorless oil.

[0290] Step 2: Preparation of (2S)-4,4-dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid [ka] To a solution of O1-tert-butyl O2-methyl(2S)-4,4-dimethylpyrrolidine-1,2-dicarboxylate (528 mg, 2.05 mmol) in DCM (5 mL) was added TFA (2.5 mL). The mixture was stirred at 25° C. for 2 hours. The mixture was concentrated in vacuo to give methyl(2S)-4,4-dimethylpyrrolidine-2-carboxylate; 2,2,2-trifluoroacetic acid (556 mg) as a yellow oil.

[0291] Example 1 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] Step 1: Preparation of benzyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a solution of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (970 mg, 2.71 mmol, Intermediate 1) in THF (20 mL) was added TEA (601 mg, 5.95 mmol) and TFAA (1131 mg, 5.41 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (80 mL × 2). The organic layer was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column eluted with PE to EtOAc / PE=10 / 1 to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.2 g) as a colorless oil. MS measured value (ESI + ) [M+H] + :455.3.

[0292] Step 2: Preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a solution of benzyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.2 g, 2.64 mmol) in MeOH (20 mL) was added Pd / C (200 mg, 10% purity). The mixture was degassed under vacuum and purged with H2 three times. The reaction mixture was stirred under a H2 balloon at 25 °C for 1 h. The mixture was filtered through a Celite pad, and the pad was washed with MeOH (10 mL × 3). The filtrate was concentrated in vacuo to give (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (960 mg) as a white solid. MS measured value (ESI + ) [M+H] + :365.2.

[0293] Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of (1R,2S,5S)-3-((2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (10 mg, 0.270 mmol) in DMF (10 mL) was added EDCI (63 mg, 0.330 mmol), HOPO (37 mg, 0.330 mmol), DIPEA (177 mg, 1.37 mmol), and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (63 mg, 0.270 mmol, Intermediate 9). The reaction mixture was stirred at 25 °C for 12 h. The mixture was diluted with EtOAc (100 mL) and washed with water (30 mL) and brine (30 mL × 3). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified on a silica gel column eluted with MeOH / DCM = 10 / 1 to give tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (110 mg) as a colorless oil. MS measured value (ESI + ) [M+H] + :576.3.

[0294] Step 4: Preparation of N-((1S)-1-((1R,2S,5S)-6,6-dimethyl-2-(2-(((3S)-2-oxopyrrolidin-3-yl)methyl)hydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3,3-dimethyl-1-oxobutan-2-yl)-2,2,2-trifluoroacetamide [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (110 mg, 0.190 mmol) in DCM (4 mL) was added TFA (4 mL). The reaction mixture was stirred at 25° C. for 1 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: YMC Triart 30 × 150 mm × 7 μm; condition: ACN (0.1% HCl) in water = 31-51%; flow rate (mL / min): 25) to give N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (80 mg) as a white solid. MS measured value (ESI + ) [M+H] + :476.2.

[0295] Step 5: Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 1) [ka] To a solution of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (80 mg, 0.170 mmol) in THF (20 mL) was added DIPEA (260 mg, 2.02 mmol) and (2R)-2-chloro-2-fluoro-acetyl chloride (110 mg, 0.840 mmol, Intermediate 10). The reaction mixture was stirred at 0 °C for 1 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (column: Phenomenex Synergi Polar-RP 100 × 25 mm × 4 μm; condition: ACN (0.1% TFA) in water = 50-70%; flow rate (mL / min): 25) to give N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (38.5 mg, Example 1) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ:ppm 11.18(s,1H),9.50(d,J=8.0 Hz,1H),7.75(s,1H),6.90(d,J=50.8 Hz,1H),4.40(d,J=8.0 Hz,1H),4.16(s,1H),3.96-3.92(m,1H),3.82-3.69(m,2H),3.47-3.48(m,1H),3.21-3.12(m,2 H),2.60-2.56(m,1H),2.20-2.08(m,1H),1.79-1.74(m,1H),1.69-1.59(m,1H),1.54(d,J=7.6 Hz,1H),1.04(s,3H),0.98(s,9H),0.92-0.86(m,3H) MS measured value (ESI + ) [M+H] + :570.2.

[0296] Example 2 N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide [ka] Analogously to the procedure described for the preparation of Example 1, benzyl (1R,2S,5S)-3-[(2S)-2-amino-2-cyclopropyl-acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate was used instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1). The title compound was prepared using (Intermediate 2) to give N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 2) as a white solid. 1H NMR(400 MHz, CDCl3)δ:ppm 10.22(s,1H),7.50-7.49(m,1H),6.65-6.52(m,1H),6.22(s,1H),4.59-4.54(m,1H),4.38-4.34(m,2H),4.01-3.97(m,1H),3.82(d,J=8.8 Hz,1 H),3.41-3.39(m,2H),2.92-2.81(m,2H),2.42-2.36(m,1H),1.70-1.69(m,1H),1.41-1.39(m,1H),1.20-1.19(m,1H) ),1.14(s,0.5H),1.07(s,3H),1.00(s,0.5H),0.92(s,3H),0.61-0.59(m,2H),0.55-0.52(m,1H),0.46-0.42(m,1H) MS measured value (ESI + )[(M+H) + ]:554.2.

[0297] Example 3 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide [ka] Step 1: Preparation of methyl (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a solution of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid (322 mg, 1.22 mmol), methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (250 mg, 1.22 mmol) in DCM (5 mL) was added DIPEA (471 mg, 3.65 mmol) and HATU (343 mg, 1.46 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated in vacuo, and the residue was purified by back-flush eluting with ACN in HO (0.1% 3.0% HO) = 0 to 70% to give (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (330 mg) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:417.2.

[0298] Step 2: Preparation of (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-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)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (330 mg, 0.790 mmol) in THF (3 mL) and water (3 mL) was added LiOH·HO (33 mg, 0.790 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with 30 mL of water and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with 40 mL of brine, dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by silica gel column eluted with PE / EtOAc = 10 / 1 to 3 / 1 to give (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (310 mg) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:403.1.

[0299] Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (310 mg, 0.770 mmol) in DMF (6 mL) was added DIPEA (497 mg, 3.85 mmol), EDCI (177 mg, 0.920 mmol), HOPO (103 mg, 0.920 mmol), and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (194 mg, 0.850 mmol, Intermediate 9). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (40 mL), dried over NaSO, filtered, and concentrated. The residue was purified on a silica gel column eluted with PE / EtOAc = 10 / 1 to 3 / 1 to give tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (460 mg) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:614.1.

[0300] Step 4: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (460 mg, 0.750 mmol) in MeOH (6 mL) was added Pd / C (150 mg). The mixture was degassed under vacuum and purged with H2 three times. The resulting mixture was stirred under H2 at 25 °C for 2 h. The reaction mixture was filtered through a Celite pad, and the pad was washed with MeOH (30 mL). The filtrate was concentrated in vacuo to give tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (310 mg) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:480.4.

[0301] Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-4-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-4-methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (310 mg, 0.65 mmol) in THF (5 mL) was added TEA (163 mg, 1.62 mmol) and TFAA (0.14 mL, 0.970 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL × 2). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by silica gel column eluted with PE / EtOAc = 20 / 1 to 5 / 1 to give tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-4-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (310 mg) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:576.4.

[0302] Step 6: Preparation of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-4-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (310 mg, 0.54 mmol) in DCM (5 mL) was added TFA (5.0 mL). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo. The residue was purified by back-flush eluting with 0-70% ACN (0.1% HCl) in HO to give N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; hydrochloride (170 mg) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:476.2.

[0303] Step 7: Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide (Example 3) [ka] To a solution of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; hydrochloride (170 mg, 0.36 mmol) in THF (60 mL) was added DIPEA (553 mg, 4.29 mmol) and (2R)-2-chloro-2-fluoro-acetyl chloride (234 mg, 1.79 mmol, Intermediate 10) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (0.1% TFA, Phenomenex luna C18 150 × 40 mm × 15 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 35% to 65%, 10 min) to give N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide (20 mg, Example 3) as an off-white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 6.87-6.68(d,1H),4.60(dd,J=4.8,9.6 Hz,1H),4.28(s,1H),4.06(dd,J=8.4,14.0 Hz,1H),3.99-3.87(m,2H),3.59(dd,J=4.8,14.0 Hz,1H),3.43-3.34(m,2H),2.74(dq,J=4.8,8.8 Hz,1H),2.38-2.25(m,1H),2.10-1.96(m,1H),1.75-1.57(m,5H),1.13(s,3H),1.06(s,3H),0.99(dd,J=6.0,11.6 Hz,6H) MS measured value (ESI + )[(M+H) + ]:570.1.

[0304] Example 4 N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] Example 4 Similar to the procedure described for the preparation of Example 1, benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) was replaced with 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. The title compound was prepared using this compound (Intermediate 3) to give N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 4) as an off-white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 7.16-6.66(m,1H),4.72-4.60(m,1H),4.09(d,J=5.6 Hz,1H),4.06-3.95(m,2H),3.78(dd,J=3.2,10.4 Hz,1H),3.59(dd,J=4.8,14.4 Hz,1H),3.42-3.33(m,2H),2.94-2.83(m,1H),2.83-2.75(m,1H),2.74(b r.s,1H),2.39-2.21(m,1H),2.09-1.70(m,6H),1.52(m,1H),1.08(s,9H). MS measured value (ESI+ )[(M+H) + ]:570.3.

[0305] Example 5 N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] Similar to the procedure described for the preparation of Example 1, benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) was replaced with benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3-azabicyclo[3.2.0]heptane-2-carboxylate. The title compound was prepared using this compound (Intermediate 4) to give N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 5) as a white solid. 1 H NMR(400 MHz,CDCl3)δ:ppm 9.83(br,s,1H),7.32-7.28(m,1H),6.62(d,J=50.4 Hz,1H),6.42(br,s,1H),4.88-4.85(m,1H),4.81(d,J=9.6Hz,1H),4.35(m,1H),3.96-3.93(m,2H) ,3.45-3.41(m,2H),3.20(m,1H),2.90(m,3H),2.39-2.35(m,2H),1.85-1.81(m,4H),1.05(s,9H). MS measured value (ESI + )[(M+H)+ ]:556.3.

[0306] Example 6 N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] Analogously to the procedure described for the preparation of Example 1, benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) was replaced with benzyl (6S)-5-[(2S)-2-amino-3,3-dimethyl-butanoyl]-5-azaspiro[2.4]heptane-6-carboxylate. The title compound was prepared using this compound (Intermediate 5) to give N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 6) as an off-white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 7.25-6.78(d,1H),4.68-4.60(m,1H),4.48(t,J=8.0 Hz,1H),3.98(dd,J=8.4,14.4 Hz,1H),3.87(d,J=10 Hz,1H),3.66-3.56(m,2H),3.41-3.34(m,2H),2.69(dt,J=4.0,8.8 Hz,1H),2.34-2.16(m,2H),2.07-1.96(m,2H),1.08(s,9H),0.81-0.60(m,4H) MS measured value (ESI + )[(M+H) + ]:556.3.

[0307] Example 7 N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] Analogously to the procedure described for the preparation of Example 1, benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) was replaced with benzyl (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate. The title compound was prepared using this compound (Intermediate 6) to give N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 7) as a white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 6.98(d,J=56.0 Hz,1H),4.85-4.86(m,1H),4.47-4.37(m,1H),4.06-3.94(m,2H),3.67-3.56(m,1H),3.48-3.34(m,3H),2.78- 2.68(m,1H),2.66-2.54(m,1H),2.35-2.23(m,1H),2.23-2.14(m,1H),2.11-1.86(m,2H),1.12-1.04(m,12H). MS measured value (ESI + )[(M+H) + ]:544.2.

[0308] Example 8 N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] Analogously to the procedure described for the preparation of Example 1, benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) was replaced with benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate. The title compound was prepared using this compound (Intermediate 7) to give N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 8) as a white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 7.10(d,J=50.4 Hz,1H),4.49-4.34(m,1H),4.09-3.93(m,1H),3.82-3.74(m,1H),3.64-3.55(m,1H),3.49-3.44(m,1H),3.41-3.34(m,2 H),2.74-2.65(m,1H),2.33-2.25(m,1H),2.13-1.96(m,2H),1.90-1.79(m,1H),1.23(s,3H),1.11(s,3H),1.08(s,9H). MS measured value (ESI + )[(M+H) + ]:558.2.

[0309] Example 9 N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] Similar to the procedure described for the preparation of Example 1, benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) was replaced with benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 2). The title compound was prepared using this compound (Intermediate 8) to give N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 9) as a white solid. 1 H NMR(400 MHz,CDCl3)δ:ppm 10.15(s,1H),7.33(s,1H),6.61-6.48(m,2H),4.95(s,1H),4.63(d,J=9.6 Hz,1H),4.43-4.39(m,1H),4.05-3.97(m,2H),3.44-3.41(m,2H),2.96-2.8 8(m,2H),2.42-2.36(m,1H),1.78-1.64(m,3H),1.00(s,9H),0.89(q,J1=7.6 Hz,J2=13.6Hz,1H),0.25(d,J=4.4Hz,1H) MS measured value (ESI + )[(M+H) + ]:541.9.

[0310] Example 10 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] The title compound was prepared using a procedure similar to that described for the preparation of Example 1, using tert-butyl N-amino-N-(1H-pyrazol-3-ylmethyl)carbamate (Intermediate 11) instead of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (Intermediate 9 in Step 3) to provide N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 10) as a white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 10.44-9.88(m,1H),7.52-7.50(m,1H),7.10-7.25(m,1H),6.64-6.52(m,1H),6.39(s,1H),5.39-4.94(m,1H),4.59(d,J=9.6 Hz,2 H),4.22-4.03(m,3H),3.87(d,J=10.0 Hz,1 H),1.60-1.68(m,1H),1.13-1.37(m,0.5H),1.03(br,s,12 H),0.98(br,s,0.5 H),0.82(s,3H) MS measured value (ESI + )[(M+H) + ]:553.2.

[0311] Example 11 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide [ka] The title compound was prepared using a procedure similar to that described for the preparation of Example 1, using 2,2-dimethylpropanoyl chloride instead of TFAA and DCM instead of THF to give N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide (Example 11) as an off-white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 6.92-6.79(m,2H),4.63(d,J=9.4 Hz,1H),4.25(s,1H),4.09-4.01(m,2H),3.94(br d,J=10.4 Hz,1H),3.66-3.57(m,1H),3.43-3.35(m,2H),2.86-2.64(m,1H),2.37-2.22(m,1H),2. 11-1.98(m,1H),1.73-1.64(m,2H),1.21(s,9H),1.12(s,3H),1.03(s,9H),0.96(s,3H) MS measured value (ESI + ) [(M+Na) + ]:558.2.

[0312] Example 12 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide [ka] The title compound was prepared using a procedure similar to that described for the preparation of Example 1, using cyclopropanecarbonyl chloride instead of TFAA, to give N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide (Example 12) as an off-white solid. 1 H NMR(400 MHz,CDCl3)δ:ppm 10.13(d,J=3.2 Hz,1H),6.86-6.65(m,1H),6.64-6.47(m,1H),6.21-6.15(m,1H),4.67(d,J=10.0 Hz,1H),4.56-4.22(m,2H),4.06-3.98(m,1H),3.98-3.91(m,1H),3.41(dd,J=5.2,8.8 Hz,2H),3.19-2.64(m,2H),2.47-2.34(m,1H),1.81(d,J=6.0 Hz,1H),1.56(m,4H),1.34(d,J=6.4 Hz,1H),1.05(s,3H),1.02-0.93(m,9H),0.89(s,3H),0.80-0.68(m,2H) MS measured value (ESI + )[(M+H) + ]:542.3.

[0313] Example 13 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide [ka] The title compound was prepared using a procedure similar to that described for the preparation of Example 1, using 2-methylpropanoyl chloride instead of TFAA, to give N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide (Example 13) as an off-white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 6.92(d,J=50.8 Hz,1H),4.54(s,1H),4.24(s,1H),4.09-3.94(m,3H),3.63-3.57(m,1H),3.43-3.35(m,2H),2.80-2.69(m,1H),2.66-2. 54(m,1H),2.37-2.25(m,1H),2.11-1.97(m,1H),1.74-1.63(m,2H),1.16-1.11(m,6H),1.09-1.03(m,12H),0.99(s,3H). MS measured value (ESI + )[(M+H) + ]:544.4.

[0314] Example 14 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide [ka] The title compound was prepared using a procedure similar to that described for the preparation of Example 1, using (2,2-difluoroacetyl) 2,2-difluoroacetate instead of TFAA to give N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide (Example 14) as an off-white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 7.00-6.79(m,1H),6.30-5.97(m,1H),4.53(s,1H),4.26(s,1H),4.10-4.00(m,2H),3.93(d,J=10.4 Hz,1H),3.59(br dd,J=4.4,14.4 Hz,1H),3.42-3.34(m,2H),2.75(dq,J=4.4,8.8 Hz,1H),2.37-2.25(m,1H),2.09-1.98(m,1H),1.75-1.63(m,2H),1.12(s,3H),1.08(s,9H),1.01(s,3H). MS measured value (ESI + )[(M+H) + ]:552.3.

[0315] Example 15 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide [ka] Step 1: Preparation of benzyl (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate [ka] To a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (75 mg, 0.67 mmol) in 1,2-dichloroethane (10 mL) was added N,N-diisopropylethylamine (0.33 mL, 1.9 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (290 mg, 0.76 mmol), and benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (229 mg, 0.638 mmol, Intermediate 1). The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated, and the residue was purified by silica gel column eluted with PE / EtOAc = 20 / 1 to 10 / 1 to give (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (230 mg) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:453.3.

[0316] Step 2: Preparation of (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a solution of benzyl (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (230 mg, 0.51 mmol) in methanol (10 mL) was added Pd / C (100 mg, 10% purity). The reaction mixture was degassed under vacuum and purged with H three times. The resulting mixture was stirred under a H balloon at 25 °C for 1 h. The suspension was filtered and the filtrate was concentrated in vacuo to give (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (170 mg) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:363.2.

[0317] Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (170 mg, 0.470 mmol) in DMF (2 mL) was added EDCI (108 mg, 0.56 mmol), HOPO (62 mg, 0.56 mmol), DIPEA (0.41 mL, 2.35 mmol), and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (118 mg, 0.520 mmol, Intermediate 9). The reaction mixture was stirred at 25 °C for 12 h. The mixture was diluted with EtOAc (30 mL) and washed with water (20 mL) and brine (20 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase (neutral conditions) eluting with ACN in 0-70% HO to afford tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (210 mg) as a white solid. MS measured value (ESI + )[(M+H) + ]:574.3.

[0318] Step 4: Preparation of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S-2-oxopyrrolidin-3-yl]methyl]carbamate (210 mg, 0.37 mmol) in DCM (2.8 mL) was added TFA (2.82 mL). The reaction mixture The mixture was stirred at 25° C. for 1 hour. The residue was purified by reverse-phase ACN in 0-70% HO (0.1% HCl) to give N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide (60 mg) as a yellow solid. MS measured value (ESI + )[(M+H) + ]:474.4.

[0319] Step 5: Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide (Example 15) [ka] To a solution of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide (60 mg, 0.120 mmol) in THF (10 mL) was added DIPEA (0.25 mL, 1.41 mmol) and (2R)-2-chloro-2-fluoroacetyl chloride (77 mg, 0.590 mmol, Intermediate 10). The reaction mixture was stirred at 0 °C for 1 h. The mixture was concentrated, and the residue was purified by preparative HPLC (0.1% TFA, 3_Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 45% to 65%, 9 min) to give N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide (31 mg, Example 15) as a white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 6.97-6.74(d,J=50.8 Hz,1H),4.60-4.51(m,1H),4.24(s,1H),4.10-3.98(m,2H),3.94-3.85(m,1H),3.67-3.58(m,1H),3.46-3.36(m,2H),2.81-2.67(m,1 H),2.50-2.40(m,1H),2.36-2.26(m,1H),2.09(s,6H),2.04-1.96(m,1H),1.72-1.64(m,2H),1.12(s,3H),1.03(s,9H),0.97(s,3H). MS measured value (ESI + )[(M+H) + ]:568.4.

[0320] Example 16 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide [ka] The title compound was prepared by using 5-(trifluoromethyl)isoxazole-3-carboxylic acid (Intermediate 12) instead of bicyclo[1.1.1]pentane-1-carboxylic acid in a similar manner to the procedure described for the preparation of Example 1 to give N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide (Example 16) as a yellow solid. 1 H NMR(400 MHz,CDCl3)δ:ppm 10.03-9.78(m,1H),7.69-7.46(m,1H),7.11(s,1H),6.78-6.56(m,1H),6.16-5.90(m,1H),4.72(d,J=9.6 Hz,1H),4.54-4.28(m,2H),4.07(dd,J=5.2,10.0 Hz,1H),4.00-3.90(m,1H),3.42(s,2H),3.09-2.65(m,2H),2.50-2.29(m,1H),1. 90-1.79(m,1H),1.63(s,1H),1.43-1.33(m,1H),1.08-1.03(m,12H),0.93(s,3H). MS measured value (ESI + )[(M+H) + ]:637.2.

[0321] Example 17 (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide [ka] Step 1: Preparation of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [ka] To a solution of (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid; hydrochloride (102 mg, 0.530 mmol) in water (2 mL) was added Na2CO3 (226 mg, 2.13 mmol), and a solution of 2-(3,5-difluorophenoxy)acetyl chloride (110 mg, 0.530 mmol, Intermediate 13) in THF (5 mL) was added. The mixture was stirred at 25 °C for 5 h. The mixture was diluted with HO (30 mL) and washed with EtOAc (20 mL). The aqueous phase was acidified to pH = 5 with concentrated HCl. The suspension was extracted with EtOAc (30 mL × 3). The combined organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated to give (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg) as a white solid. MS measured value (ESI + )[(M+H) + ]:326.1.

[0322] Step 2: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (110 mg, 0.340 mmol) in DMF (10 mL) was added DIPEA (131 mg, 1.01 mmol), tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (78 mg, 0.340 mmol, Intermediate 9), EDCI (155 mg, 0.410 mmol), and HOPO (45 mg, 0.410 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with EtOAc (40 ml) and poured into water (50 mL). After separation, the aqueous phase was extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel column eluted with PE / EtOAc = 10 / 1 to 4 / 1 to give tert-butyl N-[[(1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (150 mg) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:537.4.

[0323] Step 3: Preparation of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (120 mg, 0.220 mmol) in DCM (3 mL) was added TFA (1.0 mL). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated, and the residue was purified by back-flash eluting with ACN in HO (0.01% HCl) = 0 to 60% to give (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (70 mg) as a white solid.

[0324] Step 4: Preparation of (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (Example 17) [ka] To a solution of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (60 mg, 0.140 mmol) in THF (14 mL) was added DIPEA (179 mg, 1.39 mmol) and a solution of n(2R)-2-chloro-2-fluoroacetyl chloride (90 mg, 0.320 mmol, Intermediate 10) in THF (4 mL) at -20 °C. The mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with MeOH (2 mL), adjusted to pH = 5 with 4 M HCl solution in dioxane at 0 °C, and concentrated in vacuo. The residue was purified by preparative HPLC (Unisi 13-100 C18 Ultra 150 × 50 mm × 3 μm; ACN in water (0.1% FA); 30% to 60%; flow rate (mL / min): 25) to give (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (21 mg, Example 17) as a white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 10.02(s,1H),6.49-6.45(m,3H),6.42-6.29(m,1H),5.67(s,1H),4.75 -4.72(m,1H),4.59-4.62(m,1H),4.42-4.35(m,2H),3.97-3.93(m,1H) ,3.65-3.63(m,1H),3.41-3.38(m,2H),2.92-2.79(m,2H),2.37-2.30( m,1H),1.85-1.75(m,2H),1.51-1.49(m,1H),1.11(s,3H),0.94(s,3H). MS measured value (ESI + )[(M+H) + ]:530.9.

[0325] Example 18 N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] The title compound was prepared in a manner similar to that described for the preparation of Example 1, using chloroacetyl chloride instead of 2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), to give N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 18) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ:ppm 10.98-10.62(m,1H),9.56-9.37(m,1H),7.82-7.61(m,1H),4.51-4.37(m,2H),4.28-4.03(m,2H),3.92(dd,J=5.6,10.4 Hz,1H),3.83-3.66(m,2H),3.22-3.10(m,2H),2.69-2.65(m,1H),2.37- 2.30(m,1H),2.24-2.06(m,1H),1.84-1.68(m,1H),1.62(dd,J=5.6,7.4 Hz,1H),1.56-1.43(m,1H),1.04(s,3H),0.99(s,9H),0.89(s,3H). MS measured value (ESI + )[(M+H) + ]:552.0.

[0326] Example 19 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] The title compound was prepared by the procedure described for the preparation of Example 1, using 2-chloro-2-fluoro-acetyl chloride (Intermediate 10-rac) instead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10), and subjected to SFC separation (Column: REGIS(S,S)WHELK-O1 (250 mm x 25 mm, 10 um); Conditions Neu-IPA Starting B 25% Purification by (end B 25%; gradient time (min) 2.8; hold time 100% B (min) 5; rate (ml / min) 50; injection 135) gave N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 19) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ:ppm 10.98(s,1H),9.46(d,J=7.2 Hz,1H),7.84-7.53(m,1H)6.83(d,J=48.8 Hz,1H),4.41(d,J=6.0 Hz,1H),4.26-4.13(m,1H),3.93(dd,J=10.4,5.2 Hz,1H),3.84-3.63(m,2H),3.52(d,J=13.20 Hz,1H),3.20-3.11(m,1H),3.05-2.95(m,1H),2.64-2.55(m,2H),2.23-2.10(m,1H),1 .85-1.71(m,1H),1.68-1.44(m,2H),1.07-1.03(m,3H)1.01-0.96(m,8H),0.89(s,3H). MS measured value (ESI + )[(M+H) + ]:570.3.

[0327] Example 20 N-[(1S)-1-Benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide [ka] Step 1: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of Cbz-Phe-OH (245 mg, 0.820 mmol) (GL Biochem, CAS number: 1161-13-3) in DCM (6 mL) was added DIPEA (0.43 mL, 2.46 mmol), HATU (231 mg, 0.98 mmol), and tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (300 mg, 0.820 mmol, Intermediate 14). The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with brine (50 mL × 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified on a silica gel column eluted with PE / EtOAc = 10 / 1 to 2 / 1 to give tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (350 mg) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:648.4.

[0328] Step 2: Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (350 mg, 0.540 mmol) in methanol (8 mL) was added Pd / C (150 mg, 10% purity) under a N atmosphere. The suspension was degassed and purged with H three times. The mixture was stirred under a H 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)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (270 mg) as a yellow oil. MS measured value (ESI + )[(M+H) + ]:514.3.

[0329] Step 3: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (270 mg, 0.530 mmol) in THF (8 mL) was added TEA (133 mg, 1.31 mmol) and TFAA (0.11 mL, 0.790 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (80 mL) and extracted with EtOAc (60 mL × 3). The organic layer was washed with brine (80 mL) and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by silica gel column eluted with ethyl acetate / Et0Ac=20 / 1 to 9 / 1 to give tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (138 mg) as a white solid. MS measured value (ESI + )[(M+H) + ]:610.2.

[0330] Step 4: Preparation of N-[(1S)-1-benzyl-2-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide [ka] To a solution of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2-[(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (138 mg, 0.230 mmol) in DCM (10 mL) was added TFA (5.0 mL). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo. The residue was purified by back-flush eluting with ACN in HO (0.01% HCl) = 0 to 60% to give N-[(1S)-1-benzyl-2-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (42 mg) as a white solid. MS measured value (ESI + )[(M+H) + ]:510.2.

[0331] Step 5: Preparation of N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 21) [ka] To a solution of N-[(1S)-1-benzyl-2-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (42 mg, 0.080 mmol) in THF (20 mL) was added DIPEA (127 mg, 0.990 mmol) and (2R)-2-chloro-2-fluoro-acetyl chloride (53.96 mg, 0.410 mmol, Intermediate 10) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The mixture was quenched with 4 M HCl / dioxane until pH = 5-6 and then concentrated in vacuo. The residue was purified by preparative HPLC (0.1% TFA, 3_Phenomenex Synergi Polar-RP 100 × 25 mm × 4 μm: [water (0.1% TFA)-ACN]; B%: 48%-68%, 7 min) to give N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (19 mg, Example 20) as an off-white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 7.36-7.21(m,5H),6.97-6.78(m,1H),4.79(dd,J=5.6,8.8 Hz,1H),4.26(s,1H),4.08(dd,J=8.8,14.0 Hz,1H),3.85-3.80(m,1H),3.79-3.72(m,1H),3.59(dd,J=4.4,14.0 Hz,1H),3.44-3.34(m,2H),3.18(dd,J=5.6,14.0 Hz,1H),2.97(dd,J=8.8,14.0 Hz,1H),2.75(dd,J=4.8,8.4 Hz,1H),2.38-2.24(m,1H),2.12-1.97(m,1H),1.74-1.59(m,2H),1.12(s,3H),1.02(s,3H). MS measured value (ESI+ )[(M+H) + ]:604.3.

[0332] Example 21 N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-phenyl-ethyl]-2,2,2-trifluoro-acetamide [ka] The title compound was prepared using a procedure similar to that described for the preparation of Example 20, using (2S)-2-(benzyloxycarbonylamino)-2-phenyl-acetic acid (GL Biochem, CAS number: 53990-33-3) instead of Cbz-Phe-OH, to give N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-phenyl-ethyl]-2,2,2-trifluoro-acetamide (Example 21) as an off-white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 7.47-7.40(m,5H),7.00-6.79(d,1H),5.70(s,1H),4.36(s,1H),4.07(dd,J=8.8,14.0 Hz,1H),3.79(d,J=10.4 Hz,1H),3.62-3.50(m,1H),3.44-3.34(m,3H),2.74(dq,J=4.8,8.8 Hz,1H),2.39-2.23(m,1H),2.12-1.96(m,1H),1.67-1.55(m,2H),1.11(s,6H). MS measured value (ESI + )[(M+H) + ]:590.3.

[0333] Example 22 N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide [ka] The title compound was prepared by a procedure similar to that described for the preparation of Example 3, using (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoic acid instead of (2S)-2-(benzyloxycarbonylamino)-4-methyl-pentanoic acid and 2,2,3,3,3-pentafluoropropanoyl 2,2,3,3,3-pentafluoropropanoate instead of TFAA, to give N-[( 1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide (Example 22) was obtained as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ:ppm 11.20(s,1H),9.55(d,J=8.4 Hz,1H),7.76(s,1H),6.85(d,J=50.4 Hz,1H),4.54-4.49(m,1H),4.17(s,1H),4.00-3.90(m,1H),3.84-3.76(m,1H),3.71(d,J=10.8 Hz,1H),3.46(dd,J=14.0,4.4 Hz,1H),3.25-3.00(m,2H),2.62-2.57(m,1H),2.30-2.10(m,1H),1.85-1.71(m,1 H),1.69-1.59(m,1H),1.57-1.53(m,1H),1.05(s,3H),0.98(s,9H),0.88(s,3H). MS measured value (ESI +)[(M+H) + ]:620.3.

[0334] Example 23 N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] Analogously to the procedure described for the preparation of Example 1, (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-(trifluoromethyl)pyrrolidine-2-carboxylate (Intermediate 1) was used instead of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 2). 15) to afford N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 23) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ:ppm 11.13(s,1H),9.57(d,J=8.0 Hz,1H),7.74(s,1H),6.91(d,J=50.4 Hz,1H),4.56-4.53(m,1H),4.36(t,J=7.6 Hz,1H),4.02-3.97(m,2H),3.73-3.67(m,1H),3.53(dd,J=4.4,14.4 Hz,1H),3.47-3.38(m,1H),3.18-3.09(m,2H),2.58-2.54(m,1H),2.41-2.35( m,1H),2.27-2.20(m,1H),2.14-2.07(m,1H),1.82-1.74(m,1H),1.00(s,9H). MS measured value (ESI + )[(M+H) + ]:598.2.

[0335] Example 24 N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide [ka] Step 1: Preparation of benzyl (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylate [ka] To a solution of (2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid (900 mg, 3.93 mmol, Intermediate 16) in DMF (2 mL) and ACN (10 mL) was added HATU (1642 mg, 4.32 mmol), followed by benzyl (6S)-5-azaspiro[2.4]heptane-6-carboxylate; hydrochloride (2033 mg, 5.89 mmol, Intermediate 17). The mixture was cooled to 0° C., and DIPEA (2537 mg, 19.63 mmol) was added dropwise to the mixture. After the addition, the mixture was warmed to 15° C. and stirred at 15° C. for 1 hour. The mixture was concentrated in vacuo. The residue was purified by silica gel column eluted with PE / EtOAc = 20 / 1 to 4 / 1 to give benzyl (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylate as a yellow oil (1.1 g). MS measured value (ESI + )[(M+H) + ]:443.1.

[0336] Step 2: Preparation of (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid [ka] To a solution of benzyl (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylate (1.0 g, 2.26 mmol) in methanol (20 mL) was added Pd(OH) / C (100 mg). The mixture was degassed under vacuum and purged with hydrogen three times. The resulting suspension was stirred under a H balloon at 25 °C for 1 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid (790 mg) as a colorless oil. MS measured value (ESI + )[(M+H) + ]:353.1.

[0337] Step 3: Preparation of (6S)-5-[(2S)-2-amino-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid; hydrochloride salt [ka] To a solution of (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid (790 mg, 2.24 mmol) in DCM (5 mL) was added 4N HCl / dioxane (5.0 mL). The reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo to give (6S)-5-[(2S)-2-amino-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid. The hydrochloride salt (640 mg) was obtained as a yellow gum.

[0338] Step 4: Preparation of (6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid [ka] To a solution of (6S)-5-[(2S)-2-amino-2-(1-methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid; hydrochloride (640 mg, 2.22 mmol) in methanol (10 mL) was added triethylamine (1.85 mL, 13.3 mmol) dropwise at 0 °C, followed by ethyl trifluoroacetate (944 mg, 6.65 mmol). The mixture was stirred at 50 °C for 12 hours. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with 1N HCl (20 mL), brine (20 mL), and dried over Na SO . After filtration and concentration, (6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid (770 mg) was obtained as a yellow gum. MS measured value (ESI + )[(M+H) + ]:349.1.

[0339] Step 5: Preparation of tert-butyl N-[[(6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of (6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid (760 mg, 2.18 mmol) in DMF (5 mL) was added EDCI (502 mg, 2.62 mmol), DIPEA (846 mg, 6.50 mmol), and HOPO (291 mg, 2.62 mmol). The mixture was stirred at 25° C. for 30 minutes, and then tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (500 mg, 2.18 mmol) was added to the mixture. The resulting mixture was stirred at 25° C. for 12 hours. The mixture was diluted with EtOAc (100 mL), washed with brine (60 mL), dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by back-flush eluting with 10% to 60% ACN (0.1% TFA) in HO to afford tert-butyl N-[[(6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (340 mg, 0.610 mmol) as a yellow foam.

[0340] MS measured value (ESI + )[(M+H) + ]:560.3. Step 6: Preparation of 2,2,2-trifluoro-N-[(1S)-1-(1-methylcyclopropyl)-2-oxo-2-[(6S)-6-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]ethyl]acetamide [ka] To a solution of tert-butyl N-[[(6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2-trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (330 mg, 0.590 mmol) in DCM (4 mL) was added TFA (2.0 mL). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with saturated aqueous NaHCO (10 mL), dried over NaSO, filtered, and the filtrate was concentrated to give 2,2,2-trifluoro-N-[(1S)-1-(1-methylcyclopropyl)-2-oxo-2-[(6S)-6-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]ethyl]acetamide (180 mg) as a yellow foam. MS measured value (ESI + )[(M+H) + ]:460.2.

[0341] Step 7: Preparation of N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 25) [ka] To a solution of 2,2,2-trifluoro-N-[(1S)-1-(1-methylcyclopropyl)-2-oxo-2-[(6S)-6-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]ethyl]acetamide (156 mg, 0.340 mmol) in THF (50 mL) was added DIPEA (439 mg, 3.4 mmol) and (2R)-2-chloro-2-fluoroacetyl chloride (222 mg, 0.680 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 30 minutes. The mixture was adjusted to pH=5 with 4N HCl / dioxane at 0° C. After concentration at 30°C, the residue was purified by reverse flash (C18, 0.1% FA-ACN in water) to give N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (62 mg, Example 24) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ:ppm 11.02(s,1H),9.83-9.74(m,1H),7.74(s,1H),6.85(d,J=10.0 Hz,1H),4.52-4.46(m,1H),4.43-4.33(m,1H),3.65-3.47(m,1H),3.64-3.54(m,2H),3.50-3.42(m,1H),3.22-3.09(m,2H),2.63-2.58( m,1H),2.15-2.00(m,2H),1.96-1.88(m,1H),1.84-1.70(m,1H),1.06(s,3H),0.87-0.77(m,1H),0.76-0.55(m,5H),0.36-0.24(m,2H). MS measured value (ESI + )[(M+H) + ]:554.2.

[0342] Example 25 N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide [ka] Analogously to the procedure described for the preparation of Example 1, benzyl (6S)-5-[(2S)-2-amino-3,3-dimethyl-butanoyl]-5-azaspiro[2.4]heptane-6-carboxylate (Intermediate 5) instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), The title compound was prepared using isobutyl chloride in place of TFAA to give N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide (Example 25) as a white solid. 1 H NMR(400 MHz,CD3OD)δ:ppm 7.85(d,J=8.6 Hz,1H),7.11(d,J=50.4 Hz,1H),4.59-4.41(m,2H),3.98(m,1H),3.85(d,J=9.8 Hz,1H),3.73-3.56(m,2H),3.42-3.34(m,2H),2.75-2.57(m,2H),2.36-2.15(m,2H),2.11-1.90(m,2H),1.12(dd,J=6.8,16.0 Hz,6H),1.05(s,9H),0.78-0.59(m,4H). MS measured value (ESI + )[(M+H) + ]:530.3.

[0343] Example 26 N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide [ka] Analogously to the procedure described for the preparation of Example 1, benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) was replaced with benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylate (Intermediate 7), The title compound was prepared using cyclopropanecarbonyl chloride in place of FAA to give N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide (Example 26) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ:ppm 11.00(s,1H),8.18(d,J=8.8 Hz,1H),7.75(s,1H),7.09(d,J=50.4 Hz,1H),4.39(d,J=8.4 Hz,1H),4.31-4.25(m,1H),3.75-3.64(m,2H),3.42(dd,J=14.0Hz,4.0 Hz,1H),3.32-3.27(m,2H),3.22-3.10(m,2H),2.18-2.05(m,1H),1.98-1.85(m,2H),1.80- 1.70(m,1H),1.67-1.56(m,1H),1.13(s,3H),0.98(s,3H),0.95(s,9H),0.68-0.58(m,4H). MS measured value (ESI + )[(M+H) + ]:530.3.

[0344] Example 27 N-[(1S)-1-[(2S,4S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide [ka] Analogous to the procedure described for the preparation of Example 1, benzyl (2S,4S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-methyl-pyrrolidine-2-carboxylate was used instead of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (intermediate 1). The title compound was prepared using (Intermediate 18) to give N-[(1S)-1-[(2S,4S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide (Example 27) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ:ppm 11.08(s,1H),9.51(d,J=8.4 Hz,1H),7.76(s,1H),7.02(d,J=50.4 Hz,1H),4.58(d,J=8.4 Hz,1H),4.30-4.22(m,1H),4.08-3.95(m,1H),3.80-3.68(m,1H),3.42(dd,J=14.0 Hz,4.0 Hz,1H),3.23-3.05(m,3H),2.35-2.22(m,2H),2.17-2.05(m,1H),1.82-1.68(m,1H),1.52-1.38(m,1H),1.23-1.14(m,1H),1.07(d,J=6.0 Hz,3H),0.98(s,9H). MS measured value (ESI+ )[(M+H) + ]:544.1.

[0345] Example 28 N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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 [ka] Similar to the procedure described for the preparation of Example 1, 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 (Intermediate 3) was used in place of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1), and TFAA was used in place of TFAA. The title compound was prepared using (2,2-difluoroacetyl) 2,2-difluoroacetate to give N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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 (Example 28) as a white solid. 1H NMR(400 MHz,CDCl3)δ:ppm 9.95(br.s,1H),7.08-7.04(m,1H),6.78-6.66(m,1H),6.08-5.81(m,2H),4.68(d,J=9.6 Hz,1H),4.47-4.42(m,1H),4.35-4.16(m,1H),4.00(dd,J=10.4 Hz,7.6 Hz,1H),3.76-3.73(m,1H),3.43-3.39(m,2H),2.88-2.64(m,4H),2.42-2.37(m,1H),1.94-1.66(m,6H),1.49-1.42(m,1H),1.04(s,9H). MS measured value (ESI + )[(M+H) + ]:552.2.

[0346] Example 29 N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide [ka] Step 1: Preparation of methyl (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate [ka] To a solution of Cbz-L-tert- (4.2 g, 15.83 mmol) in DMF (50 mL) was added methyl (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carboxylate hydrochloride (4.23 g, 15.83 mmol) and HATU (7.2 g, 19.0 mmol) at 0 °C. DIPEA (10.2 g, 79.16 mmol) was then added to the above solution to give a yellow solution. The mixture was stirred at 25 °C for 12 h. The mixture was diluted with EtOAc (400 mL), washed with brine (60 mL × 4), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column eluted with PE-PE / EtOAc=6 / 1 to give methyl (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (6.5 g) as a yellow gum. MS measured value (ESI + )[(M+H) + ]:417.2.

[0347] Step 2: Preparation of (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid [ka] To a solution of methyl (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate (6.5 g, 15.61 mmol) in THF (100 mL) was added a solution of LiOH·HO (2.0 g, 46.82 mmol) in water (40 mL). The mixture was stirred at 25 °C for 1 h. The mixture was acidified to pH = 4 with 1 N HCl. The mixture was extracted with EtOAc (100 mL × 3). The organic layer was washed with brine (60 mL), dried over NaSO, filtered, and concentrated in vacuo to give (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (5.96 g) as a yellow foam. MS measured value (ESI + )[(M+H) + ]:403.1.

[0348] Step 3: Preparation of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (5.9 g, 14.66 mmol) in DMF (60 mL) was added DIPEA (5.7 g, 43.99 mmol), EDCI (3.4 g, 17.6 mmol), HOPO (1.95 g, 17.6 mmol), and tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (3.4 g, 14.67 mmol, Intermediate 9). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with EtOAc (300 mL), washed with brine (60 mL × 4), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography ([water (0.1% TFA)-ACN]; B%: 50% to 55%, 25 min) to give tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (6.2 g) as a yellow foam. MS measured value (ESI + )[(M+H) + ]:614.4.

[0349] Step 4: Preparation of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (6.2 g, 10.1 mmol) in methanol (60 mL) was added Pd / C (600 mg, 10% purity). The suspension was degassed under vacuum and purged with hydrogen three times. The resulting mixture was stirred under a H2 balloon at 25 °C for 2 h. The mixture was filtered, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated in vacuo to give tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (4.5 g) as a yellow foam. MS measured value (ESI + )[(M+H) + ]:480.2.

[0350] Step 5: Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-4-methyl-2-[(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate [ka] To a solution of tert-butyl N-[...

Claims

1. Formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein L is C １ ~C ６ - alkyl, L １ represents a covalent bond, O, NH, and 【Chemistry 2】 is selected from A is C ６ ~C １４ aryl and 3- to 14-membered heteroaryl; R １ is the base 【Transformation 3】 and groups 【Chemistry 4】 is selected from 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, wherein said C ３ ~C １０ -Cycloalkyl is one C １ ~C ６ - optionally substituted with alkyl substituents, or R １ and R ２ together with the carbon atom to which they are attached form a 3- to 14-membered heteroaryl or C ６ ~C １４ -aryl, and the 3- to 14-membered heteroaryl or C ６ ~C １４ -aryl is halogen and halo-C １ ~C ６ - optionally substituted with 1 to 2 substituents selected from alkyl, R １ａ is 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, wherein said C ３ ~C １０ - cycloalkyl and 3- to 14-membered heteroaryl are substituted with halogen, C １ ~C ６ -Alkyl and halo-C １ ~C ６ - optionally substituted with 1 to 2 substituents selected from 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 a 3- to 14-membered heterocycloalkyl, a 3- to 14-membered heteroaryl, carbamoyl, and C １ ~C ６ -alkyl-NH-C(O)-, wherein said 3 to 14 membered heterocycloalkyl is optionally substituted with one oxo substituent; R ６ is selected from fluoro and chloro; R ７ is selected from hydrogen, chloro, and acyl; R ８ and R ９ are each independently hydrogen, halogen, and halo-C １ ~C ６ -alkyl, or a pharmaceutically acceptable salt thereof.

2. L １ is a covalent bond, O, NH, and 【Transformation 5】 is selected from A is C ６ ~C １４ aryl and 3- to 14-membered heteroaryl; R １ But, 【Transformation 6】 and groups 【Transformation 7】 is selected from R ２ But hydrogen, C ３ -C １０ -cycloalkyl, C ３ ~C １０ -cycloalkyl-C １ ~C ６ -alkyl, (3- to 14-membered heteroaryl)-C １ ~C ６ -Alkyl, C １ ~C ６ -Alkyl, C ６ ~C １４ -aryl, C ６ ~C １４ -aryl-C １ ~C ６ -alkyl, and C １ ~C ６ -Alkyl-S-C １ ~C ６ -alkyl, wherein said C ３ ~C １０ -cycloalkyl is one C １ ~C ６ - optionally substituted with alkyl substituents, or R １ and R ２ together with the carbon atoms to which they are attached, form halogens and halo-C １ ~C ６ -C substituted with two substituents selected from alkyl ６ ~C １４ - forms an aryl, R １ａ But 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, wherein said C ３ ~C １０ - cycloalkyl and 3- to 14-membered heteroaryl are selected from halogen, C １ ~C ６ -Alkyl and halo-C １ ~C ６ - optionally substituted with 1 to 2 substituents selected from alkyl, R ８ and R ９ are each independently hydrogen, halogen, and halo-C １ ~C ６ 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: - alkyl is selected from:

3. L １ is a covalent bond, O, NH, and 【Transformation 8】 is selected from A is selected from phenyl, pyridyl, pyrimidinyl; R １ But, 【Chemistry 9】 and groups 【Chemistry 10】 is selected from R ２ is selected from hydrogen, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1-bicyclo[1.1.1]pentanylmethyl, methyl, ethyl, propyl, sec-butyl, tert-butyl, isobutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2-methylsulfanylethyl, phenyl, benzyl and pyridylmethyl; or R １ and R ２ together with the carbon atoms to which they are attached, form fluoro and CF ３ forming a phenyl substituted with two substituents selected from R １ａ bicyclo[1.1.1]pentanyl, cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 1-methylcyclopropyl, 1-fluorocyclobutyl, 3,3-difluorocyclobutyl, cyclobutyl, phenyl, isoxazolyl, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, CHFCl, CHCl ２ , CHF ２ , C.F. ３ , 1-fluoro-1-methyl-ethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1-fluoroethyl and 1,1,2,2,2-pentachloroethyl; R ８ and R ９ are each independently hydrogen, fluoro and CF ３ 2. The compound of formula (I) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

4. R １ But, 【Chemistry 11】 and R ２ But C ３ ~C １０ -cycloalkyl and C １ ~C ６ - alkyl, R １ａ But C ３ ~C １０ -cycloalkyl, C １ ~C ６ -Alkyl and halo-C １ ~C ６ -alkyl, wherein said C ３ ~C １０ 3. A compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein -cycloalkyl is optionally substituted with 1 to 2 halogen substituents.

5. R １ But, 【Chemistry 12】 and R ２ is selected from cyclopropyl, 1,1-dimethylpropyl, 1-ethylpropyl, sec-butyl, and tert-butyl; R １ａ cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, isopropyl, tert-butyl, 1-fluoroethyl, CHFCl, CF ３ and CHF ２ 5. The compound of formula (I) according to claim 4, selected from: or a pharmaceutically acceptable salt thereof.

6. R ３ａ But C １ ~C ６ -alkyl, and R ３ｂ is hydrogen or C １ ~C ６ -alkyl, and R ４ａ and R ４ｂ are both hydrogen, or R ３ａ and R ３ｂ together with the carbon atoms to which they are attached, C ３ ~C １０ - forms a cycloalkyl, R ４ａ and R ４ｂ are both hydrogen, or 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 6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, optionally substituted with an alkyl substituent.

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

8. R ３ａ and R ３ｂ are both methyl, and R ４ａ and R ４ｂ are both hydrogen, or R ３ａ and R ３ｂ together with the carbon atom to which they are attached form a cyclopropyl, and R ４ａ and R ４ｂ are both hydrogen, or R ３ａ and R ４ａ together with the carbon atom to which they are attached form cyclopropyl or cyclopentyl, R ３ｂ and R ４ｂ 8. The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein: are both hydrogen and said cyclopropyl is substituted with two methyl substituents.

9. L is C １ ~C ６ - alkyl, R ５ is selected from 3-14 membered heterocycloalkyl and 3-14 membered heteroaryl, and said 3-14 membered heterocycloalkyl is substituted with one oxo substituent; or a pharmaceutically acceptable salt thereof.

10. L is C １ ~C ６ - alkyl, R ５ 10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein is a 3- to 14-membered heterocycloalkyl substituted with one oxo substituent.

11. L is CH ２ and R ５ but, 【Chemistry 13】 11. The compound of formula (I) according to claim 10, wherein:

12. R ６ is selected from fluoro and chloro; R ７ A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and chloro.

13. R ６ But it is fluoro, R ７ 13. The compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt thereof, wherein is chloro.

14. L is C １ ~C ６ - alkyl, L １ is a covalent bond, O, NH, and 【Chemistry 14】 is selected from A is C ６ ~C １４ aryl and 3- to 14-membered heteroaryl; R １ But, 【Chemistry 15】 and groups 【Chemistry 16】 is selected from R ２ But hydrogen, C ３ ~C １０ -cycloalkyl, C ３ ~C １０ -cycloalkyl-C １ ~C ６ -alkyl, (3- to 14-membered heteroaryl)-C １ ~C ６ -Alkyl, C １ ~C ６ -Alkyl, C ６ ~C １４ -aryl, C ６ ~C １４ -aryl-C １ ~C ６ -Alkyl and C １ ~C ６ -Alkyl-S-C １ ~C ６ -alkyl, wherein said C ３ ~C １０ -cycloalkyl is one C １ ~C ６ - optionally substituted with alkyl substituents, or R １ and R ２ together with the carbon atoms to which they are attached, form halogens and halo-C １ ~C ６ -C substituted with two substituents selected from alkyl ６ ~C １４ - forms an aryl, R １ａ But 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, wherein said C ３ ~C １０ - cycloalkyl and 3- to 14-membered heteroaryl are selected from halogen, C １ ~C ６ -Alkyl and halo-C １ ~C ６ - optionally substituted with 1 to 2 substituents selected from alkyl, R ２ But hydrogen, C ３ ~C １０ -cycloalkyl, C ３ ~C １０ -cycloalkyl-C １ ~C ６ -alkyl, (3- to 14-membered heteroaryl)-C １ ~C ６ -Alkyl and C １ ~C ６ -alkyl, wherein said C ３ ~C １０ -cycloalkyl is one C １ ~C ６ - optionally substituted with alkyl substituents; R ３ａ But C １ ~C ６ -alkyl, and R ３ｂ is hydrogen or C １ ~C ６ -alkyl, and R ４ａ and R ４ｂ are both hydrogen, or R ３ａ and R ３ｂ together with the carbon atoms to which they are attached, C ３ ~C １０ - forms a cycloalkyl, R ４ａ and R ４ｂ are both hydrogen, or 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 - optionally substituted with alkyl substituents; R ５ is selected from 3- to 14-membered heterocycloalkyl and 3- to 14-membered heteroaryl, wherein said 3- to 14-membered heterocycloalkyl is substituted with one oxo substituent; R ６ is selected from fluoro and chloro; R ７ is selected from hydrogen and chloro; R ８ and R ９ are each independently hydrogen, halogen, and halo-C １ ~C ６ 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: - alkyl is selected from:

15. L is C １ ~C ６ - alkyl, R １ But, 【Chemistry 17】 and R １ａ But C ３ ~C １０ -cycloalkyl, C １ ~C ６ -Alkyl and halo-C １ ~C ６ alkyl, wherein C ３ ~C １０ -cycloalkyl optionally substituted with 1 to 2 halogen substituents; R ２ But C ３ ~C １０ -cycloalkyl and C １ ~C ６ - alkyl, R ３ａ and R ３ｂ But both are C １ ~C ６ -alkyl, and R ４ａ and R ４ｂ are both hydrogen, or R ３ａ and R ３ｂ together with the carbon atoms to which they are attached, C ３ ~C １０ - forms a cycloalkyl, R ４ａ and R ４ｂ are both hydrogen, or 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 two C １ ~C ６ - optionally substituted with alkyl substituents; R ５ is a 3- to 14-membered heterocycloalkyl substituted with one oxo substituent; R ６ But it is fluoro, R ７ 15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, wherein is chloro.

16. L is CH ２ and R １ But, [Chemistry 18] and R １ａ cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, isopropyl, tert-butyl, 1-fluoroethyl, CHFCl, CF ３ , and CHF ２ is selected from R ２ is selected from cyclopropyl, 1,1-dimethylpropyl, 1-ethylpropyl, sec-butyl, and tert-butyl; R ３ａ and R ３ｂ are both methyl, and R ４ａ and R ４ｂ are both hydrogen, or R ３ａ and R ３ｂ together with the carbon atom to which they are attached form a cyclopropyl, and R ４ａ and R ４ｂ are both hydrogen, or 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 is substituted with two methyl substituents; R ５ but, 【Chemistry 19】 and R ６ But it is fluoro, R ７ 16. The compound of formula (I) according to claim 15, or a pharmaceutically acceptable salt thereof, wherein is chloro.

17. 2. A compound of formula (I) according to claim 1, selected from the following: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1-carboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[but-2-ynoyl-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-(1H-pyrazol-3-ylmethyl)amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-5-(trifluoromethyl)isoxazole-3-carboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[(2-chloroacetyl)-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-phenyl-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-benzyl-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; 3-[[(2R)-2-chloro-2-fluoro-acetyl]-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]amino]propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methylsulfanyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptan-5-yl]-1-(1-methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-(4-pyridylmethyl)ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-(1-bicyclo[1.1.1]pentanylmethyl)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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; (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (3R,3aR,6aS)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3,5-difluorophenoxy)acetyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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-propanamide; N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-cyclobutyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; N-[(1S)-1-[(2S,4S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-methyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1-methyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]propanamide; Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-methyl-cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; Rac-2,2-difluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3,3-trifluoro-propanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]butanamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-fluoro-2-methyl-propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2-fluoro-2-methyl-propanamide; Rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]propyl]propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-dichloro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-dichloro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide; Rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[rac-(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]propanamide; N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,3,3,3-pentafluoro-propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-propanamide; Rac-2-fluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,3,3,3-pentafluoro-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; 2,2-dichloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]acetamide; Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-dimethyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]benzamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1R)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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; (1R)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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)-2-oxopyrrolidin-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)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-1-fluoro-cyclopropanecarboxamide; (1R)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide; 2,2-difluoro-N-[rac-(1S,2S)-2-methyl-1-[rac-(1R,2S,5S)-6,6-dimethyl-2-[[[rac-(2S)-2-chloro-2-fluoro-acetyl]-[[rac-(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; 2,2-difluoro-N-[rac-(1S,2R)-2-methyl-1-[rac-(1R,2S,5S)-6,6-dimethyl-2-[[[rac-(2R)-2-chloro-2-fluoro-acetyl]-[[rac-(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2R)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; (2S)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]cyclopropanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2S)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; (2R)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; rac-2,2-difluoro-N-[(1S,2R)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]-3,3-difluoro-cyclobutanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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; rac-2-fluoro-N-[(1S)-2-ethyl-1-[(2S)-4,4-dimethyl-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]pyrrolidine-1-carbonyl]butyl]propanamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; (2S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; (2R)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; rac-2-fluoro-N-[(1S)-2,2-dimethyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]butyl]propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclobutyl-2-oxo-ethyl]-1-fluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(2S,4R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(2S,4R)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4-(trifluoromethyl)pyrrolidine-1-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3,3-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]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)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]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)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; (1R,2S,5S)-3-[3,5-bis(trifluoromethyl)benzoyl]-N'-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)-3-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-N'-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[3-fluoro-5-(trifluoromethyl)benzoyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)-3-[(E)-3-[3,5-bis(trifluoromethyl)phenyl]prop-2-enoyl]-N'-[(2R)-2-chloro-2-fluoro-acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[(E)-3-(3,5-difluorophenyl)prop-2-enoyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide; (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(5-fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-3,3-dimethyl-2-(2-pyridylamino)butanoyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2S)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2R)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2S)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]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]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide.

18. 18. A compound of formula (I) according to claim 17, selected from the following: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide; (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; (1R)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide; N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide; (2S)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-ethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-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-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2-fluoro-propanamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-1-fluoro-cyclopropanecarboxamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; (1S)-N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-cyclopropanecarboxamide; N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-butyl]-2,2-difluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(2S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide; (2R)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide; and (2S)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide.

19. A method for preparing a compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, comprising: (a) Formula (XI) 【Chemistry 20】 (In the formula, R １ａ , R ２ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ and L is as defined in any one of claims 1 to 5, Formula (XI-1) 【Chemistry 21】 (In the formula, R ６ and R ７ is as defined in any one of claims 1 to 5, and LG ２ is a leaving group) in the presence of a coupling reagent and a base, Formula (I-a) 【Chemistry 22】 (In the formula, R １ａ , R ２ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ , R ６ , R ７ and L is as defined in any one of claims 1 to 5, or (b) Formula (XXIII) 【Chemistry 23】 (In the formula, R １ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ and L is as defined in any one of claims 1 to 5). The compound of formula (XI-1) 【Chemistry 24】 (In the formula, R ６ and R ７ is as defined in any one of claims 1 to 5, and LG ２ is a leaving group) in the presence of a coupling reagent and a base, Formula (Ib) 【Chemistry 25】 (In the formula, R １ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ , R ６ , R ７ and L is as defined in any one of claims 1 to 5.

20. A compound of formula (XI) or a salt thereof 【Chemistry 26】 (In the formula, R １ａ , R ２ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ and L is as defined in any one of claims 1 to 5).

21. A compound of formula (XXIII) or a salt thereof 【Chemistry 27】 (In the formula, R １ , R ３ａ , R ３ｂ , R ４ａ , R ４ｂ , R ５ and L is as defined in any one of claims 1 to 5).

22. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

24. 10. A method for the treatment or prevention of coronavirus infection, comprising administering a therapeutically active amount of a compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof to a non-human subject in need thereof.

25. A method for inhibiting the enzymatic activity of a 3C-like protease in a non-human subject, said method comprising contacting the 3C-like protease with a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5.

26. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the treatment or prevention of coronavirus infection or for inhibiting the enzymatic activity of a 3C-like protease.

27. 10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment or prevention of coronavirus infections.

28. Use of a compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting the enzymatic activity of a 3C-like protease.

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