2-azabicyclo [3.1. 1] heptane compounds

Abstract

The present invention addresses the problem of providing a novel compound which functions as an agonist for an orexin type 2 receptor and which can be used in the treatment of diseases associated with the orexin type 2 receptor, in particular narcolepsy. Provided is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. [Formula 1] # imgabs0 # (In formula (I), R1, R2, R3, R4, R5, R6, and Z are each as defined in the description).

Description

Technical Field

[0001] The present invention relates to a compound having a specific chemical structure or a pharmaceutically acceptable salt thereof that can be used as an agonist of orexin receptor type 2. Background Art

[0002] Orexin is a neuropeptide produced specifically in specific nerve cells localized in the lateral hypothalamic region of the brain and is an endogenous ligand for the orexin receptor, a G protein-coupled receptor predominantly present in the brain.

[0003] It has been reported that orexin-deficient mice exhibit symptoms very similar to human narcolepsy (Non-Patent Document 1), and that intracerebroventricular administration of orexin peptides has been shown to improve symptoms such as suppression of cataplexy and increased wakefulness (Non-Patent Document 2). Furthermore, it has been reported that orexin concentrations in the cerebrospinal fluid of narcolepsy patients are significantly reduced (Non-Patent Document 3), suggesting that narcolepsy is caused by orexin deficiency.

[0004] There are two subtypes of orexin receptors, type 1 (OX1R) and type 2 (OX2R) (non-patent document 4). As a cause of hereditary narcolepsy in dogs, mutations in OX2R have been reported (non-patent document 5). In addition, it is known that OX2R-deficient mice show narcolepsy-like symptoms (non-patent document 6), suggesting that OX2R is closely related to the role of maintaining wakefulness. From such a background, it is suggested that OX2R agonists can become therapeutic drugs for narcolepsy or diseases showing symptoms of sleepiness (non-patent document 7). So far, as OX2R agonists, compounds such as those described in patent documents 1 to 9 have been reported, but any of them are structurally different from the compounds of the present invention.

[0005] In addition, idiosyncratic liver toxicity (IDT) caused by taking drugs is a serious toxicity observed in about 1 in 100,000 people, and it is very difficult to predict by animal experiments (non-patent literature 8). As one of the pathogenesis, it is known that there is a covalent bond between electrophilic reactive metabolites (ERMs) produced during drug metabolism and biopolymers (non-patent literature 9). In an in vitro metabolic reaction system using human liver microsomes, it is useful to coexist glutathione (GSH) as a nucleophile and use GSH conjugate generation as an indicator to reduce the risk of IDT.

[0006] Prior art literature

[0007] Patent Literature

[0008] [Patent Document 1] International Publication No. WO2017 / 135306 (Patent Document 1) (U.S. Patent Application Publication No. 2016 / 075240)

[0009] [Patent Document 2] International Publication No. WO2019 / 027058 (Patent Document 2)

[0010] [Patent Document 3] International Publication No. WO2020 / 158958 (Patent Document 3) (U.S. Patent Application Publication No. 2017 / 427490)

[0011] [Patent Document 4] International Publication No. WO2021 / 108628 Pamphlet

[0012] [Patent Document 5] International Publication No. WO2020 / 167701 Pamphlet

[0013] [Patent Document 6] International Publication No. WO2022 / 051596 Pamphlet

[0014] [Patent Document 7] International Publication No. WO2021 / 107023 (Patent Document 7)

[0015] [Patent Document 8] International Publication No. WO2022 / 014680 Pamphlet

[0016] [Patent Document 9] International Publication No. WO2015 / 088000 (Patent Document 9)

[0017] Non-patent literature

[0018] [Non-patent document 1] Cell, 98, 1999, 437-451

[0019] [Non-patent document 2] Proc. Natl. Acad. Sci. USA, 101, 2004, 4649-4654

[0020] [Non-patent document 3] Lancet, 355, 2000, 39-40

[0021] [Non-patent document 4] Cell, 92, 1998, 573-585

[0022] [Non-patent document 5] Cell, 98, 1999, 365-376

[0023] [Non-patent document 6] Neuron, 38, 2003, 715-730

[0024] [Non-patent document 7] CNSDrugs, 27, 2013, 83-90

[0025] [Non-patent document 8] Chem. Res. Toxicol. 17, 2004, 3-16

[0026] [Non-patent document 9] Curr. Opin. Drug Discovery Dev. 4, 2001, 55-59 Summary of the Invention

[0027] Problems to be solved by the invention

[0028] The present invention aims to provide a novel compound that acts as an agonist at orexin type 2 receptor and is useful for treating diseases associated with orexin type 2 receptor, particularly narcolepsy.

[0029] Means to solve problems

[0030] The present invention relates to the following (1) to (14).

[0031] (1) a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

[0032] [Chemistry 1]

[0033]

[0034] [In formula (I),

[0035] R 1 represents a phenyl group or a pyridyl group which may have 1 or 2 substituents independently selected from the following Group A, a phenyl group substituted with 5 deuterium atoms, a 2,2-difluoro-1,3-benzodioxolyl group, or a 5-membered heteroaryl group containing 1 or 2 atoms independently selected from the group consisting of a nitrogen atom and a sulfur atom in the ring,

[0036] The heteroaryl group may have 1 or 2 substituents independently selected from the following Group B,

[0037] R 2represents a C1-C6 alkyl group which may have 1 to 5 substituents independently selected from the following Group C, a C3-C6 cycloalkyl group which may have 1 or 2 substituents selected from the following Group D, a 4- or 5-membered saturated heterocyclic group containing one atom selected from the group consisting of nitrogen and oxygen atoms in the ring, a 5-membered heteroaryl group containing one or two atoms independently selected from the group consisting of nitrogen and oxygen atoms in the ring, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a diC1-C6 alkylamino group, or a dicyclopentyl group,

[0038] R 3 represents a hydrogen atom or a halogen atom,

[0039] R 4 represents a hydrogen atom or a halogen atom,

[0040] R 5 represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a diC1-C6 alkylamino group, or a vinyl group which may be substituted by 1 to 3 halogen atoms,

[0041] R 6 represents a hydrogen atom or a halogen atom,

[0042] Z represents CH or a nitrogen atom];

[0043] Group A: halogen atoms, C1-C6 alkyl groups which may be substituted by 1 to 3 halogen atoms, C1-C6 alkoxy groups which may be substituted by 1 to 3 halogen atoms, C3-C6 cycloalkyl groups, and cyano groups;

[0044] Group B: halogen atoms, C1-C6 alkyl groups;

[0045] Group C: hydroxyl, halogen, deuterium, C1-C6 alkoxy, C3-C6 cycloalkyl, pyrazolyl;

[0046] Group D: halogen atoms, C1-C6 alkyl groups which may be substituted with 1 to 3 hydroxyl groups, cyano groups, and hydroxyl groups.

[0047] (2) The compound as described in (1) or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), R 1 represents a phenyl group or a pyridyl group which may have one or two substituents independently selected from the group consisting of a fluorine atom, a chlorine atom, a difluoromethyl group, a trifluoromethyl group, and a cyclopropyl group.

[0048] (3) The compound according to (1) or (2) or a pharmaceutically acceptable salt thereof, wherein in the above formula (I),

[0049] R 2represents a C1-C6 alkyl group which may have 1 to 5 substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, and a deuterium atom, a cyclopropyl group which may be substituted with 1 or 2 fluorine atoms, or an isoxazolyl group.

[0050] (4) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein in the above formula (I),

[0051] R 3 represents a fluorine atom,

[0052] R 4 represents a hydrogen atom or a fluorine atom,

[0053] Z represents CH or a nitrogen atom.

[0054] (5) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein in the above formula (I),

[0055] R 5 represents a methyl group, an ethyl group, a monofluoromethyl group, or a cyclopropyl group,

[0056] R 6 represents a hydrogen atom or a fluorine atom.

[0057] (6) The compound or pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein in the above formula (I),

[0058] R 1 represents the following formula (II),

[0059] [Chemistry 2]

[0060]

[0061] [In formula (II),

[0062] R 11 and R 12 each independently represents a hydrogen atom, a fluorine atom or a chlorine atom],

[0063] R 2 Indicates the following R 2a to R 2e Any one of

[0064] [Chemistry 3]

[0065]

[0066] R 3 、R 4 and R 6 each independently represents a hydrogen atom or a fluorine atom,

[0067] R5 represents a methyl or ethyl group,

[0068] Z represents CH or a nitrogen atom.

[0069] (7) A compound selected from the group consisting of any one of the following, or a pharmaceutically acceptable salt thereof: N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide,

[0070] N-{(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide,

[0071] N-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide,

[0072] N-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide,

[0073] N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide,

[0074] N-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide,

[0075] N-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide,

[0076] as well as

[0077] N-{(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide.

[0078] (8) A compound selected from any one of the following groups or a pharmaceutically acceptable salt thereof:

[0079] N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide,

[0080] as well as

[0081] N-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide.

[0082] (9) A pharmaceutical composition comprising the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof.

[0083] (10) An orexin type 2 receptor agonist comprising the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof.

[0084] (11) A preventive or therapeutic agent for narcolepsy, comprising the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof.

[0085] (12) A method for preventing or treating narcolepsy, characterized by administering an effective amount of the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof.

[0086] (13) The compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of narcolepsy.

[0087] (14) Use of the compound according to any one of (1) to (8) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating narcolepsy.

[0088] Effects of the Invention

[0089] The compounds of the present invention or pharmaceutically acceptable salts thereof act as excellent orexin type 2 receptor agonists. Furthermore, specific compounds of the present invention or pharmaceutically acceptable salts thereof can provide excellent metabolic stability and / or a low risk of IDT. DETAILED DESCRIPTION

[0090] In the present invention, the "halogen atom" refers to, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0091] In the present invention, "C1-C6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, for example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, or 4-methylpentyl.

[0092] In the present invention, "C1-C6 alkoxy" refers to an alkoxy group formed by the above-mentioned C1-C6 alkyl group, for example: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutoxy, neopentyloxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, or 4-methylpentyloxy.

[0093] In the present invention, the "C3-C6 cycloalkyl group" refers to, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

[0094] In the present invention, "C1-C6 alkylamino" refers to a group in which one of the above-mentioned C1-C6 alkyl groups is combined with an amino group, for example: methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino, isohexylamino, or 4-methylpentylamino.

[0095] In the present invention, "di-C1-C6 alkylamino group" refers to a group in which two identical or different C1-C6 alkyl groups are bonded to an amino group, and examples thereof include dimethylamino group, methylethylamino group, and diethylamino group.

[0096] In the present invention, "C1-C6 alkyl groups which may be substituted with 1 to 3 halogen atoms" refers to the aforementioned C1-C6 alkyl groups and groups in which the aforementioned C1-C6 alkyl groups are substituted with the same or different halogen atoms. Examples of the aforementioned C1-C6 alkyl groups substituted with the same or different halogen atoms include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl groups.

[0097] In the present invention, "C1-C6 alkyl groups which may be substituted with 1 to 3 hydroxyl groups" refers to the aforementioned C1-C6 alkyl groups and groups in which the aforementioned C1-C6 alkyl groups are substituted with hydroxyl groups. Examples of the aforementioned C1-C6 alkyl groups substituted with hydroxyl groups include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxy-1-methylethyl, and 2-hydroxy-1-methylethyl.

[0098] In the present invention, "C1-C6 alkoxy groups which may be substituted with 1 to 3 halogen atoms" refers to the aforementioned C1-C6 alkoxy groups and groups in which the aforementioned C1-C6 alkoxy groups are substituted with the same or different halogen atoms. Examples of the aforementioned C1-C6 alkoxy groups substituted with the same or different halogen atoms include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy groups.

[0099] In the present invention, a "saturated heterocycle" means a saturated ring containing a heteroatom within the ring.

[0100] In the present invention, "heteroaryl" means a substituent derived from an aromatic group containing a heteroatom in the ring.

[0101] In the present invention, "biaryl group" means a substituent having a structure in which two aromatic rings are linked by a single bond, wherein one or both of the aromatic rings constituting the biaryl group may be a heteroaryl group.

[0102] In the present invention, the “5-membered heteroaryl group containing 1 or 2 atoms independently selected from the group consisting of nitrogen and sulfur atoms in the ring” refers to, for example, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, or isothiazolyl.

[0103] In the present invention, the “5-membered heteroaryl group containing 1 or 2 atoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring” refers to, for example, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl or oxazolyl.

[0104] In the present invention, the "4- or 5-membered saturated heterocyclic group containing one atom selected from the group consisting of a nitrogen atom and an oxygen atom in the ring" refers to, for example, azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl.

[0105] Next, suitable substituents in the general formula (I) are described.

[0106] R 1 It is preferably a phenyl group, a 3,5-difluorophenyl group, or a 3-chlorophenyl group, and more preferably a phenyl group.

[0107] R 2 Suitable for the following R 2a to R2e Any one of them is more suitable for R 2d or R 2e .

[0108] [Chemistry 4]

[0109]

[0110] R 3 、R 4 The suitable combination of R and Z is as follows 3a to R 3c Any one of them is more suitable for R 3a or R 3c .

[0111] [Chemistry 5]

[0112]

[0113] In the formula, *1 is bonded to the phenyl group, and *2 is bonded to the methylene group.

[0114] R 5 It is preferably a methyl group or an ethyl group, and more preferably a methyl group.

[0115] R 6 Suitable is a hydrogen atom or a fluorine atom.

[0116] In another embodiment, the combination of suitable substituents in the general formula (I) is R 1 is phenyl, R 2 R 2d or R 2e , R 3 、R 4 The combination of R and Z is 3a or R 3c , R 5 is methyl, R 6 is a hydrogen atom or a fluorine atom.

[0117] Another embodiment of the present invention is represented by the following general formula (III).

[0118] [Chemistry 6]

[0119]

[0120] In formula (III), R 1 、R 2 、R 3 、R 4 、R 5 、R 6 The definitions of and Z, suitable combinations, etc. are the same as those in the general formula (I) in this specification.

[0121] The compound represented by the general formula (I) of the present invention can be prepared as a pharmaceutically acceptable salt as desired. A pharmaceutically acceptable salt is a salt that can be administered to animals (including humans) for use as a drug. When the compound represented by the general formula (I) of the present invention has an acidic or basic group, it can be prepared as a salt by reacting it with a base or acid.

[0122] As salts based on acidic groups, for example, there can be mentioned: alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as magnesium salts and calcium salts; organic base salts such as N-methylmorpholine salts, triethylamine salts, tributylamine salts, diisopropylethylamine salts, dicyclohexylamine salts, N-methylpiperidinium salts, pyridine salts, 4-pyrrolidinopyridine salts, and picoline salts; or amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate salts, and aspartate salts.

[0123] As salts based on basic groups, for example, there can be mentioned: hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; aryl sulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and maleate; or amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate.

[0124] The compound represented by general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may absorb moisture, adsorb water, or form a hydrate when exposed to the atmosphere or undergo recrystallization. The present invention also includes such various hydrates, solvates, and crystalline polymorphs.

[0125] The compounds represented by the general formula (I) of the present invention, their pharmaceutically acceptable salts or solvates thereof may exist in various isomers such as geometric isomers such as cis-isomers and trans-isomers, tautomers, rotational isomers or optical isomers such as d-isomers and l-isomers (including enantiomers and diastereomers) depending on the type and combination of substituents. The compounds of the present invention, unless otherwise specified, also include all isomers, stereoisomers and mixtures of these isomers and stereoisomers in any ratio. Mixtures of these isomers can be separated by known separation means. In the case where the compound of the present invention is a mixture of isomers, the ratio of a specific diastereomer depends on the matrix, solvent and base, but is not particularly limited. In the mixture of isomers of the compound of the present invention, for example, the ratio of a specific diastereomer (which may be a racemate): a stereoisomer other than a specific diastereomer may be 1:1 or higher, or may be a single diastereomer. Here, in the present invention, "single diastereomer" means that in a mixture of isomers in the compound of the present invention, the ratio of stereoisomers other than the specific diastereomer (which may be a racemate) to the specific diastereomer is 20:5 (20 / 5) or greater, 20:3 (20 / 3) or greater, or 20:1 (20 / 1) or greater. Furthermore, when the compound of the present invention is a mixture of enantiomers, the enantiomeric excess is not particularly limited and may be, for example, 0% ee or greater (including racemates), 20% ee or greater, 40% ee or greater, 60% ee or greater, 80% ee or greater, 85% ee or greater, or 90% ee or greater. In the compounds of the present invention, "single enantiomer" refers to the enantiomeric excess of the mixture of enantiomers of the present invention, and may contain, for example, 92% ee or more, 94% ee or more, 96% ee or more, or 99% ee or more.

[0126] The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof further includes a label, that is, one or more atoms of the compound are isotopically (for example, 2 H. 3 H. 13 C. 14 C. 35 S, etc.) substituted compounds.

[0127] The compounds represented by the general formula (I) of the present invention or their pharmaceutically acceptable salts are generally named according to the nomenclature of the International Union of Pure and Applied Chemistry (IUPAC).

[0128] In the names of the compounds of the present invention, when there is an asymmetric center atom in the structure of the compound, the absolute configuration may be represented by R and S (described together with the position number).

[0129] The relative configuration is obtained by adding an * symbol (R* and S*) to the configuration notation originally described when the configuration of the asymmetric center is set to R or S, and sometimes the prefix (symbol) rel- (meaning relative) is placed before the name.

[0130] A racemic mixture is usually not specifically represented by R and S to indicate its absolute configuration, but may be represented by using the symbols RS and SR instead of R* and S*, or by placing the prefix (symbol) rac- (meaning racemic) before the name.

[0131] In addition, the present invention also includes so-called prodrugs. Prodrugs refer to compounds having amino, hydroxyl, carboxyl, and other groups that can be converted into compounds by hydrolysis or under physiological conditions. As for the groups that form such prodrugs, they are the groups described in Prog. Med., Vol. 5, pp. 2157-2161, 1985, etc. As such prodrugs, more specifically,

[0132] (1) When an amino group exists in a compound, the following examples are mentioned:

[0133] Compounds whose amino groups are acylated, alkylated, or phosphorylated (for example, compounds whose amino groups are eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated, tetrahydrofurylated, pyrrolidinylmethylated, pivaloyloxymethylated, or tert-butylated, etc.);

[0134] (2) When a hydroxyl group exists in the compound, the following examples are mentioned:

[0135] Compounds whose hydroxyl groups are acylated, alkylated, phosphorylated, or borated (for example, compounds whose hydroxyl groups are acetylated, palmitoylated, propionylated, pivalolylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated);

[0136] (3) In addition, when a carboxyl group exists in the compound, the following examples are mentioned:

[0137] Compounds whose carboxyl groups are esterified or amidated (for example, compounds whose carboxyl groups are ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated, or methylamidated, etc.) and the like.

[0138] (Applicable diseases)

[0139] The compounds of the present invention can be used as drugs in the treatment and / or prevention of narcolepsy. In addition, in addition to narcolepsy, the compounds of the present invention can also be used as drugs in the treatment, relief, and / or prevention of idiopathic hypersomnia, sleep apnea syndrome, other hypersomnias (for example, hypersomnia associated with neurodegenerative diseases such as Parkinson's disease and Lewy body dementia, major depressive disorder, schizophrenia, bipolar disorder, and other psychiatric diseases), circadian rhythm disorders, obesity, diabetes, and the treatment, relief, and / or prevention of hypersomnia symptoms associated with analgesics such as morphine. The use of the compounds of the present invention in the treatment and prevention of the above-mentioned diseases is supported by the following: the compounds of the present invention can be used as orexin type 2 receptor agonists, and orexin is believed to be related not only to the effects on sleep and wakefulness, but also to the effects on food intake, mood, cognitive function, etc. In addition, in order to prevent excessive daytime sleepiness, cataplexy, etc. and improve daytime quality of life, the compounds of the present invention can also be used as drugs in the prevention of the occurrence of the above-mentioned diseases.

[0140] Furthermore, the compounds of the present invention not only activate activity in individuals with orexin deficiency but can also be used as orexin type 2 receptor agonists in individuals without orexin deficiency. Furthermore, the compounds of the present invention can be used in embodiments in which the active period (e.g., approximately 12 to 16 hours) within a 24-hour period maintains wakefulness, while the drug effect disappears before sleep onset, making it less likely to inhibit sleep.

[0141] (Combined therapy)

[0142] The compounds of the present invention can be used in combination with existing narcolepsy therapeutics such as modafinil, sodium oxybate, pitolisant, methylphenidate, and antidepressants. Furthermore, when the compounds of the present invention are used to treat drug-induced hypersomnia, they can be used in combination with the causative drug.

[0143] (Dosage form, dosage, and usage of the pharmaceutical composition)

[0144] The pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt thereof, and may also comprise a pharmaceutically acceptable carrier, and can be administered as various injections such as intravenous injection, intramuscular injection, and subcutaneous injection, or by various methods such as oral administration and transdermal administration. A pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material (e.g., excipient, diluent, additive, solvent, etc.) that participates in transporting the compound of the present invention or a composition comprising the compound of the present invention from one organ or viscera to another.

[0145] Preparations containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient are prepared using conventional pharmaceutical additives such as carriers and excipients. The compound of the present invention can be administered orally via tablets, pills, capsules, granules, powders, or liquids, or parenterally via intra-articular, intravenous, or intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, or other forms.

[0146] Solid compositions for oral administration include tablets, powders, granules, and the like. Such solid compositions contain one or more active ingredients and at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and / or magnesium aluminum metasilicate. Following conventional methods, the solid composition may contain inert additives, such as glidants such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, stabilizers, and solubilizers. Tablets or pills may be coated with a sugar coating or a film of a gastric-soluble or enteric-soluble substance, as desired.

[0147] When used as tablets, as carriers, for example, excipients such as lactose, sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and polyvinyl pyrrolidone; dry starch, sodium alginate, agar powder, kelp powder, sodium bicarbonate, calcium carbonate, polyoxyethylene propylene glycol, and the like. Disintegrants include ethylene sorbitan fatty acid esters, sodium lauryl sulfate, monostearin, starch, and lactose; disintegration inhibitors include white sugar, stearin, cocoa butter, and hydrogenated oil; absorption enhancers include quaternary ammonium salts and sodium lauryl sulfate; humectants include glycerin and starch; adsorbents include starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants include purified talc, stearates, boric acid powder, and polyethylene glycol. Tablets can also be coated with conventional coatings, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double-layer or multi-layer tablets, as needed.

[0148] When used as pills, as carriers, excipients such as glucose, lactose, cocoa butter, starch, hardened vegetable oil, kaolin, talc, etc.; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, etc.; disintegrants such as kelp, agar, etc. can be used.

[0149] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs. Commonly used inert diluents, such as purified water or ethanol, may be added to such liquid compositions. In addition to the inert diluent, the liquid composition may also contain adjuvants such as solubilizers and wetting agents, sweeteners, flavoring agents, aromatics, and preservatives.

[0150] As injections for parenteral administration, sterile aqueous or non-aqueous solutions, suspensions, or emulsions are used. Examples of aqueous solvents include distilled water for injection or physiological saline. Examples of non-aqueous solvents include propylene glycol, polyethylene glycol, or vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80. Such injection compositions may further include isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or cosolvents. These injection compositions can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of a bactericide, or by irradiation. Alternatively, these injection compositions can be prepared as sterile solid compositions and dissolved or suspended in sterile water or a sterile injection solvent prior to use.

[0151] When used as an injection, it can be used as a liquid, emulsion or suspension. These liquids, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used in the preparation of these liquids, emulsions or suspensions is not particularly limited as long as it can be used as a diluent for medical use. Examples thereof include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. In addition, in this case, in order to prepare an isotonic solution, a sufficient amount of salt, glucose or glycerol can be included in the preparation, and a common solubilizing agent, buffer, soothing agent, etc. can also be included.

[0152] Furthermore, the above-mentioned preparations may contain colorants, preservatives, fragrances, flavoring agents, sweeteners, etc. as needed, and may also contain other pharmaceutical products.

[0153] The amount of the compound contained in the above-mentioned preparation is not particularly limited and can be appropriately selected from a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.

[0154] The dosage and frequency of administration of the compound of the present invention are appropriately determined in consideration of the symptoms, age, etc. of the patient (warm-blooded animal, particularly human). In general, in the case of oral administration, the daily dosage is about 0.001-100 mg / kg per body weight, preferably 0.1-30 mg / kg, more preferably 0.1-10 mg / kg, which is administered once or divided into two or more doses. In the case of intravenous administration, the daily dosage is about 0.0001-10 mg / kg per body weight, which is administered once a day or divided into multiple doses.

[0155] The compound of the present invention can be administered, for example, in a dosage that is orally administered once a day upon waking from sleep (e.g., in the morning) so that the drug effect disappears before the end of the active time of the day (e.g., about 12 to 16 hours) and the onset of the next sleep time, without inhibiting sleep.

[0156] (Preparation Method)

[0157] Representative methods for preparing the compound represented by general formula (1) or a pharmaceutically acceptable salt thereof are described below. The compound of the present invention can be prepared by various methods, and the following method is an example. The present invention should not be construed as being limited thereto.

[0158] The compound represented by general formula (1) or a pharmaceutically acceptable salt thereof can be prepared by applying various well-known preparation methods based on the characteristics of its basic skeleton or the types of substituents. Examples of well-known methods include those described in "Organic Functional Group Preparations", 2nd edition, Academic Press, Inc., 1989; "Comprehensive Organic Transformations", VCH Publishers Inc., 1989, etc.

[0159] In this case, depending on the type of functional group present in the compound, it may be technically effective to protect the functional group with an appropriate protecting group or replace it with a group that can be easily converted into the functional group at the stage from the raw material to the intermediate.

[0160] Examples of such functional groups include amino, hydroxyl, and carboxyl groups, and examples of their protecting groups include those described in "Greene's Protective Groups in Organic Synthesis (4th edition, John Wiley & Sons, Inc., 2006)" by TW Greene and PG Wuts.

[0161] The protecting group or the group that can be easily converted into the functional group may be appropriately selected and used depending on the reaction conditions of the production method to be used for the production of the compound.

[0162] According to this method, after the group is introduced and the reaction is carried out, the desired compound can be obtained by removing the protecting group as needed or converting it into a desired group.

[0163] Representative methods for producing the compound represented by the general formula (1) of the present invention or a pharmaceutically acceptable salt thereof are shown below. The production methods of the present invention are not limited to the examples shown below.

[0164] (Method A)

[0165] Method A is a method for producing a compound represented by general formula (1) from a compound represented by general formula (2).

[0166] [Chemistry 7]

[0167]

[0168] (Where R 1 to R 6 , Z are the same as above, R 13 Represents R 2or precursors of those.)

[0169] (Step A-1)

[0170] Step A-1 includes the essential reactions of Step A-1a, Step A-1b, Step A-1c, and Step A-1d, and may also include Step A-1e and Step A-1f as needed. Steps A-1b to A-1f can be performed in any order, and the order can be easily selected by those skilled in the art.

[0171] Step A-1a: Reaction of introducing a methylene biaryl group or a methylene aryl group by substitution reaction of a β-keto ester with a bromoalkane

[0172] Step A-1b: Decarbonation reaction from β-ketoester

[0173] Step A-1c: Conversion of ketone to amine

[0174] Step A-1d: Sulfonylation or sulfonylation of amine

[0175] Step A-1e: Reaction of converting the bromine atom on the aromatic ring of a methylene aryl group into an aryl or heteroaryl group

[0176] Step A-1f: Reduction of olefins

[0177] (Step A-1a)

[0178] This step is a step of introducing a methylenebiaryl group or a methylenearyl group into a β-ketoester using an appropriate base and a bromoalkane in an inert solvent.

[0179] The solvent that can be used is not particularly limited as long as it dissolves the starting materials to a certain extent without inhibiting the reaction, and can be selected from the following group of solvents, for example: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; alcohols such as methanol, deuterated methanol, ethanol, deuterated ethanol, and tert-butanol; esters such as ethyl acetate and propyl acetate; nitriles such as acetonitrile; amides such as formamide and N,N-dimethylformamide; sulfoxides such as dimethyl sulfoxide; organic acids such as acetic acid; water; and mixtures thereof.

[0180] The base used is not particularly limited as long as it is used as a base in a conventional reaction, but suitable examples include organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, lutidine, and pyridine; alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate; alkaline earth metal carbonates such as magnesium carbonate; alkali metal hydrogen carbonates such as potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; alkali metal hydroxides such as sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide; alkali metal phosphates such as tripotassium phosphate, etc.

[0181] The reaction temperature varies depending on the starting compound, reagent, etc., but is usually -20°C to 120°C, preferably 0°C to 80°C.

[0182] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0183] After the reaction, the target compound of this reaction can be obtained by, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc., and then distilling off the solvent.

[0184] The obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography, etc., if necessary.

[0185] (Step A-1b)

[0186] Step A-1b is a step of decarbonating the β-ketoester compound.

[0187] The necessary reactions include step A-1b1: decarbonation reaction and step A-1b2: tert-butoxycarbonylation reaction, if necessary.

[0188] (Step A-1b1)

[0189] This step is a step of decarbonating the β-ketoester using an acid or a metal salt.

[0190] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0191] The acid used is not particularly limited as long as it is used as an acid in a general reaction, but suitable examples include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid.

[0192] The metal salt used is not particularly limited, but examples thereof include lithium chloride and lithium sulfate.

[0193] The reaction temperature varies depending on the starting compound, reagents, etc., but is usually 0°C to 160°C, preferably 80°C to 140°C.

[0194] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 96 hours, preferably 1 hour to 48 hours.

[0195] After the reaction is completed, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by a conventional method in the same manner as above, if necessary.

[0196] (Step A-1b2)

[0197] This step is a step of carrying out tert-butoxycarbonylation in the presence or absence of a suitable base.

[0198] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0199] The tert-butoxycarbonylating agent used is not particularly limited as long as it is used as a tert-butoxycarbonylating agent in a general reaction, and suitable examples include di-tert-butyl dicarbonate and tert-butylphthalamide carbonate.

[0200] The base used can be the same as the base used in the above-mentioned Step A-1a.

[0201] The reaction temperature varies depending on the starting compound, reagents, etc., but is usually -40°C to 100°C, preferably 0°C to 60°C.

[0202] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 1 hour to 24 hours.

[0203] After completion of the reaction, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in Step A-1a above, and can be further purified by conventional methods in the same manner as above, if necessary.

[0204] (Step A-1c)

[0205] Step A-1c is carried out by converting a ketone into an oxime and then reducing it to an amine.

[0206] The necessary reactions include step A-1c1: condensation reaction of ketone and hydroxylamine hydrochloride; and step A-1c2: reduction reaction of oxime to amine.

[0207] (Step A-1c1)

[0208] This step is a step of converting a ketone into an oxime using a suitable base and hydroxylamine hydrochloride in an inert solvent.

[0209] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0210] The base used can be the same as the base used in the above-mentioned Step A-1a.

[0211] The reaction temperature varies depending on the starting compound, reagent, etc., but is usually -20°C to 120°C, preferably 0°C to 80°C.

[0212] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 30 minutes to 24 hours.

[0213] After completion of the reaction, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by conventional methods as needed.

[0214] (Step A-1c2)

[0215] This step is a step of converting oxime to amine using a suitable reducing agent in an inert solvent in the presence or absence of an additive.

[0216] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0217] The reducing agent used is not particularly limited, and examples thereof include sodium borohydride, lithium borohydride, lithium aluminum hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and zinc powder.

[0218] The additive used is not particularly limited as long as it is used in a known method, but suitable examples include metal oxides such as molybdenum (VI) oxide and metal salts such as nickel (II) chloride.

[0219] The reaction temperature varies depending on the starting compound, reagent, etc., but is usually -20°C to 120°C, preferably 0°C to 80°C.

[0220] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 96 hours, preferably 30 minutes to 48 hours.

[0221] After completion of the reaction, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by conventional methods as needed.

[0222] When column chromatography using a chiral column is performed, an optically active compound can be obtained.

[0223] (Step A-1d)

[0224] This step is a step of sulfonylation or sulfamination of an amine using a suitable base and sulfonyl chloride or sulfamate chloride in an inert solvent in the presence or absence of an additive.

[0225] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0226] The base used can be the same as the base used in the above-mentioned Step A-1a.

[0227] The additive used is not particularly limited as long as it is used in a known method, but N,N-dimethylaminopyridine and the like are preferably mentioned.

[0228] The reaction temperature varies depending on the starting compound, reagent, etc., but is usually -20°C to 120°C, preferably 0°C to 80°C.

[0229] After completion of the reaction, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by conventional methods as needed.

[0230] When column chromatography using a chiral column is performed, an optically active compound can be obtained.

[0231] (Step A-1e)

[0232] This step converts the bromine atom on the aryl or heteroaryl ring introduced in step A-1a into an aryl or heteroaryl group. The following methods are described here, but are not limited to these methods: a method using boronic acid or its ester in the presence of a suitable base and a suitable metal catalyst (step A-1e1); or a method in which the bromine atom is converted to a boric ester using a boron compound in the presence of a suitable base and a suitable metal catalyst, followed by the addition of a halogenated aryl or heteroaryl group in the presence of a suitable base and a suitable metal catalyst (step A-1e2).

[0233] (Step A-1e1)

[0234] Step A-1e1 is a step of converting a bromine atom on an aryl or heteroaryl ring into an aryl or heteroaryl group using boronic acid or its ester in an inert solvent in the presence of a suitable base and a suitable metal catalyst.

[0235] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0236] The base used may be the same as that used in the above-mentioned step A-1a, or metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide may be used.

[0237] The metal catalyst used is not particularly limited as long as it is used in a known method, but suitable examples include tetrakis(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)dipalladium, bis[1,2-bis(diphenylphosphino)ethane]palladium, (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate ((2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) nyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)), and palladium-activated carbon catalysts.

[0238] The boric acid used is not particularly limited, but examples thereof include phenylboric acid, 3-chlorophenylboric acid, and 3,5-difluorophenylboric acid.

[0239] The boric acid ester used is not particularly limited, but examples thereof include 3-cyclopropylphenyl boronic acid pinacol ester.

[0240] The reaction temperature varies depending on the starting compound, reagents, etc., but is usually 0°C to 150°C, preferably 20°C to 120°C.

[0241] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0242] After completion of the reaction, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by conventional methods as needed.

[0243] (Step A-1e2)

[0244] Step A-1e2 is carried out by converting the bromine atom on the aryl ring or heteroaryl ring into a borate ester, and then reacting the bromine atom with a halogenated aryl group or a halogenated heteroaryl group.

[0245] The necessary reactions include step A-1e2a: a reaction of converting a bromine atom on an aryl or heteroaryl ring into a borate ester; and step A-1e2b: a reaction of converting a borate ester and a halogenated aryl or heteroaryl group into a biaryl compound.

[0246] (Step A-1e2a)

[0247] Step A-1e2a is a step of converting a bromine atom on an aryl ring or a heteroaryl ring into a boronate ester using a boron compound in an inert solvent in the presence of a suitable base and a suitable metal catalyst.

[0248] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0249] The base used may be the same as that used in the above-mentioned step A-1a, or metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide may be used.

[0250] The metal catalyst used can be the same as the metal catalyst used in the above-mentioned step A-1e1.

[0251] Examples of the boron compound used include bis(pinacolato)diboron and pinacolborane.

[0252] The reaction temperature varies depending on the starting compound, reagents, etc., but is usually 0°C to 150°C, preferably 20°C to 120°C.

[0253] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0254] After completion of the reaction, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by conventional methods as needed.

[0255] (Step A-1e2b)

[0256] Step A-1e2b is a step of converting a boric acid ester into an aryl group or a heteroaryl group using a halogenated aryl group or a halogenated heteroaryl group in an inert solvent in the presence of a suitable base and in the presence of a suitable metal catalyst.

[0257] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0258] The base used may be the same as that used in the above-mentioned Step A-1a, or metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide may be used.

[0259] The metal catalyst used can be the same as the metal catalyst used in the above-mentioned step A-1e1.

[0260] Examples of the halogenated aryl group include 1-bromo-3-(difluoromethyl)-5-fluorobenzene.

[0261] Examples of the halogenated heteroaryl group include 2,6-dichloropyridine and 2-bromo-6-cyclopropylpyridine.

[0262] The reaction temperature varies depending on the starting compound, reagents, etc., but is usually 0°C to 150°C, preferably 20°C to 120°C.

[0263] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0264] After the reaction, the target compound of this reaction can be obtained by, for example, concentrating the reaction mixture, adding an organic solvent such as ethyl acetate, washing with water, separating the organic layer containing the target compound, drying over anhydrous sodium sulfate, etc., and then distilling off the solvent.

[0265] The obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography, etc., if necessary.

[0266] (Step A-1f)

[0267] This step is a step of reducing olefin using hydrogen in an inert solvent in the presence of a suitable metal catalyst.

[0268] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0269] The metal catalyst used is not particularly limited, but suitable examples include metal catalysts such as palladium-activated carbon, platinum-activated carbon, nickel, and osmium-activated carbon.

[0270] Examples of the hydrogen source include hydrogen gas, ammonium formate, and hydrazine.

[0271] The reaction temperature varies depending on the starting compound, reagent, etc., but is usually -10°C to 150°C, preferably 0°C to 80°C.

[0272] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.

[0273] After completion of the reaction, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by conventional methods as needed.

[0274] When column chromatography using a chiral column is performed, an optically active compound can be obtained.

[0275] (Step A-2)

[0276] Step A-2 is a step for preparing a compound represented by general formula (4) from a compound represented by general formula (3). Although the step of removing the tert-butoxycarbonyl group of the compound represented by general formula (3) using an appropriate acid in an inert solvent is described here, the present invention is not limited thereto.

[0277] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0278] The acid used is not particularly limited as long as it is used as an acid in a general reaction, but suitable examples include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; and organic acids such as trifluoroacetic acid.

[0279] The reaction temperature varies depending on the starting compound, reagents, etc., but is usually -10°C to 100°C, preferably 0°C to 50°C.

[0280] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

[0281] After completion of the reaction, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by conventional methods as needed.

[0282] (Step A-3)

[0283] Step A-3 is a step of producing a compound represented by the general formula (1) from a compound represented by the general formula (4).

[0284] As essential reactions, step A-3a: a reaction for converting the compound represented by general formula (4) into an amide, urea, or carbamate compound can be mentioned. Furthermore, step A-3b: a reaction for solvolysis of an ester; or step A-3c: a reaction for converting pyruvic acid amide into deuterated lactic acid amide can be added as needed.

[0285] (Step A-3a)

[0286] This step is a step for converting the compound represented by the general formula (4) into an amide, urea, or carbamate compound. The following methods are described herein, but are not limited thereto: a method in which the compound represented by the general formula (4) is treated with an acid chloride, isocyanate, chloroformate, or di-tert-butyl dicarbonate in the presence or absence of a suitable base (Step A-3a1); or a method in which the compound represented by the general formula (4) is amidated with a carboxylic acid using a suitable condensing agent (Step A-3a2).

[0287] (Step A-3a1)

[0288] This step is a step of converting the compound represented by the general formula (4) into an amide, urea or carbamate compound using an acid chloride, isocyanate or chloroformate in an inert solvent in the presence or absence of an appropriate base.

[0289] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0290] The base used can be the same as the base used in the above-mentioned Step A-1a.

[0291] The acid chloride used is not particularly limited as long as it is used in a general reaction, but examples thereof include acetyl chloride and carboxylic acid chlorides.

[0292] The isocyanate used is not particularly limited as long as it is used in a general reaction, but methyl isocyanate and the like are exemplified.

[0293] The chloroformate used is not particularly limited as long as it is used in a general reaction, but ethyl chloroformate and the like can be mentioned.

[0294] The reaction temperature varies depending on the starting compound, reagent, etc., but is usually -20°C to 120°C, preferably 0°C to 50°C.

[0295] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0296] After the reaction is completed, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by conventional methods as needed.

[0297] (Step A-3a2)

[0298] This step is a step of condensing the compound represented by the general formula (4) with a carboxylic acid, and is carried out in an inert solvent in the presence or absence of a base using a condensing agent.

[0299] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0300] The base used can be the same as the base used in the above-mentioned Step A-1a.

[0301] The condensing agent used is not particularly limited as long as it is used as a condensing agent for forming an amide bond (for example, the methods described in Masakazu Kusumoto et al., Lectures on Experimental Science IV, The Chemical Society of Japan, Maruzen, 1990; or Nobuo Izumiya et al., Fundamentals and Experiments of Peptide Synthesis, Maruzen, 1985). Suitable examples include O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 4-(2-{[(cyclohexylimino)methylene]amino}ethyl-4-methylmorpholin-4-ium p-toluenesulfonate p-Toluenesulfonate (CMC), dicyclohexylcarbodiimide (DCC), 1,1'-carbonylbis(1H-imidazole) (CDI), (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBOP), bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (PyBrOP), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), 2-chloro-4,6-dimethoxy-1,3,5-triazine (DMT), etc. Additives such as 1-hydroxybenzotriazole (HOBT) and N,N-dimethylaminopyridine may also be added.

[0302] The reaction temperature varies depending on the starting compound, reagent, etc., but is usually -10°C to 150°C, preferably 0°C to 100°C.

[0303] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0304] After completion of the reaction, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by conventional methods as needed.

[0305] The optically active compound represented by the general formula (1) can be obtained by column chromatography using a chiral column.

[0306] (Step A-3b)

[0307] In this step, R of the compound represented by the general formula (1) is reacted with a methyl alcohol in an inert solvent in the presence of a suitable base. 13 The contained carboxylic acid ester is subjected to a solvolysis step.

[0308] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0309] The base used can be the same as the base used in the above-mentioned Step A-1a.

[0310] The reaction temperature varies depending on the starting compound, reagent, etc., but is usually -10°C to 100°C, preferably 0°C to 60°C.

[0311] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0312] The target compound of this reaction can be obtained, for example, through steps such as concentration, separation, and drying in the same manner as in the above-mentioned Step A-1a, and can be further purified by conventional methods as needed.

[0313] The optically active compound represented by the general formula (1) can be obtained by column chromatography using a chiral column.

[0314] (Step A-3c)

[0315] Step A-3c is a step of converting pyruvic acid amide contained in the compound represented by the general formula (1) into deuterated lactic acid amide.

[0316] The essential reaction includes step A-3c1: a reaction of converting a ketone into an alcohol using a deuterated reducing agent. If necessary, step A-3c2: a reaction of deuterating a methyl group may be added before step A-3c1.

[0317] (Step A-3c1)

[0318] This step is a step of converting a ketone into an alcohol in an inert solvent in the presence of an appropriate deuterated reducing agent.

[0319] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0320] The deuterated reducing agent used is not particularly limited as long as it is used in a general reaction, and examples thereof include sodium borodeuteride, lithium aluminum deuteride, deuterium, and sodium deuterated formate.

[0321] The reaction temperature varies depending on the starting compound, reagent, etc., but is usually -20°C to 90°C, preferably 0°C to 50°C.

[0322] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0323] After completion of the reaction, the target compound of this reaction can be obtained by, for example, concentration, separation, drying, etc. in the same manner as in the above-mentioned step A-1a, and can be further purified by conventional methods as needed.

[0324] The optically active compound represented by the general formula (1) can be obtained by column chromatography using a chiral column.

[0325] (Step A-3c2)

[0326] This step is a step of deuterating the methyl group of pyruvic acid amide in an inert solvent in the presence of a suitable base.

[0327] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0328] The base used can be the same as the base used in the above-mentioned Step A-1a.

[0329] The reaction temperature varies depending on the starting compound, reagent, etc., but is usually -10°C to 100°C, preferably 0°C to 60°C.

[0330] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 72 hours, preferably 10 minutes to 24 hours.

[0331] After the reaction is completed, the target compound of this reaction can be used for the subsequent reaction without purification.

[0332] The compound represented by the general formula (1) of the present invention can also be obtained by the method described below as another method.

[0333] (Method B)

[0334] Method B is a method for producing a compound represented by general formula (1) from a compound represented by general formula (2).

[0335] [Chemistry 8]

[0336]

[0337] (Where R 1 to R 6 、Z represents the same as above, R 13 Represents R 2 or those precursors, R14 Represents R 1 or halogen atoms.)

[0338] Hereinafter, each step will be described in detail.

[0339] (Step B-1)

[0340] This step is a step of condensing the compound represented by the general formula (2) with a bromoalkane to produce the compound represented by the general formula (5), and is carried out according to step A-1a.

[0341] (Step B-2)

[0342] Step B-2 is a step of producing a compound represented by the general formula (6) from a compound represented by the general formula (5).

[0343] The necessary reactions include step B-2a: a decarbonation reaction accompanied by the elimination of the tert-butoxycarbonyl group; and step B-2b: a reaction for conversion to an amide or a carbamate.

[0344] (Step B-2a)

[0345] This step is a step of decarbonating the β-ketoester with the removal of the tert-butoxycarbonyl group using an acid.

[0346] The solvent used can be the same as that used in the above-mentioned step A-1a.

[0347] The acid used is not particularly limited as long as it is used as an acid in a general reaction, but suitable examples include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid.

[0348] The reaction temperature varies depending on the starting compound, reagents, etc., but is usually 0°C to 160°C, preferably 80°C to 140°C.

[0349] The reaction time varies depending on the starting compound, reagent, etc., but is usually 5 minutes to 96 hours, preferably 1 hour to 48 hours.

[0350] After completion of the reaction, the target compound of the present reaction can be obtained by, for example, distilling off the solvent of the reaction mixture.

[0351] The obtained compound can be further purified by conventional methods such as recrystallization, reprecipitation, silica gel column chromatography, etc., if necessary.

[0352] (Step B-2b)

[0353] This step is a step of converting the compound represented by the general formula (6) and is carried out according to step A-3a1.

[0354] (Step B-3)

[0355] Step B-3 is a step of producing a compound represented by the general formula (1) from a compound represented by the general formula (6).

[0356] Essential reactions include step B-3a: the conversion of a ketone to an amine; and step B-3b: the sulfonylation or sulfonylation of an amine. Furthermore, step B-3c: the conversion of a bromine atom to an aryl or heteroaryl group; and step B-3d: the solvolysis of an ester may be added as needed.

[0357] (Step B-3a)

[0358] This step is a step of converting a ketone into an oxime and then reducing it to an amine, and is carried out according to step A-1c.

[0359] (Step B-3b)

[0360] This step is a step of sulfonylation of amine or sulfonylation of amine, and is carried out according to step A-1d.

[0361] (Step B-3c)

[0362] This step is a step for converting a bromine atom on an aryl ring or a heteroaryl ring into an aryl group or a heteroaryl group, and is carried out according to step A-1e.

[0363] (B-3d step)

[0364] This step is to convert the R 13 The step of solvolysis of the contained carboxylic acid ester is carried out according to step A-3b.

[0365] The compound represented by the general formula (1) of the present invention can also be obtained by the method described below as another method.

[0366] (C Method)

[0367] Method C is a method for producing a compound represented by general formula (1) from a compound represented by general formula (2).

[0368] [Chemistry 9]

[0369]

[0370] (Where R 1 to R 6 、Z represents the same as above, R 13 Represents R 2 or precursors of those.)

[0371] Hereinafter, each step will be described in detail.

[0372] (Step C-1)

[0373] This step is a step for producing a compound represented by the general formula (7) by a substitution reaction between a compound represented by the general formula (2) and a bromoalkane, and is carried out according to step A-1a.

[0374] (Step C-2)

[0375] Step C-2 is a step for producing the compound represented by the general formula (8) from the compound represented by the general formula (7) by decarbonation reaction, and is carried out in the same manner as Step A-1b.

[0376] (Step C-3)

[0377] Step C-3 is a step of producing a compound represented by the general formula (9) from a compound represented by the general formula (8).

[0378] Necessary reactions include step C-3a: the removal reaction of the tert-butoxycarbonyl group; step C-3b: the conversion reaction into an amide or carbamate; step C-3c: the conversion reaction of a ketone into an amine; and step C-3d: the sulfonylation reaction of an amine or the sulfonylation reaction of an amine.

[0379] (Step C-3a)

[0380] Step C-3a is a step of removing the tert-butoxycarbonyl group using a suitable acid, and is carried out in the same manner as Step A-2.

[0381] (Step C-3b)

[0382] This step is a step for converting the compound represented by the general formula (9) and is carried out according to step A-3a1.

[0383] (Step C-3c)

[0384] This step is a step of converting a ketone into an oxime and then reducing it to an amine, and is carried out according to step A-1c.

[0385] (C-3d step)

[0386] This step is a step of sulfonylation of amine or sulfonylation of amine, and is carried out according to step A-1d.

[0387] (Step C-4)

[0388] Step C-4 is a step of producing a compound represented by the general formula (1) from a compound represented by the general formula (9).

[0389] As a necessary reaction, step C-4a: the reaction of converting a bromine atom on an aryl or heteroaryl ring into an aryl or heteroaryl group can be mentioned. In addition, step C-4b: the reaction of subjecting an ester to solvolysis can be added as needed.

[0390] (Step C-4a)

[0391] Step C-4a is a step of converting a bromine atom on an aryl ring or a heteroaryl ring into an aryl group or a heteroaryl group, and is carried out according to Step A-1e.

[0392] (Step C-4b)

[0393] Step C-4b is to convert the R 13 The step of solvolysis of the contained carboxylic acid ester is carried out according to step A-3b.

[0394] Example

[0395] The present invention is described in detail below with reference to Examples, but the present invention is not limited thereto and should not be construed as limiting in any sense. In addition, reagents, solvents, and starting materials not specifically described in this specification can be easily obtained from commercially available sources.

[0396] The abbreviations used in the examples have the following meanings.

[0397] mg: milligram, g: gram, mL: milliliter, mol: mole, MHz: million Hertz, Boc: tert-butyloxycarbonyl, D: deuterium, MS (mass spectrometry), ESI (electrospray ionization), APCI (atmospheric pressure chemical ionization), DMSO (dimethyl sulfoxide)

[0398] In the following examples, nuclear magnetic resonance (1H NMR: 400 MHz) spectra were obtained using chloroform-d, methanol-d4, and dimethyl sulfoxide-d6 as deuterated solvents, and tetramethylsilane as a standard substance. Chemical shift values ​​are reported as δ (ppm). Splitting patterns are represented by s for singlets, d for doublets, dd for double doublets, dt for double triplets, t for triplets, td for triple doublets, q for quartets, m for multiplets, and br for broad peaks.

[0399] In addition, limited to the present embodiment shown below, "single diastereomer" means a specific diastereomer (which may be a racemate): the ratio of stereoisomers other than the specific diastereomer is 20:1 (20 / 1) or more, and "single enantiomer" means 96% ee (er = 98 / 2) or more.

[0400] Example 1

[0401] N-{(3S,4S)-2-(2-Hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0402] (1A) 3-(Bromomethyl)-2,3',5'-trifluoro[biphenyl]

[0403] A mixture of 1,3-difluoro-5-(2-fluoro-3-methylphenyl)benzene (CAS registration number: 2409648-15-1, 50 g), N-bromosuccinimide (50 g), azobisisobutyronitrile (4.0 g), and acetonitrile (500 mL) was degassed and then stirred at 80°C for 6 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 40 / 60 to 20 / 80 (v / v)] to obtain 55 g of the title compound (yield: 81%).

[0404] (1B) 2-tert-Butyl 3-methyl 4-oxo-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[0405] To a mixture of 04-tert-butyl 03-methyl 2-oxo-4-azabicyclo[3.1.1]heptane-3,4-dicarboxylate (CAS Registry No.: 2241048-56-4, 0.600 g) and N,N-dimethylformamide (9.0 mL) were added the compound synthesized in Example 1A (0.671 g) and cesium carbonate (1.45 g), and the mixture was stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride and water were added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 67 / 33 (v / v)] to obtain 0.77 g of the title compound (yield: 71%).

[0406] (1C) 2-methyl-1-oxo-1-{4-oxo-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}propan-2-yl acetate

[0407] Hydrochloric acid (12M, 28.6mL) was added to a mixture of the compound synthesized in Example 1B (2.86g) and acetic acid (5.72mL), and the mixture was stirred at room temperature for 30 minutes. Lithium chloride (0.248g) was added to the reaction mixture, stirred at 100°C for 6 hours, and cooled to room temperature. The solvent was distilled off under reduced pressure, and toluene was added to perform azeotropy three times. Triethylamine (4.05mL) and 2-acetoxyisobutyryl chloride (1.27mL) were added to a mixture of the obtained residue and tetrahydrofuran (43mL) at 0°C, and stirred at room temperature for 2 hours. After adding saturated ammonium chloride aqueous solution and water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 - 0 / 100 (V / V)] to obtain 1.99 g (yield: 74%) of the title compound.

[0408] (1D) 1-{4-amino-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]hept-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0409] Hydroxylamine hydrochloride (0.328 g) and sodium acetate (0.387 g) were added to a mixture of the compound synthesized in Example 1C (0.620 g) and ethanol (6.2 mL). The mixture was stirred at 80°C for 2 hours and then cooled to room temperature. The solvent was distilled off under reduced pressure, and water and saturated sodium chloride were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. Molybdenum (VI) oxide (0.583 g) was added to a mixture of the resulting residue and methanol (6.2 mL) at 0°C, and sodium borohydride (1.02 g) was slowly added in small portions. The mixture was stirred at 0°C for 2 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction mixture, which was then filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride water and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 0.622 g of the crude title compound.

[0410] (1E) 2-Methyl-1-{(3S*,4S*)-4-[(methylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-1-oxopropan-2-yl acetate

[0411] Methanesulfonyl chloride (0.104 mL) was added to a mixture of the compound synthesized in Example 1D (205 mg), triethylamine (0.371 mL), and tetrahydrofuran (4.1 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After addition of saturated sodium bicarbonate aqueous solution, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100 (v / v)] to obtain 167 mg of the title compound as a single diastereomer (racemic form) (yield: 70%).

[0412] (1F) N-{(3S*,4S*)-2-(2-Hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0413] Lithium hydroxide monohydrate (0.26 g) was added to a mixture of the compound synthesized in Example 1E (167 mg), tetrahydrofuran (2.00 mL), and water (0.668 mL) at room temperature and stirred at 50°C for 12 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100 (v / v)] to obtain 0.154 g of the title compound as a single diastereomer (racemic form) (yield: quantitative).

[0414] (1G) N-{(3S,4S)-2-(2-Hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0415] The compound synthesized in Example 1F (154 mg) was subjected to chiral HPLC [column: CHIRALPAK (registered trademark) IA (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 70 / 30 (V / V), temperature: 40°C] to obtain 41.3 mg (yield: 27%) of the title compound that eluted first as a single diastereomer and a single enantiomer.

[0416] Example 2

[0417] N'-{(3S,4S)-2-(2-hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}-N,N-dimethylsulfonamide

[0418] (2A) 1-{4-(hydroxyimino)-3-[(2,3′,5′-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]hept-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0419] Hydroxylamine hydrochloride (30 g) and sodium acetate (44 g) were added to a mixture of the compound synthesized in Example 1C (55 g) and ethanol (700 mL) at room temperature and stirred at 80°C for 2 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 60 g of the crude title compound.

[0420] (2B) 1-{(3S*,4S*)-4-amino-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]hept-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0421] Sodium borohydride (50 g) was added to a mixture of the compound synthesized in Example 2A (60 g), molybdenum (VI) oxide (27 g), and methanol (1000 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was added to an aqueous ammonium chloride solution (500 mL), and the insoluble matter was removed by filtration. The filtrate was extracted twice with ethyl acetate, and the organic layers were combined and washed with saturated brine. After drying over sodium sulfate, the mixture was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.1% trifluoroacetic acid aqueous solution / acetonitrile = 72 / 28 to 52 / 48 (V / V)] to obtain 30 g of the title compound as a single diastereomer (racemic form) (yield: 52%).

[0422] (2C) 1-{(3S,4S)-4-amino-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0423] The compound synthesized in Example 2B (23 g) was subjected to chiral SFC [column: CHIRALPAK (registered trademark) AD (50 mm I.D. × 250 mm), mobile phase: carbon dioxide / 2-propanol = 60 / 40 (V / V)] to obtain 11 g of the title compound that eluted first as a single diastereomer and a single enantiomer (yield: 44%).

[0424] (2D) 1-{(3S,4S)-4-[(dimethylsulfamoyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0425] Dimethylaminesulfonyl chloride (50 mg) was added to a mixture of the compound synthesized in Example 2C (100 mg), N,N-dimethylaminopyridine (30 mg), N,N-diisopropylethylamine (74 mg), and tetrahydrofuran (5.0 mL) at room temperature, and the mixture was stirred at 40°C for 10 hours. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 10 mM aqueous ammonium carbonate / acetonitrile = 59 / 41 to 29 / 71 (V / V)] to obtain 30 mg of the title compound as a single diastereomer and a single enantiomer (yield: 24%).

[0426] (2E)N'-{(3S,4S)-2-(2-Hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}-N,N-dimethylsulfonamide

[0427] Lithium hydroxide monohydrate (6.0 mg) was added to a mixture of the compound synthesized in Example 2D (30 mg), water (1.0 mL), and methanol (5.0 mL) at room temperature and stirred for 10 hours. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 52 / 48 to 22 / 78 (V / V)] to obtain 9.2 mg (yield: 33%) of the title compound as a single diastereomer and a single enantiomer.

[0428] Example 3

[0429] N-{(3S,4S)-2-(2-Hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[0430] (3A) 1-{(3S,4S)-4-[(ethylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0431] Ethyl chloride (0.267 mL) was added to a mixture of the compound synthesized in Example 2C (1.00 g), triethylamine (0.602 mL), and tetrahydrofuran (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 6 hours. After adding saturated sodium bicarbonate aqueous solution, the mixture was extracted with ethyl acetate, washed with saturated brine, and the organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 0 / 100 (v / v)] to obtain 1.20 g of the title compound as a single diastereomer and a single enantiomer (yield: quantitative).

[0432] (3B) N-{(3S,4S)-2-(2-Hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[0433] Lithium hydroxide monohydrate (1.82 g) was added to a mixture of the compound synthesized in Example 3A (1.20 g), tetrahydrofuran (14 mL), and water (4.8 mL) at room temperature and stirred at 50°C for 12 hours. After adding saturated brine, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100 (v / v)] to obtain 0.448 g (yield: 40%) of the title compound as a single diastereomer and a single enantiomer.

[0434] Example 4

[0435] N-{(3S,4S)-2-(2-Hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}propane-2-sulfonamide

[0436] (4A) 2-methyl-1-oxo-1-{(3S,4S)-4-[(propan-2-ylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}propan-2-yl acetate

[0437] 1,8-Diazabicyclo[5.4.0]-7-undecene (41 mg) and isopropylsulfonyl chloride (23 mg) were added to a mixture of the compound synthesized in Example 2C (50 mg) and tetrahydrofuran (1.0 mL) at 0°C, followed by stirring at room temperature for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 45 / 55 to 25 / 75 (V / V)] to obtain 15 mg of the title compound as a single diastereomer and a single enantiomer (yield: 24%).

[0438] (4B) N-{(3S,4S)-2-(2-hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}propane-2-sulfonamide

[0439] Lithium hydroxide monohydrate (4.0 mg) was added to a mixture of the compound synthesized in Example 4A (15 mg), water (0.3 mL), and methanol (1.5 mL) at room temperature and stirred for 12 hours. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 52 / 48 to 32 / 68 (V / V)] to obtain 10 mg of the title compound as a single diastereomer and a single enantiomer (yield: 74%).

[0440] Example 5

[0441] N-{2-(Bicyclo[1.1.1]pentan-1-ylcarbonyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}ethanesulfonamide

[0442] (5A) 3-[(2,3',5'-Trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-one hydrochloride

[0443] Hydrochloric acid (12M, 320 mL) was added to a mixture of the compound synthesized in Example 1B (63 g), lithium chloride (5.4 g), and acetic acid (320 mL) at room temperature, and the mixture was stirred at 100°C for 12 hours. The solvent was distilled off under reduced pressure to obtain 55 g of the crude title compound.

[0444] (5B) tert-Butyl 4-oxo-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0445] Di-tert-butyl dicarbonate (18 g) was added to a mixture of the compound synthesized in Example 5A (23 g), triethylamine (33 g), and tetrahydrofuran (500 mL) at room temperature and stirred for 1 hour. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 10 / 1 to 5 / 1 (v / v)] to obtain 11 g of the title compound (yield: 41%).

[0446] (5C) tert-Butyl 4-(hydroxyimino)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0447] Using the compound (11 g) synthesized in Example 5B, 12 g of the crude title compound was obtained by the same method as in Example 2A.

[0448] (5D) tert-Butyl 4-amino-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0449] Sodium borohydride (10 g) was added to a mixture of the compound synthesized in Example 5C (12 g), molybdenum (VI) oxide (5.8 g), and methanol (200 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. The mixture was added to an aqueous ammonium chloride solution (500 mL), and the insoluble matter was removed by filtration. The filtrate was extracted twice with ethyl acetate, and the organic layers were combined and washed with saturated brine. After drying over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by reverse phase silica gel column chromatography [elution solvent: 0.1% trifluoroacetic acid aqueous solution / acetonitrile = 70 / 30-45 / 55 (V / V)] to obtain 7.0 g (yield: 58%) of the title compound as a single diastereomer (racemic body).

[0450] (5E) tert-Butyl 4-amino-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0451] The compound synthesized in Example 5D (7.0 g) was subjected to chiral SFC [column: CHIRALPAK (registered trademark) IG (50 mm ID×250 mm), mobile phase: carbon dioxide / 2-propanol = 55 / 45 (V / V)] to obtain 2.3 g (yield: 33%) of the title compound that eluted first as a single diastereomer and a single enantiomer.

[0452] (5F) tert-Butyl 4-[(ethylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0453] Ethyl chloride (952 mg) was added to a mixture of the compound synthesized in Example 5E (1.4 g), N,N-diisopropylethylamine (1.0 g), and tetrahydrofuran (20 mL) at room temperature and stirred for 10 hours. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 50 / 50 to 20 / 80 (V / V)] to obtain 0.90 g (yield: 53%) of the title compound as a single diastereomer and a single enantiomer.

[0454] (5G) N-{3-[(2,3',5'-Trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide hydrochloride

[0455] A 4 M solution of hydrogen chloride in ethyl acetate (8.0 mL) was added to a mixture of the compound synthesized in Example 5F (0.90 g) and ethyl acetate (10 mL) at room temperature and stirred for 10 hours. The solvent was distilled off under reduced pressure to obtain 0.80 g of the crude title compound as a single diastereomer and a single enantiomer.

[0456] (5H)N-{2-(Bicyclo[1.1.1]pentan-1-ylcarbonyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}ethanesulfonamide

[0457] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (40 mg) was added to a mixture of bicyclo[1.1.1]pentane-1-carboxylic acid (CAS Registry No.: 22287-28-1, 10 mg) and N,N-dimethylformamide (2.0 mL) at room temperature and stirred at 35°C for 10 minutes. The compound synthesized in Example 5G (30 mg) and triethylamine (35 mg) were added, followed by stirring at 35°C for 2 hours. Insoluble matter was removed by filtration, the filtrate was concentrated, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 43 / 57 to 23 / 77 (V / V)] to obtain 14 mg of the title compound as a single diastereomer and a single enantiomer (yield: 41%).

[0458] Example 6

[0459] 1-Fluoro-N-{2-(2-hydroxy-2-methylpropionyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0460] (6A) tert-Butyl 4-{[(fluoromethyl)sulfonyl]amino}-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0461] The compound synthesized in Example 5E (50 mg) and fluoromethanesulfonyl chloride (20 mg) were used in the same manner as in Example 5F to obtain 40 mg of the title compound as a single diastereomer and a single enantiomer (yield: 65%).

[0462] (6B) 1-Fluoro-N-{3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0463] A 4M solution of hydrogen chloride in ethyl acetate (3.0 mL) was added to a mixture of the compound synthesized in Example 6A (40 mg) and ethyl acetate (2.0 mL) at room temperature and stirred for 10 hours. The solvent was distilled off under reduced pressure to obtain 40 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0464] (6C) 1-(4-{[(fluoromethyl)sulfonyl]amino}-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl)-2-methyl-1-oxopropan-2-yl acetate

[0465] 2-Acetoxyisobutyryl chloride (30 mg) was added to a mixture of the compound synthesized in Example 6B (40 mg), triethylamine (28.3 mg), and tetrahydrofuran (5.0 mL) at room temperature and stirred for 10 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 50 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0466] (6D) 1-Fluoro-N-{2-(2-hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0467] Lithium hydroxide monohydrate (18.9 mg) was added to a mixture of the compound synthesized in Example 6C (50 mg), water (1.0 mL), and methanol (5.0 mL) at room temperature and stirred for 10 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 55 / 45 to 35 / 65 (v / v)] to obtain 11 mg of the title compound as a single diastereomer and a single enantiomer (yield: 24%).

[0468] Example 7

[0469] 4-[(Ethylsulfonyl)amino]-N,N-dimethyl-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxamide

[0470] (7A) 4-[(Ethylsulfonyl)amino]-N,N-dimethyl-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxamide

[0471] N,N-Dimethylcarbamyl chloride (17 mg) was added to a mixture of the compound synthesized in Example 5G (50 mg), triethylamine (33 mg), and tetrahydrofuran (5.0 mL) at room temperature and stirred for 10 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 53 / 47 to 23 / 77 (v / v)] to obtain 15 mg of the title compound as a single diastereomer and a single enantiomer (yield: 28%).

[0472] Example 8

[0473] N-{(3S,4S)-2-(2-Hydroxy-2-methylpropanoyl)-3-[(2,2',3'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0474] (8A) 2-tert-Butyl 3-(3-bromo-2-fluorobenzyl)-4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[0475] Cesium carbonate (9.0 g) was added to a mixture of 2-oxo-4-azabicyclo[3.1.1]heptane-3,4-dicarboxylic acid 4-tert-butyl ester 3-methyl ester (CAS Reg. No. 2241048-56-4, 5.0 g), 1-bromo-3-(bromomethyl)-2-fluorobenzene (CAS Reg. No. 149947-16-0, 6.0 g), and N,N-dimethylformamide (60 mL) at room temperature and stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 0 to 9 / 1 (v / v)] to obtain 6.0 g of the title compound (yield: 71%).

[0476] (8B) 3-(3-Bromo-2-fluorobenzyl)-2-azabicyclo[3.1.1]heptan-4-one hydrochloride

[0477] Hydrochloric acid (12M, 30 mL) was added to a mixture of the compound synthesized in Example 8A (6.0 g), lithium chloride (557 mg) and acetic acid (30 mL), and stirred at 100° C. for 12 hours. The solvent was distilled off under reduced pressure to obtain 10 g of the crude title compound.

[0478] (8C) tert-Butyl 3-(3-bromo-2-fluorobenzyl)-4-oxo-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0479] Di-tert-butyl dicarbonate (6.0 g) and triethylamine (9.0 g) were added to a mixture of the compound synthesized in Example 8B (6.0 g) and tetrahydrofuran (60 mL) at 0°C and stirred at 0°C for 2 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 0 to 9 / 1 (v / v)] to obtain 3.2 g of the title compound (yield: 45%).

[0480] (8D) tert-Butyl 3-(3-bromo-2-fluorobenzyl)-4-(hydroxyimino)-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0481] A mixture of the compound synthesized in Example 8C (3.2 g), hydroxylamine hydrochloride (2.5 g), sodium acetate (2.6 g), and ethanol (40 mL) was stirred at 80°C for 12 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 3.0 g of the crude title compound.

[0482] (8E)(3S*,4S*)-tert-Butyl 4-amino-3-(3-bromo-2-fluorobenzyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0483] Sodium borohydride (6.0 g) was added to a mixture of the compound synthesized in Example 8D (3.0 g), molybdenum (VI) oxide (1.6 g), and methanol (100 mL) at 0°C, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the title compound was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 80 / 20 to 50 / 50 (V / V)] to obtain a single diastereomer (racemic compound).

[0484] (8F)(3S,4S)-tert-Butyl 4-amino-3-(3-bromo-2-fluorobenzyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0485] The entire amount of the compound synthesized in Example 8E was subjected to chiral SFC [column: CHIRALPAK (registered trademark) AD (30 mm I.D. × 250 mm), mobile phase: carbon dioxide / 2-propanol = 70 / 30 (V / V)] to obtain 800 mg of the title compound that eluted first as a single diastereomer and a single enantiomer (yield: 28%).

[0486] (8G) tert-Butyl (3S,4S)-3-(3-bromo-2-fluorobenzyl)-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0487] Methanesulfonyl chloride (0.57 g) was added to a mixture of the compound synthesized in Example 8F (1.0 g), N,N-diisopropylethylamine (0.97 g), and tetrahydrofuran (20 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the product was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 57 / 43-27 / 73 (V / V)] to obtain 1.0 g of the title compound as a single diastereomer and a single enantiomer (yield: 84%).

[0488] (8H)N-[(3S,4S)-3-(3-Bromo-2-fluorobenzyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide hydrochloride

[0489] A 4 M solution of hydrogen chloride in 1,4-dioxane (20 mL) was added to a mixture of the compound synthesized in Example 8G (1.0 g) and methanol (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain 0.80 g of the crude title compound as a single diastereomer and a single enantiomer.

[0490] (8I) 1-{(3S,4S)-3-(3-bromo-2-fluorobenzyl)-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0491] 2-Acetoxyisobutyryl chloride (0.32 g) was added to a mixture of the compound synthesized in Example 8H (0.80 g), N,N-diisopropylethylamine (1.25 g), and tetrahydrofuran (10 mL) at room temperature and stirred for 1 hour. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 58 / 42 to 38 / 62 (v / v)] to obtain 700 mg of the title compound as a single diastereomer and a single enantiomer (yield: 72%).

[0492] (8J) 2-methyl-1-{(3S,4S)-4-[(methylsulfonyl)amino]-3-[(2,2',3'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-yl}-1-oxopropane-2-yl acetate

[0493] A mixture of the compound synthesized in Example 8I (50 mg), 2,3-difluorophenylboronic acid (19 mg), tripotassium phosphate (63 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (4.0 mg), water (0.3 mL), and tetrahydrofuran (2.0 mL) was degassed and stirred at 70°C for 2 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer silica gel chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 1 (v / v)] to obtain 30 mg of the title compound as a single diastereomer and a single enantiomer (yield: 56%).

[0494] (8K) N-{(3S,4S)-2-(2-Hydroxy-2-methylpropanoyl)-3-[(2,2',3'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0495] Lithium hydroxide (7.0 mg) was added to a mixture of the compound synthesized in Example 8J (30 mg), water (0.4 mL), and methanol (2.0 mL) at room temperature and stirred for 1 hour. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 61 / 39 to 41 / 59 (v / v)] to obtain 34 mg of the title compound as a single diastereomer and a single enantiomer (yield: 61%).

[0496] Example 9

[0497] N-{2-(azetidin-1-ylcarbonyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}ethanesulfonamide

[0498] (9A) N-{2-(azetidin-1-ylcarbonyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[0499] Triethylamine (66 mg) and 4-nitrophenyl chloroformate (55 mg) were added to a mixture of the compound synthesized in Example 5G (100 mg) and dichloromethane (8.0 mL) at 0°C, followed by stirring at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was added to a mixture of azetidine hydrochloride (89 mg), N,N-diisopropylethylamine (84 mg), and N,N-dimethylformamide (5.0 mL), followed by stirring at 80°C for 12 hours. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine. After drying over sodium sulfate, the mixture was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 50 / 50-30 / 70 (V / V)] to obtain 13 mg of the title compound as a single diastereomer and a single enantiomer (yield: 12%).

[0500] Example 10

[0501] N-[(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0502] (10A) 1-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0503] The compound synthesized in Example 8I (50 mg) and phenylboronic acid (12 mg) were used in the same manner as in Example 8J to obtain 40 mg of the title compound as a single diastereomer and a single enantiomer (yield: 78%).

[0504] (10B) N-[(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0505] Lithium hydroxide (10 mg) was added to a mixture of the compound synthesized in Example 10A (40 mg), methanol (1.5 mL), and water (0.3 mL) at room temperature and stirred for 12 hours. The solvent was distilled off under reduced pressure, and the pH was adjusted to 3 by adding hydrochloric acid (2 M). The mixture was extracted with ethyl acetate, and the organic layer was concentrated. The residue was then purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 58 / 42 to 38 / 62 (v / v)] to obtain 17 mg of the title compound as a single diastereomer and a single enantiomer (yield: 46%).

[0506] Example 11

[0507] N-[(3S,4S)-3-[(2-Fluoro-3'-methyl[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0508] (11A) 1-{(3S,4S)-3-[(2-fluoro-3'-methyl[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-yl}-2-methyl-1-oxopropane-2-yl acetate

[0509] The compound synthesized in Example 8I (50 mg) and 3-methylphenylboronic acid (16 mg) were used in the same manner as in Example 8J to obtain 44 mg of the title compound as a single diastereomer and a single enantiomer (yield: 86%).

[0510] (11B) N-[(3S,4S)-3-[(2-fluoro-3'-methyl[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0511] Lithium hydroxide monohydrate (17 mg) was added to a mixture of the compound synthesized in Example 11A (42 mg), methanol (3.0 mL), and water (0.5 mL) at room temperature and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 62 / 38 to 32 / 68 (V / V)] to obtain 21 mg of the title compound as a single diastereomer and a single enantiomer (yield: 55%).

[0512] Example 12

[0513] N-{5-Fluoro-2-(2-hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0514] (12A) Methyl 3-{trans-3-[(tert-butoxycarbonyl)amino]-1-fluorocyclobutyl}-3-oxopropanoate

[0515] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (20 g) was added to a mixture of trans-3-(tert-butoxycarbonylamino)-1-fluoro-cyclobutanecarboxylic acid (CAS Registry Number: 2408768-09-0, 20 g), 2,2-dimethyl-1,3-dioxane-4,6-dione (15 g), N,N-dimethylaminopyridine (16 g), and dichloromethane (200 mL) at room temperature and stirred for 12 hours. The mixture was diluted with dichloromethane, washed sequentially with aqueous potassium bisulfate solution and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and methanol (200 mL) was added to the residue, followed by stirring at 90°C for 3 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 0-5 / 1 (V / V)] to obtain 19 g of the title compound (yield: 77%).

[0516] (12B) Methyl 3-{trans-3-[(tert-butoxycarbonyl)amino]-1-fluorocyclobutyl}-2-diazo-3-oxopropanoate

[0517] Triethylamine (38 g) was added to a mixture of the compound synthesized in Example 12A (35 g), 4-acetamidobenzenesulfonyl azide (31 g), and acetonitrile (500 mL) at 0°C, followed by stirring at room temperature for 2 hours. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. Dichloromethane was added, and the insoluble matter was again removed by filtration. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 1 / 0 to 10 / 1 (v / v)] to obtain 25 g of the title compound (yield: 66%).

[0518] (12C) 2-tert-Butyl 3-methyl 5-fluoro-4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[0519] Rhodium (II) acetate dimer (0.0729 g) was added to a mixture of the compound synthesized in Example 12B (1.04 g) and toluene (20.8 mL), stirred at 90°C for 10 minutes, and cooled to room temperature. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 2 / 1 (v / v)] to obtain 0.948 g of the title compound (yield: quantitative).

[0520] (12D) 2-tert-Butyl 3-methyl 5-fluoro-4-oxo-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[0521] 3-(Bromomethyl)-2,3',5'-trifluoro[biphenyl] (0.994 g) and cesium carbonate (1.61 g) from Example 1A were added to a mixture of the compound synthesized in Example 12C (0.948 g) and N,N-dimethylformamide (14.2 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 3 / 1 (v / v)] to obtain 1.22 g of the title compound (yield: 73%).

[0522] (12E) 1-{5-fluoro-4-oxo-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0523] Hydrochloric acid (12 M, 12.2 mL) was added to a mixture of the compound synthesized in Example 12D (1.22 g) and acetic acid (2.44 mL), and the mixture was stirred at room temperature for 30 minutes. Lithium chloride (1.02 g) was added to the reaction mixture, stirred at 100°C for 8 hours, and then cooled to room temperature. The solvent was distilled off under reduced pressure, and toluene was added to perform azeotropy twice. To a mixture of the obtained residue and tetrahydrofuran (18.3 mL) were added triethylamine (1.67 mL) and 2-acetoxyisobutyryl chloride (0.522 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 1 / 2 (v / v)] to obtain 160 mg of the title compound (yield: 14%).

[0524] (12F) 1-{4-amino-5-fluoro-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]hept-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0525] Hydroxylamine hydrochloride (68.8 mg) and sodium acetate (81.2 mg) were added to a mixture of the compound synthesized in Example 12E (135 mg) and ethanol (13.5 mL), stirred at 80°C for 12 hours, and cooled to room temperature. Saturated brine and water were added, extracted with ethyl acetate, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Molybdenum (VI) oxide (1.22 g) was added to a mixture of the obtained residue and methanol (6.7 mL) at 0°C, and sodium borohydride (1.60 g) was slowly added little by little, and stirred at 0°C for 2 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction mixture, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0-50 / 50 (V / V)] to obtain 94.5 mg (yield: 70%) of the title compound as a single diastereomer (racemic form).

[0526] (12G) 1-{5-fluoro-4-[(methylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0527] Methanesulfonyl chloride (0.0429 mL) was added to a mixture of the compound synthesized in Example 12F (94.5 mg), triethylamine (0.127 mL), and tetrahydrofuran (1.89 mL) at room temperature and stirred for 2 hours. After addition of saturated brine, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100 (v / v)] to obtain 51.2 mg (yield: 50%) of the title compound as a single diastereomer (racemate).

[0528] (12H)N-{5-Fluoro-2-(2-hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0529] Lithium hydroxide monohydrate (71.8 mg) was added to a mixture of the compound synthesized in Example 12G (51.2 mg), tetrahydrofuran (0.51 mL), methanol (0.26 mL), and water (0.26 mL) at room temperature and stirred at 50°C for 6 hours. After addition of saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100 (v / v)] to obtain 35.3 mg of the title compound as a single diastereomer (racemic form) (yield: 80%).

[0530] (12I) N-{5-Fluoro-2-(2-hydroxy-2-methylpropanoyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0531] The compound synthesized in Example 12H (191 mg) was subjected to chiral HPLC [column: CHIRALPAK (registered trademark) IA (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 70 / 30 (V / V), temperature: 40°C] to obtain 82.3 mg (yield: 43%) of the title compound that eluted first as a single diastereomer and a single enantiomer.

[0532] Example 13

[0533] N-{3-[(3',5'-difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0534] (13A) 2-tert-Butyl 3-(3-bromobenzyl)-4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[0535] Using 2-oxo-4-azabicyclo[3.1.1]heptane-3,4-dicarboxylic acid 4-tert-butyl 3-methyl ester (CAS registration number: 2241048-56-4, 200 mg) and 3-bromobenzyl bromide (0.223 g), the title compound (274 mg, yield: 84%) was obtained by the same method as in Example 1B.

[0536] (13B) 1-[3-(3-bromobenzyl)-4-oxo-2-azabicyclo[3.1.1]hept-2-yl]-2-methyl-1-oxopropan-2-yl acetate

[0537] Hydrochloric acid (12M, 2.74 mL) was added to a mixture of the compound synthesized in Example 13A (274 mg) and acetic acid (0.548 mL), and the mixture was stirred at room temperature for 30 minutes. Lithium chloride (26.5 mg) was added to the reaction mixture, stirred at 100°C for 9 hours, and cooled to room temperature. The solvent was distilled off under reduced pressure, and toluene was added to perform azeotropy twice. Triethylamine (0.433 mL) and 2-acetoxyisobutyryl chloride (0.136 mL) were added to a mixture of the obtained residue and tetrahydrofuran (4.11 mL) at 0°C, and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 - 50 / 50 (V / V)] to obtain 222 mg of the title compound (yield: 87%).

[0538] (13C) 1-[4-amino-3-(3-bromobenzyl)-2-azabicyclo[3.1.1]heptan-2-yl]-2-methyl-1-oxopropan-2-yl acetate

[0539] Hydroxylamine hydrochloride (0.132 g) and sodium acetate (0.156 g) were added to a mixture of the compound synthesized in Example 13B (222 mg) and ethanol (2.22 mL), stirred at 80°C for 2 hours, and cooled to room temperature. The solvent was distilled off under reduced pressure, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Molybdenum (VI) oxide (0.392 g) was added to a mixture of the obtained residue and methanol (6.66 mL) at 0°C, and sodium borohydride (0.412 g) was added little by little, and stirred at 0°C for 2 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction mixture, which was then filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 0.223 g of the crude title compound.

[0540] (13D) 1-{3-(3-bromobenzyl)-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0541] The compound synthesized in Example 13C (239 mg) and methanesulfonyl chloride (0.127 mL) were used in the same manner as in Example 1E to obtain 111 mg (yield: 42%) of the title compound as a single diastereomer (racemate).

[0542] (13E) 1-{3-[(3',5'-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0543] The compound synthesized in Example 13D (111 mg) and 3,5-difluorophenylboronic acid (53.9 mg) were used in the same manner as in Example 8J to obtain 118 mg of the title compound as a single diastereomer (racemate) (yield: 99%).

[0544] (13F) N-{3-[(3',5'-difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0545] The compound synthesized in Example 13E (118 mg) was used in the same manner as in Example 12H to obtain 76 mg (yield: 75%) of the title compound as a single diastereomer (racemate).

[0546] Example 14

[0547] N-[(3S,4S)-3-[(2-Fluoro-3'-methoxy[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0548] (14A) 1-{(3S,4S)-3-[(2-fluoro-3'-methoxy[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0549] The compound synthesized in Example 8I (50 mg) and 3-methoxyphenylboronic acid (20 mg) were used to obtain 30 mg of the title compound as a single diastereomer and a single enantiomer (yield: 57%) by the same method as in Example 8J.

[0550] (14B) N-[(3S,4S)-3-[(2-fluoro-3'-methoxy[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0551] Lithium hydroxide (8 mg) was added to a mixture of the compound synthesized in Example 14A (30 mg), methanol (2.0 mL), and water (0.5 mL) at room temperature and stirred for 12 hours. The solvent was distilled off under reduced pressure, and the pH was adjusted to 3 by adding hydrochloric acid (2 M). The mixture was extracted with ethyl acetate, and the organic layer was concentrated. The residue was then purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 57 / 43 to 37 / 63 (V / V)] to obtain 17 mg of the title compound as a single diastereomer and a single enantiomer (yield: 60%).

[0552] Example 15

[0553] N-{(3S,4S)-2-[(2S)-2-hydroxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0554] (15A) (3S,4S)-tert-Butyl 4-[(methylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0555] The compound synthesized in Example 8G (96.0 mg) and 3,5-difluorophenylboronic acid (48 mg) were used to obtain 99 mg of the title compound as a single diastereomer and a single enantiomer (yield: 96%) by the same method as in Example 8J.

[0556] (15B) N-{(3S,4S)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0557] Using the compound synthesized in Example 15A (99 mg), the crude title compound (91 mg) was obtained as a single diastereomer and a single enantiomer by the same method as in Example 8H.

[0558] (15C) N-{(3S,4S)-2-[(2S)-2-hydroxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0559] The compound synthesized in Example 15B (50 mg) and 2-hydroxypropionic acid (12 mg) were used in the same manner as in Example 5H to obtain 6.7 mg of the title compound as a single diastereomer and a single enantiomer (yield: 12%).

[0560] Example 16

[0561] N-{(3S,4S)-2-[(2R)-2-hydroxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0562] (16A) N-{(3S,4S)-2-[(2R)-2-hydroxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0563] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (40 mg) was added to a mixture of (R)-2-hydroxypropionic acid (8.0 mg) and N,N-dimethylformamide (1.0 mL), followed by stirring at 35° C. for 1.5 hours. N-{(3S,4S)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide monohydrochloride (30 mg) and triethylamine (35 mg) from Example 15B were added, followed by stirring at 35° C. for 2.5 hours. The insoluble material was removed by filtration, and the filtrate was concentrated and purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 60 / 40-40 / 60 (V / V)] to obtain 14 mg of the title compound as a single diastereomer and a single enantiomer (yield: 43%).

[0564] Example 17

[0565] N-{(3S,4S)-2-[(2R)-Tetrahydrofuran-2-ylcarbonyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0566] (17A) N-{(3S,4S)-2-[(2R)-tetrahydrofuran-2-ylcarbonyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0567] The compound synthesized in Example 15B (50 mg) and (R)-tetrahydrofuran-2-carboxylic acid (16 mg) were used in the same manner as in Example 5H to obtain 27 mg of the title compound as a single diastereomer and a single enantiomer (yield: 47%).

[0568] Example 18

[0569] N-[(3S,4S)-3-{[2-fluoro-3'-(trifluoromethyl)[biphenyl]-3-yl]methyl}-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0570] (18A) 1-{(3S,4S)-3-{[2-fluoro-3'-(trifluoromethyl)[biphenyl]-3-yl]methyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0571] The compound synthesized in Example 8I (50 mg) and 3-trifluoromethylphenylboronic acid (24 mg) were used to obtain 60 mg of the crude title compound as a single diastereomer and a single enantiomer by the same method as in Example 8J.

[0572] (18B) N-[(3S,4S)-3-{[2-fluoro-3'-(trifluoromethyl)[biphenyl]-3-yl]methyl}-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0573] Lithium hydroxide monohydrate (22 mg) was added to a mixture of the compound synthesized in Example 18A (60 mg), methanol (5.0 mL), and water (1.0 mL) at room temperature and stirred for 10 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 53 / 47 to 33 / 67 (v / v)] to obtain 16 mg of the title compound as a single diastereomer and a single enantiomer (yield: 30%).

[0574] Example 19

[0575] N-{(3S,4S)-2-[(1-Fluorocyclopropyl)carbonyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0576] (19A) N-{(3S,4S)-2-[(1-fluorocyclopropyl)carbonyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0577] The compound synthesized in Example 15B (30 mg) and 1-fluorocyclopropanecarboxylic acid (10 mg) were used in the same manner as in Example 5H to obtain 29 mg of the title compound as a single diastereomer and a single enantiomer (yield: 88%).

[0578] Example 20

[0579] N-{(3S,4S)-2-(Cyclopropylcarbonyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0580] (20A) N-{(3S,4S)-2-(cyclopropylcarbonyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0581] N,N-diisopropylethylamine (236 mg) and cyclopropanecarbonyl chloride (46 mg) were added to a mixture of the compound synthesized in Example 15B (150 mg) and tetrahydrofuran (5.0 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% formic acid aqueous solution / acetonitrile = 55 / 45-25 / 75 (V / V)] to obtain 96 mg of the title compound as a single diastereomer and a single enantiomer (yield: 55%).

[0582] Example 21

[0583] N-[(3S,4S)-3-[3-(6-chloropyridin-2-yl)-2-fluorobenzyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0584] (21A) (3S,4S)-tert-Butyl 3-[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0585] A mixture of the compound synthesized in Example 8G (200 mg), bis(pinacolato)diboron (220 mg), potassium acetate (65 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (35 mg), and 1,4-dioxane (5.0 mL) was degassed and stirred at 100°C for 2 hours under a nitrogen atmosphere. After filtration, the solvent was distilled off under reduced pressure to obtain 110 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0586] (21B) (3S,4S)-tert-Butyl 3-[3-(6-chloropyridin-2-yl)-2-fluorobenzyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0587] A mixture of the compound synthesized in Example 21A (110 mg), cesium carbonate (140 mg), 2,6-dichloropyridine (45 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (10 mg), water (0.5 mL), and 1,4-dioxane (3.0 mL) was degassed and stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine. The mixture was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative thin-layer silica gel chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 1 (v / v)] to obtain 90 mg of the title compound as a single diastereomer and a single enantiomer (yield: 84%).

[0588] (21C) N-{(3S,4S)-3-[3-(6-chloropyridin-2-yl)-2-fluorobenzyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide hydrochloride

[0589] Using the compound synthesized in Example 21B (90 mg), the same procedure as in Example 8H was followed to obtain 80 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0590] (21D) 1-{(3S,4S)-3-[3-(6-chloropyridin-2-yl)-2-fluorobenzyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0591] N,N-diisopropylethylamine (118 mg) and 2-acetoxyisobutyryl chloride (45 mg) were added to a mixture of the compound synthesized in Example 21C (80 mg) and tetrahydrofuran (2.0 mL) at room temperature and stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer silica gel chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 1 (V / V)] to obtain 80 mg of the title compound as a single diastereomer and a single enantiomer (yield: 96%).

[0592] (21E) N-[(3S,4S)-3-[3-(6-chloropyridin-2-yl)-2-fluorobenzyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0593] Lithium hydroxide (20 mg) was added to a mixture of the compound synthesized in Example 21D (80 mg), water (0.5 mL), and tetrahydrofuran (2.0 mL) at room temperature and stirred for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse phase silica gel column chromatography [elution solvent: 0.225% formic acid aqueous solution / acetonitrile = 68 / 32-38 / 62 (V / V)] to obtain 18 mg of the title compound as a single diastereomer and a single enantiomer (yield: 23%).

[0594] Example 22

[0595] N-[2-(Cyclopropylcarbonyl)-3-{[2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]methyl}-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0596] (22A) 2-(3,5-difluorophenyl)-3-fluoro-4-methylpyridine

[0597] Potassium carbonate (14 g) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (2.0 g) were added to a mixture of 2-bromo-3-fluoro-4-methylpyridine (CAS Reg. No.: 884494-37-5, 9.5 g), 3,5-difluorophenylboronic acid (10.5 g), water (5.0 mL), and 1,4-dioxane (100 mL), and stirred at 100°C for 12 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 10 / 1 (v / v)] to obtain 10.2 g of the title compound (yield: 91%).

[0598] (22B) 4-(Bromomethyl)-2-(3,5-difluorophenyl)-3-fluoropyridine

[0599] N-Bromosuccinimide (8.0 g) and benzoyl peroxide (1.3 g) were added to a mixture of the compound synthesized in Example 22A (8.0 g) and carbon tetrachloride (80 mL), and the mixture was stirred at 80°C for 12 hours. After washing with water, the solvent was distilled off under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 45 / 55 to 25 / 75 (v / v)] to obtain 5.8 g of the title compound (yield: 54%).

[0600] (22C) 2-tert-Butyl 3-{[2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]methyl}-4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[0601] Cesium carbonate (3.63 g) was added to a mixture of the compound synthesized in Example 22B (2.69 g), 2-oxo-4-azabicyclo[3.1.1]heptane-3,4-dicarboxylic acid O4-tert-butyl O3-methyl ester (CAS Registry No. 2241048-56-4, 2.0 g), and N,N-dimethylformamide (30 mL) at room temperature and stirred for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 10 / 1 to 4 / 1 (v / v)] to obtain 2.95 g of the title compound (yield: 81%).

[0602] (22D) tert-Butyl 3-{[2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]methyl}-4-oxo-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0603] A mixture of the compound synthesized in Example 22C (1.1 g), lithium chloride (380 mg), and dimethyl sulfoxide (20 mL) was stirred at 130°C for 1 hour. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 970 mg of the crude title compound.

[0604] (22E) 3-{[2-(3,5-Difluorophenyl)-3-fluoropyridin-4-yl]methyl}-2-azabicyclo[3.1.1]heptan-4-one hydrochloride

[0605] A solution of hydrogen chloride in ethyl acetate (4M, 10 mL) was added to a mixture of the compound synthesized in Example 22D (970 mg) and ethyl acetate (10 mL) at room temperature and stirred for 10 minutes. The solvent was distilled off under reduced pressure to obtain 800 mg of the crude title compound.

[0606] (22F)2-(Cyclopropylcarbonyl)-3-{[2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]methyl}-2-azabicyclo[3.1.1]heptan-4-one

[0607] Cyclopropanecarbonyl chloride (453 mg) was added to a mixture of the compound synthesized in Example 22E (800 mg), N,N-diisopropylethylamine (1.40 g), and dichloromethane (20 mL) at room temperature and stirred for 30 minutes. The mixture was diluted with dichloromethane, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1 (v / v)] to obtain 550 mg of the title compound (yield: 63%).

[0608] (22G) Cyclopropyl[3-{[2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]methyl}-4-(hydroxyimino)-2-azabicyclo[3.1.1]heptan-2-yl]methanone

[0609] A mixture of the compound synthesized in Example 22F (550 mg), hydroxylamine hydrochloride (286 mg), sodium acetate (450 mg), and ethanol (10 mL) was stirred at 80°C for 2 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 500 mg of the crude title compound.

[0610] (22H)(4-amino-3-{[2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]methyl}-2-azabicyclo[3.1.1]heptan-2-yl)(cyclopropyl)methanone

[0611] Sodium borohydride (634 mg) was added to a mixture of the compound synthesized in Example 22G (500 mg), molybdenum (VI) oxide (259 mg), and methanol (20 mL) at 0°C, followed by stirring at room temperature for 2 hours. The reaction solution was poured into an aqueous ammonium chloride solution, and the insoluble matter was removed by filtration. Extraction was performed with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the product was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 87 / 13 to 67 / 33 (V / V)] to obtain 60 mg of the title compound as a single diastereomer (racemic form) (yield: 12%).

[0612] (22I) N-[2-(Cyclopropylcarbonyl)-3-{[2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]methyl}-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0613] Methanesulfonyl chloride (425 mg) was added to a mixture of the compound synthesized in Example 22H (240 mg), N,N-diisopropylethylamine (309 mg), and tetrahydrofuran (10 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the product was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 64 / 36 to 34 / 66 (V / V)] to obtain 250 mg of the title compound as a single diastereomer (racemic form) (yield: 87%).

[0614] (22J) N-[2-(Cyclopropylcarbonyl)-3-{[2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]methyl}-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0615] The compound synthesized in Example 22I (250 mg) was subjected to chiral SFC [column: CHIRALPAK (registered trademark) IG (30 mm ID×250 mm), mobile phase: carbon dioxide / methanol = 70 / 30 (V / V)] to obtain 96 mg (yield: 39%) of the title compound that eluted first as a single diastereomer and a single enantiomer.

[0616] Example 23

[0617] N-{(3S,4R)-5-fluoro-2-[(2R)-2-hydroxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide or N-{(3R,4S)-5-fluoro-2-[(2R)-2-hydroxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0618] (23A) 2-tert-Butyl 3-(3-bromo-2-fluorobenzyl)-5-fluoro-4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[0619] Cesium carbonate (4.12 g) was added to a mixture of the compound synthesized in Example 12C (2.42 g), 3-bromo-2-fluorobenzyl bromide (2.71 g), and N,N-dimethylformamide (40 mL) at 0°C. The mixture was stirred for 10 minutes and then at room temperature for 4.5 hours. Water was added, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 95 / 5 to 75 / 25 (v / v)] to obtain 2.14 g of the title compound (yield: 54%).

[0620] (23B) tert-Butyl 3-(3-bromo-2-fluorobenzyl)-5-fluoro-4-oxo-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0621] A mixture of the compound synthesized in Example 23A (1.77 g), lithium chloride (532 mg), and dimethyl sulfoxide (44 mL) was stirred at 130°C for 1 hour. After adding brine, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30 (v / v)] to obtain 1.05 g of the title compound (yield: 68%).

[0622] (23C) tert-Butyl 3-(3-bromo-2-fluorobenzyl)-5-fluoro-4-(hydroxyimino)-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0623] A mixture of the compound synthesized in Example 23B (1.15 g), hydroxylamine hydrochloride (1.15 g), sodium acetate (1.36 g), and ethanol (25 mL) was stirred at 90°C for 5 hours. After adding brine, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration,

[0624] The residue was concentrated under reduced pressure and purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 - 40 / 60 (V / V)] to obtain 833 mg of the title compound (yield: 70%).

[0625] (23D) tert-Butyl 4-amino-3-(3-bromo-2-fluorobenzyl)-5-fluoro-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0626] To a mixture of the compound synthesized in Example 23C (100 mg) and methanol (4 mL) was added platinum (VI) oxide (167 mg) at 0°C, followed by the addition of sodium borohydride (175 mg) little by little, and the mixture was stirred at 35°C for 4 hours. Platinum (VI) oxide (167 mg) was added at room temperature, followed by the addition of sodium borohydride (175 mg) little by little, and the mixture was stirred at 45°C for 2 hours. Platinum (VI) oxide (167 mg) was added at room temperature, followed by the addition of sodium borohydride (175 mg) little by little, and the mixture was stirred at 45°C for 4 hours. To a mixture of tert-butyl 3-(3-bromo-2-fluorobenzyl)-5-fluoro-4-(hydroxyimino)-2-azabicyclo[3.1.1]heptane-2-carboxylate (708 mg) prepared separately from Example 23C and methanol (25 mL) was added platinum (VI) oxide (1.18 g) at 0°C, followed by the addition of sodium borohydride (1.24 g) little by little, and the mixture was stirred at 45°C for 4 hours. Platinum (VI) oxide (1.18 g) at 0°C, followed by the addition of sodium borohydride (1.24 g) little by little, and the mixture was stirred at 45°C for 6 hours. Platinum (VI) oxide (1.18 g) at 0°C, followed by the addition of sodium borohydride (1.24 g) little by little, and the mixture was stirred at 45°C for 2 hours. To this was added molybdenum (VI) oxide (1.18 g) at room temperature, followed by the addition of sodium borohydride (1.24 g) little by little, and the mixture was stirred at 45°C for 5 hours. The reaction mixtures were combined and added to a mixture of saturated sodium bicarbonate water and ethyl acetate at 0°C, followed by stirring at room temperature for 1 hour. After filtering to remove insoluble matter, the filtrate was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 85 / 15-20 / 80 (V / V)] to obtain 449 mg of the title compound (yield: 57%).

[0627] (23E)(3S*,4R*)-tert-Butyl 3-(3-bromo-2-fluorobenzyl)-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0628] A solution of methanesulfonyl chloride (370 mg) in tetrahydrofuran (2 mL) was added to a mixture of the compound synthesized in Example 23D (449 mg), triethylamine (0.746 mL), and tetrahydrofuran (10 mL) at 0°C, and the mixture was stirred overnight at room temperature. Water was added, followed by extraction with ethyl acetate, washing with saturated brine, and drying over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 85 / 15 to 25 / 75 (v / v)] to obtain 504 mg of the title compound as a single diastereomer (racemic form) (yield: 95%).

[0629] (23F)(3S*,4R*)-tert-Butyl 5-fluoro-4-[(methylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0630] A mixture of the compound synthesized in Example 23E (150 mg), 3,5-difluorophenylboronic acid (71.7 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (25.6 mg), tripotassium phosphate (193 mg), tetrahydrofuran (3 mL), and water (1 mL) was stirred at 65°C for 2 hours. After adding water, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60 (v / v)] to obtain 189 mg of the title compound as a single diastereomer (racemic form) (yield: quantitative).

[0631] (23G) N-{(3S*,4R*)-5-Fluoro-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0632] A 4 M solution of hydrogen chloride in 1,4-dioxane (6 mL) was added to a mixture of the compound synthesized in Example 23F (189 mg) and 1,4-dioxane (2 mL) at room temperature and stirred for 4 hours. The reaction mixture was diluted with toluene and concentrated under reduced pressure to obtain 141 mg of the crude title compound as a single diastereomer (racemate).

[0633] (23H) (2R)-1-{(3S*,4R*)-5-fluoro-4-[(methylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-1-oxopropan-2-yl acetate

[0634] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (132 mg) was added to a mixture of the compound synthesized in Example 23G (81.0 mg), (R)-2-acetoxypropionic acid (46.0 mg), triethylamine (0.0966 mL), and N,N-dimethylformamide (3.5 mL) at room temperature, followed by stirring at 35°C for 4 hours. Water was added, followed by extraction with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 10 / 90 (v / v)] to obtain 101 mg of the title compound (yield: quantitative).

[0635] (23I) N-{(3S*,4R*)-5-Fluoro-2-[(2R)-2-hydroxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0636] Lithium hydroxide monohydrate (21.9 mg) was added to a mixture of the compound synthesized in Example 23H (101 mg), tetrahydrofuran (2.4 mL), methanol (0.8 mL), and water (0.8 mL) at room temperature and stirred for 5 hours. After adding brine, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100 (v / v)] to obtain 80.6 mg of the title compound (yield: 93%).

[0637] (23J) N-{(3S,4R)-5-fluoro-2-[(2R)-2-hydroxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide or N-{(3R,4S)-5-fluoro-2-[(2R)-2-hydroxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0638] The compound synthesized in Example 23I (80.1 mg) was purified by chiral HPLC [column: CHIRALPAK (registered trademark) IH (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 50 / 50 (V / V), temperature: 40°C] to obtain 32.3 mg (yield: 40%) of the title compound that eluted earlier as a single diastereomer and a single enantiomer.

[0639] Example 24

[0640] N-{(3S,4S)-3-{[3'-(Difluoromethyl)-2-fluoro[biphenyl]-3-yl]methyl}-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0641] (24A) (3S,4S)-tert-Butyl 3-{[3'-(difluoromethyl)-2-fluoro[biphenyl]-3-yl]methyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0642] The compound synthesized in Example 8G (100 mg) and 3-(difluoromethyl)phenylboronic acid (54 mg) were used in the same manner as in Example 8J to obtain 200 mg of the title compound as a single diastereomer and a single enantiomer contaminated with a by-product.

[0643] (24B) N-[(3S,4S)-3-{[3'-(difluoromethyl)-2-fluoro[biphenyl]-3-yl]methyl}-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0644] A 4 M solution of hydrogen chloride in ethyl acetate (2.0 mL) was added to a mixture of the compound synthesized in Example 24A (200 mg) and ethyl acetate (5.0 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.05% aqueous ammonia / acetonitrile = 67 / 33 to 37 / 63 (v / v)] to obtain 110 mg of the title compound as a single diastereomer and a single enantiomer (yield: 68%).

[0645] (24C) N-{(3S,4S)-3-{[3'-(difluoromethyl)-2-fluoro[biphenyl]-3-yl]methyl}-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0646] The compound synthesized in Example 24B (50 mg) and (R)-2-hydroxypropionic acid (21 mg) were used in the same manner as in Example 5H to obtain 15 mg of the title compound as a single diastereomer and a single enantiomer (yield: 26%).

[0647] Example 25

[0648] N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0649] (25A) (3S,4S)-tert-Butyl 3-[(2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0650] Phenylboronic acid (153 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (44 mg), and tripotassium phosphate (667 mg) were added to a mixture of the compound synthesized in Example 8G (500 mg) and tetrahydrofuran (5.0 mL). After degassing, the mixture was stirred at 70°C for 1.5 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 10 / 1 to 2 / 1 (v / v)] to obtain 400 mg of the title compound as a single diastereomer and a single enantiomer (yield: 80%).

[0651] (25B) N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0652] A 4M solution of hydrogen chloride in ethyl acetate (5.0 mL) was added to a mixture of the compound synthesized in Example 25A (400 mg) and ethyl acetate (5.0 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain 280 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0653] (25C) N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0654] The compound synthesized in Example 25B (100 mg) and triethylamine (135 mg) were added to a mixture of (R)-2-hydroxypropionic acid (48 mg), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (152 mg), and N,N-dimethylformamide (2.0 mL), and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the mixture was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 70 / 30 to 40 / 60 (V / V)] to obtain 44 mg of the title compound as a single diastereomer and a single enantiomer (yield: 37%).

[0655] Example 26

[0656] N-{(3S,4S)-2-[(2R)-2-hydroxybutyryl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0657] (26A) N-{(3S,4S)-2-[(2R)-2-hydroxybutyryl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0658] The compound synthesized in Example 15B (100 mg) and (R)-2-hydroxybutyric acid (35 mg) were used in the same manner as in Example 5H to obtain 25 mg of the title compound as a single diastereomer and a single enantiomer (yield: 23%).

[0659] Example 27

[0660] (3S,4S)-N-Methyl-4-[(methylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxamide

[0661] (27A) (3S,4S)-N-Methyl-4-[(methylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxamide

[0662] N-Methylcarbamoyl chloride (16 mg) was added to a mixture of the compound synthesized in Example 15B (50 mg), N,N-diisopropylethylamine (72 mg), and tetrahydrofuran (2.0 mL), and stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 61 / 39 to 31 / 69 (v / v)] to obtain 17 mg of the title compound as a single diastereomer and a single enantiomer (yield: 34%).

[0663] Example 28

[0664] N-{(3S,4S)-2-(Methoxyacetyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0665] (28A) N-{(3S,4S)-2-(methoxyacetyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0666] N,N-diisopropylethylamine (78 mg) and 2-methoxyacetyl chloride (15 mg) were added to a mixture of the compound synthesized in Example 15B (50 mg) and tetrahydrofuran (1.0 mL) at room temperature and stirred for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and then washed with saturated brine. The mixture was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% formic acid aqueous solution / acetonitrile = 61 / 39-31 / 69 (V / V)] to obtain 32 mg of the title compound as a single diastereomer and a single enantiomer (yield: 55%).

[0667] Example 29

[0668] N-{(3S,4S)-2-{[(1R,2S)-2-Fluorocyclopropyl]carbonyl}-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0669] (29A) N-{(3S,4S)-2-{[(1R,2S)-2-fluorocyclopropyl]carbonyl}-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0670] Triethylamine (0.047 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (31 mg), and (1R,2S)-2-fluorocyclopropane-1-carboxylic acid (8 mg) were added to a mixture of the compound synthesized in Example 15B (30.0 mg) and dichloromethane (2 mL). The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 50 / 50 to 20 / 80 (v / v)] to obtain 31 mg of the title compound as a single diastereomer and a single enantiomer (yield: 93%).

[0671] Example 30

[0672] N-{(3S,4S)-2-{[(1S,2R)-2-fluorocyclopropyl]carbonyl}-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0673] (30A) N-{(3S,4S)-2-{[(1S,2R)-2-fluorocyclopropyl]carbonyl}-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0674] The compound synthesized in Example 15B (30.0 mg) and (1S,2R)-2-fluorocyclopropane-1-carboxylic acid (8.0 mg) were used to obtain 32 mg of the title compound as a single diastereomer and a single enantiomer (yield: 96%) by the same method as in Example 29A.

[0675] Example 31

[0676] N-{(3S,4S)-3-[(3'-cyano-2,5'-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0677] (31A) (3S,4S)-tert-Butyl 3-[(3'-cyano-2,5'-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0678] The compound synthesized in Example 8G (49.2 mg) and 3-cyano-5-fluorophenylboronic acid (25.5 mg) were used to obtain 62.4 mg of the title compound as a single diastereomer and a single enantiomer (yield: 99%) by the same method as in Example 8J.

[0679] (31B) N-{(3S,4S)-3-[(3'-cyano-2,5'-difluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0680] A 1,4-dioxane solution of hydrogen chloride (4 M, 1.0 mL) was added to the compound synthesized in Example 31A (62.4 mg) at room temperature and stirred for 3 hours. The solvent was distilled off under reduced pressure, and the mixture was washed with ethyl acetate to obtain 37.0 mg of the title compound as a single diastereomer and a single enantiomer (yield: 79%).

[0681] (31C) (2R)-1-{(3S,4S)-3-[(3'-cyano-2,5'-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-1-oxopropan-2-yl acetate

[0682] N,N-Diisopropylethylamine (0.0227 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (33.0 mg) were added to a mixture of the compound synthesized in Example 31B (19.7 mg), (R)-2-acetoxypropionic acid (0.0058 mL), and N,N-dimethylformamide (1.0 mL) at room temperature and stirred for 1 hour. Water was added, followed by extraction with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 20 / 80 (v / v)] to obtain 27.3 mg of the title compound as a single diastereomer and a single enantiomer (yield: quantitative).

[0683] (31D) N-{(3S,4S)-3-[(3'-cyano-2,5'-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0684] Potassium carbonate (12.0 mg) was added to a mixture of the compound synthesized in Example 31C (27.3 mg) and methanol (1.0 mL) at room temperature and stirred for 1.5 hours. After adding aqueous ammonium chloride, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 1 / 1 to 0 / 1 (v / v)] to obtain 11.4 mg (yield: 54%) of the title compound as a single diastereomer and a single enantiomer.

[0685] Example 32

[0686] N-{(3S,4S)-3-[2-Fluoro-3-(1-methyl-1H-pyrazol-3-yl)benzyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0687] (32A) (3S,4S)-tert-Butyl 3-[2-fluoro-3-(1-methyl-1H-pyrazol-3-yl)benzyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0688] Using the compound synthesized in Example 8G (50.2 mg) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32.8 mg), the title compound 58.8 mg (yield: 99%) was obtained as a single diastereomer and a single enantiomer by the same method as in Example 8J.

[0689] (32B) N-{(3S,4S)-3-[2-Fluoro-3-(1-methyl-1H-pyrazol-3-yl)benzyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide hydrochloride

[0690] A 1,4-dioxane solution of hydrogen chloride (4 M, 1.0 mL) was added to the compound synthesized in Example 32A (58.8 mg) at room temperature and stirred for 3 hours. The solvent was distilled off under reduced pressure, and the mixture was washed with ethyl acetate to obtain 38.8 mg of the title compound as a single diastereomer and a single enantiomer (yield: 89%).

[0691] (32C) (2R)-1-{(3S,4S)-3-[2-fluoro-3-(1-methyl-1H-pyrazol-3-yl)benzyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-1-oxopropan-2-yl acetate

[0692] The compound synthesized in Example 32B (19.8 mg) and (R)-2-acetoxypropionic acid (0.0064 mL) were used in the same manner as in Example 31C to obtain 8.2 mg of the title compound as a single diastereomer and a single enantiomer (yield: 35%).

[0693] (32D) N-{(3S,4S)-3-[2-Fluoro-3-(1-methyl-1H-pyrazol-3-yl)benzyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0694] The compound synthesized in Example 32C (8.2 mg) was used in the same manner as in Example 31D to obtain 7.3 mg (yield: 97%) of the title compound as a single diastereomer and a single enantiomer.

[0695] Example 33

[0696] N-{(3S,4S)-2-[(1-Cyanocyclopropyl)carbonyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0697] (33A) N-{(3S,4S)-2-[(1-Cyanocyclopropyl)carbonyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0698] The compound synthesized in Example 15B (22.3 mg) and 1-cyano-1-cyclopropanecarboxylic acid (6.7 mg) were used to obtain 25.6 mg of the title compound as a single diastereomer and a single enantiomer (yield: quantitative) by the same method as in Example 31C.

[0699] Example 34

[0700] N-{(3S,4S)-2-(Hydroxyacetyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0701] (34A) 2-{(3S,4S)-4-[(methylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-2-oxoethyl acetate

[0702] 2-Acetoxyacetyl chloride (18 mg) was added to a mixture of the compound synthesized in Example 15B (50 mg), N,N-diisopropylethylamine (72 mg), and tetrahydrofuran (0.5 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 50 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0703] (34B) N-{(3S,4S)-2-(hydroxyacetyl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0704] Lithium hydroxide (12 mg) was added to a mixture of the compound synthesized in Example 34A (50 mg), methanol (2.0 mL), and water (0.2 mL), and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 59 / 41 to 39 / 61 (v / v)] to obtain 33 mg of the title compound as a single diastereomer and a single enantiomer (yield: 72%).

[0705] Example 35

[0706] (3S,4S)-4-[(Methylsulfonyl)amino]-N-(propan-2-yl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxamide

[0707] (35A) (3S,4S)-4-[(Methylsulfonyl)amino]-N-(propan-2-yl)-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxamide

[0708] Isopropyl isocyanate (7 mg) was added to a mixture of the compound synthesized in Example 15B (30 mg), N,N-diisopropylethylamine (43 mg), and tetrahydrofuran (0.5 mL), and stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 53 / 47 to 23 / 77 (v / v)] to obtain 23 mg of the title compound as a single diastereomer and a single enantiomer (yield: 69%).

[0709] Example 36

[0710] N-{(3S,4R)-2-(cyclopropylcarbonyl)-5-fluoro-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide or N-{(3R,4S)-2-(cyclopropylcarbonyl)-5-fluoro-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0711] (36A) N-{(3S*,4R*)-2-(Cyclopropylcarbonyl)-5-fluoro-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0712] Cyclopropanecarbonyl chloride (0.0235 mL) was added to a mixture of the compound synthesized in Example 23G (60.0 mg), N,N-diisopropylethylamine (0.0878 mL), and tetrahydrofuran (2.5 mL) and stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 70 / 30 to 10 / 90 (v / v)] to obtain 60.2 mg (yield: 94%) of the title compound as a single diastereomer (racemate).

[0713] (36B) N-{(3S,4R)-2-(cyclopropylcarbonyl)-5-fluoro-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide or N-{(3R,4S)-2-(cyclopropylcarbonyl)-5-fluoro-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0714] The compound synthesized in Example 36A (60.2 mg) was subjected to chiral HPLC [column: CHIRALPAK (registered trademark) IG (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 60 / 40 (V / V), temperature: 40°C] to obtain 27.5 mg (yield: 46%) of the title compound that eluted first as a single diastereomer and a single enantiomer.

[0715] Example 37

[0716] (3S,4S)-N-Ethyl-3-[(2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxamide

[0717] (37A) (3S,4S)-N-Ethyl-3-[(2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxamide

[0718] Ethyl isocyanate (18 mg) was added to a mixture of the compound synthesized in Example 25B (70 mg), N,N-diisopropylethylamine (66 mg), and tetrahydrofuran (1.0 mL) at 0°C, followed by stirring at room temperature for 30 minutes. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 64 / 36 to 34 / 66 (v / v)] to obtain 46 mg of the title compound as a single diastereomer and a single enantiomer (yield: 60%).

[0719] Example 38

[0720] N-{(3S,4S)-3-[3-(2,2-difluoro-1,3-benzodioxole-4-yl)-2-fluorobenzyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0721] (38A) (3S,4S)-tert-Butyl 3-[3-(2,2-difluoro-1,3-benzodioxol-4-yl)-2-fluorobenzyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0722] Using the compound synthesized in Example 8G (100 mg) and (2,2-difluoro-1,3-benzodioxol-4-yl)boronic acid (50 mg), the title compound (100 mg) was obtained as a single diastereomer and a single enantiomer by the same method as in Example 8J (yield: 86%).

[0723] (38B) N-{(3S,4S)-3-[3-(2,2-difluoro-1,3-benzodioxol-4-yl)-2-fluorobenzyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0724] Using the compound synthesized in Example 38A (100 mg), the crude title compound (75 mg) was obtained as a single diastereomer and a single enantiomer by the same method as in Example 5G.

[0725] (38C) N-{(3S,4S)-3-[3-(2,2-difluoro-1,3-benzodioxol-4-yl)-2-fluorobenzyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0726] The compound synthesized in Example 38B (65 mg) and (R)-2-hydroxypropionic acid (26 mg) were used in the same manner as in Example 5H to obtain 10 mg of the title compound as a single diastereomer and a single enantiomer (yield: 13%).

[0727] Example 39

[0728] (3S,4S)-N-(Cyclopropylmethyl)-4-[(methylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxamide

[0729] (39A) (3S,4S)-N-(Cyclopropylmethyl)-4-[(methylsulfonyl)amino]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxamide

[0730] A solution of triphosgene (65 mg) in dichloromethane (1.0 mL) was added to a mixture of cyclopropylmethylamine (16 mg), N,N-diisopropylethylamine (87 mg), and dichloromethane (2.0 mL) at 0°C and stirred at 0°C for 3 hours. The compound synthesized in Example 15B (100 mg) was added and stirred at room temperature for 1 hour. Water was added, the mixture was extracted with dichloromethane, washed with saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer silica gel chromatography [eluting solvent: petroleum ether / ethyl acetate = 1 / 1 (v / v)] to obtain 24 mg of the title compound as a single diastereomer and a single enantiomer (yield: 21%).

[0731] Example 40

[0732] N-{(3S,4S)-3-[(2,3'-Difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0733] (40A) (3S,4S)-tert-Butyl 3-[(2,3'-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0734] The compound synthesized in Example 8G (150 mg) and 3-fluorophenylboronic acid (66 mg) were used in the same manner as in Example 8J to obtain 130 mg of the title compound as a single diastereomer and a single enantiomer (yield: 84%).

[0735] (40B) N-{(3S,4S)-3-[(2,3'-difluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0736] The compound synthesized in Example 40A (130 mg) was used to obtain 100 mg of the crude title compound as a single diastereomer and a single enantiomer by the same method as in Example 5G.

[0737] (40C) (2R)-1-{(3S,4S)-3-[(2,3'-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-1-oxopropan-2-yl acetate

[0738] The compound synthesized in Example 40B (30 mg) and (R)-2-acetoxypropionyl chloride (15 mg) were used in the same manner as in Example 5H to obtain 20 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0739] (40D) N-{(3S,4S)-3-[(2,3'-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0740] Lithium hydroxide (5.0 mg) and water (0.4 mL) were added to a mixture of the compound synthesized in Example 40C (20 mg) and methanol (3.0 mL) at room temperature and stirred for 2 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the mixture was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 67 / 33 to 37 / 63 (v / v)] to obtain 5.9 mg of the title compound as a single diastereomer and a single enantiomer (yield: 31%).

[0741] Example 41

[0742] N-{(3S,4S)-3-[(3'-Cyclopropyl-2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0743] (41A) (3S,4S)-tert-Butyl 3-[(3'-cyclopropyl-2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0744] Using the compound synthesized in Example 8G (100 mg) and 2-(3-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg), the title compound (60 mg, yield: 56%) was obtained as a single diastereomer and a single enantiomer by the same method as in Example 8J.

[0745] (41B) N-{(3S,4S)-3-[(3'-cyclopropyl-2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0746] The compound synthesized in Example 41A (60 mg) was used in the same manner as in Example 5G to obtain 40 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0747] (41C) (2R)-1-{(3S,4S)-3-[(3'-cyclopropyl-2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-1-oxopropan-2-yl acetate

[0748] The compound synthesized in Example 41B (40 mg) and (R)-2-acetoxypropionyl chloride (20 mg) were used in the same manner as in Example 34A to obtain 40 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0749] (41D) N-{(3S,4S)-3-[(3'-cyclopropyl-2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0750] Lithium hydroxide (13 mg) was added to a mixture of the compound synthesized in Example 41C (40 mg), tetrahydrofuran (1.0 mL), and water (0.3 mL) at room temperature and stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 54 / 46 to 34 / 66 (v / v)] to obtain 33 mg of the title compound as a single diastereomer and a single enantiomer (yield: 90%).

[0751] Example 42

[0752] N-{(3S,4S)-3-{[2-Fluoro-3'-(trifluoromethoxy)[biphenyl]-3-yl]methyl}-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0753] (42A) (3S,4S)-tert-Butyl 3-{[2-fluoro-3'-(trifluoromethoxy)[biphenyl]-3-yl]methyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0754] 3-(Trifluoromethoxy)phenylboronic acid (45 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (16 mg), and sodium carbonate (45 mg) were added to a mixture of the compound synthesized in Example 8G (100 mg), 1,4-dioxane (6.0 mL), and water (1.0 mL), and stirred at 100°C for 3 hours. Insoluble matter was removed by filtration, washed with ethyl acetate, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer silica gel chromatography [eluting solvent: petroleum ether / ethyl acetate = 3 / 1 (v / v)] to obtain 80 mg of the title compound as a single diastereomer and a single enantiomer, contaminated with byproducts.

[0755] (42B) N-[(3S,4S)-3-{[2-fluoro-3'-(trifluoromethoxy)[biphenyl]-3-yl]methyl}-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide hydrochloride

[0756] The compound synthesized in Example 42A (80 mg) was used in the same manner as in Example 5G to obtain 50 mg of a crude title compound as a single diastereomer and a single enantiomer.

[0757] (42C) N-{(3S,4S)-3-{[2-Fluoro-3'-(trifluoromethoxy)[biphenyl]-3-yl]methyl}-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0758] The compound synthesized in Example 42B (40 mg) and (R)-2-hydroxypropionic acid (24 mg) were used in the same manner as in Example 31C to obtain 3.1 mg of the title compound as a single diastereomer and a single enantiomer (yield: 6%).

[0759] Example 43

[0760] N-{(3S,4S)-3-[3-(6-cyclopropylpyridin-2-yl)-2-fluorobenzyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0761] (43A) (3S,4S)-tert-Butyl 3-[3-(6-cyclopropylpyridin-2-yl)-2-fluorobenzyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0762] A mixture of the compound synthesized in Example 21A (60 mg), cesium carbonate (75 mg), 2-bromo-6-cyclopropylpyridine (CAS Registry Number: 1086381-26-1, 40 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (6 mg), water (0.5 mL), and 1,4-dioxane (3.0 mL) was degassed and stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer silica gel chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 1 (V / V)] to obtain 50 mg of the title compound as a single diastereomer and a single enantiomer (yield: 85%).

[0763] (43B) N-{(3S,4S)-3-[3-(6-cyclopropylpyridin-2-yl)-2-fluorobenzyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0764] The compound synthesized in Example 43A (50 mg) was used and the same method as in Example 5G was used to obtain 40 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0765] (43C) (2R)-1-{(3S,4S)-3-[3-(6-cyclopropylpyridin-2-yl)-2-fluorobenzyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-1-oxopropan-2-yl acetate

[0766] The compound synthesized in Example 43B (80 mg) and (R)-2-acetoxypropionyl chloride (20 mg) were used in the same manner as in Example 34A to obtain 40 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0767] (43D) N-{(3S,4S)-3-[3-(6-cyclopropylpyridin-2-yl)-2-fluorobenzyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0768] Lithium hydroxide (13 mg) was added to a mixture of the compound synthesized in Example 43C (40 mg), water (0.3 mL), and tetrahydrofuran (1.0 mL) at room temperature and stirred for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse phase silica gel column chromatography [elution solvent: 0.225% formic acid aqueous solution / acetonitrile = 85 / 15-65 / 35 (V / V)] to obtain 31 mg of the title compound as a single diastereomer and a single enantiomer (yield: 81%).

[0769] Example 44

[0770] N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}cyclopropanesulfonamide

[0771] (44A) tert-Butyl (3S,4S)-3-(3-bromo-2-fluorobenzyl)-4-[(cyclopropylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0772] Cyclopropanesulfonyl chloride (0.0393 mL) was added to a mixture of the compound synthesized in Example 8F (110 mg), triethylamine (0.0764 mL), and tetrahydrofuran (2.3 mL) under ice-cooling, followed by stirring at room temperature for 1.5 hours. 4-Dimethylaminopyridine (33.7 mg), triethylamine (0.0764 mL), and cyclopropanesulfonyl chloride (0.0393 mL) were then added, followed by stirring at 40°C for 3 hours. The mixture was diluted with ethyl acetate, washed sequentially with hydrochloric acid (1 M) and aqueous sodium bicarbonate, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 139 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0773] (44B) tert-Butyl (3S,4S)-4-[(cyclopropylsulfonyl)amino]-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0774] To a mixture of the compound synthesized in Example 44A (139 mg), phenylboronic acid (47.1 mg), potassium carbonate (114 mg), and 1,4-dioxane (1.8 mL) was added (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (11.7 mg) and water (0.46 mL) at room temperature, and the mixture was stirred at 80°C for 1.5 hours under a nitrogen atmosphere. Phenylboronic acid (24 mg), potassium carbonate (50 mg), and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (5.0 mg) were then added, and the mixture was stirred at 80°C for 3 hours. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 9 / 1-3 / 2 (v / v)] to obtain 127 mg of the title compound as a single diastereomer and a single enantiomer (yield: 92%).

[0775] (44C) N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}cyclopropanesulfonamide hydrochloride

[0776] The compound synthesized in Example 44B (127 mg) was used in the same manner as in Example 8H to obtain 106 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0777] (44D) (2R)-1-{(3S,4S)-4-[(cyclopropylsulfonyl)amino]-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-1-oxopropan-2-yl acetate

[0778] Triethylamine (0.0295 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20.4 mg) were added to a mixture of the compound synthesized in Example 44C (31.0 mg), (R)-2-acetoxypropionic acid (0.0119 mL), 1-hydroxy-7-azabenzotriazole (9.7 mg), and dichloromethane (0.70 mL) at room temperature and stirred for 30 hours. The mixture was diluted with ethyl acetate, washed sequentially with hydrochloric acid (1 M), aqueous sodium bicarbonate, and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 32.0 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0779] (44E) N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}cyclopropanesulfonamide

[0780] The compound synthesized in Example 44D (32.0 mg) was used to obtain 20.8 mg of the title compound as a single diastereomer and a single enantiomer by the same method as in Example 12H (yield: 71%).

[0781] Example 45

[0782] N-[(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-{[(1R,2R)-2-fluorocyclopropyl]carbonyl}-2-azabicyclo[3.1.1]hept-4-yl]cyclopropanesulfonamide

[0783] (45A) N-[(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-{[(1R,2R)-2-fluorocyclopropyl]carbonyl}-2-azabicyclo[3.1.1]heptane-4-yl]cyclopropanesulfonamide

[0784] The compound synthesized in Example 44C (25.0 mg) and (1R,2R)-2-fluorocyclopropane-1-carboxylic acid (8.9 mg) were used to obtain 26.6 mg of the title compound as a single diastereomer and a single enantiomer (yield: 96%) by the same method as in Example 5H.

[0785] Example 46

[0786] N-{(3S,4R)-2-Acetyl-3-[(3'-chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0787] (46A) tert-Butyl 4-amino-3-(3-bromo-2-fluorobenzyl)-5-fluoro-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0788] Sodium borohydride (50 g) was added to a mixture of the compound synthesized in Example 23C (1.5 g), molybdenum (VI) oxide (1.0 g) and methanol (150 mL) at 0°C, and the mixture was stirred at room temperature for 23 hours. Sodium borohydride (20 g) was added, and the mixture was stirred at room temperature for 18 hours. Sodium borohydride (20 g) was added, and the mixture was stirred at room temperature for 4 hours. Sodium borohydride (10 g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into an aqueous ammonium chloride solution, extracted with ethyl acetate, and washed with saturated brine. Drying over sodium sulfate and filtering were performed, and the solvent was distilled off under reduced pressure. The residue was purified by reverse phase silica gel column chromatography [elution solvent: 0.225% formic acid aqueous solution / acetonitrile = 88 / 12-58 / 42 (V / V)] to obtain the title compound.

[0789] (46B) tert-Butyl (3S,4R)-4-amino-3-(3-bromo-2-fluorobenzyl)-5-fluoro-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0790] The entire amount of the compound synthesized in Example 46A was subjected to chiral SFC [column: Phenomenex-Cellulose-2 (30 mm ID×250 mm), mobile phase: carbon dioxide / methanol = 65 / 35 (V / V)] to obtain 150 mg of the title compound as a single diastereomer and a single enantiomer eluting later (yield: 10%).

[0791] (46C) tert-Butyl (3S,4R)-3-(3-bromo-2-fluorobenzyl)-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0792] Methanesulfonyl chloride (500 mg) was added to a mixture of the compound synthesized in Example 46B (150 mg), N,N-diisopropylethylamine (140 mg), and tetrahydrofuran (5.0 mL) at 0°C, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into aqueous sodium bicarbonate, extracted with ethyl acetate, and washed with saturated brine. The mixture was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 150 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0793] (46D) (3S,4R)-tert-Butyl 3-[(3'-chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0794] A mixture of the compound synthesized in Example 46C (100 mg), 3-chlorophenylboronic acid (50 mg), cesium carbonate (130 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (11 mg), and 1,4-dioxane (1.0 mL) was degassed and stirred at 100°C for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into water, extracted with ethyl acetate, and washed with saturated brine. The mixture was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 88 / 12 to 58 / 42 (v / v)] to obtain 10 mg of the title compound as a single diastereomer and a single enantiomer (yield: 9%).

[0795] (46E) N-{(3S,4R)-3-[(3'-Chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide trifluoroacetate

[0796] Trifluoroacetic acid (4 g) was added to a mixture of the compound synthesized in Example 46D (25 mg) and dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain 20 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0797] (46F) N-{(3S,4R)-2-Acetyl-3-[(3'-chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0798] N,N-Diisopropylethylamine (30 mg) was added to a mixture of the compound synthesized in Example 46E (20 mg), acetic anhydride (10 mg), and N,N-dimethylformamide (1.0 mL). The mixture was stirred at room temperature for 2 hours. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 56 / 44 to 36 / 64 (v / v)] to obtain 23 mg of the title compound as a single diastereomer and a single enantiomer (yield: quantitative).

[0799] Example 47

[0800] N-{(3S,4S)-3-{3-[6-(Difluoromethyl)pyridin-2-yl]-2-fluorobenzyl}-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0801] (47A) (3S,4S)-tert-Butyl 3-{3-[6-(difluoromethyl)pyridin-2-yl]-2-fluorobenzyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0802] A mixture of the compound synthesized in Example 21A (109 mg), cesium carbonate (135 mg), 2-bromo-6-(difluoromethyl)pyridine (CAS Registry Number: 872365-91-8, 43 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (18 mg), water (0.8 mL), and 1,4-dioxane (4.0 mL) was degassed and stirred at 100°C for 2 hours under a nitrogen atmosphere. Insoluble matter was removed by filtration, and the mixture was diluted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography [elution solvent: aqueous ammonium bicarbonate solution / acetonitrile = 75 / 25-45 / 55 (V / V)] to obtain 56 mg of the title compound as a single diastereomer and a single enantiomer (yield: 51%).

[0803] (47B) N-[(3S,4S)-3-{3-[6-(difluoromethyl)pyridin-2-yl]-2-fluorobenzyl}-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide hydrochloride

[0804] The compound synthesized in Example 47A (50 mg) was used in the same manner as in Example 5G to obtain 44 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0805] (47C) (2R)-1-{(3S,4S)-3-{3-[6-(difluoromethyl)pyridin-2-yl]-2-fluorobenzyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-1-oxopropan-2-yl acetate

[0806] The compound synthesized in Example 47C (40 mg) and (R)-2-acetoxypropionyl chloride (15 mg) were used in the same manner as in Example 34A to obtain 48 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0807] (47D) N-{(3S,4S)-3-{3-[6-(difluoromethyl)pyridin-2-yl]-2-fluorobenzyl}-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0808] Lithium hydroxide (10 mg) was added to a mixture of the compound synthesized in Example 47C (48 mg), water (0.5 mL), and tetrahydrofuran (2.0 mL) at room temperature and stirred for 2 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 72 / 28 to 42 / 58 (v / v)] to obtain 18 mg of the title compound as a single diastereomer and a single enantiomer (yield: 40%).

[0809] Example 48

[0810] N-{(3S,4S)-2-[(2R)-2-methoxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0811] (48A) N-{(3S,4S)-2-[(2R)-2-methoxypropanoyl]-3-[(2,3',5'-trifluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0812] The compound synthesized in Example 15B (50 mg) and (R)-2-methoxypropionic acid (17 mg) were used in the same manner as in Example 31C to obtain 42.5 mg of the title compound as a single diastereomer and a single enantiomer (yield: 77%).

[0813] Example 49

[0814] N-[(3S,4R)-3-{[3'-(Difluoromethyl)-2-fluoro[biphenyl]-3-yl]methyl}-5-fluoro-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0815] (49A) (3S,4R)-tert-Butyl 3-{[3'-(difluoromethyl)-2-fluoro[biphenyl]-3-yl]methyl}-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0816] The compound synthesized in Example 46C (40 mg) and 3-(difluoromethyl)phenylboronic acid (20 mg) were used in the same manner as in Example 8J to obtain 20 mg of the title compound as a single diastereomer and a single enantiomer (yield: 46%).

[0817] (49B) N-[(3S,4R)-3-{[3'-(difluoromethyl)-2-fluoro[biphenyl]-3-yl]methyl}-5-fluoro-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide trifluoroacetate

[0818] Trifluoroacetic acid (462 mg) was added to a mixture of the compound synthesized in Example 49A (20 mg) and dichloromethane (1.0 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain 20 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0819] (49C) 1-{(3S,4R)-3-{[3'-(difluoromethyl)-2-fluoro[biphenyl]-3-yl]methyl}-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0820] The compound synthesized in Example 49B (20 mg) and 2-acetoxyisobutyryl chloride (12 mg) were used in the same manner as in Example 34A to obtain 20 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0821] (49D) N-[(3S,4R)-3-{[3'-(difluoromethyl)-2-fluoro[biphenyl]-3-yl]methyl}-5-fluoro-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0822] Lithium hydroxide (10 mg) was added to a mixture of the compound synthesized in Example 49C (20 mg), water (0.3 mL), and tetrahydrofuran (1.0 mL) at room temperature and stirred for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and washed with saturated brine. The mixture was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 55 / 45 to 35 / 65 (v / v)] to obtain 11 mg of the title compound as a single diastereomer and a single enantiomer (yield: 57%).

[0823] Example 50

[0824] N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0825] (50A) (3S,4R)-tert-Butyl 5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0826] The compound synthesized in Example 46C (120 mg) and phenylboronic acid (48 mg) were used in the same manner as in Example 8J to obtain 60 mg of the title compound as a single diastereomer and a single enantiomer (yield: 50%).

[0827] (50B) N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide trifluoroacetate

[0828] Trifluoroacetic acid (0.62 mL) was added to a mixture of the compound synthesized in Example 50A (60 mg) and dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain 60 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0829] (50C) 1-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0830] The compound synthesized in Example 50B (20 mg) and 2-acetoxyisobutyryl chloride (13 mg) were used in the same manner as in Example 34A to obtain 20 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0831] (50D) N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0832] Lithium hydroxide (10 mg) was added to a mixture of the compound synthesized in Example 50C (20 mg), water (0.3 mL), and tetrahydrofuran (1.0 mL) at room temperature and stirred for 6 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and washed with saturated brine. The mixture was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 58 / 42 to 38 / 62 (v / v)] to obtain 11 mg of the title compound as a single diastereomer and a single enantiomer (yield: 58%).

[0833] Example 51

[0834] N-[(3S,4S)-3-{[3'-(difluoromethyl)-2,5'-difluoro[biphenyl]-3-yl]methyl}-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0835] (51A) (3S,4S)-tert-Butyl 3-{[3'-(difluoromethyl)-2,5'-difluoro[biphenyl]-3-yl]methyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0836] A mixture of the compound synthesized in Example 21A (100 mg), cesium carbonate (124 mg), 1-bromo-3-(difluoromethyl)-5-fluorobenzene (51 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (16 mg), water (0.5 mL), and tetrahydrofuran (5.0 mL) was degassed and stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer silica gel chromatography [elution solvent: petroleum ether / ethyl acetate = 2 / 1 (v / v)] to obtain 60 mg of the title compound as a single diastereomer and a single enantiomer (yield: 58%).

[0837] (51B) N-[(3S,4S)-3-{[3'-(difluoromethyl)-2,5'-difluoro[biphenyl]-3-yl]methyl}-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide hydrochloride

[0838] The compound synthesized in Example 51A (50 mg) was used in the same manner as in Example 5G to obtain 60 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0839] (51C) 1-{(3S,4S)-3-{[3'-(difluoromethyl)-2,5'-difluoro[biphenyl]-3-yl]methyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0840] The compound synthesized in Example 51B (60 mg) and 2-acetoxyisobutyryl chloride (31 mg) were used in the same manner as in Example 34A to obtain 50 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0841] (51D) N-[(3S,4S)-3-{[3'-(difluoromethyl)-2,5'-difluoro[biphenyl]-3-yl]methyl}-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0842] Lithium hydroxide (10 mg) was added to a mixture of the compound synthesized in Example 51C (50 mg), water (0.3 mL), and methanol (3.0 mL) at room temperature and stirred for 2 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 60 / 40 to 30 / 70 (v / v)] to obtain 35 mg of the title compound as a single diastereomer and a single enantiomer (yield: 76%).

[0843] Example 52

[0844] N-[(3S,4S)-3-[(3'-chloro-2,5'-difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0845] (52A) (3S,4S)-tert-Butyl 3-[(3'-chloro-2,5'-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0846] The compound synthesized in Example 8G (100 mg) and 3-chloro-5-fluorophenylboronic acid (55 mg) were used in the same manner as in Example 8J to obtain 35 mg of the title compound as a single diastereomer and a single enantiomer (yield: 32%).

[0847] (52B) N-{(3S,4S)-3-[(3'-chloro-2,5'-difluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0848] The compound synthesized in Example 52A (30 mg) was used in the same manner as in Example 5G to obtain 26 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0849] (52C) ​​1-{(3S,4S)-3-[(3'-chloro-2,5'-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0850] The compound synthesized in Example 52B (26 mg) and 2-acetoxyisobutyryl chloride (9.0 mg) were used in the same manner as in Example 34A to obtain 31 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0851] (52D) N-[(3S,4S)-3-[(3'-chloro-2,5'-difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0852] Lithium hydroxide monohydrate (11 mg) was added to a mixture of the compound synthesized in Example 52C (28 mg), water (1.0 mL), and tetrahydrofuran (3.0 mL) at room temperature and stirred for 12 hours. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The mixture was dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 50 / 50 to 30 / 70 (v / v)] to obtain 20 mg of the title compound as a single diastereomer and a single enantiomer (yield: 77%).

[0853] Example 53

[0854] N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0855] (53A) (2R)-1-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-1-oxopropan-2-yl acetate

[0856] N,N-Diisopropylethylamine (60 mg) and (R)-2-acetoxypropionyl chloride (12 mg) were added to a mixture of the compound synthesized in Example 50B (20 mg) and tetrahydrofuran (1.0 mL) at room temperature and stirred for 30 minutes. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 20 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0857] (53B) N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0858] Lithium hydroxide (10 mg) was added to a mixture of the compound synthesized in Example 53A (20 mg), water (0.3 mL), and tetrahydrofuran (1.0 mL) at room temperature and stirred for 6 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 63 / 37 to 43 / 57 (v / v)] to obtain 12 mg of the title compound as a single diastereomer and a single enantiomer (yield: 68%).

[0859] Example 54

[0860] N-{(3S,4S)-3-{[2-fluoro(2',3',4',5',6'- 2 H5) [Biphenyl]-3-yl]methyl}-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0861] (54A)(3S,4S)-3-{[2-fluoro(2',3',4',5',6'- 2 H5) tert-Butyl [biphenyl]-3-yl]methyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0862] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (3.2 mg) and water (0.09 mL) were added to a mixture of the compound synthesized in Example 8G (26.3 mg), phenyl-d5-boronic acid (10.5 mg), potassium carbonate (22.9 mg), and 1,4-dioxane (0.37 mL) at room temperature. The mixture was stirred at 60°C under a nitrogen atmosphere for 2.5 hours. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 9 / 1 to 1 / 1 (v / v)] to obtain 12.4 mg of the title compound as a single diastereomer and a single enantiomer (yield: 47%).

[0863] (54B)N-[(3S,4S)-3-{[2-fluoro(2',3',4',5',6'- 2H5) [Biphenyl]-3-yl]methyl}-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide hydrochloride

[0864] The compound synthesized in Example 54A (12.4 mg) was used in the same manner as in Example 8H to obtain 9.7 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0865] (54C) Acetic acid (2R)-1-{(3S,4S)-3-{[2-fluoro(2',3',4',5',6'- 2 H5) [Biphenyl]-3-yl]methyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-1-oxopropan-2-yl ester

[0866] Triethylamine (0.0097 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (13 mg) were added to a mixture of the compound synthesized in Example 54B (9.7 mg), (R)-2-acetoxypropionic acid (0.0039 mL), and N,N-dimethylformamide (0.23 mL) at room temperature and stirred for 1 hour. (R)-2-acetoxypropionic acid (0.0028 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.5 mg), and triethylamine (0.0097 mL) were added and stirred for 1 hour. The mixture was diluted with ethyl acetate, washed sequentially with sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 12.0 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0867] (54D)N-{(3S,4S)-3-{[2-fluoro(2',3',4',5',6'- 2 H5) [Biphenyl]-3-yl]methyl}-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0868] The compound synthesized in Example 54C (12.0 mg) was used to obtain 8.5 mg of the title compound as a single diastereomer and a single enantiomer by the same method as in Example 12H (yield: 77%).

[0869] Example 55

[0870] N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(1,3-oxazol-4-ylcarbonyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0871] (55A) N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(1,3-oxazol-4-ylcarbonyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0872] The compound synthesized in Example 50B (12 mg) and oxazole-4-carboxylic acid (5.0 mg) were used in the same manner as in Example 5H to obtain 13 mg of the title compound as a single diastereomer and a single enantiomer (yield: 89%).

[0873] Example 56

[0874] N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-propionyl-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0875] (56A) N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-propionyl-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0876] Propionyl chloride (11 mg) was added to a mixture of the compound synthesized in Example 25B (40 mg), N,N-diisopropylethylamine (38 mg), and tetrahydrofuran (1.0 mL) at room temperature and stirred for 30 minutes. The reaction solution was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 58 / 42 to 38 / 62 (V / V)] to obtain 19 mg of the title compound as a single diastereomer and a single enantiomer (yield: 46%).

[0877] Example 57

[0878] N-[(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-(2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0879] (57A) N-[(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0880] The compound synthesized in Example 25B (40 mg) and isobutyryl chloride (12 mg) were used in the same manner as in Example 56A to obtain 16 mg of the title compound as a single diastereomer and a single enantiomer (yield: 38%).

[0881] Example 58

[0882] N-{(3S,4S)-3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0883] (58A) 2-tert-Butyl 3-(3-bromo-2,5-difluorobenzyl)-4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[0884] Cesium carbonate (1.64 g) was added to a mixture of 2-oxo-4-azabicyclo[3.1.1]heptane-3,4-dicarboxylic acid 4-tert-butyl ester 3-methyl ester (CAS Reg. No. 2241048-56-4, 902 mg), 1-bromo-3-(bromomethyl)-2,5-difluorobenzene (CAS Reg. No. 1805523-99-2, 1.15 g), and N,N-dimethylformamide (11 mL) at room temperature and stirred for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the mixture was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 to 75 / 25 (v / v)] to obtain 1.52 g of the title compound (yield: 96%).

[0885] (58B) 3-(3-Bromo-2,5-difluorobenzyl)-2-azabicyclo[3.1.1]heptan-4-one hydrochloride

[0886] A mixture of the compound synthesized in Example 58A (1.52 g), lithium chloride (136 mg), hydrochloric acid (12 M, 16 mL), and acetic acid (3.2 mL) was stirred at 100° C. for 7 hours and then at 120° C. for 10 hours. The solvent was distilled off under reduced pressure to obtain 1.13 g of the crude title compound.

[0887] (58C) tert-Butyl 3-(3-bromo-2,5-difluorobenzyl)-4-oxo-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0888] A solution of di-tert-butyl dicarbonate (1.40 g) in dichloromethane (11 mL) and triethylamine (1.33 mL) were added to a mixture of the compound synthesized in Example 58B (1.13 g) and dichloromethane (11 mL) at room temperature, and the mixture was stirred at room temperature for 17 hours. After adding aqueous sodium bicarbonate, the mixture was extracted with dichloromethane, washed with saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 95 / 5 to 75 / 25 (v / v)] to obtain 698 mg of the title compound (yield: 52%).

[0889] (58D) tert-Butyl 3-(3-bromo-2,5-difluorobenzyl)-4-(hydroxyimino)-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0890] Hydroxylamine hydrochloride (699 mg) and sodium acetate (825 mg) were added to a mixture of the compound synthesized in Example 58C (698 mg) and ethanol (5.6 mL). The mixture was stirred at room temperature for 1.5 hours and then at 50°C for 1 hour. The solvent was distilled off under reduced pressure, and water and ethyl acetate were added. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 744 mg of the crude title compound.

[0891] (58E) tert-Butyl 4-amino-3-(3-bromo-2,5-difluorobenzyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0892] Molybdenum (VI) oxide (1.21 g) and sodium borohydride (1.27 g) were added to a mixture of the compound synthesized in Example 58D (744 mg) and methanol (8.4 mL) at 0°C, and the mixture was stirred at room temperature for 18 hours. After adding aqueous sodium bicarbonate, the insoluble matter was removed by filtration through celite and washed with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 637 mg of the crude title compound.

[0893] (58F)(3S*,4S*)-tert-Butyl 3-(3-bromo-2,5-difluorobenzyl)-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0894] Triethylamine (0.532 mL) and methanesulfonyl chloride (0.179 mL) were added to a mixture of the compound synthesized in Example 58E (320 mg) and tetrahydrofuran (10 mL) under ice cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 50 / 50 (v / v)] to obtain 344 mg of the title compound as a single diastereomer (racemic form) (yield: 90%).

[0895] (58G) (3S*,4S*)-tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0896] To a mixture of the compound synthesized in Example 58F (344 mg), phenylboronic acid (127 mg), tripotassium phosphate (442 mg), and tetrahydrofuran (5.16 mL) (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (29.4 mg) and water (1.72 mL) was added. The mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100 (v / v)] to obtain 358 mg of the title compound as a single diastereomer (racemic form) (yield: quantitative).

[0897] (58H)N-{(3S*,4S*)-3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0898] A 4M solution of hydrogen chloride in 1,4-dioxane (1.79 mL, 1.79 mL) was added to a mixture of the compound synthesized in Example 58G (357 mg) and methanol (1.79 mL) at room temperature and stirred for 3 hours. The solvent was distilled off under reduced pressure, and ethyl acetate was added and stirred for 1 hour. The precipitated solid was filtered to obtain 230 mg of the title compound as a single diastereomer (racemate) (yield: 74%).

[0899] (58I) (2R)-1-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-yl}-1-oxopropane-2-yl acetate

[0900] Triethylamine (0.0646 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (88.6 mg) were added to a mixture of the compound synthesized in Example 58H (50.0 mg), (R)-2-acetoxypropionic acid (0.0261 mL), and N,N-dimethylformamide (2.33 mL) at room temperature and stirred for 3 hours. After addition of saturated brine, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100 (v / v)] to obtain 38.6 mg of the title compound as a single diastereomer and a single enantiomer (yield: 65%).

[0901] (58J) N-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0902] Lithium hydroxide monohydrate (63.6 mg) was added to a mixture of the compound synthesized in Example 58I (38.4 mg), tetrahydrofuran (2.00 mL), methanol (1.00 mL), and water (1.00 mL) at room temperature and stirred at 50°C for 6 hours. After adding saturated sodium bicarbonate solution, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100 (v / v)] to obtain 18.4 mg of the title compound as a single diastereomer and a single enantiomer (yield: 52%).

[0903] Example 59

[0904] N-[(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide or N-[(3R,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0905] (59A) 1-{(3S*,4S*)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-yl}-2-methyl-1-oxopropane-2-yl acetate

[0906] 2-Acetoxyisobutyryl chloride (0.0761 mL) was added to a mixture of the compound synthesized in Example 58H (75.1 mg), triethylamine (0.121 mL), and tetrahydrofuran (1.13 mL) at room temperature and stirred for 2 hours. After addition of saturated brine, the mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100 (v / v)] to obtain 90.0 mg (yield: 99%) of the title compound as a single diastereomer (racemate).

[0907] (59B) N-[(3S*,4S*)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0908] The compound synthesized in Example 59A (90.0 mg) was used to obtain 70.1 mg (yield: 85%) of the title compound as a single diastereomer (racemate) in the same manner as in Example 12H.

[0909] (59C) N-[(3S,4S)-3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide or N-[(3R,4R)-3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0910] The compound synthesized in Example 59B (70.1 mg) was subjected to chiral HPLC [column: CHIRALPAK (registered trademark) IG (20 mm ID × 250 mm), mobile phase: n-hexane / 2-propanol = 70 / 30 (V / V), temperature: 40°C] to obtain 32.4 mg (yield: 46%) of the title compound that eluted first as a single diastereomer and a single enantiomer.

[0911] Example 60

[0912] N-[3-{[2-(3-chlorophenyl)-3-fluoropyridin-4-yl]methyl}-2-(cyclopropylcarbonyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0913] (60A) 2-tert-Butyl 3-[(2-bromo-3-fluoropyridin-4-yl)methyl]-4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[0914] Using 2-bromo-4-(bromomethyl)-3-fluoropyridine (CAS registration number: 1227585-59-2, 1.00 g) and 2-oxo-4-azabicyclo[3.1.1]heptane-3,4-dicarboxylic acid O4-tert-butyl ester O3-methyl ester (CAS registration number: 2241048-56-4, 1.00 g), the title compound (1.46 g, yield: 84%) was obtained by the same method as in Example 1B.

[0915] (60B) tert-Butyl 3-[(2-bromo-3-fluoropyridin-4-yl)methyl]-4-oxo-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0916] Lithium chloride (528 mg) was added to a mixture of the compound synthesized in Example 60A (1.48 g) and dimethyl sulfoxide (10 mL), stirred at 130° C. for 3 hours, and cooled to room temperature. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0-60 / 40 (V / V)] to obtain 815 mg of the title compound (yield: 66%).

[0917] (60C) tert-Butyl 3-[(2-bromo-3-fluoropyridin-4-yl)methyl]-4-(hydroxyimino)-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0918] The crude title compound was obtained by the same method as in Example 2A using the compound synthesized in Example 60B (815 mg).

[0919] (60D) tert-Butyl 4-amino-3-[(2-bromo-3-fluoropyridin-4-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0920] At 0°C, molybdenum (VI) oxide (441 mg) and sodium borohydride (541 mg) were added to a mixture of the compound synthesized in Example 60C (846 mg) and methanol (10 mL), and the mixture was stirred at 0°C for 1 hour. The mixture was warmed to room temperature and stirred for 1 hour. Sodium borohydride (541 mg) and molybdenum (VI) oxide (441 mg) were added at 0°C, and the mixture was stirred at 0°C for 1 hour. Sodium borohydride (541 mg) and molybdenum (VI) oxide (441 mg) were added, and the mixture was stirred at 0°C for another 1 hour. Saturated sodium bicarbonate water was added, and the mixture was stirred at room temperature for 16 hours. Filtered through celite and washed with ethyl acetate. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain the crude title compound.

[0921] (60E) tert-Butyl 3-[(2-bromo-3-fluoropyridin-4-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0922] The compound synthesized in Example 60D (817 mg) and methanesulfonyl chloride (468 mg) were used to obtain 518 mg of the title compound as a single diastereomer (racemate) by the same method as in Example 5F (yield: 53% in 3 steps).

[0923] (60F) tert-Butyl 3-{[2-(3-chlorophenyl)-3-fluoropyridin-4-yl]methyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0924] 3-Chlorophenylboronic acid (254 mg), sodium carbonate (861 mg), and tetrakis(triphenylphosphine)palladium(0) (63 mg) were added to a mixture of the compound synthesized in Example 60E (518 mg), 1,2-dimethoxyethane (8 mL), and water (4 mL), and stirred at 120°C for 90 minutes. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 - 20 / 80 (V / V)] to obtain 491 mg of the title compound as a single diastereomer (racemic form) (yield: 89%).

[0925] (60G) tert-Butyl 3-{[2-(3-chlorophenyl)-3-fluoropyridin-4-yl]methyl}-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0926] The compound synthesized in Example 60F (550 mg) was subjected to chiral HPLC [column: CHIRALPAK (registered trademark) IA (20 mm ID × 250 mm), mobile phase: n-hexane / tetrahydrofuran = 70 / 30 (V / V), temperature: 40°C] to obtain 217 mg (yield: 39%) of the title compound that eluted first as a single diastereomer and a single enantiomer.

[0927] (60H) N-[3-{[2-(3-chlorophenyl)-3-fluoropyridin-4-yl]methyl}-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide hydrochloride

[0928] The compound synthesized in Example 60G (217 mg) was used in the same manner as in Example 8H to obtain 227 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0929] (60I) N-[3-{[2-(3-chlorophenyl)-3-fluoropyridin-4-yl]methyl}-2-(cyclopropylcarbonyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0930] N,N-Diisopropylethylamine (0.062 mL) and cyclopropanecarbonyl chloride (0.013 mL) were added to a mixture of the compound synthesized in Example 60H (35.0 mg) and tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 40 / 60 to 0 / 100 (v / v)]. Diethyl ether was added, and the mixture was sonicated to solidify. The title compound was collected by filtration to obtain 34 mg (yield: 98%) of a single diastereomer and a single enantiomer.

[0931] Example 61

[0932] N-[(3S,4R)-3-[(3'-Chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide or N-[(3R,4S)-3-[(3'-Chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0933] (61A) (3S*,4R*)-tert-Butyl 3-[(3'-chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0934] A mixture of the compound synthesized in Example 23E (115 mg), 3-chlorophenylboronic acid (54.5 mg), tetrakis(triphenylphosphine)palladium(0) (20.1 mg), potassium carbonate (96.3 mg), 1,4-dioxane (3.2 mL), and water (0.8 mL) was stirred at 100°C for 4 hours. After adding water, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 - 40 / 60 (V / V)] to obtain 137 mg of the title compound as a single diastereomer (racemic form) (yield: quantitative).

[0935] (61B) N-{(3S*,4R*)-3-[(3'-chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0936] The compound synthesized in Example 61A (137 mg) was used in the same manner as in Example 8H to obtain 104 mg (yield: 97%) of the crude title compound as a single diastereomer (racemate).

[0937] (61C) 1-{(3S*,4R*)-3-[(3'-chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0938] 2-Acetoxyisobutyryl chloride (0.0338 mL) was added to a mixture of the compound synthesized in Example 61B (54.0 mg), triethylamine (0.0808 mL), and tetrahydrofuran (2 mL) at room temperature and stirred overnight. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 60 / 40 to 20 / 80 (v / v)] to obtain 65.1 mg of the title compound as a single diastereomer (racemic form) (yield: quantitative).

[0939] (61D) N-[(3S*,4R*)-3-[(3'-Chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0940] The compound synthesized in Example 61C (65.1 mg) was used to obtain 56.8 mg (yield: 95%) of the title compound as a single diastereomer (racemate) by the same method as in Example 12H.

[0941] (61E) N-[(3S,4R)-3-[(3'-Chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide or N-[(3R,4S)-3-[(3'-Chloro-2-fluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0942] The compound synthesized in Example 61D (56.8 mg) was purified by chiral HPLC [column: CHIRALPAK (registered trademark) IA (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 60 / 40 (V / V), temperature: 40°C] to obtain 26.9 mg (yield: 47%) of the title compound that eluted first as a single diastereomer and a single enantiomer.

[0943] Example 62

[0944] N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-[(1-hydroxycyclobutyl)carbonyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0945] (62A) N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(1-hydroxycyclobutyl)carbonyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0946] The compound synthesized in Example 25B (50 mg) and 1-hydroxycyclobutanecarboxylic acid (17 mg) were used in the same manner as in Example 31C to obtain 18 mg of the title compound as a single diastereomer and a single enantiomer (yield: 31%).

[0947] Example 63

[0948] N-{(3S,4R)-3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0949] (63A) 2-tert-Butyl 3-(3-bromo-2,5-difluorobenzyl)-5-fluoro-4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[0950] Cesium carbonate (850 mg) was added to a mixture of the compound synthesized in Example 12C (500 mg), 1-bromo-3-(bromomethyl)-2,5-difluorobenzene (CAS Registry No.: 1805523-99-2, 597 mg), and N,N-dimethylformamide (8.7 mL) at 0°C, followed by stirring at room temperature for 3.5 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30 (v / v)] to obtain 399 mg of the title compound (yield: 47%).

[0951] (63B) tert-Butyl 3-(3-bromo-2,5-difluorobenzyl)-5-fluoro-4-oxo-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0952] Lithium chloride (80 mg) was added to a mixture of the compound synthesized in Example 63A (275 mg) and dimethyl sulfoxide (7.0 mL) at room temperature, followed by stirring at 130°C for 2 hours. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The mixture was dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30 (v / v)] to obtain 160 mg of the title compound (yield: 66%).

[0953] (63C) tert-Butyl 3-(3-bromo-2,5-difluorobenzyl)-5-fluoro-4-(hydroxyimino)-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0954] Sodium acetate (180 mg) was added to a mixture of the compound synthesized in Example 63B (189 mg), hydroxylamine hydrochloride (152 mg), and ethanol (3.6 mL) at room temperature, and the mixture was stirred at 90°C for 3 hours. Approximately 2 mL of the solvent was distilled off under reduced pressure, and the mixture was diluted with ethyl acetate. The mixture was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50 (v / v)] to obtain 123 mg of the title compound (yield: 63%).

[0955] (63D) tert-Butyl 4-amino-3-(3-bromo-2,5-difluorobenzyl)-5-fluoro-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0956] A solution of lithium borohydride in tetrahydrofuran (2.0 M, 16 mL) was added to a mixture of the compound synthesized in Example 63C (1.23 g), platinum (VI) oxide (1.18 g), and methanol (45 mL) at room temperature over 30 minutes, followed by stirring for 1 hour. Saturated sodium bicarbonate water was added to the reaction mixture, stirred for 30 minutes, and then the insoluble matter was removed by filtration and washed with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 1.19 g of the crude title compound.

[0957] (63E)(3S*,4R*)-tert-Butyl 3-(3-bromo-2,5-difluorobenzyl)-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0958] Methanesulfonyl chloride (1.1 g) was added to a mixture of the compound synthesized in Example 63D (1.19 g), triethylamine (1.90 mL), and tetrahydrofuran (35 mL) at 0°C, followed by stirring at room temperature for 3 hours. Water was added, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 100 / 0 to 30 / 70 (v / v)] to obtain 400 mg of the title compound as a single diastereomer (racemic form) (yield: 28%).

[0959] (63F)(3S*,4R*)-tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0960] A mixture of the compound synthesized in Example 63E (84 mg), phenylboronic acid (30 mg), tripotassium phosphate (104 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (9.6 mg), tetrahydrofuran (1.6 mL), and water (0.5 mL) was stirred at 70°C for 2 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50 (v / v)] to obtain 77 mg of the title compound as a single diastereomer (racemic form) (yield: 93%).

[0961] (63G) N-{(3S*,4R*)-3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0962] A 1,4-dioxane solution of hydrogen chloride (4 M, 2.0 mL) was added to the compound synthesized in Example 63F (77 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure to obtain 68 mg of the crude title compound as a single diastereomer (racemate).

[0963] (63H) (2R)-1-{(3S*,4R*)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-1-oxopropan-2-yl acetate

[0964] N,N-Diisopropylethylamine (0.085 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (93 mg) were added to a mixture of the compound synthesized in Example 63G (68 mg), (R)-2-acetoxypropionic acid (0.027 mL), and N,N-dimethylformamide (1.5 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 60 / 40 to 40 / 60 (v / v)] to obtain 97 mg of the title compound.

[0965] (63I) N-{(3S*,4R*)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0966] Lithium hydroxide monohydrate (23 mg) was added to a mixture of the compound synthesized in Example 63H (97 mg), tetrahydrofuran (2.6 mL), methanol (1.0 mL), and water (1.0 mL) at room temperature and stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 to 30 / 70 (v / v)] to obtain 78 mg of the title compound (yield: 87%).

[0967] (63J) N-{(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0968] The compound synthesized in Example 63I (78 mg) was subjected to chiral HPLC [column: CHIRAL ART Amylose-SA (4.6 mm I.D. × 250 mm), mobile phase: n-hexane / ethanol = 70 / 30 (V / V), temperature: 40°C] to obtain 31 mg of the title compound that eluted first as a single diastereomer and a single enantiomer (yield: 40%).

[0969] Example 64

[0970] N-{(3S,4S)-2-[(2R)-2-Cyclopropyl-2-hydroxyacetyl]-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[0971] (64A) N-{(3S,4S)-2-[(2R)-2-cyclopropyl-2-hydroxyacetyl]-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[0972] The compound synthesized in Example 25B (50 mg) and (R)-2-hydroxy-2-cyclopropylacetic acid (14 mg) were used to obtain 22 mg of the title compound as a single diastereomer and a single enantiomer (yield: 38%) by the same method as in Example 31C.

[0973] Example 65

[0974] (3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylic acid ethyl ester

[0975] (65A) (3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylic acid ethyl ester

[0976] Ethyl chloroformate (14 mg) was added to a mixture of the compound synthesized in Example 25B (30 mg), N,N-diisopropylethylamine (50 mg), and tetrahydrofuran (1.0 mL) at room temperature and stirred for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 50 / 50 to 30 / 70 (v / v)] to obtain 16 mg of the title compound as a single diastereomer and a single enantiomer (yield: 46%).

[0977] Example 66

[0978] N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-{[(1S,2S)-2-fluorocyclopropyl]carbonyl}-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0979] (66A) (3S*,4R*)-tert-Butyl 5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0980] A mixture of the compound synthesized in Example 23E (1.56 g), phenylboronic acid (576 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (200 mg), potassium carbonate (2.01 g), tetrahydrofuran (30 mL), and water (10 mL) was stirred at 65°C for 4 hours. After adding water, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 80 / 20 to 40 / 60 (v / v)] to obtain 1.59 g of the title compound as a single diastereomer (racemic form) (yield: quantitative).

[0981] (66B) (3S,4R)-tert-Butyl 5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0982] The compound synthesized in Example 66A (1.59 g) was subjected to chiral HPLC [column: CHIRALPAK (registered trademark) IC (20 mm ID × 250 mm), mobile phase: n-hexane / 2-propanol = 55 / 45 (V / V), temperature: 40°C] to obtain 679 mg (yield: 43%) of the title compound as a single diastereomer and a single enantiomer eluting later.

[0983] (66C) N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0984] A 4 M solution of hydrogen chloride in 1,4-dioxane (30 mL) was added to a mixture of the compound synthesized in Example 66B (626 mg) and 1,4-dioxane (5 mL) at room temperature and stirred for 3 hours. The reaction mixture was diluted with toluene and concentrated under reduced pressure to obtain 518 mg of the crude title compound as a single diastereomer and a single enantiomer.

[0985] (66D) N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-{[(1S,2S)-2-fluorocyclopropyl]carbonyl}-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0986] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20.1 mg) was added to a mixture of the compound synthesized in Example 66C (30.0 mg), (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (10.9 mg), 1-hydroxy-7-azabenzotriazole (9.5 mg), triethylamine (0.0388 mL), and N,N-dimethylformamide (1 mL) at room temperature. The mixture was stirred at 35°C for 2 hours. The mixture was diluted with ethyl acetate and washed sequentially with water, hydrochloric acid (0.5 M), saturated sodium bicarbonate solution, and saturated brine, and then dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 10 / 90 (v / v)] to obtain 32.0 mg of the title compound as a single diastereomer and a single enantiomer (yield: 96%).

[0987] Example 67

[0988] N-[(3S,4S)-3-[(3'-chloro-2,5-difluoro-biphenyl-3-yl)methyl]-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide or N-[(3R,4R)-3-[(3'-chloro-2,5-difluoro-biphenyl-3-yl)methyl]-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[0989] (67A) (3S*,4S*)-tert-Butyl 3-[(3'-chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[0990] 3-Chlorophenylboronic acid (120 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (20 mg), cesium carbonate (340 mg), and water (1.0 mL) were added to a mixture of the compound synthesized in Example 58F (250 mg) and 1,4-dioxane (4.0 mL). After degassing, the mixture was stirred at 100°C for 2 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 100 / 0 to 70 / 30 (v / v)] to obtain 200 mg of the title compound as a single diastereomer (racemic form) (yield: 75%).

[0991] (67B) N-{(3S*,4S*)-3-[(3'-chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[0992] A 4M solution of hydrogen chloride in ethyl acetate (4.0 mL) was added to a mixture of the compound synthesized in Example 67A (200 mg) and ethyl acetate (1.0 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure to obtain 160 mg of the crude title compound as a single diastereomer (racemate).

[0993] (67C) 1-{(3S*,4S*)-3-[(3'-chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[0994] N,N-Diisopropylethylamine (208 mg) was added to a mixture of the compound synthesized in Example 67B (80 mg), 2-acetoxyisobutyryl chloride (44 mg), and tetrahydrofuran (5.0 mL) at room temperature and stirred for 2 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 100 mg of the crude title compound as a single diastereomer (racemate).

[0995] (67D) N-[(3S*,4S*)-3-[(3'-chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0996] Lithium hydroxide (22 mg) was added to a mixture of the compound synthesized in Example 67C (100 mg), water (0.6 mL), and tetrahydrofuran (2.0 mL), and stirred at 45°C for 12 hours. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The mixture was dried over sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 55 / 45 to 25 / 75 (v / v)] to obtain the title compound as a single diastereomer (racemic form).

[0997] (67E) N-[(3S,4S)-3-[(3'-Chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide or N-[(3R,4R)-3-[(3'-Chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-2-(2-hydroxy-2-methylpropionyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[0998] The entire amount of the compound synthesized in Example 67D was subjected to chiral SFC [column: CHIRALCEL OJ (30 mm I.D. × 250 mm), mobile phase: carbon dioxide / methanol = 40 / 60 (V / V)] to obtain 32 mg of the title compound as a single diastereomer and a single enantiomer eluting later (yield: 35%).

[0999] Example 68

[1000] N-{(3S,4S)-3-[3-(5-chlorothien-3-yl)-2-fluorobenzyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1001] (68A) (3S,4S)-tert-Butyl 3-[3-(5-chlorothien-3-yl)-2-fluorobenzyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1002] A mixture of the compound synthesized in Example 21A (100 mg), cesium carbonate (155 mg), 4-bromo-2-chlorothiophene (40 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (16 mg), water (1.0 mL), and 1,4-dioxane (6.0 mL) was stirred at 80°C for 10 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The mixture was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by preparative thin-layer silica gel chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 1 (v / v)] to obtain 80 mg of the title compound as a single diastereomer and a single enantiomer (yield: 81%).

[1003] (68B) N-{(3S,4S)-3-[3-(5-chlorothien-3-yl)-2-fluorobenzyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[1004] Using the compound synthesized in Example 68A (80 mg), the crude title compound (80 mg) was obtained as a single diastereomer and a single enantiomer by the same method as in Example 5G.

[1005] (68C) (2R)-1-{(3S,4S)-3-[3-(5-chlorothien-3-yl)-2-fluorobenzyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]hept-2-yl}-1-oxopropan-2-yl acetate

[1006] Using the compound synthesized in Example 68B (80 mg) and (R)-2-acetoxypropionyl chloride (40 mg), the crude title compound (100 mg) was obtained as a single diastereomer and a single enantiomer by the same method as in Example 34A.

[1007] (68D) N-{(3S,4S)-3-[3-(5-chlorothien-3-yl)-2-fluorobenzyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1008] Lithium hydroxide monohydrate (24 mg) was added to a mixture of the compound synthesized in Example 68C (100 mg), water (1.0 mL), and tetrahydrofuran (5.0 mL) at room temperature and stirred for 10 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 60 / 40 to 30 / 70 (v / v)] to obtain 16 mg of the title compound as a single diastereomer and a single enantiomer (yield: 17%).

[1009] Example 69

[1010] N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2S)-3,3,3-trifluoro-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1011] (69A) N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2S)-3,3,3-trifluoro-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1012] 1-Chloro-N,N,2-trimethyl-1-propenylamine (0.0617 mL) was added to a mixture of (S)-3,3,3-trifluoro-2-hydroxypropionic acid (53.7 mg) and dichloromethane (1 mL) at 0°C, followed by stirring at room temperature for 1 hour while ultrasonicating. This reaction mixture was added to a separately prepared mixture of the compound synthesized in Example 66C (40.0 mg), N,N-diisopropylethylamine (0.111 mL), and dichloromethane (1 mL) at 0°C, followed by stirring at room temperature for 2 hours. The mixture was diluted with ethyl acetate and washed sequentially with water, hydrochloric acid (1 M), saturated sodium bicarbonate solution, and saturated brine, and then dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified sequentially by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30-20 / 80 (V / V)] and preparative thin-layer silica gel chromatography [elution solvent: n-hexane / ethyl acetate = 40 / 60 (V / V)] to obtain 15.5 mg (yield: 32%) of the title compound as a single diastereomer and a single enantiomer.

[1013] Example 70

[1014] N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-oxetan-2-ylcarbonyl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[1015] (70A) N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-oxetan-2-ylcarbonyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1016] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20.1 mg) was added to a mixture of the compound synthesized in Example 66C (30.0 mg), (2R)-oxetane-2-carboxylic acid (10.7 mg), 1-hydroxy-7-azabenzotriazole (9.5 mg), triethylamine (0.0388 mL), and N,N-dimethylformamide (1 mL) at room temperature, followed by stirring at 30°C for 3 hours. The mixture was diluted with ethyl acetate, washed sequentially with water, hydrochloric acid (0.5 M), saturated sodium bicarbonate solution, and saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100 (v / v)] to obtain 33.4 mg of the title compound as a single diastereomer and a single enantiomer (yield: quantitative).

[1017] Example 71

[1018] N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(1-hydroxycyclopropyl)carbonyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1019] (71A) N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(1-hydroxycyclopropyl)carbonyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1020] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20.1 mg) was added to a mixture of the compound synthesized in Example 66C (30.0 mg), 1-hydroxy-1-cyclopropanecarboxylic acid (10.7 mg), 1-hydroxy-7-azabenzotriazole (9.5 mg), triethylamine (0.0388 mL), and N,N-dimethylformamide (1 mL) at room temperature, and stirred at 35°C for 2.5 hours. The mixture was diluted with ethyl acetate, washed sequentially with water, hydrochloric acid (0.5 M), saturated sodium bicarbonate solution, and saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 60 / 40 to 20 / 80 (v / v)] to obtain 27.7 mg of the title compound as a single diastereomer and a single enantiomer (yield: 83%).

[1021] Example 72

[1022] N-{(3S,4S)-2-(3,3-Difluoro-2-hydroxypropanoyl)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1023] (72A) N-{(3S,4S)-2-(3,3-Difluoro-2-hydroxypropanoyl)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1024] The compound synthesized in Example 25B (100 mg) and 3,3-difluorolactic acid (36 mg) were used in the same manner as in Example 5H to obtain 40 mg of the title compound (yield: 34%).

[1025] (72B) N-{(3S,4S)-2-(3,3-Difluoro-2-hydroxypropanoyl)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1026] The compound synthesized in Example 72A (40 mg) was subjected to chiral SFC [column: CHIRALCEL (registered trademark) OJ (30 mm ID×250 mm), mobile phase: carbon dioxide / 2-propanol = 65 / 35 (V / V)] to obtain 19 mg of the title compound that eluted first as a single diastereomer and a single enantiomer (yield: 48%).

[1027] Example 73

[1028] N-[(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-{[1-(hydroxymethyl)cyclopropyl]carbonyl}-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[1029] (73A) N-[(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-{[1-(hydroxymethyl)cyclopropyl]carbonyl}-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1030] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (41 mg) was added to a mixture of 1-(hydroxymethyl)cyclopropanecarboxylic acid (CAS Registry No.: 49640-66-6, 8 mg) and N,N-dimethylformamide (1.0 mL) and stirred at 40°C for 1 hour. The compound synthesized in Example 25B (30 mg) and triethylamine (73 mg) were added and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the product was purified by reverse-phase silica gel column chromatography [elution solvent: 0.225% aqueous formic acid / acetonitrile = 70 / 30 to 40 / 60 (v / v)] to obtain 28 mg of the title compound as a single diastereomer and a single enantiomer (yield: 81%).

[1031] Example 74

[1032] N-[(3S,4R)-3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1033] (74A) tert-Butyl (3S,4R)-3-(3-bromo-2,5-difluorobenzyl)-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1034] The compound synthesized in Example 63E (990 mg) was subjected to chiral HPLC [column: CHIRAL ART Amylose-SA (20 mm I.D. × 250 mm), mobile phase: n-hexane / 2-propanol = 85 / 15 (V / V), temperature: 40°C] to obtain 371 mg of the title compound that eluted first as a single diastereomer and a single enantiomer (yield: 37%).

[1035] (74B) (3S,4R)-tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1036] A mixture of the compound synthesized in Example 74A (178 mg), phenylboronic acid (64 mg), tripotassium phosphate (211 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (21 mg), tetrahydrofuran (3.5 mL), and water (1.2 mL) was stirred at 70°C for 3 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50 (v / v)] to obtain 173 mg of the title compound as a single diastereomer and a single enantiomer (yield: 97%).

[1037] (74C) N-{(3S,4R)-3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[1038] A 1,4-dioxane solution of hydrogen chloride (4 M, 4.0 mL) was added to the compound synthesized in Example 74B (173 mg), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain 151 mg of the crude title compound as a single diastereomer and a single enantiomer.

[1039] (74D) 1-{(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[1040] Triethylamine (0.054 mL) and 2-acetoxyisobutyryl chloride (0.023 mL) were added to a mixture of the compound synthesized in Example 74C (35 mg) and tetrahydrofuran (1.0 mL) at room temperature and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 to 10 / 90 (v / v)] to obtain 36 mg of the title compound as a single diastereomer and a single enantiomer (yield: 84%).

[1041] (74E) N-[(3S,4R)-3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1042] Lithium hydroxide monohydrate (42 mg) was added to a mixture of the compound synthesized in Example 74D (36 mg), tetrahydrofuran (1.0 mL), methanol (0.5 mL), and water (0.5 mL) at room temperature, and the mixture was stirred at 40°C for 2 hours. After adding hydrochloric acid (2 M), the mixture was diluted with ethyl acetate and washed with water and saturated brine. The mixture was dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 50 / 50 (v / v)] to obtain 32 mg of the title compound as a single diastereomer and a single enantiomer (yield: 97%).

[1043] Example 75

[1044] N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-[(2S)-3-fluoro-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1045] (75A) N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-[(2S)-3-fluoro-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1046] Using the compound synthesized in Example 25B (18.0 mg) and (2S)-3-fluoro-2-hydroxypropionic acid (CAS registration number: 97643-52-2, 6.15 mg), the title compound (12.2 mg, yield: 60%) was obtained as a single diastereomer and a single enantiomer by the same method as in Example 5H.

[1047] Example 76

[1048] N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1049] (76A) N-[(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(2-oxopropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1050] N,N-Diisopropylethylamine (0.134 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (134 mg) were added to a mixture of the compound synthesized in Example 25B (107 mg), pyruvic acid (0.0234 mL), and N,N-dimethylformamide (2.6 mL) at room temperature and stirred for 1.5 hours. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 2 / 1-1 / 2 (v / v)] to obtain 108 mg of the title compound as a single diastereomer and a single enantiomer (yield: 93%).

[1051] (76B) N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1052] Potassium carbonate (9.3 mg) was added to a mixture of the compound synthesized in Example 76A (20.0 mg), tetrahydrofuran (0.45 mL), and methanol-d4 (0.45 mL) at room temperature, and the mixture was stirred for 1.5 hours. A solution of acetic acid (0.0077 mL) in methanol-d4 (0.15 mL) was added, followed by sodium borodeuteride (3.8 mg), and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, and aqueous ammonium chloride was added. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer silica gel chromatography [eluting solvent: ethyl acetate] to obtain 10.3 mg of the title compound as a single diastereomer and a single enantiomer (yield: 51%).

[1053] Example 77

[1054] N-[(3S,4R)-3-[(3'-Chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1055] (77A) (3S,4R)-tert-Butyl 3-[(3'-chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1056] A mixture of the compound synthesized in Example 74A (192 mg), 3-chlorophenylboronic acid (88 mg), potassium carbonate (155 mg), tetrakis(triphenylphosphine)palladium(0) (33 mg), 1,4-dioxane (6.2 mL), and water (1.5 mL) was stirred at 100°C for 2.5 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 to 40 / 60 (V / V)] and then purified by reverse-phase silica gel column chromatography [elution solvent: 0.1% formic acid aqueous solution / acetonitrile = 100 / 0 to 0 / 100 (V / V)] to obtain 124 mg of the title compound as a single diastereomer and a single enantiomer (yield: 61%).

[1057] (77B) N-{(3S,4R)-3-[(3'-chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[1058] The compound synthesized in Example 77A (124 mg) was used in the same manner as in Example 8H to obtain 110 mg of the crude title compound as a single diastereomer and a single enantiomer.

[1059] (77C) 1-{(3S,4R)-3-[(3'-chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptan-2-yl}-2-methyl-1-oxopropan-2-yl acetate

[1060] Triethylamine (0.038 mL) and 2-acetoxyisobutyryl chloride (0.016 mL) were added to a mixture of the compound synthesized in Example 77B (26 mg) and tetrahydrofuran (1.1 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 60 / 40 to 40 / 60 (v / v)] to obtain 26 mg of the title compound as a single diastereomer and a single enantiomer (yield: 83%).

[1061] (77D) N-[(3S,4R)-3-[(3'-Chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-(2-hydroxy-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1062] The compound synthesized in Example 77C (26 mg) was used to obtain 26 mg of the title compound as a single diastereomer and a single enantiomer by the same method as in Example 12H (yield: quantitative).

[1063] Example 78

[1064] N-{(3S,4R)-2-{[(1S)-2,2-Difluorocyclopropyl]carbonyl}-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1065] (78A) N-{(3S,4R)-2-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1066] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (20.1 mg) was added to a mixture of the compound synthesized in Example 66C (30.0 mg), (1S)-2,2-difluorocyclopropane-1-carboxylic acid (12.8 mg), 1-hydroxy-7-azabenzotriazole (9.5 mg), triethylamine (0.0388 mL), and N,N-dimethylformamide (1 mL) at room temperature. The mixture was stirred at 30°C for 3 hours. The mixture was diluted with ethyl acetate and washed sequentially with water, hydrochloric acid (0.5 M), saturated sodium bicarbonate solution, and saturated brine, and then dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 20 / 80 (v / v)] to obtain 33.4 mg of the title compound as a single diastereomer and a single enantiomer (yield: 96%).

[1067] Example 79

[1068] N-{(3S,4R)-3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2S)-3,3,3-trifluoro-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1069] (79A) N-{(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2S)-3,3,3-trifluoro-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1070] 1-Chloro-N,N,2-trimethyl-1-propenylamine (0.23 mL) was added to a mixture of (S)-3,3,3-trifluoro-2-hydroxypropionic acid (242 mg) and dichloromethane (3.4 mL) at 0°C, followed by stirring at room temperature for 45 minutes. This reaction mixture and N,N-diisopropylethylamine (0.33 mL) were added to a mixture of the compound synthesized separately in Example 74C (50 mg) and dichloromethane (3.0 mL) at room temperature over 30 minutes, followed by stirring for 15 minutes. 10% aqueous ammonia (3.0 mL) was added, stirred for 5 minutes, and then aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 50 / 50-0 / 100 (V / V)] to obtain 15 mg of the title compound as a single diastereomer and a single enantiomer (yield: 25%).

[1071] Example 80

[1072] N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1073] (80A) tert-Butyl (3S,4S)-3-(3-bromo-2-fluorobenzyl)-4-[(ethylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1074] Ethyl chloride (204 mg) was added to a mixture of the compound synthesized in Example 8F (300 mg), triethylamine (0.105 mL), and tetrahydrofuran (3.0 mL), and stirred at room temperature for 12 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the mixture was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 52 / 48 to 22 / 78 (v / v)] to obtain 120 mg of the title compound as a single diastereomer and a single enantiomer (yield: 33%).

[1075] (80B) tert-Butyl (3S,4S)-4-[(ethylsulfonyl)amino]-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1076] (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (24 mg) was added to a mixture of the compound synthesized in Example 80A (270 mg), phenylboronic acid (134 mg), tripotassium phosphate (236 mg), and tetrahydrofuran (3.0 mL) at room temperature. The mixture was stirred at 80°C for 12 hours under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1 (v / v)] to obtain 250 mg of the title compound as a single diastereomer and a single enantiomer (yield: 93%).

[1077] (80C) N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide hydrochloride

[1078] To a mixture of the compound synthesized in Example 80B (250 mg) and ethyl acetate (2.0 mL) was added a 4 M solution of hydrogen chloride in ethyl acetate (5.0 mL) at room temperature and stirred for 2 hours. The solvent was distilled off under reduced pressure to obtain 200 mg of the crude title compound as a single diastereomer and a single enantiomer.

[1079] (80D) (2R)-1-{(3S,4S)-4-[(ethylsulfonyl)amino]-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-1-oxopropan-2-yl acetate

[1080] (R)-2-Acetoxypropanoyl chloride (60 mg) was added to a mixture of the compound synthesized in Example 80C (100 mg), N,N-diisopropylethylamine (0.40 mL), and tetrahydrofuran (5.0 mL) at room temperature and stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 130 mg of the crude title compound as a single diastereomer and a single enantiomer.

[1081] (80E) N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1082] Lithium hydroxide monohydrate (106 mg) was added to a mixture of the compound synthesized in Example 80D (130 mg), tetrahydrofuran (2.0 mL), and water (2.0 mL) at room temperature and stirred for 12 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 65 / 35 to 35 / 65 (v / v)] to obtain 42 mg of the title compound as a single diastereomer and a single enantiomer (yield: 35%).

[1083] Example 81

[1084] N-{3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1085] (81A) tert-Butyl 3-(3-bromo-2,5-difluorobenzyl)-4-[(ethylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1086] Ethyl chloride (277 mg) was added to a mixture of the compound synthesized in Example 58E (600 mg), triethylamine (437 mg), and tetrahydrofuran (4.0 mL), and stirred at room temperature for 1 hour. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the product was purified by silica gel column chromatography [eluting solvent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1 (v / v)] to obtain 570 mg of the title compound as a single diastereomer (racemic form) (yield: 78%).

[1087] (81B) tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(ethylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1088] To a mixture of the compound synthesized in Example 81A (570 mg), phenylboronic acid (205 mg), tripotassium phosphate (475 mg), and tetrahydrofuran (6.0 mL) was added (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (95 mg) at room temperature. The mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1 (v / v)] to obtain 500 mg of the title compound as a single diastereomer (racemate) (yield: 88%).

[1089] (81C) N-{3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide hydrochloride

[1090] To a mixture of the compound synthesized in Example 81B (500 mg) and ethyl acetate (5.0 mL) was added a 4 M solution of hydrogen chloride in ethyl acetate (6.0 mL) at room temperature and stirred for 2 hours. The solvent was distilled off under reduced pressure to obtain 450 mg of the crude title compound as a single diastereomer (racemate).

[1091] (81D) (2R)-1-{3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(ethylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-yl}-1-oxopropane-2-yl acetate

[1092] (R)-2-Acetoxypropanoyl chloride (76 mg) was added to a mixture of the compound synthesized in Example 81C (150 mg), N,N-diisopropylethylamine (437 mg), and dichloromethane (1.0 mL) at room temperature and stirred for 1 hour. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 150 mg of the crude title compound.

[1093] (81E) N-{3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1094] Lithium hydroxide (34 mg) was added to a mixture of the compound synthesized in Example 81D (150 mg), tetrahydrofuran (2.0 mL), and water (0.5 mL) at room temperature and stirred for 12 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography [eluting solvent: 0.225% aqueous formic acid / acetonitrile = 58 / 42 to 38 / 62 (v / v)] to obtain 80 mg of the title compound (yield: 58%).

[1095] (81F) N-{3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1096] The compound synthesized in Example 81E (60 mg) was subjected to chiral SFC [column: Phenomenex-Cellulose-2 (30 mm ID×250 mm), mobile phase: carbon dioxide / ethanol = 65 / 35 (V / V)] to obtain 28 mg of the title compound that eluted first as a single diastereomer and a single enantiomer (yield: 46%).

[1097] Example 82

[1098] N-{(3S,4R)-3-[(3'-Chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2S)-3,3,3-trifluoro-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1099] (82A) N-{(3S,4R)-3-[(3'-Chloro-2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2S)-3,3,3-trifluoro-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1100] 1-Chloro-N,N,2-trimethyl-1-propenylamine (0.23 mL) was added to a mixture of (S)-3,3,3-trifluoro-2-hydroxypropionic acid (242 mg) and dichloromethane (3.4 mL) at 0°C, followed by stirring at room temperature for 45 minutes. This reaction mixture and N,N-diisopropylethylamine (0.33 mL) were added to a mixture of the compound synthesized separately in Example 77B (57 mg) and dichloromethane (3.0 mL) at room temperature over 30 minutes, followed by stirring for 15 minutes. 10% aqueous ammonia (3.0 mL) was added, and after stirring for 5 minutes, hydrochloric acid (2M, 6 mL) and saturated sodium bicarbonate solution (3 mL) were added in that order. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified sequentially by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 80 / 20-50 / 50 (V / V)] and NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 50 / 50-0 / 100 (V / V)] to obtain 25 mg of the title compound as a single diastereomer and a single enantiomer (yield: 38%).

[1101] Example 83

[1102] N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1103] (83A)(3S*,4R*)-tert-Butyl 4-amino-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1104] A mixture of the compound synthesized in Example 23D (15.0 mg), phenylboronic acid (8.8 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (3.0 mg), tripotassium phosphate (22.9 mg), tetrahydrofuran (0.6 mL), and water (0.2 mL) was stirred at 60°C for 1.5 hours. A mixture of the compound synthesized in Example 23D (255 mg), phenylboronic acid (149 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (51.7 mg), tripotassium phosphate (389 mg), tetrahydrofuran (6 mL), and water (2 mL) was stirred at 60°C for 2 hours. The reaction mixtures were combined, added with saturated brine, extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 60 / 40 to 20 / 80 (v / v)] to obtain 252 mg of the title compound as a single diastereomer (racemic form) (yield: 94%).

[1105] (83B) (3S*,4R*)-tert-Butyl 4-[(vinylsulfonyl)amino]-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1106] A solution of ethylenesulfonyl chloride (154 mg) in tetrahydrofuran (1 mL) was added to a mixture of the compound synthesized in Example 83A (252 mg), triethylamine (0.253 mL), and tetrahydrofuran (5 mL) at 0°C, followed by stirring at room temperature for 2 hours. Water was added, followed by extraction with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 75 / 25 to 50 / 50 (v / v)] to obtain 294 mg of the title compound as a single diastereomer (racemic form) (yield: 96%).

[1107] (83C)(3S*,4R*)-tert-Butyl 4-[(ethylsulfonyl)amino]-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1108] A mixture of the compound synthesized in Example 83B (10.0 mg), 10% palladium on carbon (5 mg), and ethyl acetate (1 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. A mixture of the compound synthesized in Example 83B (284 mg), 10% palladium on carbon (120 mg), and ethyl acetate (8 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction mixtures were combined, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 75 / 25 to 40 / 60 (v / v)] to obtain 264 mg (yield: 89%) of the title compound as a single diastereomer (racemate).

[1109] (83D) tert-Butyl (3S,4R)-4-[(ethylsulfonyl)amino]-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1110] The compound synthesized in Example 83C (264 mg) was purified by chiral HPLC [column: CHIRALPAK (registered trademark) IC (20 mm ID×250 mm), mobile phase: n-hexane / 2-propanol = 55 / 45 (V / V), temperature: 40°C] to obtain 112 mg (yield: 42%) of the title compound as a single diastereomer and a single enantiomer eluting later.

[1111] (83E) N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide hydrochloride

[1112] A 4 M solution of hydrogen chloride in 1,4-dioxane (5 mL) was added to a mixture of the compound synthesized in Example 83D (112 mg) and 1,4-dioxane (2.5 mL) at room temperature and stirred for 4 hours. The reaction mixture was diluted with toluene and concentrated under reduced pressure to obtain 91.7 mg of the crude title compound.

[1113] (83F) (2R)-1-{(3S,4R)-4-[(ethylsulfonyl)amino]-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptan-2-yl}-1-oxopropan-2-yl acetate

[1114] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42.9 mg) was added to a mixture of the compound synthesized in Example 83E (25.0 mg), (R)-2-acetoxypropionic acid (14.9 mg), triethylamine (0.0313 mL), and N,N-dimethylformamide (1.5 mL) at room temperature and stirred overnight. The mixture was diluted with ethyl acetate and washed sequentially with water, hydrochloric acid (0.5 M), saturated sodium bicarbonate solution, and saturated brine, and then dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 60 / 40 to 20 / 80 (v / v)] to obtain 28.9 mg of the title compound as a single diastereomer and a single enantiomer (yield: 98%).

[1115] (83G) N-{(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1116] Lithium hydroxide monohydrate (7.0 mg) was added to a mixture of the compound synthesized in Example 83F (28.9 mg), tetrahydrofuran (1.2 mL), methanol (0.4 mL), and water (0.4 mL) at room temperature and stirred overnight. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 0 / 100 (v / v)] to obtain 23.7 mg (yield: 89%) of the title compound as a single diastereomer and a single enantiomer.

[1117] Example 84

[1118] N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(1,2-oxazol-3-ylcarbonyl)-2-azabicyclo[3.1.1]heptan-4-yl]methanesulfonamide

[1119] (84A) N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(1,2-oxazol-3-ylcarbonyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1120] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.4 mg) was added to a mixture of the compound synthesized in Example 66C (20.0 mg), isoxazole-3-carboxylic acid (7.9 mg), 1-hydroxy-7-azabenzotriazole (6.4 mg), triethylamine (0.0259 mL), and N,N-dimethylformamide (1 mL) at room temperature, followed by stirring at 30°C for 2 hours. The mixture was diluted with ethyl acetate, washed sequentially with water, hydrochloric acid (0.5 M), saturated sodium bicarbonate solution, and saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 70 / 30 to 30 / 70 (v / v)] to obtain 9.2 mg of the title compound as a single diastereomer and a single enantiomer (yield: 43%).

[1121] Example 85

[1122] N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(2-fluoro-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1123] (85A) N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(2-fluoro-2-methylpropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1124] The compound synthesized in Example 66C (20.0 mg) and 2-fluoroisobutyric acid (7.4 mg) were used in the same manner as in Example 84A to obtain 18.6 mg of the title compound as a single diastereomer and a single enantiomer (yield: 83%).

[1125] Example 86

[1126] N-{(3S,4S)-3-[(2-Fluoro[biphenyl]-3-yl)methyl]-2-[(3S)-3-hydroxybutyryl]-2-azabicyclo[3.1.1]heptan-4-yl}methanesulfonamide

[1127] (86A) N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(3S)-3-hydroxybutyryl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1128] The compound synthesized in Example 25B (100 mg) and 3-hydroxybutyric acid (30 mg) were used in the same manner as in Example 31C to obtain 72 mg of the title compound as a single diastereomer and a single enantiomer (yield: 65%).

[1129] Example 87

[1130] N-{(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1131] (87A) N-[(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-(2-oxopropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1132] N,N-Diisopropylethylamine (0.0696 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (115 mg) were added to a mixture of the compound synthesized in Example 74C (45.0 mg), pyruvic acid (0.0216 mL), and N,N-dimethylformamide (1.01 mL) at room temperature and stirred for 1 hour. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100 (v / v)] to obtain 50.7 mg of the title compound as a single diastereomer and a single enantiomer (yield: quantitative).

[1133] (87B) N-{(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1134] Potassium carbonate (21.9 mg) was added to a mixture of the compound synthesized in Example 87A (50.7 mg), tetrahydrofuran (1.06 mL), and methanol-d4 (1.06 mL) at room temperature and stirred for 3 hours. A solution of acetic acid (0.0181 mL) in methanol-d4 (0.181 mL) was added, followed by sodium borodeuteride (8.83 mg) under ice-cooling and stirring for 1 hour. The mixture was diluted with ethyl acetate, and an aqueous ammonium chloride solution was added. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin-layer silica gel chromatography [eluting solvent: ethyl acetate] to obtain 43.6 mg of the title compound (yield: 85%).

[1135] (87C) N-{(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2R)-2-hydroxy(2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1136] The compound synthesized in Example 87B (43.6 mg) was subjected to chiral HPLC [column: CHIRALPAK (registered trademark) IG (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 70 / 30 (V / V), temperature: 40°C] to obtain 19.2 mg (yield: 44%) of the title compound as a single diastereomer and a single enantiomer eluting later.

[1137] Example 88

[1138] N-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1139] (88A)2,5-Difluoro-3-methyl[biphenyl]

[1140] (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (169 mg) and water (8.8 mL) were added to a mixture of 3-bromo-2,5-difluorotoluene (CAS No.: 1416354-32-9, 550 mg), phenylboronic acid (648 mg), tripotassium phosphate (1.69 g), and tetrahydrofuran (26.6 mL) at room temperature. The mixture was stirred at 60°C under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was diluted with n-hexane, washed with saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane] to obtain 508 mg of the title compound (yield: 94%).

[1141] (88B) 3-(Bromomethyl)-2,5-difluoro[biphenyl]

[1142] N-Bromosuccinimide (552 mg) and benzoyl peroxide (125 mg) were added to a mixture of the compound synthesized in Example 88A (528 mg) and carbon tetrachloride (9.0 mL) at room temperature and heated under reflux for 3 hours. After cooling to room temperature, saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added, and the mixture was diluted with n-hexane. The mixture was washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane] to obtain 679 mg of the title compound (yield: 93%).

[1143] (88C) 2-tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

[1144] 2-Oxo-4-azabicyclo[3.1.1]heptane-3,4-dicarboxylic acid O4-tert-butyl ester O3-methyl ester (CAS Registry No.: 2241048-56-4, 18.2 g) and cesium carbonate (99.2 g) were added to a mixture of the compound synthesized in Example 88B (19.2 g) and N,N-dimethylformamide (230 mL), and stirred at room temperature for 3 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 90 / 10 to 70 / 30 (v / v)] to obtain 28.7 g of the title compound (yield: 90%).

[1145] (88D) tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-oxo-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1146] Lithium chloride (12.8 g) was added to a mixture of the compound synthesized in Example 88C (35.6 g) and dimethyl sulfoxide (250 mL). The mixture was stirred at 130°C for 4 hours and then cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 80 / 20 (v / v)] to obtain a mixture of the title compound and 2-tert-butyl 3-methyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate. Methanol (600 mL) and a 1 M aqueous sodium hydroxide solution (151 mL) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 24.7 g of the title compound (yield: 79%).

[1147] (88E) tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-(hydroxyimino)-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1148] Hydroxylamine hydrochloride (13.6 g) and sodium acetate (21.5 g) were added to a mixture of the compound synthesized in Example 88D (27.0 g) and ethanol (320 mL). The mixture was stirred at 80°C for 2 hours and cooled to room temperature. The solvent was distilled off under reduced pressure, and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 28.7 g of the crude title compound.

[1149] (88F) tert-Butyl 4-amino-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1150] To a mixture of the compound synthesized in Example 88E (4.33 g) and methanol (100 mL) was added molybdenum (VI) oxide (7.27 g) at 0°C, followed by the addition of sodium borohydride (7.65 g) in small portions, and the mixture was stirred at 0°C for 1 hour. Molybdenum (VI) oxide (1.45 g) was added at 0°C, followed by the addition of sodium borohydride (1.53 g) in small portions, and the mixture was stirred at 0°C for 1 hour. Saturated sodium bicarbonate solution was added to the reaction mixture. In a separate container, a mixture of the compound synthesized in Example 88E (11.3 g) and methanol (260 mL) was prepared, and to this mixture was added molybdenum (VI) oxide (22.8 g) at 0°C, followed by the addition of sodium borohydride (23.9 g) in small portions, and the mixture was stirred at 0°C for 1 hour. Saturated sodium bicarbonate solution was added to the reaction mixture. In another container, a mixture of the compound synthesized in Example 88E (12.7 g) and methanol (300 mL) was prepared, molybdenum (VI) oxide (25.7 g) was added at 0°C, sodium borohydride (27.0 g) was added little by little, and the mixture was stirred at 0°C for 1 hour. Saturated sodium bicarbonate water was added to the reaction mixture. These were combined, ethyl acetate was added, diatomaceous earth was filtered twice, and the mixture was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 23.5 g of the crude title compound.

[1151] (88G)(3S*,4S*)-tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1152] N,N-Diisopropylethylamine (29.5 mL) was added to a mixture of the compound synthesized in Example 88F (23.8 g) and tetrahydrofuran (290 mL) at 0°C, followed by the gradual dropwise addition of methanesulfonyl chloride (13.3 g). After stirring at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 90 / 10 to 55 / 45 (v / v)] to obtain 16.4 g of the title compound as a single diastereomer (racemic form) (yield over three steps: 51%).

[1153] (88H)(3S,4S)-tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(methylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1154] The compound synthesized in Example 88G (10 g) was subjected to chiral HPLC [column: CHIRALPAK (registered trademark) IC (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 70 / 30 (V / V), temperature: 40°C] to obtain 4.6 g (yield: 46%) of the title compound eluting later as a single diastereomer and a single enantiomer.

[1155] (88I) N-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide hydrochloride

[1156] A 4M solution of hydrogen chloride in ethyl acetate (2 mL) was added to a mixture of the compound synthesized in Example 88H (55 mg) and methanol (4 mL), and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure to obtain 51 mg of the crude title compound as a single diastereomer and a single enantiomer.

[1157] (88J) N-[(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-(2-oxopropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1158] Pyruvic acid (0.010 mL), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (59 mg), and N,N-diisopropylethylamine (0.061 mL) were added to a mixture of the compound synthesized in Example 88I (51.0 mg) and N,N-dimethylformamide (2 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 60 / 40 to 35 / 65 (v / v)]. The residue was further purified by NH silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 20 / 80-10 / 90 (V / V)] to obtain 39 mg of the title compound as a single diastereomer and a single enantiomer (yield: 71%).

[1159] (88K)N-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1160] Potassium carbonate (18 mg) was added to a mixture of the compound synthesized in Example 88J (39.0 mg), tetrahydrofuran (0.7 mL), and methanol-d4 (0.7 mL), and stirred at room temperature for 1 hour. A mixture of methanol-d4 (0.7 mL) and acetic acid (0.015 mL) was added for neutralization, followed by sodium borodeuteride (8 mg) and stirring at room temperature for 1 hour. Saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 55 / 45 to 20 / 80 (v / v)]. Diethyl ether was added, the mixture was sonicated, and the title compound was collected by filtration to obtain 27 mg (yield: 68%) of the title compound as a single diastereomer and a single enantiomer.

[1161] Example 89

[1162] N-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1163] (89A) N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(2-oxopropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]methanesulfonamide

[1164] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (54.4 mg) was added to a mixture of the compound synthesized in Example 66C (40.9 mg), pyruvic acid (0.0100 mL), triethylamine (0.0397 mL), and N,N-dimethylformamide (3 mL) at room temperature and stirred for 3 hours. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 60 / 40 to 20 / 80 (v / v)] to obtain 45.1 mg of the title compound as a single diastereomer and a single enantiomer (yield: quantitative).

[1165] (89B) N-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1166] Potassium carbonate (19.8 mg) was added to a mixture of the compound synthesized in Example 89A (45.1 mg), tetrahydrofuran (0.954 mL), and methanol-d4 (0.954 mL) at room temperature, and the mixture was stirred for 1 hour. A solution of acetic acid (0.0164 mL) in methanol-d4 (0.328 mL) and sodium borodeuteride (8.0 mg) were added to the reaction mixture at room temperature, and the mixture was stirred for 1 hour. After adding aqueous ammonium chloride, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100 (v / v)] to obtain 46.4 mg of the title compound (yield: quantitative).

[1167] (89C)N-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}methanesulfonamide

[1168] The compound synthesized in Example 89B (46.4 mg) was subjected to chiral HPLC [column: CHIRALPAK (registered trademark) IG (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 50 / 50 (V / V), temperature: 40°C] to obtain 28.4 mg (yield: 61%) of the title compound eluting later as a single diastereomer and a single enantiomer.

[1169] Example 90

[1170] N-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1171] (90A) N-[(3S,4R)-5-Fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-(2-oxopropanoyl)-2-azabicyclo[3.1.1]heptane-4-yl]ethanesulfonamide

[1172] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (56.4 mg) was added to a mixture of the compound synthesized in Example 83E (43.8 mg), pyruvic acid (0.0105 mL), triethylamine (0.0411 mL), and N,N-dimethylformamide (3 mL) at room temperature and stirred for 2 hours. The mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [elution solvent: n-hexane / ethyl acetate = 60 / 40 to 20 / 80 (v / v)] to obtain 47.2 mg of the title compound as a single diastereomer and a single enantiomer (yield: quantitative).

[1173] (90B) N-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1174] Potassium carbonate (20.5 mg) was added to a mixture of the compound synthesized in Example 90A (47.2 mg), tetrahydrofuran (0.989 mL), and methanol-d4 (0.989 mL) at room temperature, and the mixture was stirred for 3.5 hours. A solution of acetic acid (0.0170 mL) in methanol-d4 (0.340 mL) was added to the reaction mixture at room temperature, and sodium borodeuteride (8.3 mg) was further added at 0°C. The mixture was then stirred at room temperature for 2 hours. After adding aqueous ammonium chloride, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100 (v / v)] to obtain 48.5 mg of the title compound (yield: quantitative).

[1175] (90C) N-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1176] The compound synthesized in Example 90B (48.5 mg) was subjected to chiral HPLC [column: CHIRALPAK (registered trademark) IG (20 mm ID × 250 mm), mobile phase: n-hexane / ethanol = 50 / 50 (V / V), temperature: 40°C] to obtain 27.7 mg (yield: 57%) of the title compound eluting later as a single diastereomer and a single enantiomer.

[1177] Example 91

[1178] N-{3-[(2,5-Difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2R)-2-hydroxypropanoyl]-2-azabicyclo[3.1.1]heptane-4-yl}ethanesulfonamide

[1179] (91A) tert-Butyl 4-amino-3-(3-bromo-2,5-difluorobenzyl)-5-fluoro-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1180] To a mixture of the compound synthesized in Example 63C (2.57 g), methanol (95 mL), and molybdenum (VI) oxide (2.47 g), lithium borohydride (approximately 2 M tetrahydrofuran solution) (34.3 mL) was slowly added dropwise at room temperature over 30 minutes, and the mixture was stirred for 30 minutes. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction mixture, and the mixture was filtered through celite. The solvent of the filtrate was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 2.40 g of the crude title compound.

[1181] (91B) tert-Butyl 4-amino-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1182] To a mixture of the compound synthesized in Example 91A (400 mg), phenylboronic acid (224 mg), tripotassium phosphate (585 mg), and tetrahydrofuran (9.2 mL) (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (77.8 mg) and water (3.1 mL) was added. The mixture was stirred at 60°C for 3 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed sequentially with water and saturated brine, and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 60 / 40 to 20 / 80 (v / v)) to obtain 251 mg of the title compound as a single diastereomer (racemic form) (yield: 63%).

[1183] (91C) tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(vinylsulfonyl)amino]-5-fluoro-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1184] Triethylamine (0.401 mL) and ethylenesulfonyl chloride (0.161 mL) were added to a mixture of the compound synthesized in Example 91B (250 mg) and tetrahydrofuran (0.50 mL) under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluting solvent: n-hexane / ethyl acetate = 100 / 0 to 20 / 80 (v / v)] to obtain 185 mg of the title compound as a single diastereomer (racemic form) (yield: 61%).

[1185] (91D) tert-Butyl 3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-4-[(ethylsulfonyl)amino]-2-azabicyclo[3.1.1]heptane-2-carboxylate

[1186] 10% palladium on carbon (water-containing) (16.3 mg) was added to a mixture of the compound synthesized in Example...

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, In formula (I), R 1 represents a phenyl group or a pyridyl group which may have 1 or 2 substituents independently selected from the following Group A, a phenyl group substituted with 5 deuterium atoms, a 2,2-difluoro-1,3-benzodioxolyl group, or a 5-membered heteroaryl group containing 1 or 2 atoms independently selected from the group consisting of a nitrogen atom and a sulfur atom in the ring, The heteroaryl group may have 1 or 2 substituents independently selected from the following Group B, R 2 represents a C1-C6 alkyl group which may have 1 to 5 substituents independently selected from the following Group C, a C3-C6 cycloalkyl group which may have 1 or 2 substituents selected from the following Group D, a 4- or 5-membered saturated heterocyclic group containing one atom selected from the group consisting of a nitrogen atom and an oxygen atom in the ring, a 5-membered heteroaryl group containing one or two atoms independently selected from the group consisting of a nitrogen atom and an oxygen atom in the ring, a C1-C6 alkoxy group, a C1-C6 alkylamino group, a diC1-C6 alkylamino group or a dicyclopentyl group, R 3 represents a hydrogen atom or a halogen atom, R 4 represents a hydrogen atom or a halogen atom, R 5 represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a diC1-C6 alkylamino group, or a vinyl group which may be substituted by 1 to 3 halogen atoms, R 6 represents a hydrogen atom or a halogen atom, Z represents CH or a nitrogen atom, in Group A: halogen atoms, C1-C6 alkyl groups which may be substituted by 1 to 3 halogen atoms, C1-C6 alkoxy groups which may be substituted by 1 to 3 halogen atoms, C3-C6 cycloalkyl groups, and cyano groups; Group B: halogen atoms, C1-C6 alkyl groups; Group C: hydroxyl, halogen, deuterium, C1-C6 alkoxy, C3-C6 cycloalkyl, pyrazolyl; Group D: halogen atoms, C1-C6 alkyl groups which may be substituted with 1 to 3 hydroxyl groups, cyano groups, and hydroxyl groups.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), R 1 represents a phenyl group or a pyridyl group which may have one or two substituents independently selected from the group consisting of a fluorine atom, a chlorine atom, a difluoromethyl group, a trifluoromethyl group, and a cyclopropyl group.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), R 2 represents a C1-C6 alkyl group which may have 1 to 5 substituents independently selected from the group consisting of a hydroxy group, a fluorine atom, and a deuterium atom, a cyclopropyl group which may be substituted with 1 or 2 fluorine atoms, or an isoxazolyl group.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), R 3 represents a fluorine atom, R 4 represents a hydrogen atom or a fluorine atom, Z represents CH or a nitrogen atom.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), R 5 represents a methyl group, an ethyl group, a monofluoromethyl group, or a cyclopropyl group, R 6 represents a hydrogen atom or a fluorine atom.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), R 1 represents the following formula (II), [Chemistry 2] In formula (II), R 11 and R 12 each independently represents a hydrogen atom, a fluorine atom or a chlorine atom, R 2 For the following R 2a to R 2e Any one of [Chemistry 3] R 3 、R 4 and R 6 each independently represents a hydrogen atom or a fluorine atom, R 5 represents a methyl or ethyl group, Z represents CH or a nitrogen atom.

7. A compound selected from any one of the following groups or a pharmaceutically acceptable salt thereof: N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[ 3.1.1] heptane-4-yl} methanesulfonamide, N-{(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[ 3.1.1] heptane-4-yl} methanesulfonamide, N-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[ 3.1.1] heptane-4-yl} methanesulfonamide, N-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy( 2 H4) propionyl]-2-azabicyclo[ 3.1.1] heptane-4-yl} methanesulfonamide, N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[ 3.1.1] heptane-4-yl} methanesulfonamide, N-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[ 3.1.1] heptane-4-yl} methanesulfonamide, N-{(3S,4R)-5-fluoro-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[ 3.1.1] heptane-4-yl} methanesulfonamide, and N-{(3S,4R)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-5-fluoro-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[ 3.1.1]heptane-4-yl}methanesulfonamide.

8. A compound selected from any one of the following groups or a pharmaceutically acceptable salt thereof: N-{(3S,4S)-3-[(2-fluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[ 3.1.1] heptane-4-yl} methanesulfonamide, and N-{(3S,4S)-3-[(2,5-difluoro[biphenyl]-3-yl)methyl]-2-[(2R)-2-hydroxy(2- 2 H) propionyl]-2-azabicyclo[ 3.1.1]heptane-4-yl}methanesulfonamide.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof. 10 . An orexin type 2 receptor agonist comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. A preventive or therapeutic agent for narcolepsy, comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

12. A method for preventing or treating narcolepsy, characterized in that: An effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof is administered.

13. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of narcolepsy.

14. Use of the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating narcolepsy.

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