Compound with slc15a4 inhibitory activity

Abstract

The present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, Y is CH2 or O, R1 is an alkyl, alkoxy, alkenyl, alkenyloxy, cycloalkyl, or cycloalkyloxy which may have a substituent, R2 is independently selected from halogens and alkyls, and R3 is independently selected from halogens and alkyls)

Description

SLC15A4 inhibitory compounds

[0001] The present invention relates to compounds having SLC15A4 inhibitory activity or pharmaceutically acceptable salts thereof.

[0002] SLC15A4 (Solute Carrier Family 15 Member 4) is a histidine and dipeptide transporter localized to endosomes and lysosomes (Non-Patent Literature 1). SLC15A4 has been reported to regulate the activation of the TLR (Toll-like receptor) 7 or TLR9 pathway, thereby controlling type I IFN (interferon) production in pDCs (plasmacytoid dendritic cells) and antibody production in B cells (Non-Patent Literature 2, Non-Patent Literature 3).

[0003] Two main mechanisms have been reported for how SLC15A4 regulates the TLR7 or TLR9 pathway. One is the regulation of lysosome maturation through transporter activity (Non-Patent Literature 3), and the other is that it functions as a scaffold protein for TASL (TLR adaptor interacting with SLC15A4 on the lysosome) and activates IRF5 (Interferon regulatory factor 5) (Non-Patent Literature 4).

[0004] Genetic polymorphisms of SLC15A4 increase the risk of developing systemic lupus erythematosus (SLE) (Non-Patent Documents 5, 6, and 7). Furthermore, it has been reported that one mechanism for this increased risk is that genetic polymorphisms of SLC15A4 increase the expression level of SLC15A4 in B cells (Non-Patent Document 7).

[0005] In mice spontaneously developing SLE-like symptoms, SLC15A4 gene deficiency has been shown to suppress the onset of SLE-like pathology, including a significant decrease in autoantibody titers and proteinuria (Non-Patent Literature 8, Non-Patent Literature 9, Non-Patent Literature 10). These reports in humans and mice suggest that SLC15A4 is involved in the pathogenesis of SLE.

[0006] In recent years, anifrolumab, a neutralizing antibody for type I IFN receptors, has been approved as a treatment for SLE (Non-Patent Literature 11). Furthermore, litifilimab, an anti-BDCA2 antibody that specifically inhibits type I IFN production by inhibiting pDC function, has shown efficacy in clinical trials targeting SLE and cutaneous lupus erythematosus (CLE) (Non-Patent Literature 12, 13, 21). It has been reported that treatment of SLE pathology can be achieved by inhibiting type I IFN production. Other conditions involving type I IFN production by pDCs include lupus nephritis, Sjögren's syndrome, systemic sclerosis, dermatomyositis, IgG4-related disease, and myasthenia gravis (Non-Patent Literature 15, 16, 17, 18, 19, 20).

[0007] Furthermore, two small molecule compounds that bind to SLC15A4 and inhibit its function have been reported (Patent Document 1, Non-Patent Document 14), and the co-crystal structures of the inhibitors and SLC15A4 have also been analyzed (Non-Patent Document 14).

[0008] International Publication No. 2021 / 174023

[0009] Mol. Pharmaceutics, 2018. 15 (2): 385-393PNAS, 2010. 107 (46): 19973-19978Immunity, 2014. 41 (3): 375-388Nature, 2020. 581: 316-322Nat Genet, 2009. 41 (11): 1234-1247European Journal of Human Genetics, 2013. 21: 994-999Cell, 2021. 184(11): 3006-3021PLoS ONE, 2021. 16(1): e0244439PNAS, 2013. 100 (8): 2940-2945PNAS, 2022. 119 (14): e2200544119N Engl J Med, 2020. 382: 211-221N Engl J Med, 2022. 387: 894-904N Engl J Med, 2022. 387:321-331Nature Communications, 2023. 6626 (14)The Journal of Rheumatology, 2022. 49 (4): 388-397Vaccines, 2020. 8 (2): 272Biology, 2023. 12 (2): 285Front Med, 2022. 24: 833114Front Immunol, 2021. 12: 713779Ann. NY Acad. Sci., 2018. 1413: 11-24J Clin Invest, 2019. 129 (3): 1359-1371

[0010] The present invention aims to provide compounds having SLC15A4 inhibitory activity or pharmaceutically acceptable salts thereof.

[0011] This embodiment relates to the following [1] to

[21] . [1] The following formula (I):

[0012]

[0013] [In the formula, Y is CH ２ or O, R １is alkyl which may have a substituent, alkoxy which may have a substituent, alkenyl which may have a substituent, alkenyloxy which may have a substituent, cycloalkyl which may have a substituent, or cycloalkyloxy which may have a substituent, and R ２ is independently selected from halogen and alkyl, and R ３ is independently selected from halogen and alkyl] and a compound represented thereby or a pharmaceutically acceptable salt thereof. [2] The above R １ is, C １ -C ６ alkyl, halogen and C ３ -C ６ cycloalkyl which may have a substituent independently selected from the group consisting of, C １ -C ６ alkoxy, C ３ -C ６ cycloalkyl which may be substituted with cycloalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkenyloxy, C １ -C ６ cycloalkyl which may be substituted with alkyl, C ３ -C ６ cycloalkyl, or C ３ -C ６ cycloalkyloxy, the compound or a pharmaceutically acceptable salt thereof according to [1]. [3] The above R ２ is selected independently from halogen and C １ -C ６ alkyl, the compound or a pharmaceutically acceptable salt thereof according to [1] or [2]. [4] The above R ３ is selected independently from halogen and C １ -C ６ alkyl, the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [3]. [5] Y is CH ２ or O, preferably CH ２ and R １ is -O-ethyl, -O-CH ２CHF ２ , -O-CH ２ -Cyclopropyl, -O-Cyclopropyl, -O-Cyclobutyl, -O-CH ２ CH=CH ２ , (1S,2S)-2-methylcyclopropyl-1-yl,-propyl, or -CH=CH-cyclopropyl, R ２ -F and -CH are independent of each other. ３ Selected from, R ３ These independently produce -F, -Cl, and -CH ３ A compound selected from [1] or a pharmaceutically acceptable salt thereof. [6] The following group:

[0014]

[0015]

[0016] A compound according to [1] or a pharmaceutically acceptable salt thereof, selected from [1]. [7] A pharmaceutical composition comprising a compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof. [8] The pharmaceutical composition according to [7], which is an SLC15A4 inhibitor. [9] The pharmaceutical composition according to [7] or [8] for the treatment of a disease associated with SLC15A4 inhibition.

[10] The pharmaceutical composition according to [9], wherein the disease associated with SLC15A4 inhibition is an autoimmune disease.

[11] The pharmaceutical composition according to [9], wherein the disease associated with SLC15A4 inhibition is systemic lupus erythematosus, lupus nephritis, or cutaneous lupus.

[12] The pharmaceutical composition according to [9], wherein the disease associated with SLC15A4 inhibition is Sjögren's syndrome.

[13] A therapeutic agent for a disease associated with SLC15A4 inhibition, comprising a compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof as an active ingredient.

[14] The therapeutic agent according to

[13] , wherein the disease associated with SLC15A4 inhibition is an autoimmune disease.

[15] The therapeutic agent according to

[13] , wherein the disease associated with SLC15A4 inhibition is systemic lupus erythematosus, lupus nephritis, or cutaneous lupus.

[16] The therapeutic agent according to

[13] , wherein the disease associated with SLC15A4 inhibition is Sjögren's syndrome.

[17] A compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[18] A compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for use in the treatment of a disease associated with SLC15A4 inhibition.

[19] Use of a compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for the treatment of a disease associated with SLC15A4 inhibition.

[20] Use of any one of the compounds described in [1] to [6] or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the treatment of diseases associated with SLC15A4 inhibition.

[21] A pharmaceutical product containing any one of the compounds described in [1] to [6] or a pharmaceutically acceptable salt thereof as an active ingredient.

[0017] According to the present invention, compounds having SLC15A4 inhibitory activity or pharmaceutically acceptable salts thereof can be provided.

[0018] In this specification, the compound represented by formula (I) will also be referred to as "compound (I)". The same applies to compounds with other formula numbers. In this specification, "C １ " means that it has one carbon atom, and is "C １ -C ６ This means that the carbon number is between 1 and 6. The same applies to the other numbers.

[0019] In this specification, some or all of the atoms in compound (I) may be replaced by their corresponding isotopic atoms, and compound (I) in this embodiment also includes compounds in which these isotopic atoms have been replaced. For example, some or all of the hydrogen atoms in compound (I) may be hydrogen atoms with an atomic weight of 2 (deuterium atoms).

[0020] In this specification, "may have substituents" means that the group may be unsubstituted or may have any substituents. Examples of substituents on each group are listed below.

[0021] In this specification, halogen refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0022] In this specification, alkyl groups include linear or branched alkyl groups. In this specification, alkyl groups include C １ -C ６ Alkyl compounds are preferred, and examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl compounds.

[0023] In this specification, alkoxys include linear or branched alkoxys. In this specification, alkoxys include C １ -C ６ Alkoxy is preferred, and examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, and the like.

[0024] In this specification, alkenyls include linear or branched alkenyls. In this specification, alkenyls include C ２ -C ６ Alkenyls are preferred, and examples include vinyl, allyl, propenyl, isopropenyl, butenyl, sec-butenyl, tert-butenyl, pentenyl, isopentenyl, neopentenyl, hexenyl, and the like.

[0025] In this specification, examples of alkenyloxy include linear or branched alkenyloxy. In this specification, examples of alkenyloxy include C ２ -C ６ Alkenyloxy is preferred, and examples include vinyloxy, allyloxy, propenyloxy, isopropenyloxy, butenyloxy, sec-butenyloxy, tert-butenyloxy, pentenyloxy, isopentenyloxy, neopentenyloxy, hexenyloxy, and the like.

[0026] In this specification, cycloalkyl refers to C ３ -C ６ Cycloalkyl groups are preferred, and examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0027] In this specification, cycloalkyloxy is defined as C ３ -C ６ Cycloalkyloxy compounds are preferred, and examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0028] In this specification, examples of substituents in "alkyl which may have substituents" or "alkoxy which may have substituents" include halogen, hydroxyl, mercapto, nitro, cyano, formyl, carboxyl, carbamoyl, and C １ -C ６ Alkoxy, C ２ -C ７ Alkylcarbonyl, C ２ -C ７ Alkylcarbonyloxy, C ２ -C７ Alkoxycarbonyl, C １ -C ６ Alkylthio, C １ -C ６ Alkylsulfonyl, C １ -C ６ Alkylamino, C ２ -C １２ Dialkylamino, C ３ -C ６ Cycloalkyl, C ３ -C ６ Cycloalkyloxy, C ６ -C １０ An aryl, an aliphatic heterocyclic group, an aromatic heterocyclic group, etc. may be mentioned, and more preferably, for example, a halogen or C ３ -C ６ Cycloalkyl may be mentioned.

[0029] [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Examples include aryl groups, aliphatic heterocyclic groups, aromatic heterocyclic groups, and more preferably, for example, halogens or C ３ -C ６ Cycloalkyl groups are examples.

[0030] In this specification, the substituents of "a cycloalkyl that may have substituents" or "a cycloalkyloxy that may have substituents" include, for example, oxo, imino, halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, and C. １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Alkoxy, C ２ -C ７ Alkylcarbonyl, C ２ -C ７ Alkylcarbonyloxy, C ２ -C ７ Alkoxycarbonyl, C １ -C ６ Alkylthio, C １ -C ６ Alkyl sulfonyl, C １ -C ６ Alkylamino, C ２ -C １２ Dialkylamino, C ３ -C ６ Cycloalkyl, C ３ -C ６ Cycloalkyloxy, C ６ -C １０ Examples include aryl groups, aliphatic heterocyclic groups, aromatic heterocyclic groups, and more preferably, for example, halogens and C １ -C ６ Alkyl, or C ３ -C ６ Cycloalkyl groups are examples.

[0031] In this specification, examples of alkynyls include linear or branched alkynyls, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0032] In this specification, examples of alkylcarbonyls include linear or branched alkylcarbonyls, such as acetyl, propionyl, butyryl, 2-methylbutanoyl, 3-methylbutanoyl, pivaloyl, pentanoyl, and hexanoyl.

[0033] In this specification, examples of alkylcarbonyloxy include linear or branched alkylcarbonyloxy, such as acetoxy, propionyloxy, butyryloxy, (2-methylbutanoyl)oxy, (3-methylbutanoyl)oxy, pivaloyloxy, pentanoyloxy, and hexanoyloxy.

[0034] In this specification, examples of alkoxycarbonyls include linear or branched alkoxycarbonyls, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, and hexyloxycarbonyl.

[0035] In this specification, alkylthio refers to linear or branched alkylthio, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, and the like.

[0036] In this specification, examples of alkylsulfonyl include linear or branched alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, and hexylsulfonyl.

[0037] In this specification, alkylaminos include linear or branched alkylaminos, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, and hexylamino.

[0038] In this specification, dialkylaminos include linear or branched dialkylaminos, such as dimethylamino, ethyl(methyl)amino, methyl(propyl)amino, isopropyl(methyl)amino, butyl(methyl)amino, tert-butyl(methyl)amino, diethylamino, ethyl(propyl)amino, ethyl(isopropyl)amino, butyl(ethyl)amino, tert-butyl(ethyl)amino, dipropylamino, and diisopropylamino.

[0039] In this specification, examples of aryls include phenyl and naphthyl. In this specification, an aliphatic heterocyclic group refers to an aliphatic heterocyclic group having at least one heteroatom selected from, for example, N (nitrogen atom), O (oxygen atom), and S (sulfur atom). In this specification, even if a heterocyclic group has some unsaturated bonds, it is considered an aliphatic heterocyclic group if the heterocycle as a whole does not have aromaticity. Examples of aliphatic heterocyclic groups include monocyclic aliphatic heterocyclic groups and polycyclic aliphatic heterocyclic groups. Examples of monocyclic aliphatic heterocyclic groups include 4-8 membered monocyclic aliphatic heterocyclic groups having at least one to three heteroatoms selected from N (nitrogen atom), O (oxygen atom), and S (sulfur atom). Examples of polycyclic aliphatic heterocyclic groups include 3-15 membered polycyclic aliphatic heterocyclic groups having at least one to four heteroatoms selected from N (nitrogen atom), O (oxygen atom), and S (sulfur atom). Here, if there are multiple heteroatoms in the aliphatic heterocyclic group, the heteroatoms may be the same or different. Examples of polycyclic aliphatic heterocyclic groups include fused aliphatic heterocyclic groups, bridging aliphatic heterocyclic groups, and spirocyclic aliphatic heterocyclic groups. A fused aliphatic heterocyclic group is a ring formed by two or more rings sharing one or more bonds with each other, containing at least one heteroatom, and having non-aromatic properties as a whole. A bridging aliphatic heterocyclic group is a ring having a covalent bond connecting two non-adjacent atoms in the ring, containing at least one heteroatom, and having non-aromatic properties as a whole. A spirocyclic aliphatic heterocyclic group is a polycyclic structure formed by two or more rings sharing one atom, containing at least one heteroatom, and having non-aromatic properties as a whole.

[0040] In this specification, aliphatic heterocyclic groups include, more specifically, azetidinil, pyrrolidinil, piperidino, piperidinil, azepanil, 1,4-diazepanil, 1,2,5,6-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, imidazolidinil, pyrazolidinil, piperazinil, homopiperazinil, pyrazolinil, oxetanil, tetrahydrofuranil, tetrahydro-2H-pyranil, 5,6-dihydro-2H-pyranil, oxazolidinil, morpholino, morpholinil, thioxazolidinil, thiomorpho Linyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromanil, isochromanil, dihydro-2H-chromanil, dihydro-1H-chromanil, dihydro-2H-thiochromanil, dihydro-1H-thiochromanil, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzo Dioxanil, tetrahydro-2H-thiopyranil, octahydropyrrolo[3,4-b]pyrrol, hexahydropyrrolo[3,4-b]pyrrol, 8-azabidiclo[3.2.1]octanil, 8-thiabicyclo[3.2.1]octanil, 1-azabicyclo[2.2.2]octanil, 4-azaspiro[2.5]octanil, 5-azaspiro[3.5]nonanil, 2,8-diazaspiro[4.5]decanil, 2,7-diazaspiro[4.4]nonanil, 1,7-diazaspiro[4.4]nonanil, 2,6-diazaspiro[3.4]octanil Lu, 1,7-diazaspiro[4.5]decanil, 2,8-diazaspiro[4.5]decanil, 6-oxa-2,9-diazaspiro[4.5]decanil, 2,6-diazaspiro[3.3]heptanil, 7-azaspiro[3.5]nonanil, 4,7-diazaspiro[2.5]octanil, 2,7-diazaspiro[3.4]octanil, 1,9-diazaspiro[4.5]decanil, 8-thiabicyclo[3.2.1]octanil, 4-azaspiro[2.5]octanil, 5-azaspiro[3.5]nonanil, dihydro-1H-pyridyl, 1,2,3,6-tetrahydropyridyl, 7-azaspiro[3.5]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 4,7-diazaspiro[2.5]octanyl, 2,7-diazaspiro[4.4]nonanyl, phosfinanyl, 3,6-diazaspiro[3.1.1]heptanyl, 1,4-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1-oxa-8-azaspiro[4.5]decanyl, 2-azaspiro[4.5]decanyl, 1-azabisi Examples include clo[2.2.1]heptanil, 2-azaspiro[3.3]heptanil, oxazepanil, 1,4-azaphosfinanil, 2-oxa-6-azaspiro[3.3]heptanil, 8-oxa-3-azabicyclo[3.2.1]octanil, 3-oxa-8-azabicyclo[3.2.1]octanil, hexahydropyrrolo[3,4-c]pyrrolyl, 1-azaspiro[4.5]decanil, 2-azaspiro[4.4]nonanil, 1-oxa-7-azabicyclo[4.4]nonanil, and 1-oxa-3,7-diazaspiro[4.4]nonanil.

[0041] In this specification, examples of aromatic heterocyclic groups include five- or six-membered monocyclic aromatic heterocyclic groups having at least one heteroatom selected from N, O, and S, and three to ten-membered fused aromatic heterocyclic groups that are bicyclic or tricyclic and have at least one heteroatom selected from N, O, and S. More specifically, examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, teto Examples include lazolyl, pyridyl, pyridadinil, pyrimidinil, pyrazinil, triazinil, benzofuranil, benzothiophenyl, benzooxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, oxazolopyrimidinil, thiazolopyrimidinil, pyrrolopyrimidinil, pyrrolopyrimidinil, imidazopyrimidinil, purinil, quinolinil, isoquinolinil, sinnolinil, phthalazinil, quinazolinil, quinoxalinil, naphthylidinil, etc.

[0042] In this specification, Y in the compound represented by formula (I) is CH ２ or O, preferably CH ２ That is the case.

[0043] The R of the compound represented by formula (I) in this specification １ This is an optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted cycloalkyl, or optionally substituted cycloalkyloxy.

[0044] The R of the compound represented by formula (I) in this specification １ Preferably, the following: C １ -C ６ Alkyl, halogen and C ３ -C ６ C may have substituents independently selected from the group consisting of cycloalkyl groups. １ -C ６ Alkoxy, C ３ -C ６ C may be substituted with a cycloalkyl group. ２ -C ６ Alkenil, C ２ -C ６ Alkenyloxy, C １ -C ６ C may be substituted with alkyl. ３ -C ６ Cycloalkyl, and C ３ -C ６ Groups selected from the group consisting of cycloalkyloxy are examples. Here, the above "halogen and C ３ -C ６ C may have substituents independently selected from the group consisting of cycloalkyl groups. １ -C ６ The number of substituents in the "alkoxy" is preferably 0 to 3. Also, the above "C ３ -C ６ C may be substituted with a cycloalkyl group. ２ -C ６ In "Alkenil", C３ -C ６ The number of cycloalkyl substitutions is preferably 0 or 1. Also, the above "C １ -C ６ C may be substituted with alkyl. ３ -C ６ In "cycloalkyl", C １ -C ６ The number of alkyl substitutions is preferably 0 or 1.

[0045] The R of the compound represented by formula (I) in this specification １ More preferably, the following: C １ -C ６ C may have substituents independently selected from the group consisting of alkyl, fluorine, and cyclopropyl atoms. １ -C ６ C may be substituted with alkoxy or cyclopropyl. ２ -C ６ Alkenil, C ２ -C ６ C may be substituted with alkenyloxy and methyl groups. ３ -C ６ Examples include groups selected from the group consisting of cycloalkyl groups. Here, the above-mentioned C may have substituents independently selected from the group consisting of fluorine atoms and cyclopropyl groups. １ -C ６ The number of substituents in the "alkoxy" is preferably 0 to 3. Also, the above "C may be substituted with cyclopropyl" ２ -C ６ In the "alkenyl" group, it is preferable that the number of cyclopropyl substitutions is 0 or 1. Furthermore, the above-mentioned "C which may be substituted with methyl" ３ -C ６ In the case of "cycloalkyl," it is preferable that the number of methyl substitutions is 0 or 1.

[0046] The R of the compound represented by formula (I) in this specification １ More preferably, -O-ethyl, -O-CH ２ CHF ２ , -O-CH２ -Cyclopropyl, -O-Cyclopropyl, -O-Cyclobutyl, -O-CH ２ CH=CH ２ The compounds are (1S,2S)-2-methylcyclopropyl-1-yl,-propyl, or-CH=CH-cyclopropyl.

[0047] The R of the compound represented by formula (I) in this specification ２ These are independently selected from halogens and alkyls, preferably halogens and C １ -C ６ Selected independently of alkyl. In a more preferred embodiment, R ２ These are independently selected from fluorine atoms and methyl atoms.

[0048] In the compound represented by formula (I) herein, R ２ The number of is 0 to 6. In an embodiment of the present invention, R ２ The number of elements is preferably 0 to 3, and more preferably 0 to 2.

[0049] The R of the compound represented by formula (I) in this specification ３ These are independently selected from halogens and alkyls, preferably halogens and C １ -C ６ Selected independently of alkyl. In a more preferred embodiment, R ３ These atoms are independently selected from fluorine, chlorine, and methyl atoms.

[0050] In the compound represented by formula (I) herein, R ３ The number of is 0 to 4. In embodiments of the present invention, preferably R ３ The number of items is between 0 and 3.

[0051] The compound (I) is preferably one of the following compounds.

[0052]

[0053]

[0054] <Method for Producing Compound (I)> Next, the method for producing Compound (I) will be described. In the production method described below, if the defined group changes under the conditions of the production method or if it is unsuitable for carrying out the production method, the target compound can be produced by using methods for introducing and removing protecting groups that are commonly used in organic synthesis chemistry [for example, the method described in Protective Groups in Organic Synthesis, third edition, by T.W. Greene, John Wiley & Sons Inc. (1999), etc.]. Furthermore, the order of reaction steps, such as the introduction of substituents, can be changed as needed.

[0055] [Manufacturing Method 1] Compound (I) can be manufactured, for example, by following the steps below.

[0056]

[0057] (In the formula, R １ , R ２ , R ３ And Y are equivalent to the above, respectively, and -OTf is -OSO ２ CF ３ (represents)

[0058] (Step A) The compound represented by formula (P-3) can be produced by reacting the compound represented by formula (P-1) and 1 to 5 equivalents of the compound represented by formula (P-2) in the presence of 1 equivalent to a large excess amount of base in a solvent at a temperature between room temperature and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0059] Examples of bases include pyrrolidine, piperidine, pyridine, triethylamine, N,N-diisopropylethylamine, imidazole, 1,8-diazabicyclo[5.4.0]7-undecene (hereinafter also referred to as DBU), potassium carbonate, sodium carbonate, cesium carbonate, and the like.

[0060] Examples of solvents include methanol, ethanol, tetrahydrofuran (hereinafter also referred to as THF), 1,4-dioxane, acetonitrile, acetone, toluene, and pyridine, which can be used individually or in combination.

[0061] The compound represented by formula (P-1) can be obtained commercially, or by known methods [for example, Experimental Chemistry Course, 5th edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004), etc.] or similar methods.

[0062] The compound represented by formula (P-2) can be obtained commercially, or by known methods [for example, Experimental Chemistry Course, 5th edition, Vol. 15, p. 153, Maruzen Co., Ltd. (2004), etc.] or similar methods.

[0063] (Step B) The compound represented by formula (P-4) can be produced by reacting the compound represented by formula (P-3) and 1 equivalent to a large excess amount of a triflating agent in a solvent in the presence of 1 equivalent to a large excess amount of a base, at a temperature between -78°C and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0064] Examples of triflating agents include trifluoromethanesulfonic anhydride, N-phenylbis(trifluoromethanesulfonimide), and N-(5-chloropyridine-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide.

[0065] Examples of bases include lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and lithium diisopropylamide.

[0066] Examples of solvents include THF, dichloromethane, and toluene, which can be used individually or in combination.

[0067] (Step C) The compound represented by formula (P-5) can be produced by reacting the compound represented by formula (P-4), 1 equivalent to a large excess of 2,4,6-trichlorophenyl formic acid, 0.001 to 3 equivalents of palladium catalyst, 0.001 to 3 equivalents of phosphorus ligand, and 1 equivalent to a large excess of base in a solvent at a temperature between room temperature and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0068] Examples of palladium catalysts include palladium acetate, tris(dibenzylideneacetone)dipalladium(Pd ２ (dba) ３ Examples include ), chloro(2-dicyclohexylphosphino-2'-4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (XPhos Pd G1), chloro(2-dicyclohexylphosphino-2'-4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2), (2-dicyclohexylphosphino-2'-4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3), etc.

[0069] Examples of phosphorus ligands include 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, triphenylphosphine, tributylphosphine, bis(diphenylphosphino)ferrocene, and 2-dicyclohexylphosphino-2'-4',6'-triisopropylbiphenyl (Xphos).

[0070] Examples of bases include potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, DBU, triethylamine, tributylamine, N,N-diisopropylethylamine, and pyridine.

[0071] Examples of solvents include toluene, THF,N,N-dimethylformamide (hereinafter also referred to as DMF), N,N-dimethylacetamide (hereinafter also referred to as DMA), acetonitrile, 1,4-dioxane, and water, which can be used individually or in combination.

[0072] (Step D) Compound (I) can be produced by reacting a compound represented by formula (P-5) and a compound represented by formula (P-6) in the presence of a base (P-5) in the presence of a compound represented by formula (P-5) in the presence of a compound represented by formula (P-6) in the presence of a compound represented by formula (P-5) in the presence of a compound represented by formula (P-6) in the presence of a base in the presence of a base

[0073] Examples of bases include pyridine, 4-dimethylaminopyridine, DBU, triethylamine, and N,N-diisopropylethylamine, which can be used individually or in combination.

[0074] Examples of solvents include toluene, THF, DMF, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, methanol, ethanol, and water, which can be used individually or in combination.

[0075] The compound represented by formula (P-6) can be a commercially available product, or it can be obtained by known methods [for example, Experimental Chemistry Course, 5th edition, Vol. 18, p. 95, Maruzen Co., Ltd. (2004), etc.] or by methods similar thereto. The compound represented by formula (P-6) when Y=O can be obtained, for example, by the method of steps 1 to 10 of Example 3.

[0076] The intermediates and target compounds in each of the above manufacturing methods can be isolated and purified by separation and purification methods commonly used in organic synthesis chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. Furthermore, the intermediates can be subjected to the next reaction without any special purification.

[0077] Some compounds (I) may have stereoisomers such as geometric isomers and optical isomers, as well as tautomers; however, compound (I) encompasses all possible isomers and mixtures thereof, including these.

[0078] Compounds in which some or all of the atoms in compound (I) are replaced with their corresponding isotopic atoms can be produced using commercially available building blocks in the same manner as the above-described production methods. Furthermore, compounds in which some or all of the hydrogen atoms in compound (I) are replaced with deuterium atoms can be produced, for example, by: 1) a method of deuterating carboxylic acids, etc., under basic conditions using deuterium peroxide (see U.S. Patent No. 3,849,458); 2) a method of deuterating alcohols, carboxylic acids, etc., using an iridium complex as a catalyst and heavy water as a deuterium source [see Journal of American Chemical Society (J.Am. Chem.Soc.), Vol. 124, No. 10, 2092 (2002)]; and 3) a method of deuterating fatty acids using palladium carbon as a catalyst and deuterium gas only as a deuterium source [see Lipids, Vol. 9, No. [See 11, 913 (1974)], 4) A method of deuterating acrylic acid, methyl acrylate, methacrylic acid, methyl methacrylate, etc. using metals such as platinum, palladium, rhodium, ruthenium, and iridium as catalysts and heavy water or heavy water and deuterium gas as a deuterium source (see Japanese Patent Publication No. 5-19536, Japanese Patent Publication No. 61-277648, and Japanese Patent Publication No. 61-275241), 5) A method of deuterating acrylic acid, methyl methacrylate, etc. using catalysts such as palladium, nickel, copper, or copper chromate and heavy water as a deuterium source (see Japanese Patent Publication No. 63-198638), etc.

[0079] When obtaining a salt of compound (I), if compound (I) is obtained in salt form, it can be purified directly. If it is obtained in free form, compound (I) can be dissolved or suspended in a suitable solvent, and an acid or base can be added to form a salt, which can then be isolated and purified.

[0080] Furthermore, compound (I) and its pharmaceutically acceptable salts may also exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention as equivalents of compound (I) and its pharmaceutically acceptable salts. Examples of adducts with water or solvents include, but are not limited to, hydrates and solvates of dioxane, tetrahydrofuran, ethanol, acetone, etc.

[0081] Pharmacologically acceptable salts of compound (I) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, etc. Examples of pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate, and organic acid salts such as acetate, oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate. Examples of pharmaceutically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of pharmaceutically acceptable ammonium salts include salts of ammonium and tetramethylammonium. Examples of pharmaceutically acceptable organic amine addition salts include addition salts of morpholine and piperidine. Examples of pharmaceutically acceptable amino acid addition salts include addition salts of lysine, glycine, phenylalanine, aspartic acid, and glutamic acid.

[0082] Compound (I) or its pharmaceutically acceptable salts can be administered alone, but it is generally preferable to provide them as various pharmaceutical formulations. These pharmaceutical formulations are intended for use in animals or humans, preferably humans.

[0083] The pharmaceutical formulations according to the present invention may contain compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient, either alone or in mixture with any other therapeutic active ingredient. These pharmaceutical formulations may also be manufactured by mixing the active ingredient with one or more pharmaceutically acceptable carriers (e.g., diluents, solvents, excipients, etc.) and using any method well known in the art of pharmaceutical formulation.

[0084] Regarding the route of administration, it is desirable to use the one that is most effective for treatment, which can be oral or parenteral, such as intravenous administration.

[0085] Examples of administration forms include tablets and injections.

[0086] Suitable for oral administration, such as tablets, can be manufactured using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, and binders such as hydroxypropyl cellulose.

[0087] Drugs suitable for parenteral administration, such as injectable preparations, can be manufactured using diluents or solvents such as saline solution, glucose solution, or a mixture of saline and glucose solution.

[0088] The dosage and frequency of administration of compound (I) or its pharmaceutically acceptable salt vary depending on the form of administration, the patient's age, weight, the nature or severity of the symptoms to be treated, etc. However, for oral administration, adults are usually given 0.01 to 1000 mg, preferably 0.05 to 100 mg, once or several times a day. For parenteral administration, such as intravenous administration, adults are given 0.001 to 1000 mg, preferably 0.01 to 100 mg, once or several times a day. However, these dosages and frequencies of administration may vary depending on the various conditions mentioned above.

[0089] According to another aspect of the present invention, a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof is provided. The pharmaceutical composition according to the present invention is used in the same route of administration, form of administration, etc. as the pharmaceutical preparation described above. The pharmaceutical composition according to the present invention may also contain a carrier together with compound (I) or a pharmaceutically acceptable salt thereof, and the carrier may be a diluent, solvent, excipient, etc., as in the pharmaceutical preparation described above. Furthermore, the pharmaceutical composition can be used as an SLC15A4 inhibitor.

[0090] Compound (I) or a pharmaceutically acceptable salt thereof according to the present invention can be used to treat diseases associated with SLC15A4 inhibition.

[0091] Therefore, the pharmaceutical composition according to the present invention is used for the treatment of diseases related to SLC15A4 inhibition.

[0092] Another aspect of the present invention provides a therapeutic method comprising administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (preferably a subject in need thereof). This subject includes animals other than humans, but is preferably human. The same applies to the following subjects. The therapeutic method according to the present invention is preferably used for the treatment of diseases associated with SLC15A4 inhibition.

[0093] According to another aspect of the present invention, compound (I) or a pharmaceutically acceptable salt thereof is provided for use as a pharmaceutical.

[0094] According to another aspect of the present invention, compound (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of diseases associated with SLC15A4 inhibition.

[0095] According to another aspect of the present invention, the use of compound (I) or a pharmaceutically acceptable salt thereof is provided for the manufacture of a drug for the treatment of diseases associated with SLC15A4 inhibition.

[0096] According to another aspect of the present invention, the use of compound (I) or a pharmaceutically acceptable salt thereof is provided for the treatment of diseases associated with SLC15A4 inhibition.

[0097] According to another aspect of the present invention, a pharmaceutical product is provided that contains compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0098] According to another aspect of the present invention, a therapeutic agent for diseases associated with SLC15A4 inhibition is provided, comprising compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0099] In this specification, diseases associated with SLC15A4 inhibition include autoimmune diseases. In particular, autoimmune diseases that can be treated by inhibiting type I IFN production from pDCs by SLC15A4 inhibition include systemic lupus erythematosus, cutaneous lupus, lupus nephritis, Sjögren's syndrome, systemic scleroderma, dermatomyositis, IgG4-related disease, and myasthenia gravis. Particularly preferred diseases associated with SLC15A4 inhibition that can be treated with compound (I) or a pharmaceutically acceptable salt thereof include systemic lupus erythematosus, lupus nephritis, cutaneous lupus, or Sjögren's syndrome. Examples of cutaneous lupus include acute cutaneous lupus, subacute cutaneous lupus, and chronic cutaneous lupus. Acute cutaneous lupus and subacute cutaneous lupus are particularly preferred among cutaneous lupus.

[0100] The present invention will be described in more detail below using examples, etc., but the present invention is not limited to these. Also, the proton nuclear magnetic resonance spectra used in the following examples, etc. ( １ The 1H NMR (H) measurements were taken at 300 MHz or 400 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. The signal multiplicity is expressed using commonly used notation, but "br" indicates an apparently broad signal. Furthermore, ChemDraw Professional version 20.1.1 was used for naming each synthesized compound as needed.

[0101] [Example 1] Ethyl (2R,2'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (Compound 1)

[0102] (Step 1) 1-(2-hydroxy-4-methylphenyl)ethane-1-one (21.2 g, 141 mmol) and tert-butyl(S)-2-methyl-4-oxopiperidine-1-carboxylate (25.1 g, 118 mmol) were dissolved in methanol (200 mL), pyrrolidine (19.7 mL, 235 mmol) was added, and the mixture was stirred overnight at 70°C. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to obtain a residue containing two isomer compounds. Each isomer compound was obtained by the following steps. First, the obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1), and the resulting isomer mixture was recrystallized from petroleum ether / ethyl acetate = 3 / 1 to obtain tert-butyl (2S,2'S)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (27.5 g, 68%). Furthermore, the solvent of the filtrate was removed under reduced pressure, and the filtrate was purified by reverse-phase high-performance liquid chromatography (HPLC) to obtain tert-butyl (2R,2'S)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (5.60 g, 14%). ESI-MS m / z: 368 (M + Na) +

[0103] (Step 2) The tert-butyl (2S,2'S)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (21.1 g, 61.1 mmol) obtained in Step 1 was dissolved in hydrogen chloride / 1,4-dioxane solution (4 mol / L, 122 mL, 488 mmol) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain the crude product of (2S,2'S)-2',7-dimethylspiro[chroman-2,4'-piperidine]-4-one hydrochloride. The crude product was dissolved in 1,4-dioxane (51 mL), and aqueous potassium hydroxide solution (3 mol / L, 51.0 mL, 153 mmol) was added and the mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to room temperature, and di-tert-butyl dicarbonate (19.2 mL, 83.5 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was recrystallized from petroleum ether / ethyl acetate = 24 / 1, and then again from petroleum ether / ethyl acetate = 10 / 1 to obtain tert-butyl (2R,2'S)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (11.9 g, 56%). ESI-MS m / z: 368 (M + Na) + 1 H NMR (DMSO-d6, δ): 1.09 (d, J = 6.8 Hz, 3H), 1.42 (s, 9H), 1.65-1.89 (m, 3H), 1.93-2.04 (m, 1H), 2.30 (s, 3H), 2.74-2.95 (m, 2H), 2.97-3.13 (m, 1H), 3.65-3.82 (m, 1H), 3.97-4.13 (m, 1H), 6.72 (s, 1H), 6.81-6.92 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H).

[0104] (Step 3) The tert-butyl (2R,2'S)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (11.0 g, 31.8 mmol) obtained in Steps 1 and 2 was dissolved in THF (120 mL), cooled to -78°C, and lithium bis(trimethylsilyl)amide (1.0 mol / L THF solution, 41.4 mL, 41.4 mmol) was added dropwise, and the mixture was stirred under a nitrogen atmosphere for 2 hours. To the reaction mixture, a THF (50 mL) solution of N-(5-chloro-2-pyridyl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (16.3 g, 41.4 mmol) was added dropwise at -78°C, the temperature was raised to room temperature, and the mixture was stirred for 10 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain tert-butyl (2R,2'S)-2',7-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromene-2,4'-piperidine]-1'-carboxylate (12.6 g, 82%). ESI-MS m / z: 378 (M + H - (tert-Boc)) +

[0105] (Step 4) The tert-butyl (2R,2'S)-2',7-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromene-2,4'-piperidine]-1'-carboxylate (17.8 g, 37.3 mmol) obtained in Step 3 was dissolved in methanol (100 mL) and DMF (200 mL), and N,N-diisopropylethylamine (19.5 mL, 112 mmol) and tetrakis(triphenylphosphine)palladium (0) (4.31 g, 3.73 mmol) were added. The reaction mixture was purged several times with carbon monoxide and stirred at 50°C for 12 hours under a carbon monoxide atmosphere (15 atm). Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain 1'-(tert-butyl) 4-methyl (2R,2'S)-2',7-dimethylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (13.1 g, 89%). ESI-MS m / z: 288 (M + H - (tert-Boc)) +

[0106] (Step 5) The 1'-(tert-butyl) 4-methyl (2R,2'S)-2',7-dimethylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (4.10 g, 10.6 mmol) obtained in Step 4 was dissolved in methanol (50 mL) and water (5 mL), lithium hydroxide (1.27 g, 52.9 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The methanol was removed under reduced pressure, and water (30 mL) and hydrochloric acid (1 mol / L) were added to the resulting residue until the aqueous layer reached approximately pH 3, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product (2R,2'S)-1'-(tert-butoxycarbonyl)-2',7-dimethylspiro[chromene-2,4'-piperidine]-4-carboxylic acid (3.91 g), which was used in the next step without purification. ESI-MS m / z: 274 (M + H - (tert-Boc))+

[0107] (Step 6) The crude product of (2R,2'S)-1'-(tert-butoxycarbonyl)-2',7-dimethylspiro[chromene-2,4'-piperidine]-4-carboxylic acid obtained in Step 5 (787 mg), triethylamine (1.0 mL, 7.2 mmol), and 4-aminobidiclo[2.2.2]octane-1-carboxamide (380 mg, 2.26 mmol) were dissolved in acetonitrile (20 mL), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (hereinafter also referred to as HATU, 860 mg, 2.26 mmol) was added, and the mixture was stirred overnight at room temperature. An aqueous solution of sodium bicarbonate was added to the reaction mixture, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 4 / 1) to obtain tert-butyl (2R,2'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (quantitative). ESI-MS m / z: 546 (M + Na) +

[0108] (Step 7) The tert-butyl (2R,2'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (1.27 g, 2.43 mmol) obtained in Step 6 was dissolved in ethyl acetate (10 mL), and hydrogen chloride / ethyl acetate solution (4 mol / L, 5.0 mL, 20 mmol) was added. The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the residue was washed with acetone, and the resulting solid was filtered to obtain (2R,2'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-4-carboxamide hydrochloride (915 mg, 82%). ESI-MS m / z: 424 (M + H) +

[0109] (Step 8) The (2R,2'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-4-carboxamide hydrochloride (120 mg, 0.283 mmol) and triethylamine (0.200 mL, 1.43 mmol) obtained in Step 7 were dissolved in acetonitrile (5.0 mL), and under ice cooling, ethyl chloroformate (0.070 mL, 0.74 mmol) was added, the mixture was heated to room temperature and stirred for 2 hours. An aqueous solution of sodium bicarbonate was added to the reaction mixture, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 3 / 1), and the resulting solid was washed with hexane / ethyl acetate = 2 / 1 to obtain ethyl (2R,2'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (88 mg, 63%). ESI-MS m / z: 496 (M + Na) + 1H NMR (DMSO-d6, δ): 1.07-1.23 (m, 6H), 1.68-1.94 (m, 16H), 2.22 (s, 3H), 3.15-3.29 (m, 1H), 3.73-3.84 (m, 1H), 4.01-4.16 (m, 3H), 5.92 (s, 1H), 6.58 (s, 1H), 6.64-6.77 (m, 2H), 6.93 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H).

[0110] [Example 2] 2,2-Difluoroethyl (2R,2'S)-4-((4-Carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-2',7-Dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (Compound 2)

[0111] (Step 1) 4-nitrophenyl chloroformate (1.5 g, 7.4 mmol) was dissolved in THF (10 mL), and under ice cooling, a THF (10 mL) solution of 2,2-difluoroethane-1-ol (620 mg, 7.6 mmol) and triethylamine (770 mg, 7.6 mmol) was added dropwise. The mixture was heated to room temperature and stirred overnight. The reaction mixture was filtered through Celite, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / 1) to obtain 2,2-difluoroethyl (4-nitrophenyl) carbonate (1.10 g, 60%). 1 H NMR (CDCl3, δ): 4.32-4.53 (m, 2H), 5.76-6.27 (m, 1H), 7.38-7.44 (m, 2H), 8.27-8.34 (m, 2H).

[0112] (Step 2) The tert-butyl (2R,2'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (2.08 g, 3.97 mmol) obtained in Step 6 of Example 1 was dissolved in ethyl acetate (10 mL), hydrogen chloride / ethyl acetate solution (4 mol / L, 10 mL, 40 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the mixture was diluted with water, neutralized with potassium carbonate, and stirred at room temperature for 3 hours. By filtering the resulting solid, (2R,2'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-4-carboxamide (1.35 g, 80%) was obtained. ESI-MS m / z: 424 (M + H) +

[0113] (Step 3) The (2R,2'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-4-carboxamide (1.30 g, 3.07 mmol) and triethylamine (1.0 mL, 7.2 mmol) obtained in Step 2 were dissolved in THF (15.0 mL), and under ice cooling, a solution of 2,2-difluoroethyl (4-nitrophenyl)carbonate (1.13 g, 4.57 mmol) obtained in Step 1 in THF (5.0 mL) was added, the mixture was heated to room temperature, and stirred overnight. The solvent was removed under reduced pressure, and the resulting residue was added to aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by aminosilica gel column chromatography (ethyl acetate / methanol = 3 / 1) to obtain 2,2-difluoroethyl (2R,2'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (1.38 g, 85%). ESI-MS m / z: 532 (M + H) + 1H NMR (DMSO-d6, 301K, δ): 1.15 (d, J = 6.8 Hz, 3H), 1.70-1.99 (m, 16H), 2.22 (s, 3H), 3.20-3.28 (m, 1H), 3.73-3.85 (m, 1H), 4.04-4.18 (m, 1H), 4.34 (td, J = 15.5, 3.4 Hz, 2H), 5.90 (s, 1H), 6.05-6.48 (m, 1H), 6.59 (s, 1H), 6.65-6.76 (m, 2H), 6.93 (s, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H).

[0114] [Example 3] Cyclopropylmethyl (2R,2'S)-4-((1-carbamoyl-2-oxabicyclo[2.2.2]octan-4-yl)carbamoyl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (Compound 3)

[0115] (Step 1) Methyltriphenylphospholinium iodide (62.1 g, 154 mmol) was dissolved in THF (500 mL), potassium tert-butoxide (1.0 mol / L THF solution, 154 mL, 154 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to 0°C, and a solution of methyl 4-oxocyclohexane-1-carboxylate (20.0 g, 128 mmol) in THF (60 mL) was added dropwise. The mixture was heated to room temperature and stirred for 14 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in petroleum ether (300 mL) and filtered. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether) to obtain methyl 4-methylenecyclohexane-1-carboxylate (12.7 g, 64%). 1H NMR (CDCl3, δ): 1.55-1.61 (m, 2H), 1.97-2.11 (m, 4H), 2.30-2.37 (m, 2H), 2.40-2.51 (m, 1H), 3.67 (s, 3H), 4.65 (s, 2H).

[0116] (Step 2) Lithium diisopropylamide (2.0 mol / L THF solution, 38.3 mL, 76.6 mmol) was dissolved in THF (100 mL), and under a nitrogen atmosphere, the THF (10 mL) solution of methyl 4-methylenecyclohexane-1-carboxylate (9.85 g, 63.9 mmol) obtained in Step 1 was added dropwise at -70°C and the mixture was stirred for 30 minutes. Paraformaldehyde (2.11 g, 70.3 mmol) was added dropwise to the reaction mixture at -70°C, the temperature was raised to room temperature and the mixture was stirred for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain methyl 1-(hydroxymethyl)-4-methylenecyclohexane-1-carboxylate (5.87 g, 50%). 1 H NMR (CDCl3, δ): 1.40-1.50 (m, 2H), 2.07-2.27 (m, 6H), 3.66 (s, 2H), 3.74 (s, 3H), 4.65 (s, 2H).

[0117] (Step 3) Methyl 1-(hydroxymethyl)-4-methylenecyclohexane-1-carboxylate (8.75 g, 47.5 mmol) obtained in Step 2 was dissolved in acetonitrile (200 mL), sodium bicarbonate (9.58 g, 114 mmol) was added, and then iodine (28.9 g, 114 mmol) was added in four portions, and the mixture was stirred at room temperature for 12 hours. A solution of sodium thiosulfate (22.5 g, 142 mmol) in water (120 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic layer was washed with saturated brine and saturated aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain methyl 1-(iodomethyl)-2-oxabicyclo[2.2.2]octane-4-carboxylate (7.00 g, 48%). 1 H NMR (CDCl3, δ): 1.69-1.82 (m, 2H), 1.91-2.03 (m, 6H), 3.16 (s, 2H), 3.67 (s, 3H), 4.00 (s, 2H).

[0118] (Step 4) The methyl 1-(iodomethyl)-2-oxabicyclo[2.2.2]octane-4-carboxylate (7.26 g, 23.4 mmol) obtained in Step 3 was dissolved in methanol (30 mL) and water (30 mL), sodium hydroxide (1.12 g, 28.1 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The methanol was removed under reduced pressure, and hydrochloric acid (1 mol / L) was added to the reaction mixture until the aqueous layer reached approximately pH 6, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product of 1-(iodomethyl)-2-oxabicyclo[2.2.2]octane-4-carboxylic acid (6.43 g), which was used in the next step without purification. 1 H NMR (DMSO-d6, δ): 1.60-1.73 (m, 2H), 1.74-1.96 (m, 6H), 3.24 (s, 2H), 3.80 (s, 2H), 11.87 (s, 1H).

[0119] (Step 5) The crude product of 1-(iodomethyl)-2-oxabicyclo[2.2.2]octane-4-carboxylic acid obtained in Step 4 (3.00 g) was dissolved in tert-butanol (60 mL), and triethylamine (1.48 mL, 10.6 mmol) was added under a nitrogen atmosphere, and the temperature was raised to 90°C. Diphenyl phosphoryl azide (2.19 mL, 10.1 mmol) was added dropwise to the reaction mixture and the mixture was stirred for 12 hours. The solvent was removed under reduced pressure, ethyl acetate (30 mL) was added, and the mixture was filtered. Sodium bicarbonate aqueous solution (50 mL) was added to the filtrate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain tert-butyl (1-(iodomethyl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamate (920 mg, 2-step yield 23%). 1 H NMR (CDCl3, δ): 1.42 (s, 9H), 1.75-1.94 (m, 4H), 1.95-2.14 (m, 4H), 3.15 (s, 2H), 3.96 (s, 2H), 4.27 (br s, 1H).

[0120] (Step 6) The tert-butyl (1-(iodomethyl)-2-oxabicyclo[2.2.2]octan-4-yl) carbamate (1.28 g, 3.49 mmol) obtained in Step 5 was dissolved in DMSO (13 mL), potassium acetate (860 mg, 8.71 mmol) was added, and the mixture was heated to 100°C and stirred for 96 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product (4-((tert-butytoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octan-1-yl)methyl acetate (1.00 g), which was used in the next step without purification. 1H NMR (CDCl3, δ): 1.42 (s, 9H), 1.60-1.70 (m, 2H), 1.78-2.00 (m, 4H), 2.02-2.16 (m, 5H), 3.93 (s, 2H), 3.96 (s, 2H), 4.28 (br s, 1H).

[0121] (Step 7) The crude product (1.00 g) of (4-((tert-butytoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octan-1-yl)methyl acetate obtained in Step 6 was dissolved in methanol (10 mL) and water (10 mL), potassium carbonate (920 mg, 6.68 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The methanol was removed under reduced pressure, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product (780 mg) of tert-butyl (1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamate, which was used in the next step without purification. 1 H NMR (CDCl3, δ): 1.42 (s, 9H), 1.54-1.59 (m, 2H), 1.77-1.87 (m, 2H), 1.96-2.13 (m, 4H), 3.39 (s, 2H), 3.96 (s, 2H), 4.29 (br s, 1H).

[0122] (Step 8) The crude product of tert-butyl (1-(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl) carbamate obtained in Step 7 (780 mg), ruthenium(III) chloride (20 mg, 0.09 mmol), and sodium hydroxide (480 mg, 12.1 mmol) were dissolved in acetonitrile (10 mL) and water (10 mL). Sodium periodate (1.95 g, 9.09 mmol) was added under ice cooling, the mixture was heated to room temperature, and stirred for 12 hours. The reaction mixture was filtered, and the residue was washed with water. The filtrate was washed with methyl tert-butyl ether, hydrochloric acid (4 mol / L) was added until the aqueous layer was approximately pH 2, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product (520 mg) of 4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octane-1-carboxylic acid, which was used in the next step without purification. 1 H NMR (DMSO-d6, δ): 1.36 (s, 9H), 1.76-1.84 (m, 2H), 1.86-1.99 (m, 6H), 3.81 (s, 2H), 6.68 (br s, 1H), 12.50 (br s, 1H).

[0123] (Step 9) The crude product of 4-((tert-butoxycarbonyl)amino)-2-oxabicyclo[2.2.2]octane-1-carboxylic acid obtained in Step 8 (300 mg), ammonium chloride (118 mg, 2.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (424 mg, 2.21 mmol), 1-hydroxybenzotriazole (299 mg, 2.21 mmol), and N,N-diisopropylethylamine (0.58 mL, 3.32 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain tert-butyl (1-carbamoyl-2-oxabicyclo[2.2.2]octan-4-yl)carbamate (170 mg, 4-step yield 31%). 1 H NMR (DMSO-d6, δ): 1.36 (s, 9H), 1.70-1.84 (m, 2H), 1.85-2.00 (m, 4H), 3.86 (s, 2H), 6.67 (br s, 1H), 6.85-7.13 (m, 2H).

[0124] (Step 10) The tert-butyl (1-carbamoyl-2-oxabicyclo[2.2.2]octan-4-yl) carbamate (170 mg, 0.63 mmol) obtained in Step 9 was dissolved in hydrogen chloride / 1.4-dioxane solution (2 mol / L, 12.6 mL, 25.2 mmol) and stirred at room temperature for 24 hours. By removing the solvent under reduced pressure, the crude product of 4-amino-2-oxabicyclo[2.2.2]octan-1-carboxamide hydrochloride (129 mg) was obtained and used in the next step without purification. ESI-MS m / z: 171 (M + H) +

[0125] (Step 11) Using the 1'-(tert-butyl) 4-methyl (2R,2'S)-2',7-dimethylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (6.20 g, 16.0 mmol) obtained in Step 4 of Example 1, the crude product of methyl (2R,2'S)-2',7-dimethylspiro[chromene-2,4'-piperidine]-4-carboxylate hydrochloride (5.15 g) was obtained in the same manner as in Step 7 of Example 1 and used in the next step without purification. ESI-MS m / z: 288 (M + H) +

[0126] (Step 12) Using cyclopropylmethanol (50.0 g, 693 mmol) and 4-nitrophenyl chloroformate (147 g, 728 mmol), cyclopropylmethyl (4-nitrophenyl)carbonate (145 g, 88%) was obtained in the same manner as in Step 1 of Example 2. 1 H NMR (DMSO-d6, δ): 0.36-0.38 (m, 2H), 0.52-0.73 (m, 2H), 1.08-1.33 (m, 1H), 4.10 (d, J = 7.2 Hz, 2H), 7.56 (d, J = 9.2 Hz, 2H), 8.31 (d, J = 9.2 Hz, 2H).

[0127] (Step 13) Using the crude product of methyl (2R,2'S)-2',7-dimethylspiro[chromene-2,4'-piperidine]-4-carboxylate hydrochloride obtained in Step 11 (4.31 g) and the cyclopropylmethyl (4-nitrophenyl)carbonate obtained in Step 12 (5.34 g, 22.5 mmol), 1'-(cyclopropylmethyl)4-methyl (2R,2'S)-2',7-dimethylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (4.47 g, 2-step yield 87%) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 386 (M + H) +

[0128] (Step 14) Using the 1'-(cyclopropylmethyl)4-methyl (2R,2'S)-2',7-dimethylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (5.50 g, 14.3 mmol) obtained in Step 13, the crude product of (2R,2'S)-1'-((cyclopropylmethoxy)carbonyl)-2',7-dimethylspiro[chromene-2,4'-piperidine]-4-carboxylic acid (4.55 g) was obtained in the same manner as in Step 5 of Example 1 and used in the next step without purification. ESI-MS m / z: 372 (M + H) +

[0129] (Step 15) The crude product of (2R,2'S)-1'-((cyclopropylmethoxy)carbonyl)-2',7-dimethylspiro[chromene-2,4'-piperidine]-4-carboxylic acid obtained in Step 14 (89.9 mg) and HATU (138 mg, 0.36 mmol) were dissolved in DMF (3 mL), and N,N-diisopropylethylamine (0.13 mL, 0.73 mmol) and the crude product of 4-amino-2-oxabicyclo[2.2.2]octane-1-carboxamide hydrochloride obtained in Step 10 (50.0 mg) were added, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by HPLC yielded cyclopropylmethyl (2R,2'S)-4-((1-carbamoyl-2-oxabicyclo[2.2.2]octan-4-yl)carbamoyl)-2',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (67.1 mg, 2-step yield 45%). ESI-MS m / z: 524 (M + H) + 1H NMR (DMSO-d6, δ): 0.22-0.32 (m, 2H), 0.45-0.56 (m, 2H), 1.05-1.18 (m, 4H), 1.73-2.12 (m, 12H), 2.23 (s, 3H), 3.18-3.26 (m, 1H), 3.75-3.84 (m, 1H), 3.84-3.91 (m, 2H), 4.05 (s, 2H), 4.09-4.19 (m, 1H), 5.91-6.04 (m, 1H), 6.56-6.64 (m, 1H), 6.68-6.77 (m, 1H), 6.92-7.12 (m, 2H), 7.14-7.31 (m, 1H), 7.85 (s, 1H).

[0130] [Example 4] Cyclopropylmethyl (2R,3'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3'-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (Compound 4)

[0131] (Step 1) Using 1-(2-hydroxy-4-methylphenyl)ethane-1-one (2.88 mL, 20.7 mmol) and tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (4.50 g, 20.7 mmol), tert-butyl (rel-(2R,3'S))-3'-fluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (2.04 g, 28%) was obtained in the same manner as in Step 1 of Example 1. ESI-MS m / z: 294 (M + H - (t-Bu)) +

[0132] (Step 2) Using the tert-butyl (rel-(2R,3'S))-3'-fluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (10.7 g, 30.7 mmol) obtained in Step 1, tert-butyl (rel-(2R,3'S))-3'-fluoro-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromen-2,4'-piperidine]-1'-carboxylate (12.6 g, 85%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 426 (M + H - (tert-Bu)) +

[0133] (Step 3) Using the tert-butyl (rel-(2R,3'S))-3'-fluoro-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromene-2,4'-piperidine]-1'-carboxylate (12.6 g, 26.2 mmol) obtained in Step 2, 1'-(tert-butyl) 4-methyl rel-(2R,3'S)-3'-fluoro-7-methylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (9.71 g, 95%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 414 (M + Na) +

[0134] (Step 4) Using the 1'-(tert-butyl) 4-methyl rel-(2R,3'S)-3'-fluoro-7-methylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (650 mg, 1.66 mmol) obtained in Step 3, the crude product of rel-(2R,3'S)-1'-(tert-butoxycarbonyl)-3'-fluoro-7-methylspiro[chromene-2,4'-piperidine]-4-carboxylic acid (584 mg) was obtained in the same manner as in Step 5 of Example 1 and used in the next step without purification. ESI-MS m / z: 322 (M + H - (tert-Bu)) +

[0135] (Step 5) Using the crude product of rel-(2R,3'S)-1'-(tert-butoxycarbonyl)-3'-fluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxylic acid obtained in Step 4 (584 mg) and 4-aminobidiclo[2.2.2]octane-1-carboxamide (260 mg, 1.55 mmol), tert-butyl rel-(2R,3'S)-4-((4-carbamoylbicyclo[2.2.2]octane-1-yl)carbamoyl)-3'-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (638 mg, 2-step yield 73%) was obtained in the same manner as in Step 6 of Example 1. ESI-MS m / z: 472 (M + H - (tert-Bu)) +

[0136] (Step 6) Using the tert-butyl rel-(2R,3'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3'-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (638 mg, 1.21 mmol) obtained in Step 5, the crude product of rel-(2R,3'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-3'-fluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide hydrochloride (561 mg) was obtained in the same manner as in Step 7 of Example 1 and used in the next step without purification. ESI-MS m / z: 428 (M + H) +

[0137] (Step 7) Using the crude product (180 mg) of rel-(2R,3'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-3'-fluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide hydrochloride obtained in Step 6 and the cyclopropylmethyl (4-nitrophenyl)carbonate (276 mg, 1.16 mmol) obtained in Step 12 of Example 3, cyclopropylmethyl rel-(2R,3'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3'-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (184 mg, 2-step yield 90%) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 526 (M + H) +

[0138] (Step 8) The cyclopropylmethyl rel-(2R,3'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3'-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (184 mg, 0.35 mmol) obtained in Step 7 was purified by chiral supercritical fluid chromatography (SFC) (DAICEL CHIRAL IF (30x250 mm, 10 μm), CO2 / 0.1% ammonia acetonitrile / ethanol solution = 50 / 50, flow rate 80 mL / min, RT1: 1.692 min, RT2: 2.101 min), and RT2: 2.101 min was obtained, thereby obtaining cyclopropylmethyl (2R,3'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3'-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (73.4 mg, 79%) was obtained. ESI-MS m / z: 526 (M + H) + 1H NMR (CDCl3D, δ): 0.23-0.33 (m, 2H), 0.48-0.61 (m, 2H), 1.07-1.20 (m, 1H), 1.87-1.98 (m, 8H), 2.02-2.10 (m, 6H), 2.30 (s, 3H), 3.06-3.33 (m, 1H), 3.34-3.61 (m, 1H), 3.85-4.09 (m, 3H), 4.25-4.46 (m, 1H), 4.48-4.77 (m, 1H), 5.29(s, 1H), 5.55 (s, 2H), 5.96 (s, 1H), 6.71 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H).

[0139] [Example 5] Cyclopropylmethyl (R or S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3',3'-difluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (Compound 5)

[0140] (Step 1) 1-(2-hydroxy-4-methylphenyl)ethane-1-one (5.36 g, 35.7 mmol) and tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (8.40 g, 35.7 mmol) were dissolved in xylene (100 mL), pyrrolidine (2.54 g, 35.7 mmol) and titanium(IV) isopropoxide (10.2 g, 35.7 mmol) were added, and the mixture was stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, the insoluble matter was filtered off, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain tert-butyl 3',3'-difluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (5.61 g, 43%). ESI-MS m / z: 312 (M + H - (t-Bu)) +

[0141] (Step 2) Using the tert-butyl 3',3'-difluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (5.61 g, 15.3 mmol) obtained in Step 1, the crude product of tert-butyl 3',3'-difluoro-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromen-2,4'-piperidine]-1'-carboxylate (6.22 g) was obtained in the same manner as in Step 3 of Example 1 and used in the next step without purification. ESI-MS m / z: 444 (M + H - (tert-Bu)) +

[0142] (Step 3) Using the crude product (6.22 g) of tert-butyl 3',3'-difluoro-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromene-2,4'-piperidine]-1'-carboxylate obtained in Step 2, 1'-(tert-butyl) 4-methyl 3',3'-difluoro-7-methylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (3.38 g, 2-step yield 54%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 354 (M + H - (tert-Bu)) +

[0143] (Step 4) Using the 1'-(tert-butyl) 4-methyl 3',3'-difluoro-7-methylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (3.38 g, 8.26 mmol) obtained in Step 3, the crude product of 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-methylspiro[chromene-2,4'-piperidine]-4-carboxylic acid (3.10 g) was obtained in the same manner as in Step 5 of Example 1 and used in the next step without purification. ESI-MS m / z: 340 (M + H - (tert-Bu)) +

[0144] (Step 5) Using the crude product of 1'-(tert-butoxycarbonyl)-3',3'-difluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxylic acid obtained in Step 4 (470 mg) and 4-aminobidiclo[2.2.2]octane-1-carboxamide (200 mg, 1.19 mmol), tert-butyl 4-((4-carbamoylbicyclo[2.2.2]octane-1-yl)carbamoyl)-3',3'-difluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (485 mg, 2-step yield 71%) was obtained in the same manner as in Step 6 of Example 1. ESI-MS m / z: 490 (M + H - (tert-Bu)) +

[0145] (Step 6) Using the tert-butyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3',3'-difluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (485 mg, 0.89 mmol) obtained in Step 5, the crude product (426 mg) of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-3',3'-difluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide hydrochloride was obtained in the same manner as in Step 7 of Example 1 and used in the next step without purification. ESI-MS m / z: 446 (M + H) +

[0146] (Step 7) Using the crude product (210 mg) of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-3',3'-difluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide hydrochloride obtained in Step 6 and the cyclopropylmethyl (4-nitrophenyl)carbonate (176 mg, 0.74 mmol) obtained in Step 12 of Example 3, cyclopropylmethyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3',3'-difluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (167 mg, 2-step yield 70%) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 544 (M + H) +

[0147] (Step 8) Cyclopropylmethyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3',3'-difluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (404 mg, 0.742 mmol) obtained in Step 7 was purified by chiral SFC (DAICEL CHIRAL AD (30x250 mm, 10 μm), CO2 / 0.1% ammonia ethanol solution = 55 / 45, flow rate 70 mL / min) to obtain cyclopropylmethyl (R or S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3',3'-difluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (83.4 mg, 41%). ESI-MS m / z: 544 (M + H) + 1H NMR (DMSO-d6, δ): 0.20-0.33 (m, 2H), 0.46-0.54 (m, 2H), 1.02-1.13 (m, 1H), 1.67-1.79 (m, 6H), 1.82-1.95 (m, 7H), 2.00-2.08 (m, 1H), 2.25 (s, 3H), 3.43-3.78 (m, 2H), 3.79-3.96 (m, 3H), 4.07-4.24 (m, 1H), 5.81 (s, 1H), 6.64-6.84 (m, 3H), 6.95 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H).

[0148] [Example 6] Cyclopropylmethyl (2S,3'R)-4-((4-carbamoylbicyclo[2,2,2]octan-1-yl)carbamoyl)-3',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (Compound 6)

[0149] (Step 1) Using the cyclopropylmethyl (4-nitrophenyl) carbonate (8.00 g, 33.7 mmol) and 3-methylpiperidine-4-one hydrochloride (5.05 g, 33.7 mmol) obtained in Step 12 of Example 3, cyclopropylmethyl 3-methyl-4-oxopiperidine-1-carboxylate (5.84 g, 82%) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 212 (M + H) +

[0150] (Step 2) Using the cyclopropylmethyl 3-methyl-4-oxopiperidine-1-carboxylate (6.24 g, 29.5 mmol) and 1-(2-hydroxy-4-methylphenyl)ethane-1-one (4.44 g, 29.5 mmol) obtained in Step 1, the crude product of cyclopropylmethyl 3',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (7.30 g) was obtained in the same manner as in Step 1 of Example 1 and used in the next step without purification. ESI-MS m / z: 344 (M + H) +

[0151] (Step 3) Using the crude product (2.00 g) of cyclopropylmethyl 3',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate obtained in Step 2, the crude product (2.70 g) of cyclopropylmethyl 3',7-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromen-2,4'-piperidine]-1'-carboxylate was obtained in the same manner as in Step 3 of Example 1 and used in the next step without purification. ESI-MS m / z: 476 (M + H) +

[0152] (Step 4) Using the crude product (2.70 g) of cyclopropylmethyl 3',7-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromene-2,4'-piperidine]-1'-carboxylate obtained in Step 3, 1'-(cyclopropylmethyl)4-methyl 3',7-dimethylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (1.47 g, 3-step yield 47%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 386 (M + H) +

[0153] (Step 5) Using the 1'-(cyclopropylmethyl)4-methyl 3',7-dimethylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (1.17 g, 3.04 mmol) obtained in Step 4, 1'-((cyclopropylmethoxy)carbonyl)-3',7-dimethylspiro[chromene-2,4'-piperidine]-4-carboxylic acid (1.02 g, 90%) was obtained in the same manner as in Step 5 of Example 1. ESI-MS m / z: 372 (M + H) +

[0154] (Step 6) Using the 1'-((cyclopropylmethoxy)carbonyl)-3',7-dimethylspiro[chromen-2,4'-piperidine]-4-carboxylic acid (300 mg, 0.81 mmol) obtained in Step 5, cyclopropylmethyl rel-(2S,3'R)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (71 mg, 17%) was obtained in the same manner as in Step 6 of Example 1. ESI-MS m / z: 522 (M + H) +

[0155] (Step 7) The cyclopropylmethyl rel-(2S,3'R)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (172 mg, 0.330 mmol) obtained in Step 6 is purified by chiral SFC (DAICEL CHIRAL OD-H (30x250 mm, 5 μm), CO2 / 0.1% ammonia methanol solution = 65 / 35, flow rate 70 mL / min) to obtain cyclopropylmethyl (2S,3'R)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-3',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (55.6 mg, A score of 32% was obtained. ESI-MS m / z: 522 (M + H) + 1H NMR (DMSO-d6, δ): 0.19-0.31 (m, 2H), 0.43-0.52 (m, 2H), 0.90 (d, J = 6.8 Hz, 3H), 1.03-1.13 (m, 1H), 1.49-1.59 (m, 1H), 1.69-1.80 (m, 6H), 1.85-2.01 (m, 8H), 2.23 (s, 3H), 3.14-3.27 (m, 1H), 3.38-3.58 (m, 2H), 3.59-3.68 (m, 1H), 3.75-3.91 (m, 2H), 5.94 (s, 1H), 6.61-6.75 (m, 3H), 6.94 (s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H).

[0156] [Example 7] Cyclopropylmethyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-7-chlorospiro[chromen-2,4'-piperidine]-1'-carboxylate (Compound 7)

[0157] (Step 1) Using the cyclopropylmethyl (4-nitrophenyl)carbonate (6.00 g, 25.3 mmol) and 4-piperidinone hydrochloride (3.43 g, 25.3 mmol) obtained in Step 12 of Example 3, a crude product of cyclopropylmethyl 4-oxopiperidine-1-carboxylate (6.0 g) was obtained in the same manner as in Step 8 of Example 1 and used in the next step without purification. ESI-MS m / z: 198 (M + H) +

[0158] (Step 2) Using the crude product of cyclopropylmethyl 4-oxopiperidine-1-carboxylate obtained in Step 1 (382 mg) and 1-(4-chloro-2-hydroxyphenyl)ethane-1-one (0.234 mL, 1.76 mmol), cyclopropylmethyl 7-chloro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (542 mg, 88%) was obtained in the same manner as in Step 1 of Example 1. ESI-MS m / z: 350 (M + H) +

[0159] (Step 3) Using the cyclopropylmethyl 7-chloro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (533 mg, 1.52 mmol) obtained in Step 2, cyclopropylmethyl 7-chloro-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromen-2,4'-piperidine]-1'-carboxylate (429 mg, 58%) was obtained in the same manner as in Step 3 of Example 1. 1 H-NMR (CDCl3, δ): 0.26-0.30 (m, 2H), 0.53-0.58 (m, 2H), 1.09-1.18 (m, 1H), 1.68-1.75 (m, 2H), 2.10 (d, J = 12.6 Hz, 2H), 3.32 (s, 2H), 3.91-4.00 (m, 4H), 5.57 (s, 1H), 6.95 (d, J = 1.8 Hz, 1H), 6.98 (dd, J = 8.1, 1.8 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H).

[0160] (Step 4) The cyclopropylmethyl 7-chloro-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromene-2,4'-piperidine]-1'-carboxylate (417 mg, 0.865 mmol) obtained in Step 3 was dissolved in toluene (4.0 mL), and 2,4,6-trichlorophenyl formic acid (234 mg, 1.04 mmol), palladium acetate (9.7 mg, 0.043 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (50 mg, 0.087 mmol), and triethylamine (0.18 mL, 1.3 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane / ethyl acetate = 1 / 1) to obtain 1'-(cyclopropylmethyl) 4-(2,4,6-trichlorophenyl) 7-chlorospiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (409 mg, 85%). 1H-NMR (CDCl3, δ): 0.27-0.31 (m, 2H), 0.54-0.58 (m, 2H), 1.15 (t, J = 6.1 Hz, 1H), 1.73-1.80 (m, 2H), 2.10 (d, J = 13.0 Hz, 2H), 3.35 (s, 2H), 3.93 (d, J = 7.2 Hz, 2H), 4.01 (d, J = 15.3 Hz, 2H), 6.91 (s, 1H), 6.96-6.99 (m, 2H), 7.43 (s, 2H), 7.93 (d, J = 9.0 Hz, 1H).

[0161] (Step 5) 1'-(cyclopropylmethyl)4-(2,4,6-trichlorophenyl)7-chlorospiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (100 mg, 0.179 mmol) obtained in Step 4 was dissolved in THF (1.8 mL), and methyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (67 mg, 0.305 mmol), N,N-dimethylaminopyridine (2.2 mg, 0.018 mmol), and triethylamine (0.25 mL, 1.8 mmol) were added, and the mixture was stirred overnight at room temperature. Water and aqueous sodium hydroxide solution (1 mol / L) were added to the reaction mixture, and it was extracted with chloroform. The organic layer was separated using a phase separator, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane / ethyl acetate = 4 / 1-0 / 1) to obtain cyclopropylmethyl 7-chloro-4-((4-(methoxycarbonyl)bicyclo[2.2.2]octan-1-yl)carbamoyl)spiro[chromen-2,4'-piperidine]-1'-carboxylate (31 mg, 32%). ESI-MS m / z: 543 (M + H) +

[0162] (Step 6) The cyclopropylmethyl 7-chloro-4-((4-(methoxycarbonyl)bicyclo[2.2.2]octan-1-yl)carbamoyl)spiro[chromen-2,4'-piperidine]-1'-carboxylate (31 mg, 0.057 mmol) obtained in Step 5 was dissolved in ethanol (0.57 mL), and an aqueous sodium hydroxide solution (2 mol / L, 0.285 mL, 0.571 mmol) was added. The mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to 0°C, and hydrochloric acid (2 mol / L) was added until the aqueous layer reached approximately pH 5. The mixture was then extracted with chloroform. The organic layer was separated using a phase separator, and the solvent was removed under reduced pressure to obtain the crude product (30 mg) of 4-(7-chloro-1'-((cyclopropylmethoxy)carbonyl)spiro[chromene-2,4'-piperidine]-4-carboxamide)bicyclo[2.2.2]octane-1-carboxylic acid, which was used in the next step without purification. ESI-MS m / z: 529 (M + H) +

[0163] (Step 7) The crude product (30 mg) of 4-(7-chloro-1'-((cyclopropylmethoxy)carbonyl)spiro[chromene-2,4'-piperidine]-4-carboxamide)bicyclo[2.2.2]octane-1-carboxylic acid obtained in Step 6 was dissolved in DMF (0.57 mL), and triethylamine (0.32 mL, 0.228 mmol), ammonium chloride (6.1 mg, 0.114 mmol), and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinium hexafluorophosphate (34 mg, 0.080 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by aminosilica gel column chromatography (chloroform / methanol = 9 / 1) to obtain cyclopropylmethyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-7-chlorospiro[chromen-2,4'-piperidine]-1'-carboxylate (21 mg, 70%). ESI-MS m / z: 528 (M + H) +1 H-NMR (CDCl3, δ): 0.26-0.30 (m, 2H), 0.53-0.58 (m, 2H), 1.10-1.18 (m, 1H), 1.60-1.67 (m, 2H), 1.91-2.06 (m, 14H), 3.30 (t, J = 12.1 Hz, 2H), 3.91-3.96 (m, 4H), 5.29 (br s, 1H), 5.48 (s, 1H), 5.54 (br s, 1H), 5.79 (s, 1H), 6.89-6.92 (m, 2H), 7.37 (d, J = 9.0 Hz, 1H).

[0164] [Example 8] Cyclopropylmethyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (Compound 8)

[0165] (Step 1) Using 1-(5-fluoro-2-hydroxy-4-methylphenyl)ethane-1-one (28.0 g, 167 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (39.8 g, 200 mmol), tert-butyl 6-fluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (28.0 g, 48%) was obtained in the same manner as in Step 1 of Example 1. ESI-MS m / z: 294 (M + H - (t-Bu)) +

[0166] (Step 2) Using the tert-butyl 6-fluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (10 g, 28.7 mmol) obtained in Step 1, tert-butyl 6-fluoro-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromen-2,4'-piperidine]-1'-carboxylate (6.0 g, 46%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 426 (M + H - (tert-Bu)) +

[0167] (Step 3) Using the tert-butyl 6-fluoro-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromene-2,4'-piperidine]-1'-carboxylate (7.2 g, 15.0 mmol) obtained in Step 2, 1'-(tert-butyl) 4-(2,4,6-trichlorophenyl) 6-fluoro-7-methylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (6.9 g, 83%) was obtained in the same manner as in Step 4 of Example 7. ESI-MS m / z: 556 (M + H) +

[0168] (Step 4) Using 1'-(tert-butyl) 4-(2,4,6-trichlorophenyl) 6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1',4-dicarboxylate (404 mg, 0.725 mmol) and 4-aminobicyclo[2.2.2]octane-1-carboxamide (122 mg, 0.725 mmol) obtained in Step 3, tert-butyl 4-((4-carbamoylbicyclo[2.2.2]octane-1-yl)carbamoyl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (324 mg, 85%) was obtained in the same manner as in Step 5 of Example 7. ESI-MS m / z: 428 (M + H - (tert-Boc)) +

[0169] (Step 5) The tert-butyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (324 mg, 0.614 mmol) obtained in Step 4 was dissolved in chloroform (4.0 mL), trifluoroacetic acid (0.94 mL, 12.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydroxide solution (4 mol / L, 4 mL) was added to the reaction mixture, and the resulting solid was filtered to obtain the crude product of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide (249 mg), which was used in the next step without purification. ESI-MS m / z: 428 (M + H) +

[0170] (Step 6) Using the crude product (20 mg) of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide obtained in Step 5 and the cyclopropylmethyl (4-nitrophenyl)carbonate (11 mg, 0.047 mmol) obtained in Step 12 of Example 3, cyclopropylmethyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (15.6 mg, 2-step yield 60%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 526 (M + H) + 1 H-NMR (CDCl3, δ): 0.16-0.24 (m, 2H), 0.44-0.53 (m, 2H), 1.01-1.11 (m, 1H), 1.50-1.61 (m, 2H), 1.78-1.88 (m, 6H), 1.92-1.99 (m, 6H), 2.15 (s, 3H), 2.81-3.00 (m, 4H), 3.13-3.30 (m, 2H), 3.80-3.91 (m, 4H), 5.69-5.75 (m, 1H), 5.82-5.93 (m, 1H), 6.60-6.69 (m, 1H), 6.97-7.07 (m, 1H).

[0171] [Example 9] Cyclopropyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (Compound 9)

[0172] (Step 1) The tert-butyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (48.9 mg, 0.093 mmol) obtained in Step 4 of Example 8 was dissolved in dichloromethane (1.0 mL), trifluoroacetic acid (0.214 mg, 2.78 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure to obtain the crude product of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide trifluoroacetate, which was used in the next step without purification.

[0173] (Step 2) Dissolve cyclopropanol (10.8 mg, 0.186 mmol) in dichloromethane (1.0 mL), add triethylamine (0.013 mL, 0.093 mmol) and 4-nitrophenyl chloroformate (37.4 mg, 0.185 mmol), and stir at room temperature for 1 hour. Add the crude product of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide trifluoroacetate obtained in Step 1 to the reaction mixture, stir at room temperature for 1 hour, add triethylamine (0.013 mL, 0.093 mmol), and stir for a further 4 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0-92 / 8) to obtain cyclopropyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (26.9 mg, 2-step yield 57%). ESI-MS m / z: 512 (M + H) + 1H-NMR (CDCl3, δ): 0.68-0.72 (m, 4H), 1.92-2.07 (m, 16H), 2.23 (d, J = 1.6 Hz, 3H), 3.22-3.30 (m, 2H), 3.76-3.98 (m, 2H), 4.06-4.11 (m, 1H), 5.25 (br s, 1H), 5.47 (s, 1H), 5.54 (br s, 1H), 5.80 (s, 1H), 6.71 (d, J = 6.7 Hz, 1H), 7.13 (d, J = 10.3 Hz, 1H).

[0174] [Example 10] Cyclobutyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (Compound 10)

[0175] (Step 1) Dissolve cyclobutanol (0.011 mL, 0.140 mmol) in DMF (0.1 mL), and under ice cooling, add N,N-diisopropylethylamine (0.041 mL, 0.23 mmol) and 4-nitrophenyl chloroformate (28.3 mg, 0.140 mmol), and stir at room temperature for 3 hours. To the reaction mixture, add a solution of the crude product of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide obtained in Step 5 of Example 8 in DMF (0.2 mL), and stir at 40°C for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by aminosilica gel column chromatography (chloroform / methanol = 9 / 1) to obtain cyclobutyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-6-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (13.7 mg, 2-step yield 57%). ESI-MS m / z: 526 (M + H) + 1H-NMR (MeOH-d4, δ): 1.58-1.69 (m, 3H), 1.83-1.90 (m, 6H), 1.90-1.97 (m, 2H), 1.99-2.10 (m, 8H), 2.17 (s, 3H), 2.25-2.34 (m, 2H), 3.17-3.38 (m, 5H), 3.80-3.92 (m, 2H), 4.84-4.91 (m, 1H), 5.80 (s, 1H), 6.73 (d, J = 6.4 Hz, 1H), 6.98 (d, J = 10.4 Hz, 1H).

[0176] [Example 11] Allyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-8-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (compound 11)

[0177] (Step 1) Using 1-(3-fluoro-2-hydroxy-4-methylphenyl)ethane-1-one (5.0 g, 29.8 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (5.94 g, 29.8 mmol), tert-butyl 8-fluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (8.0 g, 77%) was obtained in the same manner as in Step 1 of Example 1. ESI-MS m / z: 350 (M + H) +

[0178] (Step 2) Using the tert-butyl 8-fluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (3.0 g, 8.59 mmol) obtained in Step 1, tert-butyl 8-fluoro-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromen-2,4'-piperidine]-1'-carboxylate (1.5 g, 36%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 426 (M + H - (tert-Bu)) +

[0179] (Step 3) Using the tert-butyl 8-fluoro-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromene-2,4'-piperidine]-1'-carboxylate (3.0 g, 6.23 mmol) obtained in Step 2, 1'-(tert-butyl) 4-(2,4,6-trichlorophenyl) 8-fluoro-7-methylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (1.4 g, 41%) was obtained in the same manner as in Step 4 of Example 7. ESI-MS m / z: 500 (M + H - (tert-Bu)) +

[0180] (Step 4) Using 1'-(tert-butyl) 4-(2,4,6-trichlorophenyl) 8-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1',4-dicarboxylate (304 mg, 0.546 mmol) and 4-aminobidiclo[2.2.2]octane-1-carboxamide (101 mg, 0.601 mmol) obtained in Step 3, tert-butyl 4-((4-carbamoylbicyclo[2.2.2]octane-1-yl)carbamoyl)-8-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (263 mg, 91%) was obtained in the same manner as in Step 5 of Example 7. ESI-MS m / z: 428 (M + H - (tert-Boc)) +

[0181] (Step 5) Using the tert-butyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-8-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (263 mg, 0.498 mmol) obtained in Step 4, the crude product of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-8-fluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide (171 mg) was obtained in the same manner as in Step 5 of Example 8 and used in the next step without purification.

[0182] (Step 6) Using the crude product of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-8-fluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide obtained in Step 5 (20 mg) and allyl chloroformate (141 mg, 1.17 mmol), allyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-8-fluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (5.9 mg, 2-step yield 20%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 512 (M + H) + 1 H-NMR (CDCl3, δ): 1.56-1.68 (m, 4H), 1.88-1.95 (m, 6H), 1.99-2.05 (m, 6H), 2.24 (s, 3H), 3.34 (br s, 2H), 3.95 (br s, 2H), 4.58 (d, J = 5.2 Hz, 2H), 5.20 (dq, J = 10.6, 2.8 Hz, 1H), 5.25-5.36 (m, 2H), 5.43-5.61 (m, 2H), 5.81 (s, 1H), 5.87-5.99 (m, 1H), 6.70 (t, J = 7.6 Hz, 1H), 7.04 (dd, J = 1.2, 8.0 Hz, 1H).

[0183] [Example 12] (2R,2'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-8-fluoro-2',7-dimethyl-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)spiro[chromen-2,4'-piperidine]-4-carboxamide (compound 12)

[0184] (Step 1) Using 1-(3-fluoro-2-hydroxy-4-methylphenyl)ethane-1-one (5.5 g, 32.7 mmol) and tert-butyl(S)-2-methyl-4-oxopiperidine-1-carboxylate (9.77 g, 49.1 mmol), tert-butyl (2R,2'S)-8-fluoro-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (350 mg, 2.9%) and tert-butyl (2S,2'S)-8-fluoro-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (1.6 g, 13%) were obtained in the same manner as in Step 1 of Example 1. ESI-MS m / z: 308 (M + H - (t-Bu)) +

[0185] (Step 2) Using the tert-butyl (2S,2'S)-8-fluoro-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (23.0 g, 63.4 mmol) obtained in Step 1, tert-butyl (2R,2'S)-8-fluoro-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (4.0 g, 14%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 308 (M + H - (t-Bu)) +

[0186] (Step 3) Using the tert-butyl (2R,2'S)-8-fluoro-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (3.0 g, 8.26 mmol) obtained in Steps 1 and 2, tert-butyl (2R,2'S)-8-fluoro-2',7-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromen-2,4'-piperidine]-1'-carboxylate (1.5 g, 37%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 496 (M + H) +

[0187] (Step 4) Using the tert-butyl (2R,2'S)-8-fluoro-2',7-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromene-2,4'-piperidine]-1'-carboxylate (2.0 g, 4.04 mmol) obtained in Step 3, 1'-(tert-butyl) 4-(2,4,6-trichlorophenyl) (2R,2'S)-8-fluoro-2',7-dimethylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (1.7 g, 74%) was obtained in the same manner as in Step 4 of Example 7. ESI-MS m / z: 570 (M + H) +

[0188] (Step 5) Using 1'-(tert-butyl) 4-(2,4,6-trichlorophenyl) (2R,2'S)-8-fluoro-2',7-dimethylspiro[chromen-2,4'-piperidine]-1',4-dicarboxylate (155 mg, 0.271 mmol) and 4-aminobidiclo[2.2.2]octane-1-carboxamide (45.7 mg, 0.271 mmol) obtained in Step 4, tert-butyl (2R,2'S)-4-((4-carbamoylbicyclo[2.2.2]octane-1-yl)carbamoyl)-8-fluoro-2',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (102 mg, 70%) was obtained in the same manner as in Step 5 of Example 7. ESI-MS m / z: 442 (M + H - (tert-Boc)) +

[0189] (Step 6) Using the tert-butyl (2R,2'S)-4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-8-fluoro-2',7-dimethylspiro[chromen-2,4'-piperidine]-1'-carboxylate (102 mg, 0.189 mmol) obtained in Step 5, the crude product of (2R,2'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-8-fluoro-2',7-dimethylspiro[chromen-2,4'-piperidine]-4-carboxamide (78.7 mg) was obtained in the same manner as in Step 5 of Example 8 and used in the next step without purification.

[0190] (Step 7) The crude product of (2R,2'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-8-fluoro-2',7-dimethylspiro[chromen-2,4'-piperidine]-4-carboxamide obtained in Step 6 (20 mg) and N,N-diisopropylethylamine (0.024 mL, 0.14 mmol) were dissolved in DMF (0.2 mL), and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (8.2 mg, 0.082 mmol) and HATU (34.5 mg, 0.091 mmol) were added, and the mixture was stirred at 50°C for 12 hours. The reaction mixture was then mixed with saturated sodium bicarbonate aqueous solution and extracted with chloroform. The organic layer was separated using a phase separator, the solvent was removed under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (chloroform / methanol = 9 / 1) to obtain (2R,2'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-8-fluoro-2',7-dimethyl-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)spiro[chromen-2,4'-piperidine]-4-carboxamide (15.6 mg, 2-step yield 62%). ESI-MS m / z: 524 (M + H) + 1H-NMR (CDCl3, δ): 0.54-0.63 (m, 1H), 1.10 (d, J = 6.0 Hz, 3H), 1.15-1.20 (m, 1H), 1.24 (d, J = 7.2 Hz, 3H), 1.32-1.41 (m, 2H), 1.86-1.94 (m, 7H), 1.94-1.98 (m, 1H), 1.98-2.04 (m, 6H), 2.04-2.11 (m, 2H), 2.23 (s, 3H), 3.07 (br s, 1H), 4.23-4.63 (m, 2H), 5.35-5.69 (m, 3H), 6.07-6.12 (m, 1H), 6.70 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H).

[0191] [Example 13] (2R,2'S)-1'-butyryl-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-8-fluoro-2',7-dimethylspiro[chromen-2,4'-piperidine]-4-carboxamide (compound 13)

[0192] (Step 1) Using the crude product (20 mg) of (2R,2'S)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-8-fluoro-2',7-dimethylspiro[chromen-2,4'-piperidine]-4-carboxamide obtained in Step 6 of Example 12 and butyric acid (0.0075 mL, 0.082 mmol), (2R,2'S)-1'-butyryl-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-8-fluoro-2',7-dimethylspiro[chromen-2,4'-piperidine]-4-carboxamide (12.2 mg, 2-step yield 50%) was obtained in the same manner as in Step 7 of Example 12. ESI-MS m / z: 512 (M + H) + 1H-NMR (CDCl3, δ): 0.96 (t, J = 7.6 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.62-1.77 (m, 4H), 1.87-1.94 (m, 7H), 1.94-1.98 (m, 1H), 1.98-2.08 (m, 8H), 2.20-2.40 (m, 5H), 3.90-4.71 (br s, 1H), 5.30-5.65 (m, 3H), 6.11 (s, 1H), 6.70 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H).

[0193] [Example 14] (E)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-1'-(3-cyclopropylacryloyl)-6,8-difluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxylate (compound 14)

[0194] (Step 1) 2,4-difluoro-3-methylphenol (2.5 g, 17.4 mmol) was dissolved in dichloromethane (20 mL), and under ice cooling, triethylamine (2.93 mL, 20.8 mmol) and acetyl chloride (1.48 mL, 20.8 mmol) were added, and the mixture was stirred for 3 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture, and it was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product of 2,4-difluoro-3-methylphenyl acetate, which was used in the next step without purification. ESI-MS m / z: 187 (M + H) +

[0195] (Step 2) 2,4-difluoro-3-methylphenyl acetate (2.58 g, 13.4 mmol) obtained in Step 1 was mixed with aluminum chloride (3.38 g, 25.4 mmol) and heated at 130°C for 3 hours. Hydrochloric acid (1 mol / L) was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7 / 3) to obtain 1-(3,5-difluoro-2-hydroxy-4-methylphenyl)ethane-1-one (2.0 g, 80%). ESI-MS m / z: 187 (M + H) +

[0196] (Step 3) Using the 1-(3,5-difluoro-2-hydroxy-4-methylphenyl)ethane-1-one (2.0 g, 10.7 mmol) obtained in Step 2, tert-butyl 6,8-difluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (4.0 g, 92%) was obtained in the same manner as in Step 1 of Example 1. ESI-MS m / z: 368 (M + H - (t-Bu)) +

[0197] (Step 4) Using the tert-butyl 6,8-difluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (1.0 g, 2.76 mmol) obtained in Step 3, tert-butyl 6,8-difluoro-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromen-2,4'-piperidine]-1'-carboxylate (2.0 g, 49%, total of 3 batches prepared similarly) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 444 (M + H - (tert-Bu)) +

[0198] (Step 5) Using the tert-butyl 6,8-difluoro-7-methyl-4-(((trifluoromethyl)sulfonyl)oxy)spiro[chromene-2,4'-piperidine]-1'-carboxylate (1.2 g, 2.42 mmol) obtained in Step 4, 1'-(tert-butyl) 4-(2,4,6-trichlorophenyl) 6,8-difluoro-7-methylspiro[chromene-2,4'-piperidine]-1',4-dicarboxylate (1.0 g, 72%) was obtained in the same manner as in Step 4 of Example 7. ESI-MS m / z: 574 (M + H) +

[0199] (Step 6) Using 1'-(tert-butyl) 4-(2,4,6-trichlorophenyl) 6,8-difluoro-7-methylspiro[chromen-2,4'-piperidine]-1',4-dicarboxylate (104 mg, 0.180 mmol) and 4-aminobidiclo[2.2.2]octane-1-carboxamide (30 mg, 0.180 mmol) obtained in Step 5, tert-butyl 4-((4-carbamoylbicyclo[2.2.2]octane-1-yl)carbamoyl)-6,8-difluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (98 mg, quantitative) was obtained in the same manner as in Step 5 of Example 7. ESI-MS m / z: 546 (M + H) +

[0200] (Step 7) Using the tert-butyl 4-((4-carbamoylbicyclo[2.2.2]octan-1-yl)carbamoyl)-6,8-difluoro-7-methylspiro[chromen-2,4'-piperidine]-1'-carboxylate (98 mg, 0.180 mmol) obtained in Step 6, the crude product of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-6,8-difluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide (85 mg) was obtained in the same manner as in Step 5 of Example 8 and used in the next step without purification.

[0201] (Step 8) Using the crude product of N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-6,8-difluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide obtained in Step 7 (20 mg) and (2E)-3-cyclopropylacrylic acid (6.0 mg, 0.054 mmol), (E)-N-(4-carbamoylbicyclo[2.2.2]octan-1-yl)-1'-(3-cyclopropylacryloyl)-6,8-difluoro-7-methylspiro[chromen-2,4'-piperidine]-4-carboxamide (12.6 mg, 2-step yield 52%) was obtained in the same manner as in Step 7 of Example 12. ESI-MS m / z: 540 (M + H) + 1 H-NMR (CDCl3, δ): 0.56-0.63 (m, 2H), 0.85-0.92 (m, 2H), 1.50-1.66 (m, 1H), 1.87-1.94 (m, 7H), 1.98-2.09 (m, 9H), 2.18 (s, 3H), 3.08-3.26 (m, 1H), 3.45-3.62 (m, 1H), 3.74-3.90 (m, 1H), 4.34-4.52 (m, 1H), 5.36-5.66 (m, 3H), 5.82 (s, 1H), 6.28-6.39 (m, 2H), 6.98 (dd, J = 1.8, 9.8 Hz, 1H).

[0202] [Reference Example 1] (2'-(2-(dimethylamino)ethyl)-7'-methyl-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-1-yl)((1S,2S)-2-methylcyclopropyl)methanone

[0203] (Step 1) 1-(2-hydroxy-4-methylphenyl)ethane-1-one (0.909 mL, 6.66 mmol) and pyridine (2.69 mL, 33.3 mmol) were dissolved in dichloromethane (20 mL), and under ice cooling, trifluoromethanesulfonic anhydride (1.24 mL, 7.32 mmol) was added. The mixture was heated to room temperature and stirred overnight. Water was added to the reaction mixture and extracted with chloroform. The organic layer was washed with hydrochloric acid (2 mol / L) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the crude product of 2-acetyl-5-methylphenyl trifluoromethanesulfonate, which was used in the next step without purification.

[0204] (Step 2) The crude product of 2-acetyl-5-methylphenyl trifluoromethanesulfonate obtained in Step 1 was dissolved in 1,4-dioxane (12 mL), and (4-methoxyphenyl)methanethiol (1.01 mL, 7.33 mmol), tris(dibenzylideneacetone)dipalladium (152 mg, 0.167 mmol), 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (193 mg, 0.333 mmol), and N,N-diisopropylethylamine (2.33 mL, 13.3 mmol) were added, and the mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with hydrochloric acid (2 mol / L) and saturated sodium bicarbonate aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (heptane / ethyl acetate = 1 / 0-6 / 4) to obtain 1-(2-((4-methoxybenzyl)thio)-4-methylphenyl)ethane-1-one (2-step yield, quantitative). 1 H NMR (CDCl3, δ): 2.37 (s, 3H), 2.57 (s, 3H), 3.80 (s, 3H), 4.09 (s, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.2 Hz, 1H).

[0205] (Step 3) The 1-(2-((4-methoxybenzyl)thio)-4-methylphenyl)ethane-1-one (1.90 g, 6.63 mmol) obtained in Step 2 was dissolved in trifluoroacetic acid (4.0 mL) and stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain the crude product of 1-(2-mercapto-4-methylphenyl)ethane-1-one, which was used in the next step without purification.

[0206] (Step 4) Using the crude product of 1-(2-mercapto-4-methylphenyl)ethane-1-one obtained in Step 3 and tert-butyl 4-oxopiperidine-1-carboxylate (1.32 g, 6.63 mmol), tert-butyl 7'-methyl-4'-oxospiro[piperidine-4,2'-thiochroman]-1-carboxylate (372 mg, 2-step yield 16%) was obtained in the same manner as in Step 1 of Example 1. 1 H NMR (CDCl3, δ): 1.45 (s, 9H), 1.63-1.70 (m, 2H), 1.91 (d, J = 12.7 Hz, 2H), 2.35 (s, 3H), 2.90 (s, 2H), 3.22 (br s, 2H), 3.87 (br s, 2H), 7.00 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 7.98 (d, J = 8.2 Hz, 1H).

[0207] (Step 5) The tert-butyl 7'-methyl-4'-oxospiro[piperidine-4,2'-thiochroman]-1-carboxylate (372 mg, 1.07 mmol) obtained in Step 4 was dissolved in dichloromethane (1.0 mL), cooled to -78°C, and then triethyl orthoformate (0.535 mL, 3.21 mmol), N,N-diisopropylethylamine (0.654 mL, 3.75 mmol), and boron trifluoride / diethyl ether complex (0.407 mL, 3.21 mmol) were added, and the mixture was stirred for 10 minutes. The mixture was then heated to room temperature and stirred for 20 minutes. The reaction mixture was azeotropically removed with ethanol, and the residue was dissolved in ethanol (4 mL). DBU (0.645 mL, 4.28 mmol) and hydrazine monohydrate (0.208 mL, 4.28 mmol) were added, and the mixture was stirred overnight at 70°C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 1 / 0-97 / 3) to obtain tert-butyl 7'-methyl-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-1-carboxylate (385 mg, 97%). 1 H-NMR (CDCl3, δ): 1.47 (s, 9H), 1.87-1.95 (m, 2H), 2.02-2.07 (m, 2H), 2.34 (s, 3H), 3.31 (br s, 2H), 3.95 (br s, 2H), 7.06 (d, J = 7.7 Hz, 1H), 7.22 (s, 1H), 7.43 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 10.32 (br s, 1H).

[0208] (Step 6) Dissolve the tert-butyl 7'-methyl-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-1-carboxylate (179 mg, 0.482 mmol) obtained in Step 5 in THF (1.5 mL), add potassium tert-butoxide (59 mg, 0.530 mmol) and methyl 2-bromoacetate (0.051 mL, 0.554 mmol), and stir at room temperature for 10 minutes. Under ice cooling, add the reaction mixture dropwise to a solution of lithium aluminum hydride (46 mg, 1.20 mmol) in THF (1.5 mL) and stir for 20 minutes. Add hydrochloric acid (2 mol / L) to the reaction mixture and extract with ethyl acetate. Wash the organic layer with saturated sodium bicarbonate aqueous solution, dry over anhydrous sodium sulfate, and remove the solvent under reduced pressure. The residue was purified by reverse-phase preparative LC-MS to obtain the crude product (87.7 mg) of tert-butyl 2'-(2-(hydroxyethyl)-7'-methyl-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-1-carboxylate.

[0209] (Step 7) The crude product (87.7 mg) of tert-butyl 2'-(2-(hydroxyethyl)-7'-methyl-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-1-carboxylate obtained in Step 6 was dissolved in dichloromethane (2.0 mL), triethylamine (0.059 mL, 0.420 mmol) and methanesulfonyl chloride (0.020 mL, 0.250 mmol) were added, and the mixture was stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure to obtain the crude product of tert-butyl 7'-methyl-2'-(2-((methylsulfonyl)oxy)ethyl)-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-1-carboxylate, which was used in the next step without purification.

[0210] (Step 8) The crude product of tert-butyl 7'-methyl-2'-(2-((methylsulfonyl)oxy)ethyl)-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-1-carboxylate obtained in Step 7 was dissolved in acetonitrile (2.0 mL), and tetrabutylammonium iodide (16 mg, 0.042 mmol), dimethylamine hydrochloride (86 mg, 1.06 mmol), and triethylamine (0.147 mL, 1.06 mmol) were added, and the mixture was stirred at 80°C for 20 hours under microwave irradiation. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with chloroform. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0-94 / 6) to obtain tert-butyl 2'-(2-(dimethylamino)ethyl)-7'-methyl-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-1-carboxylate (69.3 mg, 3-step yield 33%). 1 H-NMR (CDCl3, δ): 1.46 (s, 9H), 1.66-1.74 (m, 2H), 1.83-1.91 (m, 2H), 2.30 (s, 6H), 2.32 (s, 3H), 2.80 (t, J = 6.8 Hz, 2H), 3.30 (br s, 2H), 3.93 (br s, 2H), 4.24 (t, J = 6.8 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 7.17 (s, 1H), 7.30 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H).

[0211] (Step 9) Using the tert-butyl 2'-(2-(dimethylamino)ethyl)-7'-methyl-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-1-carboxylate (693 mg, 1.57 mmol) obtained in Step 8, the crude product (650 mg) of N,N-dimethyl-2-(7'-methyl-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-2'-yl)ethane-1-amine hydrochloride was obtained in the same manner as in Step 7 of Example 1 and used in the next step without purification. ESI-MS m / z: 343 (M + H) +

[0212] (Step 10) Using the crude product of N,N-dimethyl-2-(7'-methyl-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-2'-yl)ethane-1-amine hydrochloride obtained in Step 9 (20 mg) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (7.2 mg, 0.072 mmol), (2'-(2-(dimethylamino)ethyl)-7'-methyl-2'H-spiro[piperidine-4,4'-thioclomeno[4,3-c]pyrazole]-1-yl)((1S,2S)-2-methylcyclopropyl)methanone (15.3 mg, 2-step yield 75%) was obtained in the same manner as in Step 7 of Example 12. ESI-MS m / z: 425 (M + H) + 1H-NMR (CDCl3, δ): 0.58 (s, 1H), 1.11 (d, J = 5.9 Hz, 3H), 1.15-1.19 (m, 1H), 1.34 (s, 1H), 1.42-1.46 (m, 1H), 1.82-1.98 (m, 2H), 2.07-2.13 (m, 2H), 2.30 (s, 6H), 2.33 (s, 3H), 2.80 (t, J = 6.8 Hz, 2H), 3.17 (t, J = 12.7 Hz, 1H), 3.69 (t, J = 12.7 Hz, 1H), 3.98 (d, J = 12.7 Hz, 1H), 4.24 (t, J = 6.8 Hz, 2H), 4.45 (d, J = 12.7 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 7.19 (s, 1H), 7.31 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H).

[0213] [Test Example 1] Inhibitory Effect of TLR9 Ligand-Induced Type I IFN Production in pDC-like Cell Lines <Summary> As described herein, inhibiting type I IFN production from pDCs is expected to have a therapeutic effect on SLE. In this test, using CAL-1 cells, which have been reported to have properties similar to pDCs, it was confirmed that type I IFN production was suppressed in the presence of the test compound even when the TLR9 ligand was added to these cells. In this cell test system, the amount of type I IFN produced was confirmed by measuring IFN-β, a type of type I IFN, as it is the most sensitive and stable quantifiable indicator.

[0214] <Cell Culture> CAL-1 cells were invented by the inventors, led by Takashi Maeda of Nagasaki University, and are known as one of the few cell lines with human pDC-like characteristics, making them a useful tool for drug discovery research targeting pDCs. Details are disclosed in Japanese Patent No. 5011520. The rights to use these cells belong to Nagasaki University. The applicant of this application has received permission from the university to use these cells, and the inventors used these cells in this study. The CAL-1 cells were cultured at 37°C in a carbon dioxide incubator (95% air, 5% CO2) in RPMI1640 medium (product number: 11875-093, Thermo Fisher Scientific) supplemented with a final concentration of 10 vol% inactivated fetal bovine serum (FBS: product number: 10099-148, Thermo Fisher Scientific) and a final concentration of 1 vol% penicillin / streptomycin solution (PS: product number: 15140-122, Thermo Fisher Scientific).

[0215] <Measurement of IFN-β Production> Cultured CAL-1 cells were seeded at a density of 50,000 cells / well in a clear 96-well plate (product number: 163320, Thermo Fisher Scientific). After seeding, the test compound was diluted in RPMI1640 medium containing the above-mentioned FBS and PS to 10 times the final concentration (6 points: 0.1, 0.3, 1, 3, 10, 30 nM), and 1 / 10 of the final solution volume of 200 μL was added to each well. At this time, the final concentration of DMSO (Dimethyl sulfoxide), the solvent for the compound, was prepared to be 0.1 vol% for all groups. After adding the test compound, the cells were incubated at 37°C in a carbon dioxide incubator for 1 hour. Subsequently, the TLR9 ligand ODN2006 (product number: tlrl-2006, InvivoGen) was prepared to a 10-fold concentration of 0.5 μM in RPMI1640 medium containing the above FBS and PS. This was added to each well by 1 / 10 of the final solution volume (200 μL), and the mixture was incubated at 37°C in a carbon dioxide incubator for 18 to 24 hours. 2 μL of the culture supernatant was collected and added to a white 384-well plate (product number: 6007290, PerkinElmer). The IFN-β concentration in the supernatant was quantified using the AlphaLISA Human IFNβ Detection Kit (product number: AL3133, PerkinElmer). Next, the IFN-β production inhibition rate was calculated using the following formula, and the concentration (IC) of the test compound showing a 50% inhibition rate was calculated. 50 The following values ​​were calculated: IFN-β production inhibition rate (%) = 100 - (A / B) × 100 A: IFN-β concentration in the culture supernatant of the well to which the test compound was added B: IFN-β concentration in the culture supernatant of the well to which DMSO was added instead of the test compound

[0216] The results are shown in the table below.

[0217]

[0218] <Results> The compound in this embodiment was confirmed to have an inhibitory effect on IFN-β production. This suggests that the compound in this embodiment is useful for treating autoimmune diseases involving type I IFN, such as SLE.

[0219] [Test Example 2] Evaluation of the binding ability of the test compound to SLC15A4 <Summary> In order to efficiently evaluate the binding activity of the compound to SLC15A4, first, the compound in Reference Example 1 was prepared as described above as a representative ligand compound for SLC15A4, and the binding strength to SLC15A4 was measured. Subsequently, the binding ability of the test compound to SLC15A4 was verified by measuring the inhibition rate of binding between the ligand compound and SLC15A4 by the test compound in the presence of the ligand compound and the test compound.

[0220] <Evaluation of ligand binding to SLC15A4 (Kd value measurement)> Human SLC15A4 (gene ID: 121260) was expressed in 293F cells (product number: A14527, Thermo Fisher Scientific), and the cells were pulverized to obtain microsomes. The obtained microsomes were diluted to 0.01 mg / mL with assay buffer (25 mmol / L Tris-HCl pH 7.5, 137 mmol / L NaCl, 2.7 mmol / L KCl, 0.005% Tween20, 1 mmol / L DTT, 1 mM EDTA). Ligand compounds were added to assay buffer at seven final concentrations: 1, 10, 100, 300, 1000, 3000, or 10000 nM. After reacting at room temperature for 1 hour, the SLC15A4-expressing microsomes bound to the ligand compounds were purified by liquid chromatography to quantify the ligand compounds bound to SLC15A4, and the binding strength of the ligand compounds was calculated as Kd = 38 nM.

[0221] <Evaluation of binding ability of test compounds to SLC15A4 (ligand compound binding inhibitory activity IC) 50For the evaluation of the test compound, the ligand compound at a final concentration of 400 nM and the test compound (7 final concentrations: 1, 10, 100, 300, 1000, 3000, or 10000 nM) were added to the microsomes prepared in the same manner as above, and the mixture was reacted at room temperature for 1 hour. Subsequently, the SLC15A4-expressing microsomes to which the test compound or ligand compound was bound were purified by liquid chromatography. The amount of ligand compound bound to SLC15A4 was quantified using a mass spectrometer attached to the liquid chromatograph used in the purification. From the obtained ligand compound concentrations, the inhibitory activity of the ligand compound in the presence of the test compound at each concentration was calculated using the following formula, and the concentration of the test compound showing a 50% inhibition rate (IC) was calculated. 50 The following values ​​were calculated: Binding inhibitory activity (%) = 100 - {(AC) / (BC)} × 100 A: Concentration of ligand compound bound to SLC15A4-expressing microsomes under conditions with the test compound added B: Concentration of ligand compound bound to SLC15A4-expressing microsomes under conditions with DMSO added instead of the test compound C: Concentration of ligand compound bound to microsomes not expressing SLC15A4

[0222] The results are shown in the table below.

[0223]

[0224] <Results> The compound according to the present invention, which was shown to have a type I IFN production inhibitory effect in Test Example 1, showed competitive activity against ligand compounds that bind to SLC15A4. From this, it was found that the compound according to this embodiment has the ability to bind to SLC15A4.

[0225] The results of Test Examples 1 and 2 are consistent with reports in non-patent literature such as 2, 3, and 4, which state that SLC15A4 controls type I IFN production via TLR9. In other words, the results of Test Examples 1 and 2 suggest that the compound according to this embodiment exerts type I IFN production inhibitory activity by directly binding to SLC15A4.

[0226] [Test Example 3] Evaluation of the IFN-α Production Inhibitory Activity of the Test Compound in Human PBMCs Stimulated with TLR7 / 8 Ligand <Summary> As described herein, inhibiting type I IFN production can be expected to have therapeutic effects on SLE and other conditions. In this test example, human peripheral blood mononuclear cells (human PBMCs) were stimulated with TLR7 / 8, and the IFN-α production inhibitory activity of the test compound was evaluated when it was added to the IFN-α produced from the human PBMCs.

[0227] <Isolation of Human PBMCs> To obtain human PBMCs, 50 mL of fresh blood from a healthy adult was first collected by heparinization. 15 mL of Ficoll-Paque PLUS (product number: 17144002, Cytiva) was dispensed into Leucosep tubes (product number: 227290, Greiner bio-one), and Ficoll-Paque PLUS was separated to the lower layer by centrifugation (1200 rpm, room temperature, 5 minutes). Peripheral blood was then dispensed to the upper layer in 25 mL portions, and the centrifuge was centrifuged at the lowest speed (2000 rpm, room temperature, 20 minutes) with the accelerator and brake set to the lowest speed. After centrifugation, the recovered PBMC layer was mixed with phosphate-buffered saline (PBS) containing 10 vol% Acid-citrate-dextrose solution A (ACD-A: product number: TP-A03ACD, Terumo) to a total volume of 50 mL, and then centrifuged again (1500 rpm, room temperature, 10 minutes). After removing the supernatant, the resulting cell precipitate was suspended in 30 mL of PBS containing 10% ACD-A, and washed twice with centrifugation (1200 rpm, room temperature, 5 minutes). After removing the supernatant, the human PBMCs were suspended in RPMI1640 medium (product number: 72400-120, Thermo Fisher Scientific) to which a final concentration of 10 vol% inactivated fetal bovine serum (FBS, product number: 10099-148, Thermo Fisher Scientific), a final concentration of 1 vol% in sodium pyruvate solution (product number: 11360-070, Thermo Fisher Scientific), and a final concentration of 1 vol% in penicillin / streptomycin solution (product number: 15140-122, Thermo Fisher Scientific) had been added to obtain a suspension containing human PBMCs.

[0228] <Measurement of IFN-α Production> The suspension containing the above human PBMCs was seeded in 160 μL portions at a rate of 500,000 cells / well in a clear 96-well plate (product number: 163320, Thermo Fisher Scientific). After seeding, each test compound was diluted in the above RPMI1640 medium to 10 times its final concentration (5 points between 0.3 nM and 1000 nM), and 1 / 10 volume of the final solution (200 μL) was added to each well. At this time, the final concentration of DMSO, the solvent for the compounds, was prepared to be 0.1 vol% for all groups. After adding the test compounds, the cells were incubated at 37°C in a carbon dioxide incubator for 2 to 4 hours. Subsequently, RNP-Sm (product number: ATR01-10, Arotec Diagnostics) and anti-RNP antibody (product number: BP2041, OriGene Technologies) were mixed in the RPMI1640 medium in a 1:2 solution ratio and incubated at room temperature for 30 minutes to prepare an immune complex that stimulates TLR7 / 8. The immune complex that stimulates TLR7 / 8 was prepared to a 10-fold concentration of 20 μg / mL, and 1 / 10 of the final solution volume of 200 μL was added to each well. The mixture was then incubated at 37°C in a carbon dioxide incubator for 18 to 24 hours. 2 μL of the culture supernatant was collected and added to a white 384-well plate (product number: 6007290, PerkinElmer), and the IFN-α concentration in the supernatant was quantified using the AlphaLISA Human IFNα Detection Kit (product number: AL297C, PerkinElmer). Next, the IFN-α production inhibition rate was calculated using the following formula, and the concentration of the test compound that showed a 50% inhibition rate (IC50 value) was calculated. IFN-α production inhibition rate (%) = 100 - {(AC) / (BC)} × 100 A: IFN-α concentration in the culture supernatant of the well to which the test compound was added B: IFN-α concentration in the culture supernatant of the well to which DMSO was added instead of the test compound C: IFN-α concentration in the culture supernatant of the well to which DMSO was added, but no immune complex that stimulates TLR7 / 8 was added The results are shown in the table below.

[0229]

[0230] Since all the test compounds used in this study showed IFN-α production inhibitory activity, it is suggested that they are effective against human autoimmune diseases involving type I IFN.

[0231] [Test Example 4] Inhibitory Effect of TLR9 Ligand-Induced Type I IFN Production in Mice <Summary> To confirm that the compound according to this embodiment exhibits an inhibitory effect on type I IFN production in mammals, a test was conducted using mice. After orally administering the test compound to mice, ODN2216, a TLR9 ligand, was intravenously administered together with 1,2-Dioleoyl-3-trimethylammonium propane (DOTAP), a liposome transfection reagent, and the amount of type I IFN in plasma induced by ODN2216 was measured. As the type I IFN in plasma to be measured, IFN-α was adopted because it has the highest detection sensitivity in this test system and is highly associated with autoimmune diseases such as SLE.

[0232] <Measurement of IFN-α production inhibitory effect in mice> Female NZBWF1 / Slc mice (obtained from Nippon SLC) were given the test compound dissolved in a 0.5 w / v% methylcellulose 400 solution (product number: 133-17815, Fujifilm Wako Pure Chemical Industries) as the administration solvent, and administered 10 mL / kg of the test compound orally (final dose: 30 mg / kg). 23 hours after administration, the same amount of the test compound was administered orally to the mice again. ODN2216 (product number: tlrl-2216-1, InvivoGen), a TLR9 ligand nucleic acid, and DOTAP (product number: 11202375001, Roche Diagnostic), a liposome transfection reagent, were mixed with distilled water (product number: K3G88, Otsuka Pharmaceutical Co., Ltd.) at concentrations of 2 μg and 10 μg, respectively, per mouse to prepare a total of 100 μL of solution. This solution was administered intravenously to mice one hour after the second oral administration of the test compound. Six or seven hours after intravenous administration, 150 μL of blood was collected from each mouse using a blood collection tube (product number: 365985, Becton Dickinson), and the plasma was isolated by centrifugation at 10000 × g for 5 minutes. The amount of IFN-α in the collected plasma was measured using the Mouse IFN Alpha All Subtype ELISA Kit (product number: 42115-1, PBL Assay Science). A control group was established in which no inhibitory activity was observed. This group received a solvent instead of the test compound (solvent control group).

[0233] The results are shown in the table below. The table shows the mean and standard deviation for each test compound or solvent control group for each trial run (N=4-5, where N is the number of mice). The results for each treatment group are presented in separate tables for each trial run.

[0234]

[0235]

[0236]

[0237] <Results> In this study, mice administered intravenously with the test compound showed inhibition of IFN-α production by TLR9. This indicates that the compound according to this embodiment inhibits IFN-α production in vivo in mice. Therefore, it is suggested that the compound of the present invention functions in vivo as a means of treating autoimmune diseases involving type I IFN, such as SLE, by inhibiting the production of type I IFN.

[0238] It will be obvious to those skilled in the art that various modifications or alterations can be conceived within the scope of the claims, and these will naturally fall within the technical scope of the present invention. Furthermore, the components of the above embodiments may be combined in any way without departing from the spirit of the invention.

[0239] This application is based on Japanese Patent Application No. 2024-230575 filed on December 26, 2024, and its contents are incorporated herein by reference.

Claims

1. The following equation (I): [In the formula, Y is CH ２ or O, R １ R is an optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted cycloalkyl, or optionally substituted cycloalkyloxy, ２ R is independently selected from halogens and alkyls. ３ A compound represented by [which is independently selected from halogens and alkyls] or a pharmaceutically acceptable salt thereof.

2. The R １ is C １ -C ６ alkyl, halogen, and C ３ -C ６ cycloalkyl, and may have a substituent independently selected from the group consisting of C １ -C ６ alkoxy, C ３ -C ６ cycloalkyl which may be substituted with C ２ -C ６ alkenyl, C[[ID=2۳]] ２ -C ６ alkenyloxy, C １ -C ６ cycloalkyl which may be substituted with alkyl, or C ３ -C ６ cycloalkyloxy, or the compound according to claim 1 or a pharmaceutically acceptable salt thereof.​​​​ 3. The aforementioned R ２ However, halogens and C １ -C ６ A compound according to claim 1, independently selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

4. The aforementioned R ３ However, halogens and C １ -C ６ A compound according to claim 1, independently selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

5. R １ -O-ethyl, -O-CH ２ CHF ２ , -O-CH ２ -Cyclopropyl, -O-Cyclopropyl, -O-Cyclobutyl, -O-CH ２ CH=CH ２ , (1S,2S)-2-methylcyclopropyl-1-yl,-propyl, or -CH=CH-cyclopropyl, R ２ These are independently -F and -CH ３ Selected from, R ３ These independently produce -F, -Cl, and -CH ３ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

6. The following groups: A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 7, which is an SLC15A4 inhibitor.

9. The pharmaceutical composition according to claim 7 for the treatment of diseases related to SLC15A4 inhibition.

10. The pharmaceutical composition according to claim 9, wherein the disease associated with the inhibition of SLC15A4 is an autoimmune disease.

11. The pharmaceutical composition according to claim 9, wherein the disease associated with SLC15A4 inhibition is systemic lupus erythematosus, lupus nephritis, or cutaneous lupus.

12. The pharmaceutical composition according to claim 9, wherein the disease associated with the inhibition of SLC15A4 is Sjögren's syndrome.

13. A therapeutic agent for diseases related to SLC15A4 inhibition, comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof as an active ingredient.

14. The therapeutic agent according to claim 13, wherein the disease associated with SLC15A4 inhibition is an autoimmune disease.

15. The therapeutic agent according to claim 13, wherein the disease associated with SLC15A4 inhibition is systemic lupus erythematosus, lupus nephritis, or cutaneous lupus.

16. The therapeutic agent according to claim 13, wherein the disease associated with SLC15A4 inhibition is Sjögren's syndrome.

Images