Compound having slc15a4 inhibitory activity

Abstract

The present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, all symbols represent the same meaning as the symbols described in the specification.)

Description

Compounds with SLC15A4 inhibitory activity

[0001] The present invention relates to compounds having SLC15A4 inhibitory activity (SLC15A4 inhibitor compounds) or pharmaceutically acceptable salts thereof, and the like.

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

[0003] Two main mechanisms by which SLC15A4 regulates the TLR7 or TLR9 pathway have been reported: one is the regulation of lysosomal maturation through transporter activity (Non-Patent Document 3), and the other is the activation of IRF5 (Interferon Regulatory Factor 5) by functioning as a scaffolding protein for TASL (TLR adaptor interacting with SLC15A4 on the lysosome) (Non-Patent Document 4).

[0004] SLC15A4 gene polymorphisms increase the risk of developing systemic lupus erythematosus (SLE) (Non-Patent Documents 5, 6, and 7). One of the mechanisms by which this risk increases has been reported to be increased expression of SLC15A4 in B cells (Non-Patent Document 7).

[0005] In mice that spontaneously develop SLE-like symptoms, it has been confirmed that SLC15A4 gene deficiency suppresses the onset of SLE-like pathology, such as by significantly reducing autoantibody titers and proteinuria (Non-Patent Documents 8, 9, and 10). These reports in humans and mice suggest that SLC15A4 is involved in the pathogenesis of SLE.

[0006] Recently, anifrolumab, a type I IFN receptor neutralizing antibody, was approved for the treatment of SLE (Non-Patent Document 11). Litifilimab, an anti-BDCA2 antibody that specifically inhibits pDC function and thereby inhibits type I IFN production, has also demonstrated efficacy in clinical trials targeting SLE and cutaneous lupus erythematosus (CLE) (Non-Patent Documents 12, 13, 21). It has been reported that inhibition of type I IFN production can be used to treat SLE pathologies. Furthermore, pathologies involving type I IFN production by pDCs have been reported, including lupus nephritis, Sjögren's syndrome, systemic sclerosis, dermatomyositis, IgG4-related disease, and myasthenia gravis (Non-Patent Documents 15, 16, 17, 18, 19, 20).

[0007] In addition, two examples of low molecular weight compounds that bind to SLC15A4 and inhibit its function have been reported (Patent Document 1, Non-Patent Document 14), and the co-crystal structure of the inhibitor with SLC15A4 has 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] An object of the present invention is to provide a compound having SLC15A4 inhibitory activity, or a pharmaceutically acceptable salt thereof, or the like.

[0011] The present invention relates to the following [1] to

[26] . [1] A compound represented by the following formula (I):

[0012]

[0013] (In the formula, Ar １ represents an optionally substituted pyrazole ring or an optionally substituted imidazole ring,２ represents an optionally substituted benzene ring or an optionally substituted pyridine ring, Cy １ represents an optionally substituted piperidine ring or an optionally substituted azetidine ring, Cy ２ represents an aliphatic heterocyclic group which may have a substituent; L represents a single bond, —CH ２ -, -CH ２ CO-, -CH ２ CONH-, -CH ２ CON (CH ３ ) -, -N(CH ３ ) -, -CO-, or -CON(CH ３ )-, R is an alkyl having 1 to 8 carbon atoms which may have a substituent, an alkenyl having 2 to 9 carbon atoms which may have a substituent, an alkoxy having 1 to 8 carbon atoms which may have a substituent, an alkenyloxy having 2 to 9 carbon atoms which may have a substituent, -NHW １ Or -N.W. ２ W ３ (W １ , W ２ and W ３ [2] A compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof: Ar is the same or different and represents an alkyl having 1 to 8 carbon atoms which may be substituted, an alkenyl having 2 to 9 carbon atoms which may be substituted, or a 3- to 10-membered cycloalkyl which may be substituted; Ar is an optionally substituted 3- to 10-membered cycloalkyl; or a 3- to 10-membered cycloalkoxy which may be substituted; and Y is O or S. １ is expressed by the following formula (Ar １ −1), (Ar １ -2), (Ar １ -3) or (Ar １ -4):

[0014]

[0015] (wherein Rx represents a hydrogen atom, a halogen atom, an alkyl having 1 to 8 carbon atoms which may have a substituent, or a cycloalkyl having 3 to 10 members which may have a substituent; Ry represents a hydrogen atom, an alkyl having 1 to 8 carbon atoms which may have a substituent, or a cycloalkyl having 3 to 10 members which may have a substituent; and * represents the point of attachment to L), or a pharmaceutically acceptable salt thereof. [3] The compound according to [1], １ is the formula (Ar １ -1), wherein L is a single bond, —CH ２ -, -CH ２ CO-, -CH ２ CONH-, -CH ２ CON (CH ３ ) -, -CO-, or -CON(CH ３ [4] The compound according to [2], or a pharmaceutically acceptable salt thereof, wherein Ar １ is the formula (Ar １ -2), wherein L is a single bond, —CH ２ -, -CO-, or -CON(CH ３ [5] The compound according to [2], or a pharmaceutically acceptable salt thereof, wherein Ar １ is the formula (Ar １ -3) or (Ar １ [6] The compound according to [2], or a pharmaceutically acceptable salt thereof, wherein Ar ２ is expressed by the following formula (Ar ２ −1), (Ar ２ -2), (Ar ２ -3) or (Ar ２ -4):

[0016]

[0017] (wherein Re are the same or different and represent halogen, alkyl having 1 to 5 carbon atoms which may have a substituent, or alkoxy having 1 to 5 carbon atoms which may have a substituent), or a pharmaceutically acceptable salt thereof. [7] Cy １ is expressed by the following formula (Cy １ -1) or (Cy １ -2):

[0018]

[0019] (wherein Rd are the same or different and each represents a halogen atom or an alkyl group having 1 to 8 carbon atoms which may have a substituent), or a pharmaceutically acceptable salt thereof. [8] Cy ２ is a group selected from the group consisting of: an optionally substituted 4-8-membered monocyclic aliphatic heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S; an optionally substituted 5-15-membered fused aliphatic heterocyclic group having 1 to 4 heteroatoms selected from N, O, and S; an optionally substituted 7-9-membered bridged cyclic aliphatic heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S; and an optionally substituted 5-12-membered spirocyclic aliphatic heterocyclic group having 1 to 4 heteroatoms selected from N, O, and S. [9] The compound according to any one of [1] to [8], or a pharmaceutically acceptable salt thereof.

[10] A compound represented by the following formula (I-1):

[0020]

[0021] (In the formula, Rx １ represents a hydrogen atom, an alkyl having 1 to 5 carbon atoms, an alkyl having 1 to 5 carbon atoms substituted with hydroxy, or a 3- to 7-membered cycloalkyl; １ is NRa １ , SO, SO ２ or SO(=NH), １ represents a hydrogen atom, hydroxy, formyl, alkylcarbonyl having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, or alkyl having 1 to 5 carbon atoms; Rb １ are the same or different and each represents halogen, alkyl having 1 to 5 carbon atoms or hydroxy; Rd １ are the same or different and each represents alkyl having 1 to 5 carbon atoms or halogen; １are the same or different and each represents a halogen, an alkyl having 1 to 5 carbon atoms, or an alkoxy having 1 to 5 carbon atoms; １ (i) alkyl having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkoxy; (ii) alkenyl having 2 to 6 carbon atoms, or alkenyl having 2 to 6 carbon atoms substituted with a 3- to 7-membered cycloalkyl; (iii) alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms substituted with a halogen, alkoxy having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or alkoxy having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl; (iv) -NHW （１－１） or -N.W. （１－２） W （１－３） (Where, （１－１） , W （１－２） , W （１－３） are each the same or different and represent an optionally substituted alkyl of 1 to 5 carbon atoms, an optionally substituted alkenyl of 2 to 6 carbon atoms, or an optionally substituted 3- to 7-membered cycloalkyl, wherein the substituents on the optionally substituted alkyl of 1 to 5 carbon atoms and the optionally substituted alkenyl of 2 to 6 carbon atoms are each the same or different and selected from halogen, a 3- to 7-membered cycloalkyl, and a 3- to 7-membered cycloalkyl substituted with a halogen; and the substituent on the optionally substituted 3- to 7-membered cycloalkyl is selected from halogen or an alkyl of 1 to 5 carbon atoms; (v) a 3- to 7-membered cycloalkyl, a 3- to 7-membered cycloalkyl substituted with an alkyl of 1 to 5 carbon atoms, or a 3- to 7-membered cycloalkyl substituted with an alkyl of 1 to 5 carbon atoms substituted with a halogen; or (vi) a 3- to 7-membered cycloalkoxy, wherein Z is CH, CRe, １

[11] A compound represented by the following formula (I-2): or a pharmaceutically acceptable salt thereof:

[0022]

[0023] (wherein the bond with a dotted line represents a double bond or a single bond; Ry ２ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; ２ is NRa ２ , SO, SO ２ , SO(=NH), or O; ２ represents a hydrogen atom, hydroxy, formyl, alkylcarbonyl having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, or alkyl having 1 to 5 carbon atoms; Rb ２ are the same or different and each represents alkyl having 1 to 5 carbon atoms; ２ are the same or different and each represents alkyl having 1 to 5 carbon atoms; ２ are the same or different and each represents a halogen or an alkyl having 1 to 5 carbon atoms; R ２ (i) alkyl having 1 to 5 carbon atoms, (ii) alkenyl having 2 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms substituted with 3- to 7-membered cycloalkyl, (iii) alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms substituted with 3- to 7-membered cycloalkyl, or alkoxy having 1 to 5 carbon atoms substituted with 3- to 7-membered cycloalkyl substituted with halogen, (iv) alkenyloxy having 2 to 6 carbon atoms, (v) -NHW （２－１） (W （２－１） represents an alkyl having 1 to 5 carbon atoms, an alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or an alkenyl having 2 to 6 carbon atoms); (vi) a 3- to 7-membered cycloalkyl, a 3- to 7-membered cycloalkyl substituted with an alkyl having 1 to 5 carbon atoms; or (vii) a 3- to 7-membered cycloalkoxy; Z is CH, CRe, ２

[12] A compound or a pharmaceutically acceptable salt thereof, wherein the compound is an SLC15A4 inhibitor.

[13] The pharmaceutical composition according to

[12] , which is an SLC15A4 inhibitor.

[14] The pharmaceutical composition according to

[12] , for treating a disease associated with SLC15A4 inhibition.

[15] The pharmaceutical composition according to

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

[16] The pharmaceutical composition according to

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

[17] The pharmaceutical composition according to

[14] , wherein the disease associated with SLC15A4 inhibition is Sjogren's syndrome.

[18] The compound or a pharmaceutically acceptable salt thereof, wherein the compound is an SLC15A4 inhibitor.

[19] The compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof for use in the treatment of a disease associated with SLC15A4 inhibition.

[20] Use of the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof for the treatment of a disease associated with SLC15A4 inhibition.

[21] Use of the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with SLC15A4 inhibition.

[22] A medicine comprising, as an active ingredient, the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof.

[23] A therapeutic agent for a disease associated with SLC15A4 inhibition, comprising, as an active ingredient, the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof.

[24] The therapeutic agent according to

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

[25] The therapeutic agent according to

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

[26] The therapeutic agent according to

[23] , wherein the disease associated with SLC15A4 inhibition is Sjogren's syndrome.

[0024] According to the present invention, a compound having SLC15A4 inhibitory activity or a pharmaceutically acceptable salt thereof can be provided.

[0025] FIG. 1A is a graph showing the results of measurement of anti-dsDNA IgG antibody titer (U / mL) in the SLE pathology model mouse of the solvent control group in Test Example 5. FIG. 1B is a graph showing the results of measurement of anti-dsDNA IgG antibody titer (U / mL) in the SLE pathology model mouse of the test compound (Compound 34) administration group (dose 30 mg / mL) in Test Example 5. FIG. 1C is a graph showing the results of measurement of anti-dsDNA IgG antibody titer (U / mL) in the SLE pathology model mouse of the prednisolone administration group in Test Example 5. FIG. 2A is a graph showing the results of measurement of urinary protein amount (mg / mL) in the SLE pathology model mouse of the solvent control group in Test Example 5. FIG. 2B is a graph showing the results of measurement of urinary protein amount (mg / mL) in the SLE pathology model mouse of the test compound (Compound 34) administration group (dose 30 mg / mL) in Test Example 5. Figure 2C is a graph showing the results of measuring the amount of urinary protein (mg / mL) in the SLE pathological model mouse of the prednisolone-administered group in Test Example 5. Figure 3 is a graph showing the results of measuring the anti-dsDNA IgG antibody titer (U / mL) in the SLE pathological model mouse of each administration group in Test Example 5. In Figure 3, (a) shows the results for the solvent control group, (b) shows the results for the test compound (Compound 6)-administered group (dose 10 mg / mL), (c) shows the results for the test compound (Compound 6)-administered group (dose 30 mg / mL), and (d) shows the results for the prednisolone-administered group. Figure 4 is a graph showing the results of measuring the amount of urinary protein (mg / mL) in the SLE pathological model mouse of each administration group in Test Example 5. In Figure 4, (a) shows the results for the solvent control group, (b) shows the results for the test compound (Compound 6) administration group (dose 10 mg / mL), (c) shows the results for the test compound (Compound 6) administration group (dose 30 mg / mL), and (d) shows the results for the prednisolone administration group. Figure 5 is a graph showing the results of flow cytometry measurement of the numbers of activated B cells and activated CD4+ T cells in submandibular gland tissues with inflammatory symptoms in Sjögren's syndrome model mice of each administration group in Test Example 6.In Figure 5, the left side shows the results for a group of Sjögren's syndrome model mice (N=10) administered with the solvent, the center side shows the results for a group of Sjögren's syndrome model mice (N=10) administered with the test compound (compound 34), and the right side shows the results for non-pathological wild-type mice (no administration, N=5). For each item, the square represents 50% of the median data, the horizontal line within the square represents the median, the upper limit represents the 75th percentile value, and the lower limit represents the 25th percentile value. The upper limit of the line extending above and below the square represents the maximum value, and the lower limit represents the minimum value.

[0026] In this specification, the compound represented by formula (I) will also be referred to as "compound (I)." The same applies to compounds having other formula numbers. In this specification, a bond crossing a wavy line in a chemical formula represents a bond.

[0027] In this specification, some or all of the atoms in compound (I) may be replaced with their corresponding isotope atoms, and compound (I) according to this embodiment also encompasses compounds in which these atoms have been replaced with isotope atoms. For example, some or all of the hydrogen atoms in compound (I) may be hydrogen atoms with an atomic weight of 2 (deuterium atoms).

[0028] In this specification, the term "optionally substituted" means that the group is unsubstituted or may have any substituent. Examples of the substituents for each group are described below.

[0029] In this specification, the term "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0030] In this specification, alkyl includes straight-chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0031] In this specification, alkenyl includes straight-chain or branched alkenyl, such as vinyl, allyl, propenyl, isopropenyl, butenyl, sec-butenyl, tert-butenyl, pentenyl, isopentenyl, neopentenyl, hexenyl, heptenyl, octenyl, nonenyl, and the like.

[0032] In the present specification, alkynyl includes straight-chain or branched alkynyl, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and the like.

[0033] In this specification, alkoxy includes straight-chain or branched alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, octyloxy, etc.

[0034] In this specification, alkenyloxy includes straight-chain or branched alkenyloxy, such as vinyloxy, allyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, and octenyloxy.

[0035] In this specification, alkylcarbonyl includes linear or branched alkylcarbonyl, such as acetyl, propionyl, butyryl, 2-methylbutanoyl, 3-methylbutanoyl, pivaloyl, pentanoyl, and hexanoyl.

[0036] In this specification, alkylcarbonyloxy includes linear or branched alkylcarbonyloxy, such as acetoxy, propionyloxy, butyryloxy, (2-methylbutanoyl)oxy, (3-methylbutanoyl)oxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, etc.

[0037] In this specification, the alkoxycarbonyl includes linear or branched alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, and octyloxycarbonyl.

[0038] In this specification, alkylthio includes straight-chain or branched alkylthio, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, octylthio, and the like.

[0039] In this specification, alkylsulfonyl includes linear or branched alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl, and the like.

[0040] In this specification, alkylamino includes linear or branched alkylamino, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, isopentylamino, neopentylamino, hexylamino, heptylamino, and octylamino.

[0041] In this specification, dialkylamino includes linear or branched dialkylamino, 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, diisopropylamino, etc.

[0042] In this specification, cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0043] In this specification, cycloalkoxy includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.

[0044] In this specification, examples of aryl include phenyl and naphthyl. In this specification, examples of an aliphatic heterocyclic group include an aliphatic heterocyclic group having at least one heteroatom selected from N (nitrogen atom), O (oxygen atom), and S (sulfur atom). In this specification, an aliphatic heterocyclic group is defined as a group having an unsaturated bond in part, but not aromatic as a whole. Examples of aliphatic heterocyclic groups include monocyclic aliphatic heterocyclic groups and polycyclic aliphatic heterocyclic groups. Examples of monocyclic aliphatic heterocyclic groups include 4- to 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- to 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, when 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, bridged cyclic aliphatic heterocyclic groups, and spirocyclic aliphatic heterocyclic groups. Here, the fused aliphatic heterocyclic group refers to a ring formed by two or more rings sharing one or more bonds, which contains at least one heteroatom, and the ring as a whole is non-aromatic. The crosslinked aliphatic heterocyclic group refers to a ring having a covalent bond connecting two non-adjacent atoms in the ring, which contains at least one heteroatom, and the ring as a whole is non-aromatic. The spirocyclic aliphatic heterocyclic group refers to a polycyclic structure formed by two or more rings sharing one atom, which contains at least one heteroatom, and the ring as a whole is non-aromatic.

[0045] In this specification, specific examples of the aliphatic heterocyclic group include azetidinyl, pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, oxazolidinyl, morpholino, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2-methyl-2H-pyran ... H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, chromanyl, isochromanyl, dihydro-2H-chromanyl, dihydro-1H-chromanyl, dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzodioxanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzodioxanyl, tetrahydroquinolyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, tetrahydroquinoxan ... Hydro-2H-thiopyranyl, Octahydropyrrolo[3,4-b]pyrrolyl, Hexahydropyrrolo[3,4-b]pyrrolyl, 8-Azabicyclo[3.2.1]octanyl, 1-Azabicyclo[2.2.2]octanyl, 5-Azaspiro[3.5]nonanyl, 1,7-Diazaspiro[4.4]nonanyl, 2,6-Diazaspiro[3.4]octanyl, 1,7-Diazaspiro[4.5]decanyl, 2,8-Diazaspiro[4.5]decanyl, 6-Oxa-2,9-Diazaspiro[4.5]decanyl, 2,6-Diazaspiro[3.3]heptanyl, 7-Azaspiro[3.5]nonanyl, 1,7-Diazaspiro[4.4]nonanyl, 2,6-Diazaspiro[3.4]octanyl, 1,7-Diazaspiro[4.5]decanyl, 2,8-Diazaspiro[4.5]decanyl, 6-Oxa-2,9-Diazaspiro[4.5]decanyl, 2,6-Diazaspiro[3.3]heptanyl, azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.4]octanyl, 1,9-diazaspiro[4.5]decanyl, 8-thiabicyclo[3.2.1]octanyl, 4-azaspiro[2.5]octanyl, 5-azaspiro[3.5]nonanyl, 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, phosphinanyl, 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-azabicyclo[2.2.1]heptanyl, 2-azaspiro[3.3]heptanyl, oxazepanyl, 1,4-azaphosphinanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 8 -oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, hexahydropyrrolo[3,4-c]pyrrolyl, 1-azaspiro[4.5]decanyl, 2-azaspiro[4.4]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 1-oxa-3,7-diazaspiro[4.4]nonanyl, 8-azabicyclo[3.2.1]octanyl, hexahydrothiopyranyl, quinuclidinyl, and the like.

[0046] In the present specification, examples of the aromatic heterocyclic group include a 5- or 6-membered monocyclic aromatic heterocyclic group having at least one heteroatom selected from N, O, and S, a bicyclic or tricyclic fused aromatic heterocyclic group having at least one heteroatom selected from N, O, and S, and the like. More specific examples include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and the like. Examples include thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, and naphthyridinyl.

[0047] <Compound (I)> The present embodiment relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[0048]

[0049] (In the formula, Ar １ represents an optionally substituted pyrazole ring or an optionally substituted imidazole ring, ２ represents an optionally substituted benzene ring or an optionally substituted pyridine ring, Cy １ represents an optionally substituted piperidine ring or an optionally substituted azetidine ring, Cy ２ represents an aliphatic heterocyclic group which may have a substituent; L represents a single bond, —CH ２ -, -CH ２ CO-, -CH ２ CONH-, -CH ２ CON (CH ３ ) -, -N(CH ３ ) -, -CO-, or -CON(CH ３ )-, R is an alkyl having 1 to 8 carbon atoms which may have a substituent, an alkenyl having 2 to 9 carbon atoms which may have a substituent, an alkoxy having 1 to 8 carbon atoms which may have a substituent, an alkenyloxy having 2 to 9 carbon atoms which may have a substituent, -NHW １ Or -N.W. ２ W ３ (W １ , W ２ and W ３ are the same or different and represent an optionally substituted alkyl having 1 to 8 carbon atoms, an optionally substituted alkenyl having 2 to 9 carbon atoms, or an optionally substituted 3- to 10-membered cycloalkyl), an optionally substituted 3- to 10-membered cycloalkyl, or an optionally substituted 3- to 10-membered cycloalkoxy, and Y represents O or S.

[0050] In formula (I), Ar １ represents an optionally substituted pyrazole ring or an optionally substituted imidazole ring.

[0051] Ar １Examples of the substituent in the "pyrazole ring which may have a substituent" or "imidazole ring which may have a substituent" include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkyl having 1 to 8 carbon atoms which may have a substituent, alkenyl having 2 to 9 carbon atoms, alkynyl having 2 to 9 carbon atoms, alkoxy having 1 to 8 carbon atoms, alkylcarbonyl having 2 to 9 carbon atoms, alkylcarbonyloxy having 2 to 9 carbon atoms, alkoxycarbonyl having 2 to 9 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulfonyl having 1 to 8 carbon atoms, alkylamino having 1 to 8 carbon atoms, dialkylamino having 2 to 10 carbon atoms, cycloalkyl having 3 to 10 members which may have a substituent, cycloalkoxy having 3 to 10 members, aryl having 6 to 10 members which may have a substituent, aliphatic heterocyclic groups, aromatic heterocyclic groups, etc. When such substituents are present, it is preferable that they are the same or different and are 1 to 2 substituents independently selected from the above-mentioned examples of the substituent. More preferably, the substituent is one substituent independently selected from the group consisting of halogen, optionally substituted alkyl having 1 to 8 carbon atoms, and optionally substituted 3- to 10-membered cycloalkyl.

[0052] Here, Ar １ is a pyrazole ring or imidazole ring optionally substituted with "an optionally substituted alkyl having 1 to 8 carbon atoms", examples of the substituent in the "an optionally substituted alkyl having 1 to 8 carbon atoms" include oxo, imino, halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, amino, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic group, aromatic heterocyclic group, etc. When such a substituent is present, for example, hydroxy and alkoxy having 1 to 5 carbon atoms are preferable.

[0053] Ar１ is a pyrazole ring or imidazole ring optionally substituted with "an optionally substituted 3- to 10-membered cycloalkyl", examples of the substituent in the "an optionally substituted 3- to 10-membered cycloalkyl" include oxo, imino, halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, amino, carbamoyl, alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic group, aromatic heterocycle, and the like.

[0054] Ar １ The following formula (Ar １ −1), (Ar １ -2), (Ar １ -3) or (Ar １ The structure represented by formula (4) is preferred.

[0055]

[0056] Rx represents a hydrogen atom, halogen, alkyl having 1 to 8 carbon atoms which may have a substituent, or 3 to 10-membered cycloalkyl which may have a substituent. Ry represents a hydrogen atom, alkyl having 1 to 8 carbon atoms which may have a substituent, or 3 to 10-membered cycloalkyl which may have a substituent. * represents the point of attachment to L.

[0057] The alkyl having 1 to 8 carbon atoms in Rx and Ry is preferably an alkyl having 1 to 5 carbon atoms, more preferably an alkyl having 1 to 3 carbon atoms, and further preferably methyl or ethyl.

[0058] The 3- to 10-membered cycloalkyl for Rx and Ry is preferably a 3- to 6-membered cycloalkyl, more preferably cyclopropyl.

[0059] Examples of the substituent in the "optionally substituted alkyl having 1 to 8 carbon atoms" of Rx and Ry include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, and aromatic heterocyclic groups. When such substituents are present, they are preferably the same or different and are 1 to 5 substituents independently selected from the above-mentioned exemplary substituents. A more preferred substituent is one hydroxyl.

[0060] Examples of the substituent in the "optionally substituted 3- to 10-membered cycloalkyl" of Rx and Ry include oxo, imino, halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic group, aromatic heterocyclic group, etc. When such substituents are present, it is preferable that they are the same or different and are 1 to 2 substituents independently selected from the above-mentioned exemplary substituents.

[0061] In formula (I), Ar ２ represents an optionally substituted benzene ring or an optionally substituted pyridine ring.

[0062] Ar ２Examples of the substituent in the "optionally substituted benzene ring" or "optionally substituted pyridine ring" include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, optionally substituted alkyl of 1 to 5 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, optionally substituted alkoxy of 1 to 5 carbon atoms, alkylcarbonyl of 2 to 6 carbon atoms, alkylcarbonyloxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms, alkylthio of 1 to 5 carbon atoms, alkylsulfonyl of 1 to 5 carbon atoms, alkylamino of 1 to 5 carbon atoms, dialkylamino of 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, aromatic heterocyclic groups, etc. When such substituents are present, it is preferable that they are the same or different and are 1 to 4 substituents selected from the above-mentioned exemplary substituents. More preferably, the substituents are 1 to 2 groups independently selected from the group consisting of halogen, alkyl having 1 to 5 carbon atoms which may have a substituent, and alkoxy having 1 to 5 carbon atoms which may have a substituent.

[0063] Here, Ar ２ is a benzene ring or pyridine ring optionally substituted with "an optionally substituted alkyl having 1 to 5 carbon atoms" or "an optionally substituted alkoxy having 1 to 5 carbon atoms", examples of the substituent in the "an optionally substituted alkyl having 1 to 5 carbon atoms" or "an optionally substituted alkoxy having 1 to 5 carbon atoms" include oxo, imino, halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, amino, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic group, aromatic heterocycle, and the like.

[0064] Ar２ The following formula (Ar ２ −1), (Ar ２ -2), (Ar ２ -3) or (Ar ２ The structure represented by formula (4) is preferred.

[0065]

[0066] Re represents halogen, alkyl having 1 to 5 carbon atoms which may have a substituent, or alkoxy having 1 to 5 carbon atoms which may have a substituent. When two or more Re are present, the structures of the individual Re may be the same or different.

[0067] The alkyl having 1 to 5 carbon atoms in Re is preferably alkyl having 1 to 3 carbon atoms, more preferably methyl. The alkoxy having 1 to 5 carbon atoms in Re is preferably alkoxy having 1 to 3 carbon atoms, more preferably methoxy.

[0068] Examples of the substituent in the "alkyl having 1 to 5 carbon atoms which may have a substituent" or "alkoxy having 1 to 5 carbon atoms which may have a substituent" of Re include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, aromatic heterocyclic groups, etc. When such substituents are present, it is preferable that they are the same or different and are 1 to 2 substituents independently selected from the above-mentioned exemplary substituents.

[0069] In formula (I), Cy １ represents an optionally substituted piperidine ring or an optionally substituted azetidine ring.

[0070] Cy １Examples of the substituent in the "optionally substituted piperidine ring" or "optionally substituted azetidine ring" include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, optionally substituted alkyl having 1 to 8 carbon atoms, alkenyl having 2 to 9 carbon atoms, alkynyl having 2 to 9 carbon atoms, alkoxy having 1 to 8 carbon atoms, alkylcarbonyl having 2 to 9 carbon atoms, alkylcarbonyloxy having 2 to 9 carbon atoms, alkoxycarbonyl having 2 to 9 carbon atoms, alkylthio having 1 to 8 carbon atoms, alkylsulfonyl having 1 to 8 carbon atoms, alkylamino having 1 to 8 carbon atoms, dialkylamino having 2 to 10 carbon atoms, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, aromatic heterocyclic groups, etc. When such substituents are present, they are preferably the same or different and are 1 to 4 substituents independently selected from the above-mentioned exemplary substituents. More preferably, the substituents are 1 to 4 groups independently selected from halogen or alkyl having 1 to 8 carbon atoms which may have a substituent.

[0071] Here, Cy １ is a piperidine ring or azetidine ring optionally substituted with "an alkyl having 1 to 8 carbon atoms which may have a substituent", examples of the substituent in the "an alkyl having 1 to 8 carbon atoms which may have a substituent" include oxo, imino, halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, amino, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic group, aromatic heterocycle, and the like.

[0072] Cy １ The following formula (Cy １ -1) or (Cy １ The structure represented by formula (2) is preferred.

[0073]

[0074] In the formula, Rd represents halogen or alkyl having 1 to 8 carbon atoms which may have a substituent. When there are two or more Rd's, the structures of the Rd's may be the same or different.

[0075] As the alkyl having 1 to 8 carbon atoms for Rd, alkyl having 1 to 3 carbon atoms is preferred, and methyl is more preferred.

[0076] Examples of the substituent in the "alkyl having 1 to 8 carbon atoms which may have a substituent" for Rd include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, aromatic heterocyclic groups, etc. When such substituents are present, it is preferable that they are the same or different and are 1 to 2 groups independently selected from the above-mentioned exemplary substituents.

[0077] In formula (I), Cy ２ represents an aliphatic heterocyclic group which may have a substituent.

[0078] Cy ２ When Cy is an aliphatic heterocyclic group which may have a substituent, examples of the heteroatom in the aliphatic heterocyclic group include N (nitrogen atom), O (oxygen atom), and S (sulfur atom). ２ When is an aliphatic heterocyclic group which may have a substituent, the aliphatic heterocyclic group has at least one heteroatom, and when it has two or more heteroatoms, they may be the same or different.

[0079] Cy ２The following structures are preferred as the heterocyclic ring: an optionally substituted 4- to 8-membered monocyclic aliphatic heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S; an optionally substituted 5- to 15-membered fused aliphatic heterocyclic group having 1 to 4 heteroatoms selected from N, O, and S; an optionally substituted 7- to 9-membered bridged cyclic aliphatic heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S; or an optionally substituted 5- to 12-membered spirocyclic aliphatic heterocyclic group having 1 to 4 heteroatoms selected from N, O, and S. The number of members in a fused aliphatic heterocycle, a bridged cyclic aliphatic heterocycle, and a spirocyclic aliphatic heterocycle refers to the total number of members in the respective rings.

[0080] Cy ２Examples of the substituents in the "optionally substituted aliphatic heterocyclic group", "optionally substituted 4- to 8-membered monocyclic aliphatic heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S", "optionally substituted 5- to 15-membered fused aliphatic heterocyclic group having 1 to 4 heteroatoms selected from N, O, and S", "optionally substituted 7- to 9-membered bridged cyclic aliphatic heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S", or "optionally substituted 5- to 12-membered spirocyclic aliphatic heterocyclic group having 1 to 4 heteroatoms selected from N, O, and S" include oxo, imino, halogen, and the like. , hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkyl having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms substituted with hydroxy, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, aromatic heterocyclic groups, etc. When such substituents are present, it is preferable that they are the same or different and are 1 to 6 substituents independently selected from the above-mentioned exemplary substituents. More preferably, the substituents are 1 to 4 groups independently selected from the group consisting of oxo, imino, halogen, hydroxy, formyl, alkyl having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, and alkylsulfonyl having 1 to 5 carbon atoms, and more preferably 1 to 4 groups independently selected from the group consisting of oxo, imino, a fluorine atom, hydroxy, formyl, methyl, ethyl, isopropyl, tert-butyl, acetyl, methoxycarbonyl, and methylsulfonyl.

[0081] In one embodiment, Cy ２is a monocyclic aliphatic heterocyclic group having one or more S, a fused aliphatic heterocyclic group having one or more S, a bridged cyclic aliphatic heterocyclic group having one or more S, or a spirocyclic aliphatic heterocyclic group having one or more S, the S atom on the ring may be substituted with 1 to 2 groups independently selected from oxo or imino. In this case, the carbon atom on the ring may be substituted with 1 to 2 groups independently selected from the group consisting of alkyl having 1 to 5 carbon atoms, hydroxy, and halogen.

[0082] In certain embodiments, the S atom may be substituted with two oxo groups to form a sulfonyl group. In certain embodiments, the S atom may be substituted with one oxo group to form a sulfinyl group. In this specification, a sulfinyl group may be represented as -S(+)-O(-). In certain embodiments, the S atom may be substituted with one oxo group and one imino group.

[0083] In one embodiment, Cy ２ is a monocyclic aliphatic heterocyclic group having one or more N atoms, a fused aliphatic heterocyclic group having one or more N atoms, a bridged cyclic aliphatic heterocyclic group having one or more N atoms, or a spirocyclic aliphatic heterocyclic group having one or more N atoms, the N atom on the ring may be substituted with one group selected from the group consisting of alkyl having 1 to 5 carbon atoms, hydroxy, formyl, alkoxycarbonyl having 2 to 6 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, and alkylsulfonyl having 1 to 5 carbon atoms. In this case, the carbon atoms on the ring may be substituted with 1 to 3 groups independently selected from the group consisting of alkyl having 1 to 5 carbon atoms, hydroxy, and halogen.

[0084] Cy ２Examples of the aryl group include piperidino, piperidinyl, 8-azabicyclo[3.2.1]octanyl, 4-azaspiro[2.5]octanyl, 5-azaspiro[3.5]nonanyl, tetrahydro-2H-thiopyranyl, 8-thiabicyclo[3.2.1]octanyl, azepanyl, pyrrolidinyl, 2,8-diazaspiro[4.5]decanyl, 2,7-diazaspiro[4.4]nonanyl, hexahydrothiopyranyl, 1,7-diazaspiro[4.4]nonanyl, 2,6 -diazaspiro[3.4]octanyl, 1,7-diazaspiro[4.5]decanyl, 6-oxa-2,9-diazaspiro[4.5]decanyl, 1,2,3,6-tetrahydropyridyl, 2,6-diazaspiro[3.3]heptanyl, 7-azaspiro[3.5]nonanyl, morpholino, morpholinyl, piperazinyl, 1,4-diazepanyl, hexahydropyrrolo[3,4-b]pyrrolyl, azetidinyl, quinuclidinyl, 4,7-diazaspiro[2.5]octanyl, or thiomorpholinyl is preferred.

[0085] In formula (I), L is a single bond, —CH ２ -, -CH ２ CO-, -CH ２ CONH-, -CH ２ CON (CH ３ ) -, -N(CH ３ ) -, -CO-, or -CON(CH ３ ) represents -.

[0086] In an embodiment, R in formula (I) is alkyl having 1 to 8 carbon atoms which may have a substituent, alkenyl having 2 to 9 carbon atoms which may have a substituent, alkoxy having 1 to 8 carbon atoms which may have a substituent, alkenyloxy having 2 to 9 carbon atoms which may have a substituent, -NHW １ Or -N.W. ２ W ３ (W １ , W ２ and W ３are the same or different and represent an alkyl having 1 to 8 carbon atoms which may have a substituent, an alkenyl having 2 to 9 carbon atoms which may have a substituent, or a 3- to 10-membered cycloalkyl which may have a substituent), an optionally substituted 3- to 10-membered cycloalkyl, or an optionally substituted 3- to 10-membered cycloalkoxy.

[0087] In another embodiment, R in formula (I) is alkyl having 1 to 8 carbon atoms which may have a substituent, alkenyl having 2 to 9 carbon atoms which may have a substituent, alkoxy having 1 to 8 carbon atoms which may have a substituent, alkenyloxy having 2 to 9 carbon atoms which may have a substituent, -NHW １ Or -N.W. ２ W ３ (W １ , W ２ and W ３ may be the same or different and represent an alkyl having 1 to 8 carbon atoms which may have a substituent, an alkenyl having 2 to 9 carbon atoms which may have a substituent, or a 3- to 10-membered cycloalkyl which may have a substituent), or an optionally substituted 3- to 10-membered cycloalkyl.

[0088] R.W. １ , W ２ or W ３ As the "alkyl having 1 to 8 carbon atoms" in the "alkyl having 1 to 8 carbon atoms which may have a substituent", alkyl having 1 to 5 carbon atoms is preferable, and alkyl having 1 to 3 carbon atoms is more preferable.

[0089] When R is "an alkyl having 1 to 8 carbon atoms which may have a substituent," examples of the substituent in the alkyl having 1 to 8 carbon atoms include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, aromatic heterocyclic groups, etc. When such substituents are present, it is preferable that they are the same or different and are 1 to 3 substituents independently selected from the above-mentioned exemplary substituents. More preferably, the substituents are 1 to 3 groups selected from the group consisting of 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, and halogen, and more preferably 1 to 2 groups independently selected from cyclopropyl or cyclopropoxy.

[0090] R.W. １ , W ２ or W ３ In the "alkenyl having 2 to 9 carbon atoms which may be substituted", the alkenyl having 2 to 9 carbon atoms is preferably an alkenyl having 2 to 6 carbon atoms, more preferably an alkenyl having 2 to 4 carbon atoms.

[0091] When R is "an alkenyl having 2 to 9 carbon atoms which may have a substituent," examples of the substituent in the alkenyl having 2 to 9 carbon atoms include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, and aromatic heterocyclic groups. When such substituents are present, they are preferably 1 to 4 substituents which may be the same or different and are independently selected from the above-mentioned substituent options. More preferably, the substituent is 1 to 2 3- to 7-membered cycloalkyl, and even more preferably 1 cyclopropyl.

[0092] In the "alkoxy having 1 to 8 carbon atoms which may have a substituent" for R, the alkoxy having 1 to 8 carbon atoms is preferably an alkoxy having 1 to 5 carbon atoms, and more preferably an alkoxy having 1 to 3 carbon atoms. Examples of the substituent in the "alkoxy having 1 to 8 carbon atoms which may have a substituent" for R include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkyl substituted with halogen, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, and aromatic heterocyclic groups. When such substituents are present, they are preferably the same or different and are 1 to 4 groups independently selected from the above-mentioned exemplary substituents. The substituents are more preferably 1 to 4 groups independently selected from the group consisting of halogen, 3- to 7-membered cycloalkyl, and 3- to 7-membered cycloalkyl substituted with halogen, and more preferably 1 to 4 groups independently selected from the group consisting of fluorine atom, cyclopropyl, and cyclopropyl substituted with a fluorine atom.

[0093] In the "alkenyloxy having 2 to 9 carbon atoms which may have a substituent" of R, the alkenyloxy having 2 to 9 carbon atoms is preferably an alkenyloxy having 2 to 6 carbon atoms, and more preferably an alkenyloxy having 2 to 4 carbon atoms.

[0094] Examples of the substituent in the "alkenyloxy having 2 to 9 carbon atoms which may have a substituent" for R include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, aromatic heterocyclic groups, etc. When such substituents are present, they are preferably the same or different and are 1 to 4 groups independently selected from the above-mentioned exemplary substituents.

[0095] R.W. １ , W ２ or W ３As the 3- to 10-membered cycloalkyl in the "optionally substituted 3- to 10-membered cycloalkyl", 3- to 7-membered cycloalkyl is preferable, and 3- to 5-membered cycloalkyl is more preferable. When R is "an optionally substituted 3- to 10-membered cycloalkyl", examples of the substituent in the 3- to 10-membered cycloalkyl include oxo, imino, halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkyl of 1 to 5 carbon atoms, alkyl of 1 to 5 carbon atoms substituted with halogen, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, alkoxy of 1 to 5 carbon atoms, alkylcarbonyl of 2 to 6 carbon atoms, alkylcarbonyloxy of 2 to 6 carbon atoms, alkoxycarbonyl of 2 to 6 carbon atoms, alkylthio of 1 to 5 carbon atoms, alkylsulfonyl of 1 to 5 carbon atoms, alkylamino of 1 to 5 carbon atoms, dialkylamino of 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, and aromatic heterocyclic groups. When such substituents are present, they are preferably the same or different and are 1 to 4 groups independently selected from the above-mentioned exemplary substituents. The substituents are more preferably 1 to 4 groups independently selected from alkyl having 1 to 5 carbon atoms or alkyl having 1 to 5 carbon atoms substituted with halogen, and even more preferably 1 group independently selected from methyl or trifluoromethyl.

[0096] As the 3- to 10-membered cycloalkoxy in the "optionally substituted 3- to 10-membered cycloalkoxy" for R, 3- to 7-membered cycloalkoxy is preferred.

[0097] Examples of the substituent in the "optionally substituted 3- to 10-membered cycloalkoxy" for R include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, amino, carbamoyl, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, aromatic heterocyclic groups, and the like.

[0098] W １ , W ２ or W ３ Examples of the substituent in the "alkyl having 1 to 8 carbon atoms which may have a substituent" include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkyl substituted with halogen, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic group, aromatic heterocyclic group, etc. When such substituents are present, they are preferably the same or different and 1 to 4 groups independently selected from the above-mentioned examples of the substituent. More preferably, the substituents are 1 to 4 groups independently selected from the group consisting of halogen, 3- to 7-membered cycloalkyl, and 3- to 7-membered cycloalkyl substituted with halogen, and more preferably 1 to 2 groups independently selected from cyclopropyl, or cyclopropyl substituted with a fluorine atom.

[0099] W １ , W ２ or W ３Examples of the substituent in the "alkenyl having 2 to 9 carbon atoms which may have a substituent" include halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkyl substituted with halogen, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic group, aromatic heterocyclic group, etc. When such substituents are present, it is preferable that they are the same or different and are 1 to 4 substituents independently selected from the above-mentioned exemplary substituents. More preferably, the substituents are 1 to 4 groups independently selected from the group consisting of halogen, 3- to 7-membered cycloalkyl, and 3- to 7-membered cycloalkyl substituted with halogen, and more preferably 1 to 4 groups independently selected from a fluorine atom or cyclopropyl.

[0100] W １ , W ２ or W ３Examples of the substituent in the "optionally substituted 3- to 10-membered cycloalkyl" include oxo, imino, halogen, hydroxy, mercapto, nitro, cyano, formyl, carboxy, carbamoyl, alkyl having 1 to 5 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkylcarbonyl having 2 to 6 carbon atoms, alkylcarbonyloxy having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylthio having 1 to 5 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, alkylamino having 1 to 5 carbon atoms, dialkylamino having 2 to 8 carbon atoms, 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkoxy, 6- to 10-membered aryl, aliphatic heterocyclic groups, aromatic heterocyclic groups, etc. When such substituents are present, it is preferable that there are 1 to 4 groups independently selected from the above-mentioned exemplary substituents. More preferably, the substituents are 1 to 4 groups independently selected from halogen or alkyl having 1 to 5 carbon atoms, and more preferably one methyl.

[0101] In formula (I), Y represents O or S, with O being more preferred.

[0102] In formula (I), Ar １ is the formula (Ar １ -1), L is a single bond, —CH ２ -, -CH ２ CO-, -CH ２ CONH-, -CH ２ CON (CH ３ ) -, -CO-, or -CON(CH ３ )- is preferred, and a single bond is more preferred.

[0103] In formula (I), Ar １ is the formula (Ar １ -2), L is a single bond, -CH ２ -, -CO-, or -CON(CH ３ )- is preferred, and a single bond is more preferred.

[0104] In formula (I), Ar １ is the formula (Ar １ -3) or formula (Ar １-4), L is a single bond, —CH ２ -, -CH ２ CO-, -CH ２ CONH-, -CH ２ CON (CH ３ ) -, -N(CH ３ ) -, -CO-, or -CON(CH ３ In this case, preferably, L represents a single bond, —CH ２ -, -CO-, -CON(CH ３ ) - or -N(CH ３ )-, and a single bond is particularly preferred.

[0105] As the compound (I), a compound represented by the following formula (I-1) or (I-2) is particularly preferred.

[0106]

[0107] In the formula, Rx １ represents a hydrogen atom, an alkyl having 1 to 5 carbon atoms, an alkyl having 1 to 5 carbon atoms substituted with hydroxy, or a 3- to 7-membered cycloalkyl; １ is NRa １ , SO, SO ２ or SO(=NH), １ represents a hydrogen atom, hydroxy, formyl, alkylcarbonyl having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, or alkyl having 1 to 5 carbon atoms; Rb １ are the same or different and each represents halogen, alkyl having 1 to 5 carbon atoms or hydroxy; Rd １ are the same or different and each represents alkyl having 1 to 5 carbon atoms or halogen; １ are the same or different and each represents a halogen, an alkyl having 1 to 5 carbon atoms, or an alkoxy having 1 to 5 carbon atoms; R １(i) alkyl having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkoxy; (ii) alkenyl having 2 to 6 carbon atoms, or alkenyl having 2 to 6 carbon atoms substituted with a 3- to 7-membered cycloalkyl; (iii) alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms substituted with a halogen, alkoxy having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or alkoxy having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl; (iv) -NHW （１－１） or -N.W. （１－２） W （１－３） (Where, （１－１） , W （１－２） , W （１－３） are each the same or different and represent an optionally substituted alkyl of 1 to 5 carbon atoms, an optionally substituted alkenyl of 2 to 6 carbon atoms, or an optionally substituted 3- to 7-membered cycloalkyl, wherein the substituents on the optionally substituted alkyl of 1 to 5 carbon atoms and the optionally substituted alkenyl of 2 to 6 carbon atoms are each the same or different and selected from halogen, a 3- to 7-membered cycloalkyl, and a 3- to 7-membered cycloalkyl substituted with a halogen, and the substituent on the optionally substituted 3- to 7-membered cycloalkyl is selected from halogen or an alkyl of 1 to 5 carbon atoms; (v) a 3- to 7-membered cycloalkyl, a 3- to 7-membered cycloalkyl substituted with an alkyl of 1 to 5 carbon atoms, or a 3- to 7-membered cycloalkyl substituted with an alkyl of 1 to 5 carbon atoms substituted with a halogen; or (vi) a 3- to 7-membered cycloalkoxy, wherein Z is CH, CRe, １ Or represents N.

[0108]

[0109] wherein the bond with a dotted line represents a double or single bond; ２ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; ２ is NRa ２ , SO, SO ２, SO(=NH), or O; ２ represents a hydrogen atom, hydroxy, formyl, alkylcarbonyl having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, or alkyl having 1 to 5 carbon atoms; Rb ２ are the same or different and each represents alkyl having 1 to 5 carbon atoms; ２ are the same or different and each represents alkyl having 1 to 5 carbon atoms; ２ are the same or different and each represents a halogen or an alkyl having 1 to 5 carbon atoms; R ２ (i) alkyl having 1 to 5 carbon atoms, (ii) alkenyl having 2 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms substituted with 3- to 7-membered cycloalkyl, (iii) alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms substituted with 3- to 7-membered cycloalkyl, or alkoxy having 1 to 5 carbon atoms substituted with 3- to 7-membered cycloalkyl substituted with halogen, (iv) alkenyloxy having 2 to 6 carbon atoms, (v) -NHW （２－１） (W （２－１） represents an alkyl having 1 to 5 carbon atoms, an alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or an alkenyl having 2 to 6 carbon atoms; (vi) a 3- to 7-membered cycloalkyl, a 3- to 7-membered cycloalkyl substituted with an alkyl having 1 to 5 carbon atoms, or (vii) a 3- to 7-membered cycloalkoxy; Z is CH, CRe, ２ Or represents N.

[0110] In the compound represented by formula (I-1), R １(i) alkyl having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkoxy; (ii) alkenyl having 2 to 6 carbon atoms, or alkenyl having 2 to 6 carbon atoms substituted with a 3- to 7-membered cycloalkyl; (iii) alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms substituted with a halogen, alkoxy having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or alkoxy having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl; (iv) -NHW （１－１） or -N.W. （１－２） W （１－３） (Where, （１－１） , W （１－２） , W （１－３） may each be the same or different and represent an optionally substituted alkyl of 1 to 5 carbon atoms, an optionally substituted alkenyl of 2 to 6 carbon atoms, or an optionally substituted 3- to 7-membered cycloalkyl, wherein the substituents on the optionally substituted alkyl of 1 to 5 carbon atoms and the optionally substituted alkenyl of 2 to 6 carbon atoms are the same or different and are selected from halogen, 3- to 7-membered cycloalkyl, and 3-membered to 7-membered cycloalkyl substituted with halogen; and the substituent on the optionally substituted 3- to 7-membered cycloalkyl is selected from halogen or alkyl of 1 to 5 carbon atoms; or (v) a 3- to 7-membered cycloalkyl, a 3- to 7-membered cycloalkyl substituted with alkyl of 1 to 5 carbon atoms, or a 3- to 7-membered cycloalkyl substituted with alkyl of 1 to 5 carbon atoms substituted with halogen.

[0111] In the compound represented by formula (I-1), Z may represent C or N.

[0112] For the compound represented by formula (I-2), R ２(i) alkyl having 1 to 5 carbon atoms, (ii) alkenyl having 2 to 6 carbon atoms, (iii) alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms substituted with 3- to 7-membered cycloalkyl, or alkoxy having 1 to 5 carbon atoms substituted with 3- to 7-membered cycloalkyl substituted with halogen, (iv) alkenyloxy having 2 to 6 carbon atoms, (v) -NHW （２－１） (W （２－１） is alkyl of 1 to 5 carbon atoms, alkyl of 1 to 5 carbon atoms substituted with 3- to 7-membered cycloalkyl, or alkenyl of 2 to 6 carbon atoms), or (vi) 3- to 7-membered cycloalkyl, 3- to 7-membered cycloalkyl substituted with alkyl of 1 to 5 carbon atoms.

[0113] In addition, for the compound represented by formula (I-2), Z may represent C or N.

[0114] As the compound (I), preferably, any of the following compounds can be mentioned.

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130] <Method for Producing Compound (I)> Next, a method for producing compound (I) will be described. In the following production methods, if the defined groups change under the conditions of the production method or are inappropriate for carrying out the production method, the target compound can be produced by using a method for introducing and removing protecting groups commonly used in organic synthetic chemistry [for example, the method described in Protective Groups in Organic Synthesis, third edition, by T.W. Greene, John Wiley & Sons Inc. (1999)]. In addition, the order of reaction steps such as introducing substituents can be changed as necessary.

[0131] [Production Method 1] Ring Ar of Formula (I) １ is a pyrazole ring optionally having a substituent, １ is the formula (Ar １ Compound (a-9) in which L is Lx can be produced according to the following steps:

[0132]

[0133] (In the formula, Rx, Cy １ , Cy ２ , R, Y and Ar ２ is as defined above, and Lx is a single bond, —CH ２ -, -CO- or -CON(CH ３ )-, and Xa represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, p-toluenesulfonyloxy, etc.

[0134] (Step 1) Compound (a-2) can be produced by reacting compound (a-1) with 1 to 5 equivalents of an iodinating agent in a solvent at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0135] Examples of the iodinating agent include N-iodosuccinimide and iodine.

[0136] Examples of the solvent include dichloromethane and acetonitrile, which can be used alone or in combination.

[0137] Compound (a-1) can be obtained as a commercially available product or by a known method [for example, Experimental Chemistry Lectures, 5th Edition, Vol. 18, p. 327, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0138] (Step 2) Compound (a-4) can be produced by reacting compound (a-2) and compound (a-3) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0139] Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, diazabidichloundecene (DBU), triethylamine, N,N-diisopropylethylamine, and the like.

[0140] Examples of the solvent include dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 1,4-dioxane, acetonitrile, dichloromethane, and chloroform, and these can be used alone or in combination.

[0141] Compound (a-3) can be obtained as a commercially available product or by a known method [for example, Jikken Kagaku Koza, 5th Edition, Vol. 13, p. 341, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0142] (Step 3) Compound (a-6) can be produced by reacting compound (a-4) with 1 to 10 equivalents of an organometallic reagent in a solvent at a temperature between −78° C. and the boiling point of the solvent used for 5 minutes to 24 hours, and then adding 1 to 10 equivalents of compound (a-5) to the reaction mixture and reacting at a temperature between −78° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0143] Examples of the organometallic reagent include n-butyllithium, s-butyllithium, t-butyllithium, isopropylmagnesium chloride-lithium chloride, and the like.

[0144] Examples of the solvent include toluene, diethyl ether, THF, 1,2-dimethoxyethane (DME), 1,4-dioxane, and hexane, which can be used alone or in combination.

[0145] Compound (a-5) can be obtained as a commercially available product or by a known method [for example, Jikken Kagaku Koza, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0146] (Step 4) Compound (a-8) can be produced by reacting compound (a-6), 1 to 10 equivalents of compound (a-7), 0.001 to 3 equivalents of a palladium catalyst, 0.001 to 3 equivalents of a phosphorus ligand, and 1 equivalent to a large excess of a base in a solvent at a temperature between room temperature and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0147] Examples of the palladium catalyst include palladium acetate and tetrakis(triphenylphosphine)palladium (Pd(PPh ３ ) ４ ), bis(triphenylphosphine)palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl ２ ), tris(dibenzylideneacetone)dipalladium (Pd ２ (dba) ３), 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), and the like.

[0148] Examples of the phosphorus ligand include triphenylphosphine, tributylphosphine, bis(diphenylphosphino)propane, bis(diphenylphosphino)butane, bis(diphenylphosphino)ferrocene, and 2-dicyclohexylphosphino-2'-4',6'-triisopropylbiphenyl (Xphos).

[0149] Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, DBU, triethylamine, N,N-diisopropylethylamine, pyridine, and the like.

[0150] Examples of the solvent include DMF, DMA, NMP, DMSO, THF, acetonitrile, 1,4-dioxane, and water, which can be used alone or in combination.

[0151] Compound (a-7) can be obtained as a commercially available product or by a known method [for example, Jikken Kagaku Koza, 5th Edition, Vol. 18, p. 95, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0152] (Step 5) Compound (a-9) can be produced by reacting compound (a-8) with 1 equivalent to a large excess of a base in a solvent at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0153] Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, DBU, triethylamine, N,N-diisopropylethylamine, pyridine, and the like.

[0154] Examples of the solvent include DMF, DMA, NMP, DMSO, THF, acetonitrile, 1,4-dioxane, and water, which can be used alone or in combination.

[0155] [Production Method 2] Ring Ar of Formula (I) １ is a pyrazole ring optionally having a substituent, １ is the formula (Ar １ -1) wherein L is -CH ２ CONH- or -CH ２ CON (CH ３ The compound (a-17) in which the formula (a-17) is a methyl group can be prepared according to the following steps.

[0156]

[0157] (In the formula, Rx, Xa, Cy １ , Cy ２ , R, Y and Ar ２ is as defined above, and Rb is H or CH ３ and Px represents an ester protecting group such as methyl, ethyl, tert-butyl, allyl, benzyl, etc.

[0158] (Step 1) Compound (a-11) can be produced by reacting compound (a-2) and compound (a-10) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0159] Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, DBU, triethylamine, N,N-diisopropylethylamine, pyridine, and the like.

[0160] Examples of the solvent include DMF, DMA, NMP, DMSO, THF, 1,4-dioxane, acetonitrile, dichloromethane, and chloroform, which can be used alone or in combination.

[0161] Compound (a-10) is commercially available, or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Edition, Vol. 13, p. 341, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0162] (Step 2) Compound (a-12) can be produced by deprotecting Px, the ester protecting group in compound (a-11), using a general deprotection reaction. For example, when Px is ethyl, compound (a-12) can be produced by reacting compound (a-11) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0163] Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, and the like.

[0164] Examples of the solvent include methanol, ethanol, DMF, DMA, NMP, DMSO, THF, acetonitrile, and water, and these can be used alone or in combination.

[0165] (Step 3) Compound (a-14) can be produced by reacting compound (a-12) with 1 to 5 equivalents of compound (a-13) in the presence of 1 equivalent to a large excess of a condensing agent, and optionally in the presence of 1 equivalent to a large excess of an additive, in a solvent at a temperature between −20° C. and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0166] Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), and the like.

[0167] Examples of the additive include 1-hydroxybenzotriazole monohydrate (HOBt), triethylamine, and N,N-diisopropylethylamine.

[0168] Examples of the solvent include chloroform, dichloromethane, DMF, DMA, THF, acetonitrile, etc., which can be used alone or in combination.

[0169] Compound (a-13) is commercially available, or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0170] (Step 4) Compound (a-15) can be produced in the same manner as in Step 3 of Production Method 1, using compound (a-14) and 1 to 10 equivalents of compound (a-5).

[0171] (Step 5) Compound (a-16) can be produced in the same manner as in Step 4 of Production Method 1, using compound (a-15) and 1 to 10 equivalents of compound (a-7).

[0172] (Step 6) Compound (a-17) can be produced in the same manner as in step 5 of Production Method 1, using compound (a-16).

[0173] [Production Method 3] Ring Ar of Formula (I) １ is a pyrazole ring optionally having a substituent, １ is the formula (Ar １ -1) wherein L is -CH ２The compound (a-22) which is CO— can be produced according to the following steps.

[0174]

[0175] (In the formula, Rx, Cy １ , Cy ２ , R, Y and Ar ２ has the same meaning as above)

[0176] (Step 1) Compound (a-19) can be produced in the same manner as in step 3 of Production Method 2, using compound (a-12) and compound (a-18).

[0177] Compound (a-18) is commercially available, or can be obtained by a known method [for example, Jikken Kagaku Koza (Experimental Chemistry Lectures), 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0178] (Step 2) Compound (a-20) can be produced in the same manner as in Step 3 of Production Method 1, using compound (a-19) and 1 to 10 equivalents of compound (a-5).

[0179] (Step 3) Compound (a-21) can be produced in the same manner as in Step 4 of Production Method 1, using compound (a-20) and 1 to 10 equivalents of compound (a-7).

[0180] (Step 4) Compound (a-22) can be produced in the same manner as in step 5 of Production Method 1, using compound (a-21).

[0181] [Production Method 4] Ring Ar of Formula (I) １ is a pyrazole ring optionally having a substituent, １ is the formula (Ar １ Compound (a-28) in which L is Lx can be produced according to the following steps:

[0182]

[0183] (In the formula, Rx, Cy １ , Cy ２ ,R.Y.,Ar ２ , Lx and Xa are as defined above.

[0184] (Step 1) Compound (a-24) can be produced by reacting compound (a-23) with 1 equivalent to a large excess of a brominating agent in the presence of 1 equivalent to a large excess of a base, in a solvent, at a temperature between −20° C. and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0185] Examples of the brominating agent include bromine and N-bromosuccinimide.

[0186] Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, sodium acetate, potassium hydroxide, and the like.

[0187] Examples of the solvent include DMF, THF, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, methanol, ethanol, water, etc., which can be used alone or in combination.

[0188] Compound (a-23) is commercially available, or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Edition, Vol. 18, p. 95, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0189] (Step 2) Compound (a-25) can be produced by reacting compound (a-24), 1 to 10 equivalents of compound (a-7), and 0.001 to 3 equivalents of a copper catalyst in the presence of 1 equivalent to a large excess of a base, in an air atmosphere, in a solvent, at a temperature between room temperature and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0190] Examples of copper catalysts include copper(II) acetate, copper(II) chloride, copper(II) oxide, and copper(II) trifluoromethanesulfonate.

[0191] Examples of the base include pyridine, 4-dimethylaminopyridine, DBU, triethylamine, N,N-diisopropylethylamine, and the like.

[0192] Examples of the solvent include chloroform, dichloromethane, DMF, acetonitrile, and methanol, which can be used alone or in combination.

[0193] (Step 3) Compound (a-26) can be produced in the same manner as in step 3 of Production Method 1, using compound (a-25) and 1 to 10 equivalents of compound (a-5).

[0194] (Step 4) Compound (a-27) can be produced in the same manner as in step 5 of Production Method 1, using compound (a-26).

[0195] (Step 5) Compound (a-28) can be produced in the same manner as in Step 4 of Production Method 1, using compound (a-27) and 1 to 10 equivalents of compound (a-3).

[0196] [Production Method 5] Ring Ar of Formula (I) １ is an imidazole ring which may have a substituent, and Ar １ is the formula (Ar １ -3) or (Ar １ Among the compounds of formula (I), compound (b-6) in which L is Ly and Ry is H can be prepared according to the following steps. １ is an imidazole ring which may have a substituent, and Ar １ is the formula (Ar １ Among the compounds of formula (I), compound (b-8) in which L is Ly and Ry is Rz can be prepared by the following steps. １ is an imidazole ring which may have a substituent, and Ar １ is the formula (Ar １ Among the compounds of formula (b-4), compound (b-9) in which L is Ly and Ry is Rz can be produced according to the following steps.

[0197]

[0198] (In the formula, Cy １ , Cy ２ ,R.Y.,Ar ２ and Xa are as defined above, Ly is a single bond, —CH ２ -, -CO-, -CH ２ CO-, -CH ２ CONH-, -CH ２ CON (CH３ ) - or -CON(CH ３ )-, and Rz represents an alkyl having 1 to 8 carbon atoms which may have a substituent or a 3- to 10-membered cycloalkyl which may have a substituent.

[0199] (Step 1) Compound (b-3) can be produced by reacting compound (b-1) with 1 to 5 equivalents of compound (b-2) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 120 hours.

[0200] Examples of the base include pyrrolidine, piperidine, pyridine, triethylamine, N,N-diisopropylethylamine, imidazole, DBU, potassium carbonate, sodium carbonate, cesium carbonate, and the like.

[0201] Examples of the solvent include methanol, ethanol, THF, 1,4-dioxane, acetonitrile, acetone, toluene, and pyridine, which can be used alone or in combination.

[0202] Compound (b-1) can be obtained as a commercially available product or by a known method [for example, Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0203] Compound (b-2) can be obtained as a commercially available product or by a known method [for example, Jikken Kagaku Koza, 5th Edition, Vol. 15, p. 153, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0204] (Step 2) Compound (b-4) can be produced by reacting compound (b-3) with 1 to 5 equivalents of isopentyl nitrate in the presence of 1 equivalent to a large excess of an acid in a solvent at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0205] The acid includes, for example, hydrochloric acid, sulfuric acid, and the like.

[0206] Examples of the solvent include methanol and ethanol, which can be used alone or in combination.

[0207] (Step 3) Compound (b-6) can be produced by reacting compound (b-4), compound (b-5), and 1 to 5 equivalents of an ammonia source in a solvent at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 120 hours.

[0208] Examples of the ammonia source include ammonia gas, aqueous ammonia, ammonium acetate, ammonium carbonate, ammonium hydrogen carbonate, and ammonium chloride.

[0209] Examples of the solvent include methanol, ethanol, water, and acetic acid, which can be used alone or in combination.

[0210] Compound (b-5) can be obtained as a commercially available product or by a known method [for example, Jikken Kagaku Koza, 5th Edition, Vol. 15, p. 1, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0211] (Step 4) Compound (b-8) and compound (b-9) can be produced by reacting compound (b-6) and compound (b-7) in the presence of 1 equivalent to a large excess of a base in a solvent at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0212] Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, and the like.

[0213] Examples of the solvent include DMF, THF, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, methanol, ethanol, water, etc., which can be used alone or in combination.

[0214] Compound (b-7) can be obtained as a commercially available product or by a known method [for example, Jikken Kagaku Koza, 5th Edition, Vol. 13, p. 341, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0215] [Production Method 6] Ring Ar of Formula (I) １ is an imidazole ring which may have a substituent, and Ar １ is the formula (Ar １ -3) or (Ar １ -4), among the compounds in which L is -N(CH ３ Compound (b-19) in which Ry is H can be prepared according to the following steps: １ is an imidazole ring which may have a substituent, and Ar １ is the formula (Ar １ -3), among the compounds in which L is -N(CH ３ Compound (b-15) in which Ry is Rz can be prepared according to the following steps. １ is an imidazole ring which may have a substituent, and Ar １ is the formula (Ar １ -4), among the compounds in which L is -N(CH ３ )- and Ry is Rz, the compound (b-14) can be produced according to the following steps.

[0216]

[0217] (In the formula, Rz, Cy １ , Cy ２ ,R.Y.,Ar ２ and Xa is as defined above, and Py represents an amine-protecting group such as benzyl or p-methoxybenzyl (PMB).

[0218] (Step 1) Compound (b-10) can be produced in the same manner as in step 3 of Production Method 5, using compound (b-4) and formic acid.

[0219] (Step 2) Compound (b-11) and compound (b-12) can be produced in the same manner as in step 4 of production method 5, using compound (b-10) and compound (b-7).

[0220] (Step 3) Compound (b-14) can be produced by reacting compound (b-11), 1 to 10 equivalents of compound (b-13), and 0.01 to 3 equivalents of a copper catalyst in the presence of 1 equivalent to a large excess of a base, in a solvent, at a temperature between room temperature and the boiling point of the solvent used, for 5 minutes to 120 hours.

[0221] Examples of the copper catalyst include copper(II) acetate and copper(II) chloride.

[0222] Examples of the base include 2,2,6,6-tetramethylpiperidinyl zinc chloride-lithium chloride complex, 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex, and the like.

[0223] Examples of the solvent include THF and 1,4-dioxane, which can be used alone or in combination.

[0224] Compound (b-13) can be obtained as a commercially available product or by a known method [for example, Experimental Chemistry Lectures, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0225] (Step 4) Compound (b-15) can be produced in the same manner as in Step 3 using compound (b-12) and compound (b-13).

[0226] (Step 5) Compound (b-17) can be produced in the same manner as in step 4 of Production Method 5, using compound (b-10) and compound (b-16).

[0227] Compound (b-16) is commercially available, or can be obtained by a known method [for example, Experimental Chemistry Lectures, 5th Edition, Vol. 13, p. 341, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0228] (Step 6) Compound (b-18) can be produced in the same manner as in Step 3 using compound (b-17) and compound (b-13).

[0229] (Step 7) Compound (b-19) can be produced by deprotecting Py, the amine-protecting group in compound (b-18), using a general deprotection reaction. For example, when Py is benzyl, compound (b-19) can be produced by reacting compound (b-18) in the presence of 0.001 to 0.5 equivalents of a palladium catalyst under a hydrogen atmosphere in a solvent at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 120 hours.

[0230] Examples of the palladium catalyst include palladium on carbon and palladium hydroxide.

[0231] Examples of the solvent include methanol, ethanol, ethyl acetate, THF, 1,4-dioxane, etc., which can be used alone or in combination.

[0232] [Production Method 7] Ring Ar of Formula (I) １ is an imidazole ring which may have a substituent, and Ar １ is the formula (Ar １ -3) or formula (Ar １ -4), wherein L is a single bond, Ry is H, and the ring Cy ２ Compound (b-24) in which the attachment point is an N atom can be prepared according to the following steps: １ is an imidazole ring which may have a substituent, and Ar １ is the formula (Ar １ -3), wherein L is a bond, Ry is Rz, and the ring Cy ２ Compound (b-22) in which the attachment point is an N atom can be prepared according to the following steps. １ is an imidazole ring which may have a substituent, and Ar １ is the formula (Ar １ -4), wherein L is a bond, Ry is Rz, and the ring Cy ２ Compound (b-21) in which the point of attachment is a N atom can be produced according to the following steps.

[0233]

[0234] (In the formula, Cy １ , Cy ２ , R, Y, Rz, Py and Ar ２ has the same meaning as above)

[0235] (Step 1) Compound (b-21) can be produced in the same manner as in step 3 of Production Method 6, using compound (b-11) and compound (b-20).

[0236] Compound (b-20) can be obtained as a commercially available product or by a known method [for example, Jikken Kagaku Koza, 5th Edition, Vol. 14, p. 351, Maruzen Co., Ltd. (2004)] or a method similar thereto.

[0237] (Step 2) Compound (b-22) can be produced in the same manner as in step 3 of Production Method 6, using compound (b-12) and compound (b-20).

[0238] (Step 3) Compound (b-23) can be produced in the same manner as in step 3 of Production Method 6, using compound (b-17) and compound (b-20).

[0239] (Step 4) Compound (b-24) can be produced in the same manner as in step 7 of Production Method 6, using compound (b-23).

[0240] The intermediates and target compounds in each of the above production methods can be isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, etc. Alternatively, the intermediates can be subjected to the next reaction without any particular purification.

[0241] Compound (I) may exist as stereoisomers such as geometric isomers and optical isomers, tautomers, etc., and compound (I) of the present embodiment encompasses all possible isomers, including these, and mixtures thereof.

[0242] Compounds in which some or all of the atoms in compound (I) are replaced with corresponding isotope atoms can be produced by the same methods as the above-mentioned methods using commercially available building blocks. Also, compounds in which some or all of the hydrogen atoms in compound (I) are replaced with deuterium atoms can be produced by, for example, 1) a method of deuterizing carboxylic acids and the like under basic conditions using deuterium peroxide (see U.S. Pat. No. 3,849,458), 2) a method of deuterizing alcohols, carboxylic acids and the like 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)], 3) a method of deuterizing fatty acids using palladium carbon as a catalyst and only deuterium gas as a deuterium source [see Lipids, Vol. 9, No. 11, 913 (1974)], 4) a method of deuterizing acrylic acid, methyl acrylate, methacrylic acid, methyl methacrylate, or the like using a metal such as platinum, palladium, rhodium, ruthenium, iridium, or the like as a catalyst and heavy water or heavy water and deuterium gas as a heavy hydrogen source (see JP-B-5-19536, JP-A-61-277648, and JP-A-61-275241), 5) a method of deuterizing acrylic acid, methyl methacrylate, or the like using a catalyst such as palladium, nickel, copper, or copper chromite, and heavy water as a heavy hydrogen source (see JP-A-63-198638), or the like.

[0243] When a salt of compound (I) is to be obtained, if compound (I) is obtained in the form of a salt, it may be purified as it is. Alternatively, if compound (I) is obtained in the free form, compound (I) may be dissolved or suspended in an appropriate solvent, and an acid or a base may be added to form a salt, which may then be isolated and purified.

[0244] In addition, compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also encompassed in compound (I) and a pharmaceutically acceptable salt thereof according to this embodiment.

[0245] Pharmaceutically 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. Pharmaceutically acceptable acid addition salts of Compound (I) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc., and organic acid salts such as acetate, oxalate, maleate, fumarate, citrate, benzoate, methanesulfonate, toluenesulfonate, etc. Pharmaceutically acceptable metal salts include, for example, alkali metal salts such as sodium salt, potassium salt, etc., alkaline earth metal salts such as magnesium salt, calcium salt, aluminum salt, zinc salt, etc. Pharmaceutically acceptable ammonium salts include, for example, ammonium, tetramethylammonium, etc. Pharmaceutically acceptable organic amine addition salts include, for example, addition salts of morpholine, piperidine, etc. Pharmaceutically acceptable amino acid addition salts include, for example, addition salts of lysine, glycine, phenylalanine, aspartic acid, glutamic acid, etc.

[0246] As the pharmaceutically acceptable salt of Compound (I), for example, hydrochloride or toluenesulfonate is preferred.

[0247] Although Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone, it is usually desirable to provide it as various pharmaceutical preparations, which are intended for use in animals or humans, preferably humans.

[0248] The pharmaceutical formulations according to this embodiment may contain Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient, either alone or in combination with any other active therapeutic ingredient. These pharmaceutical formulations are prepared by mixing the active ingredient with one or more pharmaceutically acceptable carriers (e.g., diluents, solvents, excipients, etc.) and by any method well known in the art of pharmaceutical preparations.

[0249] The route of administration is preferably the most effective route for the treatment, and may be oral or parenteral, for example, intravenous.

[0250] Examples of dosage forms include tablets and injections.

[0251] Tablets suitable for oral administration can be prepared using excipients such as lactose, disintegrating agents such as starch, lubricants such as magnesium stearate, binders such as hydroxypropyl cellulose, and the like.

[0252] Suitable preparations for parenteral administration, such as injections, can be prepared using diluents or solvents such as saline solution, glucose solution, or a mixture of saline and glucose solution.

[0253] The dosage and frequency of administration of Compound (I) or a pharmaceutically acceptable salt thereof will vary depending on factors such as the dosage form, the patient's age and body weight, and the nature and severity of the condition being treated. Oral administration typically involves administering 0.01 to 1000 mg, preferably 0.05 to 100 mg, per adult, once or several times per day. Parenteral administration, such as intravenous administration, typically involves administering 0.001 to 1000 mg, preferably 0.01 to 100 mg, per adult, once or several times per day. However, these dosages and frequency of administration will vary depending on the various conditions described above.

[0254] According to another aspect of this embodiment, there is provided a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of this embodiment is used with the same administration route, dosage form, etc. as the pharmaceutical formulation described above. The pharmaceutical composition of this embodiment 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., similar to the pharmaceutical formulation described above. Furthermore, the pharmaceutical composition described above can be used as an SLC15A4 inhibitor.

[0255] Compound (I) according to this embodiment or a pharmaceutically acceptable salt thereof can be used to treat diseases associated with SLC15A4 inhibition.

[0256] Therefore, the pharmaceutical composition of this embodiment is used for treating diseases associated with SLC15A4 inhibition. That is, this embodiment provides a composition for treating diseases associated with SLC15A4 inhibition.

[0257] According to another aspect of this embodiment, there is provided a therapeutic method comprising administering compound (I) or a pharmaceutically acceptable salt thereof to a subject (preferably a subject in need thereof). The subject includes animals other than humans, but is preferably a human. The same applies to the following subjects. The therapeutic method of this embodiment is preferably used for treating a disease associated with SLC15A4 inhibition.

[0258] According to another aspect of the present embodiment, there is provided Compound (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0259] According to another aspect of the present embodiment, there is provided compound (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease associated with SLC15A4 inhibition.

[0260] According to another aspect of this embodiment, there is provided a use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with SLC15A4 inhibition.

[0261] According to another aspect of this embodiment, there is provided use of compound (I) or a pharmaceutically acceptable salt thereof for the treatment of a disease associated with SLC15A4 inhibition.

[0262] According to another aspect of this embodiment, there is provided a pharmaceutical comprising compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0263] According to another aspect of this embodiment, there is provided a therapeutic agent for a disease associated with SLC15A4 inhibition, which comprises compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0264] As used herein, diseases associated with SLC15A4 inhibition include autoimmune diseases. In particular, autoimmune diseases that can be treated by inhibiting type I IFN production from pDCs through SLC15A4 inhibition include systemic lupus erythematosus, cutaneous lupus, lupus nephritis, Sjögren's syndrome, systemic sclerosis, dermatomyositis, IgG4-related disease, and myasthenia gravis. Preferred diseases associated with SLC15A4 inhibition that can be treated with compound (I) according to this embodiment or a pharmaceutically acceptable salt thereof include systemic lupus erythematosus or cutaneous lupus. Preferred diseases associated with SLC15A4 inhibition that can be treated with compound (I) according to this embodiment or a pharmaceutically acceptable salt thereof include systemic lupus erythematosus, lupus nephritis, cutaneous lupus, and Sjögren's syndrome. Cutaneous lupus includes acute cutaneous lupus, subacute cutaneous lupus, and chronic cutaneous lupus. As the cutaneous lupus, acute cutaneous lupus and subacute cutaneous lupus are particularly preferred.

[0265] The present invention will be described in more detail below using examples, but the present invention is not limited to these. 1 H NMR was measured at 300 MHz or 400 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. Signal multiplicity is indicated by the usual notation, with br indicating an apparently broad signal. ChemDraw Professional version 20.1.1 was used to name each synthesized compound, as necessary.

[0266] Example 1: Ethyl (R)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (Compound 1)

[0267] (Step 1) Benzyl 4-oxopiperidine-1-carboxylate (343 g, 1.47 mol), 1-(2-hydroxyphenyl)ethan-1-one (200 g, 1.47 mol), and pyrrolidine (104 g, 1.47 mol) were dissolved in methanol (2.00 L) and stirred at 80°C overnight. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the resulting residue, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was slurried with ethyl acetate to give benzyl 4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (420 g, 81%). ESI-MS m / z: 352 (M + H) +

[0268] (Step 2) Benzyl 4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (220 g, 626 mmol) obtained in Step 1 was dissolved in THF (3.00 L) and cooled to -78°C. Lithium diisopropylamide (2.0 mol / L THF solution, 470 mL, 940 mmol) was added dropwise and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Acetaldehyde (41.4 g, 939 mmol) was added dropwise to the reaction mixture at -78°C and the mixture was stirred for an additional 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture at -78°C, 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 evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give benzyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (135 g, 55%). ESI-MS m / z: 396 (M + H). +

[0269] (Step 3) Benzyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (135 g, 341 mmol) obtained in Step 2 and Dess-Martin periodinane (434 g, 1.02 mol) were dissolved in dichloromethane (2.00 L) and stirred overnight at room temperature. Water was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-2 / 1) to give benzyl (Z)-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (100 g, 75%). ESI-MS m / z: 394 (M + H). +

[0270] (Step 4) Benzyl (Z)-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (100 g, 254 mmol) obtained in Step 3 and hydrazine monohydrate (25.5 g, 508 mmol) were dissolved in acetic acid (1.00 L) and stirred overnight at room temperature. 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 evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to give benzyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (50.0 g, 51%). ESI-MS m / z: 390 (M + H) +

[0271] (Step 5) tert-Butyl 4-hydroxy-2,2-dimethylpiperidine-1-carboxylate (22.0 g, 95.9 mmol) and triethylamine (29.0 g, 288 mmol) were dissolved in dichloromethane (200 mL). Methanesulfonyl chloride (22.0 g, 192 mmol) was added under ice cooling, and the mixture was stirred at 0°C for 2 hours. Water was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-4 / 1) to give tert-butyl 2,2-dimethyl-4((methylsulfonyl)oxy)piperidine-1-carboxylate (22.0 g, 75%). ESI-MS m / z: 308 (M + H). + 1 H NMR (CDCl3, δ): 4.95-4.85 (m, 1H), 3.75-3.65 (m, 1H), 3.35-3.20 (m, 1H), 3.21 (s, 3H), 2.25-2.10 (m, 1H), 2.00-1.90 (m, 1H), 1.85-1.60 (m, 2H), 1.46 (s, 3H), 1.40 (s, 9H), 1.31 (s, 3H).

[0272] (Step 6) Benzyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (50.0 g, 128 mmol) obtained in Step 4, tert-butyl 2,2-dimethyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (39.5 g, 128 mmol) obtained in Step 5, and cesium carbonate (125 g, 385 mmol) were dissolved in DMF (1.00 L) and stirred overnight at 100°C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give benzyl 2-(1-tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (17.0 g, 22%). ESI-MS m / z: 601 (M + H). +

[0273] (Step 7) Benzyl 2-(1-tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (400 mg, 0.67 mmol) obtained in Step 6 and 10% palladium on carbon (100 mg) were suspended in methanol (10 mL) and stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, washed with methanol, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10 / 1) to give tert-butyl 2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (290 mg, 93%). ESI-MS m / z: 467 (M + H) +

[0274] (Step 8) tert-Butyl 2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (290 mg, 0.620 mmol) obtained in Step 7 and triethylamine (189 mg, 1.86 mmol) were dissolved in dichloromethane (10.0 mL), and ethyl chloroformate (101 mg, 0.930 mmol) was added dropwise under ice cooling. The mixture was warmed to room temperature and stirred for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to give ethyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (150 mg, 45%). ESI-MS m / z: 539 (M + H). +

[0275] (Step 9) Ethyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (150 mg, 0.280 mmol) obtained in Step 8 was dissolved in dichloromethane (6.0 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give a crude product of ethyl 2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate trifluoroacetate (130 mg), which was used in the next step without further purification. ESI-MS m / z: 439 (M + H). +

[0276] (Step 10) The crude product (70 mg) of ethyl 2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate trifluoroacetate obtained in Step 9 was purified by chiral supercritical fluid chromatography (SFC) (Lux® Cellulose-2 (30×150 mm, 5 μm), CO₂ / 0.1% ammonia methanol solution=40 / 60, flow rate 100 mL / min, RT1: 9.2 min, RT2: 11.2 min) to obtain ethyl (R)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 1) (25.8 mg, 39% yield over two steps) was obtained. ESI-MS m / z: 439 (M + H) + 1 H NMR (CDCl3, δ): 7.76 (dd, J = 7.6, 1.7 Hz, 1H), 7.20-7.10 (m, 1H), 7.02-6.90 (m, 2H), 4.45-4.35 (m, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.17-4.00 (m, 2H), 3.45-3.30 (m, 2H), 3.30-3.20 (m, 1H), 3.15-3.00 (m, 1H), 2.31 (s, 3H), 2.30-2.15 (m, 2H), 2.15-2.05 (m, 3H), 2.05-1.90 (m, 4H), 1.35 (s, 6H), 1.29 (t, J = 7.2 Hz, 3H).

[0277] Example 2 (R)-1-(2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-1′-yl)butan-1-one (Compound 2)

[0278] (Step 1) Using tert-butyl 2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (450 mg, 0.96 mmol) obtained in Step 7 of Example 1 and butyryl chloride (77 mg, 0.72 mmol), the procedure was repeated in the same manner as in Step 8 of Example 1 to obtain tert-butyl 4-(1'-butyryl-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1'-carboxylate (300 mg, 56%). ESI-MS m / z: 537 (M + H) +

[0279] (Step 2) tert-butyl 4-(1'-butyryl-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1'-carboxylate (85 mg, 0.16 mmol) obtained in Step 1 was purified by chiral SFC (CHIRALPAK ID (20x250 mm, 5 µm), hexane (0.2% diethylamine) / ethanol, flow rate 20 mL / min, RT1: 7.19 min, RT2: 12.5 min) to obtain tert-butyl 4-(1'-butyryl-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1'-carboxylate (85 mg, 0.16 mmol). (R)-4-(1'-butyryl-3-methyl-2H-spiro-[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1'-carboxylate (35 mg, 41%) was obtained.

[0280] (Step 3) tert-Butyl (R)-4-(1'-butyryl-3-methyl-2H-spiro-[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1'-carboxylate (35 mg, 0.06 mmol) obtained in Step 2 and trifluoroacetic acid (0.5 mL, 6.73 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 1 hour. Aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by reverse-phase high-performance liquid chromatography (HPLC) to give (R)-1-(2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazol-4,4'-piperidin]-1'-yl)butan-1-one (compound 2) (5.2 mg, 18%). ESI-MS m / z: 437 (M + H). + 1 H NMR (CDCl3, δ): 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 7.20-7.10 (m, 1H), 7.00-6.90 (m, 2H), 4.70-4.60 (m, 1H), 4.40-4.30 (m, 1H), 3.80-3.60 (m, 2H), 3.25-3.00 (m, 3H), 2.41-2.33 (m, 2H), 2.29 (s, 3H), 2.25-2.10 (m, 4H), 2.10-2.02 (m, 2H), 2.00-1.80 (m, 2H), 1.80-1.60 (m, 3H), 1.30 (s, 6H), 1.00 (t, J = 7.2 Hz, 3H).

[0281] Example 3 (R)-Cyclopropyl(2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-1′-yl)methanone (Compound 3)

[0282] (Step 1) Tert-butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (24.8 g, 109 mmol), Chiralscreen® OH E-007, and the reagent solution G included with E-007 were suspended in distilled water (200 mL) and stirred overnight at room temperature. Ethyl acetate (100 mL) and aqueous sodium hydroxide solution (1 mol / L, 60 mL) were added to the reaction mixture, followed by extraction with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give crude tert-butyl (S)-4-hydroxy-2,2-dimethylpiperidine-1-carboxylate (25.1 g), which was used in the next step without further purification. ESI-MS m / z: 230 (M + H). +

[0283] (Step 2) Using the crude tert-butyl (S)-4-hydroxy-2,2-dimethylpiperidine-1-carboxylate obtained in Step 1, tert-butyl (S)-2,2-dimethyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (6.52 g, 96% yield over two steps) was obtained in the same manner as in Step 5 of Example 1. ESI-MS m / z: 308 (M + H) +

[0284] (Step 3) Using benzyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1 g, 2.57 mmol) obtained in Step 4 of Example 1 and tert-butyl (S)-2,2-dimethyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.58 g, 5.14 mmol) obtained in Step 2, the crude product of benzyl (R)-2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate was obtained in the same manner as in Step 6 of Example 1, and was used in the next step without purification. ESI-MS m / z: 601 (M + H) +

[0285] (Step 4) Using the crude product of benzyl (R)-2-(1-tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 3, tert-butyl (R)-2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (600 mg, 77% yield over two steps) was obtained in the same manner as in Step 7 of Example 1. ESI-MS m / z: 467 (M + H) +

[0286] (Step 5) Using tert-butyl (R)-2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (80 mg, 0.171 mmol) obtained in Step 4 and cyclopropanecarbonyl chloride (35.8 mg, 0.343 mmol), the crude product tert-butyl (R)-4-(1'-(cyclopropanecarbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate was obtained in the same manner as in Step 8 of Example 1, and was used in the next step without further purification. ESI-MS m / z: 535 (M + H). +

[0287] (Step 6) Using the crude product of tert-butyl (R)-4-(1'-(cyclopropanecarbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate obtained in Step 5, (R)-cyclopropyl(2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)methanone (compound 3) (18.9 mg, 25% yield over two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 435 (M + H)+ 1 H NMR (CDCl3, δ): 7.74 (dd, J = 7.7, 1.8 Hz, 1H), 7.15 (td, J = 7.7, 1.6 Hz, 1H), 6.98-6.93 (m, 2H), 4.57 (d, J = 12.1 Hz, 1H), 4.36-4.23 (m, 1H), 4.08 (d, J = 12.6 Hz, 1H), 3.69 (t, J = 13.0 Hz, 1H), 3.25-3.03 (m, 2H), 2.97 (td, J = 13.2, 2.7Hz, 1H), 2.25 (s, 3H), 2.12-2.03 (m, 3H), 1.95-1.75 (m, 6H), 1.25-1.21 (m, 7H), 1.00 (dt, J = 7.8, 3.4 Hz, 2H), 0.77 (dt, J = 11.4, 3.3 Hz, 2H)

[0288] Example 4 (R)-2-Cyclopropyl-1-(2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-1′-yl)ethan-1-one (Compound 4)

[0289] (Step 1) tert-Butyl (R)-2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (80 mg, 0.171 mol) obtained in Step 4 of Example 3 and 2-cyclopropylacetic acid (34.3 mg, 0.343 mmol) were dissolved in dichloromethane (1 mL), and HATU (98 mg, 0.257 mmol) and triethylamine (52 mg, 0.514 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium bicarbonate, extracted with chloroform, and the solvent was evaporated under reduced pressure to give crude tert-butyl (R)-4-(1'-(2-cyclopropylacetyl)-3-methyl-2H-spiro[chromeno[4,3,c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate, which was used in the next step without further purification. ESI-MS m / z: 549 (M + H). +

[0290] (Step 2) Using the crude product of tert-butyl (R)-4-(1'-(2-cyclopropylacetyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate obtained in Step 1, (R)-2-cyclopropyl-1-(2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)ethan-1-one (compound 4) (16.2 mg, 21% yield over two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 449 (M + H) + 1H NMR (CDCl3, δ): 7.73 (dd, J = 7.6, 1.3 Hz, 1H), 7.15 (td, J = 7.6, 1.6 Hz, 1H), 6.98-6.92 (m, 2H), 4.62 (d, J = 9.4 Hz, 1H), 4.29 (tt, J = 11.9, 4.0 Hz, 1H), 3.74-3.57 (m, 2H), 3.19-3.06 (m, 2H), 2.98 (td, J = 13.2, 2.7 Hz, 1H), 2.32 (t, J = 6.5 Hz, 2H), 2.27 (s, 3H), 2.12-1.75 (m, 7H), 1.22 (d, J = 9.0 Hz, 8H), 1.12-1.02 (m, 1H), 0.58-0.56 (m, 2H), 0.20-0.18 (m, 2H)

[0291] Example 5 (R,E)-3-cyclopropyl-1-(2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-1′-yl)prop-2-en-1-one (Compound 5)

[0292] (Step 1) Using tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol), the procedure was repeated in the same manner as in Step 1 of Example 1 to obtain tert-butyl 4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (1.05 g, 66%). ESI-MS m / z: 318 (M + H)+

[0293] (Step 2) Using tert-butyl 4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (30.0 g, 94.5 mmol) obtained in Step 1, tert-butyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (15.0 g, 44%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 362 (M + H)+

[0294] (Step 3) Using tert-butyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (15.0 g, 41.5 mmol) obtained in Step 2, tert-butyl (Z)-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (14.0 g, 94%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 360 (M + H)+

[0295] (Step 4) Using tert-butyl (Z)-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (14.0 g, 39.0 mmol) obtained in Step 3, tert-butyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (8.70 g, 63%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 356 (M + H)+

[0296] (Step 5) tert-Butyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (8.7 g, 24.5 mmol) obtained in Step 4 was added to a hydrogen chloride / 1,4-dioxane solution (4 mol / L, 200 mL, 800 mmol) and stirred overnight at room temperature. The solvent was evaporated under reduced pressure to give crude 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]hydrochloride (7.50 g), which was used in the next step without further purification.

[0297] (Step 6) Using the crude product (1.5 g) of 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] hydrochloride obtained in Step 5 and (E)-3-cyclopropylacrylic acid (0.58 g, 5.14 mmol), (E)-3-cyclopropyl-1-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)prop-2-en-1-one (900 mg, 50% yield over two steps) was obtained in the same manner as in Step 1 of Example 4. ESI-MS m / z: 350 (M + H) +

[0298] (Step 7) Using (E)-3-cyclopropyl-1-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)prop-2-en-1-one (900 mg, 2.58 mmol) obtained in Step 6, tert-butyl (E)-4-(1'-(3-cyclopropylacryloyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (600 mg, 42%) was obtained in the same manner as in Step 6 of Example 1. ESI-MS m / z: 561 (M + H) +

[0299] (Step 8) Using tert-butyl (E)-4-(1'-(3-cyclopropylacryloyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (150 mg, 0.27 mmol) obtained in Step 7, (E)-3-cyclopropyl-1-(2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)prop-2-en-1-one (42.4 mg, 34%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 461 (M + H) +

[0300] (Step 9) Using (E)-3-cyclopropyl-1-(2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)prop-2-en-1-one' (55 mg, 0.12 mmol) obtained in Step 8, (R,E)-3-cyclopropyl-1-(2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)prop-2-en-1-one (Compound 5) (7.5 mg, 14%) was obtained in the same manner as in Step 10 of Example 1. ESI-MS m / z: 461 (M + H) + 1 H-NMR (CDCl3, δ): 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.20-7.10 (m, 1H), 7.05-6.90 (m, 2H), 6.40-6.30 (m, 2H), 4.75-4.60 (m, 1H), 4.45-4.30 (m, 1H), 3.95-3.80 (m, 1H), 3.75-3.60 (m, 1H), 3.55-3.45 (m, 1H), 3.30-3.10 (m, 2H), 2.60-2.40 (m, 2H), 2.30 (s, 3H), 2.25-2.10 (m, 4H), 2.10-1.92 (m, 3H), 1.60-1.50 (m, 1H), 1.55 (s, 3H), 1.53 (s, 3H), 1.00-0.90 (m, 2H), 0.75-0.65 (m, 2H).

[0301] Example 6 (2-((R)-2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-1′-yl)((1S,2S)-2-methylcyclopropyl)methanone (Compound 6)

[0302] (Step 1) Using tert-butyl 2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (500 mg, 1.07 mmol) obtained in Step 7 of Example 1 and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (118 mg, 1.18 mmol), the procedure was repeated in the same manner as in Step 1 of Example 4 to obtain tert-butyl 2,2-dimethyl-4-(3-methyl-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (600 mg, 98%). ESI-MS m / z: 549 (M + H) +

[0303] (Step 2) Using tert-butyl 2,2-dimethyl-4-(3-methyl-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (50 mg, 0.091 mmol) obtained in Step 1, (2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (14.5 mg, 36%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 449 (M + H) +

[0304] (Step 3) (2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-1′-yl)((1S,2S)-2-methylcyclopropyl)methanone (50 mg, 0.111 mmol) obtained in Step 2 was purified by chiral SFC (Lux® Cellulose-2 (21.2×250 mm, 5 μm), hexane (0.2% diethylamine) / ethanol=95 / 5, flow rate 20 mL / min, RT1: 26.1 min, RT2: 29.1 min). min to give (2-((R)-2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (compound 6) (17.1 mg, 34%). ESI-MS m / z: 449 (M + H). + 1 H-NMR (CDCl3,δ): 7.76 (dd, J = 7.4, 1.6 Hz, 1H), 7.20-7.15 (m, 1H), 7.00-6.95 (m, 2H), 4.60-4.55 (m, 1H), 4.36-4.28 (m, 1H), 4.08-4.05 (m, 1H), 3.73-3.66 (m, 1H), 3.21-3.10 (m, 2H), 3.03-2.96 (m, 1H), 2.29 (s, 3H), 2.18-2.08 (m, 3H), 2.02-1.78 (m, 6H), 1.52-1.48 (m, 1H), 1.42-1.36 (m, 1H), 1.25 (s, 3H), 1.23 (s, 3H), 1.21-1.17 (m, 1H), 1.14 (d, J = 6.3 Hz, 3H), 0.63-0.58 (m, 1H).

[0305] The hydrochloride salt of compound 6 was obtained by dissolving the isolated compound 6 in a hydrogen chloride / 1,4-dioxane solution and evaporating the solvent under reduced pressure.

[0306] Example 7 (2-((R)-2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-1′-yl)((1S,2S)-2-(trifluoromethyl)cyclopropyl)methanone (Compound 7)

[0307] (Step 1) Using tert-butyl (R)-2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (30.0 mg, 0.064 mmol) obtained in Step 4 of Example 3 and (1S,2S)-2-(trifluoromethyl)cyclopropane-1-carboxylic acid (30.0 mg, 0.193 mmol), the crude product of tert-butyl (R)-2,2-dimethyl-4-(3-methyl-1'-((1S,2S)-2-(trifluoromethyl)cyclopropane-1-carbonyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate was obtained in the same manner as in Step 1 of Example 4, and was used in the next step without purification.

[0308] (Step 2) The crude product of tert-butyl (R)-2,2-dimethyl-4-(3-methyl-1'-((1S,2S)-2-(trifluoromethyl)cyclopropane-1-carbonyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate obtained in Step 1 was dissolved in dichloromethane (0.6 mL), trifluoroacetic acid (0.247 mL, 3.20 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Aqueous sodium hydroxide solution (2.0 mol / L) was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was separated using a phase separator, and the solvent was evaporated under reduced pressure. The residue was purified by aminosilica gel column chromatography (chloroform / methanol = 1 / 0-19 / 1) to give (2-((R)-2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-(trifluoromethyl)cyclopropyl)methanone (compound 7) (32.0 mg, 99% yield over two steps). ESI-MS m / z: 503 (M + H). + 1 H-NMR (CDCl3,δ): 7.76 (dd, J = 7.6, 1.3 Hz, 1H), 7.20-7.15 (m, 1H), 7.01-6.94 (m, 2H), 4.58-4.52 (m, 1H), 4.36-4.28 (m, 1H), 4.04-3.99 (m, 1H), 3.80-3.72 (m, 1H), 3.27-3.19 (m, 1H), 3.15-3.10 (m, 1H), 3.04-2.96 (m, 1H), 2.30 (s, 3H), 2.23-2.07 (m, 5H), 2.03-1.88 (m, 4H), 1.82-1.77 (m, 1H), 1.60-1.57 (m, 1H), 1.45-1.38 (m, 1H), 1.25-1.23 (m, 1H), 1.25 (s, 3H), 1.23 (s, 3H).

[0309] Example 8 (R)-3-Methyl-N-propyl-2-(1,2,2-trimethylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 8)

[0310] (Step 1) tert-Butyl (R)-2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (50 mg, 0.11 mmol) obtained in Step 4 of Example 3 was dissolved in dichloromethane (1.1 mL), and propyl isocyanate (0.013 mL, 0.14 mmol) was added and stirred at room temperature for 2 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was separated using a phase separator, and the solvent was evaporated under reduced pressure to give crude tert-butyl (R)-2,2-dimethyl-4-(3-methyl-1'-(propylcarbamoyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate, which was used in the next step without further purification. ESI-MS m / z: 552 (M + H). +

[0311] (Step 2) Using the crude product of tert-butyl (R)-2,2-dimethyl-4-(3-methyl-1'-(propylcarbamoyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-2-yl)piperidine-1-carboxylate obtained in Step 1, (R)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-N-propyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (37 mg, two-step yield 77%) was obtained in the same manner as in Step 3 of Example 2.

[0312] (Step 3) (R)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-N-propyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (27 mg, 0.060 mmol) obtained in Step 2 was dissolved in THF (0.6 mL), and 36% aqueous formaldehyde (0.47 mL, 6.0 mmol), sodium triacetoxyborohydride (32 mg, 0.12 mmol), and acetic acid (0.034 mL, 0.60 mmol) were added. The mixture was stirred at room temperature for 2 hours. Aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform. The organic layer was separated using a phase separator, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 1 / 0-19 / 1) to give (R)-3-methyl-N-propyl-2-(1,2,2-trimethylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (compound 8) (21 mg, 75%). ESI-MS m / z: 466 (M + H). + 1H-NMR (CDCl3) δ: 7.73 (dd, J = 7.5, 1.6 Hz, 1H), 7.15 (td, J = 7.6, 1.6 Hz, 1H), 6.96 (td, J = 7.5, 1.3 Hz, 1H), 6.92 (dd, J = 7.6, 1.3 Hz, 1H), 4.53 (t, J = 5.4 Hz, 1H), 4.27-4.18 (m, 1H), 3.86-3.80 (m, 2H), 3.40-3.33 (m, 2H), 3.26-3.21 (m, 2H), 2.83-2.78 (m, 1H), 2.65-2.58 (m, 1H), 2.46-2.35 (m, 1H), 2.30 (s, 3H), 2.28 (s, 3H), 2.25-2.18 (m, 1H), 2.09-2.04 (m, 2H), 1.95-1.87 (m, 3H), 1.70-1.66 (m, 1H), 1.55 (td, J = 14.6, 7.5 Hz, 2H), 1.22 (s, 3H), 1.06 (s, 3H), 0.94 (t, J = 7.4 Hz, 3H).

[0313] Example 9 (R)-N-Cyclobutyl-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 9)

[0314] (Step 1) Cyclobutanecarboxylic acid (19 mg, 0.19 mmol) was dissolved in 1,2-dichloroethane, and triethylamine (0.045 mL, 0.321 mmol) and diphenylphosphoryl azide (0.041 mL, 0.19 mmol) were added. The mixture was stirred at 80° C. for 5 hours. To the reaction mixture was added a solution of tert-butyl (R)-2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-2-yl)piperidine-1-carboxylate (30 mg, 0.064 mmol) obtained in Step 4 of Example 3 in dichloromethane (0.5 mL), and the mixture was stirred overnight at room temperature. 40% aqueous methylamine solution (0.1 mL) was added to the reaction mixture, and the mixture was stirred for 5 minutes. Then, aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude tert-butyl (R)-4-(1'-(cyclobutylcarbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate, which was used in the next step without further purification.

[0315] (Step 2) Using the crude product of tert-butyl (R)-4-(1'-(cyclobutylcarbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate obtained in Step 1, (R)-N-cyclobutyl-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 9) (22 mg, 74% yield over two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 464 (M + H) + 1H-NMR (CDCl3,δ): 7.75 (dd, J = 7.4, 1.6 Hz, 1H), 7.16 (td, J = 7.7, 1.6 Hz, 1H), 6.99-6.92 (m, 2H), 4.60 (d, J = 7.6 Hz, 1H), 4.35-4.27 (m, 2H), 3.85-3.80 (m, 2H), 3.40-3.32 (m, 2H), 3.15-3.09 (m, 1H), 3.03-2.96 (m, 1H), 2.41-2.34 (m, 2H), 2.29 (s, 3H), 2.11-1.99 (m, 3H), 1.96-1.87 (m, 3H), 1.85-1.77 (m, 3H), 1.73-1.65 (m, 4H), 1.25 (s, 3H), 1.23 (s, 3H).

[0316] Example 10: (R)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-N-(1-methylcyclopropyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 10)

[0317] (Step 1) Using tert-butyl (R)-2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (50 mg, 0.11 mmol) obtained in Step 4 of Example 3 and 1-methylcyclopropane-1-carboxylic acid (32 mg, 0.32 mmol), the crude product of tert-butyl (R)-2,2-dimethyl-4-(3-methyl-1'-((1-methylcyclopropyl)carbamoyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate was obtained in the same manner as in Step 1 of Example 9, and was used in the next step without purification.

[0318] (Step 2) Using the crude product of tert-butyl (R)-2,2-dimethyl-4-(3-methyl-1'-((1-methylcyclopropyl)carbamoyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-2-yl)piperidine-1-carboxylate obtained in Step 1, (R)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-N-(1-methylcyclopropyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 10) (5.2 mg, 10% yield in two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 464 (M + H) + 1 H-NMR (CDCl3,δ): 7.74 (dd, J = 7.5, 1.6 Hz, 1H), 7.16 (td, J = 7.6, 1.6 Hz, 1H), 6.97 (td, J = 7.5, 1.2 Hz, 1H), 6.93 (dd, J = 7.6, 1.2 Hz, 1H), 4.90 (br s, 1H), 4.35-4.28 (m, 1H), 3.81-3.75 (m, 2H), 3.37-3.29 (m, 2H), 3.15-3.10 (m, 1H), 3.00 (td, J = 13.2, 2.7 Hz, 1H), 2.29 (s, 3H), 2.12-1.96 (m, 5H), 1.94-1.86 (m, 3H), 1.82-1.77 (m, 1H), 1.41 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H), 0.75-0.72 (m, 2H), 0.65-0.62 (m, 2H).

[0319] Example 11: (R)—N-(cyclopropylmethyl)-3-methyl-2-(1,2,2-trimethylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 11)

[0320] (Step 1) 4-Nitrophenyl chloroformate (5.67 g, 28.1 mmol) was dissolved in dichloromethane (80 mL), and cyclopropylmethylamine (2.00 g, 28.1 mmol) and triethylamine (8.54 g, 84.4 mmol) were added dropwise under ice cooling. The mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give 4-nitrophenyl(cyclopropylmethyl)carbamate (1.02 g, 15%). ESI-MS m / z: 237 (M + H) + 1 H NMR (CDCl3, δ): 8.24 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 5.28 (s, 1H), 3.17 (d, J = 5.6 Hz, 2H), 1.12-0.98 (m, 1H), 0.64-0.49 (m, 2H), 0.32-0.25 (m, 2H).

[0321] (Step 2) Using tert-butyl (R)-2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (1.70 g, 3.64 mmol) obtained in Step 4 of Example 3 and 4-nitrophenyl(cyclopropylmethyl)carbamate (1.12 g, 4.74 mmol) obtained in Step 1, the procedure was repeated in the same manner as in Step 8 of Example 1 to obtain tert-butyl (R)-4-(1'-((cyclopropylmethyl)carbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (1.92 g, 93%). ESI-MS m / z: 564 (M + H) +

[0322] (Step 3) tert-Butyl (R)-4-(1'-((cyclopropylmethyl)carbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (1.92 g, 3.41 mmol) obtained in Step 2 was dissolved in 1,4-dioxane (34.0 mL), and a hydrogen chloride / 1,4-dioxane solution (4 mol / L, 17 mL, 68 mmol) was added, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure to give the crude product (R)-N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide hydrochloride, which was used in the next step without purification.

[0323] (Step 4) The crude (R)-N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide hydrochloride obtained in Step 3 was dissolved in THF (34 mL), and triethylamine (1.43 mL, 10.2 mmol), 37% aqueous formaldehyde (26.8 mL, 341 mmol), sodium borohydride (1.81 g, 6.82 mmol), and acetic acid (1.95 mL, 34.1 mmol) were added and stirred at room temperature for 2 hours. Aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 1 / 0-97 / 3) to give (R)-N-(cyclopropylmethyl)-3-methyl-2-(1,2,2-trimethylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 11) (1.45 g, 89% yield over two steps). ESI-MS m / z: 478 (M + H). + 1H-NMR (CDCl3, δ): 7.73 (dd, J = 7.6, 1.3 Hz, 1H), 7.15 (td, J = 7.6, 1.6 Hz, 1H), 6.99-6.92 (m, 2H), 4.58 (t, J = 5.2 Hz, 1H), 4.28-4.19 (m, 1H), 3.89-3.83 (m, 2H), 3.42-3.34 (m, 2H), 3.13 (dd, J = 7.2, 5.4 Hz, 2H), 2.85-2.78 (m, 1H), 2.66-2.58 (m, 1H), 2.47-2.37 (m, 1H), 2.31 (s, 3H), 2.29 (s, 3H), 2.26-2.20 (m, 1H), 2.10-2.05 (m, 2H), 1.96-1.87 (m, 3H), 1.69 (t, J = 6.5 Hz, 1H), 1.22 (s, 3H), 1.06 (s, 3H), 1.03-0.97 (m, 1H), 0.53-0.48 (m, 2H), 0.23-0.19 (m, 2H).

[0324] Example 12: N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-N,3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 12)

[0325] (Step 1) Using 4-nitrophenyl chloroformate (1.66 g, 8.22 mmol) and 1-cyclopropyl-N-methyl-methanamine hydrochloride (1.00 g, 8.22 mmol), the procedure was repeated as in Step 1 of Example 11 to obtain 4-nitrophenyl(cyclopropylmethyl)(methyl)carbamate (1.16 g, 56%). ESI-MS m / z: 251 (M + H). + 1 H NMR (CDCl3, δ): 8.25 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 3.40-3.30 (m, 2H), 3.25 (s, 3H), 1.20-1.05 (m, 1H), 0.70-0.55 (m, 2H), 0.40-0.30 (m, 2H).

[0326] (Step 2) Using tert-butyl 2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (44 mg, 0.094 mmol) obtained in Step 7 of Example 1 and 4-nitrophenyl(cyclopropylmethyl)(methyl)carbamate (35 mg, 0.14 mmol) obtained in Step 1, the procedure was repeated in the same manner as in Step 8 of Example 1 to obtain tert-butyl 4-(1'-((cyclopropylmethyl)(methyl)carbamoyl-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (35 mg, 64%). ESI-MS m / z: 578 (M + H) +

[0327] (Step 3) Using tert-butyl 4-(1'-((cyclopropylmethyl)(methyl)carbamoyl-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (35 mg, 0.061 mmol) obtained in Step 2, N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-N,3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 12) (29 mg, 100%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 478 (M + H) + 1H-NMR (CDCl3, δ): 7.74 (dd, J = 7.6, 1.8 Hz, 1H), 7.16 (td, J = 7.9, 1.8 Hz, 1H), 6.98-6.93 (m, 2H), 4.35-4.27 (m, 1H), 3.61-3.57 (m, 2H), 3.43-3.36 (m, 2H), 3.13-3.07 (m, 3H), 2.99 (td, J = 13.2, 3.0 Hz, 1H), 2.93 (s, 3H), 2.31 (s, 3H), 2.09-1.87 (m, 7H), 1.81-1.76 (m, 1H), 1.56 (br s, 1H), 1.24 (s, 3H), 1.21 (s, 3H), 1.01-0.94 (m, 1H), 0.56-0.51 (m, 2H), 0.22-0.18 (m, 2H).

[0328] Example 13 (R)—N-(cyclopropylmethyl-d2)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 13)

[0329] (Step 1) Cyclopropanecarboxylic acid (1.00 g, 11.6 mmol) was dissolved in THF (15.0 mL). Under ice cooling, sodium borodeuteride (1.12 g, 26.7 mmol) was added, and a solution of iodine (2.95 g, 11.6 mmol) in THF (8.0 mL) was added dropwise. The mixture was warmed to room temperature and stirred for 6 hours. The reaction mixture was cooled to 0°C, water was added, and the mixture was extracted with dichloromethane. The mixture was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product cyclopropylmethane-d2-ol, which was used in the next step without purification.

[0330] (Step 2) The crude cyclopropylmethane-d2-ol obtained in Step 1 was dissolved in toluene (10 mL), triphenylphosphine (3.66 g, 13.9 mmol), N-(tert-butoxycarbonyl)-2-nitrobenzenesulfonamide (4.22 g, 13.9 mmol), and diisopropyl azodicarboxylate (2.71 mL, 13.9 mmol) were added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane / ethyl acetate = 1 / 0-1 / 1) to give crude tert-butyl (cyclopropylmethyl-d2)(2-nitrophenyl)sulfonyl)carbamate, which was used in the next step without further purification.

[0331] (Step 3) The crude product of tert-butyl (cyclopropylmethyl-d2)(2-nitrophenyl)sulfonyl)carbamate obtained in Step 2 was dissolved in acetonitrile (30 mL), and cesium carbonate (8.06 g, 24.7 mmol) and 4-tert-butylthiophenol (3.14 mL, 18.7 mmol) were added, followed by stirring at 50°C for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (heptane / ethyl acetate = 1 / 0 to 1 / 1) to obtain the crude product of tert-butyl (cyclopropylmethyl-d2)carbamate, which was used in the next step without further purification.

[0332] (Step 4) The crude tert-butyl (cyclopropylmethyl-d2)carbamate obtained in Step 3 was dissolved in a hydrogen chloride / 1,4-dioxane solution (4 mol / L, 20 mL) and stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and extracted with hydrochloric acid (2 mol / L). The solvent was evaporated under reduced pressure, and the residue was slurried with diisopropyl ether to give cyclopropylmethane-d2-amine hydrochloride (613 mg, 48% yield for four steps).

[0333] (Step 5) Cyclopropylmethane-d2-amine hydrochloride (34.0 mg, 0.309 mmol) obtained in Step 4 was dissolved in dichloromethane (2.0 mL), and triethylamine (0.430 mL, 0.309 mmol) and 4-nitrophenyl chloroformate (62.0 mg, 0.309 mmol) were added under ice cooling, followed by stirring at room temperature for 1 hour. tert-Butyl (R)-2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (90.0 mg, 0.193 mmol) obtained in Step 4 of Example 3 was added to the reaction mixture, followed by stirring at room temperature for another 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (chloroform / methanol = 1 / 0-24 / 1) to give tert-butyl (R)-4-(1'-((cyclopropylmethyl-d2)carbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (quantitative). ESI-MS m / z: 566 (M + H). +

[0334] (Step 6) Using tert-butyl (R)-4-(1'-((cyclopropylmethyl-d2)carbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (109 mg, 0.193 mmol) obtained in Step 5, (R)—N-(cyclopropylmethyl-d2)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 13) (22 mg, 24%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 466 (M + H) + 1H-NMR (CDCl3, δ): 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.16 (td, J = 7.9, 1.8 Hz, 1H), 6.99-6.93 (m, 2H), 4.58 (s, 1H), 4.31 (tt, J = 11.9, 4.1 Hz, 1H), 3.89-3.83 (m, 2H), 3.39 (td, J = 12.9, 2.5 Hz, 2H), 3.14-3.08 (m, 1H), 2.99 (td, J = 13.2, 2.7 Hz, 1H), 2.30 (s, 3H), 2.17 (s, 1H), 2.10-2.06 (m, 3H), 1.98-1.89 (m, 4H), 1.81-1.76 (m, 1H), 1.24 (s, 3H), 1.22 (s, 3H), 1.02-0.96 (m, 1H), 0.53-0.48 (m, 2H), 0.23-0.19 (m, 2H).

[0335] Example 14: (R)-2-(2,2-dimethylpiperidin-4-yl)-N-(2-fluoroallyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 14)

[0336] (Step 1) Using tert-butyl (R)-2,2-dimethyl-4-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)piperidine-1-carboxylate (134 mg, 0.287 mmol) obtained in Step 4 of Example 3 and 2-fluoro-2-propen-1-amine hydrochloride (51.0 mg, 0.459 mmol), the procedure was repeated in the same manner as in Step 5 of Example 13 to obtain a crude product of tert-butyl (R)-4-(1'-((2-fluoroallyl)carbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (147 mg), which was used in the next step without purification.

[0337] (Step 2) Using the crude product (147 mg) of tert-butyl (R)-4-(1'-((2-fluoroallyl)carbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate obtained in Step 1, (R)-2-(2,2-dimethylpiperidin-4-yl)-N-(2-fluoroallyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 14) (48 mg, 36% yield over two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 468 (M + H) + 1 H-NMR (CDCl3, δ): 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.16 (td, J = 7.7, 1.6 Hz, 1H), 6.99-6.92 (m, 2H), 4.83 (t, J = 5.8 Hz, 1H), 4.67 (dd, J = 16.6, 2.7 Hz, 1H), 4.52 (dd, J = 48.9, 3.1 Hz, 1H), 4.36-4.27 (m, 1H), 4.01 (dd, J = 13.5, 5.4 Hz, 2H), 3.86 (d, J = 13.0 Hz, 2H), 3.45-3.38 (m, 2H), 3.14-3.09 (m, 1H), 3.00 (td, J = 13.2, 2.7 Hz, 1H), 2.29 (s, 3H), 2.11-2.07 (m, 3H), 1.99-1.88 (m, 4H), 1.81-1.77 (m, 2H), 1.25 (s, 3H), 1.22 (s, 3H).

[0338] Example 15: Cyclopropylmethyl-2-(1-(tert-butyl)piperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 15)

[0339] (Step 1) Using the crude product (7.50 g) of 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] hydrochloride obtained in Step 5 of Example 5 and allyl chloroformate (2.89 g, 24.0 mmol), allyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (5.75 g, 69% yield over two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 340 (M + H) +

[0340] (Step 2) 1-(tert-butyl)piperidin-4-one (545 mg, 3.51 mmol) was dissolved in ethanol (4.0 mL), and p-toluenesulfonyl hydrazide (654 mg, 3.51 mmol) was added. The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure to give crude N'-(1-(tert-butyl)piperidin-4-ylidene)-4-methylbenzenesulfonohydrazide, which was used in the next step without further purification.

[0341] (Step 3) Allyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (200 mg, 0.589 mmol) obtained in Step 1 was dissolved in 1,4-dioxane (4.0 mL), and the crude N'-(1-(tert-butyl)piperidin-4-ylidene)-4-methylbenzenesulfonohydrazide (248 mg) obtained in Step 2, cesium carbonate (768 mg, 2.36 mmol), and copper(II) acetylacetonate (46.0 mg, 0.177 mmol) were added, followed by stirring overnight at 110°C. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was separated using a phase separator, and the solvent was evaporated under reduced pressure to give crude allyl 2-(1-(tert-butyl)piperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate, which was used in the next step without further purification. ESI-MS m / z: 479 (M + H). +

[0342] (Step 4) The crude product of allyl 2-(1-(tert-butyl)piperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 3 was dissolved in dichloromethane (6.0 mL), pyrrolidine (0.495 mL, 5.99 mmol) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.030 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the residue was purified by aminosilica gel column chromatography (chloroform / methanol = 1 / 0 to 97 / 3) and further purified by reverse-phase preparative LCMS to give 2-(1-(tert-butyl)piperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] (47.0 mg, 20% yield over two steps). ESI-MS m / z: 395 (M + H) +

[0343] (Step 5) Using cyclopropylmethanol (7.00 g, 97.1 mmol), the crude product of cyclopropylmethyl (4-nitrophenyl) carbonate (20.0 g) was obtained in the same manner as in Step 1 of Example 11, and was used in the next step without purification. ESI-MS m / z: 238 (M + H). +

[0344] (Step 6) Using 2-(1-(tert-butyl)piperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] (22 mg, 0.056 mmol) obtained in Step 4 and the crude product of cyclopropylmethyl (4-nitrophenyl) carbonate (13 mg) obtained in Step 5, cyclopropylmethyl 2-(1-(tert-butyl)piperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 15) (24 mg, 87% yield for both steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 493 (M + H) + 1H-NMR (CDCl3, δ): 7.72 (dd, J = 7.4, 1.6 Hz, 1H), 7.15 (td, J = 7.6, 1.6 Hz, 1H), 6.98-6.92 (m, 2H), 4.09 (br s, 2H), 3.98-3.92 (m, 3H), 3.37 (br s, 2H), 3.21 (d, J = 10.8 Hz, 2H), 2.37-2.19 (m, 7H), 2.07 (d, J = 13.0 Hz, 2H), 1.90 (d, J = 11.7 Hz, 4H), 1.19-1.14 (m, 1H), 1.12 (s, 9H), 0.58-0.53 (m, 2H), 0.31-0.27 (m, 2H).

[0345] Example 16: Cyclopropylmethyl 2-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 16)

[0346] (Step 1) Using tert-butyl 4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (60.0 g, 189 mmol) obtained in Step 1 of Example 5, spiro[chroman-2,4'-piperidin]-4-one hydrochloride (50.0 g, 94%) was obtained in the same manner as in Step 5 of Example 5. ESI-MS m / z: 218 (M + H) +

[0347] (Step 2) Using spiro[chroman-2,4'-piperidin]-4-one hydrochloride (50.0 g, 177 mmol) obtained in Step 1 and cyclopropylmethyl (4-nitrophenyl) carbonate (41.9 g, 177 mmol) obtained in Step 5 of Example 15, cyclopropylmethyl 4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (40.0 g, 72%) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 316 (M + H) +

[0348] (Step 3) Using cyclopropylmethyl 4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (20.0 g, 63.4 mmol) obtained in Step 2, cyclopropylmethyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (12.0 g, 53%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 360 (M + H) +

[0349] (Step 4) Using cyclopropylmethyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (11.0 g, 28.0 mmol) obtained in Step 3, cyclopropylmethyl (Z)-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (10.0 g, 92%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 358 (M + H) +

[0350] (Step 5) Using cyclopropylmethyl (Z)-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (10.0 g, 28.0 mmol) obtained in Step 4, cyclopropylmethyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (5.50 g, 56%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 354 (M + H) +

[0351] (Step 6) tert-Butyl (1R,3r,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (2.00 g, 8.80 mmol) was dissolved in dichloromethane (20 mL). N,N,N',N'-tetramethylethylenediamine (1.99 mL, 13.2 mmol) and methanesulfonyl chloride (0.754 mL, 9.68 mmol) were added under ice cooling. The mixture was warmed to room temperature and stirred for 2 hours. N,N,N',N'-tetramethylethylenediamine (0.93 mL, 6.2 mmol) and methanesulfonyl chloride (0.343 mL, 4.40 mmol) were then added, and the mixture was stirred at room temperature for 1 hour. Water and saturated aqueous sodium bicarbonate were added to the reaction mixture, which was then extracted with chloroform. The organic layer was separated using a phase separator, and the solvent was evaporated under reduced pressure to give crude tert-butyl (1R,3r,5S)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.86 g), which was used in the next step without further purification.

[0352] (Step 7) Cyclopropylmethyl 2-((1R,3s,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (217 mg, 0.707 mmol) obtained in Step 5 and tert-butyl (1R,3r,5S)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octan-8-carboxylate (238 mg, 0.778 mmol) obtained in Step 6 were used in the same manner as in Step 6 of Example 1. 55%). ESI-MS m / z: 563 (M + H) +

[0353] (Step 8) Using cyclopropylmethyl 2-((1R,3s,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (217 mg, 0.386 mmol) obtained in Step 7, cyclopropylmethyl 2-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 16) (154 mg, 86%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 463 (M + H) + 1 H-NMR (CDCl3, δ): 7.73 (dd, J = 7.6, 1.8 Hz, 1H), 7.16 (td, J = 7.9, 1.9 Hz, 1H), 6.99-6.92 (m, 2H), 4.47-4.39 (m, 1H), 4.09 (br s, 2H), 3.95 (d, J = 6.7 Hz, 2H), 3.73-3.70 (m, 2H), 3.36 (br s, 2H), 2.32-2.25 (m, 5H), 2.06 (d, J = 12.6 Hz, 2H), 2.00-1.97 (m, 2H), 1.92-1.81 (m, 4H), 1.78-1.73 (m, 3H), 1.19-1.12 (m, 1H), 0.58-0.53 (m, 2H), 0.32-0.28 (m, 2H).

[0354] Example 17: Cyclopropylmethyl 3-methyl-2-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 17)

[0355] (Step 1) Using cyclopropylmethyl 2-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (50.0 mg, 0.108 mmol) obtained in Step 8 of Example 16, the procedure was repeated in the same manner as in Step 3 of Example 8 to obtain cyclopropylmethyl 3-methyl-2-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 17) (39.0 mg, 76%). ESI-MS m / z: 477 (M + H) + 1 H-NMR (CDCl3, δ): 7.74 (dd, J = 7.4, 1.6 Hz, 1H), 7.15 (td, J = 7.9, 1.8 Hz, 1H), 6.98-6.92 (m, 2H), 4.39-4.30 (m, 1H), 4.09 (br s, 2H), 3.95 (d, J = 6.7 Hz, 2H), 3.40-3.33 (m, 4H), 2.54-2.48 (m, 2H), 2.43 (s, 3H), 2.28 (s, 3H), 2.18-2.14 (m, 2H), 2.06 (d, J = 13.0 Hz, 2H), 1.94-1.82 (m, 2H), 1.71-1.64 (m, 4H), 1.21-1.10 (m, 1H), 0.58-0.53 (m, 2H), 0.31-0.27 (m, 2H).

[0356] Example 18: Cyclopropylmethyl 2-((1R,3s,5S)-8-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 18)

[0357] (Step 1) Cyclopropylmethyl 2-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (62.0 mg, 0.134 mmol) obtained in Step 8 of Example 16 was dissolved in DMF (1.3 mL), and benzoyl peroxide (29 mg, 0.121 mmol) and dipotassium hydrogen phosphate (47 mg, 0.268 mmol) were added, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was separated using a phase separator, the solvent was evaporated under reduced pressure, and the residue was purified by amino silica gel column chromatography (heptane / ethyl acetate = 7 / 3-0 / 1) to give cyclopropylmethyl 2-((1R,3s,5S)-8-benzoyloxy-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (59.0 mg, 76%). ESI-MS m / z: 583 (M + H). +

[0358] (Step 2) Cyclopropylmethyl 2-((1R,3s,5S)-8-benzoyloxy-8-azabicyclo[3.2.1]octan-3-yl)-3-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (59.0 mg, 0.101 mmol) obtained in Step 1 was dissolved in ethanol (1.0 mL), and aqueous sodium hydroxide solution (1.0 mol / L, 1.0 mL, 1.0 mmol) was added, followed by stirring at room temperature for 2 hours. Hydrochloric acid (1 mol / L) was added to the reaction mixture until the aqueous layer reached approximately pH 5, and the mixture was extracted with chloroform. The organic layer was separated using a phase separator, the solvent was evaporated under reduced pressure, and the residue was purified by amino silica gel column chromatography (heptane / ethyl acetate = 3 / 2-1 / 9) to give cyclopropylmethyl 2-((1R,3s,5S)-8-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (compound 18) (33.0 mg, 68%). ESI-MS m / z: 479 (M + H). + 1 H-NMR (CDCl3, δ): 7.75 (dd, J = 7.4, 1.6 Hz, 1H), 7.16 (td, J = 7.9, 1.6 Hz, 1H), 6.99-6.92 (m, 2H), 4.29-4.21 (m, 1H), 4.10 (s, 2H), 3.95 (d, J = 6.7 Hz, 2H), 3.74 (s, 2H), 3.36 (s, 2H), 2.53 (t, J = 11.9 Hz, 2H), 2.37-2.33 (m, 2H), 2.28 (s, 3H), 2.07-2.03 (m, 3H), 1.90-1.82 (m, 4H), 1.75-1.69 (m, 2H), 1.21-1.10 (m, 1H), 0.58-0.53 (m, 2H), 0.32-0.28 (m, 2H).

[0359] Example 19: (R)—N-(cyclopropylmethyl)-3-methyl-2-(4-azaspiro[2.5]octan-7-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 19)

[0360] (Step 1) tert-Butyl 7-oxo-4-azaspiro[2.5]octane-4-carboxylate (2.50 g, 11.1 mmol) was dissolved in methanol (40.0 mL), and sodium borohydride (840 mg, 22.2 mmol) was added under ice cooling. The mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture, 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 evaporated under reduced pressure to give crude tert-butyl 7-hydroxy-4-azaspiro[2.5]octane-4-carboxylate (2.50 g), which was used in the next step without further purification. ESI-MS m / z: 228 (M + H). +

[0361] (Step 2) Using the crude tert-butyl 7-hydroxy-4-azaspiro[2.5]octane-4-carboxylate (2.50 g) obtained in Step 1, the same procedure as in Step 5 of Example 1 was repeated to obtain crude tert-butyl 7-((methylsulfonyl)oxy)-4-azaspiro[2.5]octane-4-carboxylate (2.50 g), which was used in the next step without further purification. ESI-MS m / z: 306 (M + H). +

[0362] (Step 3) Using the crude tert-butyl 7-((methylsulfonyl)oxy)-4-azaspiro[2.5]octane-4-carboxylate (3.14 g) obtained in Step 2 and benzyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (4.00 g, 10.3 mmol) obtained in Step 4 of Example 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain benzyl 2-(4-(tert-butoxycarbonyl)-4-azaspiro[2.5]octan-7-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.70 g, 28%). ESI-MS m / z: 599 (M + H) +

[0363] (Step 4) Using benzyl 2-(4-(tert-butoxycarbonyl)-4-azaspiro[2.5]octan-7-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.70 g, 2.85 mmol) obtained in Step 3, the procedure was repeated in the same manner as in Step 7 of Example 1 to obtain tert-butyl 7-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-4-azaspiro[2.5]octane-4-carboxylate (1.00 g, 76%). ESI-MS m / z: 465 (M + H) +

[0364] (Step 5) Using tert-butyl 7-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-4-azaspiro[2.5]octane-4-carboxylate (330 mg, 0.710 mmol) obtained in Step 4 and 4-nitrophenyl(cyclopropylmethyl)carbamate (168 mg, 0.710 mmol) obtained in Step 1 of Example 11, the procedure was repeated in the same manner as in Step 8 of Example 1 to obtain tert-butyl 7-(1'-((cyclopropylmethyl)carbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-4-azaspiro[2.5]octane-4-carboxylate (300 mg, 75%). ESI-MS m / z: 562 (M + H) +

[0365] (Step 6) Using tert-butyl 7-(1'-((cyclopropylmethyl)carbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-4-azaspiro[2.5]octane-4-carboxylate (110 mg, 0.200 mmol) obtained in Step 5, tert-butyl (R)-7-(1'-((cyclopropylmethyl)carbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-4-azaspiro[2.5]octane-4-carboxylate (45.0 mg, 41%) was obtained in the same manner as in Step 10 of Example 1. ESI-MS m / z: 562 (M + H) +

[0366] (Step 7) Using tert-butyl (R)-7-(1'-((cyclopropylmethyl)carbamoyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-2-yl)-4-azaspiro[2.5]octane-4-carboxylate (45.0 mg, 0.080 mmol) obtained in Step 6, (R)—N-(cyclopropylmethyl)-3-methyl-2-(4-azaspiro[2.5]octan-7-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 19) (22.4 mg, 61%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 462 (M + H) + 1 H NMR (CDCl3, δ): 7.75 (dd, J = 7.6, 1.6 Hz, 1H), 7.20-7.10 (m, 1H), 7.05-6.95 (m, 2H), 4.70-4.60 (m, 1H), 4.45-4.30 (m, 1H), 4.00-3.85 (m, 2H), 3.60-3.45 (m, 4H), 3.20-3.05 (m, 3H), 2.85-2.75 (m, 1H), 2.45-2.35 (m, 1H), 2.33 (s, 3H), 2.25-2.10 (m, 3H), 2.10-1.95 (m, 2H), 1.55-1.45 (m, 1H), 1.25-1.05 (m, 3H), 0.80-0.60 (m, 2H), 0.60-0.50 (m, 2H), 0.35-0.25 (m, 2H).

[0367] Example 20 (R)—N-(cyclobutylmethyl)-3-methyl-2-(5-azaspiro[3.5]nonan-8-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 20)

[0368] (Step 1) Using tert-butyl 8-oxo-5-azaspiro[3.5]nonane-5-carboxylate (1.79 g, 9.61 mmol), the procedure was repeated in the same manner as in Step 2 of Example 15 to obtain tert-butyl 8-(2-tosylhydrazinylidene)-5-azaspiro[3.5]nonane-5-carboxylate (3.00 g, 69%). ESI-MS m / z: 408 (M + H). +

[0369] (Step 2) Using tert-butyl 8-(2-tosylhydrazine ylidene)-5-azaspiro[3.5]nonane-5-carboxylate (6.88 g, 16.9 mmol) obtained in Step 1 and tert-butyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (3.00 g, 8.44 mmol) obtained in Step 4 of Example 5, the procedure was repeated in the same manner as in Step 3 of Example 15 to obtain tert-butyl 2-(5-(tert-butoxycarbonyl)-5-azaspiro[3.5]nonan-8-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.30 g, 24%). ESI-MS m / z: 579 (M + H) +

[0370] (Step 3) tert-Butyl 2-(5-(tert-butoxycarbonyl)-5-azaspiro[3.5]nonan-8-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.30 g, 2.24 mmol) obtained in Step 2 was dissolved in dichloromethane (20 mL), trifluoroacetic acid (4.00 mL) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give a crude product of 3-methyl-2-(5-azaspiro[3.5]nonan-8-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] ditrifluoroacetate (1.00 g), which was used in the next step without purification. ESI-MS m / z: 379 (M + H) +

[0371] (Step 4) Using the crude product (320 mg) of 3-methyl-2-(5-azaspiro[3.5]nonan-8-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] ditrifluoroacetate obtained in Step 3 and 4-nitrophenyl(cyclopropylmethyl)carbamate (200 mg, 0.840 mmol) obtained in Step 1 of Example 11, N-(cyclopropylmethyl)-3-methyl-2-(5-azaspiro[3.5]nonan-8-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (13.0 mg, 3.8% yield over two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 476 (M + H) +

[0372] (Step 5) N-(cyclopropylmethyl)-3-methyl-2-(5-azaspiro[3.5]nonan-8-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (70 mg, 0.147 mmol) obtained in Step 4 was purified by chiral SFC (CHIRALPAK IA (20x250 mm, 5 μm), hexane (0.2% diethylamine) / ethanol = 90 / 10, flow rate 20 mL / min, RT1: 11.6 min, RT2: 14.4 min). min to give (R)-N-(cyclopropylmethyl)-3-methyl-2-(5-azaspiro[3.5]nonan-8-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (compound 20) (23.9 mg, 34%). ESI-MS m / z: 476 (M + H). + 1H NMR (CDCl3, δ): 7.75 (dd, J = 7.6, 1.6 Hz, 1H), 7.17 (td, J = 7.6, 1.6 Hz, 1H), 7.02-6.90 (m, 2H), 4.59 (t, J = 5.2 Hz, 1H), 4.25-4.15 (m, 1H), 3.91-3.83 (m, 2H), 3.50-3.39 (m, 2H), 3.25-3.10 (m, 3H), 2.95-2.80 (m, 1H), 2.32 (s, 3H), 2.31-2.20 (m, 4H), 2.20-2.05 (m, 6H), 2.05-1.85 (m, 5H), 1.15-1.00 (m, 1H), 0.56-0.45 (m, 2H), 0.25-0.20 (m, 2H).

[0373] Example 21: Cyclopropylmethyl (R)-2-(2,2-dimethyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole4,4'-piperidine]-1'-carboxylate (Compound 21)

[0374] (Step 1) Using 2,2-dimethylthian-4-one (1 g, 6.93 mmol), the procedure was repeated as in Step 1 of Example 19 to obtain 2,2-dimethyltetrahydro-2H-thiopyran-4-ol (1 g, 99%). ESI-MS m / z: 147 (M + H). +

[0375] (Step 2) Using 2,2-dimethyltetrahydro-2H-thiopyran-4-ol (1 g, 6.84 mmol) obtained in Step 1, 2,2-dimethyltetrahydro-2H-thiopyran-4-yl methanesulfonate (1.1 g, 72%) was obtained in the same manner as in Step 5 of Example 1. ESI-MS m / z: 225 (M + H) +

[0376] (Step 3) Using 2,2-dimethyltetrahydro-2H-thiopyran-4-yl methanesulfonate (630 mg, 2.82 mmol) obtained in Step 2 and cyclopropylmethyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.0 g, 2.82 mmol) obtained in Step 5 of Example 16, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain cyclopropylmethyl 2-(2,2-dimethyltetrahydro-2H-thiopyran-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (300 mg, 22%). ESI-MS m / z: 482 (M + H) +

[0377] (Step 4) Cyclopropylmethyl 2-(2,2-dimethyltetrahydro-2H-thiopyran-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (300 mg, 0.62 mmol) obtained in Step 3 and m-chloroperbenzoic acid (322 mg, 1.87 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 5 hours. The reaction mixture was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by reverse-phase column chromatography (water / acetonitrile = 9 / 1-3 / 7) and SFC (CO₂ / 0.1% ammonia in methanol = 68 / 32) to give cyclopropylmethyl 2-(2,2-dimethyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (32 mg, 21%). ESI-MS m / z: 514 (M + H). +

[0378] (Step 5) Using cyclopropylmethyl 2-(2,2-dimethyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole4,4'-piperidine]-1'-carboxylate (50 mg, 0.097 mmol) obtained in Step 4, cyclopropylmethyl (R)-2-(2,2-dimethyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole4,4'-piperidine]-1'-carboxylate (Compound 21) (13.0 mg, 26%) was obtained in the same manner as in Step 10 of Example 1. ESI-MS m / z: 514 (M + H) + 1 H NMR (CDCl3, δ): 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 7.26-7.15 (m, 1H), 7.05-6.95 (m, 2H), 4.60-4.50 (m, 1H), 4.20-4.10 (m, 2H), 3.95 (d, J = 7.2 Hz, 2H), 3.42-3.30 (m, 3H), 3.22-3.12 (m, 1H), 3.10-3.00 (m, 1H), 3.00-2.86 (m, 1H), 2.32 (s, 3H), 2.32-2.25 (m, 1H), 2.15-2.08 (m, 2H), 2.03-1.80 (m, 3H), 1.62 (s, 3H), 1.44 (s, 3H), 1.23-1.08 (m, 1H), 0.61-0.50 (m, 2H), 0.34-0.25 (m, 2H).

[0379] Example 22: Cyclopropylmethyl 2-((1R,3s,5S)-8,8-dioxide-8-thiabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (Compound 22)

[0380] (Step 1) (1R,5S)-8-Methyl-8-azabicyclo[3.2.1]octan-3-one (10 g, 71.8 mmol) and methyl iodide (15.3 g, 108 mmol) were dissolved in diethyl ether (20 mL) and stirred at room temperature for 16 hours. The resulting solid was collected by filtration to give (1R,5S)-8,8-dimethyl-3-oxo-8-azabicyclo[3.2.1]octan-8-ium iodide (7.5 g, 37%). ESI-MS m / z: 154 (M) +

[0381] (Step 2) (1R,5S)-8,8-dimethyl-3-oxo-8-azabicyclo[3.2.1]octan-8-ium iodide (20.2 g, 71.8 mmol) obtained in Step 1 and sodium sulfide (19.0 g, 79.0 mmol) were dissolved in water (200 mL) and stirred at 85°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give crude (1R,5S)-8-thiabicyclo[3.2.1]octan-3-one (11.1 g), which was used in the next step without further purification. ESI-MS m / z: 143 (M + H). +

[0382] (Step 3) Using the crude (10.2 g) (1R,5S)-8-thiabicyclo[3.2.1]octan-3-one obtained in Step 2, (1R,3r,5S)-8-thiabicyclo[3.2.1]octan-3-ol (3.06 g, 29% yield in two steps) was obtained in the same manner as in Step 1 of Example 19. ESI-MS m / z: 145 (M + H) +

[0383] (Step 4) Using (1R,3r,5S)-8-thiabicyclo[3.2.1]octan-3-ol (500 mg, 3.47 mmol) obtained in Step 3, (1R,3r,5S)-8-thiabicyclo[3.2.1]octan-3-yl methanesulfonate (668 mg, 87%) was obtained in the same manner as in Step 5 of Example 1. ESI-MS m / z: 223 (M + H) +

[0384] (Step 5) Using (1R,3r,5S)-8-thiabicyclo[3.2.1]octan-3-yl methanesulfonate (3.8 g, 17.1 mmol) obtained in Step 4 and cyclopropylmethyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (6.04 g, 17.1 mmol) obtained in Step 5 of Example 16, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain cyclopropylmethyl 2-((1R,3s,5S)-8-thiabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.0 g, 24%). ESI-MS m / z: 480 (M + H) +

[0385] (Step 6) Using cyclopropylmethyl 2-((1R,3s,5S)-8-thiabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole4,4'-piperidine]-1'-carboxylate (200 mg, 0.42 mmol) obtained in Step 5, cyclopropylmethyl 2-((1R,3s,5S)-8,8-dioxide-8-thiabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole4,4'-piperidine]-1'-carboxylate (Compound 22) (22.2 mg, 10%) was obtained in the same manner as in Step 4 of Example 21. ESI-MS (m / z): 512 (M + H) + 1H NMR (CDCl3, δ):7.80 (d, J = 7.6 Hz, 1H), 7.30-7.15 (m, 1H), 7.05-6.92 (m, 2H), 4.85-4.70 (m, 1H), 4.25-4.10 (m, 1H), 3.95 (d, J = 7.2 Hz, 2H), 3.45-3.30 (m, 2H), 3.30-3.10 (m, 4H), 2.65-2.50 (m, 2H), 2.38 (s, 3H), 2.30-2.15 (m, 4H), 2.15-2.05 (m, 2H), 1.93-1.83 (m, 3H), 1.25-1.15 (m, 1H), 0.61-0.51 (m, 2H), 0.40-0.30 (m, 2H).

[0386] Example 23: Cyclopropylmethyl 3-methyl-2-((1R,3s,5S)-8-oxido-8-thiabicyclo[3.2.1]octan-3-yl)-2H-spiro[chromeno[4,3-c]pyrazole 4,4'-piperidine]-1'-carboxylate (Compound 23)

[0387] (Step 1) Cyclopropylmethyl 2-((1R,3s,5S)-8-thiabicyclo[3.2.1]octan-3-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole4,4'-piperidine]-1'-carboxylate (500 mg, 1.04 mmol) obtained in Step 5 of Example 22 and m-chloroperbenzoic acid (179 mg, 1.04 mmol) were dissolved in dichloromethane and stirred overnight at room temperature. The reaction mixture was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by reverse-phase HPLC and SFC to give cyclopropylmethyl 3-methyl-2-((1R,3s,5S)-8-oxido-8-thiabicyclo[3.2.1]octan-3-yl)-2H-spiro[chromeno[4,3-c]pyrazole 4,4'-piperidine]-1'-carboxylate (Compound 23) (70.2 mg, 46%). ESI-MS (m / z): 496 [M+H] + 1H NMR (CDCl3, δ): 7.78 (d, J = 7.6 Hz, 1H), 7.25-7.15 (m, 1H), 7.04-6.91 (m, 2H), 4.45-4.30 (m, 1H), 4.20-4.05 (m, 2H), 3.95 (d, J = 7.2 Hz, 2H), 3.75-3.67 (m, 2H), 3.45-3.30 (m, 2H), 2.85-2.75 (m, 2H), 2.65-2.55 (m, 2H), 2.31 (s, 3H), 2.24-2.14 (m, 2H), 2.14-2.05 (m, 4H), 2.00-1.85 (m, 2H), 1.23-1.08 (m, 1H), 0.60-0.50 (m, 2H), 0.40-0.30 (m, 2H).

[0388] Example 24: (2-((R)-2,2-dimethylpiperidin-4-yl)-3-ethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-1′-yl)((1S,2S)-2-methylcyclopropyl)methanone (Compound 24)

[0389] (Step 1) Using spiro[chroman-2,4'-piperidin]-4-one (7.00 g, 32.2 mmol) obtained from spiro[chroman-2,4'-piperidin]-4-one hydrochloride obtained in Step 1 of Example 16 and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (3.23 g, 32.2 mmol), 1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)spiro[chroman-2,4'-piperidin]-4-one (7.00 g, 65% yield over two steps) was obtained in the same manner as in Step 1 of Example 4. ESI-MS m / z: 300 (M + H) +

[0390] (Step 2) Using 1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)spiro[chroman-2,4'-piperidin]-4-one (5.00 g, 16.7 mmol) obtained in Step 1 and propionaldehyde (1.94 g, 33.4 mmol), 3-(1-hydroxypropyl)-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)spiro[chroman-2,4'-piperidin]-4-one (2.40 g, 36%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 358 (M + H) +

[0391] (Step 3) Using 3-(1-hydroxypropyl)-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)spiro[chroman-2,4'-piperidin]-4-one (2.40 g, 6.71 mmol) obtained in Step 2, (Z)-3-(1-hydroxypropylidene)-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)spiro[chroman-2,4'-piperidin]-4-one (2.00 g, 77%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 356 (M + H) +

[0392] (Step 4) Using (Z)-3-(1-hydroxypropylidene)-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)spiro[chroman-2,4'-piperidin]-4-one (2.00 g, 5.62 mmol) obtained in Step 3, (3-ethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (1.00 g, 47%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 352 (M + H) +

[0393] (Step 5) Using (3-ethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (1.00 g, 2.84 mmol) obtained in Step 4 and tert-butyl 2,2-dimethyl-4((methylsulfonyl)oxy)piperidine-1-carboxylate (1.75 g, 5.69 mmol) obtained in Step 5 of Example 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain tert-butyl 4-(3-ethyl-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (800 mg, 45%). ESI-MS m / z: 563 (M + H) +

[0394] (Step 6) tert-Butyl 4-(3-ethyl-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (800 mg, 1.42 mmol) obtained in Step 5 was dissolved in a hydrogen chloride / 1,4-dioxane solution (4 mol / L, 10 mL, 40 mmol) and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and an aqueous sodium bicarbonate solution was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by SFC to give (2-(2,2-dimethylpiperidin-4-yl)-3-ethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (33.3 mg, 5.1%). ESI-MS m / z: 463 (M + H). +

[0395] (Step 7) (2-(2,2-dimethylpiperidin-4-yl)-3-ethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (80.0 mg, 0.17 mmol) obtained in Step 6 was purified by chiral SFC (CHIRALPAK IE (20x250 mm, 5 µm), hexane (0.2% diethylamine) / isopropanol = 75 / 25, flow rate 20 mL / min, RT1: 14.8 min, RT2: 17.0 min). min to give (2-((R)-2,2-dimethylpiperidin-4-yl)-3-ethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (compound 24) (35.7 mg, 45%). ESI-MS m / z: 463 (M + H). + 1 H NMR (CDCl3, δ): 7.77 (dd, J = 7.6, 1.8 Hz, 1H), 7.18 (td, J = 7.6, 1.8 Hz, 1H), 7.04-6.93 (m, 2H), 4.70-4.58 (m, 1H), 4.42-4.30 (m, 1H), 4.15-4.05 (m, 1H), 3.80-3.69 (m, 1H), 3.32-3.23 (m, 2H), 3.25-3.10 (m, 2H), 2.66 (q, J = 7.2 Hz, 2H), 2.43-2.23 (m, 3H), 2.23-2.10 (m, 2H), 1.99-1.78 (m, 4H), 1.55-1.50 (m, 1H), 1.37 (s, 6H), 1.28-1.10 (m, 7H), 0.70-0.60 (m, 1H).

[0396] Example 25: (3-cyclopropyl-2-((R)-2,2-dimethylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-1′-yl)((1S,2S)-2-methylcyclopropyl)methanone (Compound 25)

[0397] (Step 1) Using tert-butyl 4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (15.0 g, 47.3 mmol) obtained in Step 1 of Example 5 and cyclopropanecarbaldehyde (6.63 g, 94.5 mmol), the procedure was repeated in the same manner as in Step 2 of Example 1 to obtain tert-butyl 3-(cyclopropyl(hydroxy)methyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (3.05 g, 14%). ESI-MS m / z: 388 (M + H) +

[0398] (Step 2) Using tert-butyl 3-(cyclopropyl(hydroxy)methyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (3.00 g, 7.74 mmol) obtained in Step 1, tert-butyl (Z)-3-(cyclopropyl(hydroxy)methylene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (2.50 g, 67%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 386 (M + H) +

[0399] (Step 3) Using tert-butyl (Z)-3-(cyclopropyl(hydroxy)methylene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (2.50 g, 6.48 mmol) obtained in Step 2, the procedure was repeated in the same manner as in Step 4 of Example 1 to obtain tert-butyl 3-cyclopropyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (950 mg, 33%). ESI-MS m / z: 382 (M + H) +

[0400] (Step 4) Using tert-butyl 3-cyclopropyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (950 mg, 2.49 mmol) obtained in Step 3 and tert-butyl 2,2-dimethyl-4((methylsulfonyl)oxy)piperidine-1-carboxylate (1.53 g, 4.90 mmol) obtained in Step 5 of Example 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain tert-butyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3-cyclopropyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1-carboxylate (800 mg, 48%). ESI-MS m / z: 593 (M + H) +

[0401] (Step 5) tert-Butyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3-cyclopropyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1-carboxylate (800 mg, 1.35 mmol) obtained in Step 4 was dissolved in dichloromethane (10 mL), and a hydrogen chloride / ethyl acetate solution (4.0 mol / L, 10 mL) was added, followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure to give crude 3-cyclopropyl-2-(2,2-dimethylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]dihydrochloride (600 mg), which was used in the next step without further purification. ESI-MS m / z: 393 (M + H) +

[0402] (Step 6) Using the crude product (600 mg) of 3-cyclopropyl-2-(2,2-dimethylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride obtained in Step 5 and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (153 mg, 1.52 mmol), (3-cyclopropyl-2-(2,2-dimethylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (19.2 mg, 3.0% yield over two steps) was obtained in the same manner as in Step 1 of Example 4. ESI-MS m / z: 475 (M + H) +

[0403] (Step 7) (3-cyclopropyl-2-(2,2-dimethylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (70 mg, 0.15 mmol) obtained in Step 6 was purified by chiral SFC (CHIRALPAK IE (20x250 mm, 5 µm), tert-butyl methyl ether (0.2% diethylamine) / hexane:isopropanol (9:1) = 90 / 10, flow rate 20 mL / min, RT1: 17.9 min, RT2: 21.3 min). min to give (3-cyclopropyl-2-((R)-2,2-dimethylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (compound 25) (6.2 mg, 8.9%). ESI-MS m / z: 475 (M + H). + 1H NMR (CDCl3, δ): 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.19 (td, J = 7.6, 1.8 Hz, 1H), 7.04-6.94 (m, 2H), 5.00-4.85 (m, 1H), 4.65-4.53 (m, 1H), 4.20-4.07 (m, 1H), 3.85-3.70 (m, 1H), 3.45-3.33 (m, 1H), 3.30-3.11 (m, 2H), 2.45-2.36 (m, 3H), 2.24-2.00 (m, 5H), 2.00-1.90 (m, 3H), 1.90-1.80 (m, 1H), 1.60-1.52 (m, 1H), 1.40 (s, 6H), 1.40-3.30 (m, 1H), 1.30-1.10 (m, 4H), 0.68-0.57 (m, 3H).

[0404] Example 26: Cyclopropylmethyl 2-(2-((2,2-dimethylpiperidin-4-yl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 26)

[0405] (Step 1) Cyclopropylmethyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (100 mg, 0.283 mmol) obtained in Step 5 of Example 16, tert-butyl 2-bromoacetate (83 mg, 0.424 mmol), and cesium carbonate (184 mg, 0.566 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane / ethyl acetate = 8 / 2-4 / 6) to give cyclopropylmethyl 2-(2-(tert-butoxy)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (127 mg, 96%). ESI-MS m / z: 468 (M + H). +

[0406] (Step 2) Cyclopropylmethyl 2-(2-(tert-butoxy)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.4 g, 2.99 mmol) obtained in Step 1 was dissolved in dichloromethane (20 mL), trifluoroacetic acid (4 mL, 52.3 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 10 / 0 to 8 / 2) to give 2-(1'-((cyclopropylmethoxy)carbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (1.24 g, quantitative yield). ESI-MS m / z: 412 (M + H). +

[0407] (Step 3) 2-(1'-((cyclopropylmethoxy)carbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (30 mg, 0.073 mmol) obtained in Step 2, tert-butyl 4-amino-2,2-dimethylpiperidine-1-carboxylate (25 mg, 0.109 mmol), HATU (41.6 mg, 0.109 mmol), and N,N-diisopropylethylamine (0.025 mL, 0.146 mmol) were dissolved in DMF (1 mL) and stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude cyclopropylmethyl 2-(2-((1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (30 mg), which was used in the next step without further purification. ESI-MS m / z: 622 (M + H). +

[0408] (Step 4) Using the crude product (30 mg) of cyclopropylmethyl 2-(2-((1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 3, cyclopropylmethyl 2-(2-((2,2-dimethylpiperidin-4-yl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 26) (21 mg, two-step yield: 55%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 522 (M + H) +1H-NMR (CDCl3, δ): 7.71 (dd, J = 7.6, 1.8 Hz, 1H), 7.23 (td, J = 7.6, 1.5 Hz, 1H), 7.04-6.97 (m, 2H), 6.06 (d, J = 7.2 Hz, 1H), 4.72 (s, 2H), 4.19-4.00 (m, 3H), 3.95 (d, J = 7.2 Hz, 2H), 3.44-3.29 (m, 2H), 2.94-2.85 (m, 2H), 2.28 (s, 3H), 2.13-2.03 (m, 3H), 1.94-1.83 (m, 3H), 1.70 (dd, J = 12.6, 2.2 Hz, 1H), 1.14 (s, 3H), 1.10 (s, 3H), 1.08-1.00 (m, 3H), 0.59-0.52 (m, 2H), 0.33-0.27 (m, 2H).

[0409] Example 27: Cyclopropylmethyl 2-(2-(azepan-4-ylamino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 27)

[0410] (Step 1) Using 2-(1'-((cyclopropylmethoxy)carbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (33 mg, 0.081 mmol) obtained in Step 2 of Example 26 and tert-butyl 4-aminoazepane-1-carboxylate (26 mg, 0.122 mmol), the crude product of cyclopropylmethyl 2-(2-((1-(tert-butoxycarbonyl)azepan-4-yl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (49 mg) was obtained in the same manner as in Step 3 of Example 26, and was used in the next step without purification. ESI-MS m / z: 608 (M + H) +

[0411] (Step 2) Using the crude product (49 mg) of cyclopropylmethyl 2-(2-((1-(tert-butoxycarbonyl)azepan-4-yl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 1, cyclopropylmethyl 2-(2-(azepan-4-ylamino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 27) (7.5 mg, 18% yield in two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 508 (M + H) + 1H-NMR (CDCl3, δ): 7.73 (d, J = 7.2 Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 7.04-6.96 (m, 2H), 6.95-6.89 (m, 1H), 4.76 (s, 2H), 4.32-4.25 (m, 1H), 4.17-4.07 (m, 2H), 3.95 (d, J = 7.2 Hz, 2H), 3.44-3.31 (m, 2H), 2.85-2.69 (m, 3H), 2.58-2.48 (m, 1H), 2.30 (s, 3H), 2.10-2.02 (m, 2H), 1.96-1.84 (m, 3H), 1.60-1.50 (m, 4H), 1.48-1.39 (m, 1H), 1.19-1.11 (m, 1H), 0.59-0.53 (m, 2H), 0.33-0.27 (m, 2H).

[0412] Example 28: Cyclopropylmethyl 2-(2-(((1R,3s,5S)-8-azabicyclo[3,2,1]octan-3-yl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 28)

[0413] (Step 1) Using 2-(1′-((cyclopropylmethoxy)carbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-2-yl)acetic acid (33 mg, 0.081 mmol) obtained in Step 2 of Example 26 and tert-butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (28 mg, 0.122 mmol), cyclopropylmethyl The crude product of 2-(2-(((1R,3s,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3,2,1]octan-3-yl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (49 mg) was obtained and used in the next step without purification. ESI-MS m / z: 620 (M + H). +

[0414] (Step 2) Using the crude product (49 mg) of cyclopropylmethyl 2-(2-(((1R,3s,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3,2,1]octan-3-yl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate obtained in Step 1, cyclopropylmethyl 2-(2-(((1R,3s,5S)-8-azabicyclo[3,2,1]octan-3-yl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (Compound 28) (8 mg, two-step yield 19%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 520 (M + H) +1H-NMR (CDCl3, δ): 7.70 (d, J = 7.6 Hz, 1H), 7.24-7.21 (m, 1H), 7.04-6.97 (m, 2H), 6.01-5.92 (m, 1H), 4.72 (s, 2H), 4.23-4.06 (m, 3H), 3.95 (d, J = 7.2 Hz, 2H), 3.60-3.54 (m, 2H), 3.44-3.29 (m, 2H), 2.27 (s, 3H), 2.12-2.03 (m, 2H), 1.96-1.74 (m, 9H), 1.38-1.29 (m, 2H), 1.20-1.11 (m, 1H), 0.59-0.53 (m, 2H), 0.32-0.27 (m, 2H).

[0415] Example 29: Cyclopropylmethyl 3-methyl-2-(2-(methyl(pyrrolidin-3-yl)amino)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 29)

[0416] (Step 1) Using 2-(1'-((cyclopropylmethoxy)carbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (33 mg, 0.081 mmol) obtained in Step 2 of Example 26 and tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (24 mg, 0.122 mmol), the crude product of cyclopropylmethyl 2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (49 mg) was obtained in the same manner as in Step 3 of Example 26, and was used in the next step without purification. ESI-MS m / z: 594 (M + H) +

[0417] (Step 2) Using the crude product (49 mg) of cyclopropylmethyl 2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 1, cyclopropylmethyl 3-methyl-2-(2-(methyl(pyrrolidin-3-yl)amino)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 29) (7 mg, 17% yield in two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 494 (M + H) + 1H-NMR (CDCl3, δ): 7.70 (d, J = 7.2 Hz, 1H), 7.22-7.15 (m, 1H), 6.99-6.93 (m, 2H), 5.05-4.90 (m, 3H), 4.17-4.03 (m, 2H), 3.94 (d, J = 7.2 Hz, 2H), 3.42-3.30 (m, 2H), 3.13-3.04 (m, 4H), 2.90-2.79 (m, 3H), 2.31-2.25 (m, 3H), 2.15-2.04 (m, 3H), 1.97-1.85 (m, 3H), 1.20-1.10 (m, 1H), 0.59-0.52 (m, 2H), 0.32-0.27 (m, 2H).

[0418] Example 30: N-methyl-2-(3-methyl-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-N-((R)-1-methylpyrrolidin-3-yl)-acetamide (Compound 30)

[0419] (Step 1) Using benzyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.00 g, 2.57 mmol) obtained in Step 4 of Example 1, the procedure was repeated in the same manner as in Step 1 of Example 26 to obtain benzyl 2-(2-(tert-butoxy)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (quantitative). ESI-MS m / z: 504 (M + H) +

[0420] (Step 2) Using the benzyl 2-(2-(tert-butoxy)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (whole amount) obtained in Step 1, the crude product of 2-(1'-((benzyloxy)carbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid was obtained in the same manner as in Step 2 of Example 26, and was used in the next step without purification. ESI-MS m / z: 448 (M + H). +

[0421] (Step 3) Using the crude product of 2-(1'-((benzyloxy)carbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid obtained in Step 2 and tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate (647 mg, 3.23 mmol), benzyl (R)-2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.19 g, 3-step yield 70%) was obtained in the same manner as in Step 3 of Example 26. ESI-MS m / z: 630 (M + H) +

[0422] (Step 4) Using benzyl (R)-2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.19 g, 1.89 mmol) obtained in Step 3, the crude product of benzyl (R)-3-methyl-2-(2-(methyl(pyrrolidin-3-yl)amino)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate was obtained in the same manner as in Step 3 of Example 2, and was used in the next step without purification. ESI-MS m / z: 530 (M + H) +

[0423] (Step 5) Using the crude product of benzyl (R)-3-methyl-2-(2-(methyl(pyrrolidin-3-yl)amino)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 4, the procedure was carried out in the same manner as in Step 3 of Example 8 to obtain benzyl (R)-3-methyl-2-(2-(methyl(1-methylpyrrolidin-3-yl)amino)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (879 mg, 86% yield over two steps). ESI-MS m / z: 544 (M + H) +

[0424] (Step 6) Using benzyl (R)-3-methyl-2-(2-(methyl(1-methylpyrrolidin-3-yl)amino)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (879 mg, 1.62 mmol) obtained in Step 5, (R)-N-methyl-2-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-N-(1-methylpyrrolidin-3-yl)acetamide (481 mg, 73%) was obtained in the same manner as in Step 7 of Example 1. ESI-MS m / z: 410 (M + H) +

[0425] (Step 7) Using (R)-N-methyl-2-(3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-N-(1-methylpyrrolidin-3-yl)acetamide (80 mg, 0.195 mmol) obtained in Step 6 and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (29.3 mg, 0.293 mmol), N-methyl-2-(3-methyl-1'-((1S,2S)-2-methylcyclopropane-1-carbonyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-N-((R)-1-methylpyrrolidin-3-yl)-acetamide (compound 30) (17.1 mg, 18%) was obtained in the same manner as in Step 1 of Example 4. ESI-MS m / z: 492 (M + H) + 1 H-NMR (CDCl3, δ): 7.77 (dd, J = 7.9, 1.6 Hz, 1H), 7.22-7.17 (m, 1H), 6.98 (dd, J = 7.4, 5.6 Hz, 2H), 5.09-4.84 (m, 3H), 4.58 (d, J = 12.6 Hz, 1H), 4.07 (d, J = 12.6 Hz, 1H), 3.68 (t, J = 12.8 Hz, 1H), 3.31 (brs, 1H), 3.18-3.14 (m, 4H), 2.93 (s, 1H), 2.75 (s, 1H), 2.62 (s, 2H), 2.40 (s, 1H), 2.25-2.13 (m, 7H), 1.92-1.89 (m, 2H), 1.51-1.47 (m, 1H), 1.37-1.29 (m, 2H), 1.20-1.19 (m, 1H), 1.13 (d, J = 5.8 Hz, 3H), 0.61-0.59 (m, 1H)

[0426] Example 31: Cyclopropylmethyl 3-methyl-2-(2-oxo-2-(2,8-diazaspiro[4.5]decan-8-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 31)

[0427] (Step 1) Using 2-(1'-((cyclopropylmethoxy)carbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (33 mg, 0.081 mmol) obtained in Step 2 of Example 26 and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (29 mg, 0.122 mmol), the crude product of cyclopropylmethyl 2-(2-(2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (49 mg) was obtained in the same manner as in Step 3 of Example 26, and was used in the next step without purification. ESI-MS m / z: 634 (M + H) +

[0428] (Step 2) Using the crude product (49 mg) of cyclopropylmethyl 2-(2-(2-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 1, cyclopropylmethyl 3-methyl-2-(2-oxo-2-(2,8-diazaspiro[4.5]decan-8-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 31) (12 mg, 41% yield in two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 534 (M + H) +1H-NMR (CDCl3, δ): 7.70 (dd, J = 7.9, 1.6 Hz, 1H), 7.18 (td, J = 7.9, 1.6 Hz, 1H), 6.99-6.93 (m, 2H), 4.97 (s, 2H), 4.17-4.03 (m, 2H), 3.94 (d, J = 7.2 Hz, 2H), 3.72-3.47 (m, 4H), 3.43-3.30 (m, 2H), 3.00 (t, J = 7.0 Hz, 2H), 2.75 (s, 2H), 2.29 (s, 3H), 2.14-2.06 (m, 2H), 1.98-1.84 (m, 2H), 1.66-1.59 (m, 3H), 1.58-1.50 (m, 4H), 1.19-1.11 (m, 1H), 0.59-0.52 (m, 2H), 0.33-0.27 (m, 2H).

[0429] Example 32: Cyclopropylmethyl 3-methyl-2-(2-oxo-2-(2,7-diazaspiro[4.4]nonan-2-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 32)

[0430] (Step 1) Using 2-(1'-((cyclopropylmethoxy)carbonyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (33 mg, 0.081 mmol) obtained in Step 2 of Example 26 and tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (28 mg, 0.122 mmol), the crude product of cyclopropylmethyl 2-(2-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (49 mg) was obtained in the same manner as in Step 3 of Example 26, and was used in the next step without purification. ESI-MS m / z: 620 (M + H) +

[0431] (Step 2) Using the crude product (49 mg) of cyclopropylmethyl 2-(2-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-2-oxoethyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 1, cyclopropylmethyl 3-methyl-2-(2-oxo-2-(2,7-diazaspiro[4.4]nonan-2-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 32) (15 mg, 44% yield in two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 520 (M + H) + 1H-NMR (CDCl3, δ): 7.72-7.67 (m, 1H), 7.18 (t, J = 7.0 Hz, 1H), 7.00-6.93 (m, 2H), 4.87 (d, J = 13.5 Hz, 2H), 4.17-4.03 (m, 2H), 3.94 (d, J = 7.2 Hz, 2H), 3.66-3.42 (m, 4H), 3.41-3.30 (m, 2H), 3.04 (q, J = 7.6 Hz, 2H), 2.92-2.78 (m, 2H), 2.31 (s, 3H), 2.13-2.06 (m, 2H), 2.00 (t, J = 7.0 Hz, 1H), 1.96-1.85 (m, 3H), 1.82-1.74 (m, 3H), 1.20-1.11 (m, 1H), 0.59-0.52 (m, 2H), 0.31-0.26 (m, 2H).

[0432] Example 33: Cyclopropylmethyl 3-methyl-2-(pyrrolidin-3-ylmethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 33)

[0433] (Step 1) Using tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (200 mg, 0.994 mmol), the procedure was repeated in the same manner as in Step 5 of Example 1 to obtain tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (115 mg, 41%). ESI-MS m / z: 280 (M + H) +

[0434] (Step 2) Using benzyl 3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (100 mg, 0.257 mmol) obtained in Step 4 of Example 1 and tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (115 mg, 0.412 mmol) obtained in Step 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain benzyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (119 mg, 81%). ESI-MS m / z: 573 (M + H) +

[0435] (Step 3) Using benzyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (119 mg, 0.207 mmol) obtained in Step 2, the procedure was repeated in the same manner as in Step 7 of Example 1 to obtain crude tert-butyl 3-((3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-2-yl)methyl)pyrrolidine-1-carboxylate (91 mg). ESI-MS m / z: 439 (M + H) +

[0436] (Step 4)

[0437] Using the crude tert-butyl 3-((3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-2-yl)methyl)pyrrolidine-1-carboxylate (45 mg) obtained in Step 3 and cyclopropylmethyl (4-nitrophenyl)carbonate (36.5 mg, 0.154 mmol) obtained in Step 5 of Example 15, cyclopropylmethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (37.5 mg, 68% yield over two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 537 (M + H) +

[0438] (Step 5) Using cyclopropylmethyl 2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (37.5 mg, 0.070 mol) obtained in Step 4, cyclopropylmethyl 3-methyl-2-(pyrrolidin-3-ylmethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 33) (8.9 mg, 29%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 437 (M + H) + 1H-NMR (CDCl3, δ): 7.77-7.68 (m, 1H), 7.20-7.10 (m, 1H), 7.01-6.87 (m, 2H), 4.07 (s, 2H), 4.02 (d, J = 5.4 Hz, 2H), 3.93 (d, J = 6.3 Hz, 2H), 3.35 (s, 2H), 3.08-2.84 (m, 3H), 2.78-2.59 (m, 2H), 2.29 (s, 3H), 2.06 (d, J = 13.5 Hz, 2H), 1.88 (s, 4H), 1.57-1.40 (m, 1H), 1.19-1.06 (m, 1H), 0.59-0.49 (m, 2H), 0.33-0.22 (m, 2H)

[0439] Example 34: Cyclopropylmethyl 7-methyl-2-(1-methylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 34)

[0440] (Step 1) Using tert-butyl 4-oxopiperidine-1-carboxylate (2.26 g, 15.1 mmol) and 1-(2-hydroxy-4-methylphenyl)ethanone (3.00 g, 15.1 mmol), the procedure was repeated in the same manner as in Step 1 of Example 1 to obtain tert-butyl 7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (3.32 g, 67%). ESI-MS m / z: 332 (M + H). +

[0441] (Step 2) Using tert-butyl 7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (20.0 g, 60.4 mmol) obtained in Step 1, the crude product of 7-methylspiro[chroman-2,4'-piperidin]-4-one hydrochloride (16.0 g) was obtained in the same manner as in Step 5 of Example 5, and was used in the next step without purification. ESI-MS m / z: 232 (M + H). +

[0442] (Step 3) Using the crude 7-methylspiro[chroman-2,4'-piperidin]-4-one hydrochloride (16.0 g) obtained in Step 2 and cyclopropylmethyl 4-nitrophenyl carbonate (16.0 g, 65.7 mmol) obtained in Step 5 of Example 15, cyclopropylmethyl 7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1-carboxylate (13.2 g, 67% yield over two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 330 (M + H) +

[0443] (Step 4) Triethyl orthoformate (20.2 g, 137 mmol) was dissolved in dichloromethane (200 mL), and boron trifluoride / diethyl ether complex (19.4 g, 137 mmol) was added at -15°C and stirred for 30 minutes. The reaction mixture was cooled to -78°C, and a solution of cyclopropylmethyl 7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (15.0 g, 45.6 mmol) obtained in Step 3 in dichloromethane (50.0 mL) and diisopropylethylamine (23.5 g, 182 mmol) was added. The mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give crude cyclopropylmethyl 3-(diethoxymethyl)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (20.0 g), which was used in the next step without further purification. ESI-MS m / z: 432 (M + H). +

[0444] (Step 5) The crude cyclopropylmethyl 3-(diethoxymethyl)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (20.0 g) obtained in Step 4 and hydrazine monohydrate (2.78 g, 55.6 mmol) were dissolved in ethanol (200 mL), DBU (10.6 g, 69.5 mmol) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to give cyclopropylmethyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (5.39 g, 33% yield for two steps). ESI-MS m / z: 354 (M + H). + 1 H NMR (DMSO-d 6, δ): 12.8 (s, 1H), 7.74 (s, 1H), 7.56-7.44 (m, 1H), 6.84-6.78 (m, 2H), 4.00-3.80 (m, 4H), 3.35-3.10 (m, 2H), 2.28 (s, 3H), 2.00-1.90 (m, 2H), 1.87-1.75 (m, 2H), 1.25-1.10 (m, 1H), 0.56-0.45 (m, 2H), 0.31-0.23 (m, 2H).

[0445] (Step 6) Using 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (1.00 g, 4.97 mmol), the procedure was repeated in the same manner as in Step 5 of Example 1 to obtain crude tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.26 g), which was used in the next step without purification.

[0446] (Step 7) Using cyclopropylmethyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.70 g, 4.80 mmol) obtained in Step 5 and the crude product of tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.41 g) obtained in Step 6, the same procedure as in Step 6 of Example 1 was carried out to obtain cyclopropylmethyl 2-(1-tert-butoxycarbonyl)piperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.19 g, 46%). ESI-MS m / z: 537 (M + H) +

[0447] (Step 8) Using cyclopropylmethyl 2-(1-tert-butoxycarbonyl)piperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.20 g, 4.10 mmol) obtained in Step 7, the crude product of cyclopropylmethyl 7-methyl-2-(piperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate hydrochloride was obtained in the same manner as in Step 3 of Example 11, and used in the next step without purification. ESI-MS m / z: 437 (M + H) +

[0448] (Step 9) Using the crude product of cyclopropylmethyl 7-methyl-2-(piperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate hydrochloride obtained in Step 8, cyclopropylmethyl 7-methyl-2-(1-methylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 34) (1.25 g, 68% yield in two steps) was obtained in the same manner as in Step 3 of Example 8. ESI-MS m / z: 451 (M + H) + 1H-NMR (CDCl3, δ): 7.62 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 6.83-6.81 (m, 2H), 4.20-4.13 (m, 1H), 4.03 (br s, 2H), 3.94 (d, J = 6.3 Hz, 2H), 3.38 (br s, 2H), 3.01 (d, J = 9.0 Hz, 2H), 2.35 (s, 3H), 2.32 (s, 3H), 2.18-2.02 (m, 8H), 1.80-1.72 (m, 2H), 1.19-1.10 (m, 1H), 0.58-0.53 (m, 2H), 0.31-0.27 (m, 2H).

[0449] Example 35: Cyclopropylmethyl 2-(azepan-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 35)

[0450] (Step 1) Using tert-butyl 7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (3.32 g, 10.0 mmol) obtained in Step 1 of Example 34, the crude product of tert-butyl 3-(diethoxymethyl)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (5.8 g) was obtained in the same manner as in Step 4 of Example 34, and used in the next step without purification. ESI-MS m / z: 434 (M + H). +

[0451] (Step 2) Using the crude tert-butyl 3-(diethoxymethyl)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (4.34 g) obtained in Step 1, tert-butyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (3.44 g, 97% yield in two steps) was obtained in the same manner as in Step 5 of Example 34. ESI-MS m / z: 356 (M + H) +

[0452] (Step 3) Using tert-butyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.50 g, 4.22 mmol) obtained in Step 2, the crude product of 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]hydrochloride was obtained in the same manner as in Step 5 of Example 5. ESI-MS m / z: 256 (M + H) +

[0453] (Step 4) Using the crude product of 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] hydrochloride obtained in Step 3 and allyl chloroformate (0.490 mL, 4.63 mmol), allyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (897 mg, 63% yield over two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 340 (M + H) +

[0454] (Step 5) Using tert-butyl 4-hydroxyazepane-1-carboxylate (600 mg, 2.79 mmol), the crude product of tert-butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate was obtained in the same manner as in Step 5 of Example 1, and was used in the next step without further purification. ESI-MS m / z: 294 (M + H). +

[0455] (Step 6) Using allyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (600 mg, 1.77 mol) obtained in Step 4 and the crude product of tert-butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate obtained in Step 5, allyl 2-(1-(tert-butoxycarbonyl)azepan-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (407 mg, 43%) was obtained in the same manner as in Step 6 of Example 1. ESI-MS m / z: 537 (M + H) +

[0456] (Step 7) Using allyl 2-(1-(tert-butoxycarbonyl)azepan-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (407 mg, 0.757 mol) obtained in Step 6, tert-butyl 4-(7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)azepan-1-carboxylate (231 mg, 67%) was obtained in the same manner as in Step 4 of Example 15. ESI-MS m / z: 453 (M + H) +

[0457] (Step 8) Using tert-butyl 4-(7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)azepane-1-carboxylate (115 mg, 0.254 mol) obtained in Step 7 and cyclopropylmethyl (4-nitrophenyl)carbonate (72.3 mg, 0.305 mmol) obtained in Step 5 of Example 15, the crude product of cyclopropylmethyl 2-(1-(tert-butoxycarbonyl)azepan-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (170 mg) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 551 (M + H) +

[0458] (Step 9) Using the crude product (70 mg) of cyclopropylmethyl 2-(1-(tert-butoxycarbonyl)azepan-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 8, cyclopropylmethyl 2-(azepan-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 35) (5.5 mg, 10% yield for two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 451 (M + H) + 1 H-NMR (CDCl3, δ): 7.63 (d, J = 4,1 Hz, 1H), 7.40(d, J = 7.7 Hz, 1H), 7.17 (s, 1H), 6.82 (d, J = 6.8 Hz, 1H), 4.49-4.42 (m, 1H), 4.02 (s, 2H), 3.94 (d, J = 6.8 Hz, 2H), 3.38 (s, 2H), 3.16-2.87 (m, 4H), 2.35-2.27(m, 4H), 2.19-2.01(m, 5H), 1.86-1.70(m, 4H), 1.20-1.10 (m, 1H), 0.62-0.50 (m, 2H), 0.29 (tt, J = 12.5, 6.3 Hz, 2H)

[0459] Example 36: Cyclopropylmethyl (R)-2-(2,2-dimethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 36)

[0460] (Step 1) Using cyclopropylmethyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (150 mg, 0.42 mmol) obtained in Step 5 of Example 34 and tert-butyl 2,2-dimethyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (196 mg, 0.64 mmol) obtained in Step 5 of Example 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain cyclopropylmethyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (120 mg, 50%). ESI-MS m / z: 565 (M + H) +

[0461] (Step 2) Using cyclopropylmethyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (110 mg, 0.20 mmol) obtained in Step 1, the procedure was repeated in the same manner as in Step 3 of Example 2 to obtain cyclopropylmethyl 2-(2,2-dimethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (35 mg, 39%). ESI-MS m / z: 465 (M + H) +

[0462] (Step 3) Using cyclopropylmethyl 2-(2,2-dimethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (110 mg, 0.20 mmol) obtained in Step 2, the procedure was repeated in the same manner as in Step 10 of Example 1 to obtain cyclopropylmethyl (R)-2-(2,2-dimethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 36) (14.9 mg, 43%). ESI-MS m / z: 465 (M + H) + 1 H NMR (DMSO-d6, δ): 7.65 (d, J = 8.0 Hz, 1H), 7.20 (s, 1H), 6.89-6.82 (m, 2H), 4.60-4.45 (m, 1H), 4.20-4.00 (m, 2H), 3.96 (d, J = 7.2 Hz, 1H), 3.50-3.30 (m, 2H), 3.30-3.20 (m, 1H), 3.20-3.05 (m, 1H), 2.35 (s, 3H), 2.35-2.25 (m, 2H), 2.20-2.10 (m, 4H), 2.05-1.95 (m, 2H), 1.90-1.70 (m, 2H), 1.36 (s, 3H), 1.34 (s, 3H), 1.26-1.10 (m, 1H), 0.70-0.60 (m, 2H), 0.40-0.30 (m, 2H).

[0463] Example 37: Cyclopropylmethyl 2-(1-ethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 37)

[0464] (Step 1) tert-Butyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.00 g, 2.82 mmol) obtained in Step 2 of Example 35 and N'-(1-ethylpiperidin-4-ylidine)-4-methylbenzenesulfonohydrazine (1.67 g, 5.65 mmol) were dissolved in 1,4-dioxane (15 mL), and bis(2,4-pentanedionato)copper(II) (0.44 g, 1.67 mmol) and cesium carbonate (3.68 g, 11.3 mmol) were added, followed by stirring overnight at 120 ° C. The reaction mixture was extracted with dichloromethane, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by reverse-phase column chromatography to give tert-butyl 2-(1-ethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (700 mg, 27%). ESI-MS m / z: 467 (M + H). +

[0465] (Step 2) Using tert-butyl 2-(1-ethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (700 mg, 1.50 mmol) obtained in Step 1, the crude product of 2-(1-ethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] hydrochloride (550 mg) was obtained in the same manner as in Step 5 of Example 5. ESI-MS m / z: 367 (M + H) +

[0466] (Step 3) Using the crude 2-(1-ethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] hydrochloride (130 mg) obtained in Step 2 and cyclopropylmethyl (4-nitrophenyl)carbamate (84 mg, 0.35 mmol) obtained in Step 5 of Example 15, cyclopropylmethyl 2-(1-ethylpiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 37) (18.3 mg, 11% yield for both steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 465 (M + H) + 1 H-NMR (CDCl3, δ): 7.63 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 6.88-6.70 (m, 2H), 6.10-5.95 (m, 1H), 5.40-5.20 (m, 2H), 3.96 (d, J = 7.2 Hz, 2H), 3.50-3.35 (m, 2H), 3.15-3.00 (m, 2H), 2.60-2.45 (m, 2H), 2.34 (s, 3H), 2.30-2.20 (m, 2H), 2.20-2.30 (m, 6H), 1.90-1.70 (m, 2H), 1.25-1.10 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H), 0.65-0.55 (m, 2H), 0.40-0.30 (m, 2H).

[0467] Example 38: Cyclopropylmethyl 2-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 38)

[0468] (Step 1) Cyclopropylmethyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (80 mg, 0.226 mmol) obtained in Step 5 of Example 34 and the crude product of tert-butyl (1R,3s,5S)-3-((methylsulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (76 mg, 0.249 mmol) obtained in Step 6 of Example 1 were used to prepare cyclopropylmethyl 2-((1R,3s,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (38.0 mg, 30%) was obtained. ESI-MS m / z: 563 (M + H). +

[0469] (Step 2) Using cyclopropylmethyl 2-((1R,3s,5S)-8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octan-3-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (60 mg, 0.11 mmol) obtained in Step 1, cyclopropylmethyl 2-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 38) (20 mg, 41%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 463 (M + H) + 1H-NMR (CDCl3, δ): 7.61 (dd, J = 6.7, 1.3 Hz, 1H), 7.19 (s, 1H), 6.83-6.80 (m, 2H), 4.60-4.52 (m, 1H), 4.06-3.93 (m, 4H), 3.74 (br s, 2H), 3.37 (br s, 2H), 2.32 (s, 3H), 2.16-2.00 (m, 5H), 1.96-1.70 (m, 8H), 1.19-1.11 (m, 1H), 0.58-0.53 (m, 2H), 0.31-0.27 (m, 2H).

[0470] Example 39: Cyclopropylmethyl 7-methyl-2-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 39)

[0471] (Step 1) Using cyclopropylmethyl 2-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (112 mg, 0.243 mmol) obtained in Step 2 of Example 38, the procedure was repeated in the same manner as in Step 3 of Example 8 to obtain cyclopropylmethyl 7-methyl-2-((1R,3s,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 39) (85 mg, 73%). ESI-MS m / z: 477 (M + H) + 1H-NMR (CDCl3, δ): 7.61 (d, J = 6.7 Hz, 1H), 7.20 (s, 1H), 6.81 (d, J = 6.7 Hz, 1H), 6.80 (s, 1H), 4.54-4.48 (m, 1H), 4.00 (d, J = 9.0 Hz, 2H), 3.94 (d, J = 7.2 Hz, 2H), 3.38 (br s, 2H), 3.31 (s, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.14-1.99 (m, 8H), 1.77-1.69 (m, 4H), 1.19-1.11 (m, 1H), 0.58-0.53 (m, 2H), 0.31-0.27 (m, 2H).

[0472] Example 40: Cyclopropylmethyl 2-((1R,3s,5S)-8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 40)

[0473] (Step 1) Using cyclopropylmethyl 2-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (100 mg, 0.216 mmol) obtained in Step 2 of Example 38 and propan-2-one (1.59 mL), the procedure was repeated in the same manner as in Step 3 of Example 8 to obtain cyclopropylmethyl 2-((1R,3s,5S)-8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (compound 40) (55 mg, 50%). ESI-MS m / z: 505 (M + H) + 1H-NMR (CDCl3, δ): 7.63 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 6.82 (d, J = 6.3 Hz, 1H), 6.81 (s, 1H), 4.61-4.52 (m, 1H), 4.01 (br s, 2H), 3.94 (d, J = 6.8 Hz, 2H), 3.65 (br s, 2H), 3.38 (br s, 2H), 2.97-2.91 (m, 1H), 2.32 (s, 3H), 2.20-2.01 (m, 6H), 1.89-1.72 (m, 6H), 1.18-1.11 (m, 7H), 0.58-0.54 (m, 2H), 0.31-0.27 (m, 2H).

[0474] Example 41 Cyclopropylmethyl 2-((3S * ,4S * )-3-Hydroxypiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (compound 41)

[0475] (Step 1) Cyclopropylmethyl 2-((3S)-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (350 mg, 0.990 mmol) obtained in Step 5 of Example 34 and tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (296 mg, 1.49 mmol) was prepared in the same manner as in Step 6 of Example 1. ＊ ,4S ＊ )-1-(tert-butoxycarbonyl)-3-hydroxypiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (155 mg, 28%) was obtained.

[0476] (Step 2) Cyclopropylmethyl 2-((3S) obtained in Step 1 * ,4S *)-1-(tert-butoxycarbonyl)-3-hydroxypiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (155 mg, 0.280 mmol) in the same manner as in Step 3 of Example 2, to prepare cyclopropylmethyl 2-((3S * ,4S * )-3-hydroxypiperidin-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (compound 41) (95 mg, 75%) was obtained. ESI-MS m / z: 453 (M + H) + 1 H-NMR (CDCl3, δ): 7.61 (d, J = 8.1 Hz, 1H), 7.21 (s, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.82 (s, 1H), 4.05-3.93 (m, 5H), 3.86 (td, J = 9.4, 4.8 Hz, 1H), 3.40-3.34 (m, 3H), 3.21-3.16 (m, 1H), 2.72 (td, J = 12.5, 2.5 Hz, 1H), 2.59 (dd, J = 12.1, 10.3 Hz, 1H), 2.33 (s, 3H), 2.15 (dq, J = 21.8, 7.2 Hz, 3H), 1.96 (ddd, J = 24.6, 12.2, 4.4 Hz, 1H), 1.76 (td, J = 13.0, 4.3 Hz, 2H), 1.17-1.13 (m, 1H), 0.58-0.53 (m, 2H), 0.31-0.27 (m, 2H).

[0477] Example 42: Cyclopropylmethyl 2-((4R)-1-imino-2,2-dimethyl-1-oxide hexahydro-1λ) 6 -thiopyran-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 42)

[0478] (Step 1) Using cyclopropylmethyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (630 mg, 1.78 mmol) obtained in Step 5 of Example 34 and the crude product of 2,2-dimethyltetrahydro-2H-thiopyran-4-yl methanesulfonate (400 mg) obtained in Step 2 of Example 21, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain cyclopropylmethyl 2-(2,2-dimethyltetrahydro-2H-thiopyran-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (220 mg, 26%). ESI-MS m / z: 482 (M + H) +

[0479] (Step 2) Cyclopropylmethyl 2-(2,2-dimethyltetrahydro-2H-thiopyran-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (140 mg, 0.291 mmol) obtained in Step 1 was dissolved in methanol (10 mL), and ammonium carbamate (57 mg, 0.73 mmol) and (diacetoxy)iodobenzene (234 mg, 0.73 mmol) were added. The mixture was stirred overnight at room temperature. Aqueous sodium sulfite was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by reversed-phase column chromatography and further purified by chiral SFC (CHIRALPAK IH (20x250 mm, 5 μm), hexane (0.2% diethylamine) / ethanol:dichloromethane (1:1) = 70 / 30, flow rate 20 mL / min, RT1: 4.91 min, RT2: 5.66 min) to obtain cyclopropylmethyl 2-((4R)-1-imino-2,2-dimethyl-1-oxidehexahydro-1λ) (RT1: 4.91 min). 6-thiopyran-4-yl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (compound 42) (8.9 mg, 6.0%) was obtained. ESI-MS m / z: 513 (M + H) + 1 H NMR (DMSO-d 6, δ): 7.89 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 6.88-6.78 (m, 2H), 4.80-4.65 (m, 1H), 4.00-3.80 (m, 4H), 3.70 (br s, 1H), 3.60-3.45 (m, 1H), 3.35-3.25 (m, 2H), 3.05-2.90 (m, 1H), 2.49-2.29 (m, 3H), 2.28 (s, 3H), 2.20-2.10 (m, 1H), 2.05-1.90 (m, 2H), 1.89-1.73 (m, 2H), 1.54 (s, 3H), 1.24 (s, 3H), 1.21-1.06 (m, 1H), 0.58-0.45 (m, 2H), 0.32-0.23 (m, 2H).

[0480] Example 43: Cyclopropylmethyl 2-(2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 43)

[0481] (Step 1) Cyclopropylmethyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.0 g, 5.66 mmol) obtained in Step 5 of Example 34 and methyl 2-bromoacetate (1.04 g, 6.79 mmol) were dissolved in THF (30 mL), potassium tert-butoxide (0.953 g, 8.49 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Acetic acid and water were added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (heptane / ethyl acetate = 70 / 30 - 20 / 80) to give cyclopropylmethyl 2-(2-methoxy-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.38 g, 57%). ESI-MS m / z: 426 (M + H). +

[0482] (Step 2) Cyclopropylmethyl 2-(2-methoxy-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.38 g, 3.25 mmol) obtained in Step 1 was dissolved in ethanol (16 mL), and aqueous sodium hydroxide (1.62 mL, 4.0 mol / L, 6.49 mmol) was added. After stirring at room temperature for 30 minutes, hydrochloric acid (1 mol / L) was added to the reaction mixture, which was then extracted with chloroform. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 2-(1'-((cyclopropylmethoxy)carbonyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (993 mg), which was used in the next step without further purification. ESI-MS m / z: 412 (M + H) +

[0483] (Step 3) Using the crude product (100 mg) of 2-(1'-((cyclopropylmethoxy)carbonyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid obtained in Step 2 and tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (59.6 mg, 0.292 mmol), the crude product of cyclopropylmethyl 2-(2-(((3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate was obtained in the same manner as in Step 3 of Example 26, and was used in the next step without purification. ESI-MS m / z: 598 (M + H) +

[0484] (Step 4) Using the crude product of cyclopropylmethyl 2-(2-(((3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 3, the crude product of cyclopropylmethyl 2-(2-(((3S,4R)-4-fluoropyrrolidin-3-yl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate was obtained in the same manner as in Step 3 of Example 2, and used in the next step without purification. ESI-MS m / z: 498 (M + H) +

[0485] (Step 5) Using the crude product of cyclopropylmethyl 2-(2-(((3S,4R)-4-fluoropyrrolidin-3-yl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 4, cyclopropylmethyl 2-(2-(((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 43) (45.8 mg, 37% yield over four steps) was obtained in the same manner as in Step 3 of Example 8. ESI-MS m / z: 512 (M + H) + 1 H-NMR (CDCl3, δ):7.61 (dd, J = 5.4, 3.1 Hz, 1H), 7.21 (s, 1H), 6.84 (t, J = 2.9 Hz, 2H), 5.14 (t, J = 4.3 Hz, 1H), 5.00 (t, J = 4.3 Hz, 1H), 4.82 (s, 2H), 4.68-4.55(m, 1H), 4.03 (d, J = 11.7 Hz, 2H), 3.94 (d, J = 6.7 Hz, 2H), 3.37 (s, 2H), 3.24-2.91(m, 3H), 2.67 (t, J = 9.0 Hz, 1H), 2.49 (s, 3H), 2.34 (s, 3H), 2.11 (d, J = 13.9 Hz, 2H), 1.81-1.71 (m, 2H), 1.17-1.12 (m, 1H), 0.58-0.53 (m, 2H), 0.30-0.28 (m, 2H)

[0486] Example 44: Allyl 2-(2-(((3S,4R)-4-fluoropyrrolidin-3-yl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 44)

[0487] (Step 1) Allyl 7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (250 mg, 0.737 mmol) obtained in Step 4 of Example 35, tert-butyl bromoacetate (0.139 mL, 0.810 mmol), and cesium carbonate (480 mg, 1.47 mmol) were dissolved in DMF (4 mL) and 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 water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude allyl 2-(2-(tert-butoxy)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (200 mg), which was used in the next step without further purification. ESI-MS m / z: 454 (M + H). +

[0488] (Step 2) Using the crude product (200 mg) of allyl 2-(2-(tert-butoxy)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 1, 2-(1'-((allyloxy)carbonyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (160 mg, 55% yield over two steps) was obtained in the same manner as in Step 2 of Example 26. ESI-MS m / z: 398 (M + H) +

[0489] (Step 3) Using 2-(1'-((allyloxy)carbonyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (80 mg, 0.201 mmol) obtained in Step 2 and tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (49.3 mg. 0.242 mmol), in the same manner as in Step 3 of Example 26, allyl 2-(2-(((3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate crude product (90 mg) was obtained and used in the next step without purification. ESI-MS m / z: 584 (M + H) +

[0490] (Step 4) Using the crude product (90 mg) of allyl 2-(2-(((3S,4R)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 3, allyl 2-(2-(((3S,4R)-4-fluoropyrrolidin-3-yl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 44) ​​(55 mg, 57% yield in two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 484 (M + H) + 1H-NMR (CDCl3, δ): 7.62 (d, J = 8.2 Hz, 1H), 7.21 (s, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.88-6.83 (m, 2H), 6.02-5.90 (m, 1H), 5.32 (dd, J = 17.2, 1.4 Hz, 1H), 5.23 (dd, J = 10.4, 1.4 Hz, 1H), 5.07-4.89 (m, 1H), 4.82 (s, 2H), 4.62 (d, J = 4.1 Hz, 2H), 4.42-4.27 (m, 1H), 4.14-3.96 (m, 2H), 3.48-3.35 (m, 2H), 3.34-3.14 (m, 3H), 2.69 (t, J = 10.2 Hz, 1H), 2.34 (s, 3H), 2.13 (d, J = 13.6 Hz, 2H), 1.84-1.73 (m, 3H).

[0491] Example 45: Cyclopropylmethyl (R)-7-methyl-2-(2-(methyl(1-methylpyrrolidin-3-yl)amino)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 45)

[0492] (Step 1) Using the crude 2-(1'-((cyclopropylmethoxy)carbonyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (80 mg) obtained in Step 2 of Example 43 and tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate (46.7 mg, 0.233 mmol), the crude cyclopropylmethyl (R)-2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate was obtained in the same manner as in Step 3 of Example 26, and used in the next step without purification. ESI-MS m / z: 594 (M + H) +

[0493] (Step 2) Using the crude product of cyclopropylmethyl (R)-2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 1, the crude product of cyclopropylmethyl (R)-7-methyl-2-(2-(methyl(pyrrolidin-3-yl)amino)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate was obtained in the same manner as in Step 3 of Example 2, and used in the next step without purification. ESI-MS m / z: 494 (M + H) +

[0494] (Step 3) Using the crude product of cyclopropylmethyl (R)-7-methyl-2-(2-(methyl(pyrrolidin-3-yl)amino)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 2, cyclopropylmethyl (R)-7-methyl-2-(2-(methyl(1-methylpyrrolidin-3-yl)amino)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 45) (29.7 mg, 30% yield over four steps) was obtained in the same manner as in Step 3 of Example 8. ESI-MS m / z: 508 (M + H) + 1H-NMR (CDCl3, δ): 7.58 (d, J = 8.1 Hz, 1H), 7.31 (dd, J = 8.1, 1.3 Hz, 1H), 6.79 (d, J = 7.2 Hz, 2H), 5.26-4.52 (m, 3H), 3.98 (brs, 2H), 3.91 (d, J = 7.2 Hz, 2H), 3.36 (t, J = 10.0 Hz, 2H), 3.07 (s, 2H), 2.92 (s, 1H), 2.86 (t, J = 7.2 Hz, 1H), 2.33-2.30 (m, 7H), 2.22-1.99 (m, 4H), 1.97-1.63 (m, 4H), 1.16-1.09 (m, 1H), 0.59-0.48 (m, 2H), 0.30-0.21 (m, 2H)

[0495] Example 46: Cyclopropylmethyl 7-methyl-2-(2-oxo-2-(1,7-diazaspiro[4.4]nonan-7-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 46)

[0496] (Step 1) Using 2-(1'-((cyclopropylmethoxy)carbonyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (50 mg, 0.122 mmol) obtained in Step 2 of Example 43 and tert-butyl 1,7-diazaspiro[4.4]nonane-1-carboxylate (33 mg, 0.146 mmol), the procedure was repeated in the same manner as in Step 3 of Example 26 to obtain cyclopropylmethyl 2-(2-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonan-7-yl)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (80 mg, quantitative). ESI-MS m / z: 620 (M + H) +

[0497] (Step 2) Using cyclopropylmethyl 2-(2-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.4]nonan-7-yl)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (75 mg, 0.121 mmol) obtained in Step 1, cyclopropylmethyl 7-methyl-2-(2-oxo-2-(1,7-diazaspiro[4.4]nonan-7-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 46) (12 mg, 19% yield over two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 520 (M + H) + 1 H-NMR (CDCl3, δ): 7.60 (dd, J = 8.4, 3.9 Hz, 1H), 7.32 (d, J = 3.2 Hz, 1H), 6.83-6.79 (m, 2H), 5.00-4.83 (m, 2H), 4.08-3.96 (m, 2H), 3.93 (d, J = 7.2 Hz, 2H), 3.74-3.59 (m, 2H), 3.50-3.34 (m, 4H), 3.12-2.93 (m, 2H), 2.32 (s, 3H), 2.12 (d, J = 13.6 Hz, 2H), 2.03-1.97 (m, 1H), 1.93-1.71 (m, 7H), 1.20-1.10 (m, 1H), 0.59-0.52 (m, 2H), 0.32-0.26 (m, 2H).

[0498] Example 47: Cyclopropylmethyl 7-methyl-2-(2-oxo-2-(2,6-diazaspiro[3.4]octan-2-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 47)

[0499] (Step 1) Using 2-(1'-((cyclopropylmethoxy)carbonyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (75 mg, 0.182 mmol) obtained in Step 2 of Example 43 and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate hydrochloride (45 mg, 0.182 mmol), the procedure was carried out in the same manner as in Step 3 of Example 26 to obtain cyclopropylmethyl 2-(2-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (50 mg, 45%). ESI-MS m / z: 606 (M + H) +

[0500] (Step 2) Using cyclopropylmethyl 2-(2-(6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.4]octan-2-yl)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (50 mg, 0.083 mmol) obtained in Step 1, cyclopropylmethyl 7-methyl-2-(2-oxo-2-(2,6-diazaspiro[3.4]octan-2-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 47) (18 mg, 43%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 506 (M + H) + 1H-NMR (CDCl3, δ): 7.60 (d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 6.85-6.81 (m, 2H), 4.77 (s, 2H), 4.07-3.96 (m, 6H), 3.94 (d, J = 7.2 Hz, 2H), 3.44-3.32 (m, 2H), 3.08-3.01 (m, 2H), 2.97 (td, J = 6.9, 2.6 Hz, 2H), 2.33 (s, 3H), 2.12 (d, J = 13.1 Hz, 2H), 2.02-1.95 (m, 2H), 1.78 (td, J = 13.1, 4.4 Hz, 2H), 1.19-1.10 (m, 1H), 0.60-0.53 (m, 2H), 0.32-0.27 (m, 2H).

[0501] Example 48: Cyclopropylmethyl 7-methyl-2-(2-oxo-2-(1,7-diazaspiro[4.5]decan-7-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 48)

[0502] (Step 1) Using 2-(1'-((cyclopropylmethoxy)carbonyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (100 mg, 0.243 mmol) obtained in Step 2 of Example 43 and tert-butyl 1,7-diazaspiro[4.5]decane-1-carboxylate (58.4 mg, 0.243 mmol), cyclopropylmethyl 2-(2-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.5]decan-7-yl)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (125 mg, 81%) was obtained in the same manner as in Step 3 of Example 26. ESI-MS m / z: 634 (M + H) +

[0503] (Step 2) Using cyclopropylmethyl 2-(2-(1-(tert-butoxycarbonyl)-1,7-diazaspiro[4.5]decan-7-yl)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (100 mg, 0.158 mmol) obtained in Step 1, cyclopropylmethyl 7-methyl-2-(2-oxo-2-(1,7-diazaspiro[4.5]decan-7-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 48) (52 mg, 62%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 534 (M + H) + 1 H-NMR (CDCl3, δ): 7.60 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 3.2 Hz, 1H), 6.83-6.79 (m, 2H), 5.09-4.97 (m, 2H), 4.06-3.98 (m, 2H), 3.93 (d, J = 6.8 Hz, 2H), 3.50-3.32 (m, 4H), 3.26 (d, J = 6.8 Hz, 1H), 3.06-2.87 (m, 2H), 2.32 (s, 3H), 2.12 (d, J = 13.1 Hz, 2H), 1.87-1.71 (m, 4H), 1.69-1.60 (m, 6H), 1.59-1.46 (m, 2H), 1.20-1.09 (m, 1H), 0.58-0.51 (m, 2H), 0.31-0.25 (m, 2H).

[0504] Example 49: Cyclopropylmethyl 7-methyl-2-(2-oxo-2-(2,8-diazaspiro[4.5]decan-2-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 49)

[0505] (Step 1) Using 2-(1'-((cyclopropylmethoxy)carbonyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)acetic acid (90 mg, 0.219 mmol) obtained in Step 2 of Example 43 and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (52.6 mg, 0.219 mmol), the procedure was carried out in the same manner as in Step 3 of Example 26 to obtain cyclopropylmethyl 2-(2-(8-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (100 mg, 72%). ESI-MS m / z: 634 (M + H) +

[0506] (Step 2) Using cyclopropylmethyl 2-(2-(8-(tert-butoxycarbonyl)-2,8-diazaspiro[4.5]decan-2-yl)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (100 mg, 0.158 mmol) obtained in Step 1, cyclopropylmethyl 7-methyl-2-(2-oxo-2-(2,8-diazaspiro[4.5]decan-2-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 49) (34 mg, 40%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 534 (M + H) + 1H-NMR (CDCl3, δ): 7.59 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 1.8 Hz, 1H), 6.84-6.79 (m, 2H), 4.90 (s, 2H), 4.07-3.98 (m, 2H), 3.93 (d, J = 7.2 Hz, 2H), 3.59 (dt, J = 18.4, 7.1 Hz, 2H), 3.45-3.31 (m, 4H), 2.94-2.86 (m, 2H), 2.83-2.74 (m, 2H), 2.32 (s, 3H), 2.12 (d, J = 13.6 Hz, 2H), 1.89 (t, J = 7.0 Hz, 1H), 1.80-1.74 (m, 4H), 1.58-1.51 (m, 4H), 1.18-1.10 (m, 1H), 0.59-0.53 (m, 2H), 0.31-0.26 (m, 2H).

[0507] Example 50: Cyclopropylmethyl 7-methyl-2-(2-(2-methyl-6-oxa-2,9-diazaspiro[4.5]decan-9-yl)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 50)

[0508] (Step 1) 2- (1'- ((cyclopropylmethoxy) carbonyl) -7-methyl-2H-spiro [chromeno [4,3-c] pyrazole-4,4'-piperidin] -2-yl) acetic acid (70 mg, 0.170 mmol) obtained in step 2 of Example 43 and tert-butyl 6-oxa-2,9-diazaspiro [4.5] decane-2-carboxylate (49.5 mg, 0.204 mmol) was used in the same manner as in step 3 of Example 26 to obtain cyclopropylmethyl 2- (2- (2- (tert- butoxycarbonyl) -6-oxa-2,9-diazaspiro [4.5] decan-9-yl) -2-oxoethyl) -7-methyl-2H-spiro [chromeno [4,3-c] pyrazole-4,4'-piperidine] -1'-carboxylate (103 mg, 95%). ESI-MS m / z: 636 (M + H) +

[0509] (Step 2) Using cyclopropylmethyl 2-(2-(2-(tert-butoxycarbonyl)-6-oxa-2,9-diazaspiro[4.5]decan-9-yl)-2-oxoethyl)-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (100 mg, 0.157 mmol) obtained in Step 1, the procedure was repeated in the same manner as in Step 3 of Example 2 to obtain cyclopropylmethyl 7-methyl-2-(2-oxo-2-(6-oxa-2,9-diazaspiro[4.5]decan-9-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (45 mg, 53%). ESI-MS m / z: 536 (M + H) +

[0510] (Step 3) Using cyclopropylmethyl 7-methyl-2-(2-oxo-2-(6-oxa-2,9-diazaspiro[4.5]decan-9-yl)ethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (20 mg, 0.037 mmol) obtained in Step 2, the procedure was repeated in the same manner as in Step 3 of Example 8 to obtain cyclopropylmethyl 7-methyl-2-(2-(2-methyl-6-oxa-2,9-diazaspiro[4.5]decan-9-yl)-2-oxoethyl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 50) (18 mg, 88%). ESI-MS m / z: 550 (M + H) + 1H-NMR (CDCl3, δ): 7.62-7.56 (m, 1H), 7.29 (d, J = 4.5 Hz, 1H), 6.84-6.80 (m, 2H), 4.99 (s, 2H), 4.09-3.98 (m, 2H), 3.93 (d, J = 6.8 Hz, 2H), 3.74-3.46 (m, 6H), 3.43-3.33 (m, 2H), 2.75-2.62 (m, 2H), 2.56-2.37 (m, 2H), 2.34-2.28 (m, 6H), 2.16-2.08 (m, 2H), 1.93-1.67 (m, 4H), 1.19-1.10 (m, 1H), 0.58-0.52 (m, 2H), 0.31-0.26 (m, 2H).

[0511] Example 51: (R,E)-1-(2-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)but-2-en-1-one (Compound 51)

[0512] (Step 1) Using tert-butyl 7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (3.00 g, 9.01 mmol) obtained in Step 1 of Example 34, tert-butyl 3-(1-hydroxyethyl)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (1.70 g, 50%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 376 (M + H) +

[0513] (Step 2) Using tert-butyl 3-(1-hydroxyethyl)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (3.40 g, 9.06 mmol) obtained in Step 1, tert-butyl (Z)-3-(1-hydroxyethylidene)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (2.90 g, 86%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 374 (M + H)+ 1 H NMR (DMSO-d6, δ): 7.62 (d, J = 8.0 Hz, 1H), 7.00-6.85 (m, 2H), 4.25 (br s, 1H), 4.00-3.80 (m, 2H), 3.30-3.00 (m, 2H), 2.34 (s, 3H), 2.24 (s, 3H), 2.05-2.00 (m, 3H), 1.75-1.60 (m, 1H), 1.41 (s, 9H).

[0514] (Step 3) Using tert-butyl (Z)-3-(1-hydroxyethylidene)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (1.66 g, 4.45 mmol) obtained in Step 2, the procedure was repeated in the same manner as in Step 4 of Example 1 to obtain tert-butyl 3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.35 g, 82%). ESI-MS m / z: 370 (M + H) + 1 H NMR (DMSO-d 6, δ): 12.9 (br s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.00-6.85 (m, 2H), 4.00-3.80 (m, 2H), 3.30-3.00 (m, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 2.05-2.00 (m, 4H), 1.41 (s, 9H).

[0515] (Step 4) Using tert-butyl 3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (580 mg, 1.57 mmol) obtained in Step 3 and tert-butyl (S)-2,2-dimethyl-4((methylsulfonyl)oxy)piperidine-1-carboxylate (965 mg, 3.14 mmol) obtained in Step 2 of Example 3, tert-butyl (R)-2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate and tert-butyl A mixture of (R)-1-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (545 mg, 60%) was obtained. ESI-MS m / z: 581 (M + H) +

[0516] (Step 5) A mixture of tert-butyl (R)-2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate obtained in Step 4 and tert-butyl (R)-1-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (545 mg, 0.938 mmol). In a similar manner to Step 5 of Example 25, using (R)-2-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride and (R)-1-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride, a crude product (410 mg) was obtained as a mixture, which was used in the next step without purification.

[0517] (Step 6) The crude mixture (50 mg) of (R)-2-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride and (R)-1-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride obtained in Step 5 was dissolved in dichloromethane (2.0 mL), and triethylamine (0.077 mL, 0.55 mmol), crotonic acid (14 mg, 0.17 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol) were added and stirred at room temperature for 1 hour. Aqueous sodium bicarbonate solution was added to the reaction mixture, 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 evaporated under reduced pressure. The residue was purified by reverse-phase preparative LCMS to give (R,E)-1-(2-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)but-2-en-1-one (compound 51) (20 mg, 39% yield over two steps). ESI-MS m / z: 449 (M + H). + 1H-NMR (CDCl3) δ: 7.63 (d, J = 8.1 Hz, 1H), 6.91 (dt, J = 21.8, 6.8 Hz, 1H), 6.81-6.79 (m, 2H), 6.34 (dd, J = 15.0, 1.6 Hz, 1H), 4.66-4.61 (m, 1H), 4.34-4.25 (m, 1H), 3.91-3.85 (m, 1H), 3.68-3.61 (m, 1H), 3.23-3.17 (m, 1H), 3.13-3.07 (m, 1H), 3.02-2.94 (m, 1H), 2.31 (s, 3H), 2.26 (s, 3H), 2.13-2.00 (m, 3H), 1.97-1.86 (m, 3H), 1.90 (dd, J = 6.8, 1.8 Hz, 3H), 1.81-1.73 (m, 3H), 1.23 (s, 3H), 1.21 (s, 3H).

[0518] Example 52: (R)-2-Cyclopropyl-1-(2-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidin]-1′-yl)ethan-1-one (Compound 52)

[0519] (Step 1) A crude mixture (50 mg) of (R)-2-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] dihydrochloride and (R)-1-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] dihydrochloride obtained in Step 5 of Example 51 and 2-cyclopropoxyacetic acid (19 mg, 0.17 Using 2,4-dimethyl-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazol-4,4'-piperidin]-1'-yl)ethan-1-one (Compound 52) (13 mg, 24% yield over two steps) was obtained in the same manner as in Step 6 of Example 51 using 2,4-dimethyl-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazol-4,4'-piperidin]-1'-yl)ethan-1-one. ESI-MS m / z: 479 (M + H). + 1H-NMR (CDCl3) δ: 7.63 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 9.4 Hz, 1H), 6.78 (s, 1H), 4.58-4.53 (m, 1H), 4.35-4.18 (m, 3H), 3.73 (d, J = 9.9 Hz, 1H), 3.65-3.58 (m, 1H), 3.51-3.46 (m, 1H), 3.18 (t, J = 12.3 Hz, 1H), 3.13-3.08 (m, 1H), 2.99 (td, J = 13.0, 3.0 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H), 2.13-1.87 (m, 7H), 1.78 (d, J = 12.6 Hz, 1H), 1.67 (br s, 1H), 1.24 (s, 3H), 1.22 (s, 3H), 0.67-0.64 (m, 2H), 0.53-0.51 (m, 2H).

[0520] Example 53: (2-((R)-5,5-dimethylpyrrolidin-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (Compound 53)

[0521] (Step 1) tert-Butyl 4-hydroxy-2,2-dimethylpyrrolidine-1-carboxylate (1.00 g, 4.64 mmol) was dissolved in dichloromethane (20 mL). N,N,N',N'-tetramethylethylenediamine (1.75 mL, 11.6 mmol) and methanesulfonyl chloride (0.611 mL, 7.90 mmol) were added under ice cooling, and the mixture was stirred at 0°C for 30 minutes. N,N-dimethylethylenediamine (1.52 mL, 13.9 mmol) was added to the reaction mixture, and the mixture was further stirred at 0°C for 30 minutes. Hydrochloric acid (1 mol / L) was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude tert-butyl 2,2-dimethyl-4-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (1.38 g), which was used in the next step without purification. 1 H-NMR (CDCl3, δ): 5.10 (br s, 1H), 3.79-3.69 (m, 2H), 3.02 (s, 3H), 2.28-2.16 (m, 2H), 1.48-1.37 (m, 15H).

[0522] (Step 2) Using tert-butyl 3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (5.00 g, 13.5 mmol) obtained in Step 3 of Example 51 and the crude product of tert-butyl 2,2-dimethyl-4((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (5.96 g) obtained in Step 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain tert-butyl 2-(1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.00 g, 26%). ESI-MS m / z: 567 (M + H) +

[0523] (Step 3) Using tert-butyl 2-(1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.00 g, 3.52 mmol) obtained in Step 2, the crude product of 2-(5,5-dimethylpyrrolidin-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride (1.20 g) was obtained in the same manner as in Step 5 of Example 25, and used in the next step without purification. ESI-MS m / z: 367 (M + H) +

[0524] (Step 4) Using the crude product (70 mg) of 2-(5,5-dimethylpyrrolidin-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride obtained in Step 3 and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (15 mg, 0.15 mmol), (2-(5,5-dimethylpyrrolidin-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (20.7 mg, 13% yield over two steps) was obtained in the same manner as in Step 1 of Example 4. ESI-MS m / z: 449 (M + H) +

[0525] (Step 5) Using (2-(5,5-dimethylpyrrolidin-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (50 mg, 0.111 mmol) obtained in Step 4, (2-((R)-5,5-dimethylpyrrolidin-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (Compound 53) (14.2 mg, 28%) was obtained in the same manner as in Step 10 of Example 1. ESI-MS m / z: 449 (M + H)+ 1 H NMR (CDCl 3, δ): 7.58 (d, J = 7.6 Hz, 1H), 6.84-6.76 (m, 2H), 4.90-4.80 (m, 1H), 4.65-4.55 (m, 1H), 4.15-4.05 (m, 1H), 3.85-3.70 (m, 1H), 3.70-3.50 (m, 2H), 3.25-3.10 (m, 1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.25-2.10 (m, 5H), 2.00-1.90 (m, 2H), 1.60 (s, 3H), 1.60-1.55 (m, 1H), 1.55-1.45 (m, 1H), 1.50 (s, 3H), 1.25-1.15 (m, 1H), 1.14 (d, J = 6.0 Hz, 3H), 0.65-0.60 (m, 1H).

[0526] Example 54 (R)—N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 54)

[0527] (Step 1) Using benzyl 4-oxopiperidine-1-carboxylate (15.5 g, 66.5 mmol) and 1-(2-hydroxy-4-methylphenyl)ethan-1-one (10.0 g, 66.6 mmol), the procedure was repeated as in Step 1 of Example 1 to obtain benzyl 7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (15.5 g, 64%). ESI-MS m / z: 366 (M + H). +

[0528] (Step 2) Using benzyl 7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (8.00 g, 21.9 mmol) obtained in Step 1, benzyl 3-(1-hydroxyethyl)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (6.00 g, 67%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 410 (M + H) +

[0529] (Step 3) Using benzyl 3-(1-hydroxyethyl)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (6.00 g, 14.7 mmol) obtained in Step 2, benzyl (Z)-3-(1-hydroxyethylidene)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (4.50 g, 75%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 408 (M + H) +

[0530] (Step 4) Using benzyl (Z)-3-(1-hydroxyethylidene)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (4.50 g, 11.0 mmol) obtained in Step 3, benzyl 3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (3.20 g, 72%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 404 (M + H) +

[0531] (Step 5) Using benzyl 3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (3.90 g, 9.67 mmol) obtained in Step 4 and tert-butyl 2,2-dimethyl-4((methylsulfonyl)oxy)piperidine-1-carboxylate (5.94 g, 19.3 mmol) obtained in Step 5 of Example 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain benzyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.20 g, 37%). ESI-MS m / z: 615 (M + H) +

[0532] (Step 6) Using benzyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.20 g, 3.58 mmol) obtained in Step 5, the crude product tert-butyl 4-(3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (1.20 g) was obtained in the same manner as in Step 7 of Example 1, and used in the next step without further purification. ESI-MS m / z: 481 (M + H) +

[0533] (Step 7) Using the crude tert-butyl 4-(3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (1.20 g) obtained in Step 6 and 4-nitrophenyl(cyclopropylmethyl)carbamate (0.88 g, 3.75 mmol) obtained in Step 1 of Example 11, tert-butyl 4-(1'-((cyclopropylmethyl)carbamoyl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (300 mg, 21% yield in two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 578 (M + H) +

[0534] (Step 8) Using tert-butyl 4-(1'-((cyclopropylmethyl)carbamoyl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (220 mg, 0.380 mmol) obtained in Step 7, tert-butyl (R)-4-(1'-((cyclopropylmethyl)carbamoyl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (80.0 mg, 36%) was obtained in the same manner as in Step 10 of Example 1. ESI-MS m / z: 578 (M + H) +

[0535] (Step 9) Using tert-butyl (R)-4-(1'-((cyclopropylmethyl)carbamoyl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (80.0 mg, 0.140 mmol) obtained in Step 8, (R)—N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 54) (30.7 mg, 46%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 478 (M + H) + 1 H NMR (CDCl3, δ): 7.63 (d, J = 7.6 Hz, 1H), 6.85-6.75 (m, 2H), 4.58 (t, J = 5.2 Hz, 1H), 4.40-4.25 (m, 1H), 3.95-3.80 (m, 2H), 3.50-3.35 (m, 2H), 3.35-3.25 (m, 1H), 3.20-3.05 (m, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 2.25-2.10 (m, 5H), 2.05-1.85 (m, 5H), 1.36 (s, 3H), 1.34 (s, 3H), 1.15-1.10 (m, 1H), 0.60-0.50 (m, 2H), 0.35-0.25 (m, 2H).

[0536] Example 55: (R)-2-(2,2-dimethylpiperidin-4-yl)-N-((1-fluorocyclopropyl)methyl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 55)

[0537] (Step 1) In the same manner as in Step 8 of Example 1, a reaction mixture was prepared using 4-nitrophenyl((1-fluorocyclopropyl)methyl)carbamate (65 mg, 0.26 mmol) obtained from the crude mixture (110 mg) of (R)-2-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] dihydrochloride obtained in Step 5 of Example 51 and (R)-1-(2,2-dimethylpiperidin-4-yl)-3,7-dimethyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] dihydrochloride and (1-fluorocyclopropyl)methanamine hydrochloride (160 mg, 1.27 mmol) in the same manner as in Step 1 of Example 11. (R)-2-(2,2-dimethylpiperidin-4-yl)-N-((1-fluorocyclopropyl)methyl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (compound 55) (40 mg, 32% yield over two steps) was obtained. ESI-MS m / z: 496 (M + H). + 1 H-NMR (CDCl3) δ: 7.63 (d, J = 7.6 Hz, 1H), 6.80-6.78 (m, 2H), 5.00 (t, J = 5.4 Hz, 1H), 4.34-4.26 (m, 1H), 3.87 (d, J = 11.2 Hz, 2H), 3.65 (dd, J = 22.7, 5.6 Hz, 2H), 3.41 (td, J = 12.9, 2.4 Hz, 2H), 3.12-2.95 (m, 2H), 2.31 (s, 3H), 2.29 (s, 3H), 2.10-2.04 (m, 3H), 2.00-1.89 (m, 4H), 1.79 (dt, J = 10.2, 3.8 Hz, 1H), 1.56 (br s, 1H), 1.25 (t, J = 7.6 Hz, 1H), 1.23 (s, 3H), 1.21 (s, 3H), 1.06 (dd, J = 18.8, 6.7 Hz, 2H).

[0538] Example 56: Cyclopropyl 2-((1R,3s,5S)-8-imino-8-oxide-8λ 6 -thiabicyclo[3.2.1]octan-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (compound 56)

[0539] (Step 1) Using cyclopropylmethyl 7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (5.00 g, 15.2 mmol) obtained in Step 3 of Example 34, the procedure was repeated in the same manner as in Step 2 of Example 1 to obtain cyclopropylmethyl 3-(1-hydroxyethyl)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (4.40 g, 78%). ESI-MS m / z: 374 (M + H) +

[0540] (Step 2) Using cyclopropylmethyl 3-(1-hydroxyethyl)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (4.40 g, 11.8 mmol) obtained in Step 1, cyclopropylmethyl (Z)-3-(1-hydroxyethylidene)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (3.00 g, 69%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 372 (M + H) + 1 H NMR (DMSO-d6, δ): 7.62 (d, J = 8.0 Hz, 1H), 7.00-6.85 (m, 2H), 4.25 (s, 1H), 4.00-3.80 (m, 4H), 3.30-3.00 (m, 2H), 2.35 (s, 3H), 2.24 (s, 3H), 2.05-2.00 (m, 3H), 1.75-1.60 (m, 1H), 1.20-1.05 (m, 1H), 0.60-0.50 (m, 2H), 0.35-0.25 (m, 2H).

[0541] (Step 3) Using cyclopropylmethyl (Z)-3-(1-hydroxyethylidene)-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (1.95 g, 5.25 mmol) obtained in Step 2, cyclopropylmethyl 3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.12 g, 58%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 368 (M + H) + 1 H NMR (DMSO-d6, δ): 12.40 (br s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H), 6.79 (dd, J = 8.0, 0.8 Hz, 1H), 4.00-3.80 (m, 4H), 3.30-3.00 (m, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 2.05-2.00 (m, 4H), 1.20-1.05 (m, 1H), 0.60-0.50 (m, 2H), 0.35-0.25 (m, 2H).

[0542] (Step 4) Using cyclopropylmethyl 3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (220 mg, 0.599 mmol) obtained in Step 3 and (1R,3r,5S)-8-thiabicyclo[3.2.1]octan-3-yl methanesulfonate (346 mg) obtained in Step 4 of Example 22, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain cyclopropylmethyl 2-(1R,3s,5S)-8-thiabicyclo[3.2.1]octan-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (196 mg, 66%). ESI-MS m / z: 494 (M + H) +

[0543] (Step 5) Using cyclopropylmethyl 2-(1R,3s,5S)-8-thiabicyclo[3.2.1]octan-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxylate (65 mg, 0.132 mmol) obtained in Step 4, cyclopropylmethyl 2-((1R,3s,5S)-8-imino-8-oxide-8λ) was obtained in the same manner as in Step 2 of Example 42. 6 -thiabicyclo[3.2.1]octan-3-yl)-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (compound 56) (13 mg, 19%) was obtained. ESI-MS m / z: 525 (M + H). + 1 H-NMR (CDCl3) δ: 7.64 (d, J = 7.6 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.78 (s, 1H), 4.68-4.62 (m, 1H), 4.10 (br s, 2H), 3.95 (d, J = 6.7 Hz, 2H), 3.36 (br s, 2H), 3.27 (t, J = 13.2 Hz, 2H), 3.13 (br s, 2H), 2.63-2.58 (m, 2H), 2.38 (s, 3H), 2.31 (s, 3H), 2.21-2.12 (m, 3H), 2.07-1.88 (m, 6H), 1.19-1.12 (m, 1H), 0.58-0.54 (m, 2H), 0.32-0.28 (m, 2H).

[0544] Example 57: Cyclopropylmethyl 7-chloro-2-(1-methylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 57)

[0545] (Step 1) Using tert-butyl 4-oxopiperidine-1-carboxylate (4.00 g, 19.9 mmol) and 1-(4-chloro-2-hydroxyphenyl)ethanone (3.40 g, 19.9 mmol), the procedure was repeated as in Step 1 of Example 1 to obtain tert-butyl 7-chloro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (4.70 g, 67%). ESI-MS m / z: 352 (M + H). +

[0546] (Step 2) Using tert-butyl 7-chloro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (4.70 g, 13.4 mmol) obtained in Step 1, the procedure was repeated in the same manner as in Step 4 of Example 34 to obtain tert-butyl 7-chloro-3-(diethoxymethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (6.00 g, 99%). ESI-MS m / z: 454 (M + H) +

[0547] (Step 3) Using tert-butyl 7-chloro-3-(diethoxymethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (6.00 g, 13.2 mmol) obtained in Step 2 and hydrazine monohydrate (2.78 g, 55.6 mmol), the procedure was repeated in the same manner as in Step 5 of Example 34 to obtain tert-butyl 7-chloro-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (3.20 g, 64%). ESI-MS m / z: 376 (M + H) + 1 H NMR (DMSO-d6, δ): 13.0 (s, 1H), 7.81 (s, 1H), 7.70-7.60 (m, 1H), 7.14 (s, 1H), 7.10-7.00 (m, 1H), 4.00-3.75 (m, 2H), 3.30-3.01 (m, 2H), 1.95-1.86 (m, 2H), 1.84-1.71 (m, 2H), 1.42 (s, 9H).

[0548] (Step 4) Using tert-butyl 7-chloro-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (100 mg, 0.266 mmol) obtained in Step 3, a crude product of 7-chloro-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride was obtained in the same manner as in Step 5 of Example 5, and was used in the next step without purification.

[0549] (Step 5) Using the crude product of 7-chloro-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride obtained in Step 4 and cyclopropylmethyl 4-nitrophenyl carbonate (76.0 mg, 0.319 mmol) obtained in Step 5 of Example 15, cyclopropylmethyl 7-chloro-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (73.6 mg, 74% yield over two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 374 (M + H) +

[0550] (Step 6) Using cyclopropylmethyl 7-chloro-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (73.6 mg, 0.197 mmol) obtained in Step 5 and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (66.0 mg, 0.238 mmol) obtained in Step 6 of Example 34, cyclopropylmethyl 2-(1-tert-butoxycarbonyl)piperidin-4-yl)-7-chloro-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (51 mg, 46%) was obtained in the same manner as in Step 6 of Example 1. ESI-MS m / z: 557 (M + H) +

[0551] (Step 7) Using cyclopropylmethyl 2-(1-tert-butoxycarbonyl)piperidin-4-yl)-7-chloro-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (51 mg, 0.092 mmol) obtained in Step 6, a crude product of cyclopropylmethyl 7-chloro-2-(piperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate hydrochloride was obtained in the same manner as in Step 3 of Example 11, and was used in the next step without purification.

[0552] (Step 8) Using the crude product of cyclopropylmethyl 7-chloro-2-(piperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate hydrochloride obtained in Step 7, the procedure was repeated in the same manner as in Step 3 of Example 8 to obtain cyclopropylmethyl 7-chloro-2-(1-methylpiperidin-4-yl)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 57) (27 mg, 63%). ESI-MS m / z: 471 (M + H) + 1 H-NMR (CDCl3, δ): 7.66 (d, J = 8.2 Hz, 1H), 7.18 (s, 1H), 7.00-6.97 (m, 2H), 4.19-4.11 (m, 1H), 4.03 (br s, 2H), 3.94 (d, J = 6.3 Hz, 2H), 3.35 (br s, 2H), 2.99 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H), 2.20-1.98 (m, 8H), 1.77 (td, J = 13.3, 4.2 Hz, 2H), 1.20-1.10 (m, 1H), 0.58-0.54 (m, 2H), 0.31-0.27 (m, 2H).

[0553] Example 58: (R)-6-chloro-N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 58)

[0554] (Step 1) Using 1-(3-chloro-2-hydroxyphenyl)ethan-1-one (500 mg, 2.93 mmol), the procedure was repeated as in Step 1 of Example 1 to obtain tert-butyl 8-chloro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (937 mg, 91%). ESI-MS m / z: 352 (M + H). +

[0555] (Step 2) Using tert-butyl 8-chloro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (971 mg, 2.76 mmol) obtained in Step 1, the procedure was repeated in the same manner as in Step 2 of Example 1 to obtain tert-butyl 8-chloro-3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (610 mg, 56%). ESI-MS m / z: 396 (M + H). +

[0556] (Step 3) Using tert-butyl 8-chloro-3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (610 mg, 1.54 mmol) obtained in Step 2, the crude product of tert-butyl (Z)-8-chloro-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate was obtained in the same manner as in Step 3 of Example 1, and was used in the next step without further purification. ESI-MS m / z: 394 (M + H). +

[0557] (Step 4) Using the crude tert-butyl (Z)-8-chloro-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate obtained in Step 3, tert-butyl 6-chloro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (571 mg, 95% yield over two steps) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 390 (M + H) +

[0558] (Step 5) Using tert-butyl 6-chloro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (571 mg, 1.47 mmol) obtained in Step 4 and tert-butyl (S)-2,2-dimethyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate (901 mg, 2.93 mmol) obtained in Step 2 of Example 3, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain tert-butyl (R)-2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-6-chloro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (713 mg, 81%). ESI-MS m / z: 601 (M + H) +

[0559] (Step 6) Using tert-butyl (R)-2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-6-chloro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (713 mg, 1.19 mmol) obtained in Step 5, the crude product (R)-6-chloro-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride (562 mg) was obtained in the same manner as in Step 5 of Example 25, and used in the next step without purification. ESI-MS m / z: 401 (M + H) +

[0560] (Step 7) Using (R)-6-chloro-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride (300 mg) and 4-nitrophenyl (cyclopropylmethyl)carbamate (104 mg, 0.433 mmol) obtained in Step 1 of Example 11, (R)-6-chloro-N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 58) (6.9 mg, 2% yield in two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 498 (M + H) + 1 H-NMR (CDCl3, δ): 7.63 (dd, J = 7.6, 1.3 Hz, 1H), 7.21 (dd, J = 8.1, 1.3 Hz, 1H), 6.89 (t, J = 7.9 Hz, 1H), 4.58 (t, J = 5.2 Hz, 1H), 4.32-4.29 (m, 1H), 3.88-3.87(m, 2H), 3.50 (td, J = 12.8, 2.5 Hz, 2H), 3.14-3.12 (m, 3H), 3.00 (td, J = 13.2, 2.7 Hz, 1H), 2.28 (d, J = 7.6 Hz, 3H), 2.1 (t, 7.6 Hz, 1H), 2.16-1.89 (m, 4H), 1.78 (dd, J = 13.0 ,2.2 Hz, 2H), 1.61-1.57 (m, 1H), 1.28-1.24 (m, 6H), 1.03-0.92 (m, 1H), 0.51-0.48 (m, 2H), 0.20-0.19 (m, 2H)

[0561] Example 59: N-allyl-2-(2,2-dimethylpiperidin-4-yl)-6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 59)

[0562] (Step 1) Using 1-(3-fluoro-2-hydroxyphenyl)ethan-1-one (10 g, 64.9 mmol), the procedure was repeated as in Step 1 of Example 1 to obtain tert-butyl 8-fluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (16 g, 74%). ESI-MS m / z: 336 (M + H). +

[0563] (Step 2) Using tert-butyl 8-fluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (15 g, 44.6 mmol) obtained in Step 1, tert-butyl 8-fluoro-3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (10 g, 59%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 380 (M + H) +

[0564] (Step 3) Using tert-butyl 8-fluoro-3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (10 g, 23.4 mmol) obtained in Step 2, tert-butyl (Z)-8-fluoro-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (8 g, 80%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 378 (M + H) +

[0565] (Step 4) Using tert-butyl (Z)-8-fluoro-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (8 g, 21.2 mmol) obtained in Step 3, the procedure was repeated in the same manner as in Step 4 of Example 1 to obtain tert-butyl 6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (6 g, 76%). ESI-MS m / z: 374 (M + H) +

[0566] (Step 5) Using tert-butyl 6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (6 g, 16.1 mmol) obtained in Step 4, the procedure was repeated in the same manner as in Step 5 of Example 5 to obtain crude 6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] hydrochloride (5 g), which was used in the next step without further purification. ESI-MS m / z: 274 (M + H). +

[0567] (Step 6) Using the crude 6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] hydrochloride (3 g) obtained in Step 5 and allyl chloroformate (1.17 g, 9.69 mmol), allyl 6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.02 g, 30% yield over two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 358 (M + H) +

[0568] (Step 7) Using allyl 6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (500 mg, 1.40 mmol) obtained in Step 6, allyl 2-(1-(tert-butoxycarbonyl)-2,2'-dimethylpiperidin-4-yl)-6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (356 mg, 45%) was obtained in the same manner as in Step 6 of Example 1. ESI-MS m / z: 569 (M + H) +

[0569] (Step 8) Using allyl 2-(1-(tert-butoxycarbonyl)-2,2'-dimethylpiperidin-4-yl)-6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (356 mg, 0.627 mmol) obtained in Step 7, the procedure was repeated in the same manner as in Step 4 of Example 15 to obtain tert-butyl 4-(6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2'-dimethylpiperidine-1'-carboxylate (140 mg, 46%). ESI-MS m / z: 485 (M + H) +

[0570] (Step 9) Using tert-butyl 4-(6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2'-dimethylpiperidine-1'-carboxylate (53 mg, 0.109 mol) obtained in Step 8 and 4-nitrophenyl allylcarbamate (29.2 mg, 0.131 mmol), the crude product of tert-butyl 4-(1'-(allylcarbamoyl)-6-fluoro-3-methyl-2H-spiro(chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 568 (M + H) +

[0571] (Step 10) Using the crude product of tert-butyl 4-(1'-(allylcarbamoyl)-6-fluoro-3-methyl-2H-spiro(chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate obtained in Step 9, N-allyl-2-(2,2-dimethylpiperidin-4-yl)-6-fluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 59) (8.0 mg, 16% yield in two steps) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 468 (M + H) + 1 H-NMR (CDCl3, δ): 7.50 (dt, J = 7.6, 1.3 Hz, 1H), 6.98-6.93 (m, 1H), 6.89-6.87 (m, 1H), 5.94-5.90 (m, 1H), 5.23-5.11 (m, 2H), 4.58 (t, J = 5.6 Hz, 1H), 4.32 (tt, J = 12.1, 4.0 Hz, 1H), 3.94-3.83 (m, 3H), 3.44 (td, J = 13.0, 2.7 Hz, 2H), 3.11 (dq, J = 13.5, 2.4 Hz, 1H), 2.99 (td, J = 13.1, 2.8 Hz, 1H), 2.30 (s, 3H), 2.13-1.88 (m, 7H), 1.78 (dt, 12.7, 1.9 Hz, 1H), 1.28-1.22 (m, 8H)

[0572] Example 60: (R)—N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 60)

[0573] (Step 1) Using tert-butyl 4-oxopiperidine-1-carboxylate (12.1 g, 60.7 mmol) and 1-(2,4-difluoro-6-hydroxyphenyl)ethanone (9.50 g, 55.2 mmol), the procedure was repeated in the same manner as in Step 1 of Example 1 to obtain tert-butyl 5,7-difluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (13.5 g, 69%). ESI-MS m / z: 354 (M + H) +

[0574] (Step 2) Using tert-butyl 5,7-difluoro-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (13.0 g, 36.8 mmol) obtained in Step 1, tert-butyl 5,7-difluoro-3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (9.0 g, 62%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 398 (M + H) +

[0575] (Step 3) Using tert-butyl 5,7-difluoro-3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (8.50 g, 21.4 mmol) obtained in Step 2, tert-butyl (Z)-5,7-difluoro-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (7.0 g, 83%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 396 (M + H) +

[0576] (Step 4) Using tert-butyl (Z)-5,7-difluoro-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (1.65 g, 32.9 mmol) obtained in Step 3, tert-butyl 7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (4.5 g, 70%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 392 (M + H) +

[0577] (Step 5) Using tert-butyl 7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.00 g, 2.56 mmol) obtained in Step 4, 7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] hydrochloride (620 mg, 74%) was obtained in the same manner as in Step 5 of Example 5. ESI-MS m / z: 292 (M + H) +

[0578] (Step 6) Using 7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] hydrochloride (620 mg, 2.13 mmol) obtained in Step 5 and 4-nitrophenyl(cyclopropylmethyl)carbamate (654 mg, 2.77 mmol) obtained in Step 1 of Example 11, N-(cyclopropylmethyl)-7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (700 mg, 85%) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 389 (M + H) +

[0579] (Step 7) Using N-(cyclopropylmethyl)-7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (670 mg, 1.72 mmol) obtained in Step 6 and tert-butyl 2,2-dimethyl-4((methylsulfonyl)oxy)piperidine-1-carboxylate (952 mg, 3.10 mmol) obtained in Step 5 of Example 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain tert-butyl 4-(1'-((cyclopropylmethyl)carbamoyl)-7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (46 mg, 4.5%). ESI-MS m / z: 600 (M + H) +

[0580] (Step 8) Using tert-butyl 4-(1'-((cyclopropylmethyl)carbamoyl)-7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (50 mg, 0.083 mmol) obtained in Step 7, the procedure was repeated in the same manner as in Step 10 of Example 1 to obtain tert-butyl (R)-4-(1'-((cyclopropylmethyl)carbamoyl)-7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (15 mg, 30%). ESI-MS m / z: 600 (M + H) +

[0581] (Step 9) Using tert-butyl (R)-4-(1'-((cyclopropylmethyl)carbamoyl)-7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (15 mg, 0.025 mmol) obtained in Step 8, (R)—N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-7,9-difluoro-3-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 60) (2.6 mg, 20%) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 500 (M + H) + 1 H NMR (CDCl3, δ): 6.60-6.50 (m, 2H), 4.58 (t, J = 5.6 Hz, 1H), 4.50-4.35 (m, 1H), 4.00-3.85 (m, 2H), 3.45-3.30 (m, 2H), 3.30-3.20 (m, 1H), 3.20-3.10 (m, 2H), 3.10-3.00 (m, 1H), 2.32 (s, 3H), 2.32-2.20 (m, 1H), 2.20-2.10 (m, 3H), 2.10-1.95 (m, 3H), 1.92-1.86 (m, 2H), 1.36 (s, 6H), 1.15-1.00 (m, 1H), 0.60-0.50 (m, 2H), 0.30-0.20 (m, 2H).

[0582] Example 61: (R)—N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-6-fluoro-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carboxamide (Compound 61)

[0583] (Step 1) 3-Bromo-5-methyl-1H-pyrazole (7 g, 43.5 mmol), N-iodosuccinimide (11.7 g, 52.2 mmol), and acetic acid (2 mL) were dissolved in dichloromethane (100 mL) and stirred at room temperature for 16 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate, water, and saturated brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give crude 3-bromo-4-iodo-5-methyl-1H-pyrazole (9.5 g), which was used in the next step without further purification. ESI-MS m / z: 287 (M + H). +

[0584] (Step 2) Using the crude 3-bromo-4-iodo-5-methyl-1H-pyrazole (9.5 g) obtained in Step 1 and tert-butyl 2,2-dimethyl-4((methylsulfonyl)oxy)piperidine-1-carboxylate (15.3 g, 49.7 mmol) obtained in Step 5 of Example 1, tert-butyl 4-(3-bromo-4-iodo-5-methyl-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate (3.19 g, 15% yield for two steps) was obtained in the same manner as in Step 6 of Example 1. ESI-MS m / z: 498 (M + H) +

[0585] (Step 3) tert-Butyl 4-(3-bromo-4-iodo-5-methyl-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate (6.00 g, 12.0 mmol) obtained in Step 2 was dissolved in THF (100 mL), and isopropylmagnesium chloride-lithium chloride complex (1.3 mol / L THF solution, 12.0 mL, 15.7 mmol) was added dropwise under a nitrogen atmosphere at 0 °C, followed by stirring at room temperature for 1 hour to prepare a Grignard reagent. tert-Butyl 4-oxopiperidine-1-carboxylate (3.60 g, 18.1 mmol) was dissolved in THF (100 mL), and lanthanum(III) chloride bis(lithium chloride) complex (0.6 mol / L THF solution, 10.0 mL, 6.02 mmol) was added dropwise under a nitrogen atmosphere at 0 °C, followed by stirring at room temperature for 1 hour. The Grignard reagent prepared above was added to the resulting reaction mixture under ice cooling, and the mixture was warmed to room temperature and stirred for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give tert-butyl 4-(3-bromo-4-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)-5-methyl-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate (3.50 g, 51%). ESI-MS m / z: 571 (M + H) +

[0586] (Step 4) tert-Butyl 4-(3-bromo-4-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)-5-methyl-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate (3.50 g, 6.12 mmol) obtained in Step 3, (2,3-difluoro-4-methylphenyl)boronic acid (2.11 g, 12.2 mmol), XPhos Pd G3 (0.52 g, 0.61 mmol), XPhos (0.58 g, 1.2 mmol), and tripotassium phosphate (5.20 g, 24.5 mmol) were dissolved in 1,4-dioxane (60 mL) and water (12 mL) under a nitrogen atmosphere and stirred at 100° C. overnight. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 3) to give tert-butyl 4-(4-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)-3-(2,3-difluoro-4-methylphenyl)-5-methyl-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate (3.00 g, 79%). ESI-MS m / z: 619 (M + H). +

[0587] (Step 5) tert-Butyl 4-(4-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)-3-(2,3-difluoro-4-methylphenyl)-5-methyl-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate (3.00 g, 4.85 mmol) obtained in Step 4 and cesium carbonate (1.11 g, 14.5 mmol) were dissolved in DMA (40 mL) and stirred at 120° C. overnight. The reaction mixture was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 1) to give tert-butyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-6-fluoro-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.4 g, 83%). ESI-MS m / z: 599 (M + H). +

[0588] (Step 6) Using tert-butyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-6-fluoro-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (1.80 g, 3.01 mmol) obtained in Step 5, the crude product of 2-(2,2-dimethylpiperidin-4-yl)-6-fluoro-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]dihydrochloride (1.3 g) was obtained in the same manner as in Step 5 of Example 25, and used in the next step without purification. ESI-MS m / z: 399 (M + H) +

[0589] (Step 7) Using the crude product (900 mg) of 2-(2,2-dimethylpiperidin-4-yl)-6-fluoro-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride obtained in Step 6 and 4-nitrophenyl(cyclopropylmethyl)carbamate (533 mg, 2.26 mmol) obtained in Step 1 of Example 11, N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-6-fluoro-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (500 mg, 48% yield in two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 496 (M + H) +

[0590] (Step 8) Using N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-6-fluoro-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (100 mg, 0.202 mmol) obtained in Step 6, (R)—N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl)-6-fluoro-3,7-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 61) (16.8 mg, 17%) was obtained in the same manner as in Step 10 of Example 1. ESI-MS m / z: 496 (M + H) + 1H NMR (CDCl3, δ): 7.39 (dd, J = 7.8, 1.2 Hz, 1H), 6.75 (t, J = 7.8 Hz, 1H), 4.59 (t, J = 5.2 Hz, 1H), 4.45-4.31 (m, 1H), 4.00-3.85 (m, 2H), 3.55-3.43 (m, 2H), 3.18-3.08 (m, 3H), 3.08-3.00 (m, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 2.18-1.96 (m,5H), 1.96-1.86 (m, 4H), 1.25 (s, 6H), 1.07-0.93 (m, 1H), 0.55-0.44 (m, 2H), 0.25-0.21 (m, 2H).

[0591] Example 62: N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl-4-d)-3-(methyl-d)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-3',3',5',5'-d-1'-carboxamide (Compound 62)

[0592] (Step 1) Allyl 4-oxopiperidine-1-carboxylate (2.09 g, 11.4 mmol), 1-(2-hydroxyphenyl)ethan-1-one (1.37 mL, 11.4 mmol), and deuterium oxide (20.0 mL, 1.11 mol) were used in the same manner as in Step 1 of Example 1 to obtain allyl 4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate-3,3,3',3',5',5'-d6 (2.27 g, 65%). ESI-MS m / z: 308 (M + H). +

[0593] (Step 2) Using allyl 4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate-3,3,3',3',5',5'-d6 (2.27 g, 7.37 mmol) obtained in Step 1, allyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate-3,3',3',5',5'-d5 (2.14 g, 83%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 351 (M + H) +

[0594] (Step 3) Using allyl 3-(1-hydroxyethyl)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate-3,3',3',5',5'-d5 (2.14 g, 6.10 mmol) obtained in Step 2, a crude product of allyl (Z)-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate-3',3',5',5'-d4 was obtained in the same manner as in Step 3 of Example 1, and was used in the next step without purification.

[0595] (Step 4) Using the crude product of allyl (Z)-3-(1-hydroxyethylidene)-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate-3',3',5',5'-d4 obtained in Step 3 and deuterium oxide (20 mL, 1.1 mmol), allyl 3-(methyl-d3)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate-3',3',5',5'-d4 (1.34 g, 64% yield over two steps) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 347 (M + H) +

[0596] (Step 5) tert-Butyl 2,2-dimethyl-4-oxopiperidine-1-carboxylate (532 mg, 2.34 mmol) was dissolved in methanol-d4 (4.0 mL), and sodium borodeuteride-d4 (196 mg, 4.68 mmol) was added under ice cooling. The mixture was warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude tert-butyl 4-hydroxy-2,2-dimethylpiperidine-1-carboxylate-4-d, which was used in the next step without purification.

[0597] (Step 6) Using the crude product of tert-butyl 4-hydroxy-2,2-dimethylpiperidine-1-carboxylate-4-d obtained in Step 5, the crude product of tert-butyl 2,2-dimethyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate-4-d was obtained in the same manner as in Step 5 of Example 1, and was used in the next step without purification.

[0598] (Step 7) Allyl 3-(methyl-d3)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate-3',3',5',5'-d4 (300 mg, 0.866 mmol) obtained in Step 4 and the crude product of tert-butyl 2,2-dimethyl-4-((methylsulfonyl)oxy)piperidine-1-carboxylate-4-d obtained in Step 6 were used to prepare allyl 3-(methyl-d3)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate-3',3',5',5'-d4 in the same manner as in Step 6 of Example 1. The crude product 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl-4-d)-3-(methyl-d3)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate-3',3',5',5'-d4 was obtained and used in the next step without purification.

[0599] (Step 8) The crude product of allyl 2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl-4-d)-3-(methyl-d3)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate-3',3',5',5'-d4 obtained in Step 7 was dissolved in dichloromethane (5.0 mL), and phenylsilane (0.319 mL, 2.60 mmo) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol) were added, followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 1 / 0-7 / 3) and further purified by reverse-phase preparative LCMS to give tert-butyl 2,2-dimethyl-4-(3-(methyl-d3)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-2-yl-3',3',5',5'-d4)piperidine-1-carboxylate-4-d (34 mg, 41% yield over two steps). ESI-MS m / z: 475 (M + H). +

[0600] (Step 9) Using tert-butyl 2,2-dimethyl-4-(3-(methyl-d3)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl-3',3',5',5'-d4)piperidine-1-carboxylate-4-d (17 mg, 0.036 mmol) obtained in Step 8 and 4-nitrophenyl (cyclopropylmethyl)carbamate (13 mg, 0.054 mmol) obtained in Step 1 of Example 11, tert-butyl 4-(1'-((cyclopropylmethyl)carbamoyl)-3-(methyl-d3)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl-3',3',5',5'-d4)-2,2-dimethylpiperidine-1-carboxylate-4-d (19 mg, 93%) was obtained. ESI-MS m / z: 572 (M + H). +

[0601] (Step 10) Using tert-butyl 4-(1'-((cyclopropylmethyl)carbamoyl)-3-(methyl-d3)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-2-yl-3',3',5',5'-d4)-2,2-dimethylpiperidine-1-carboxylate-4-d (19 mg, 0.033 mmol) obtained in Step 9, N-(cyclopropylmethyl)-2-(2,2-dimethylpiperidin-4-yl-4-d)-3-(methyl-d3)-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-3',3',5',5'-d4-1'-carboxamide (Compound 62) (16 mg, quantitative) was obtained in the same manner as in Step 3 of Example 2. ESI-MS m / z: 472 (M + H) + 1 H-NMR (CDCl3, δ): 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.16 (td, J = 7.7, 1.8 Hz, 1H), 6.99-6.93 (m, 2H), 4.58 (t, J = 5.2 Hz, 1H), 3.85 (dd, J = 13.0, 3.1 Hz, 2H), 3.37 (d, J = 13.0 Hz, 2H), 3.15-3.08 (m, 3H), 2.99 (td, J = 13.2, 2.7 Hz, 1H), 2.07 (td, J = 12.8, 4.9 Hz, 1H), 1.97 (d, J = 13.0 Hz, 1H), 1.89 (d, J = 12.6 Hz, 1H), 1.78 (d, J = 12.6 Hz, 1H), 1.23 (s, 3H), 1.21 (s, 3H), 1.04-0.96 (m, 1H), 0.53-0.49 (m, 2H), 0.23-0.19 (m, 2H).

[0602] Example 63: Ethyl (2'S,4R)-2-((R)-2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 63)

[0603] (Step 1) Using tert-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (10.0 g, 46.9 mmol) and 1-(2-hydroxyphenyl)ethan-1-one (7.02 g, 51.6 mmol), the procedure was repeated in the same manner as in Step 1 of Example 1 to obtain tert-butyl (2'S)-2'-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (10.4 g, 67%).

[0604] (Step 2) Using tert-butyl (2'S)-2'-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (25.0 g, 75.4 mmol) obtained in Step 1, the crude product of (2'S)-2'-methylspiro[chroman-2,4'-piperidin]-4-one hydrochloride was obtained in the same manner as in Step 5 of Example 5. The crude product was dissolved in 1,4-dioxane (60 mL), and aqueous potassium hydroxide solution (3.0 mol / L, 62 mL, 180 mmol) was added, followed by stirring at 90°C overnight. The reaction mixture was cooled to room temperature, and di-tert-butyl dicarbonate (19.6 g, 90.0 mmol) was added, followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from petroleum ether / ethyl acetate = 10 / 1 to give tert-butyl (2R,2'S)-2'-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (20.0 g, 80%). ESI-MS m / z: 332 (M + H) +

[0605] (Step 3) Using tert-butyl (2R,2'S)-2'-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (15.0 g, 45.3 mmol) obtained in Step 2, tert-butyl (2R,2'S)-3-(1-hydroxyethyl)-2'-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (10.0 g, 59%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 376 (M + H) +

[0606] (Step 4) Using tert-butyl (2R,2'S)-3-(1-hydroxyethyl)-2'-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (10.0 g, 26.6 mmol) obtained in Step 3, tert-butyl (2R,2'S,Z)-3-(1-hydroxyethylidene)-2'-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (8.00 g, 80%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 374 (M + H) +

[0607] (Step 5) Using tert-butyl (2R,2'S,Z)-3-(1-hydroxyethylidene)-2'-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (8.00 g, 21.4 mmol) obtained in Step 4, tert-butyl (2'S,4R)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (7.00 g, 88%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 370 (M + H) +

[0608] (Step 6) Using tert-butyl (2'S,4R)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (3.50 g, 9.47 mmol) obtained in Step 5 and tert-butyl 2,2-dimethyl-4((methylsulfonyl)oxy)piperidine-1-carboxylate (2.91 g, 9.47 mmol) obtained in Step 5 of Example 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain tert-butyl (2'S,4R)-2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.40 g, 44%). ESI-MS m / z: 581 (M + H) +

[0609] (Step 7) Using tert-butyl (2'S,4R)-2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.40 g, 4.13 mmol) obtained in Step 6, the crude product (2'S,4R)-2-(2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride (2.0 g) was obtained in the same manner as in Step 5 of Example 25, and used in the next step without purification. ESI-MS m / z: 381 (M + H) +

[0610] (Step 8) Using the crude (2'S,4R)-2-(2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride (480 mg) obtained in Step 7 and ethyl chloroformate (136 mg, 1.26 mmol), ethyl (2'S,4R)-2-(2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (90 mg, 20% yield over two steps) was obtained in the same manner as in Step 8 of Example 1. ESI-MS m / z: 453 (M + H) +

[0611] (Step 9) Using ethyl (2'S,4R)-2-(2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (50 mg, 0.11 mmol) obtained in Step 8, the procedure was repeated in the same manner as in Step 10 of Example 1 to obtain ethyl (2'S,4R)-2-((R)-2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 63) (22 mg, 44%). ESI-MS m / z: 453 (M + H) + 1H NMR (CDCl3, δ): 7.72 (dd, J = 7.6, 1.8 Hz, 1H), 7.15 (td, J = 7.6, 1.8 Hz, 1H), 6.96 (td, J = 8.0, 1.2 Hz, 1H), 6.87 (dd, J = 8.0, 1.2 Hz, 1H), 4.40-4.31 (m, 1H), 4.23 (d, J = 7.2 Hz, 2H), 4.23-4.15 (m, 1H), 3.95-3.84 (m, 1H), 3.50-3.40 (m, 1H), 3.20-3.10 (m, 1H), 3.10-3.00 (m, 1H), 2.30-2.25 (m, 1H), 2.29 (s, 3H), 2.25-2.00 (m, 3H), 2.00-1.80 (m, 3H), 1.80-1.68 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.29-1.23 (m, 9H).

[0612] Example 64: 2,2-Difluoroethyl (2'S,4R)-2-((R)-2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 64)

[0613] (Step 1) Using the crude product (480 mg) of (2'S,4R)-2-(2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride obtained in Step 7 of Example 63 and difluoroethanol, 2,2-difluoroethyl (4-nitrophenyl) carbonate (311 mg, 1.26 mmol) obtained in the same manner as in Step 5 of Example 15 was used to obtain 2,2-difluoroethyl (2'S,4R)-2-(2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (16.5 mg, two-step yield 3.4%) in the same manner as in Step 8 of Example 1. ESI-MS m / z: 489 (M + H) +

[0614] (Step 2) Using 2,2-difluoroethyl (2'S,4R)-2-(2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (50 mg, 0.102 mmol) obtained in Step 1, 2,2-difluoroethyl (2'S,4R)-2-((R)-2,2-dimethylpiperidin-4-yl)-2',3-dimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (Compound 64) (22.7 mg, 45%) was obtained in the same manner as in Step 10 of Example 1. ESI-MS m / z: 489 (M + H) + 1 H NMR (CDCl3, δ): 7.73 (dd, J = 7.6, 1.6 Hz, 1H), 7.15 (td, J = 7.6, 1.6 Hz, 1H), 6.97 (td, J = 8.0, 1.2 Hz, 1H), 6.86 (dd, J = 8.0, 1.2 Hz, 1H), 6.02 (tt, J =148, 4.1 Hz, 1H), 4.45-4.26 (m, 3H), 4.22-4.11 (m, 1H), 4.00-3.91 (m, 1H), 3.55-3.45 (m, 1H), 3.25-3.15 (m, 1H), 3.12-3.00 (m, 1H), 2.35-2.28 (m, 1H), 2.30 (s, 3H), 2.25-2.15 (m, 2H), 2.13-1.99 (m, 2H), 1.99-1.90 (m, 2H), 1.85-1.75 (m, 1H), 1.75-1.65 (m, 1H), 1.28 (d, J = 6.3 Hz, 3H), 1.26 (s, 6H).

[0615] Example 65 ((2'S,4R)-2-((R)-2,2-dimethylpiperidin-4-yl)-2',3,7-trimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (Compound 65)

[0616] (Step 1) tert-Butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (34.2 g, 160 mmol) was dissolved in hydrogen chloride / 1,4-dioxane solution (4 mol / L, 150 mL) and stirred at room temperature for 4 hours. The solvent was evaporated under reduced pressure to give (S)-2-methylpiperidin-4-one hydrochloride (23.8 g, 99%).

[0617] (Step 2) (S)-2-Methylpiperidin-4-one hydrochloride (23.8 g, 159 mmol) obtained in Step 1 and 1-(2-hydroxy-4-methylphenyl)ethanone (44.2 mL, 318 mmol) were dissolved in methanol (300 mL), pyrrolidine (53.1 mL, 636 mmol) was added, and the mixture was stirred at 50°C overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and extracted with hydrochloric acid (1 mol / L). Aqueous ammonia was added until the aqueous layer reached approximately pH 10, 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 evaporated under reduced pressure to obtain crude (2'S)-2',7-dimethylspiro[chroman-2,4'-piperidin]-4-one (38.4 g), which was used in the next step without further purification. ESI-MS m / z: 246 (M + H). +

[0618] (Step 3) The crude product (38.4 g) of (2'S)-2',7-dimethylspiro[chroman-2,4'-piperidin]-4-one obtained in Step 2 was dissolved in dichloromethane (150 mL), triethylamine (47.3 mL, 340 mmol) and di-tert-butyl dicarbonate (33.8 mL, 147 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 500 / 1-20 / 1) to obtain crude tert-butyl (2'S)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate. The crude product was recrystallized from petroleum ether / ethyl acetate (2 / 1) to give tert-butyl (2R,2'S)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (15 g, 38% yield over two steps). ESI-MS m / z: 246 ((M - Boc) + H). +

[0619] (Step 4) Using tert-butyl (2R,2'S)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (20.0 g, 57.9 mmol) obtained in Step 3, tert-butyl (2R,2'S)-3-(1-hydroxyethyl)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (18.8 g, 83%) was obtained in the same manner as in Step 2 of Example 1. ESI-MS m / z: 390 (M + H) +

[0620] (Step 5) Using tert-butyl (2R,2'S)-3-(1-hydroxyethyl)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (18.8 g, 48.0 mmol) obtained in Step 4, tert-butyl (2R,2'S,Z)-3-(1-hydroxyethylidene)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (15.4 g, 82%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m / z: 388 (M + H) +

[0621] (Step 6) Using tert-butyl (2R,2'S,Z)-3-(1-hydroxyethylidene)-2',7-dimethyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (15.4 g, 39.7 mmol) obtained in Step 5, tert-butyl (2'S,4R)-2',3,7-trimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (5.90 g, 39%) was obtained in the same manner as in Step 4 of Example 1. ESI-MS m / z: 384 (M + H) +

[0622] (Step 7) Using tert-butyl (2'S,4R)-2',3,7-trimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (5.90 g, 15.4 mmol) obtained in Step 6 and tert-butyl 2,2-dimethyl-4((methylsulfonyl)oxy)piperidine-1-carboxylate (9.46 g, 30.8 mmol) obtained in Step 5 of Example 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain tert-butyl (2'S,4R)-2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-2',3,7-trimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.60 g, 28%). ESI-MS m / z: 595 (M + H) +

[0623] (Step 8) Using tert-butyl (2'S,4R)-2-(1-(tert-butoxycarbonyl)-2,2-dimethylpiperidin-4-yl)-2',3,7-trimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (2.60 g, 4.37 mmol) obtained in Step 7, the crude product (2'S,4R)-2-(2,2-dimethylpiperidin-4-yl)-2',3,7-trimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride (1.5 g) was obtained in the same manner as in Step 5 of Example 25, and used in the next step without purification. ESI-MS m / z: 395 (M + H) +

[0624] (Step 9) Using the crude (100 mg) (2'S,4R)-2-(2,2-dimethylpiperidin-4-yl)-2',3,7-trimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride obtained in Step 8 and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (25 mg, 0.25 mmol), ((2'S,4R)-2-(-2,2-dimethylpiperidin-4-yl)-2',3,7-trimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (17.3 mg, 12% yield over two steps) was obtained in the same manner as in Step 1 of Example 4. ESI-MS m / z: 477 (M + H) +

[0625] (Step 10) ((2'S,4R)-2-(-2,2-dimethylpiperidin-4-yl)-2',3,7-trimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (50 mg, 0.11 mmol) obtained in Step 9 was purified by chiral SFC (CHIRALPAK IE (20x250 mm, 5 µm), tert-butyl methyl ether (0.2% diethylamine) / hexane:ethanol (4:1) = 60 / 40, flow rate 20 mL / min, RT1: 12.1 min, RT2: 14.6 min). min to give ((2'S,4R)-2-((R)-2,2-dimethylpiperidin-4-yl)-2',3,7-trimethyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-1'-yl)((1S,2S)-2-methylcyclopropyl)methanone (compound 65) (17 mg, 32%). ESI-MS m / z: 477 (M + H). + 1 H NMR (CDCl3, δ): 7.61 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 4.45-4.27 (m, 3H), 3.35-3.21 (m, 2H), 3.20-3.05 (m, 1H), 2.43-2.32 (m, 3H), 2.33 (s, 6H), 2.17-2.05 (m, 2H), 2.00-1.80 (m, 5H), 1.60-1.50 (m, 2H), 1.44 (s, 6H), 1.31 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H), 0.80-0.67 (m, 1H).

[0626] [Example 66] (3'S * ,4R * )-N-(cyclopropylmethyl)-2-((R)-2,2-dimethylpiperidin-4-yl)-3'-fluoro-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (Compound 66)

[0627] (Step 1) Using tert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (1.23 g, 5.66 mmol) and 1-(2-hydroxy-4-methylphenyl)ethanone (0.928 mL, 6.79 mmol), tert-butyl (2R * ,3'S * )-3'-fluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate (829 mg, 42%) was obtained. ESI-MS m / z: 294 (M - tert-Bu + H) +

[0628] (Step 2) tert-butyl (2R * ,3'S * )-3′-fluoro-7-methyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (829 mg, 2.37 mmol) in the same manner as in Step 4 of Example 34 to prepare tert-butyl (2R * ,3'S * The crude product of 3-(diethoxymethyl)-3'-fluoro-7-methyl-4-oxospiro[chroman-2,4'-piperidine]-1'-carboxylate was obtained and used in the next step without purification.

[0629] (Step 3) The tert-butyl (2R * ,3'S * )-3-(diethoxymethyl)-3′-fluoro-7-methyl-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate in the same manner as in Step 5 of Example 34. * ,4R * )-3'-fluoro-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (620 mg, 70%). ESI-MS m / z: 374 (M + H) +

[0630] (Step 4) tert-Butyl (3'S) obtained in Step 3 * ,4R * (3'S)-3'-fluoro-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxylate (620 mg, 1.66 mmol) was used in the same manner as in Step 5 of Example 5 to prepare (3'S * ,4R * The crude product of 2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]dihydrochloride (574 mg) was obtained and used in the next step without purification.

[0631] (Step 5) (3'S) obtained in Step 4 * ,4R * Using the crude product of 287 mg of 3'-fluoro-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine] dihydrochloride and 215 mg (0.912 mmol) of 4-nitrophenyl(cyclopropylmethyl)carbamate obtained in Step 1 of Example 11, (3'S * ,4R * The crude product of -N-(cyclopropylmethyl)-3'-fluoro-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide was obtained and used in the next step without purification. ESI-MS m / z: 371 (M + H). +

[0632] (Step 6) (3'S) obtained in Step 5 * ,4R * tert-butyl (R)-4-((3'S * ,4R *)-1'-((cyclopropylmethyl)carbamoyl)-3'-fluoro-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (204 mg, 3-step yield 42%). ESI-MS m / z: 582 (M + H) +

[0633] (Step 7) tert-butyl (R)-4-((3'S) obtained in Step 6 * ,4R * )-1'-((cyclopropylmethyl)carbamoyl)-3'-fluoro-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidin]-2-yl)-2,2-dimethylpiperidine-1-carboxylate (204 mg, 0.351 mmol) in the same manner as in Step 3 of Example 2 to prepare (3'S * ,4R * )-N-(cyclopropylmethyl)-2-((R)-2,2-dimethylpiperidin-4-yl)-3'-fluoro-7-methyl-2H-spiro[chromeno[4,3-c]pyrazole-4,4'-piperidine]-1'-carboxamide (compound 66) (76 mg, 45%) was obtained. ESI-MS m / z: 482 (M + H). + 1H-NMR (CDCl3) δ: 7.62 (d, J = 7.6 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 6.82 (dd, J = 7.6, 2.2 Hz, 1H), 6.77 (s, 1H), 4.66-4.62 (m, 1.5H), 4.52 (br s, 0.5H), 4.44 (tt, J = 12.3, 4.0 Hz, 1H), 4.23-4.16 (m, 1H), 3.91-3.86 (m, 1H), 3.60 (d, J = 14.8 Hz, 0.5H), 3.49 (d, J = 14.8Hz, 0.5H), 3.32-3.25 (m, 1H), 3.12-2.94 (m, 4H), 2.30 (s, 3H), 2.18-2.14 (m, 1H), 2.07-1.97 (m, 3H), 1.78-1.65 (m, 3H), 1.21 (s, 3H), 1.20 (s, 3H), 1.02-0.94 (m, 1H), 0.51-0.46 (m, 2H), 0.21-0.17 (m, 2H).

[0634] Example 67: Ethyl (R)-3'-methyl-2'-(1,2,2-trimethylpiperidin-4-yl)-2'H-spiro[piperidine-4,4'-pyrazolo[3',4':4,5]pyrano[3,2-b]pyridine]-1-carboxylate (Compound 67)

[0635] (Step 1) Using 3-bromo-5-methyl-1H-pyrazole (3.00 g, 18.6 mmol) and tert-butyl 2,2-dimethyl-4((methylsulfonyl)oxy)piperidine-1-carboxylate (5.73 g, 18.6 mmol) obtained in Step 5 of Example 1, the procedure was repeated in the same manner as in Step 6 of Example 1 to obtain tert-butyl 4-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate (1.20 g, 17%). ESI-MS m / z: 372 (M + H). +

[0636] (Step 2) tert-Butyl 4-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2,2-dimethylpiperidine-1-carboxylate (1.20 g, 3.22 mmol) obtained in Step 1, bis(pinacolato)diboron (1.23 g, 4.84 mmol), potassium acetate (950 mg, 9.67 mmol), and Pd(dppf)Cl dichloromethane complex (262 mg, 0.32 mmol) were dissolved in 1,4-dioxane (20 mL) and stirred at 85° C. under a nitrogen atmosphere for 5 hours. The reaction mixture was filtered, and the residue was washed with methanol. The solvent was evaporated under reduced pressure, and the residue was purified by reverse-phase column chromatography to give tert-butyl 2,2-dimethyl-4-(5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (700 mg, 64%). ESI-MS m / z: 420 (M + H). +

[0637] (Step 3) tert-Butyl 2,2-dimethyl 4- (5-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H- pyrazol-1-yl) piperidine-1-carboxylate (700 mg, 1.67 ...

Claims

1. Formula (I): (In the formula, Ar １ represents an optionally substituted pyrazole ring or an optionally substituted imidazole ring, ２ represents an optionally substituted benzene ring or an optionally substituted pyridine ring, Cy １ represents an optionally substituted piperidine ring or an optionally substituted azetidine ring, Cy ２ represents an aliphatic heterocyclic group which may have a substituent; L represents a single bond, —CH ２ -, -CH ２ CO-, -CH ２ CONH-, -CH ２ CON (CH ３ ) -, -N(CH ３ ) -, -CO-, or -CON(CH ３ )-, R represents an alkyl having 1 to 8 carbon atoms which may have a substituent, an alkenyl having 2 to 9 carbon atoms which may have a substituent, an alkoxy having 1 to 8 carbon atoms which may have a substituent, an alkenyloxy having 2 to 9 carbon atoms which may have a substituent, -NHW １ Or -N.W. ２ W ３ (W １ , W ２ and W ３ are the same or different and represent an optionally substituted alkyl of 1 to 8 carbon atoms, an optionally substituted alkenyl of 2 to 9 carbon atoms, or an optionally substituted 3-membered to 10-membered cycloalkyl), an optionally substituted 3-membered to 10-membered cycloalkyl, or an optionally substituted 3-membered to 10-membered cycloalkoxy, and Y represents O or S, or a pharmaceutically acceptable salt thereof.

2. Ar １ is expressed by the following formula (Ar １ −1), (Ar １ -2), (Ar １ -3) or (Ar １ -4): (wherein Rx represents a hydrogen atom, a halogen atom, an optionally substituted alkyl of 1 to 8 carbon atoms, or an optionally substituted 3- to 10-membered cycloalkyl; Ry represents a hydrogen atom, an optionally substituted alkyl of 1 to 8 carbon atoms, or an optionally substituted 3- to 10-membered cycloalkyl; and * represents the point of attachment to L), or a pharmaceutically acceptable salt thereof.

3. Ar １ is the formula (Ar １ -1), wherein L is a single bond, —CH ２ -, -CH ２ CO-, -CH ２ CONH-, -CH ２ CON (CH ３ ) -, -CO-, or -CON(CH ３ 3. The compound of claim 2, wherein R 1 is 1 or 2; or a pharmaceutically acceptable salt thereof.

4. Ar １ is the formula (Ar １ -2), wherein L is a single bond, —CH ２ -, -CO-, or -CON(CH ３ 3. The compound of claim 2, wherein R 1 is 1 or 2; or a pharmaceutically acceptable salt thereof.

5. Ar １ is the formula (Ar １ -3) or (Ar １ 3. The compound according to claim 2, wherein R 1 is -R 2 or -R 3 .

6. Ar ２ is expressed by the following formula (Ar ２ −1), (Ar ２ -2), (Ar ２ -3) or (Ar ２ -4): (wherein Re are the same or different and each represents a halogen atom, an alkyl group having 1 to 5 carbon atoms which may have a substituent, or an alkoxy group having 1 to 5 carbon atoms which may have a substituent), or a pharmaceutically acceptable salt thereof.

7. Cy １ is expressed by the following formula (Cy １ -1) or (Cy １ -2): (wherein Rd's are the same or different and each represents a halogen atom or an alkyl group having 1 to 8 carbon atoms which may have a substituent), or a pharmaceutically acceptable salt thereof.

8. Cy ２ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein is one group selected from the group consisting of: an optionally substituted 4-8-membered monocyclic aliphatic heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S; an optionally substituted 5-15-membered fused aliphatic heterocyclic group having 1 to 4 heteroatoms selected from N, O, and S; an optionally substituted 7-9-membered bridged cyclic aliphatic heterocyclic group having 1 to 3 heteroatoms selected from N, O, and S; and an optionally substituted 5-12-membered spirocyclic aliphatic heterocyclic group having 1 to 4 heteroatoms selected from N, O, and S.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Y is O.

10. The following formula (I-1): (In the formula, Rx １ represents a hydrogen atom, an alkyl having 1 to 5 carbon atoms, an alkyl having 1 to 5 carbon atoms substituted with hydroxy, or a 3- to 7-membered cycloalkyl; １ is NRa １ , SO, SO ２ or SO(=NH), １ represents a hydrogen atom, hydroxy, formyl, alkylcarbonyl having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, or alkyl having 1 to 5 carbon atoms; Rb １ are the same or different and each represents halogen, alkyl having 1 to 5 carbon atoms or hydroxy; Rd １ are the same or different and each represents alkyl having 1 to 5 carbon atoms or halogen; １ are the same or different and each represents a halogen, an alkyl having 1 to 5 carbon atoms, or an alkoxy having 1 to 5 carbon atoms; R １ (i) alkyl having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkoxy; (ii) alkenyl having 2 to 6 carbon atoms, or alkenyl having 2 to 6 carbon atoms substituted with a 3- to 7-membered cycloalkyl; (iii) alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms substituted with a halogen, alkoxy having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or alkoxy having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl; (iv) -NHW （１－１） or -N.W. （１－２） W （１－３） (Where, （１－１） , W （１－２） , W （１－３） are each the same or different and represent an optionally substituted alkyl of 1 to 5 carbon atoms, an optionally substituted alkenyl of 2 to 6 carbon atoms, or an optionally substituted 3- to 7-membered cycloalkyl, wherein the substituents on the optionally substituted alkyl of 1 to 5 carbon atoms and the optionally substituted alkenyl of 2 to 6 carbon atoms are each the same or different and selected from halogen, a 3- to 7-membered cycloalkyl, and a 3- to 7-membered cycloalkyl substituted with a halogen; and the substituent on the optionally substituted 3- to 7-membered cycloalkyl is selected from halogen or an alkyl of 1 to 5 carbon atoms; (v) a 3- to 7-membered cycloalkyl, a 3- to 7-membered cycloalkyl substituted with an alkyl of 1 to 5 carbon atoms, or a 3- to 7-membered cycloalkyl substituted with an alkyl of 1 to 5 carbon atoms substituted with a halogen; or (vi) a 3- to 7-membered cycloalkoxy, wherein Z is CH, CRe, １ or N), or a pharmaceutically acceptable salt thereof.

11. The following formula (I-2): (wherein the bond with a dotted line represents a double bond or a single bond; Ry ２ represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms; ２ is NRa ２ , SO, SO ２ , SO(=NH), or O; ２ represents a hydrogen atom, hydroxy, formyl, alkylcarbonyl having 2 to 6 carbon atoms, alkoxycarbonyl having 2 to 6 carbon atoms, alkylsulfonyl having 1 to 5 carbon atoms, or alkyl having 1 to 5 carbon atoms; Rb ２ are the same or different and each represents alkyl having 1 to 5 carbon atoms; ２ are the same or different and each represents alkyl having 1 to 5 carbon atoms; ２ are the same or different and each represents a halogen or an alkyl having 1 to 5 carbon atoms; R ２ (i) alkyl having 1 to 5 carbon atoms, (ii) alkenyl having 2 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms substituted with 3- to 7-membered cycloalkyl, (iii) alkoxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms substituted with 3- to 7-membered cycloalkyl, or alkoxy having 1 to 5 carbon atoms substituted with 3- to 7-membered cycloalkyl substituted with halogen, (iv) alkenyloxy having 2 to 6 carbon atoms, (v) -NHW （２－１） (W （２－１） represents an alkyl having 1 to 5 carbon atoms, an alkyl having 1 to 5 carbon atoms substituted with a 3- to 7-membered cycloalkyl, or an alkenyl having 2 to 6 carbon atoms); (vi) a 3- to 7-membered cycloalkyl, a 3- to 7-membered cycloalkyl substituted with an alkyl having 1 to 5 carbon atoms; or (vii) a 3- to 7-membered cycloalkoxy; Z is CH, CRe, ２ or N), or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 12, which is an SLC15A4 inhibitor.

14. A pharmaceutical composition according to claim 12 for the treatment of diseases associated with SLC15A4 inhibition.

15. The pharmaceutical composition according to claim 14, wherein the disease associated with SLC15A4 inhibition is an autoimmune disease.

16. The pharmaceutical composition according to claim 14, wherein the disease associated with SLC15A4 inhibition is systemic lupus erythematosus, lupus nephritis, or cutaneous lupus.

17. The pharmaceutical composition according to claim 14, wherein the disease associated with SLC15A4 inhibition is Sjogren's syndrome.

18. A therapeutic agent for diseases associated with SLC15A4 inhibition, comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

19. The therapeutic agent according to claim 18, wherein the disease associated with SLC15A4 inhibition is an autoimmune disease.

20. The therapeutic agent according to claim 18, wherein the disease associated with SLC15A4 inhibition is systemic lupus erythematosus, lupus nephritis, or cutaneous lupus.

21. The therapeutic agent according to claim 18, wherein the disease associated with SLC15A4 inhibition is Sjogren's syndrome.

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