Pharmaceutical composition containing GBA1 and GCS dual control agent

Abstract

To provide a pharmaceutical composition containing a compound having dual regulatory activity for GBA1 and GCS in the prevention and / or treatment of diseases related to GBA1 and / or GCS. [Solution] Formula (I): The compound represented by TIFF2026047293000047.tif28169 (wherein all symbols have the same meaning as the symbols described in the specification), or a pharmaceutically acceptable salt thereof, has GBA1 and GCS dual regulatory activity; therefore, a pharmaceutical composition comprising the compound represented by formula (I), or a pharmaceutically acceptable salt thereof, is useful as a prophylactic and / or therapeutic agent for diseases associated with GBA1 and / or GCS.

Description

[Technical Field]

[0001] This disclosure relates to pharmaceutical compositions, etc., containing compounds having GBA1 and GCS dual regulatory activity, or pharmaceutically acceptable salts thereof. Specifically, formula (I): [ka] This invention relates to a pharmaceutical product containing a compound represented by (wherein all symbols have the same meaning as described below) or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as "the disclosed compound"). [Background technology]

[0002] Beta-glucocerebrosidase (GBA1) is an enzyme that hydrolyzes glucosylceramide, a glycolipid. Gene mutations in GBA1 are known risk factors for developing Gaucher disease, Parkinson's disease, and related synucleinopathy. In Gaucher disease, GBA1 gene mutations cause glucosylceramide to accumulate in the liver, spleen, bones, and brain, leading to anemia, thrombocytopenia, hepatosplenomegaly, fractures, and severe neurological symptoms. The development of pharmacological chaperones and gene therapies is considered an effective treatment strategy for Gaucher disease (Non-Patent Literature 1).

[0003] Glucosylceramide is known to be synthesized by glucosylceramide synthase (GCS), and inhibiting GCS may reduce glucosylceramide levels, potentially affecting the progression of synucleinopathy (Non-Patent Literature 2). Therefore, compounds that modulate GBA1 and GCS may be useful in the treatment of Gaucher disease, Parkinson's disease, and related synucleinopathy.

[0004] On the other hand, Patent Document 1 describes a compound represented by the following formula (A) as having ceramide glucosyltransferase inhibitory activity, β-glucocerebrosidase inhibitory activity, and β-glucocerebrosidase chaperone activity.

[0005] Formula (A) is as follows. [Chemical formula] In the formula, R A is: [Chemical formula] R 1A is a substituted or unsubstituted alkyl group; W 1A-4A are each independently selected from hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted haloalkyl group, a substituted or unsubstituted alkanoyl group, a substituted or unsubstituted aroyl group, or a substituted or unsubstituted haloalkanoyl group; X 1A-5A are each independently selected from H, NO2, N3 or NH2; Y A is absent or is a substituted or unsubstituted C1-alkyl group other than carbonyl; and Z A is selected from a bond or NH (The definition of the group is partially excerpted.).

[0006] Also, Patent Document 2 describes that the compound represented by the following formula (B) is a compound having high GCS inhibitory activity and / or high inhibitory activity against GBA2 and / or low GBA1 inhibitory activity.

[0007] Formula (B) is as follows. [Chemical formula] In the formula, R 19B -R 26B are each independently selected from H, F, Me or Et; [[ID=5'4]] R 27B and R 28B are each independently selected from the group consisting of H, F, CF3 and C1-C8 linear or branched alkyl; X B is a 5-6 membered cyclic group substituted with a 5-6 membered cyclic group (The definition of the group is partially excerpted). [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2014 / 179438 Pamphlet [Patent Document 2] International Publication No. 2015 / 147639 brochure [Non-patent literature]

[0009] [Non-Patent Document 1] Molecular Neurodegeneration(2019)14:36 [Non-Patent Document 2] Neurobiology of Disease 159(2021)105507 [Overview of the Initiative] [Problems that the invention aims to solve]

[0010] The object of the present invention is to provide a pharmaceutical composition containing a compound having dual regulatory activity of GBA1 and GCS. [Means for solving the problem]

[0011] As a result of diligent research to solve the above problems, the inventors have found that a pharmaceutical composition containing the compound shown in formula (I) has potent GBA1 and GCS dual regulatory activity.

[0012] In other words, this disclosure is, in one manner, [A] Equation (I): [ka] (In the formula, L 1 This represents (1) C4-7 alkylene, (2) C4-7 alkenylene, or (3) C4-7 alkynylene. L 1 is 1-5 R L1 It may also be replaced with R L1 This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a hydroxyl group. Multiple R L1 They may be the same or different. L 2 This represents (1) C1-3 alkylene, (2) C2-3 alkenylene, or (3) C2-3 alkynylene. L 2 is 1-4 R L2 It may also be replaced with R L2 This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a hydroxyl group. Multiple R L2 They may be the same or different. X represents (1) a bond, (2) -O-, (3) -S-, (4) -SO-, or (5) -SO2-, Ring1 represents (1) a benzene ring, (2) a naphthalene ring, or (3) a 5-10 membered heterocycle. R 1 (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, (10) C5-7 carbon ring, (11) 5-7 membered heterocycle, (12)-O-(C5-7 carbon ring), or (13)-O-(5-7 membered heterocycle). Multiple R 1They may be the same or different. R 1 (2)-(13) are 1-5 R 1-1 It may also be replaced with R 1-1 This represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, (10) a C1-6 alkylsulfonyl group, (11) a cyano group, or (12) a phenyl group. Multiple R 1-1 They may be the same or different. [ka] This indicates that the substituents are bonded in an α configuration, a β configuration, or any ratio of α and β configurations. A pharmaceutical composition containing a compound represented by (where n is an integer from 0 to 5) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] [B] The pharmaceutical composition described in [A] above, which is a GBA1 chaperone regulator. [C] The pharmaceutical composition described in [A] above, which is a GCS inhibitor. [Effects of the Invention]

[0014] Because the disclosed compound has dual regulatory activity for GBA1 and GCS, pharmaceutical compositions containing the disclosed compound are useful as agents for preventing and / or treating diseases related to GBA1 and / or GCS. [Brief explanation of the drawing]

[0015] [Figure 1]Figure 1 shows the powder X-ray diffraction spectrum chart of the crystalline (3S,4R,5R,6S)-1-{6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (the vertical axis represents intensity (counts), and the horizontal axis represents 2θ (degrees)). [Figure 2] Figure 2 shows the differential scanning calorimetry (DSC) chart of the crystals of (3S,4R,5R,6S)-1-{6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (the vertical axis represents heat flux (W / g) and the horizontal axis represents temperature (°C)). [Modes for carrying out the invention]

[0016] The details of this disclosure are described below.

[0017] In this specification, GBA1 and GCS dual regulatory activity means both GBA1 chaperone activity and GCS inhibitory activity.

[0018] In this specification, examples of halogen atoms include fluorine, chlorine, bromine, and iodine atoms.

[0019] In this specification, C1-6 alkyl includes linear or branched C1-6 alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and their isomers.

[0020] In this specification, the C2-6 alkenyl group includes linear or branched C2-6 alkenyl groups, such as ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, or isomers thereof.

[0021] In this specification, the C2-6 alkynyl group includes linear or branched C2-6 alkynyl groups, such as ethynyl, propynyl, butynyl, butadiinyl, pentynyl, pentadinyl, hexynyl, hexadinyl, or their isomers.

[0022] In this specification, examples of C1-3 alkylenes include methylene, ethylene, propylene, or isomers thereof.

[0023] In this specification, C2-3 alkenylenes include linear or branched C2-3 alkenylenes, such as vinylene, propenylene, or their isomers.

[0024] In this specification, C2-3 alkynylenes include linear or branched C2-3 alkynylenes, such as ethynylene, propynylene, or their isomers.

[0025] In this specification, C3-6 alkylenes include linear or branched C3-6 alkylenes, such as propylene, butylene, pentylene, hexylene, or their isomers.

[0026] In this specification, C3-6 alkenylenes include linear or branched C3-6 alkenylenes, such as propenylene, butenylene, pentenylene, hexenylene, or their isomers.

[0027] In this specification, C3-6 alkynylene includes linear or branched C3-6 alkynylenes, such as propynylene, butynylene, pentynylene, hexynylene, or their isomers.

[0028] In this specification, C4-7 alkylenes include linear or branched C4-7 alkylenes, such as butylene, pentylene, hexylene, heptylene, or their isomers.

[0029] In this specification, C4-7 alkenylenes include linear or branched C4-7 alkenylenes, such as butenylene, pentenylene, hexenylene, heptenylene, or their isomers.

[0030] In this specification, C4-7 alkynylenes include linear or branched C4-7 alkynylenes, such as butynylene, pentynylene, hexynylene, heptynylene, or their isomers.

[0031] In this specification, a C1-6 haloalkyl group refers to a linear or branched alkyl group substituted with, for example, one or more halogen atoms. Specific examples of C1-6 haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 4-bromobutyl, 5,5,5-trifluoropentyl, 6,6-trifluorohexyl, or their isomers.

[0032] In this specification, a C2-6 haloalkenyl group refers to, for example, a linear or branched alkenyl group substituted with one or more halogen atoms. Specific examples of C2-6 haloalkenyl groups include 1-fluoroethenyl, 2-fluoroethenyl, 2-chloroethenyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4-bromobutenyl, 5,5,5-trifluoropentenyl, 6,6,6-trifluorohexenyl, or their isomers.

[0033] In this specification, a C2-6 haloalkynyl group refers to, for example, a linear or branched alkynyl group substituted with one or more halogen atoms. Specific examples of C2-6 haloalkynyl groups include 2-fluoroethynyl, 2-chloroethynyl, 3-fluoropropynyl, 3-chloropropynyl, 4-bromobutynyl, 5,5,5-trifluoropentynyl, 6,6,6-trifluorohexynyl, or isomers thereof.

[0034] In this specification, the C1-6 alkoxy group includes linear or branched C1-6 alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy groups, or isomers thereof.

[0035] In this specification, a C1-6 haloalkoxy group refers to, for example, a linear or branched alkoxy group substituted with one or more halogen atoms. Specific examples of C1-6 haloalkoxy groups include fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, pentafluoroethoxy, 1-fluoropropoxy, 2-fluoropropoxy, 2-chloropropoxy, 2-chloropropoxy, 3-fluoropropoxy, 3-chloropropoxy, 4,4,4-trifluorobutoxy, 4-bromobutoxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluorohexyloxy, or isomers thereof.

[0036] In this specification, examples of C5-7 carbon rings include cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, and benzene rings.

[0037] In this specification, 5-7 membered heterocyclic compounds include, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiadin, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidin, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, Dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, tetrahydropyridazine, tetrahydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydro Dioxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydrothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxadiazine, tetrahydrothiadiazine, tetrahydro Dorothiadiazine, tetrahydrothiadiazole, tetrahydrothiadiazine (thiadiazolidine), dihydrothiadin, tetrahydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxatian, dioxolane, dioxolane, dioxane, dithiolan, dithian, azepine, diazepine, oxepin, oxazepine, oxadiazepine, thiazepine, thiadiazepine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine,Examples include dihydrooxapine, tetrahydrooxepine, perhydrooxepine, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazepine, dihydrooxazepine, dihydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, perhydrooxadiazepine, dihydrothiazepine, dihydrothiazepine, perhydrothiazepine, dihydrothiazepine, dihydrothiazepine, dihydrothiazepine, perhydrothiazepine, perhydrothiazepine, perhydrothiazepine ring, etc.

[0038] In this specification, for example, as a 5-10 membered heterocycle, in addition to the 5-7 membered heterocycle, indole, isoindole, indidine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, ditiananaphthalene, indazole, quinoline, isoquinoline, quinoridine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzoflazan, benzothiadiazole, benzotriazole, indole Isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, dihydroisobenzofuran, perhydrobenzofuran, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroquinoline, dihydroquinoline, dihydroquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydro Dronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, perhydroquinazoline, dihydrosinnoline, tetrahydrosinnoline, perhydrosinnoline, benzoxatian, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, dioxadane, benzodioxane, ku Roman, benzodithiolane, benzodithiane, azaspiro[4.4]nonane, oxazaspiro[4.4]nonane, dioxaspiro[4.4]nonane, azaspiro[4.5]decane, thiaspiro[4.5]decane, dithiaspiro[4.5]decane, dioxaspiro[4.5]decane, oxazaspiro[4.5]decane, azabicyclo[3.2.1]octane, oxabicyclo[3.2.1]octane, thieno[3,2-c]pyrazole, thieno[2,3-c]pyrazole, thieno[2,3-d]thiazole, thieno[2,3-d][1.2.Examples include triazole, dihydropyrano[3,4-d]thiazole, dihydrothieno[2,3-b]pyran, dihydrothieno[3,2-c]pyran, dihydrothieno[3,2-b]pyran, dihydrothieno[3,2-c]thiopyran, tetrahydrothieno[3,2-b]pyridine, tetrahydrothieno[3,2-c]pyridine, and thieno[3,2-c]pyridine rings.

[0039] In this disclosure, L 1 Preferably, it is a C4-7 alkylene group, and more preferably a hexylene group.

[0040] In this disclosure, L 2 Preferably, it is methylene.

[0041] In this disclosure, X is preferably -O- or -S-, and more preferably -O-.

[0042] In this disclosure, Ring 1 is preferably a benzene ring or a 5-7 membered heterocycle, more preferably a benzene ring, a thiazole ring, an oxazole ring, or a pyridazine ring, and even more preferably the following compounds: [ka] (In the formula, * indicates L) 2 This indicates the bonding position with ). It is a ring structure selected from the group consisting of ).

[0043] In this disclosure, R 1 Preferably, the member is a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a benzene ring, or a 5-6 membered heterocycle; more preferably, a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, or a benzene ring; and even more preferably, a C1-6 alkyl group or a benzene ring.

[0044] In this disclosure, R L1 Preferably, it is a halogen atom, and more preferably, a fluorine atom.

[0045] In this disclosure, R L2 Preferably, the element is a halogen atom or a C1-6 alkyl group, and more preferably a methyl group.

[0046] In this disclosure, R 1-1 Preferably, the group is a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group, and more preferably, a halogen atom, a methyl group, or a methoxy group.

[0047] In this disclosure, n is preferably 0, 1, or 2.

[0048] In this disclosure, the compound represented by formula (I) is preferably formula (I-1): [ka] (In the formula, R L1-1 (1) represents a halogen atom or (2) a C1-6 alkyl group, m represents an integer between 1 and 2. Ring2 has the following ring structure: [ka] (In the formula, the * indicates the bond position with methylene.) This represents a ring structure selected from the group consisting of the above, and other symbols have the same meaning as the symbols above.) A compound represented by formula (I-2): [ka] (In the formula, R 1-2 R represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C1-6 alkoxy group, or (4) a phenyl group. 1-2 The parts (2)-(4) inside are 1-5 R 1-1 It may be substituted with, and the other symbols have the same meaning as the above symbols. ) This is a compound represented by ).

[0049] In this disclosure, the compound represented by formula (I) is preferably the L 1 , L 2 X, Ring1, R 1 , R L1 , R L2 , R 1-1 This is a combination of preferred definitions of , and n.

[0050] In this disclosure, the compound represented by formula (I-1) is preferably Ring2, R 1 , R L1-1 , R 1-1 This is a combination of preferred definitions for m and n.

[0051] In this disclosure, the compound represented by formula (I-2) is preferably Ring2, R 1-2 , R L1-1 , R 1-1 This is a combination of preferred definitions of , and n.

[0052] In this disclosure, the most preferred alternative embodiment of the compound represented by formula (I) is the example compound described in the following examples, or a pharmaceutically acceptable salt thereof.

[0053] In this disclosure, isomers are encompassed unless otherwise specified. For example, alkyl groups, alkoxy groups, and alkylene groups include both linear and branched forms. Furthermore, isomers at double bonds, rings, and fused rings (E, Z, cis, and trans isomers), isomers due to the presence of chiral carbons (R, S, α, β, enantiomers, and diastereomers), optically active isomers with optical activity (D, L, d, and l isomers), polar isomers separated by chromatography (highly polar and low polar isomers), equilibrium compounds, rotational isomers, mixtures of these in any proportion, and racemic mixtures are all included in this disclosure. In addition, isomers resulting from tautomerism are also encompassed in this disclosure.

[0054] In this disclosure, unless otherwise specified, as will be obvious to those skilled in the art. [ka] This indicates that it is coupled to the other side of the paper (i.e., in an α-configuration). [ka] This indicates that it is bonded to the front side of the paper (i.e., in a β-configuration). [ka] This indicates an α-configuration, a β-configuration, or any mixture of α-configuration and β-configuration.

[0055] [salt] The compound represented by formula (I) can be converted to a salt by known methods. As a salt, it is a pharmaceutically acceptable salt. A water-soluble salt is preferable.

[0056] Examples of pharmaceutically acceptable salts include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts.

[0057] Examples of acid addition salts include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, and nitrate, or organic salts such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, or gluconate.

[0058] Examples of alkali metal salts include potassium salts and sodium salts. Examples of alkaline earth metal salts include calcium salts and magnesium salts.

[0059] Examples of ammonium salts include tetramethylammonium salt.

[0060] Examples of amine salts include triethylamine salt, methylamine salt, dimethylamine salt, cyclopentylamine salt, benzylamine salt, phenethylamine salt, piperidine salt, monoethanolamine salt, diethanolamine salt, tris(hydroxymethyl)aminomethane salt, lysine salt, arginine salt, and N-methyl-D-glucamine salt.

[0061] Furthermore, the disclosed compounds can be converted into N-oxide compounds by any method. An N-oxide compound refers to a compound in which the nitrogen atom of the compound represented by general formula (I) has been oxidized.

[0062] Compounds represented by general formula (I) and their pharmaceutically acceptable salts may exist in an unsolvated form or in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. Hydrates are preferred as solvates. Compounds represented by general formula (I) and their pharmaceutically acceptable salts can be converted to solvates.

[0063] Compounds represented by general formula (I) can form cocrystals with suitable cocrystal-forming agents. Preferably, the cocrystals are pharmaceutically acceptable and formed with pharmaceutically acceptable cocrystal-forming agents. A cocrystal is typically defined as a crystal formed by two or more different molecules through intermolecular interactions other than ionic bonding. A cocrystal may also be a complex of a neutral molecule and a salt. Cocrystals can be prepared by known methods, such as by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable cocrystal-forming agents include those described in WO2006 / 007448.

[0064] In this disclosure, all references to the disclosed compounds include the compound represented by general formula (I), its pharmaceutically acceptable salt, its N-oxide, its solvate (e.g., hydrate), or its cocrystal, or the N-oxide, solvate (e.g., hydrate), or cocrystal of a pharmaceutically acceptable salt of the compound represented by general formula (I).

[0065] In this disclosure, the crystalline form of the example compounds is identified by the physicochemical data described herein; however, each spectral data may vary slightly due to its properties and should not be interpreted strictly.

[0066] For example, in powder X-ray diffraction spectral data, due to its nature, the diffraction angle (2θ) and overall pattern are important for determining the identity of a crystal, while the relative intensity can vary somewhat depending on the crystal growth direction, particle size, and measurement conditions.

[0067] Furthermore, in DSC data as well, the overall pattern is important for determining the identity of the crystal, and this can vary slightly depending on the measurement conditions.

[0068] Therefore, in each crystal form of the disclosed compound, those whose powder X-ray diffraction spectrum or DSC pattern is generally similar to that of the disclosed compound are included in the said crystal form.

[0069] In this disclosure, the description of the diffraction angle (2θ (degrees)) in a powder X-ray diffraction pattern and the onset temperature (°C) and peak temperature (°C) of the endothermic peak in DSC analysis means that they include the error range normally permissible in the data measurement method and are approximate to the diffraction angle and onset temperature and peak temperature of the endothermic peak. For example, "approximately" for the diffraction angle (2θ (degrees)) in a powder X-ray diffraction pattern means in one aspect ±0.2 degrees and in another aspect ±0.1 degrees. The "approximately" for the onset temperature (°C) or peak temperature (°C) of the endothermic peak in DSC analysis means in one aspect ±2°C and in another aspect ±1°C.

[0070] [Prodrug] A prodrug of a compound represented by general formula (I) is a compound that is converted into a compound represented by general formula (I) in the body by reactions with enzymes or gastric acid. Examples of prodrugs of a compound represented by general formula (I) include, if the compound represented by general formula (I) has an amino group, a compound in which the amino group has been acylated, alkylated, or phosphorylated (for example, a compound in which the amino group of the compound represented by general formula (I) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); if the compound represented by general formula (I) has a hydroxyl group, a compound in which the hydroxyl group has been acylated, alkylated, phosphorylated, or borated (for example, a compound in which the hydroxyl group of the compound represented by general formula (I) has been acetylated, palmitoylated, or propanoylated Examples include compounds that have been esterified, pivaloylated, succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated; and if the compound represented by general formula (I) has a carboxyl group, examples include compounds in which the carboxyl group has been esterified or amidized (for example, compounds in which the carboxyl group of the compound represented by general formula (I) has been ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolenn-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, or methylamidized). These compounds can be produced by known methods. Furthermore, the prodrug of the compound represented by general formula (I) may be either a hydrate or an unhydrated form. Furthermore, the prodrug of the compound represented by general formula (I) may be one that transforms into the compound represented by general formula (I) under physiological conditions, as described on pages 163-198 of "Molecular Design," Volume 7 of "Pharmaceutical Development," published by Hirokawa Shoten in 1990.

[0071] Furthermore, each atom constituting the compound represented by general formula (I) is its isotope (for example, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 16 N, 17 O, 18 O, 18 F, 35 S, 36 Cl, 77 Br, 125 It may be replaced with something like I.

[0072] [Method for producing the disclosed compound] The compounds disclosed herein can be produced by appropriately modifying and combining known methods, such as those described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or the methods shown in the examples. Salts may be used as starting materials. The order of the reactions can be appropriately changed depending on the protecting groups introduced and the reaction conditions.

[0073] Furthermore, compounds having an amino group, a carboxyl group, or a hydroxyl group can be prepared by using a commonly used protecting group for these groups, for example, a compound protected with a protecting group described in TW Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, and then performing a known deprotection reaction after an appropriate reaction step.

[0074] Examples of protecting groups for carboxyl groups include methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, and 2-chlorotrityl.

[0075] Examples of protecting groups for amino groups or tetrazolyl groups include benzyloxycarbonyl group, tert-butoxycarbonyl group, allyloxycarbonyl (Alloc) group, 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) group, trifluoroacetyl group, 9-fluorenylmethoxycarbonyl group, benzyl (Bn) group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, and 2-(trimethylsilyl)ethoxymethyl (SEM) group.

[0076] Examples of protecting groups for hydroxyl groups or hydroxamic acids include methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), and 2,2,2-trichloroethoxycarbonyl (Troc).

[0077] Deprotection reactions are well known and can be carried out by the following methods. For example, (1) Deprotection reaction by alkaline hydrolysis, (2) Deprotection reaction under acidic conditions, (3) Deprotection reaction by hydrolysis, (4) Deprotection reaction of silyl group, (5) Deprotection reactions using metals, (6) Examples include deprotection reactions using metal complexes.

[0078] To explain these methods in detail, (1) Deprotection reactions by alkaline hydrolysis are carried out at 0 to 40°C in an organic solvent (e.g., methanol, tetrahydrofuran (hereinafter referred to as THF), dioxane, etc.) using alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (e.g., barium hydroxide, calcium hydroxide, etc.), or carbonates (e.g., sodium carbonate, potassium carbonate, etc.), or aqueous solutions thereof, or mixtures thereof.

[0079] (2) The deprotection reaction under acidic conditions is carried out at 0-100°C in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole, etc.), an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), with or without 2,2,2-trifluoroethanol.

[0080] (3) The deprotection reaction by hydrolysis is carried out at 0 to 200°C in a solvent (e.g., ether-based solvents (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based solvents (e.g., methanol, ethanol, etc.), benzene-based solvents (e.g., benzene, toluene, etc.), ketone-based solvents (e.g., acetone, methyl ethyl ketone, etc.), nitrile-based solvents (e.g., acetonitrile, etc.), amide-based solvents (e.g., N,N-dimethylformamide (hereinafter DMF), etc.), water, ethyl acetate, acetic acid, or a mixture of two or more of these solvents, etc.) in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium-carbon hydroxide, platinum oxide, Raney nickel, etc.), under atmospheric pressure or under a pressurized hydrogen atmosphere, or in the presence of ammonium formate.

[0081] (4) The deprotection reaction of the silyl group is carried out at 0 to 40°C using tetrabutylammonium fluoride in an organic solvent that is miscible with water (e.g., THF, acetonitrile, etc.). Alternatively, it may be carried out at -10 to 100°C in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.).

[0082] (5) Deprotection reactions using metals are carried out at 0 to 40°C in the presence of powdered zinc in an acidic solvent (e.g., acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of these solutions with an organic solvent such as THF), while sonication is applied if necessary.

[0083] (6) Deprotection reactions using metal complexes are carried out at 0 to 40°C in an organic solvent (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or a mixture thereof, in the presence of a trap reagent (e.g., tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), an organic acid (e.g., acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or an organic acid salt (e.g., sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine reagent (e.g., triphenylphosphine, etc.), using a metal complex (e.g., tetrakistriphenylphosphine palladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, etc.).

[0084] The compound represented by general formula (I) can be produced by reaction step 1. [ka] (In the formula, A represents a leaving group (e.g., a halogen atom, an aryl sulfonate, or an alkyl sulfonate), and the other symbols have the same meanings as described above.)

[0085] In reaction step formula 1, reaction 1-1 is an alkylation reaction of an amino group. Alkylation reactions of amino groups are well known and are carried out, for example, in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.), in the presence of a base (triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.), in the presence of an inorganic salt (potassium iodide), an aqueous solution, or a mixture thereof, at 0°C to 200°C.

[0086] The compound represented by formula (1b) can be produced by reaction step formula 2. [ka] (In the formula, X 1 represents OH or SH, A 1 (The symbol represents a halogen atom, and the other symbols have the same meaning as above.)

[0087] In reaction step formula 2, reaction 2-1 is an alkylation reaction of a hydroxyl group or a thiol group. The alkylation reaction of a hydroxyl group is well known and is carried out, for example, in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.), in the presence of a base (triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, potassium t-butoxide, sodium hydride, etc.), in the presence of an inorganic salt (potassium iodide), in the presence of a phase transfer catalyst (tetrabutylammonium bromide, tetrabutylammonium iodide, etc.), an aqueous solution, or a mixture thereof, at 0°C to 200°C.

[0088] In reaction step 2, reaction 2-2 is a sulfonylation reaction of a hydroxyl group. Sulfonylation reactions of hydroxyl groups are well known and are carried out, for example, in an organic solvent (acetonitrile, chloroform, dichloromethane, pyridine, etc.), in the presence of a sulfonylation agent (p-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, lithium bromide, etc.), in the presence or absence of a base (triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, etc.), an aqueous solution, or a mixture thereof, at 0°C to 100°C.

[0089] In reaction step 2, reactions 2-3 are halogenation reactions of hydroxyl groups. Halogenation reactions of hydroxyl groups are well known and are carried out, for example, in an organic solvent (THF, toluene, chloroform, dichloromethane, pyridine, etc.), in the presence of a halogenating agent (carbon tetrabromide, triphenylphosphine, phosphorus tribromide, methanesulfonic anhydride, lithium bromide, etc.), in the presence of a base (triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, etc.), an aqueous solution, or a mixture thereof, at 0°C to 100°C.

[0090] The compound represented by formula (3b) can be produced by reaction step formula 3. [ka] In the formula, L 1-A The symbols represent (1) C3-6 alkylene, (2) C3-6 alkenylene, or (3) C3-6 alkynylene, and the other symbols have the same meaning as above.

[0091] In reaction step 3, reaction 3-1 is reductive amination. Reductive amination is well known and is carried out, for example, in an organic solvent (e.g., dichloroethane, dichloromethane, dimethylformamide, acetic acid, or a mixture thereof) in the presence of a reducing agent (sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc.) at 0°C to 40°C.

[0092] In one embodiment, the compound corresponding to the compound represented by formula (4g) can be produced by reaction step formula 4. [ka] (In the formula, PG represents a protecting group, and the other symbols have the same meanings as above.)

[0093] In reaction step 4, reaction 4-1 is a fluorination reaction. Fluorination reactions are well known and are carried out, for example, in an organic solvent (e.g., THF, acetonitrile, toluene, chloroform, isopropyl alcohol, or mixtures thereof) in the presence of a hydrofluoric acid salt (e.g., triethylaminetris(hydrogen fluoride), pyridine hydrogen fluoride, potassium hydrogen fluoride, etc.) and an organocatalyst (e.g., DL-proline, L-proline, D-proline, (5R)-(+)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone dichloroacetic acid, (5S)-(+)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone dichloroacetic acid, etc.) at -20°C to 40°C.

[0094] In reaction step 4, reaction 4-2 is a reduction reaction of an aldehyde group, carried out in an organic solvent (dichloroethane, dichloromethane, DMF, THF, or a mixture thereof) in the presence of a reducing agent (e.g., sodium borohydride) at 0°C to 40°C.

[0095] In reaction step 4, reaction 4-3 is a fluorination reaction. Fluorination reactions are well known and are carried out, for example, in an organic solvent (e.g., dichloromethane, chloroform, 1,2-dichloroethane, toluene, diethyl ether, or a mixture thereof) in the presence of a hydrofluoric acid salt (e.g., triethylaminetris(hydrogen fluoride), pyridine hydrogen fluoride, potassium hydrogen fluoride, etc.) at -20°C to 70°C.

[0096] In reaction step 4, reaction 4-4 is an alkylation reaction of a hydroxyl group, which is well known and is carried out as described in reaction 2-1 in reaction step 2.

[0097] In reaction step 4, reactions 4-5 are known deprotection reactions of protecting groups and are carried out as described above.

[0098] In one embodiment, the compound corresponding to the compound represented by formula (5d) can be produced by reaction step formula 5. [ka] (In the formula, PG represents a protecting group, and the other symbols have the same meanings as above.) In reaction step equation 5, reaction 5-1 is an ether formation reaction. Ether formation reactions are well known and are carried out, for example, in an organic solvent (e.g., t-BuOH, H2O, or a mixture thereof) in the presence of an inorganic base (such as sodium hydroxide) and a phase transfer catalyst (such as tetrabutylammonium iodide) at 20°C to 100°C.

[0099] In reaction step formula 5, reaction 5-2 is a fluorination reaction. Fluorination reactions are well known and are carried out, for example, in an organic solvent (e.g., dichloromethane, THF, toluene, or mixtures thereof), in the presence of a fluorinating agent (e.g., diethylamino-sulfur trifluoride, perfluorobutanesulfonyl fluoride, 2-pyridinesulfonyl fluoride, etc.), in the presence or absence of a base (e.g., triethylamine, diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, etc.), in the presence or absence of a hydrofluoric acid salt (e.g., triethylaminetris(hydrogen fluoride)), at a temperature of -20°C to 40°C.

[0100] In reaction step 5, reaction 5-3 is a deprotection reaction of a protecting group, which is well known and is carried out as described above.

[0101] In one embodiment, the compound corresponding to the compound represented by formula (6k) can be produced by reaction step formula 6. [ka] (In the formula, PG 1 The protecting group of the aldehyde is PG 2(The symbol represents a protecting group of a carboxylic acid, and the other symbols have the same meaning as above.)

[0102] In reaction step 6, reaction 6-1 is the alkylation reaction of a malonic acid diester. The alkylation reaction of malonic acid diesters is well known and is carried out, for example, in an organic solvent (DMF, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, THF, methyl t-butyl ether, etc.) in the presence of a base (e.g., sodium hydride, potassium t-butoxide, potassium carbonate, etc.) at 0°C to 100°C.

[0103] In reaction step 6, reaction 6-2 is a fluorination reaction. Fluorination reactions are well known and are carried out, for example, in an organic solvent (diethyl ether, THF, methyl t-butyl ether, acetonitrile, DMF, etc.) in the presence of a fluorinating agent (e.g., 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octanbis(tetrafluoroborate), N-fluoro-bis[(trifluoromethyl)sulfonyl]imide, N-fluorodibenzenesulfonimide, etc.) and in or without a base (sodium hydride, lithium diisopropylamide, cesium carbonate, etc.) at 0°C to 100°C.

[0104] In reaction step 6, reaction 6-3 is the alkylation reaction of 2-fluoromalonic acid diester, which is well known and is carried out as described in reaction 6-1.

[0105] In reaction step 6, reaction 6-4 is a deprotection reaction of a protecting group, which is well known and is carried out as described above.

[0106] In reaction step 6, reaction 6-5 is a decarboxylation reaction. Decarboxylation reactions are well known and are carried out, for example, in an organic solvent (DMF, dimethyl sulfoxide, pyridine, etc.), in or without a base (triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, cesium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.), in or without an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid), an inorganic acid (e.g., hydrochloric acid, sulfuric acid), or a mixture thereof, at 20°C to 200°C.

[0107] In reaction step 6, reaction 6-6 is the reduction of a carboxylic acid. The reduction of carboxylic acids is well known and is carried out, for example, in an organic solvent (diethyl ether, THF, methyl t-butyl ether, etc.) in the presence of a reducing agent (e.g., BH3-SMe2, BH3-THF, LiAlH4, etc.) at 20-200°C.

[0108] In reaction step 6, reactions 6-7 are alkylation reactions of hydroxyl groups, which are known and are carried out as described in reaction 2-1 in reaction scheme 2.

[0109] Reactions 6-8 in reaction sequence 6 are known deprotection reactions of protecting groups and are carried out as described above (for example, deprotection reactions under acidic conditions).

[0110] In each reaction described herein, the compounds represented by formulas 1a, 2a, 2b, 2d, 2e, 3a, 4a, 4c, 4e, 5a, 6a, 6b, 6e, and 6i, used as starting materials, are either known or can be easily produced by combining known methods, such as those described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or by modifying known methods.

[0111] Among the disclosed compounds, those having optical activity can be produced by using optically active starting materials or reagents, by optically resolving a racemic intermediate and then proceeding to the disclosed compound, or by optically resolving a racemic compound of the disclosed compound.

[0112] This optical resolution is well known, and examples include forming salts or complexes with other optically active compounds, recrystallizing them, and then isolating the target compound, or separating it directly using a chiral column or the like.

[0113] In each of the reactions described herein, reactions involving heating can be carried out using a water bath, an oil bath, a sand bath, or a microwave, as will be obvious to those skilled in the art.

[0114] In each reaction described herein, a solid-phase supported reagent supported on a polymer (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

[0115] In each reaction described herein, the reaction product can be purified by conventional purification methods, such as distillation under atmospheric or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion exchange resin, scavenger resin, or column chromatography, or by washing and recrystallization. Purification may be performed after each reaction or after several reactions have been completed. When recrystallization, seed crystals may or may not be used.

[0116] [toxicity] Since the toxicity of the disclosed compound is low, pharmaceutical compositions containing the disclosed compound can be safely used as pharmaceuticals.

[0117] [Application to pharmaceuticals] Because the disclosed compound has dual regulatory activity for GBA1 and GCS, pharmaceutical compositions containing the disclosed compound are useful as preventive and / or therapeutic agents for diseases related to GBA1 and / or GCS, such as Parkinson's disease, Lewy body dementia, Gaucher disease, multiple system atrophy, Fabry disease, Niemann-Pick disease type C, lysosomal storage disorders, dementia, epilepsy, bipolar disorder, schizophrenia, anxiety disorders, major depressive disorder, Sandhoff disease, Tay-Sachs disease, multiple sclerosis, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, cognitive impairment, learning disabilities, motor disorders, sleep disorders, neurological disorders, CNS disorders, polycystic kidney disease, diabetes mellitus, cancer, open-angle glaucoma, endometriosis, multiple myeloma, viral diseases, inflammation, systemic lupus erythematosus, hepatitis, Guillain-Barré syndrome, diabetic nephropathy, and skin disorders.

[0118] Preferred diseases associated with GBA1 and / or GCS include Parkinson's disease, Lewy body dementia, or Gaucher disease.

[0119] To use the disclosed compounds for the purpose of preventing and / or treating the aforementioned diseases, the active ingredient is usually formulated with pharmaceutically acceptable carriers such as various additives or solvents, and then administered systemically or topically, orally or parenterally. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient that is generally used in the formulation of pharmaceuticals. A pharmaceutically acceptable carrier is preferably one that does not exhibit pharmacological effects at the dosage of the formulation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. Furthermore, pharmaceutically acceptable carriers can also be used for purposes such as enhancing the usefulness of the active ingredient and formulation, facilitating formulation, stabilizing quality, or improving usability. Specifically, substances such as those listed in the "Dictionary of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association), published by Yakuji Nippo Co., Ltd. in 2021, can be appropriately selected according to the purpose.

[0120] The disclosed compounds are administered to mammals (preferably humans, more preferably human patients) in pharmaceutically effective amounts.

[0121] The dosage of the disclosed compound will inevitably vary depending on age, weight, symptoms, desired therapeutic effect, route of administration, and duration of treatment. Generally, it is administered orally to each patient in doses ranging from 0.1 ng to 1000 mg, or parenterally to each patient in doses ranging from 0.01 ng to 100 mg, or by continuous intravenous infusion.

[0122] Of course, as mentioned above, the dosage varies depending on various conditions, so in some cases a smaller amount than the aforementioned dosage may be sufficient, while in other cases an amount exceeding the range may be necessary.

[0123] Dosage forms used for administration include, for example, oral preparations (e.g., tablets, capsules, granules, powders, oral solutions, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, semi-solid oral preparations, gargles, etc.), injectable preparations (e.g., injectable preparations, etc.), dialysis preparations (e.g., dialysis preparations, etc.), inhalation preparations (e.g., inhalants, etc.), ophthalmic preparations (e.g., eye drops, eye ointments, etc.), otological preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal sprays, etc.), rectal preparations (e.g., suppositories, semi-solid rectal preparations, enema preparations, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological preparations (e.g., external solid preparations, external solutions, sprays, ointments, creams, gels, patches, etc.).

[0124] [Oral administration formulation] Orally administered formulations include, for example, tablets, capsules, granules, powders, oral solutions, syrups, and oral jellies. Orally administered formulations also include rapidly disintegrating formulations, which do not have any particular control over the release of the active ingredient from the formulation, and release-controlled formulations, such as enteric-coated formulations and sustained-release formulations, in which the release is adjusted for a specific purpose through unique formulation design and manufacturing methods. Enteric-coated formulations are formulations designed to prevent the breakdown of the active ingredient in the stomach or to reduce the irritating effect of the active ingredient on the stomach, by not releasing the active ingredient in the stomach and instead releasing it mainly in the small intestine. They can usually be manufactured by coating the formulation with an acid-insoluble enteric-coated base. Sustained-release formulations are formulations in which the release rate, release time, and release site of the active ingredient from the formulation are adjusted for purposes such as reducing the number of administrations or reducing side effects. They can usually be manufactured by using an appropriate sustained-release agent. For oral formulations such as capsules, granules, and tablets, a suitable coating agent such as sugars, sugar alcohols, or high-molecular-weight compounds may be applied to facilitate administration or prevent the breakdown of the active ingredient.

[0125] (1) Tablets Tablets are solid preparations with a specific shape that are administered orally. These include not only commonly referred to tablets such as uncoated tablets, film-coated tablets, sugar-coated tablets, multilayer tablets, and core tablets, but also orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolvable tablets. When manufacturing uncoated tablets, the following methods (a), (b), or (c) are typically used: (a) Add excipients such as excipients, binders, and disintegrants to the active ingredient and mix until homogenized. Then, using water or a binder-containing solution, form granules by an appropriate method, add lubricants and other additives, mix, and compress and mold. (b) The active ingredient is mixed with additives such as excipients, binders, and disintegrants to form a homogenous mixture, which is then directly compressed and molded, or granules prepared in advance with additives are mixed with the active ingredient and lubricants to form a homogenous mixture, which is then compressed and molded; (c) Additives such as excipients and binders to the active ingredient and mix until homogenized. The mixture, moistened with a solvent, is poured into a mold and shaped, and then dried by an appropriate method. These are used. Film-coated tablets can usually be manufactured by applying a thin coating to an uncoated tablet with a suitable coating agent such as a polymer compound. Sugar-coated tablets can usually be manufactured by applying a coating to an uncoated tablet with a coating agent containing sugars or sugar alcohols. Multilayer tablets can be manufactured by stacking powders and granules of different compositions in layers using an appropriate method and then compressing them. Core tablets can be manufactured by covering an inner core tablet with outer layers of different compositions. Tablets can also be made into enteric-coated or sustained-release tablets using known appropriate methods. Orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that have been given unique functions by the appropriate selection of additives, and can be manufactured in accordance with the manufacturing methods of the tablets described above. Orally disintegrating tablets are tablets that can be quickly dissolved or disintegrated in the mouth for administration; chewable tablets are tablets that are chewed before administration; effervescent tablets are tablets that dissolve or disperse rapidly in water while effervescent; dispersible tablets are tablets that are dispersed in water for administration; and dissolvable tablets are tablets that are dissolved in water for administration. Effervescent tablets can be manufactured by using appropriate acidic substances, carbonates, bicarbonates, etc., as additives.

[0126] (2) Capsules Capsules are preparations in which a substance is filled into a capsule or encapsulated in a capsule base, and include hard capsules, soft capsules, etc. Hard capsules can be manufactured by mixing an active ingredient with excipients and other additives to make a homogeneous mixture, or by forming the mixture into granules or molded products using an appropriate method, and then filling the capsule as is or after light molding. Soft capsules can be manufactured by encapsulating an active ingredient with additives in a suitable capsule base such as gelatin with increased plasticity due to the addition of glycerin, D-sorbitol, etc., into a specific shape. Capsules can also be made into enteric-coated capsules or sustained-release capsules using known appropriate methods, and colorants or preservatives can be added to the capsule base.

[0127] (3) Granules Granules are formulations that have been granulated into granular form, and include not only those commonly referred to as granules, but also effervescent granules, etc. When manufacturing granules, the following methods (a), (b), or (c) are usually used: (a) After mixing the active ingredient in powder form with excipients, binders, disintegrants, or other additives to make it homogenized, it is formed into granules by an appropriate method; (b) Add excipients and other additives to the active ingredient which has been prepared in granular form in advance, and mix until homogenized; (c) Add excipients and other additives to the active ingredient that has been prepared in granular form in advance, mix, and form granules by an appropriate method; These are used. The granules may be coated as needed, and can also be made into enteric-coated or sustained-release granules using known appropriate methods. Effervescent granules can be manufactured by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives. Effervescent granules refer to granules that dissolve or disperse rapidly in water while effervescent. Granules can also be made into fine granules by adjusting the particle size.

[0128] (4) Powder Powdered preparations are powdered formulations that can usually be manufactured by mixing an active ingredient with excipients or other additives to create a homogeneous mixture.

[0129] (5) Oral liquid preparations Oral solutions are liquid or fluid, viscous gel-like preparations, and generally include not only those referred to as oral solutions, but also elixirs, suspensions, emulsions, and lemonades. Oral solutions can usually be manufactured by adding an active ingredient, an additive, and purified water, mixing and dissolving them homogeneously, or emulsifying or suspending them, and filtering as necessary. An elixir is a clear, liquid oral solution containing ethanol with a sweet taste and aroma, and can usually be manufactured by dissolving a solid active ingredient or its extract with ethanol, purified water, a flavoring agent, and sucrose, other sugars, or a sweetener, and then filtering or otherwise obtaining a clear liquid. A suspension is an oral solution in which the active ingredient is finely and homogeneously suspended, and can usually be manufactured by adding a suspending agent or other additive and purified water or oil to a solid active ingredient, suspending it in an appropriate manner, and making the whole mixture homogeneous. An emulsion is an oral liquid preparation in which the active ingredient is emulsified into a fine, homogeneous form. It can usually be manufactured by adding an emulsifier and purified water to a liquid active ingredient, emulsifying it using an appropriate method, and ensuring the entire mixture is homogeneous. A limonade, on the other hand, is a clear, liquid oral preparation with a sweet and sour taste.

[0130] (6) Syrup Syrups are viscous liquid or solid preparations containing sugars or sweeteners, and include syrup preparations. Syrups can usually be manufactured by adding an active ingredient to a solution of sucrose, other sugars, or sweeteners, or to a simple syrup, dissolving, mixing, suspending, or emulsifying it, boiling the mixture as needed, and then filtering it while hot. Syrup preparations are granular or powdered preparations that become syrups when water is added, and are sometimes called dry syrup preparations. Syrup preparations can usually be manufactured using sugars or sweeteners as additives, in accordance with the manufacturing methods of the granular or powdered preparations described above.

[0131] (7) Oral jelly Oral jelly preparations are non-flowing, molded gel-like formulations that can usually be manufactured by mixing an active ingredient with additives and a polymer gel base, gelling it using an appropriate method, and then molding it into a specific shape.

[0132] [Injectable preparation] (1) Injectable Injectable preparations are sterile formulations, solutions, suspensions, emulsions, or solid preparations that are administered directly to body tissues or organs such as subcutaneously, intramuscularly, or intravascularly. These include not only what are commonly referred to as injectable preparations, but also lyophilized injectable preparations, powder injectable preparations, pre-filled syringes, cartridges, infusions, implantable injectable preparations, and sustained-release injectable preparations. When manufacturing injectable preparations, the following methods (a) or (b) are typically used: (a) The active ingredient, either as is or with additives added, is dissolved, suspended, or emulsified in sterile water for injection, other aqueous solvents, or non-aqueous solvents to form a homogeneous mixture, which is then filled into a container for injection, sealed, and sterilized; (b) The active ingredient, either as is or with additives added, is dissolved, suspended, or emulsified in water for injection, another aqueous solvent, or a non-aqueous solvent, and the resulting mixture is aseptically filtered, or the mixture is aseptically prepared and homogenized, and then filled into a container for injection and sealed; These are used. Lyophilized injectable preparations can usually be manufactured by dissolving the active ingredient as is, or the active ingredient and excipients in sterile water for injection, aseptically filtering it, filling it into an injectable container, and then lyophilizing it, or by lyophilizing it in a dedicated container and then filling it directly into a container. Powdered injectable preparations can usually be manufactured by processing them by aseptic filtration, then adding the powder obtained by crystallization or the powder to which sterilized additives have been added, and then filling it into an injectable container. Pre-filled syringe preparations can usually be manufactured by preparing a solution, suspension, or emulsion using the active ingredient as is, or using the active ingredient and additives, and then filling it into a syringe. Cartridge preparations refer to injectable preparations in which a cartridge filled with drug solution is placed in a dedicated syringe, and cartridges filled with drug solution can usually be manufactured by preparing a solution, suspension, or emulsion using the active ingredient as is, or using the active ingredient and additives, and then filling it into a cartridge. Infusion preparations refer to injectable preparations that are administered intravenously, usually in quantities of 100 mL or more. Implantable injectable drugs refer to solid or gel-type injections administered subcutaneously, intramuscularly, or via implantation devices, or surgically, for the purpose of releasing active ingredients over a long period. Implantable injectable drugs can usually be manufactured using biodegradable polymer compounds in the form of pellets, microspheres, or gels. Sustained-release injectable drugs refer to injections administered intramuscularly or elsewhere for the purpose of releasing active ingredients over a long period, and can usually be manufactured by dissolving or suspending the active ingredient in vegetable oil or other substances, or by creating a suspension of microspheres using biodegradable polymer compounds.

[0133] A pharmaceutical composition containing the disclosed compound is 1) Complementing and / or enhancing the preventive and / or therapeutic effects of the compound, 2) Improvement of the kinetics and absorption of the compound, reduction of dosage, and / or 3) The compound may be administered as a pharmaceutical composition (or combination agent) in combination with other drugs to reduce the side effects of the compound.

[0134] The pharmaceutical composition (or combination agent) may be administered in the form of a formulation in which both components are formulated in one preparation, or may be administered in the form of separate preparations. When administered in the form of separate preparations, it includes simultaneous administration and administration with a time difference. In the case of administration with a time difference, the compound of the present disclosure may be administered first and other drugs may be administered later, or other drugs may be administered first and the compound of the present disclosure may be administered later. Each administration method may be the same or different.

[0135] The diseases for which the pharmaceutical composition (or combination agent) exhibits a preventive and / or therapeutic effect are not particularly limited, and any disease that complements and / or enhances the preventive and / or therapeutic effect of the compound of the present disclosure may be used.

[0136] Examples of other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present disclosure against Parkinson's disease include, for example, levodopa, carbidopa, pramipexole, ropinirole, rotigotine, apomorphine, zonisamide, droxidopa, cabergoline, pergolide, tolcapone, entacapone, selegiline, rasagiline, safinamide, istradefylline, phosphocarbidopa / phosphocarbidopa, benserazide, bromocriptine, talipexole, amantadine, trihexyphenidyl, and biperiden.

[0137] Examples of other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present disclosure against Lewy body disease include, for example, donepezil hydrochloride, and zonisamide.

[0138] Examples of other drugs for complementing and / or enhancing the preventive and / or therapeutic effect of the compound of the present disclosure against Gaucher's disease include, for example, imiglucerase, velaglucerase alfa, eliglustat, alglucerase, and miglustat.

[0139] Two or more of the other drugs may be administered in combination. In addition, other agents that complement and / or enhance the preventive and / or therapeutic effects of the compounds of the present disclosure include not only those found to date but also those that may be found in the future, based on the mechanisms described above.

[0140] Unless otherwise defined, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0141] Also, in this specification, the contents of all patent documents, non-patent documents, or reference documents explicitly cited may all be cited herein as part of this specification.

[0142] In one aspect, the present disclosure [1] Formula (I):

Chemical formula

[0143] [2]L 1 The pharmaceutical composition according to [1] above, wherein [1] is a hexylene group, [3] The pharmaceutical composition according to [1] or [2] above, wherein X is -O-, [4]L 2 The pharmaceutical composition according to any one of [1] to [3] above, wherein [1] is a methylene group, [5] Ring1 is the following ring structure:

Chemical formula

[0144] [7] A compound represented by formula (I) or a pharmaceutically acceptable salt thereof is represented by formula (I-1):

Chemical formula

Chemical formula

[0145] [8] The compound represented by formula (I), or a pharmaceutically acceptable salt thereof, is (1) (3S,4R,5R,6S)-1-{6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepanetetrol, (2) (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepanetetrol, (3) (3S,4R,5R,6S)-1-{ (5R)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanetetrol, (4) (3S,4R,5R,6S)-1-{ (5S)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanetetrol, (5) (3S,4R,5R,6S)-1-[(5R)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl]-3,4,5,6-azepanetetrol, (6) (3S,4R,5R,6S)-1-[(5S)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl]-3,4,5,6-azepanetetrol, (7) (3S,4R,5R,6S)-1-[(5R)-6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazol-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanetetrol, (8)(3S,4R,5R,6S)-1-[(5S)-6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetrol, (9)(3S,4R,5R,6S)-1-{(5S)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanthetol, (10)(3S,4R,5R,6S)-1-{(5R)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanthetol, (11)(3S,4R,5R,6S)-1-{(5S)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanthetol, (12)(3S,4R,5R,6S)-1-{(5R)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanthetol, (13)(3S,4R,5R,6S)-1-{(5S)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepanthetol, (14)(3S,4R,5R,6S)-1-{(5R)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepanthetol, (15)(3S,4R,5R,6S)-1-[(5S)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetrol, and (16)(3S,4R,5R,6S)-1-[(5R)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetrol, A pharmaceutical composition according to any one of the above [1]-[7], which is a compound selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

[0146] [9] A pharmaceutical composition according to any one of the above [1]-[8], which is a GBA1 chaperone modifier.

[10] A pharmaceutical composition according to any one of the above [1]-[8], which is a GCS inhibitor.

[11] A pharmaceutical composition according to any one of the above [1]-[8], which is a GBA1 and GCS dual control agent.

[12] A pharmaceutical composition according to any one of the above [9]-

[11] , which is a therapeutic and / or prophylactic agent for diseases related to GBA1 and / or GCS.

[13] The pharmaceutical composition according to

[12] above, wherein the disease associated with GBA1 and / or GCS is selected from the group consisting of Parkinson's disease, Lewy body disease, Gaucher disease, multiple system atrophy, Fabry disease, Niemann-Pick disease type C, lysosomal storage disorder, dementia, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depressive disorder, Sandhoff disease, Tay-Sachs disease, multiple sclerosis, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, cognitive impairment, learning disability, motor disorder, sleep disorder, neurological disorder, CNS disorder, polycystic kidney disease, diabetes mellitus, cancer, open-angle glaucoma, endometriosis, multiple myeloma, viral disease, inflammation, systemic lupus erythematosus, hepatitis, Guillain-Barré syndrome, diabetic nephropathy, and skin disorders.

[14] The pharmaceutical composition according to

[12] , wherein the disease associated with GBA1 and / or GCS is selected from the group consisting of Parkinson's disease, Lewy body dementia, and Gaucher disease.

[15] A pharmaceutical composition according to any one of the above [9]-

[11] , comprising co-administration of one or more drugs selected from the group consisting of levodopa, carbidopa, pramipexole, ropinirole, rotigotine, apomorphine, zonisamide, droxidopa, cabergoline, pergolide, tolcapone, entacapone, selegiline, rasagiline, safinamide, istradefylline, foslevodopa / foscarbidopa, benserazide, bromocriptine, talipexole, amantadine, trihexyphenidyl, biperiden, donepezil hydrochloride, imiglucerase, veraglucerase alfa, eliglustat, alglucerase, and miglustat,

[16] A therapeutic and / or prophylactic agent for diseases associated with GBA1 and / or GCS, comprising a compound described in any one of the preceding paragraphs [1]-[8] or a pharmaceutically acceptable salt thereof.

[17] A method for preventing and / or treating a disease associated with GBA1 and / or GCS, characterized by administering to a patient in need of prevention and / or treatment of a disease associated with GBA1 and / or GCS a pharmaceutical composition containing a compound described in any one of the above [1]-[8], or a pharmaceutically acceptable salt thereof.

[18] A pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof described in any one of the above [1]-[8], used for the prevention and / or treatment of diseases associated with GBA1 and / or GCS.

[19] Use of any compound described in any one of the above [1]-[8] or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention and / or treatment of diseases associated with GBA1 and / or GCS, The present invention provides embodiments such as those described above. [Examples]

[0147] The solvents indicated in parentheses in the chromatography separation section and the TLC section represent the elution or developing solvent used, and the percentages are expressed as volume ratios.

[0148] The information in parentheses next to "NMR" indicates the solvent used for the measurement. The compound names used herein are generally named using ACD / Name®, a computer program from Advanced Chemistry Development, which names compounds according to IUPAC rules, or by following IUPAC nomenclature.

[0149] LC-MS analysis was performed under the following conditions. Method A: Reverse-phase LC-MS analysis was performed using a SHIMADZU LC20-MS2020 equipped with an ESI source. MS parameters: Mobile phase: 1.5 ml / 4 L TFA aqueous solution (solvent A) and 0.75 ml / 4 L TFA acetonitrile solution (solvent B), with an elution gradient of 5%-95% (solvent B) for 0.7 minutes and 95% for 0.4 minutes at a flow rate of 1.5 mL / min; Column: Agilent Pursit 5 C18 20*2.0 mm; Wavelength: UV 220 nm, 254 nm; Column temperature: 50 °C; MS ionization: ESI.

[0150] Method B: Reverse-phase LC-MS analysis was performed using a SHIMADZU LC20-MS2020 equipped with an ESI source. MS parameters: Mobile phase: 0.8 mL / 4 L aqueous NH3·H2O solution (solvent A) and acetonitrile (solvent B), with an elution gradient of 10%-80% (solvent B) for 2 minutes and 80% for 0.48 minutes at a flow rate of 1.2 mL / min; Column: Xbridge C18 2.1 × 50 mm 5 μm; Wavelength: UV 220 nm and 254 nm; Column temperature: 50 °C; MS ionization: ESI.

[0151] Method C: Reverse-phase LC-MS analysis was performed using a SHIMADZU LC20-MS2020 equipped with an ESI source. MS parameters: Mobile phase: 0.8 mL / 4 L aqueous NH3·H2O solution (solvent A) and acetonitrile (solvent B), with an elution gradient of 10%-80% (solvent B) for 6 minutes and 80% for 0.5 minutes at a flow rate of 0.8 mL / min; Column: Xbridge C18 2.1 × 50 mm 5 μm; Wavelength: UV 220 nm and 254 nm; Column temperature: 50 °C; MS ionization: ESI.

[0152] Preparative HPLC was performed under the following conditions or with different solvent gradients and columns. Prep-HPLC(HCl): Mobile phase: A 0.1% HCl aqueous solution (solvent A) / acetonitrile solution (solvent B) was used, and elution was performed at a flow rate of 30 mL / min with a gradient of 25%-55% (solvent B) for 8 minutes, followed by retention at 100% for 2 minutes; Column: Phenomenex Synergi C18 150 × 30 mm × 4 μm.

[0153] Prep-HPLC (FA): Mobile phase: A 0.225% FA aqueous solution (solvent A) / acetonitrile solution (solvent B) was used, and elution was performed at a flow rate of 30 mL / min with a gradient of 55%-85% (solvent B) for 8 minutes, followed by retention at 100% for 2 minutes; Column: Welch Xtimate C18 100 × 40 mm × 3 μm.

[0154] Prep-HPLC (base): Mobile phase: An aqueous solution of 0.05% NH3·H2O and 10 mM NH4HCO3 (solvent A) and a solution of acetonitrile (solvent B) were used. Elution was performed at a flow rate of 30 mL / min with a gradient of 30%-60% (solvent B) for 20 minutes, followed by retention at 100% for 5 minutes. Column: Xtimate C18 150×40 mm×5 μm.

[0155] Prep-HPLC (neutral) Mobile phase: A 10 mM NH4HCO3 solution of water (solvent A) / acetonitrile (solvent B) was used, and elution was performed at a flow rate of 30 mL / min with a gradient of 35%-65% (solvent B) for 9.5 minutes, followed by retention at 100% for 2 minutes; Column: Phenomenex Gemini C18 75×40 mm×3 μm.

[0156] The SFC analysis was conducted under the following conditions. Preparative SFC was performed under the same conditions as the analytical method, or with different mobile phases, gradients, and columns. Method A1: Waters UPCC with PDA detector, column: cellulose 2 150×4.6mm ID, 5μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%-40% of B for 5 minutes, 40% for 2.5 minutes, then 5% of B for 2.5 minutes, flow rate: 2.5 mL / min, column temperature: 35℃, ABPR: 1500 psi.

[0157] Method A2: Waters UPCC with PDA detector, column: cellulose 2 100×4.6mm ID, 3μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), mobile phase composition: 40% B, flow rate: 2.8 mL / min, column temperature: 35℃, ABPR: 1500 psi.

[0158] Method A3: Waters UPCC with PDA detector, column: cellulose 2 150×4.6mm ID, 5μm, mobile phase: A: CO2, B: methanol (0.05% DEA), mobile phase composition: 40% B, flow rate: 2.5 mL / min, column temperature: 35℃, ABPR: 1500 psi.

[0159] Method B1: Waters UPCC with PDA detector, column: Chiralpak AD-3 150×4.6mm ID, 3μm, mobile phase: 50% ethanol (0.05% DEA) in CO2, flow rate: 2.2mL / min, column temperature: 35℃, ABPR: 1500psi.

[0160] Method B2: Waters UPCC with PDA detector, column: Chiralpak AD-3 150×4.6mm ID, 3μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%-40% of B for 4 minutes, 40% for 2 minutes, then 5% of B for 2 minutes, flow rate: 2.5 mL / min, column temperature: 35℃, ABPR: 1500 psi.

[0161] Method B3: Waters UPCC with PDA detector, column: Chiralpak AD-3 150×4.6mm ID, 3μm, mobile phase: 40% methanol in CO2 (0.05% DEA), flow rate: 2.5mL / min, column temperature: 35℃, ABPR: 1500psi.

[0162] Method B4: Agilent 1260 with DAD detector, column: Chiralpak AD-3 150×4.6mm ID, 3μm, mobile phase: A: CO2, B: methanol (0.05% DEA), gradient: 5%-40% of B for 5.5 minutes, 40% for 3 minutes, then 5% of B for 1.5 minutes, flow rate: 2.5 mL / min, column temperature: 40℃, ABPR: 1500 psi.

[0163] Method B5: Waters UPCC with PDA detector, column: Chiralpak AD-3 150×4.6mm ID, 3μm, mobile phase: A: CO2, B: methanol (0.05% DEA), gradient: 5%-40% of B for 5 minutes, 40% for 2.5 minutes, then 5% of B for 2.5 minutes, flow rate: 2.5 mL / min, column temperature: 35℃, ABPR: 1500 psi.

[0164] Method B6: Agilent 1260 with DAD detector, column: Chiralpak AD-3 150×4.6mm ID, 3μm, mobile phase: A: CO2, B: methanol (0.05% DEA), mobile phase composition: 40% B, flow rate: 2.5 mL / min, column temperature: 40℃, ABPR: 1500 psi.

[0165] Method B7: Agilent 1260 with DAD detector, column: Chiralpak AD-3 50×4.6mm ID, 3μm, mobile phase: A: CO2, B: methanol (0.05% DEA), mobile phase composition: 40% B, flow rate: 4 mL / min, column temperature: 35℃, ABPR: 1500 psi.

[0166] Method B8: Waters UPCC with PDA detector, column: Chiralpak AS-3 150×4.6mm ID, 3μm, mobile phase: 40% isopropanol in CO2 (0.05% DEA), flow rate: 2.5mL / min, column temperature: 35℃, ABPR: 1500psi.

[0167] Method D1: Waters UPCC with PDA detector, column: Chiralcel OD-3 150×4.6mm ID, 3μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%-40% of B for 4 minutes, 40% for 2 minutes, then 5% of B for 2 minutes, flow rate: 2.5 mL / min, column temperature: 35℃, ABPR: 1500 psi.

[0168] Method E1: Waters UPCC with PDA detector, Column: Chiralcel OJ-3 100×4.6mm ID, 3μm, Mobile phase: A: CO2, B: Ethanol (0.05% DEA), Gradient: 5%-40% of B for 4 minutes, 40% for 0.5 minutes, then 5% of B for 1.5 minutes, hold 5%-40% of B for 4 minutes, hold 40% for 0.5 minutes, then hold 5% of B for 1.5 minutes, Flow rate: 2.8 mL / min, Column temperature: 35℃, ABPR: 1500 psi.

[0169] Method F1: Waters UPCC with PDA detector, column: Chiralpak IG-3 100×4.6mm ID, 3μm, mobile phase: 40% ethanol (0.05% DEA) in CO2, flow rate: 2.8mL / min, column temperature: 35℃, ABPR: 1500psi.

[0170] Method F2: Waters UPCC with PDA detector, column: Chiralpak IG-3 50×4.6mm ID, 3μm, mobile phase: 40% ethanol (0.05% DEA) in CO2, flow rate: 4mL / min, column temperature: 35℃, ABPR: 1500psi.

[0171] Method F3: Agilent 1260 with DAD detector, column: Chiralpak IG-3 100×4.6mm ID, 3μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%-40% of B for 4 minutes, 40% for 2.5 minutes, then 5% of B for 1.5 minutes, flow rate: 2.8 mL / min, column temperature: 35℃, ABPR: 1500 psi.

[0172] Method F4: Waters UPCC with PDA detector, column: Chiralpak IG-3 50×4.6mm ID, 3μm, mobile phase: A: CO2, B: methanol (0.05% DEA), gradient: 5%-40% of B for 2 minutes, 40% for 1.2 minutes, then 5% of B for 0.8 minutes, flow rate: 4 mL / min, column temperature: 35℃, ABPR: 1500 psi.

[0173] Method F5: Agilent 1260 with DAD detector, column: Chiralpak IG-3 100×4.6mm ID, 3μm, mobile phase: A: CO2, B: methanol (0.05% DEA), gradient: 5%-40% of B for 4 minutes, 40% for 3 minutes, then 5% of B for 1 minute, flow rate: 2.5 mL / min, column temperature: 40℃, ABPR: 1500 psi.

[0174] Method F6: Waters UPCC with PDA detector, column: Chiralpak IG-3 50×4.6mm ID, 3μm, mobile phase: A: CO2, B: isopropanol (0.05% DEA), mobile phase composition: 40% B, flow rate: 4 mL / min, column temperature: 35℃, ABPR: 1500 psi.

[0175] Method G1: Agilent 1260 with DAD detector, column: cellulose-4, 100 x 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%-40% of B for 4 minutes, 40% for 2.5 minutes, then 5% of B for 1.5 minutes, flow rate: 2.8 mL / min, column temperature: 40°C, back pressure: 100 bar.

[0176] Method G2: Agilent 1260 with DAD detector, column: cellulose-4, 100 x 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), mobile phase composition: 40% B, flow rate: 2.8 mL / min, column temperature: 40°C, back pressure: 100 bar.

[0177] Method H1: Agilent 1260 with DAD detector, column: ChiralPak AY-3 150×4.6mm ID, 3μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%-40% of B for 5.5 minutes, 40% for 3 minutes, then 5% of B for 1.5 minutes, flow rate: 2.5 mL / min, column temperature: 40℃, ABPR: 100 bar.

[0178] Method J1: Agilent 1260 with DAD detector, column: Chiralcel OJ-H 150×4.6mm ID, 5μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%-40% of B for 4.5 minutes, then 5% of B for 1.5 minutes, flow rate: 2.5 mL / min, column temperature: 40℃, ABPR: 1500 psi.

[0179] The abbreviations used in the following examples are as follows: FA is formic acid; TFA is trifluoroacetic acid; TEA is triethylamine; DIEA is N,N-diisopropylethylamine; DIAD is diisopropyl azodicarboxylic acid; DAST is N,N-diethylaminosulfur trifluoride; DCM is dichloromethane; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; Â is ethyl acetate; PE is petroleum ether; THF is tetrahydrofuran; DMP is desmartin periodinane; Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); TBAI is tetrabutylammonium iodide; TBAF is tetrabutylammonium fluoride; DMAP is N,N-dimethyl-4-aminopyridine; IPA is isopropanol; MTBE is methyl tert-butyl ether; NFSI is N-fluorobis(phenylsulfonyl)amine; PBSF is perfluoro-1-butanesulfonyl fluoride; DBU is 1,8-diazabicyclo[5.4.0]-7-undecene; DMA is N,N-dimethylacetamide; TBAB is tetrabutylammonium bromide; mCPBA is metachloroperbenzoic acid.

[0180] Reference Example 1: 6-iodohexyl 4-methylbenzyl ether (4-methylphenyl)methanol (CAS No.: 589-18-4, 0.16 mL) and t-BuOK (207 mg) in THF (5 mL) were mixed with 1,6-diiodohexane (CAS No.: 629-09-40.61 mL) at 25 °C. The reaction mixture was stirred at 40 °C for 14 hours. After dilution with DCM, the mixture was concentrated to dryness. The crude product was purified using a silica gel flash column (PE ~ 15% EtOAC in PE) to obtain the labeled compound (103 mg). 1 H-NMR(CDCl3): δ7.29, 7.24, 4.48, 3.54-3.44, 3.19, 2.49-2.33, 1.94-1.82, 1.66-1.57, 1.53-1.37.

[0181] Example 1: (3S,4R,5R,6S)-1-{6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepanthetrol [ka]

[0182] To a mixture of KI (57 mg) and DMF (2 mL), the compound prepared in Reference Example 1 (103 mg), (3S,4R,5R,6S)-azepane-3,4,5,6-tetrol hydrochloride (CAS number: 170210-58-9, 93 mg), and DIEA (0.26 mL) were added at 25 °C and mixed. The reaction was stirred at 80 °C for 16 hours. The mixture was purified by prep-HPLC (base) to obtain the labeled compound (67 mg) as a crystalline solid.

[0183] LCMS retention time: 1.622 min (method B); MS(ESI, Pos.):m / z368.2(M+H)+; 1 H-NMR(CDCl3):δ7.26, 7.18, 4.45, 3.72-3.65, 3.60-3.53, 3.44, 2.89, 2.60, 2.53, 2.34, 1.63-1.55, 1.52-1.43, 1.41-1.34, 1.33-1.26.

[0184] Figure 1 shows the powder X-ray diffraction spectrum chart of the crystal measured under the following conditions, and Figure 2 shows the DSC chart.

[0185] (1) Powder X-ray diffraction spectrum Measurement conditions Device: Rigaku SmartLab Target: Cu Voltage: 45kV Current: 200mA Scanning speed: 3 degrees / min Optical system: Focused beam method Table 1 shows the diffraction angle (2θ) (degrees) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays. [Table 1]

[0186] (2) Differential scanning calorimetry (DSC) Measurement conditions Equipment: Discovery DSC manufactured by T.A. Instruments Sample cell: Aluminum pan Nitrogen gas flow rate: 50 mL / min Sample amount: 1.27 mg Heating rate: 10℃ / min Endothermic peak: Onset temperature approximately 82°C, peak temperature approximately 83°C

[0187] Examples 2-60: Examples 2-60 were synthesized using the same method as in Reference Example 1 and Example 1, but with the corresponding alcohol compound used instead of (4-methylphenyl)methanol.

[0188] Example 2: (3S,4R,5R,6S)-1-[6-(4-biphenylylmethoxy)hexyl]-3,4,5,6-azepanthetrol LCMS retention time: 1.835 min (method B); MS(ESI, Pos.):m / z430.3(M+H)+; 1 H-NMR (CD3OD): δ7.62-7.54, 7.48-7.36, 7.37-7.30, 4.54, 3.60-3.50, 3.42-3.36, 2.80, 2.56-2.49, 1.69-1.60, 1.50-1.31.

[0189] Example 3: (3S,4R,5R,6S)-1-{6-[(3-phenyl-2-propyne-1-yl)oxy]hexyl}-3,4,5,6-azepanthetrol hydrochloride (1:1) LCMS retention time: 0.67 min (method A); MS(ESI, Pos.):m / z378.1(M+H)+; 1 H-NMR(D2O): δ7.44, 7.39-7.29, 4.33, 4.10-3.95, 3.76-3.44, 3.39-3.07, 1.72-1.52, 1.38-1.27.

[0190] Example 4: (3S,4R,5R,6S)-1-(6-{[2-(4-fluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetol LCMS retention time: 0.692 minutes (Method A); MS(ESI, Pos.): m / z 455.2(M+H)+; 1 H-NMR(CDCl3): δ7.95-7.89, 7.20, 7.20-7.08, 4.65, 4.48-3.75, 3.66, 3.66-3.51, 2.84-2.81, 2.59-2.46, 1.66-1.60, 1.46-1.26.

[0191] Example 5: (3S,4R,5R,6S)-1-{6-[(2-phenyl-1,3-thiazole-4-yl)methoxy]hexyl}-3,4,5,6-azepanthetrol hydrochloride (1:1) LCMS retention time: 0.688 minutes (Method A); MS(ESI, Pos.): m / z 437.1(M+H)+; 1 H-NMR(CD3OD): δ8.05-7.95, 7.54-7.52, 4.68, 4.21-4.04, 3.86, 3.69-3.55, 3.44-3.36, 3.29-3.14, 1.90-1.65, 1.56-1.40.

[0192] Example 6: (3S,4R,5R,6S)-1-[6-({2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-4-yl}methoxy)hexyl]-3,4,5,6-azepanthetrol hydrochloride (1:1) LCMS retention time: 0.751 minutes (Method A); MS(ESI, Pos.): m / z 505.1(M+H)+; 1 H-NMR(CD3OD): δ8.17, 7.82, 7.59, 4.71, 4.22-4.08, 3.88, 3.70-3.59, 3.48-3.38, 3.31-3.16, 1.91-1.67, 1.59-1.43.

[0193] Example 7: (3S,4R,5R,6S)-1-[6-({2-[3-(trifluoromethyl)phenyl]-1,3-thiazole-4-yl}methoxy)hexyl]-3,4,5,6-azepanthetrol hydrochloride (1:1) LCMS retention time: 0.75 minutes (Method A); MS(ESI, Pos.): m / z 505.1(M+H)+; 1H-NMR(CD3OD): δ8.29, 8.21, 7.83, 7.74, 7.58, 4.71, 4.21-4.05, 3.90-3.85, 3.68-3.55, 3.46-3.35, 3.29-3.14, 1.87-1.65, 1.58-1.38.

[0194] Example 8: (3S,4R,5R,6S)-1-(6-{[2-(3-fluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol hydrochloride (1:1) LCMS retention time: 0.698 minutes (Method A); MS(ESI, Pos.): m / z 455.1(M+H)+; 1 H-NMR(CD3OD): δ7.86-7.71, 7.61-7.48, 7.30-7.20, 4.68, 4.19-4.02, 3.84, 3.65-3.57, 3.45-3.34, 3.27-3.14, 1.92-1.63, 1.57-1.37.

[0195] Example 9: (3S,4R,5R,6S)-1-(6-{[2-(2-methylphenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol hydrochloride (1:1) LCMS retention time: 0.701 minutes (Method A); MS(ESI, Pos.): m / z 451.1(M+H)+; 1 H-NMR(CD3OD): δ7.89, 7.65, 7.57-7.33, 4.72, 4.19-4.03, 3.83, 3.67-3.53, 3.43-3.32, 3.27-3.11, 2.51, 1.89-1.63, 1.56-1.37.

[0196] Example 10: (3S,4R,5R,6S)-1-(6-{[2-(2-fluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol hydrochloride (1:1) LCMS retention time: 0.704 minutes (Method A); MS(ESI, Pos.): m / z 455.1(M+H)+; 1 H-NMR(CD3OD): δ8.25, 7.62, 7.58-7.48, 7.41-7.27, 4.71, 4.22-4.06, 3.86, 3.68-3.56, 3.46-3.36, 3.27-3.14, 1.89-1.65, 1.57-1.38.

[0197] Example 11: (3S,4R,5R,6S)-1-{6-[(5-phenyl-2-pyrazinyl)methoxy]hexyl}-3,4,5,6-azepantetrole LCMS retention time: 0.676 minutes (Method A); MS(ESI, Pos.): m / z 432.1(M+H)+; 1 H-NMR(CD3OD): δ9.05, 8.75, 8.04, 7.64-7.46, 4.72, 3.68-3.57, 3.44-3.37, 2.81, 2.61-2.45, 1.73-1.63, 1.55-1.28.

[0198] Example 12: (3S,4R,5R,6S)-1-(6-{[2-(4-fluorophenyl)-1,3-thiazole-5-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1) LCMS retention time: 0.739 minutes (Method A); MS(ESI, Pos.): m / z 455.2(M+H)+; 1 H-NMR(D2O): δ7.92-7.86, 7.27, 4.78, 4.08-4.06, 3.72, 3.60, 3.33, 3.20-3.15, 1.70-1.56, 1.35-1.29.

[0199] Example 13: (3S,4R,5R,6S)-1-(6-{[4-(4-fluorophenyl)-1,3-thiazole-2-yl]methoxy}hexyl)-3,4,5,6-azepanthetol LCMS retention time: 0.755 minutes (Method A); MS(ESI, Pos.): m / z 455.2(M+H)+; 1 H-NMR(CD3OD): δ7.94-7.89, 7.75, 7.15, 4.82, 3.65, 3.58-3.56, 3.40-3.37, 2.83, 2.57-2.51, 1.70-1.64, 1.51-1.35.

[0200] Example 14: (3S,4R,5R,6S)-1-(6-{[2-(4-fluorophenyl)-1,3-oxazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol hydrochloride (1:1) LCMS retention time: 0.731 minutes (Method A); MS(ESI, Pos.): m / z 439.2(M+H)+; 1 H-NMR(D2O): δ7.96-7.88, 7.22, 4.45, 4.07-4.05, 3.74, 3.60-3.50, 3.42-3.23, 3.17-3.12, 1.70-1.53​​, 1.34-1.30.

[0201] Example 15: (3S,4R,5R,6S)-1-(6-{[2-(4-fluorophenyl)-5-methyl-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol hydrochloride (1:1) LCMS retention time: 0.712 minutes (Method A); MS(ESI, Pos.): m / z469(M+H)+; 1 H-NMR(D2O): δ7.88-7.73, 7.22, 4.56, 4.08-3.92, 3.70, 3.60-3.50, 3.41-2.99, 2.44, 1.75-1.43, 1.38-1.14.

[0202] Example 16: (3S,4R,5R,6S)-1-{6-[(3'-fluoro-4-biphenylyl)methoxy]hexyl}-3,4,5,6-azepanthetrol LCMS retention time: 0.744 minutes (Method A); MS(ESI, Pos.): m / z 448.1(M+H)+; 1 H-NMR(CD3CN): δ7.63, 7.55-7.36, 7.20-7.05, 4.51, 3.86-3.30, 2.78, 2.50, 1.68-1.51, 1.52-1.24.

[0203] Example 17: (3S,4R,5R,6S)-1-(6-{[3'-(trifluoromethyl)-4-biphenylyl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 0.767 minutes (Method A); MS(ESI, Pos.): m / z 498.1(M+H)+; 1 H-NMR(CDCl3): δ7.81, 7.73, 7.61-7.48, 7.41, 4.52, 3.70, 3.58, 3.48, 2.88, 2.66-2.46, 1.71-1.18.

[0204] Example 18: (3S,4R,5R,6S)-1-(6-{[4'-(trifluoromethyl)-4-biphenylyl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 0.785 minutes (Method A); MS(ESI, Pos.): m / z 498.1(M+H)+; 1 H-NMR(CDCl3): δ7.70-7.60, 7.55, 7.40, 4.51, 3.84, 3.69, 3.47, 2.99, 2.84-2.58, 1.69-1.46, 1.43-1.19.

[0205] Example 19: (3S,4R,5R,6S)-1-(6-{[2-(4-chlorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 0.72 minutes (Method A); MS(ESI, Pos.): m / z471(M+H)+; 1 H-NMR(CD3OD): δ7.95, 7.56-7.48, 4.66, 3.64-3.55, 3.46-3.38, 2.82, 2.60-2.45, 1.72-1.61, 1.56-1.29.

[0206] Example 20: (3S,4R,5R,6S)-1-(6-{[2-(3,4-difluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetol LCMS retention time: 0.707 minutes (Method A); MS(ESI, Pos.): m / z 473.1(M+H)+; 1 H-NMR(CD3OD): δ7.95-7.82, 7.80-7.69, 7.49, 7.45-7.34, 4.63, 3.65-3.52, 3.43-3.36, 2.81, 2.57-2.49, 1.71-1.59, 1.56-1.27.

[0207] Example 21: (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol

change

[0208] Example 22: (3S,4R,5R,6S)-1-(6-{[2-(4-methylphenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 0.71 minutes (Method A); MS(ESI, Pos.): m / z 451.1(M+H)+; 1H-NMR(CD3OD): δ7.84, 7.42, 7.31, 4.64, 3.70-3.55, 3.44-3.38, 2.82, 2.65-2.47, 2.41, 1.72-1.60, 1.56-1.29.

[0209] Example 23: (3S,4R,5R,6S)-1-(6-{[2-(4-methoxyphenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetol LCMS retention time: 0.749 minutes (Method A); MS(ESI, Pos.): m / z 467.1(M+H)+; 1 H-NMR(CD3OD): δ7.91, 7.39, 7.06, 4.64, 3.89, 3.68-3.56, 3.44, 2.86, 2.74-2.48, 1.72-1.60, 1.59-1.29.

[0210] Example 24: (3S,4R,5R,6S)-1-(6-{[2-(3,4,5-trifluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 0.724 minutes (Method A); MS(ESI, Pos.): m / z491(M+H)+; 1 H-NMR(CD3OD): δ7.81-7.70, 7.54, 4.64, 3.72, 3.59, 3.48, 2.94, 2.84-2.60, 1.70-1.51, 1.49-1.30.

[0211] Example 25: (3S,4R,5R,6S)-1-(6-{[2-(3-chloro-4-fluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrole hydrochloride (1:1) LCMS retention time: 0.725 minutes (Method A); MS(ESI, Pos.): m / z489(M+H)+; 1 H-NMR(CD3OD): δ8.13, 7.99-7.88, 7.53, 7.40, 4.66, 4.22-4.04, 3.85, 3.69-3.52, 3.47-3.35, 3.29-3.14, 1.91-1.65, 1.55-1.37.

[0212] Example 26: (3S,4R,5R,6S)-1-[6-({2-[4-(trifluoromethoxy)phenyl]-1,3-thiazole-4-yl}methoxy)hexyl]-3,4,5,6-azepanthetrol LCMS retention time: 0.746 minutes (Method A); MS(ESI, Pos.): m / z521.1(M+H)+; 1 H-NMR(CD3OD): δ8.07, 7.50, 7.40, 4.65, 3.66-3.51, 3.40-3.36, 2.78, 2.56-2.50, 1.72-1.58, 1.54-1.26.

[0213] Example 27: (3S,4R,5R,6S)-1-(6-{[2-(3-methoxyphenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetol LCMS retention time: 0.696 minutes (Method A); MS(ESI, Pos.): m / z 467.1(M+H)+; 1 H-NMR(CD3OD): δ7.54-7.46, 7.39, 7.04, 4.58, 3.85, 3.61-3.55, 3.46, 2.78, 2.50-2.42, 1.63-1.54, 1.47-1.24.

[0214] Example 28: (3S,4R,5R,6S)-1-[6-(3-biphenylylmethoxy)hexyl]-3,4,5,6-azepanthetrol LCMS retention time: 0.726 minutes (Method A); MS(ESI, Pos.): m / z 430.1(M+H)+; 1 H-NMR(CD3OD): δ7.65-7.57, 7.54, 7.48-7.39, 7.38-7.28, 4.57, 3.61-3.55, 3.53, 3.41-3.36, 2.80, 2.58-2.46, 1.71-1.58, 1.54-1.29.

[0215] Example 29: (3S,4R,5R,6S)-1-(6-{[4-(1,3-thiazole-4-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1) LCMS retention time: 0.669 minutes (Method A); MS(ESI, Pos.): m / z 437.1(M+H)+; 1 H-NMR(D2O): δ9.07, 7.88-7.71, 7.40, 4.48, 4.07-3.92, 3.67, 3.60-3.39, 3.37-2.97, 1.72-1.40, 1.35-1.12.

[0216] Example 30: (3S,4R,5R,6S)-1-[6-({2-[3-(trifluoromethoxy)phenyl]-1,3-thiazole-4-yl}methoxy)hexyl]-3,4,5,6-azepanthetrol LCMS retention time: 0.721 minutes (Method A); MS(ESI, Pos.): m / z521.1(M+H)+; 1 H-NMR(CD3OD): δ7.96-7.86, 7.58, 7.52, 7.38, 4.65, 3.65-3.55, 3.43-3.36, 2.82, 2.66-2.45, 1.69-1.60, 1.55-1.46, 1.46-1.38, 1.37-1.29.

[0217] Example 31: 3-{4-[({6-[(3S,4R,5R,6S)-3,4,5,6-tetrahydroxy-1-azepanyl]hexyl}oxy)methyl]-1,3-thiazole-2-yl}benzonitrile LCMS retention time: 0.678 minutes (Method A); MS(ESI, Pos.): m / z 462.1(M+H)+; 1 H-NMR(CD3OD): δ8.34, 8.26, 7.83, 7.69, 7.57, 4.67, 3.65-3.53, 3.43-3.36, 2.80, 2.60-2.46, 1.72-1.61, 1.56-1.25.

[0218] Example 32: 4-{4-[({6-[(3S,4R,5R,6S)-3,4,5,6-tetrahydroxy-1-azepanyl]hexyl}oxy)methyl]-1,3-thiazole-2-yl}benzonitrile LCMS retention time: 0.673 minutes (Method A); MS(ESI, Pos.): m / z 462.2(M+H)+; 1 H-NMR(CD3OD): δ8.15, 7.86, 7.60, 4.68, 3.67-3.52, 3.46-3.36, 2.81, 2.64-2.45, 1.71-1.60, 1.57-1.26.

[0219] Example 33: (3S,4R,5R,6S)-1-(6-{[2-(4-fluoro-3-methoxyphenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetol LCMS retention time: 0.703 minutes (Method A); MS(ESI, Pos.): m / z 485.1(M+H)+; 1H-NMR(CD3OD): δ7.72, 7.51-7.42, 7.19, 4.63, 3.96, 3.65-3.55, 3.44-3.37, 2.83, 2.64-2.49, 1.71-1.58, 1.56-1.27.

[0220] Example 34: (3S,4R,5R,6S)-1-[6-({2-[4-(methylsulfonyl)phenyl]-1,3-thiazole-4-yl}methoxy)hexyl]-3,4,5,6-azepanthetrol LCMS retention time: 0.656 minutes (Method A); MS(ESI, Pos.): m / z515(M+H)+; 1 H-NMR(CD3OD): δ8.25, 8.09, 7.62, 4.70, 3.66-3.55, 3.43-3.38, 3.20, 2.82, 2.62-2.47, 1.72-1.61, 1.56-1.30.

[0221] Example 35: (3S,4R,5R,6S)-1-(6-{[6-(3-fluoro-5-methoxyphenyl)-3-pyridinyl]methoxy}hexyl)-3,4,5,6-azepantetrole hydrochloride (1:1) LCMS hold time: 1.031 minutes (D method); MS(ESI, Pos.): m / z 479.2(M+H)+; 1 H-NMR(D2O): δ8.74, 8.59, 8.26, 7.32-7.15, 7.05, 4.10, 3.89, 3.86-3.02, 1.84-1.57, 1.46-1.31.

[0222] Example 36: (3S,4R,5R,6S)-1-(6-{[5-(3-fluoro-5-methoxyphenyl)-2-pyridinyl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 0.665 minutes (Method A); MS(ESI, Pos.): m / z 479.1(M+H)+; 1 H-NMR(CD3OD): δ8.73, 8.10, 7.61, 7.12-6.94, 6.76, 4.64, 3.87, 3.65-3.52, 3.43-3.35, 2.81, 2.62-2.44, 1.74-1.61, 1.58-1.40, 1.40-1.30.

[0223] Example 37: (3S,4R,5R,6S)-1-(6-{[2-(3-chloro-5-methoxyphenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetol LCMS retention time: 1.808 minutes (Method B); MS(ESI, Pos.): m / z 501.2(M+H)+; 1 H-NMR(CD3OD): δ7.60-7.50, 7.49, 7.09, 4.67, 3.91, 3.70-3.55, 3.43, 2.85, 2.64-2.53, 1.71-1.65, 1.55-1.36.

[0224] Example 38: (3S,4R,5R,6S)-1-{6-[(2-cyclohexyl-1,3-thiazole-4-yl)methoxy]hexyl}-3,4,5,6-azepanthetrol LCMS retention time: 0.715 minutes (Method A); MS(ESI, Pos.): m / z443(M+H)+; 1 H-NMR(CD3OD): δ7.28, 4.53, 3.62-3.52, 3.44-3.37, 3.05-2.95, 2.82, 2.60-2.48, 2.16-2.09, 1.92-1.84, 1.82-1.75, 1.67-1.20.

[0225] Example 39: (3S,4R,5R,6S)-1-{6-[(2-propyl-1,3-thiazole-4-yl)methoxy]hexyl}-3,4,5,6-azepanthetrol LCMS retention time: 0.655 minutes (Method A); MS(ESI, Pos.): m / z403(M+H)+; 1 H-NMR(CD3OD): δ7.32, 4.57, 3.68-3.53, 3.45-3.39, 3.01, 2.84, 2.67-2.50, 1.96-1.75, 1.69-1.60, 1.58-1.30, 1.04.

[0226] Example 40: (3S,4R,5R,6S)-1-(6-{[2-(2,4-difluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 0.723 minutes (Method A); MS(ESI, Pos.): m / z 473.1(M+H)+; 1 H-NMR(CD3OD): δ8.28, 7.56, 7.22-7.08, 4.67, 3.61-3.54, 3.42-3.35, 2.80, 2.58-2.48, 1.69-1.60, 1.55-1.46, 1.45-1.37, 1.36-1.29.

[0227] Example 41: (3S,4R,5R,6S)-1-(6-{[2-(2,5-difluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetol LCMS retention time: 0.764 minutes (Method A); MS(ESI, Pos.): m / z 473.2(M+H)+; 1 H-NMR(CD3OD): δ8.02-7.95, 7.63, 7.40-7.35, 7.27-7.20, 4.69, 3.70-3.57, 3.42, 2.92-2.80, 2.69-2.51, 1.70-1.61, 1.66-1.55, 1.48-1.41, 1.39-1.32.

[0228] Example 42: (3S,4R,5R,6S)-1-(6-{[2-(2,6-difluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1) LCMS retention time: 0.689 minutes (Method A); MS(ESI, Pos.): m / z 473.1(M+H)+; 1 H-NMR(D2O): δ7.76, 7.57-7.51, 7.20-7.15, 4.69, 4.18-4.02, 3.88-3.53, 3.49-3.10, 1.84-1.53​​, 1.43-1.24.

[0229] Example 43: (3S,4R,5R,6S)-1-(6-{[2-(2,3,4-trifluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetol LCMS retention time: 0.78 minutes (Method A); MS(ESI, Pos.): m / z 491.2(M+H)+; 1 H-NMR(CD3OD): δ8.10-8.00, 7.63, 7.35-7.24, 4.68, 3.63-3.51, 3.43-3.34, 2.79, 2.59-2.44, 1.70-1.59, 1.55-1.27.

[0230] Example 44: (3S,4R,5R,6S)-1-(6-{[2-(2,4,6-trifluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepantethrol hydrochloride (1:1) LCMS retention time: 0.749 minutes (Method A); MS(ESI, Pos.): m / z 491.2(M+H)+; 1H-NMR(CD3OD): δ7.71, 7.15-7.04, 4.68, 3.65-3.53, 3.45-3.37, 2.84, 2.63-2.50, 1.66-1.33.

[0231] Example 45: (3S,4R,5R,6S)-1-[6-({2-[(E)-2-phenylvinyl]-1,3-thiazole-4-yl}methoxy)hexyl]-3,4,5,6-azepanthetol LCMS retention time: 1.706 minutes (Method B); MS(ESI, Pos.): m / z 463.2(M+H)+; 1 H-NMR(CD3OD): δ7.64, 7.55-7.48, 7.46-7.35, 4.62, 3.63-3.56, 3.44-3.40, 2.83, 2.60-2.51, 1.70-1.63, 1.57-1.33.

[0232] Example 46: (3S,4R,5R,6S)-1-[6-(2-naphthylmethoxy)hexyl]-3,4,5,6-azepanthetrol LCMS retention time: 1.729 minutes (Method B); MS(ESI, Pos.): m / z 404.3(M+H)+; 1 H-NMR(CD3OD): δ7.90-7.79, 7.62-7.35, 4.67, 3.60-3.53, 3.42-3.37, 2.81, 2.58-2.47, 1.70-1.62, 1.54-1.41, 1.37-1.30.

[0233] Example 47: (3S,4R,5R,6S)-1-[6-(2-biphenylylmethoxy)hexyl]-3,4,5,6-azepanthetrol LCMS retention time: 1.828 minutes (Method B); MS(ESI, Pos.): m / z 430.3(M+H)+; 1 H-NMR(DMSO-d6): δ7.54-7.51, 7.51-7.33, 7.30-7.23, 4.36, 3.64-3.52, 3.44-3.34, 2.83, 2.63-2.43, 1.59-1.43, 1.38-1.26.

[0234] Example 48: (3S,4R,5R,6S)-1-{6-[(3',5'-difluoro-2-biphenylyl)methoxy]hexyl}-3,4,5,6-azepanthetrol LCMS retention time: 1.89 minutes (Method B); MS(ESI, Pos.): m / z 466.3(M+H)+; 1 H-NMR(CD3OD): δ7.56-7.25, 7.22-6.91, 4.35, 3.63-3.50, 3.45-3.36, 2.80, 2.56-2.49, 1.61-1.44, 1.41-1.26.

[0235] Example 49: (3S,4R,5R,6S)-1-{6-[(3,4-dipropylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole LCMS retention time: 2.148 minutes (Method B); MS(ESI, Pos.): m / z 438.4(M+H)+; 1 H-NMR(CD3OD): δ7.15-7.01, 4.43, 3.60-3.53, 3.47, 3.40-3.35, 2.79, 2.63-2.46, 1.64-1.55, 1.52-1.45, 1.42-1.36, 1.34-1.28, 1.02-0.97.

[0236] Example 50: (3S,4R,5R,6S)-1-(6-{[2-(3-methylbutyl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrole formate (1:1) LCMS retention time: 0.756 minutes (Method A); MS(ESI, Pos.): m / z 424.2(M+H)+; 1 H-NMR(DMSO-d6): δ8.18, 7.37-7.08, 4.44, 3.31-2.99, 2.66, 2.62-2.57, 2.57-2.54, 2.46-2.39, 1.64-1.47, 1.44-1.22, 0.93.

[0237] Example 51: (3S,4R,5R,6S)-1-{6-[(4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole LCMS retention time: 1.854 minutes (Method B); MS(ESI, Pos.): m / z 396.4(M+H)+; 1 H-NMR(CD3OD): δ7.24, 7.17, 4.45, 3.60, 3.48, 3.44-3.37, 2.84, 2.64-2.49, 1.67-1.56, 1.54-1.46, 1.43-1.29, 0.93.

[0238] Example 52: (3S,4R,5R,6S)-1-(6-{[4-(1-cyclohexen-1-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrole LCMS retention time: 0.781 minutes (Method A); MS(ESI, Pos.):m / z456.2(M+Na)+; 1 H-NMR(CDCl3): δ7.35, 7.26, 6.16-6.05, 4.46, 3.75, 3.60, 3.44, 2.93, 2.76-2.63, 2.63-2.52, 2.41-2.37, 2.22-2.17, 1.81-1.73, 1.69-1.56, 1.54-1.45, 1.38-1.25.

[0239] Example 53: (3S,4R,5R,6S)-1-(6-{[3-(1-cyclohexen-1-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrole LCMS retention time: 1.996 minutes (Method B); MS(ESI, Pos.): m / z 434.4(M+H)+; 1 H-NMR(CD3OD): δ7.36-7.23, 7.17, 6.11, 4.48, 3.58, 3.49, 3.43-3.35, 2.81, 2.61-2.47, 2.41, 2.28-2.17, 1.86-1.75, 1.74-1.57, 1.55-1.45, 1.43-1.28.

[0240] Example 54: (3S,4R,5R,6S)-1-{6-[(3-cyclohexylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole LCMS retention time: 0.865 minutes (Method A); MS(ESI, Pos.): m / z 436.3(M+H)+; 1 H-NMR(CD3OD): δ7.30-7.06, 4.46, 3.65-3.52, 3.52-3.44, 3.43-3.35, 2.83, 2.61-2.44, 1.92-1.80, 1.80-1.71, 1.65-1.56, 1.54-1.27.

[0241] Example 55: (3S,4R,5R,6S)-1-(6-{[2-(1-cyclohexen-1-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrole LCMS retention time: 0.75 minutes (Method A); MS(ESI, Pos.): m / z 434.2(M+H)+; 1 H-NMR(DMSO-d6): δ7.39-7.32, 7.26-7.18, 7.13-7.05, 5.55-5.49, 4.67, 4.49, 4.37, 3.42-3.36, 3.22-3.13, 2.68-2.59, 2.44-2.34, 2.20-2.07, 1.75-1.57, 1.56-1.46, 1.41-1.18.

[0242] Example 56: (3S,4R,5R,6S)-1-{6-[(2-cyclohexylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole LCMS retention time: 0.758 minutes (Method A); MS(ESI, Pos.): m / z 436.2(M+H)+; 1 H-NMR(DMSO-d6): δ7.30-7.22, 7.16-7.09, 4.67, 4.48, 4.45, 3.42, 3.22-3.13, 2.83-2.71, 2.63, 2.43-2.34, 1.81-1.68, 1.58-1.47, 1.47-1.16.

[0243] Example 57: (3S,4R,5R,6S)-1-{6-[(4-cyclohexylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole LCMS retention time: 2.08 minutes (Method B); MS(ESI, Pos.): m / z 436.4(M+H)+; 1 H-NMR(CDCl3): δ7.26, 7.18, 4.45, 3.80-3.72, 3.64-3.57, 3.45, 2.98-2.90, 2.72-2.56, 2.52-2.45, 1.76-1.72, 1.63-1.56, 1.56-1.42, 1.42-1.28.

[0244] Example 58: (3S,4R,5R,6S)-1-(6-{[3-(3,5-difluorophenyl)-1,2-oxazole-5-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 1.69 minutes (Method B); MS(ESI, Pos.): m / z 457.4(M+H)+; 1H-NMR(DMSO-d6):δ7.68-7.59, 7.43, 7.17, 4.68, 4.64, 4.49, 3.50, 3.39-3.32, 3.21-3.14, 2.69-2.58, 2.44-2.31, 1.59-1.48, 1.42-1.34, 1.33-1.22.

[0245] Example 59: (3S,4R,5R,6S)-1-(6-{[5-(3,5-difluorophenyl)-1,2-oxazole-3-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 0.783 min (method A); MS(ESI, Pos.):m / z457.3(M+H)+; 1 H-NMR (CD3OD): δ7.53-7.44, 7.15-7.05, 6.96, 4.60, 3.59-3.53, 3.41-3.35, 2.79, 2.56-2.47, 1.68-1.58, 1.56-1.44, 1.44-1.31.

[0246] Example 60: (3S,4R,5R,6S)-1-{6-[(4-ethylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole LCMS retention time: 0.708 min (method A); MS(ESI, Pos.):m / z382.1(M+H)+; 1 H-NMR (CD3OD): δ7.25, 7.19, 4.45, 3.61-3.52, 3.47, 3.43-3.35, 2.80, 2.63, 2.58-2.45, 1.65-1.28, 1.22.

[0247] Reference example 2: (3S,4R,5R,6S)-1-{6-[(4-bromobenzyl)oxy]hexyl}-3,4,5,6-azepantetrole The indicated compound was synthesized using (4-bromophenyl)methanol (CAS number 873-75-6) instead of (4-methylphenyl)methanol, in the same manner as in Reference Example 1 and Example 1. LCMS retention time: 0.702 min (method A); MS(ESI, Pos.): m / z431.8, 433.8[M+H]+.

[0248] Example 61: (3S,4R,5R,6S)-1-(6-{[4-(3,6-dihydro-2H-pyran-4-yl)benzyl]oxy}hexyl)-3,4,5,6-azepanthetrol To a solution of the compound (150 mg) prepared in Reference Example 2 in 1,4-dioxane (2 mL) and water (0.5 mL), K2CO3 (144 mg), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS number: 287944-16-5, 109 mg), and Pd(dppf)Cl2 (12.7 mg) were added at 20-25°C. The reaction mixture was stirred at 100°C for 16 hours to obtain a brown solution. The reaction mixture was concentrated to dryness. The residue was purified using a reversed-phase column (30-40% MeCN aqueous solution) to obtain the labeled compound (35 mg). LCMS retention time: 0.69 min (method A); MS(ESI, Pos.):m / z436.1(M+H)+; 1 H-NMR(CD3OD):δ7.42, 7.31, 6.25-6.14, 4.48, 4.30, 3.92, 3.59, 3.49, 3.44-3.37, 2.83, 2.65-2.46, 1.66-1.57, 1.66-1.57, 1.45-1.36, 1.36-1.27.

[0249] Examples 62-67: Examples 62-67 were synthesized in the same manner as in Example 61, using the corresponding boronic acid or boronic acid ester instead of the compound prepared in Reference Example 2 and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0250] Example 62: (3S,4R,5R,6S)-1-{6-[(4'-fluoro-4-biphenylyl)methoxy]hexyl}-3,4,5,6-azepanthetrol LCMS retention time: 0.739 min (method A); MS(ESI, Pos.):m / z448.1(M+H)+; 1 H-NMR(CDCl3): δ7.58-7.48, 7.40, 7.12, 4.53, 3.65, 3.59-3.52, 3.49, 2.88, 2.62-2.47, 1.68-1.60, 1.51-1.24.

[0251] Example 63: 4'-[({6-[(3S,4R,5R,6S)-3,4,5,6-tetrahydroxy-1-azepanyl]hexyl}oxy)methyl]-3-biphenylcarbonitrile LCMS retention time: 0.716 minutes (Method A); MS(ESI, Pos.): m / z 455.1(M+H)+; 1 H-NMR(CD3OD): δ7.99, 7.95, 7.75-7.58, 7.46, 4.55, 3.63-3.56, 3.52, 3.45-3.31, 2.90-3.75, 2.62-2.45, 1.71-1.59, 1.56-1.45, 1.45-1.39, 1.39-1.28.

[0252] Example 64: (3S,4R,5R,6S)-1-{6-[(4'-fluoro-3'-methoxy-4-biphenylyl)methoxy]hexyl}-3,4,5,6-azepanthetrol LCMS retention time: 0.729 minutes (Method A); MS(ESI, Pos.): m / z 478.1(M+H)+; 1 H-NMR(CD3OD): δ7.59, 7.41, 7.33-7.26, 7.18-7.12, 4.53, 3.94, 3.61, 3.52, 3.46-3.37, 2.85, 2.68-2.49, 1.69-1.58, 1.58-1.46, 1.46-1.28.

[0253] Example 65: 4'-[({6-[(3S,4R,5R,6S)-3,4,5,6-tetrahydroxy-1-azepanyl]hexyl}oxy)methyl]-4-biphenylcarbonitrine LCMS retention time: 0.721 minutes (Method A); MS(ESI, Pos.): m / z 455.1(M+H)+; 1 H-NMR(CD3OD): δ7.86-7.77, 7.68, 7.48, 4.56, 3.67, 3.53, 3.45, 2.89, 2.64, 1.69-1.60, 1.55, 1.49-1.39, 1.39-1.30.

[0254] Example 66: 4'-[({6-[(3S,4R,5R,6S)-3,4,5,6-tetrahydroxy-1-azepanyl]hexyl}oxy)methyl]-2-biphenylcarbonitrile LCMS retention time: 0.715 minutes (Method A); MS(ESI, Pos.): m / z 455.1(M+H)+; 1H-NMR(CD3OD):δ7.82, 7.78-7.70, 7.65-7.44, 4.58, 3.62-3.51, 3.44-3.35, 2.82, 2.61-2.45, 1.69-1.58, 1.56-1.47, 1.47-1.39, 1.39-1.25.

[0255] Example 67: (3S,4R,5R,6S)-1-{6-[(3'-fluoro-5'-methoxy-4-biphenylyl)methoxy]hexyl}-3,4,5,6-azepanthetrol LCMS retention time: 0.75 min (method A); MS(ESI, Pos.):m / z478.1(M+H)+; 1 H-NMR(CD3OD):δ7.60, 7.42, 7.03-6.90, 6.69, 4.54, 3.85, 3.71-3.57, 3.52, 3.43, 2.96-2.79, 2.76-2.50, 1.68-1.59, 1.59-1.49, 1.47-1.39, 1.38-1.28.

[0256] Example 68: (3S,4R,5R,6S)-1-(6-{[4-(tetrahydro-2H-pyran-4-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrole A methanol (1 mL) solution of the compound (20 mg) prepared in Example 61 was mixed with Pd / C (5 mg, wet, 10%) and then purged with H2 (15 psi). The reaction was stirred at 20-25°C for 15 hours to obtain a black suspension. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (neutral) and concentrated to obtain the labeled compound (18.2 mg). LCMS retention time: 0.689 min (method A); MS(ESI, Pos.):m / z438.1(M+H)+; 1 H-NMR(CD3OD):δ7.28, 7.24, 4.46, 4.08-3.98, 3.66, 3.61-3.52, 3.51-3.40, 2.99-2.84, 2.84-2.74, 2.74-2.48, 1.85-1.71, 1.66-1.47, 1.46-1.26.

[0257] Reference Example 3: Methyl 4-phenoxy-2-pyrimidine carboxylate 2-chloro-4-phenoxypyrimidine (CAS number: 18214-00-1, 2.0 g) was dissolved in methanol (115 mL) and toluene (23 mL), to which TEA (4.04 mL) and Pd(dppf)Cl2 (708 mg) were added. The mixture was heated to 150 °C under CO (3 MPa) for 15 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure to obtain the residue. The residue was diluted with H2O and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was purified using a silica gel flash column (PE-30% ethyl acetate / PE) to obtain the labeled compound (1.3 g). LCMS retention time: 0.689 min (method A); MS(ESI, Pos.):m / z230.9[M+H]+.

[0258] Reference Example 4: (4-phenoxy-2-pyrimidinyl)methanol NaBH4 (98.6 mg) was added to a methanol (6 mL) solution of the compound (500 mg) prepared in Reference Example 3 at 0°C. The resulting mixture was stirred at 20-25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with H2O and saturated brine, and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to obtain the labeled compound (470 mg, crude product). The crude product was used directly in the next step.

[0259] Reference Example 5: 2-(bromomethyl)-4-phenoxypyrimidine To a solution of the compound (150 mg) prepared in Reference Example 4 and PPh3 (292 mg) in DCM (2 mL), CBr4 (492 mg) in DCM (1 mL) was added at 0-5°C. The mixture was refluxed for 6 hours. After diluting the reaction solution with DCM, it was washed with H2O and extracted with DCM. The organic phase was washed with saturated saline solution, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / siRNA=3 / 1) to obtain the labeled compound (100 mg). 1 H-NMR (CDCl3): δ8.61-8.53, 7.50-7.42, 7.34-7.28, 7.21-7.15, 6.69, 4.45.

[0260] Reference example 6: 6-[(4-phenoxy-2-pyrimidinyl)methoxy]-1-hexanol To a THF solution (4.5 mL) of the compound prepared in Reference Example 5 (150 mg) and t-BuOK (95 mg), hexane-1,6-diol (CAS No. 629-11-8, 0.12 mL) was added dropwise. The mixture was stirred at 20-25°C for 16 hours. The reaction mixture was diluted with H2O and extracted by DCM. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / siRNA = 1 / 1) to obtain the labeled compound (30 mg). LCMS retention time: 0.756 min (method A); MS(ESI, Pos.):m / z302.9[M+H]+.

[0261] Reference Example 7: 6-[(4-phenoxy-2-pyrimidinyl)methoxy]hexyl 4-methylbenzenesulfonate To a solution of the compound (45 mg) prepared in Reference Example 6 in DCM (0.64 mL) and pyridine (0.010 mL), TsCl (34 mg) was added at 0-5°C. The mixture was stirred at 20-25°C for 5 hours. The reaction solution was diluted with DCM, washed with H2O, and extracted with DCM. The organic phase was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / Ã=3 / 1) to obtain the labeled compound (15 mg). LCMS retention time: 0.956 min (method A); MS(ESI, Pos.):m / z457.0[M+H]+.

[0262] Example 69: (3S,4R,5R,6S)-1-{6-[(4-phenoxy-2-pyrimidinyl)methoxy]hexyl}-3,4,5,6-azepanthetrol DIEA (0.03 mL) was added to a solution of the compound prepared in Reference Example 7 (15 mg) and (3S,4R,5R,6S)-azepane-3,4,5,6-tetrol hydrochloride (9.8 mg) in DMSO (0.18 mL). The resulting mixture was heated at 80-90°C for 2 hours. The mixture was purified by prep-HPLC (base) to obtain the labeled compound (6.6 mg). LCMS retention time: 0.667 min (method A); MS(ESI, Pos.):m / z448(M+H)+; 1H-NMR (CD3OD): δ8.44, 7.35-7.21, 7.02-6.88, 6.79, 5.18, 4.38, 3.71, 3.48, 3.06-2.60, 1.84-1.70, 1.63-1.29.

[0263] Reference example 8: 1-bromo-2-({[6-(trityloxy)hexyl]oxy}methyl)benzene (2-bromophenyl)methanol (CAS number: 18982-54-2, 500 mg) was dissolved in DMF (5 mL) and NaH (160 mg, 60% in oil) was added at 0-5°C. The mixture was stirred at 0-5°C for 0.5 hours. Next, 1,1',1''-{[(6-bromohexyl)oxy]methanetriyl}tribenzene (CAS number: 113354-79-3, 2.3 g) and KI (44.3 mg) were added to the reaction mixture at 0-5°C. The reaction mixture was stirred at 20°C for 1.5 hours to obtain a brown solution. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified using a silica gel flash column (PE ~ 0% ethyl acetate / PE) to obtain the labeled compound (1.1 g). TLC: Rf 0.5 (PE / Ã=1 / 1).

[0264] Reference example 9: 6-[(2-bromobenzyl)oxy]-1-hexanol To a DCM solution (12 mL) of the compound (1.1 g) prepared in Reference Example 8, formic acid (0.80 mL) was added at 20°C. The mixture was stirred at 20°C for 17 hours to obtain a colorless solution. The reaction solution was poured into water and extracted with DCM. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using a silica gel flash column (PE-25% siRNA / PE) to obtain the labeled compound (300 mg). TLC: Rf 0.3 (PE / SiO = 3 / 1).

[0265] Reference Example 10: 6-{[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]oxy}-1-hexanol 300 mg of the compound prepared in Reference Example 9 was dissolved in 4 mL of 1,4-dioxane, and KOAc (308 mg), 4,4,4',4',5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (531 mg), and Pd(dppf)Cl2 (38.2 mg) were added at 20-25°C. The reaction mixture was stirred under a nitrogen atmosphere at 80°C for 15 hours. The reaction mixture was filtered. The filtrate was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated to obtain the labeled compound (300 mg). LCMS retention time: 0.927 min (method A); MS(ESI, Pos.):m / z357.1[M+Na]+.

[0266] Reference Example 11: 6-{[2-(4,6-difluoro-2-pyridinyl)benzyl]oxy}-1-hexanol To a solution of 2-bromo-4,6-difluoropyridine (CAS number: 41404-63-1,100 mg) in 1,4-dioxane (5 mL) and water (1 mL), the compound prepared in Reference Example 10 (214 mg), K2CO3 (258 mg), and Pd(dppf)Cl2 (37.7 mg) were added at 20-25°C. The reaction mixture was stirred at 80°C for 4 hours to obtain a yellow suspension. The reaction mixture was filtered. The filtrate was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified using a silica gel flash column (PE-20% ethyl acetate / PE) to obtain the labeled compound (190 mg). TLC: Rf 0.3 (PE / SiO = 3 / 1).

[0267] Reference Example 12: 6-{[2-(4,6-difluoro-2-pyridinyl)benzyl]oxy}hexanal To a solution of the compound (190 mg) prepared in Reference Example 11 in DCM (4 mL), DMP (377 mg) was added at 20°C. The mixture was stirred at 20°C for 1 hour. The reaction was stopped with a saturated aqueous Na2S2O3 solution and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified using a silica gel flash column (PE-10% siRNA / PE) to obtain the labeled compound (60.0 mg). TLC: Rf 0.50 (PE / Ã=3 / 1).

[0268] Example 70: (3S,4R,5R,6S)-1-(6-{[2-(4,6-difluoro-2-pyridinyl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrole To a methanol (3 mL) solution of the compound (60 mg) prepared in Reference Example 12, (3S,4R,5R,6S)-azepane-3,4,5,6-tetrol hydrochloride (41 mg) and NaOAc (73 mg) were added at 20°C. The reaction mixture was stirred at 20°C for 0.5 hours to obtain a yellow solution. Then, NaBH3CN (35 mg) was added at 20°C. The reaction mixture was stirred at 20°C for 15 hours. The reaction mixture was concentrated to dryness. The residue was purified by prep-HPLC (neutral) to obtain the labeled compound (34 mg). LCMS retention time: 0.693 min (method A); MS(ESI, Pos.):m / z489.1(M+Na)+; 1 H-NMR(DMSO-d6):δ7.59-7.53, 7.52-7.47, 7.46-7.40, 7.31-7.22, 4.66, 4.57, 4.48, 3.40-3.36, 3.32-3.29, 3.19-3.15, 2.62, 2.37, 1.43-1.29, 1.21-1.13.

[0269] Reference Example 13: 1-[(4-ethoxy-3-fluorobenzyl)oxy]-6-[(triisopropylsilyl)oxy]-2-hexanol To a solution of (3-ethoxy-4-fluorophenyl)methanol (CAS No.: 1000207-64-6,800 mg) in t-BuOH (5 mL), 15% NaOHaq was added (5 mL). Triisopropyl[4-(2-oxyranyl)butoxy]silane (CAS No.: 2734792-44-81, 41 g) and TBAI (758 mg) were added at 20-25°C. The resulting mixture was purged three times with nitrogen gas and stirred at 90°C for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using a silica gel flash column (PE-PE containing 15% ethyl acetate) to obtain the labeled compound (660 mg). TLC: Rf 0.40 (PE / ا = 5 / 1).

[0270] Reference Example 14: ({6-[(4-ethoxy-3-fluorobenzyl)oxy]-5-fluorohexyl}oxy)(triisopropyl)silane DAST (0.26 mL) was added to a DCM solution (1 mL) of the compound (660 mg) prepared in Reference Example 13 at 0°C. The mixture was stirred for 5 minutes. The reaction of the mixture was stopped with saturated NaHCO3 aqueous solution, washed with water, and extracted with DCM. The organic phase was concentrated and purified using a silica gel flash column (PE-5% Â, PE) to obtain the labeled compound (160 mg). TLC: Rf 0.60 (PE / alkyl = 10 / 1).

[0271] Reference Example 15: 6-[(4-ethoxy-3-fluorobenzyl)oxy]-5-fluoro-1-hexanol A solution of the compound prepared in Reference Example 14 (160 mg) in THF (2 mL) was mixed with a solution of 1 M TBAF in THF (0.54 mL) at 20°C. The reaction was stirred at 20°C for 1 hour to obtain a yellow solution. The reaction was concentrated to dryness. The residue was directly purified using a silica gel flash column (PE-35% Â, PE) to obtain the labeled compound (90 mg). TLC: Rf 0.20 (PE / ethyl = 2 / 1).

[0272] Reference Example 16: 6-[(4-ethoxy-3-fluorobenzyl)oxy]-5-fluorohexyl 4-methylbenzene sulfonate To a solution of the compound (85 mg) prepared in Reference Example 15 in DCM (2 mL), 4-methylbenzenesulfonyl chloride (0.090 mL), TEA (0.12 mL), and DMAP (13 mg) were added at 25 °C. The reaction mixture was stirred at 25 °C for 15 hours. The reaction mixture was concentrated to dryness. The residue was purified using a silica gel flash column (PE-20% Â, PE) to obtain the labeled compound (100 mg). TLC: Rf 0.60 (PE / ethyl = 3 / 1).

[0273] Example 71: (3S,4R,5R,6S)-1-{(5R)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 1) Example 72: (3S,4R,5R,6S)-1-{(5S)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) [ka] [ka] To a solution of (3S,4R,5R,6S)-azepane-3,4,5,6-tetrol hydrochloride (68 mg) in DMSO (1.5 mL), DIEA (0.19 mL), KI (19 mg), and the compound prepared in Reference Example 16 (100 mg) were added at 20-25 °C. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated to dryness. The residue was purified by prep-HPLC (base), and isomer 1 (5.0 mg) and isomer 2 (15 mg) were obtained by chiral SFC separation.

[0274] Example 71 (Isomer 1): LC-MS retention time: 0.683 minutes (Method A); MS(ESI, Pos.):m / z434.1(M+H)+; 1 H-NMR(CD3OD):δ7.12-7.00, 6.92-6.84, 4.73-4.65, 4.51, 4.10, 3.67-3.50, 3.43-3.36, 2.81, 2.61-2.47, 1.74-1.35; SFC retention time: 6.027 min (method A1).

[0275] Example 72 (Isomer 2): LC-MS retention time: 0.688 minutes (Method A); MS(ESI, Pos.):m / z434.1(M+H)+; 1 H-NMR(CD3OD):δ7.13-7.00, 6.92-6.84, 4.75-4.65, 4.51, 4.10, 3.68-3.50, 3.44-3.35, 2.80, 2.59-2.44, 1.74-1.39; SFC retention time: 6.254 min (method A1).

[0276] Examples 73-86: Examples 73-86 were synthesized using the same method as in Reference Examples 13, 14, 15, 16 and Examples 71, 72, with the corresponding alcohol compound used instead of (3-ethoxy-4-fluorophenyl)methanol.

[0277] Example 73: (3S,4R,5R,6S)-1-[(5R)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl]-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 1.612 minutes (Method B); MS(ESI, Pos.): m / z 473.1(M+H)+; 1 H-NMR(CD3OD): δ7.99, 7.48, 7.26-7.19, 4.75-4.57, 4.72, 3.75-3.65, 3.60-3.52, 3.41-3.37, 2.79, 2.60-2.44, 1.73-1.40; SFC retention time: 4.734 minutes (Method B8).

[0278] Example 74: (3S,4R,5R,6S)-1-[(5S)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl]-3,4,5,6-azepanthetrol (isomer 2)

change

[0279] Example 75: (3S,4R,5R,6S)-1-{5-fluoro-6-[(3,4,5-trifluorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 0.726 minutes (Method A); MS(ESI, Pos.): m / z 426.1(M+H)+; 1 H-NMR(CD3OD): δ7.13-7.10, 4.75-4.60, 4.53, 3.68-3.63, 3.61-3.53, 3.40-3.37, 2.81, 2.58-2.49, 1.74-1.30; SFC holding time: 1.826 minutes (method F4).

[0280] Example 76: (3S,4R,5R,6S)-1-{5-fluoro-6-[(3,4,5-trifluorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 0.741 minutes (Method A); MS(ESI, Pos.): m / z 426.1(M+H)+; 1 H-NMR(CD3OD): δ7.13-7.10, 4.75-4.60, 4.53, 3.71-3.53, 3.41-3.37, 2.81, 2.60-2.49, 1.73-1.51, 1.51-1.37; SFC retention time: 1.965 minutes (Method F4).

[0281] Example 77: (3S,4R,5R,6S)-1-[6-(benzyloxy)-5-fluorohexyl]-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 1.384 minutes (Method B); MS(ESI, Pos.): m / z 372.1(M+H)+; 1 H-NMR(CD3OD): δ7.42-7.21, 4.72-4.55, 4.55, 3.68-3.50, 3.42-3.35, 2.81, 2.59-2.46, 1.73-1.28; SFC holding time: 6.251 minutes (Method B5).

[0282] Example 78: (3S,4R,5R,6S)-1-[6-(benzyloxy)-5-fluorohexyl]-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 1.394 minutes (Method B); MS(ESI, Pos.): m / z 372.1(M+H)+; 1 H-NMR(CD3OD): δ7.39-7.23, 4.72-4.55, 4.56, 3.66-3.51, 3.43-3.35, 2.80, 2.58-2.47, 1.73-1.33; SFC retention time: 6.795 minutes (Method B5).

[0283] Example 79: (3S,4R,5R,6S)-1-{5-fluoro-6-[(4-fluorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 1.448 minutes (Method B); MS(ESI, Pos.): m / z 390.1(M+H)+; 1 H-NMR(CD3OD): δ7.37, 7.07, 4.72-4.55, 3.67-3.51, 3.43-3.36, 2.80, 2.59-2.47, 1.75-1.36; SFC retention time: 6.3 minutes (Method B4).

[0284] Example 80: (3S,4R,5R,6S)-1-{5-fluoro-6-[(4-fluorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 0.666 minutes (Method A); MS(ESI, Pos.): m / z 390(M+H)+; 1 H-NMR(CD3OD): δ7.37, 7.07, 4.73-4.60, 4.53, 3.66-3.49, 3.44-3.35, 2.80, 2.59-2.46, 1.72-1.37; SFC retention time: 6.799 minutes (Method B4).

[0285] Example 81: (3S,4R,5R,6S)-1-{6-[(2-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 0.696 minutes (Method A); MS(ESI, Pos.): m / z 406.1(M+H)+; 1 H-NMR(CDCl3): δ7.47, 7.39-7.33, 7.31-7.28, 7.25-7.20, 4.78-4.55, 4.66, 3.72-3.65, 3.65-3.61, 3.61-3.50, 2.91, 2.66-2.52, 1.55-1.41; SFC holding time: 4.572 minutes (Method G1).

[0286] Example 82: (3S,4R,5R,6S)-1-{6-[(2-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 0.694 minutes (Method A); MS(ESI, Pos.): m / z406(M+H)+; 1 H-NMR(CDCl3): δ7.52-7.45, 7.40-7.32, 7.31-7.28, 7.25-7.18, 4.77-4.56, 4.67, 3.73-3.58, 3.58-3.50, 2.91, 2.64-2.49, 1.58-1.35; SFC retention time: 4.809 minutes (Method G1).

[0287] Example 83: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(1-propyne-1-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 0.687 minutes (Method A); MS(ESI, Pos.): m / z 410.1(M+H)+; 1 H-NMR(CDCl3): δ7.47-7.35, 7.32-7.27, 7.24-7.17, 4.82-4.55, 4.72, 3.72-3.48, 2.87, 2.64-2.49, 2.09, 1.73-1.65, 1.54-1.39; SFC retention time: 4.628 minutes (Method G1).

[0288] Example 84: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(1-propyne-1-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 0.693 minutes (Method A); MS(ESI, Pos.): m / z 410.1(M+H)+; 1 H-NMR(CDCl3): δ7.46-7.36, 7.32-7.26, 7.23-7.17, 4.77-4.56, 4.74, 3.69-3.52, 2.87, 2.62-2.50, 2.08, 1.75-1.65, 1.50-1.30; SFC holding time: 4.865 minutes (Method G1).

[0289] Example 85: (3S,4R,5R,6S)-1-{6-[(2-chloro-4-methylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 0.707 minutes (Method A); MS(ESI, Pos.): m / z 420.1(M+H)+; 1 H-NMR(CD3OD): δ7.36, 7.22, 7.12, 4.73-4.50, 4.59, 3.71-3.52, 3.44-3.34, 2.81, 2.62-2.47, 2.33, 1.73-1.27; SFC holding time: 1.855 minutes (Method G2).

[0290] Example 86: (3S,4R,5R,6S)-1-{6-[(2-chloro-4-methylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 0.703 minutes (Method A); MS(ESI, Pos.): m / z 420.1(M+H)+; 1H-NMR(CD3OD):δ7.36, 7.22, 7.13, 4.73-4.50, 4.58, 3.69-3.54, 3.42-3.36, 2.81, 2.61-2.45, 2.33, 1.74-1.28; SFC retention time: 2.103 minutes (method G2).

[0291] Examples 87-98: Examples 87-98 were synthesized using the same method as in Reference Examples 13, 14, 15, 16 and Example 69, but with the corresponding alcohol compound used instead of (3-ethoxy-4-fluorophenyl)methanol.

[0292] Example 87: (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepanthetrol (a mixture of two isomers) LCMS retention time: 0.711 min (method A); MS(ESI, Pos.):m / z491.1(M+H)+; 1 H-NMR(DMSO-d6):δ7.75, 7.68-7.60, 7.45-7.36, 4.77-4.67, 4.66, 4.65-4.58, 4.49, 3.76-3.58, 3.37, 3.19, 2.64, 2.44-2.31, 1.65-1.28; SFC retention time: 3.525 / 3.851 min (method B1).

[0293] Example 88: (3S,4R,5R,6S)-1-{6-[(3',5'-difluoro-2-biphenylyl)methoxy]-5-fluorohexyl}-3,4,5,6-azepanthetrol (mixture of two isomers) LCMS retention time: 1.802 min (method B); MS(ESI, Pos.):m / z484.4(M+H)+; 1 H-NMR(CD3OD):δ7.66-7.26, 7.19-6.85, 4.70-4.65, 4.57-4.38, 3.67-3.50, 3.43, 2.87, 2.80-2.43, 1.76-1.35; SFC retention time: 2.082 / 2.139 min (method E1).

[0294] Example 89: (3S,4R,5R,6S)-1-(6-{[2-(3-chloro-5-fluorophenyl)-1,3-thiazole-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepanthetrol (a mixture of two isomers) LCMS retention time: 1.793 min (method B); MS(ESI, Pos.): m / z 507.4(M+H)+; 1 H-NMR(CD3OD): δ7.82, 7.72-7.64, 7.57, 7.36-7.29, 4.72, 4.61-4.53, 3.79-3.65, 3.60-3.53, 3.42-3.35, 2.86-2.74, 2.57-2.47, 1.75-1.33.

[0295] Example 90: (3S,4R,5R,6S)-1-(6-{[2-(3-chloro-5-methoxyphenyl)-1,3-thiazole-4-yl]methoxy}5-fluorohexyl)-3,4,5,6-azepantetrole (a mixture of two isomers) LCMS retention time: 1.779 minutes (Method B); MS(ESI, Pos.): m / z 519.4(M+H)+; 1 H-NMR(CD3OD): δ7.57-7.49, 7.48-7.42, 7.07, 4.72, 4.59, 3.88, 3.78-3.65, 3.57, 3.43-3.34, 2.80, 2.59-2.44, 1.75-1.32.

[0296] Example 91: (3S,4R,5R,6S)-1-{5-fluoro-6-[(3'-fluoro-2-biphenylyl)methoxy]hexyl}-3,4,5,6-azepantetrole hydrochloride (1:1) (mixture of two isomers) LCMS retention time: 0.735 minutes (Method A); MS(ESI, Pos.): m / z 466.2(M+H)+; 1 H-NMR(CD3OD): δ7.56-7.49, 7.47-7.37, 7.33-7.27, 7.23-7.07, 4.71-4.50, 4.48-4.34, 4.19-4.03, 3.84, 3.65-3.55, 3.54-3.49, 3.41, 3.35, 3.29-3.12, 1.94-1.39; SFC retention time: 2.298 / 2.342 minutes (Method E1).

[0297] Example 92: (3S,4R,5R,6S)-1-{6-[(3',4'-difluoro-2-biphenylyl)methoxy]-5-fluorohexyl}-3,4,5,6-azepanthetrol (a mixture of two isomers) LCMS retention time: 0.743 minutes (Method A); MS(ESI, Pos.): m / z 484.1(M+H)+; 1H-NMR(DMSO-d6): δ7.55-7.45, 7.45-7.37, 7.32-7.27, 7.24, 4.78-4.43, 4.42-4.32, 3.57-3.42, 3.37, 3.18, 2.64, 2.44-2.29, 1.62-1.24; SFC retention time: 2.275 / 2.393 minutes (Method E1).

[0298] Example 93: (3S,4R,5R,6S)-1-{5-fluoro-6-[(4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (a mixture of two isomers) LCMS retention time: 1.789 minutes (Method B); MS(ESI, Pos.): m / z 414.2(M+H)+; 1 H-NMR(CD3OD): δ7.26, 7.17, 4.71-4.50, 4.52, 3.62-3.53, 3.39, 2.82, 2.61-2.50, 1.68-1.37, 0.93.

[0299] Example 94: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(3,4,5-trifluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrole (a mixture of two isomers) LCMS retention time: 0.718 minutes (Method A); MS(ESI, Pos.):m / z531.1(M+Na)(M+H)+; 1 H-NMR(CD3OD): δ7.80-7.71, 7.56, 4.71, 4.60-4.56, 3.75-3.71, 3.69-3.66, 3.60-3.52, 3.41-3.35, 2.79, 2.57-2.49, 1.74-1.58, 1.55-1.40; SFC retention time: 3.254 / 3.307 minutes (Method J1).

[0300] Example 95: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(2,3,4-trifluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrole (a mixture of two isomers) LCMS retention time: 0.734 minutes (Method A); MS(ESI, Pos.):m / z531.1(M+Na)(M+H)+; 1H-NMR(CD3OD): δ8.09-8.00, 7.66, 7.35-7.22, 4.75, 4.63-4.56, 3.79-3.65, 3.65-3.55, 3.46-3.37, 2.84, 2.67-2.48, 1.76-1.35; SFC holding time: 2.657 / 2.747 minutes (Method E1).

[0301] Example 96: (3S,4R,5R,6S)-1-(6-{[5-(3,5-difluorophenyl)-1,2-oxazole-3-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepanthetrol (a mixture of two isomers) LCMS retention time: 0.799 minutes (Method A); MS(ESI, Pos.): m / z 475.2(M+H)+; 1 H-NMR(CDCl3): δ7.33-7.27, 6.95-6.81, 6.65, 4.80-4.51, 4.70, 3.76, 3.69-3.53, 2.94, 2.81-2.47, 1.83-1.32.

[0302] Example 97: (3S,4R,5R,6S)-1-{5-fluoro-6-[(5-methyl-2-propyl-1,3-thiazole-4-yl)methoxy]hexyl}-3,4,5,6-azepanthetrol (a mixture of two isomers) LCMS retention time: 1.531 minutes (Method B); MS(ESI, Pos.): m / z 435.2(M+H)+; 1 H-NMR(DMSO-d6): δ4.82-4.50, 4.50-4.34, 3.60-3.37, 3.21-3.14, 2.82, 2.69-2.59, 2.44-2.31, 1.67, 1.59-1.19, 0.92; SFC holding time: 3.529 / 3.618 minutes (Method D1).

[0303] Example 98: (3S,4R,5R,6S)-1-{5-fluoro-6-[(4-isopropylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (a mixture of two isomers) LCMS retention time: 1.811 minutes (Method B); MS(ESI, Pos.): m / z 414.2(M+H)+; 1 H-NMR(DMSO-d6): δ7.27-7.19, 4.71, 4.62-4.36, 3.63-3.41, 3.19, 2.94-2.80, 2.69-2.60, 2.52-2.51, 2.46-2.30, 1.66-1.28, 1.19; SFC retention time: 4.438 / 4.795 min (method B2).

[0304] Reference Example 17: 2-Fluoro-6-[(triisopropylsilyl)oxy]hexanal A solution of NFSI (90g), DL-proline (33g), THF (560mL), and IPA (70mL) was stirred at 20°C for 15 minutes. Then, a THF solution of 6-[(triisopropylsilyl)oxy]hexanal (CAS number: 245124-09-8, 78g) (100mL) was added. The mixture was stirred at 20°C for 16 hours. MTBE was added to the reaction mixture. The mixture was stirred at -78°C for 30 minutes and then filtered. The filtrate was washed with saturated NaHCO3 aqueous solution and saturated brine, dried over Na2SO4, and concentrated to obtain the title compound (78g). The title compound was used in the next step without further purification.

[0305] Reference Example 18: 2-Fluoro-6-[(triisopropylsilyl)oxy]-1-hexanol NaBH4 (28g) was added to a solution of the compound (39g) prepared in Reference Example 17 in DCM (400mL) and EtOH (400mL) at 0°C. The mixture was stirred at 0°C for 0.5 hours. The reaction reaction was stopped at 0°C with saturated NH4Cl aqueous solution (500mL). The mixture was stirred vigorously for 0.5 hours. The mixture was extracted with DCM and washed with saturated NaHCO3 aqueous solution. The organic phase was concentrated to obtain the crude product. Two batches of the crude product were mixed and purified by silica gel column chromatography (siRNA / PE = 0-4%) to obtain the labeled compound (30g). 1 H-NMR (CD3OD): δ4.58-4.38, 3.77-3.65, 1.84-1.62, 1.56-1.33, 109-1.04.

[0306] Reference Example 19: Methyl 5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole-4-carboxylate The marked compound was synthesized using methyl 5-bromo-2-methyl-1,3-oxazole-4-carboxylate (CAS number: 1935479-67-6) and (3,5-difluorophenyl)boronic acid (CAS number: 156545-07-2) in the same manner as in Reference Example 11, and used in the next step without purification.

[0307] Reference Example 20: [5-(3,5-difluorophenyl)-2-methyl-1,3-oxazol-4-yl]methanol To a solution of the compound (5.00 g) prepared in Reference Example 19 in THF (200 mL), a 3.5 M Red-Al toluene solution (7 mL) was added at 0°C. The mixture was stirred at 0°C for 15 minutes. 1 M hydrochloric acid was added to stop the reaction, and the mixture was stirred for 10 minutes. After washing with water, the mixture was extracted with ethyl acetate. The aqueous phase was washed with saturated brine and extracted with ethyl acetate. The combined organic phase was dried over Na₂SO₄. Crude products (5.00 g x 6 batches) were purified by silica gel column chromatography (PE-28% ethyl acetate / PE) to obtain the labeled compound (14.5 g). TLC: Rf 0.40 (PE / SiO = 1 / 1)

[0308] Reference Example 21: 4-(bromomethyl)-5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole The compound (12g) prepared in Reference Example 20 was mixed with DCM (150mL) and heated to dissolve. After cooling, DIEA (19mL) and LiBr (14g) were added at 0°C. The mixture was stirred at 0°C for 10 minutes. Then, Ms2O (12g) was added and the mixture was stirred at 30°C for 1 hour. The mixture was washed with water and extracted with DCM. The organic phase was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified using a silica gel column (PE-10% SiO2, PE) to obtain the labeled compound (12g). TLC: Rf 0.70 (PE / SiO = 3 / 1).

[0309] Reference Example 22: 5-(3,5-difluorophenyl)-4-[({2-fluoro-6-[(triisopropylsilyl)oxy]hexyl}oxy)methyl]-2-methyl-1,3-oxazole To a solution of the compound (17g) prepared in Reference Example 18 in THF (300mL), NaH (4.7g, 60% in oil) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. The compound (17g) prepared in Reference Example 21 was added, and the mixture was stirred at 0°C for 16 hours. After washing the mixture with water, it was extracted with SiO2. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using a silica column (PE-5% SiO2, PE) to obtain the labeled compound (22g). TLC: Rf 0.8 (PE / SiO = 3 / 1)

[0310] Example 99: (3S,4R,5R,6S)-1-[(5R)-6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetrol (isomer 1)

[0311] Example 100: (3S,4R,5R,6S)-1-[(5S)-6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetrol (isomer 2) [ka] [ka] The listed compound was synthesized using the compound prepared in Reference Example 22 instead of the compound prepared in Reference Example 14, in the same manner as in Reference Examples 15, 16, and Examples 71 and 72.

[0312] Example 99 (Isomer 1): LC-MS retention time: 0.681 minutes (Method A); MS(ESI, Pos.):m / z489.1(M+H)+; 1 H-NMR(CD3OD):δ7.40-7.27, 7.05-6.95, 4.73-4.55, 4.60, 3.76-3.53, 3.43-3.35, 2.79, 2.57-2.45, 1.73-1.33; SFC retention time: 3.312 min (method A2).

[0313] Example 100 (Isomer 2): LC-MS retention time: 0.688 minutes (Method A); MS(ESI, Pos.):m / z489.1(M+H)+; 1 H-NMR(CD3OD):δ7.40-7.27, 7.05-6.95, 4.73-4.55, 4.60, 3.76-3.53, 3.43-3.35, 2.79, 2.57-2.45, 1.73-1.33; SFC retention time: 4.893 min (method A2).

[0314] Reference Example 23: 1-[(4-ethylbenzyl)oxy]-6-[(triisopropylsilyl)oxy]-2-hexanol (4-ethylphenyl)methanol (CAS number: 768-59-2, 66 g) and triisopropyl (4-(oxiran-2-yl)butoxy)silane (158 g) were dissolved in t-BuOH (150 mL) to which TBAI (31 g) and 15% NaOHaq (150 mL) were added at 20 °C. The reaction mixture was stirred at 80 °C for 16 hours. The mixture was extracted with ethylethanol and washed with saturated brine. The organic phase was concentrated and purified by silica gel flash column (ethylethanol in PE = 0-3%) to obtain the labeled compound (34 g). 1 H-NMR(CDCl3): δ7.26, 7.20-7.16, 4.52, 3.86-3.75, 3.68, 3.52-3.47, 3.31, 2.65, 1.49-1.38, 1.28-1.18, 1.06-1.04.

[0315] Reference example 24: 6-[(4-ethylbenzyl)oxy]-1,5-hexanediol To a solution of the compound (60 g) prepared in Reference Example 23 in THF (400 mL), TBAF (152 mL) was added at 20 °C. The reaction was stirred at 20 °C for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified using a silica gel flash column (ethyl acetate PE = 55-65%) to obtain the labeled compound (30 g). 1 H-NMR(CDCl3): δ7.26-7.22, 7.20-7.16, 4.51, 3.86-3.76, 3.61, 3.48, 3.31, 2.64, 1.63-1.51, 1.48-1.37, 1.26-1.20.

[0316] Reference Example 25: 6-[(4-ethylbenzyl)oxy]-5-hydroxyhexyl 4-methylbenzenesulfonate To a 400 mL solution of the compound prepared in Reference Example 24 in DCM, TsCl (33 g) and TEA (72 mL) were added at 0°C. The mixture was stirred at 20°C for 16 hours. The mixture was washed with water and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica column chromatography (PE-35% siRNA / PE) to obtain the labeled compound (33 g). 1H-NMR(CDCl3):δ7.77, 7.35-7.29, 7.25-7.21, 7.20-7.15, 4.49, 4.01, 3.76-3.67, 3.43, 3.27, 2.64, 2.44-2.42, 1.71-1.59, 1.42-1.31, 1.23.

[0317] Reference Example 26: 6-[(4-ethylbenzyl)oxy]-5-fluorohexyl 4-methylbenzenesulfonate

[0318] To a solution of the compound (39 g) prepared in Reference Example 25 in THF (400 mL), PBSF (33 mL), a triethylamine solution of hydrogen fluoride (31 mL), and TEA (80 mL) were added at 0°C. The reaction was stirred for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated. The residue was purified using a silica gel flash column (PE-4% ethyl acetate / PE) to obtain the labeled compound (12 g). 1 H-NMR(CDCl3):δ7.78, 7.34, 7.26(s,2H), 7.21-7.17, 4.64, 4.55-4.48, 4.03, 3.57-3.47, 2.65, 2.44, 1.73-1.63, 1.56-1.33, 1.23.

[0319] Example 101: (3S,4R,5R,6S)-1-{(5S)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanthetrol (isomer 1)

[0320] Example 102: (3S,4R,5R,6S)-1-{(5R)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) [ka] [ka]

[0321] The compound prepared in Reference Example 26 (16 g) was dissolved in DMF (150 mL), and (3S,4R,5R,6S)-azepane-3,4,5,6-tetrol hydrochloride (9.5 g), KI (12 g), and DIEA (33 mL) were added at 25 °C. The reaction mixture was stirred at 80 °C for 15 hours. The mixture was treated with NaHCO3 and subsequently extracted with SiO2. The organic phase was washed with water. After drying the organic phase over Na2SO4, it was concentrated under reduced pressure to obtain the crude product of the marked compound (14 g). Two batches of the crude product (36 g) were purified by SFC to obtain isomer 1 (14 g) and isomer 2 (14 g).

[0322] Example 101 (Isomer 1): LC-MS retention time: 0.697 minutes (Method A); MS(ESI, Pos.):m / z400.1(M+H)+; 1 H-NMR(CD3OD):δ7.26, 7.20, 4.70-4.54, 4.52, 3.61-3.51, 3.43-3.36, 2.80, 2.67-2.59, 2.59-2.45, 1.73-1.31, 1.22; SFC retention time: 2.827 minutes (Method B6). Example 102 (Isomer 2): LC-MS retention time: 0.691 minutes (Method A); MS(ESI, Pos.):m / z400.1(M+H)+; 1 H-NMR(CD3OD):δ7.26, 7.20, 4.73-4.54, 4.52, 3.67-3.51, 3.48-3.37, 2.89-2.68, 2.67-2.48, 1.76-1.56, 1.56-1.32, 1.22; SFC retention time: 3.852 min (method B6).

[0323] Examples 103-134: Examples 103-134 were synthesized using the corresponding alcohol compound instead of (4-ethylphenyl)methanol, in the same manner as in Reference Examples 23, 24, 25, 26, and Examples 71 and 72.

[0324] Example 103: (3S,4R,5R,6S)-1-[(5R)-5-fluoro-6-{[2-(3-methoxyphenyl)-1,3-thiazole-4-yl]methoxy}hexyl]-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 0.715 minutes (Method A); MS(ESI, Pos.): m / z 485.1(M+H)+; 1 H-NMR(CD3OD): δ7.56-7.44, 7.38, 7.04, 4.71, 4.75-4.56, 3.87, 3.77-3.64, 3.60-3.51, 3.41-3.35, 2.79, 2.58-2.44, 1.74-1.34; SFC holding time: 5.341 minutes (Method B7).

[0325] Example 104: (3S,4R,5R,6S)-1-[(5S)-5-fluoro-6-{[2-(3-methoxyphenyl)-1,3-thiazole-4-yl]methoxy}hexyl]-3,4,5,6-azepanthetrol (isomer 2) LCMS retention time: 0.711 minutes (Method A); MS(ESI, Pos.): m / z 485.1(M+H)+; 1 H-NMR(CD3OD): δ7.54-7.46, 7.38, 7.06-7.01, 4.71, 4.75-4.59, 3.87, 3.76-3.66, 3.60-3.52, 3.42-3.35, 2.79, 2.60-2.42, 1.75-1.60, 1.57-1.34; SFC retention time: 6.714 minutes (Method B7).

[0326] Example 105: (3S,4R,5R,6S)-1-(6-{[2-(3,4-difluorophenyl)-1,3-thiazole-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 1.665 minutes (Method B); MS(ESI, Pos.): m / z 491.1(M+H)+; 1 H-NMR(CD3OD): δ7.95-7.88, 7.81-7.72, 7.53, 7.45-7.35, 4.71, 4.62-4.59, 3.76-3.72, 3.69-3.65, 3.59, 3.40-3.35, 2.82, 2.63-2.50, 1.78-1.34; SFC retention time: 2.95 minutes (Method E1).

[0327] Example 106: (3S,4R,5R,6S)-1-(6-{[2-(3,4-difluorophenyl)-1,3-thiazole-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepanthetrol (isomer 2) LCMS retention time: 1.658 minutes (Method B); MS(ESI, Pos.): m / z 491.1(M+H)+; 1 H-NMR(CD3OD): δ7.95-7.88, 7.80-7.75, 7.53, 7.41-7.33, 4.71, 4.62-4.59, 3.76-3.72, 3.69-3.66, 3.61-3.54, 3.39, 2.81, 2.59-2.49, 1.75-1.49; SFC retention time: 2.858 minutes (Method E1).

[0328] Example 107: (3S,4R,5R,6S)-1-{(5S)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 1)

change

[0329] Example 108: (3S,4R,5R,6S)-1-{(5R)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 0.696 minutes (Method A); MS(ESI, Pos.): m / z 406.1(M+H)+; 1 H-NMR(CDCl3): δ7.37-7.29, 4.77-4.60, 4.56, 3.71, 3.64-3.50, 2.92, 2.69-2.52, 1.59-1.37; SFC retention time: 2.973 minutes (Method F4).

[0330] Example 109: (3S,4R,5R,6S)-1-{6-[(3,4-difluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 0.676 minutes (Method A); MS(ESI, Pos.):m / z430.1(M+Na)+; 1H-NMR(CD3OD): δ7.31-7.18, 7.16-7.08, 4.74-4.60, 4.53, 3.67-3.62, 3.62-3.51, 3.44-3.35, 2.82, 2.62-2.45, 1.81-1.22; SFC retention time: 2.01 minutes (Method F4).

[0331] Example 110: (3S,4R,5R,6S)-1-{6-[(3,4-difluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 0.672 minutes (Method A); MS (ESI, Pos.): m / z 430(M+Na)+; 1 H-NMR(CD3OD): δ7.31-7.19, 7.17-7.09, 4.74-4.60, 4.53, 3.66-3.62, 3.60-3.52, 3.43-3.35, 2.80, 2.60-2.44, 1.73-1.39; SFC retention time: 2.15 minutes (Method F4).

[0332] Example 111: (3S,4R,5R,6S)-1-{6-[(3-ethoxybenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 1.536 minutes (Method B); MS(ESI, Pos.): m / z 416.2(M+H)+; 1 H-NMR(CD3OD): δ7.24, 6.94-6.87, 6.85-6.79, 4.72-4.50, 4.53, 4.03, 3.63-3.53, 3.41-3.37, 2.80, 2.59-2.47, 1.72-1.43, 1.38; SFC holding time: 4.762 minutes (Method G1).

[0333] Example 112: (3S,4R,5R,6S)-1-{6-[(3-ethoxybenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 1.534 minutes (Method B); MS(ESI, Pos.): m / z 416.1(M+H)+; 1H-NMR(CD3OD): δ7.24, 6.94-6.87, 6.85-6.79, 4.73-4.50, 4.53, 4.03, 3.65-3.52, 3.39, 2.81, 2.60-2.46, 1.74-1.42, 1.38; SFC retention time: 4.577 minutes (Method G1).

[0334] Example 113: (3S,4R,5R,6S)-1-{6-[(2,4-difluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 1.461 minutes (Method B); MS(ESI, Pos.): m / z 408.1(M+H)+; 1 H-NMR(CD3OD): δ7.53-7.42, 7.00-6.91, 4.70-4.60, 4.58, 3.68-3.62, 3.61-3.52, 3.42-3.35, 2.80, 2.60-2.47, 1.75-1.58, 1.56-1.33; SFC retention time: 4.784 minutes (method F5).

[0335] Example 114: (3S,4R,5R,6S)-1-{6-[(2,4-difluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 1.47 minutes (Method B); MS(ESI, Pos.): m / z 408.1(M+H)+; 1 H-NMR(CD3OD): δ7.53-7.43, 7.03-6.91, 4.70-4.60, 4.59, 3.68-3.63, 3.61-3.53, 3.42-3.36, 2.80, 2.60-2.48, 1.74-1.58, 1.57-1.38; SFC retention time: 5.027 minutes (method F5).

[0336] Example 115: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 0.719 minutes (Method A); MS(ESI, Pos.): m / z 414.1(M+H)+; 1H-NMR(CD3OD): δ7.31, 7.26-7.12, 4.72-4.50, 3.69-3.51, 3.43-3.35, 2.81, 2.70-2.62, 2.59-2.45, 1.74-1.32, 0.98; SFC retention time: 2.744 minutes (Method E1).

[0337] Example 116: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 0.721 minutes (Method A); MS(ESI, Pos.): m / z 414.1(M+H)+; 1 H-NMR(CD3OD): δ7.31, 7.25-7.10, 4.71-4.52, 3.68-3.51, 3.43-3.35, 2.81, 2.66, 2.59-2.45, 1.74-1.34, 0.98;

[0338] SFC retention time: 2.997 minutes (Method E1).

[0339] Example 117: (3S,4R,5R,6S)-1-{6-[(4-ethyl-2-methylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 0.725 minutes (Method A); MS(ESI, Pos.): m / z 414.1(M+H)+; 1 H-NMR(CD3OD): δ7.18, 7.05-6.95, 4.72-4.63, 4.53, 3.62-3.51, 3.43-3.36, 2.80, 2.63-2.49, 2.32, 1.74-1.60, 1.54-1.34, 1.21; SFC retention time: 5.967 minutes (Method B4).

[0340] Example 118: (3S,4R,5R,6S)-1-{6-[(4-ethyl-2-methylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepanthetrol (isomer 2) LCMS retention time: 0.73 minutes (Method A); MS(ESI, Pos.): m / z 414.1(M+H)+; 1H-NMR(CD3OD): δ7.18, 7.05-6.96, 4.71-4.61, 4.53, 3.66-3.52, 3.45-3.36, 2.82, 2.64-2.49, 2.32, 1.72-1.60, 1.55-1.36, 1.21; SFC retention time: 6.48 minutes (Method B4).

[0341] Example 119: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(4-methylphenyl)-1,3-oxazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 0.702 minutes (Method A); MS(ESI, Pos.):m / z475.2(M+Na)+; 1 H-NMR(CD3OD): δ7.92, 7.91, 7.33, 4.73-4.56, 4.54, 3.72-3.67, 3.65-3.62, 3.62-3.54, 3.44-3.37, 2.82, 2.62-2.48, 2.41, 1.70-1.33; SFC retention time: 4.729 minutes (Method F1).

[0342] Example 120: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(4-methylphenyl)-1,3-oxazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol (isomer 2) LCMS retention time: 0.697 minutes (Method A); MS(ESI, Pos.):m / z475.1(M+Na)+; 1 H-NMR(CD3OD): δ7.92, 7.91, 7.33, 4.73-4.56, 4.55, 3.73-3.63, 3.62-3.54, 3.45-3.38, 2.83, 2.63-2.51, 2.41, 1.70-1.35; SFC holding time: 6.14 minutes (Method F1).

[0343] Example 121: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(4-fluorophenyl)-1,3-oxazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 0.677 minutes (Method A); MS(ESI, Pos.): m / z 457.1(M+H)+; 1H-NMR(CD3OD): δ8.07, 7.95, 7.28-7.23, 4.74-4.60, 4.57, 3.73-3.68, 3.66-3.62, 3.60-3.53, 3.41-3.36, 2.79, 2.58-2.44, 1.74-1.60, 1.57-1.46; SFC retention time: 5.91 minutes (Method F3).

[0344] Example 122: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(4-fluorophenyl)-1,3-oxazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol (isomer 2) LCMS retention time: 0.689 minutes (Method A); MS(ESI, Pos.): m / z 457.1(M+H)+; 1 H-NMR(CD3OD): δ8.08, 7.95, 7.28-7.23, 4.73-4.60, 4.56, 3.72-3.68, 3.66-3.62, 3.59-3.52, 3.40-3.36, 2.79, 2.57-2.47, 1.73-1.63, 1.55-1.32; SFC retention time: 6.763 minutes (Method F3).

[0345] Example 123: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(3-fluorophenyl)-1,3-oxazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 0.689 minutes (Method A); MS(ESI, Pos.): m / z 457.1(M+H)+; 1 H-NMR(CD3OD): δ7.98, 7.86, 7.79-7.70, 7.59-7.50, 7.31-7.22, 4.75-4.60, 4.58, 3.73-3.69, 3.67-3.63, 3.60-3.51, 3.41-3.37, 2.80, 2.58-2.48, 1.75-1.58, 1.56-1.34; SFC retention time: 1.704 minutes (Method F2).

[0346] Example 124: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(3-fluorophenyl)-1,3-oxazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol (isomer 2) LCMS retention time: 0.687 minutes (Method A); MS(ESI, Pos.): m / z 457.1(M+H)+; 1H-NMR(CD3OD): δ7.98, 7.86, 7.79-7.73, 7.59-7.50, 7.30-7.22, 4.73-4.60, 4.58, 3.73-3.69, 3.66-3.63, 3.60-3.52, 3.40-3.37, 2.80, 2.57-2.47, 1.74-1.62, 1.57-1.36; SFC retention time: 2.442 minutes (Method F2).

[0347] Example 125: (3S,4R,5R,6S)-1-{6-[(4-butylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 0.757 minutes (Method A); MS(ESI, Pos.): m / z 428.2(M+H)+; 1 H-NMR(CD3OD): δ7.25, 7.17, 4.72-4.63, 4.52, 3.63-3.51, 3.42-3.35, 2.80, 2.64-2.47, 1.71-1.49, 1.47-1.27, 0.94; SFC retention time: 0.8 minutes (Method B7).

[0348] Example 126: (3S,4R,5R,6S)-1-{6-[(4-butylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 4.203 minutes (Method C); MS(ESI, Pos.): m / z 428.2(M+H)+; 1 H-NMR(CD3OD): δ7.24, 7.16, 4.73-4.53, 4.52, 3.69-3.53, 3.46-3.39, 2.88, 2.70-2.55, 1.72-1.51, 1.48-1.29, 0.94; SFC retention time: 1.292 minutes (Method B7).

[0349] Example 127: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-fluoro-4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 1.8 minutes (Method B); MS(ESI, Pos.): m / z 432.2(M+H)+; 1H-NMR(CD3OD): δ7.32, 7.00, 6.94, 4.73-4.55, 4.58, 3.65-3.50, 3.50-3.52, 3.41-3.37, 2.89-2.76, 2.63-2.48, 1.67-1.38, 0.94; SFC retention time: 3.093 minutes (Method A3).

[0350] Example 128: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-fluoro-4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 1.793 minutes (Method B); MS(ESI, Pos.): m / z 432.1(M+H)+; 1 H-NMR(CD3OD): δ7.32, 7.00, 6.93, 4.72-4.55, 4.58, 3.65-3.52, 3.44-3.36, 2.86-2.75, 2.63-2.45, 1.71-1.55, 1.55-1.35, 0.94; SFC retention time: 3.485 minutes (Method A3).

[0351] Example 129: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-methyl-4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 0.755 minutes (Method A); MS(ESI, Pos.): m / z 428.2(M+H)+; 1 H-NMR(CD3OD): δ7.21-7.15, 7.02-6.94, 4.75-4.67, 4.58-4.49, 3.71-3.50, 3.46-3.36, 2.84, 2.65-2.49, 2.32, 1.73-1.30, 0.92; SFC retention time: 5.982 minutes (Method B4).

[0352] Example 130: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-methyl-4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 0.75 minutes (Method A); MS(ESI, Pos.): m / z 428.1(M+H)+; 1H-NMR(CD3OD): δ7.17, 7.03-6.91, 4.70-4.62, 4.57-4.49, 3.68-3.51, 3.45-3.37, 2.85, 2.68-2.47, 2.31, 1.68-1.33, 0.92; SFC retention time: 6.677 minutes (Method B4).

[0353] Example 131: (3S,4R,5R,6S)-1-{6-[(2,6-difluoro-4-propylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 0.749 minutes (Method A); MS(ESI, Pos.): m / z 450.1(M+H)+; 1 H-NMR(CD3OD): δ6.84, 4.60, 4.63-4.47, 3.67-3.51, 3.45-3.35, 2.83, 2.64-2.46, 1.72-1.32, 0.94; SFC retention time: 6.545 minutes (Method A3).

[0354] Example 132: (3S,4R,5R,6S)-1-{6-[(2,6-difluoro-4-propylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 0.753 minutes (Method A); MS(ESI, Pos.): m / z 450.1(M+H)+; 1 H-NMR(CD3OD): δ6.85, 4.61, 4.63-4.48, 3.68-3.52, 3.44-3.36, 2.83, 2.65-2.50, 1.70-1.57, 1.55-1.31, 0.95; SFC retention time: 6.945 minutes (Method A3).

[0355] Example 133: (3S,4R,5R,6S)-1-{6-[(2,4-dimethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 1) LCMS retention time: 1.601 minutes (Method B); MS(ESI, Pos.): m / z 400.2(M+H)+; 1 H-NMR(CD3OD): δ7.15, 7.00, 6.96, 4.69-4.50, 3.63-3.51, 3.40-3.36, 2.80, 2.59-2.42, 2.30, 2.28, 1.73-1.29; SFC retention time: 4.069 min (Method H1).

[0356] Example 134: (3S,4R,5R,6S)-1-{6-[(2,4-dimethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (isomer 2) LCMS retention time: 1.597 min (method B); MS(ESI, Pos.): m / z 400.2(M+H)+; 1 H-NMR(CD3OD):δ7.15, 7.00, 6.96, 4.70-4.52, 3.64-3.56, 3.56-3.53, 3.46-3.37, 2.84, 2.59-2.42, 2.30, 1.76-1.32; SFC retention time: 4.58 min (Method H1).

[0357] Reference Example 27: 1-[(4-methylbenzyl)oxy]-6-[(triisopropylsilyl)oxy]-2-hexanol To a solution of (4-methylphenyl)methanol (50 g) in t-BuOH (250 mL), 15% NaOHaq (250 mL), triisopropyl(4-(oxiran-2-yl)butoxy)silane (123 g) and TBAI (66 g) were added at 20 °C. The reaction was stirred at 90 °C for 15 hours. The mixture was poured into water and extracted with ethyl acetate. The organic phase was concentrated and purified by silica gel flash column (PE-5% ethyl acetate / PE) to obtain the labeled compound (79.5 g). TLC: Rf 0.40 (PE / ا = 5 / 1).

[0358] Reference example 28: 6-[(4-methylbenzyl)oxy]-1,5-hexanediol To a THF (250 mL) solution of the compound (79.5 g) prepared in Reference Example 27, a THF solution (292 mL) of 1 M TBAF was added at 20°C. The reaction was stirred at 20°C for 1 hour. The reaction mixture was concentrated, and the residue was purified using a silica gel flash column (PE-35% siRNA / PE) to obtain the labeled compound (44.7 g). TLC: Rf 0.20 (PE / ethyl = 2 / 1).

[0359] Reference Example 29: 5-Hydroxy-6-[(4-methylbenzyl)oxy]hexyl 4-methylbenzenesulfonate To a solution of the compound prepared in Reference Example 28 (44.7 g) in DCM (400 mL), TsCl (36.3 g) and TEA (52.3 mL) were added at 0°C. The mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated, and the residue was purified using a silica gel flash column (PE-20% HCl / PE) to obtain the labeled compound (45.4 g). TLC: Rf 0.60 (PE / ethyl = 3 / 1).

[0360] Reference Example 30: 5-Fluoro-6-[(4-methylbenzyl)oxy]hexyl 4-methylbenzenesulfonate

[0361] To a solution of the compound prepared in Reference Example 29 (45.4 g) in THF (450 mL), PBSF (39.9 mL), a triethylamine solution of hydrogen fluoride (37.7 mL), and TEA (53.1 mL) were added at 0°C. The reaction was stirred at 20°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated. The residue was purified using a silica gel flash column (PE-4% ethyl acetate / PE) to obtain the labeled compound (22.7 g). TLC: Rf 0.50 (PE / τ = 5 / 1).

[0362] Example 135: (3S,4R,5R,6S)-1-{(5S)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 1) [ka]

[0363] Example 136: (3S,4R,5R,6S)-1-{(5R)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole (isomer 2) (3S,4R,5R,6S)-azepane-3,4,5,6-tetrol hydrochloride (700 mg) was added to a 5 mL solution of DMF with 5.5 mL of DIEA, 53 mg of KI, and 1.25 g of the compound prepared in Reference Example 30 at 20-25°C. The reaction mixture was stirred at 80°C for 16 hours. The mixture was treated with saturated aqueous NaHCO3 and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated to dryness. The residue was purified by C18 reversed-phase column (10-30% MeCN aqueous solution) and chiral SFC separation to obtain isomer 1 (403 mg) and isomer 2 (358 mg).

[0364] Example 135 (Isomer 1): LC-MS retention time: 1.514 minutes (Method B); MS(ESI, Pos.):m / z386.1(M+H)+; 1 H-NMR(CD3OD):δ7.22, 7.16, 4.70-4.51, 4.50, 3.61-3.50, 3.41-3.37, 2.80, 2.60-2.48, 2.33, 1.75-1.58, 1.57-1.31; SFC retention time: 3.123 minutes (Method B3).

[0365] Example 136 (Isomer 2): LC-MS retention time: 1.495 minutes (Method B); MS(ESI, Pos.):m / z386.2(M+H)+; 1 H-NMR(CD3OD):δ7.22, 7.16, 4.70-4.51, 4.50, 3.64-3.55, 3.44-3.37, 2.83, 2.64-2.48, 2.33, 1.73-1.57, 1.56-1.32; SFC retention time: 3.884 min (method B3).

[0366] Reference Example 31: Methyl 2-(3,5-difluorophenyl)-1,3-oxazole-4-carboxylate To a DMA (10 mL) solution of methyl 2-amino-3-hydroxypropanoate hydrochloride (CAS No.: 5680-80-8, 500 mg) and 3,5-difluorobenzaldehyde (CAS No.: 32085-88-4, 460 mg), K2CO3 (888 mg) was added and the mixture was stirred at 25°C for 16 hours. At 0°C, BrCCl3 (1.9 g) and DBU (1.4 mL) were added and the mixture was stirred at 25°C for 16 hours. The mixture was purified using a silica gel flash column (ÂinPE = 0-40%) to obtain the title compound (390 mg). TLC: Rf 0.50 (Ã / PE = 1 / 3).

[0367] Reference Example 32: [2-(3,5-difluorophenyl)-1,3-oxazol-4-yl]methanol To a solution of the compound (100 mg) prepared in Reference Example 31 in THF (3 mL), LiAlH4 (20 mg) was added at 0°C, and the mixture was stirred at 0°C for 3 hours to obtain a yellow solution. The reaction mixture was stopped with water, 15% NaOHaq, and water. The mixture was dried over Na2SO4 and filtered. The filtrate was concentrated and purified using a silica gel flash column (ÂiinPE = 0-50%) to obtain the labeled compound (74 mg). TLC: Rf 0.30 (SiO / PE = 1 / 3).

[0368] Examples 137 and 138: Examples 137 and 138 were synthesized using the same method as in Reference Examples 23, 24, 25, 26, and Examples 71 and 72, with the corresponding alcohol prepared in Reference Example 32 instead of (4-ethylphenyl)methanol.

[0369] Example 137: (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-oxazole-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepanthetrol (isomer 1) LCMS retention time: 0.778 min (method A); MS(ESI, Pos.):m / z475.2(M+H)+; 1 H-NMR(CD3OD):δ8.00, 7.64-7.56, 7.22-7.06, 4.74-4.69, 4.59, 3.77-3.51, 3.47-3.35, 2.83, 2.69-2.44, 1.76-1.35; SFC retention time: 2.37 min (method F2).

[0370] Example 138: (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-oxazole-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepanthetrol (isomer 2) LCMS retention time: 0.781 min (method A); MS(ESI, Pos.):m / z475.2(M+H)+; 1 H-NMR(CD3OD):δ8.00, 7.66-7.49, 7.19-7.05, 4.74-4.65, 4.59, 3.76-3.49, 3.42-3.34, 2.79, 2.58-2.43, 1.75-1.34; SFC retention time: 3.083 min (method F2).

[0371] Reference Example 33: Methyl 6-(3,5-difluorophenyl)-3-pyridazine carboxylate To a solution of methyl 6-chloro-3-pyridazine carboxylate (CAS number: 65202-50-8, 25 g) and (3,5-difluorophenyl)boronic acid (32 g) in DMF (250 mL), K3PO4 (40 g) and Pd(dppf)Cl2 (1.1 g) were added under a nitrogen atmosphere. The mixture was stirred at 70°C for 12 hours under a nitrogen atmosphere. After cooling to 20°C, the mixture was poured into water and filtered. The filtered solid was washed with water. The filtrate was treated with MeOH and dried under reduced pressure to obtain the labeled compound (10 g). No further purification was performed, and the compound was used in the next step.

[0372] Reference Example 34: [6-(3,5-difluorophenyl)-3-pyridazinyl]methanol To a solution of the compound (4.2 g) prepared in Reference Example 33 in THF (80 mL), CaCl2 (1.9 g) and NaBH4 (0.95 g) were added at 0°C. After stirring at 10°C for 0.5 hours, MeOH (4 mL) was added dropwise at 0°C. The reaction mixture was stirred at 10°C for 2 hours to obtain a yellow solution. The reaction mixture was acidified with 1 M HCl to adjust the pH to 8. Water and HCl were added to the mixture and filtered. The filtrate was extracted with HCl. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified using a silica gel flash column (0%-40% HClinPE) to obtain the labeled compound (2.3 g). TLC: Rf 0.10 (PE / SiO = 2 / 1).

[0373] Examples 139 and 140: Examples 139 and 140 were synthesized using the same method as in Reference Examples 23, 24, 25, 26 and Examples 71 and 72, but with the corresponding alcohol prepared in Reference Example 34 instead of (4-ethylphenyl)methanol.

[0374] Example 139: (3S,4R,5R,6S)-1-[(5S)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetrol (isomer 1) [ka] LCMS retention time: 0.658 min (method A); MS(ESI, Pos.):m / z486.1(M+H)+; 1 H-NMR(CD3OD):δ8.25, 7.92, 7.82-7.71, 7.19-7.08, 4.94, 4.80-4.63, 3.85-3.70, 3.60-3.52, 3.43-3.36, 2.81, 2.59-2.49, 1.76-1.42; SFC retention time: 1.838 min (method F6).

[0375] Example 140: (3S,4R,5R,6S)-1-[(5R)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetrol (isomer 2) LCMS retention time: 0.662 min (method A); MS(ESI, Pos.):m / z486.1(M+H)+; 1 H-NMR(CD3OD):δ8.25, 7.93, 7.82-7.71, 7.19-7.08, 4.94, 4.79-4.63, 3.89-3.68, 3.60-3.52, 3.43-3.36, 2.81, 2.62-2.44, 1.76-1.35; SFC retention time: 3.359 min (method F6).

[0376] Reference Example 35: (3E)-6-(4-biphenylylmethoxy)-3-hexen-1-ol To a solution of 4-(bromomethyl)-1,1'-biphenyl (CAS No.: 2567-29-5, 250 mg) in THF (3 mL) and H2O (0.6 mL), 33 mg of TBAB, 0.28 mL of aqueous sodium hydroxide solution, and (E)-hexa-3-ene-1,6-diol (CAS No.: 71655-17-9, 141 mg) were added at 20-25°C and stirred at 60°C for 15 hours to obtain a yellow solution. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified using a silica gel flash column (PE-15% ethyl acetate / PE) to obtain the labeled compound (130 mg). 1 H-NMR(CDCl3): δ7.62-7.56, 7.47-7.38, 7.37-7.32, 5.65-5.55, 5.54-5.45, 4.56, 3.64, 3.54, 2.42-2.34, 2.29.

[0377] Example 141: (3S,4R,5R,6S)-1-[(3E)-6-(4-biphenylylmethoxy)-3-hexen-1-yl]-3,4,5,6-azepanthetrol Example 141 was synthesized using the corresponding alcohol prepared in Reference Example 35 instead of the compound prepared in Reference Example 6, in the same manner as in Reference Example 7 and Example 69. LCMS retention time: 0.725 min (method A); MS(ESI, Pos.):m / z428.1(M+H)+; 1 H-NMR(DMSO-d6):δ7.68-7.62, 7.50-7.43, 7.40, 7.38-7.33, 5.49-5.44, 4.68, 4.50, 3.45, 3.40-3.34, 3.21-3.16, 2.67, 2.48-2.38, 2.29-2.21, 2.14-2.05.

[0378] Examples 142-146: Examples 142-146 were synthesized using the same method as in Reference Example 7 and Example 69, but with the corresponding alcohol instead of the compound prepared in Reference Example 6.

[0379] Example 142: (3S,4R,5R,6S)-1-[(3E)-6-{[2-(2,3,4-trifluorophenyl)-1,3-thiazole-4-yl]methoxy}-3-hexen-1-yl]-3,4,5,6-azepanthetrol LCMS retention time: 1.705 min (method B); MS(ESI, Pos.):m / z489.1(M+H)+; 1 H-NMR (CD3OD): δ8.16-7.93, 7.63, 7.36-7.21, 5.59-5.46, 4.70, 3.63-3.52, 3.41-3.34, 2.81, 2.59-2.51, 2.36-2.29, 2.23-2.15.

[0380] Example 143: (3S,4R,5R,6S)-1-{(3E)-6-[(4-propylbenzyl)oxy]-3-hexen-1-yl}-3,4,5,6-azepantetrole LCMS retention time: 1.784 min (method B); MS(ESI, Pos.):m / z394.4(M+H)+; 1H-NMR(CD3OD): δ7.24, 7.15, 5.54-5.48, 4.46, 3.59-3.54, 3.48, 3.41-3.37, 2.83, 2.61-2.52, 2.31-2.23, 2.23-2.17, 1.68-1.54, 0.93.

[0381] Example 144: (3S,4R,5R,6S)-1-[(3E)-6-{[2-(3,4-difluorophenyl)-1,3-thiazole-4-yl]methoxy}-3-hexen-1-yl]-3,4,5,6-azepanthetrol LCMS retention time: 1.663 minutes (Method B); MS(ESI, Pos.): m / z 471.1(M+H)+; 1 H-NMR(CD3OD): δ7.90-7.86, 7.81-7.72, 7.49, 7.45-7.35, 5.60-5.45, 4.65, 3.65-3.51, 3.42-3.35, 2.82, 2.59-2.52, 2.37-2.27, 2.25-2.14.

[0382] Example 145: (3S,4R,5R,6S)-1-[(3E)-6-{[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methoxy}-3-hexen-1-yl]-3,4,5,6-azepanthetrol LCMS retention time: 1.671 minutes (Method B); MS(ESI, Pos.): m / z 471.2(M+H)+; 1 H-NMR(CD3OD): δ7.70-7.46, 7.19-6.97, 5.57-5.48, 4.66, 3.64-3.53, 3.40-3.37, 2.82, 2.62-2.50, 2.33, 2.25-2.15.

[0383] Example 146: (3S,4R,5R,6S)-1-[(3E)-6-{[2-(4-fluorophenyl)-1,3-thiazole-4-yl]methoxy}-3-hexen-1-yl]-3,4,5,6-azepanthetrol LCMS retention time: 0.68 minutes (Method A); MS(ESI, Pos.): m / z 453.1(M+H)+; 1 H-NMR(DMSO-d6): δ7.98, 7.59, 7.34, 5.46, 4.67, 4.58, 4.49, 3.51, 3.36, 3.20-3.15, 2.66, 2.48-2.37, 2.25, 2.09.

[0384] Reference example 36: 6-{[2-(2-bromo-1,3-thiazole-4-yl)-2-propanyl]oxy}-1-hexanol To a solution of 2-(2-bromo-1,3-thiazole-4-yl)-2-propanol (CAS number: 2228788-36-9, 180 mg) in DCM (3 mL), TsOH (167 mg) and 1,6-hexanediol (0.44 mL) were added. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was purified by silica gel column chromatography (PE-18% siRNA / PE) to obtain the labeled compound (48 mg). TLC: Rf 0.2 (PE / SiO = 3 / 1).

[0385] Reference example 37: 6-({2-[2-(1-propyne-1-yl)-1,3-thiazole-4-yl]-2-propanyl}oxy)-1-hexanol To a solution of the compound (48 mg) prepared in Reference Example 36 in THF (1 mL), TEA (0.041 mL) was added, followed by CuI (1.4 mg) and Pd(PPh3)2Cl2 (5.2 mg). After stirring at 20°C for 5 minutes, 1-propyne (1 mol / L THF solution, 0.89 mL) was added dropwise. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was diluted with HCl (10 mL) and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (PE-20% HCl / PE) to obtain the labeled compound (25 mg). TLC: Rf 0.2 (PE / SiO = 2 / 1).

[0386] Example 147: (3S,4R,5R,6S)-1-[6-({2-[2-(1-propin-1-yl)-1,3-thiazole-4-yl]-2-propanyl}oxy)hexyl]-3,4,5,6-azepanthetrol Example 147 was synthesized using the compound produced in Reference Example 37 instead of the compound produced in Reference Example 7, in the same manner as in Reference Example 16 and Example 69. LCMS retention time: 0.665 min (method A); MS(ESI, Pos.):m / z427.1(M+H)+; 1 H-NMR (CD3OD): δ7.35,3.59,3.40,3.23,2.88-2.78,2.63-2.47,2.13,1.55,1.53-1.44,1.39-1.23.

[0387] Reference Example 38: Ethyl [2-(4-chloro-3-fluorophenyl)-1,3-oxazole-4-yl]acetate A mixture of 4-chloro-3-fluorobenzamide (CAS No.: 874781-07-4, 1.0 g) and ethyl 4-chloro-3-oxobutanoate (CAS No.: 638-07-3, 1.9 g) was stirred at 140°C for 2 hours. The reaction mixture was diluted with H2O and extracted with siRNA. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to obtain the residue. The residue was purified using a silica gel flash column (PE containing 5% siRNA) to obtain the labeled compound (760 mg). 1 H-NMR (CDCl3): δ7.83-7.70, 7.54-7.41, 4.27-4.18, 3.68, 1.33-1.27.

[0388] Reference Example 39: 2-[2-(4-chloro-3-fluorophenyl)-1,3-oxazole-4-yl]ethanol To a solution of the compound (400 mg) prepared in Reference Example 38 in THF (4 mL), LiAlH4 (64 mg) was added at 0°C and the mixture was stirred at 20°C for 1 hour. The reaction was stopped with water and 15% NaOHaq. The mixture was stirred for 10 minutes. The suspension was diluted with ELISA, filtered, and the filtered solid was washed with ELISA. The filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the labeled compound (320 mg). Esi / ms:241.8[m+h]+. Reference example 40: 2-(4-chloro-3-fluorophenyl)-4-[2-(4-iodobutoxy)ethyl]-1,3-oxazole To a solution of the compound (50 mg) prepared in Reference Example 39 in THF (0.50 mL), 15% NaOHaq (2.5 mL), 1,4-diiodobutane (CAS No.: 628-21-7, 0.050 mL), and TBAI (67 mg) were added at 20°C. The reaction mixture was stirred at 50°C for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep-TLC (PE / ethyl acetate = 5 / 1, Rf = 0.4) to obtain the labeled compound (25 mg). TLC: Rf 0.40 (PE / ا = 5 / 1).

[0389] Example 148: (3S,4R,5R,6S)-1-(4-{2-[2-(4-chloro-3-fluorophenyl)-1,3-oxazole-4-yl]ethoxy}butyl)-3,4,5,6-azepantetrole Example 148 was synthesized in the same manner as in Example 1, using the iodide prepared in Reference Example 40 instead of the compound prepared in Reference Example 1. LCMS retention time: 0.69 min (method A); MS(ESI, Pos.):m / z458.9(M+H)+; 1 H-NMR (CD3OD): δ7.92-7.80, 7.69-7.62, 3.76, 3.63, 3.53, 3.44, 2.88, 2.61, 1.61.

[0390] Examples 149-153: Examples 149-153 were synthesized using 1,5-diiodopentane (CAS number 628-77-3) and the corresponding alcohol compound, in the same manner as in Reference Example 1 and Example 1.

[0391] Example 149: (3S,4R,5R,6S)-1-[5-(4-biphenylylmethoxy)pentyl]-3,4,5,6-azepanthetol LCMS retention time: 1.734 min (method B); MS(ESI, Pos.):m / z416.3(M+H)+; 1 H-NMR (CD3OD): δ7.61, 7.46-7.40, 7.32, 4.55, 3.61-3.51, 3.43-3.37, 2.81, 2.59-2.48, 1.72-1.61, 1.59-1.48, 1.46-1.37.

[0392] Example 150: (3S,4R,5R,6S)-1-(5-{[4-(4-fluorophenyl)-1,3-thiazole-2-yl]methoxy}pentyl)-3,4,5,6-azepantetrole hydrochloride (1:1) LCMS retention time: 0.739 min (method A); MS(ESI, Pos.):m / z441.2(M+H)+; 1 H-NMR(D2O): δ7.81-7.73, 7.19, 4.85, 4.08-4.06, 3.69-3.66, 3.34, 3.23-3.18, 1.73-1.63, 1.62-1.39.

[0393] Example 151: (3S,4R,5R,6S)-1-[5-(3-biphenylylmethoxy)pentyl]-3,4,5,6-azepanthetrol LCMS retention time: 0.708 min (method A); MS(ESI, Pos.):m / z416.1(M+H)+; 1 H-NMR(CD3OD):δ7.63-7.58, 7.54, 7.47-7.40, 7.37-7.29, 4.57, 3.59, 3.54, 3.43-3.38, 2.83, 2.63-2.51, 1.70-1.61, 1.59-1.48, 1.47-1.36.

[0394] Example 152: (3S,4R,5R,6S)-1-(5-{[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methoxy}pentyl)-3,4,5,6-azepanthetol LCMS retention time: 1.632 min (method B); MS(ESI, Pos.):m / z459.2(M+H)+; 1 H-NMR (CD3OD): δ7.64-7.49, 7.13-7.03, 4.65, 3.64-3.53, 3.42-3.35, 2.82, 2.78, 2.58-2.48, 1.70-1.61, 1.58-1.48, 1.47-1.37.

[0395] Example 153: (3S,4R,5R,6S)-1-[5-(2-biphenylylmethoxy)pentyl]-3,4,5,6-azepanthetrol LCMS retention time: 1.736 min (method B); MS(ESI, Pos.):m / z416.3(M+H)+; 1 H-NMR(CD3OD):δ7.52-7.47, 7.44-7.39, 7.39-7.32, 7.28-7.22, 4.36, 3.60-3.54, 3.41-3.36, 2.80, 2.57-2.47, 1.58-1.43, 1.37-1.28.

[0396] Reference Example 41: 2-[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]ethanol The compound in question was synthesized using the same method as in Reference Example 39, with ethyl 2-(2-(3,5-difluorophenyl)thiazole-4-yl) acetate (CAS number: 1501541-90-7) instead of the compound prepared in Reference Example 38. TLC: Rf 0.40 (PE / SiO = 3 / 1).

[0397] Example 154: (3S,4R,5R,6S)-1-(5-{2-[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]ethoxy}pentyl)-3,4,5,6-azepanthetol Example 154 was synthesized using 1,5-diiodopentane and the compound prepared in Reference Example 41, in the same manner as in Reference Example 1 and Example 1. LCMS retention time: 0.706 min (method A); MS(ESI, Pos.):m / z473(M+H)+; 1 H-NMR(DMSO-d6):δ7.64-7.57, 7.51, 7.40-7.32, 4.66, 4.48, 3.71, 3.42-3.37, 3.19-3.14, 2.99, 2.61, 2.40-2.31, 1.52-1.40, 1.40-1.29, 1.28-1.17.

[0398] Examples 155 and 156: Examples 155 and 156 were synthesized using 1,7-diiodoheptane (CAS number 51526-03-5) and the corresponding alcohol compound, in the same manner as in Reference Example 1 and Example 1.

[0399] Example 155: (3S,4R,5R,6S)-1-(7-{[4-(4-fluorophenyl)-1,3-thiazole-2-yl]methoxy}heptyl)-3,4,5,6-azepanthetol LCMS retention time: 0.781 min (Method C); MS(ESI, Pos.):m / z469.2(M+H)+; 1 H-NMR (CD3OD): δ7.99-7.90, 7.76, 7.18-7.12, 4.82, 3.64, 3.58-3.57, 3.40-3.38, 2.85-2.72, 2.57-2.50, 1.68-1.64, 1.50-1.33.

[0400] Example 156: (3S,4R,5R,6S)-1-(7-{[2-(4-fluorophenyl)-1,3-thiazole-4-yl]methoxy}heptyl)-3,4,5,6-azepanthetol LCMS retention time: 0.702 min (method A); MS(ESI, Pos.):m / z469.1(M+H)+; 1H-NMR(DMSO-d6):δ7.98, 7.58, 7.34, 4.68, 4.56, 4.49, 3.50, 3.45-3.37, 3.24-3.11, 2.75-2.55, 2.47-2.26, 1.62-1.47, 1.44-1.18.

[0401] Example 157: (3S,4R,5R,6S)-1-{4-[(4'-methyl-4-biphenylyl)methoxy]butyl}-3,4,5,6-azepanthetrol Example 157 was synthesized using 1,4-diiodobutane and the corresponding alcohol compound, in the same manner as in Reference Example 1 and Example 1. LCMS retention time: 0.723 min (method A); MS(ESI, Pos.):m / z416.1(M+H)+; 1 H-NMR(CDCl3): δ7.55, 7.48, 7.37, 7.23, 4.51, 3.64, 3.58-3.36, 2.85, 2.66-2.46, 2.38, 2.11-1.70, 1.68-1.48, 1.35-1.23.

[0402] Reference Example 42: Methyl 4,4-difluoro-6-hydroxyhexanoate 5,5-Difluorooxepant-2-one (CAS No.: 35196-95-3, 1.7 g) was dissolved in methanol (20 mL) and MeONa (600 mg) was added. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was stopped with saturated NH4Cl aqueous solution and extracted by DCM. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the labeled compound (1.7 g). This compound was used in the next step without purification.

[0403] Reference Example 43: Methyl 4,4-difluoro-6-[(triisopropylsilyl)oxy]hexanoate To a mixture of the compound (0.70 g) prepared in Reference Example 42 with DMF (10 mL), chlorotriisopropylsilane (0.90 mL) and imidazole (520 mg) were added. The reaction mixture was stirred at 25°C for 16 hours to obtain a brown mixture. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (PE-10% ethyl acetate / PE) to obtain the labeled compound (0.73 g). TLC: Rf 0.4 (PE / SiO = 20 / 1).

[0404] Reference example 44: 4,4-difluoro-6-[(triisopropylsilyl)oxy]-1-hexanol LiAlH4 (123 mg) was added to a THF (9 mL) solution of the compound (730 mg) prepared in Reference Example 43, and the mixture was stirred at 25°C for 2 hours. The reaction was stopped with water and 15% NaOHaq. After dilution with THF, the mixture was filtered. The filtered solid was washed with THF. The filtrate was concentrated under reduced pressure to obtain the labeled compound (640 mg). This compound was used in the next step without purification.

[0405] Reference Example 45: [(3,3-difluoro-6-iodohexyl)oxy](triisopropyl)silane To a solution of I2 (785 mg) in DCM (8 mL), PPh3 (811 mg), imidazole (281 mg), and the compound prepared in Reference Example 44 (640 mg) were added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with DCM and filtered. The filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by silica column chromatography (0-6% ÂnPE) to obtain the labeled compound (360 mg). TLC: Rf 0.7 (PE / SiO = 10 / 1).

[0406] Reference example 46: 2-(3,5-difluorophenyl)-4-[({4,4-difluoro-6-[(triisopropylsilyl)oxy]hexyl}oxy)methyl]-1,3-thiazole [2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methanol (CAS No.: 1480594-24-8, 100 mg) / DMF (2 mL) mixture was mixed with NaH (35 mg, 60% in oil) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then the compound prepared in Reference Example 45 (222 mg) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was purified by flash column using silica gel (PE containing 0-8% ethyl acetate) to obtain the labeled compound (110 mg). TLC: Rf 0.7 (PE / SiO = 10 / 1).

[0407] Example 158: (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methoxy}-3,3-difluorohexyl)-3,4,5,6-azepanthetrol Example 158 was synthesized using the compound prepared in Reference Example 46 instead of the compound prepared in Reference Example 14, in the same manner as in Reference Examples 15, 16, and Example 69. LCMS retention time: 0.732 min (method A); MS(ESI, Pos.):m / z531.1(M+Na)+; 1 H-NMR (CD3OD): δ7.62-7.53, 7.13-7.04, 4.67, 3.63, 3.58-3.52, 3.38, 2.81, 2.74-2.66, 2.54, 2.14-1.92, 1.87-1.75.

[0408] Examples 159-161: Examples 159-161 were synthesized using the same method as in Reference Examples 46, 15, 16 and Example 69, but with the corresponding alcohol compound used instead of [2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methanol.

[0409] Example 159: (3S,4R,5R,6S)-1-(6-{[2-(3,4-difluorophenyl)-1,3-thiazole-4-yl]methoxy}-3,3-difluorohexyl)-3,4,5,6-azepanthetrol LCMS retention time: 1.724 min (method B); MS(ESI, Pos.):m / z509.1(M+H)+; 1H-NMR(CD3OD):δ7.96-7.86, 7.80-7.73, 7.51, 7.44-7.30, 4.65, 3.62, 3.59-3.52, 3.40-3.36, 2.81, 2.75-2.65, 2.54, 2.15-1.90, 1.85-1.75.

[0410] Example 160: (3S,4R,5R,6S)-1-(3,3-difluoro-6-{[2-(2,3,4-trifluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 1.753 min (method B); MS(ESI, Pos.):m / z527.1(M+H)+; 1 H-NMR (CD3OD): δ8.19-7.91, 7.64, 7.38-7.21, 4.69, 3.63, 3.58-3.52, 3.43-3.34, 2.81, 2.70, 2.59-2.50, 2.13-1.92, 1.86-1.75.

[0411] Example 161: (3S,4R,5R,6S)-1-(3,3-difluoro-6-{[2-(4-fluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol LCMS retention time: 1.649 min (method B); MS(ESI, Pos.):m / z491.2(M+H)+; 1 H-NMR (CD3OD): δ8.03-7.95, 7.46, 7.27-7.19, 4.65, 3.62, 3.58-3.50, 3.41-3.36, 2.81, 2.74-2.66, 2.54, 2.14-1.91, 1.85-1.75.

[0412] Reference Example 47: 4,4-difluoro-6-[(triisopropylsilyl)oxy]hexyl benzoate To a solution of the compound (15 g) prepared in Reference Example 44 in DCM (500 mL), TEA (10 mL), DMAP (590 mg), and benzoyl chloride (6.7 mL) were added at 0-5°C. The reaction mixture was stirred at 20°C for 1 hour to obtain a yellow solution. The reaction mixture was poured into water and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified using a silica gel flash column (Â0-10%PE) to obtain the labeled compound (18 g). 1H-NMR (CDCl3): δ8.03, 7.56, 7.44, 4.36, 3.89, 2.23-1.91, 1.12-0.99.

[0413] Reference example 48: 4,4-difluoro-6-hydroxyhexyl benzoate To a solution of the compound (15 g) prepared in Reference Example 47 in THF (100 mL), a solution of 1 M TBAF in THF (54.3 mL) was added at 20°C. The reaction mixture was stirred at 20°C for 0.5 hours to obtain a yellow solution. The reaction mixture was concentrated to dryness. The residue was purified using a silica gel flash column (Â0-50%PE) to obtain the labeled compound (8.5 g). 1 H-NMR (CDCl3): δ8.04, 7.57, 7.45, 4.37, 3.89, 2.24-1.99.

[0414] Reference example 49: 6-[(4-ethylbenzyl)oxy]-4,4-difluoro-1-hexanol To a solution of the compound (93 mg) prepared in Reference Example 48 in DMF (2 mL), NaH (11 mg, 60% in oil) was added at 0°C. After stirring at 0°C for 30 minutes, 1-(bromomethyl)-4-ethylbenzene (CAS number: 57825-30-6, 100 mg) and TBAI (13 mg) were added. The reaction mixture was stirred at 25°C for 12 hours. After diluting the reaction mixture with water, it was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, and filtered. The filtration was concentrated. The residue was purified by flash column using silica gel (PE containing 0-30% ethyl acetate) to obtain the labeled compound (60 mg). 1 H-NMR(CDCl3): δ7.23, 7.20-7.16, 4.47, 3.73-3.58, 2.64, 2.26-2.12, 2.03-1.91, 1.81-1.70, 1.25-1.20, 1.25-1.20.

[0415] Example 162: (3S,4R,5R,6S)-1-{6-[(4-ethylbenzyl)oxy]-4,4-difluorohexyl}-3,4,5,6-azepantetrole Example 162 was synthesized using the compound produced in Reference Example 49 instead of the compound produced in Reference Example 6, in the same manner as in Reference Example 7 and Example 69. LCMS retention time: 1.711 min (method B); MS(ESI, Pos.):m / z418.2(M+H)+; 1 H-NMR (CD3CN): δ7.26, 7.21, 4.44, 3.63-3.25, 2.85-2.42, 1.93-1.83, 1.67-1.54, 1.20.

[0416] Reference Example 50: 1-{[2-(3-methoxyphenyl)-1,3-thiazole-4-yl]methoxy}-6-[(triisopropylsilyl)oxy]-2-hexanol (2-(3-methoxyphenyl)thiazole-4-yl)methanol (CAS No.: 885280-53-5, 500 mg) was dissolved in tert-butanol (5 mL) and 15% NaOHaq (5 mL), TBAI (728 mg), and triisopropyl(4-(oxiran-2-yl)butoxy)silane (0.92 g) were added at 20 °C. The reaction mixture was stirred at 90 °C for 15 hours to obtain a yellow solution. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified using a silica gel flash column (PE-20% ethyl acetate / PE) to obtain the labeled compound (390 mg). TLC: Rf 0.50 (PE / Ã=3 / 1).

[0417] Reference Example 51: 1-{[2-(3-methoxyphenyl)-1,3-thiazole-4-yl]methoxy}-6-[(triisopropylsilyl)oxy]-2-hexanone To a solution of the compound (200 mg) prepared in Reference Example 50 in DCM (5 mL), DMP (259 mg) was added at 20°C. The reaction was stirred at 20°C for 2 hours. The reaction mixture was poured into a saturated NaHCO3 aqueous solution and extracted with DCM. The organic phase was washed with a saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified using a silica gel flash column (PE-15% siRNA in PE) to obtain the labeled compound (140 mg). TLC: Rf 0.60 (PE / ethyl = 3 / 1).

[0418] Reference Example 52: 4-[({2,2-difluoro-6-[(triisopropylsilyl)oxy]hexyl}oxy)methyl]-2-(3-methoxyphenyl)-1,3-thiazole To a solution of the compound (140 mg) prepared in Reference Example 51 in DCM (3 mL), diethylaminosulfur trifluoride (0.30 mL) was added at 20 °C. The reaction mixture was stirred at 35 °C for 15 hours to obtain a yellow solution. The reaction was stopped with saturated NaHCO3 aqueous solution and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified using a silica gel flash column (PE-8% Â / PE) to obtain the labeled compound (80 mg). TLC: Rf 0.80 (PE / SiO = 3 / 1).

[0419] Example 163: (3S,4R,5R,6S)-1-(5,5-difluoro-6-{[2-(3-methoxyphenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol Example 163 was synthesized using the compound prepared in Reference Example 52 instead of the compound prepared in Reference Example 14, in the same manner as in Reference Examples 15, 16, and Example 69. LCMS retention time: 0.696 min (method A); MS(ESI, Pos.):m / z503.1(M+H)+; 1 H-NMR(DMSO-d6):δ7.68, 7.51, 7.45-7.40, 7.09-7.04, 4.71, 4.68, 4.50, 3.83, 3.78, 3.42-3.35, 3.20-3.15, 2.62, 2.41-2.32, 1.98-1.83, 1.39.

[0420] Reference example 53: 4-[(4-biphenylylmethyl)thio]-1-butanol 4-(bromomethyl)-1,1'-biphenyl (200 mg) and 4-mercapto-1-butanol (CAS No. 14970-83-3, 103 mg) were dissolved in DMF (5 mL) and K2CO3 (224 mg) was added. The mixture was stirred at 25°C for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified using a silica gel flash column (ethyl acetate 0-90% PE) to obtain the labeled compound (200 mg). 1 H-NMR (CDCl3): δ7.70-7.52, 7.49-7.32, 3.83-3.73, 3.71-3.58, 2.50, 1.77-1.59.

[0421] Example 164: (3S,4R,5R,6S)-1-{4-[(4-biphenylylmethyl)thio]butyl}-3,4,5,6-azepanthetrol Example 164 was synthesized using the compound produced in Reference Example 53 instead of the compound produced in Reference Example 11, in the same manner as in Reference Example 12 and Example 70. LCMS retention time: 0.784 min (method A); MS(ESI, Pos.):m / z418.1(M+H)+; 1 H-NMR (CD3OD): δ7.62-7.55, 7.45-7.37, 7.36-7.27, 3.75, 3.61-3.49, 3.44-3.35, 2.78, 2.56-2.44, 1.64-1.52.

[0422] Reference example 54: 4-(2-bromoethyl)-2-(4-fluorophenyl)-1,3-thiazole 2-[2-(4-fluorophenyl)-1,3-thiazole-4-yl]ethanol (CAS No. 871689-11-1, 220 mg) was dissolved in THF (5 mL) and PPh3 (550 mg) and CBr4 (660 mg) were added at 0 °C. The mixture was stirred at 15-20 °C for 5 hours to obtain a yellow suspension. The reaction mixture was stopped with water and extracted with ethyl acetate. The organic phase was concentrated to dryness. The residue was purified by silica gel flash column (ethyl acetate PE = 0-20%) and concentrated to obtain the labeled compound (260 mg). TLC: Rf 0.70 (PE / SiO = 3 / 1).

[0423] Reference example 55: 4-({2-[2-(4-fluorophenyl)-1,3-thiazole-4-yl]ethyl}thio)-1-butanol To a solution of the compound (260 mg) prepared in Reference Example 54 in DMF (5 mL), K2CO3 (251 mg) and 4-mercapto-1-butanol (0.10 mL) were added at 20 °C. The resulting mixture was stirred at 15-20 °C for 16 hours. The reaction solution was washed with water and extracted with ethyl acetate. The organic phase was concentrated and purified using a silica gel flash column (ethyl acetate PE = 10-30%) to obtain the labeled compound (290 mg). TLC: Rf 0.20 (ethyl / PE = 1 / 3).

[0424] Reference example 56: 4-({2-[2-(4-fluorophenyl)-1,3-thiazole-4-yl]ethyl}thiobutanal To a solution of the compound (100 mg) prepared in Reference Example 55 in DMSO (1 mL) and DCM (2 mL), TEA (0.22 mL) and Py.SO3 (340 mg) were added, and the mixture was stirred at 0°C and then at 0-20°C for 18 hours to obtain a white suspension. The reaction of the mixture was stopped with water, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and purified using a silica gel flash column (ethyl acetate PE = 0-20%) to obtain the labeled compound (30 mg). LCMS retention time: 0.898 min (method A); MS(ESI, Pos.):m / z309.9[M+H]+.

[0425] Example 165: (3S,4R,5R,6S)-1-[4-({2-[2-(4-fluorophenyl)-1,3-thiazole-4-yl]ethyl}thio)butyl]-3,4,5,6-azepantethrol hydrochloride (1:1) Example 165 was synthesized in the same manner as in Example 70, using the compound prepared in Reference Example 56 instead of the compound prepared in Reference Example 12. LCMS retention time: 0.701 min (method A); MS(ESI, Pos.):m / z457(M+H)+; 1 H-NMR(D2O): δ7.85, 7.46, 7.25, 4.09-3.99, 3.83-3.06, 2.94, 2.53, 1.86-1.66, 1.63-1.52.

[0426] Reference Example 57: S-{2-[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]ethyl} ethanethioate To a solution of PPh3 (435 mg) in THF (2 mL), DIAD (0.33 mL) was added at 0-5°C and stirred for 0.5 hours at 0-5°C to obtain a white suspension. Then, at 0-5°C, a solution of thioacetic acid (CAS No.: 507-09-5, 0.12 mL) and 2-[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]ethanol (CAS No.: 1874632-93-5, 200 mg) in THF (1 mL) was added. After stirring at 0-5°C for 2 hours, the mixture was stirred at 20°C for 15 hours. The reaction mixture was concentrated to dryness. The residue was purified by preparative TLC (PE / Â=5 / 1, Rf=0.6) to obtain the labeled compound (240 mg). TLC: Rf 0.60 (PE / ا=5 / 1).

[0427] Reference example 58: 5-({2-[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]ethyl}thio)-1-pentanol To a methanol (1 mL) solution of the compound (100 mg) prepared in Reference Example 54, K2CO3 (138 mg) was added at 20°C and the mixture was stirred at 20°C for 1 hour. Then, 5-bromo-1-pentanol (CAS number: 34626-51-2, 279 mg) was added and the mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified using a silica gel flash column (PE-25% ethyl acetate, PE) to obtain the labeled compound (70 mg). TLC: Rf 0.30 (PE / SiO = 3 / 1).

[0428] Example 166: (3S,4R,5R,6S)-1-[5-({2-[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]ethyl}thio)pentyl]-3,4,5,6-azepanthetol Example 166 was synthesized using the compound prepared in Reference Example 58 instead of the compound prepared in Reference Example 11, in the same manner as in Reference Example 12 and Example 70. LCMS retention time: 0.732 min (method A); MS(ESI, Pos.):m / z489(M+H)+; 1 H-NMR(DMSO-d6):δ7.61, 7.54, 7.35, 3.55-3.49, 3.39-3.32, 3.21-3.15, 3.04-2.98, 2.91-2.84, 2.65-2.57, 2.40-2.29, 1.55-1.42, 1.40-1.24.

[0429] Reference example 59: 4-({2-[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]ethyl}thio)-1-butanol The listed compound was synthesized using the compound prepared in Reference Example 41, in the same manner as in Reference Examples 54 and 55. LCMS retention time: 0.926 min (method A); MS(ESI, Pos.):m / z330.0[M+H]+.

[0430] Reference example 60: 2-(3,5-difluorophenyl)-4-{2-[(4-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}butyl)thio]ethyl}-1,3-thiazole To a mixture of the compound (120 mg) prepared in Reference Example 59 and DMF (4 mL), tert-butyldimethylchlorosilane (60 mg) and imidazole (50 mg) were added. The reaction was stirred at 20°C for 16 hours to obtain a colorless solution. The mixture was washed with water and extracted with ethyl acetate. The organic phase was dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified using a silica column (PE-8% ethyl acetate / PE) to obtain the labeled compound (196 mg). LCMS retention time: 1.264 min (method A); MS(ESI, Pos.):m / z444.1[M+H]+.

[0431] Reference Example 61: 2-(3,5-difluorophenyl)-4-{2-[(4-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}butyl)sulfonyl]ethyl}-1,3-thiazole mCPBA (60 mg) was added to a solution of the compound (140 mg) prepared in Reference Example 60 in DCM (1.5 mL). The mixture was stirred at 20°C for 16 hours to obtain a colorless solution. Then, mCPBA (60 mg) was added and the mixture was stirred at 20°C for 3 hours to obtain a white suspension. The mixture was washed with water and extracted with ethyl acetate. The organic phase was dried over Na₂SO₄ and concentrated. The residue was purified using a silica column (PE-24% ethyl acetate / PE) to obtain the labeled compound (104 mg). LCMS retention time: 1.116 min (method A); MS(ESI, Pos.):m / z476.2[M+H]+.

[0432] Reference example 62: 4-({2-[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]ethyl}sulfonyl)-1-butanol A mixture of the compound (104 mg) prepared in Reference Example 61 and THF (2 mL) was mixed with 1 M TBAF in THF (0.44 mL). The reaction was stirred at 20°C for 16 hours to obtain a yellow mixture. The mixture was concentrated under reduced pressure. The residue was purified using a silica gel column (DCM → 6% MeOH / DCM) to obtain the labeled compound (60 mg). LCMS retention time: 0.812 min (method A); MS(ESI, Pos.):m / z362.0[M+H]+.

[0433] Example 167: (3S,4R,5R,6S)-1-[4-({2-[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]ethyl}sulfonyl)butyl]-3,4,5,6-azepanthetol Example 167 was synthesized using the compound produced in Reference Example 62 instead of the compound produced in Reference Example 6, in the same manner as in Reference Example 7 and Example 69. LCMS retention time: 1.467 min (method B); MS(ESI, Pos.):m / z507.1(M+H)+; 1 H-NMR (CD3OD): δ7.63-7.58, 7.49, 7.15-7.04, 3.65-3.56, 3.47-3.35, 3.17-3.08, 2.94-2.81, 2.62, 1.92-1.84, 1.71-1.61.

[0434] Reference example 63: 2-[2-(4-fluorophenyl)-1,3-thiazole-4-yl]-2-propanol 2-(4-fluorophenyl)thiazole-4-carboxylate ethyl (CAS number: 132089-35-10.50 g) was mixed with THF (10 mL) and MeMgBr (2.7 mL) at 0 °C. The mixture was stirred under N2 at 20 °C for 16 hours to obtain a brown mixture. The reaction was stopped with saturated NH4Cl aqueous solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified using a silica gel flash column (PE-40% siRNA / PE) to obtain the labeled compound (0.45 g). TLC: Rf 0.50 (PE / Ã=3 / 1).

[0435] Reference example 64: 4-{2-[(6-bromohexyl)oxy]-2-propanyl}-2-(4-fluorophenyl)-1,3-thiazole To a solution of the compound (150 mg) prepared in Reference Example 63 in DMF (2 mL), NaH (51 mg) and 1,6-dibromohexane (CAS No. 629-03-8, 0.29 mL) were added, and the mixture was stirred at 60°C for 16 hours. The reaction was stopped with saturated aqueous solution NH4Cl, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified using a silica gel flash column (ethyl acetate 5%-10% PE) to obtain the labeled compound (120 mg). 1 H-NMR(CDCl3): δ7.90-7.86, 7.07-7.02, 3.32-3.22, 1.85-1.75, 1.55, 1.54-1.36.

[0436] Example 168: (3S,4R,5R,6S)-1-[6-({2-[2-(4-fluorophenyl)-1,3-thiazole-4-yl]-2-propanyl}oxy)hexyl]-3,4,5,6-azepanthetrol Example 168 was synthesized in the same manner as in Example 1, using the compound prepared in Reference Example 64 instead of the compound prepared in Reference Example 1. LCMS retention time: 0.724 min (method A); MS(ESI, Pos.):m / z483.1(M+H)+; 1 H-NMR(CD3OD):δ8.00, 7.37, 7.22, 3.57, 3.42-3.36, 3.31-3.28, 2.78, 2.59-2.41, 1.63, 1.58-1.49, 1.48-1.40, 1.39-1.31, 1.30-1.21.

[0437] Reference example 65: {[7-(2-biphenylylmethoxy)-5-heptin-1-yl]oxy}(triisopropyl)silane The marked compound was synthesized using 7-[(triisopropylsilyl)oxy]-2-heptin-1-ol (CAS number: 1802596-80-0) and 2-(bromomethyl)biphenyl (CAS number: 19853-09-9) in the same manner as in Reference Example 6. TLC: Rf 0.75 (PE / τ = 5 / 1).

[0438] Example 169: (3S,4R,5R,6S)-1-[7-(2-biphenylylmethoxy)-5-heptin-1-yl]-3,4,5,6-azepantetrole hydrochloride (1:1) The listed compound was synthesized using the compound prepared in Reference Example 65 instead of the compound prepared in Reference Example 14, in the same manner as in Reference Examples 15, 16, and Example 69. LCMS retention time: 0.733 min (method A); MS(ESI, Pos.):m / z440.2(M+H)+; 1 H-NMR(CD3OD):δ7.53-7.48, 7.46-7.40, 7.40-7.34, 7.31-7.25, 4.45, 4.16-4.01, 3.83, 3.60-3.56, 3.45-3.32, 3.27-3.13, 2.33-2.20, 1.95-1.73, 1.58-1.47.

[0439] Examples 170 and 171: Examples 170 and 171 were synthesized using [2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methanol instead of [5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole-4-yl]methanol, in the same manner as in Reference Examples 21, 22, 15, 16, and Examples 71 and 72.

[0440] Example 170: (3S,4R,5R,6S)-1-[(5R)-6-{[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetrol hydrochloride (1:1) (isomer 1) LCMS retention time: 0.792 min (method A); MS(ESI, Pos.):m / z491.3(M+H)+; 1 H-NMR(DMSO-d6):δ9.39, 7.76, 7.64, 7.41, 4.86-4.61, 3.96-3.84, 3.76-3.53, 3.34, 3.28-3.20, 3.16-3.03, 1.82-1.54, 1.47-1.28; SFC retention time: 4.121 min (method A3).

[0441] Example 171: (3S,4R,5R,6S)-1-[(5S)-6-{[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetrol hydrochloride (1:1) (isomer 2) LCMS retention time: 0.694 min (method A); MS(ESI, Pos.):m / z491.3(M+H)+; 1 H-NMR(DMSO-d6):δ9.57, 7.76, 7.68-7.59, 7.41, 4.82-4.60, 4.66, 3.98-3.83, 3.75-3.56, 3.34, 3.29-2.96, 1.83-1.2; SFC retention time: 4.535 min (method A3).

[0442] Examples 172-174: Examples 172-174 were synthesized using the same method as in Reference Example 1 and Example 1, but with the corresponding alcohol compound used instead of (4-methylphenyl)methanol.

[0443] Example 172: (3S,4R,5R,6S)-1-{6-[(3-ethoxy-4-fluorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrole LCMS retention time: 0.681 minutes (Method A); MS(ESI, Pos.): m / z 416.1(M+H)+; 1 H-NMR(CD3OD): δ7.11-7.00, 6.92-6.82, 4.44, 4.10, 3.59, 3.48, 3.45-3.31, 2.90-2.76, 2.54, 1.66-1.48, 1.45-1.24.

[0444] Example 173: (3S,4R,5R,6S)-1-{6-[(4-chlorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrole LCMS retention time: 0.683 minutes (Method A); MS(ESI, Pos.): m / z 388.1(M+H)+; 1 H-NMR(CD3OD): δ7.33, 4.47, 3.70-3.43, 3.39, 2.86-2.74, 2.61-2.43, 1.71-1.44, 1.41-1.27.

[0445] Example 174: (3S,4R,5R,6S)-1-(6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetrol hydrochloride (1:1) LCMS retention time: 0.689 minutes (Method A); MS(ESI, Pos.):m / z493.1(M+Na)+; 1 H-NMR(CD3OD): δ7.44-7.28, 7.22, 4.54, 4.17-4.03, 3.84, 3.63-3.56, 3.42-3.33, 3.22-3.04, 2.54, 1.83-1.62, 1.51-1.37.

[0446] Pharmacological experiment example 1: Evaluation of human GBA1 enzyme inhibitory activity Inhibitory activity was measured in a 384-well format using recombinant GBA enzyme and 4-methylumbelliferyl-β-D-glucopyranoside (4-MUG) as the substrate. The reaction was carried out in acidic assay buffer (pH 5.2 McIlvaine buffer, 0.25% sodium taurocholate, 0.1% Triton® X-100). Four 5 μL solutions of the test compound were pre-incubated with 10 μL of GBA enzyme (0.1 ng / μL) at room temperature for 5 minutes. The reaction was started by adding 5 μL of 2 mmol / L substrate solution and incubated at 37°C for 60 minutes. The reaction was stopped by adding an equal volume of stop solution (1 mol / L glycine solution adjusted to pH 10 with 1 mol / L NaOH), and the pH was raised to obtain the optimal fluorescence intensity. The released 4-methylumbelliferyl (4-MU) was measured by fluorescence spectrophotometer (excitation wavelength 355 nm, fluorescence wavelength 450 nm). The blank contained GBA, and the reaction stop solution and substrate were added sequentially. The inhibitory rate was set to 100% for the blank group and 0% for the untreated group. The inhibitory activity (IC) of the test substance was determined from the inhibition rate of 4-MU production at each compound concentration. 50 The value was calculated.

[0447] From the aforementioned pharmacological experiments, it was found that the disclosed compounds possess GBA1 inhibitory activity. For example, IC of several disclosed compounds 50 The values ​​are shown in Table 2. These data suggest that the compounds disclosed herein may be able to bind to GBA1 and stabilize GBA1 to the extent that it can protect GBA1 from degradation.

[0448] Pharmacological experiment example 2: Evaluation of human GCS enzyme inhibitory activity This assay used lysates of HL60 cells. HL60 cells were thawed and cultured in RPMI1640 medium containing 10% FBS. Cells were passaged once before use. Cells were collected in centrifuge tubes, washed three times with PBS, and then counted. 1 mL / 4 × 10 7To individual cells, M-PER(R) (Mammalian Protein Extraction Reagent) (1:100), containing a protease cocktail inhibitor, was added and the cells were lysed on ice for 30 minutes, mixing every 5 minutes. The cell lysates were sonicated in an ice bath for 15 minutes, and then centrifuged at 4°C and 1000 rpm for 10 minutes. The supernatant was collected, and the protein concentration was measured using a BCA assay. The supernatant was aliquoted and stored at -80°C as an enzyme source. 100 mmol / L Tris buffer (pH 7.5) containing 10 μmol / L NBD-C6 ceramide, 25 μmol / L UDP-glucose, 35 μmol / L dioleoylphosphatidylcholine, 1 mmol / L dithiothreitol, and 1 mmol / L EGTA was prepared, and 15 μL was dispensed into each well. 10 μL of cell lysate (1 mg / mL) was added to the wells to initiate the reaction. The plate was held at 37°C for 90 minutes, and 75 μL of stop solution (methanol:acetonitrile (6:5) containing 200 ng / mL of tolbutamide as an internal control) was added to terminate the reaction. The reaction mixture was vortexed and centrifuged to obtain the supernatant for further LC / MSMS analysis. The reaction product, NBD-C6-glucosylceramide, was analyzed using an AB Sciex triple quadrupole mass spectrometer. The inhibitory activity (IC) of the test compound was determined from the inhibition rate of NBD-C6-glucosylceramide production at each compound concentration, with the mean value for the blank group set as 100% inhibition and the mean value for the untreated group set as 0% inhibition. 50 The value was calculated.

[0449] From the aforementioned pharmacological experiments, it was found that the disclosed compounds possess potent GCS inhibitory activity. For example, IC of several disclosed compounds 50 The values ​​are shown in Table 2.

[0450] Pharmacological Experiment Example 3: Evaluation of Human GBA2 Enzyme Inhibitory Activity Human GBA2 plasmids were prepared using the following method. Complete open reading frames of GBA2 (human NM_20944.2) were amplified from human tissue using specific primers containing restriction sites and extended Kozak sequences before the start codon. The PCR products were cloned into pGEM-T vectors and their sequences were validated. Appropriate fragments were subcloned into pcDNA-3.1 using the added restriction sites. Human GBA2 plasmids were transiently transfected into HEK293T cells using Lipo3000 reagent. Transduced cells were homogenized in four times the volume of ice-cold 25 mM potassium phosphate (pH 5.5), sonicated for 3 × 1 minute, and centrifuged at 100,000 × g for 1 hour. The supernatant was discarded, the pellet was resuspended, and centrifuged again. The membrane pellet was resuspended in ice-cold 25 mM potassium phosphate (pH 5.5) and used as crude enzyme in the following enzyme assays.

[0451] Inhibitory activity was measured in a 384-well format using the GBA2-rich membrane suspension prepared as described above and 4-MUG as the substrate. The reaction was carried out in assay buffer (pH 5.2 McIlvaine buffer, 0.25% sodium taurocholate, 0.1% Triton® X-100). 10 μg of the enzyme suspension was pre-incubated with 1 mmol / L conjulitol B epoxide (CBE) at 4°C for 30 minutes to inhibit GBA1. The reaction was started by adding 0.5 mmol / L (final concentration) of substrate solution and incubated at 37°C for 45 minutes. The reaction was stopped by adding a stop solution (400 mmol / L glycine solution adjusted to pH 10.6 with 1 mol / L NaOH). The released 4-methylumbelliferone was measured by fluorescence spectrophotometer (excitation wavelength 362 nm, fluorescence wavelength 450 nm). The inhibitory activity (IC) of the test substance was determined from the inhibition rate of 4-MU production at each compound concentration, with the mean of the blank group set as 100% and the mean of the untreated group set as 0%. 50 The value was calculated.

[0452] From the aforementioned pharmacological experiments, it was found that the disclosed compounds do not possess potent GBA2 inhibitory activity. The disclosed compounds were found to be less likely to cause concerns about glycolipid accumulation due to GBA2 inhibition. For example, ICs of several disclosed compounds... 50 The values ​​are shown in Table 2. [Table 2]

[0453] The inhibitory activity of GBA1, GCS, and GBA2 was measured using UV6.2 (comparative compound A) or UV6.8 (comparative compound B) from Patent Document 1, or compound 3 (comparative compound C) from Patent Document 2, as the comparative compound. IC of the comparative compound 50 The values ​​are shown in Table 3 below.

[0454] [ka] [Table 3] From these results, it was found that the disclosed compound exhibits lower GBA2 inhibitory activity than the comparative compound.

[0455] Pharmacological Experiment Example 4: Evaluation of Human GBA1 Cell Activity Gaucher cell line (Coriell Institute, Cat.GM00372) possessing the N307S β-glucocerebrosidase mutation was cultured and grown in EMEM containing 15% FBS. The cells were passaged at least twice and were usable up to 20 passages. The cells were placed in 1.25 × 10⁶ well plates in a 96-well plate. 4Cells were seeded at a density of cells / well. After overnight incubation, 50 μL of cell medium was discarded and 50 μL of diluted compound (with 0.3% DMSO added) was added. Cells were treated with the compound for 6 days. On day 6, cells were washed once with HBSS and incubated in HBSS for 3 hours. Then, cells were lysed on a shaker at 4°C for 5 minutes with 30 μL of assay buffer (pH 5.2 McLvaine buffer with 0.25% sodium taurocholate, 0.5% Triton® X-100 and protease cocktail inhibitor). For the GBA enzyme assay, 5 μL of 4-MUG (6 mmol / L) was added to 15 μL of cell lysate and incubated in 384 wells for 60 minutes. Then, 20 μL of stop solution (1 mmol / L glycine solution adjusted to pH 10 with 1 mol / L NaOH) was added. The reaction product of 4-MU was measured using a fluorescence spectrophotometer (excitation wavelength 355 nm, fluorescence wavelength 450 nm). For protein quantification, 4 μL of cell lysate was mixed with 36 μL of Pierce BCA reagent for 30 minutes. Proteins were detected according to the manufacturer's instructions. Enzyme activity in the cell lysate was normalized to the protein concentration. The blank contained the substrate and assay buffer, and a stop solution was added. Enzyme activity of cells treated with DMSO was used as a negative control, and the results were shown as the percentage change in enzyme activity of cells treated with each compound. For example, the percentage change in intracellular enzyme activity is shown in Table 4 below.

[0456] The aforementioned pharmacological experiments revealed that the disclosed compound possesses potent GBA1 chaperone activity. [Table 4]

[0457] Pharmacological Experiment Example 5: Evaluation of Sphingolipid-Reducing Effect Gaucher cell line (Coriell Institute, Cat.GM00372) possessing the N307S β-glucocerebrosidase mutation was cultured and grown in EMEM containing 15% FBS. After thawing, the cells were passaged at least twice. Cell density: 1 × 10⁶ 5Cells from cells / dish were seeded in a 6 cm dish. After overnight incubation, the cell medium was discarded and 4 mL of the test compound solution (with 0.1% DMSO added) was added. The cells were treated with the compound for 6 days. On day 6, the cells were washed twice with PBS. Then, 1 mL of 20 mmol / L acetate / ethanol was added, and the cells were collected using a cell scraper. This procedure was repeated to obtain 2 mL of cell extract. To this, 10 μL of internal standards (β-GlcCer d18:1 / 17:0 (200 ng / mL), β-GalSPB d18:1 (d5) (200 ng / mL), and β-LacCer d18:1 / 17:0 (200 ng / mL), Cer d18:1 / 17:0 (200 ng / mL)) are added and vortexed, then 1 mL of chloroform is added. The mixture is sonicated under ice for 10 minutes, vortexed again, and then centrifuged at 2,130 × g for 3 minutes at 4°C. The supernatant is collected using a centrifuge and allowed to dry. After drying, it is dissolved in 0.2 mL of chloroform / methanol mixture (2:1, v / v) and the sphingolipids are measured by SFC / MS / MS.

[0458] Pharmacological experiment example 6: Evaluation of cognitive impairment in mice. The evaluation of the pharmacological activity of a test compound includes the improvement of cognitive impairment in mice. For example, the improvement of cognitive impairment by a compound can be evaluated using the following methods.

[0459] The study uses male C57BL / 6 mice (16-23 months old, manufactured by Charles River Co., Ltd.). The test substance and its medium are administered orally once daily for two weeks. Cognitive function is then evaluated using a novel object recognition (NOR) test with a plastic box (460mm x 300mm x 450mm) equipped with a video camera as the experimental apparatus. The evaluation is conducted in a darkroom, with the light intensity near the experimental apparatus adjusted to approximately 20 lux. To allow the animals to acclimate to the evaluation environment, the mice are moved to the evaluation room at least one hour before the start of the test. The test is conducted over three days. On the first day, to allow the mice to adapt to the experimental apparatus, they are placed in a cage and allowed to move freely for 10 minutes. This step is repeated twice at 4-hour intervals. In the acquisition trial on the second day, two identical objects (familiar objects) are placed on top of the cage, and the same method is used for 10 minutes. The two objects are placed far apart on a line parallel to the long side of one cage. The distance between the object and the inner walls of the two adjacent surfaces is 10 cm. In the third day's trial, one of the objects used in the acquisition trial is replaced with a new object of different color and shape, and the subject is made to behave in the same way for 10 minutes. The test trial is started 24 hours after the acquisition trial (acceptable range: 23-25 ​​hours). The search time for each object is measured from the video images recorded in the test trial. The total search time and the novel object recognition rate are calculated from the search times for familiar and novel objects using the following formula.

[0460] Total search time (seconds) = Search time for familiar objects + Search time for novel objects Recognition rate (%) = 100 × (Time spent searching for novel objects / Total search time)

[0461] [Examples of formulations] Examples of formulations After mixing the following components by conventional methods and compressing them into tablets, approximately 10,000 tablets containing 10 mg of the active ingredient per tablet are obtained.

[0462] (3S,4R,5R,6S)-1-{6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol......100g

[0463] • Carboxymethylcellulose calcium (disintegrant)...20g Magnesium stearate (lubricant)......10g Crystalline cellulose......870g

[0464] [Industrial applicability] Because the disclosed compound has dual regulatory activity for GBA1 and GCS, a pharmaceutical composition containing the disclosed compound as an active ingredient is useful as a preventive and / or therapeutic agent for diseases related to GBA1 and / or GCS.

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, L １ This represents (1) C4-7 alkylene, (2) C4-7 alkenylene, or (3) C4-7 alkynylene. L １ is 1-5 R Ｌ１ It may also be replaced with R Ｌ１ (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, or (10) hydroxyl group. Multiple R Ｌ１ They may be the same or different. L ２ This represents (1) C1-3 alkylene, (2) C2-3 alkenylene, or (3) C2-3 alkynylene. L ２ is 1-4 R Ｌ２ It may also be replaced with R Ｌ２ represents (1) a halogen atom, (2) a C1-6 alkyl group, (3) a C2-6 alkenyl group, (4) a C2-6 alkynyl group, (5) a C1-6 alkoxy group, (6) a C1-6 haloalkyl group, (7) a C2-6 haloalkenyl group, (8) a C2-6 haloalkynyl group, (9) a C1-6 haloalkoxy group, or (10) a hydroxyl group, Multiple R Ｌ２ They may be the same or different. X is (1) a joint, (2) -O-, (3) -S-, (4) -SO-, or (5) -SO ２ - represents, Ring1 represents (1) a benzene ring, (2) a naphthalene ring, or (3) a 5-10 membered heterocycle. R １ (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, (10) C5-7 carbon ring, (11) 5-7 membered heterocycle, (12) -O-(C5-7 carbon ring), or (13) -O-(5-7 membered heterocycle). Multiple R １ They may be the same or different. R １ (2)-(13) are 1-5 R １－１ It may also be replaced with R １－１ (1) halogen atom, (2) C1-6 alkyl group, (3) C2-6 alkenyl group, (4) C2-6 alkynyl group, (5) C1-6 alkoxy group, (6) C1-6 haloalkyl group, (7) C2-6 haloalkenyl group, (8) C2-6 haloalkynyl group, (9) C1-6 haloalkoxy group, (10) C1-6 alkylsulfonyl group, (11) cyano group, or (12) phenyl group. Multiple R １－１ They may be the same or different. 【Chemistry 2】 This indicates that the substituents are bonded in an α configuration, a β configuration, or any ratio of α and β configurations. A pharmaceutical composition comprising a compound represented by (where n is an integer between 0 and 5) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

2. L １ The pharmaceutical composition according to claim 1, wherein is a hexylene group.

3. The pharmaceutical composition according to claim 1 or 2, wherein X is -O-.

4. L ２ The pharmaceutical composition according to any one of claims 1 to 3, wherein is a methylene group.

5. Ring1 has the following ring structure: 【Transformation 3】 (In the formula, * indicates L) ２ The pharmaceutical composition according to any one of claims 1 to 4, wherein the ring structure is selected from the group consisting of (which indicates the bonding position with ).

6. R Ｌ１ The pharmaceutical composition according to any one of claims 1 to 5, wherein (1) a halogen atom or (2) a C1-6 alkyl group.

7. The compound represented by formula (I), or a pharmaceutically acceptable salt thereof, is given by formula (I-1): 【Chemistry 4】 (In the formula, R Ｌ１－１ (1) represents a halogen atom, or (2) a C1-6 alkyl group. Multiple R Ｌ１－１ They may be the same or different. m represents an integer between 1 and 2. Ring2 has the following ring structure: 【Transformation 5】 A pharmaceutical composition according to any one of claims 1 to 6, wherein the compound represented by (wherein the formula, the * indicates the bond position with methylene) is a compound represented by or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of (wherein the formula, the * indicates the bond position with methylene), and the other symbols have the same meaning as the symbols described in claim 1.

8. The compound represented by formula (I), or a pharmaceutically acceptable salt thereof, (1) (3S,4R,5R,6S)-1-{6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepanthetol, (2) (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl)-3,4,5,6-azepanthetol, (3) (3S, 4R, 5R, 6S)-1-{(5R)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole, (4) (3S, 4R, 5R, 6S)-1-{(5S)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole, (5) (3S,4R,5R,6S)-1-[(5R)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl]-3,4,5,6-azepanthetrol, (6) (3S,4R,5R,6S)-1-[(5S)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazole-4-yl]methoxy}hexyl]-3,4,5,6-azepanthetrol, (7) (3S,4R,5R,6S)-1-[(5R)-6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetol, (8) (3S,4R,5R,6S)-1-[(5S)-6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetol, (9) (3S,4R,5R,6S)-1-{(5S)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole, (10) (3S,4R,5R,6S)-1-{(5R)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole, (11) (3S, 4R, 5R, 6S)-1-{(5S)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole, (12) (3S, 4R, 5R, 6S)-1-{(5R)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrole, (13) (3S,4R,5R,6S)-1-{(5S)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrole, (14) (3S,4R,5R,6S)-1-{(5R)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepanthetrol, (15) (3S,4R,5R,6S)-1-[(5S)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepanthetrol, and The pharmaceutical composition according to any one of claims 1 to 7, wherein (16) a compound selected from the group consisting of (3S,4R,5R,6S)-1-[(5R)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrole, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition according to any one of claims 1 to 8, which is a GBA1 chaperone regulator.

10. A pharmaceutical composition according to any one of claims 1 to 8, which is a GCS inhibitor.

11. A pharmaceutical composition according to any one of claims 1 to 8, which is a GBA1 and GCS dual control agent.

12. A pharmaceutical composition according to any one of claims 9-11, which is a therapeutic and / or prophylactic agent for diseases related to GBA1 and / or GCS.

13. The pharmaceutical composition according to claim 12, wherein the disease associated with GBA1 and / or GCS is selected from the group consisting of Parkinson's disease, Lewy body dementia, Gaucher disease, multiple system atrophy, Fabry disease, Niemann-Pick disease type C, lysosomal storage disorder, dementia, epilepsy, bipolar disorder, schizophrenia, anxiety disorder, major depressive disorder, Sandhoff disease, Tay-Sachs disease, multiple sclerosis, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, cognitive impairment, learning disability, motor disorder, sleep disorder, neurological disorder, CNS disorder, polycystic kidney disease, diabetes mellitus, cancer, open-angle glaucoma, endometriosis, multiple myeloma, viral disease, inflammation, systemic lupus erythematosus, hepatitis, Guillain-Barré syndrome, diabetic nephropathy, and skin disorders.

14. The pharmaceutical composition according to claim 12, wherein the disease associated with GBA1 and / or GCS is selected from the group consisting of Parkinson's disease, Lewy body dementia, and Gaucher disease.

15. A pharmaceutical composition according to any one of claims 9 to 14, characterized in that it is administered in combination with at least one selected from the group consisting of levodopa, carbidopa, pramipexole, ropinirole, rotigotine, apomorphine, zonisamide, droxidopa, cabergoline, pergolide, tolcapone, entacapone, selegiline, rasagiline, safinamide, istradefylline, foslevodopa / foscarbidopa, benserazide, bromocriptine, talipexole, amantadine, trihexyphenidyl, biperiden, donepezil hydrochloride, imiglucerase, veraglucerase alfa, eliglustat, alglucerase, and miglustat.

16. A therapeutic and / or prophylactic agent for diseases associated with GBA1 and / or GCS, comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

17. A method for preventing and / or treating a disease related to GBA1 and / or GCS, characterized by administering a pharmaceutical composition containing a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, to a patient who requires prevention and / or treatment of a disease related to GBA1 and / or GCS.

18. A pharmaceutical composition comprising a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of diseases associated with GBA1 and / or GCS.

19. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmacopoeia for the prevention and / or treatment of diseases associated with GBA1 and / or GCS.

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