GBA1 and GCS dual regulator

Abstract

The present invention provides a drug containing, as an active ingredient, a compound having GBA1 and GCS dual regulating activity in the prevention and / or treatment of diseases related to GBA1 and / or GCS. [Solution] Formula (I): The compound represented by the formula TIFF2026508294000044.tif28170 (wherein all symbols have the same meaning as those described in the specification), or a pharmaceutically acceptable salt thereof, is useful as a pharmaceutical ingredient having GBA1 and GCS dual regulatory activity in the prevention and / or treatment of diseases associated with GBA1 and / or GCS.

Description

[Technical Field]

[0001] The present disclosure relates to a compound having dual GBA1 and GCS regulating activity, or a pharmaceutically acceptable salt thereof, specifically, a compound represented by formula (I): [ka]

[0002] (wherein all symbols have the same meanings as defined below) or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as "the compound of the present disclosure"). [Background technology]

[0003] β-Glucocerebrosidase (GBA1) is an enzyme that hydrolyzes the glycolipid glucosylceramide. Genetic mutations in GBA1 are known to be a risk factor for the development of Gaucher disease, Parkinson's disease, and related synucleinopathies. In Gaucher disease, GBA1 genetic mutations cause glucosylceramide to accumulate in the liver, spleen, bones, and brain, resulting in anemia, thrombocytopenia, hepatosplenomegaly, fractures, and severe neurological symptoms. The development of pharmacological chaperones and gene therapy is considered effective treatment strategies for Gaucher disease (Non-Patent Document 1).

[0004] Glucosylceramide is known to be synthesized by glucosylceramide synthase (GCS), and inhibiting GCS reduces the amount of glucosylceramide, potentially affecting the progression of synucleinopathies (Non-Patent Document 2). Therefore, compounds that regulate GBA1 and GCS may be useful for the treatment of Gaucher disease, Parkinson's disease, and related synucleinopathies.

[0005] On the other hand, Patent Document 1 describes that the compound represented by the following formula (A) is a compound that inhibits ceramide glucosyltransferase, inhibits β-glucocerebrosidase, and has β-glucocerebrosidase chaperone activity.

[0006] Formula (A) is as follows: [ka]

[0007] In the formula, R A teeth: [ka]

[0008] R 1A is a substituted or unsubstituted alkyl group;

[0009] 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;

[0010] X 1A-5A are each independently selected from H, NO2, N3, or NH2;

[0011] Y A is absent or is a substituted or unsubstituted C1-alkyl group other than carbonyl; and

[0012] Z A is selected from a bond or NH (partial definition of groups is excerpted).

[0013] Furthermore, Patent Document 2 describes that a compound represented by the following formula (B) is a compound that has high inhibitory activity against GCS, high inhibitory activity against GBA2, and low inhibitory activity against GBA1.

[0014] Formula (B) is as follows: [ka]

[0015] In the formula, R 19B -R 26B are each independently selected from H, F, Me, or Et;

[0016] R 27B and R 28B are each independently selected from the group consisting of H, F, CF3, and C1-C8 straight or branched chain alkyl;

[0017] X B is a 5- or 6-membered cyclic group substituted with a 5- or 6-membered cyclic group (the definition of the group is partially excerpted).

[0018] [Prior art documents] [Patent documents]

[0019] [Patent Document 1] International Publication No. 2014 / 179438 Brochure

[0020] [Patent Document 2] International Publication No. 2015 / 147639 Brochure

[0021] [Non-patent literature]

[0022] [Non-Patent Document 1] Molecular Neurodegeneration(2019)14:36

[0023] [Non-patent document 2] Neurobiology of Disease 159(2021)105507 Summary of the Invention [Problem to be solved by the invention]

[0024] An object of the present invention is to provide a compound having dual GBA1 and GCS regulatory activity.

[0025] [Means for solving the problem]

[0026] As a result of intensive research conducted by the present inventors to solve the above problems, they found that the compound represented by formula (I) has potent GBA1 and GCS dual regulatory activity.

[0027] That is, in one aspect, the present disclosure provides:

[0028] [A] Formula (I): [ka]

[0029] (In the formula,

[0030] L 1 represents (1) C4-7 alkylene, (2) C4-7 alkenylene, or (3) C4-7 alkynylene;

[0031] L 1 1-5 R L1 may be substituted with

[0032] R L1 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a hydroxyl group;

[0033] Multiple R L1 may be the same or different,

[0034] L 2represents (1) C1-3 alkylene, (2) C2-3 alkenylene, or (3) C2-3 alkynylene;

[0035] L 2 1-4 R L2 may be substituted with

[0036] R L2 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a hydroxyl group;

[0037] Multiple R L2 may be the same or different,

[0038] X represents (1) a bond, (2) —O—, (3) —S—, (4) —SO—, or (5) —SO—;

[0039] Ring 1 represents (1) a benzene ring, (2) a naphthalene ring, or (3) a 5- to 10-membered heterocycle;

[0040] R 1 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, (10) a C carbocycle, (11) a 5- to 7-membered heterocycle, (12) -O-(C carbocycle), or (13) -O-(5- to 7-membered heterocycle);

[0041] Multiple R 1 may be the same or different,

[0042] R 1 (2)-(13) are 1-5 R 1-1 may be substituted with

[0043] R 1-1 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, (10) a C alkylsulfonyl group, (11) a cyano group, or (12) a phenyl group;

[0044] Multiple R 1-1 may be the same or different,

[0045] symbol: [ka]

[0046] indicates that the substituents are bonded in an appropriate ratio to form an α-configuration, a β-configuration, or a mixture of the α-configuration and the β-configuration,

[0047] n represents an integer of 0 to 5, or a pharmaceutically acceptable salt thereof;

[0048] [B] A pharmaceutical composition comprising the compound according to the above [A] or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

[0049] [C] The pharmaceutical composition according to the above [B], which is a GBA1 chaperone modulator;

[0050] [D] The pharmaceutical composition according to the above [B], which is a GCS inhibitor. [Effects of the Invention]

[0051] The compounds of the present disclosure have GBA1 and GCS dual regulatory activity and are therefore useful as drugs for preventing and / or treating diseases associated with GBA1 and / or GCS. DETAILED DESCRIPTION OF THE INVENTION

[0052] The present disclosure is described in detail below.

[0053] As used herein, the GBA1 and GCS dual regulatory activity refers to both the GBA1 chaperone activity and the GCS inhibitory activity.

[0054] In this specification, examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms.

[0055] In this specification, C1-6 alkyl includes straight or branched chain C1-6 alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomers thereof.

[0056] In this specification, the term "C2-6 alkenyl group" includes straight-chain or branched-chain C2-6 alkenyl groups, such as ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, and isomers thereof.

[0057] In this specification, the term "C2-6 alkynyl group" includes straight-chain or branched-chain C2-6 alkynyl groups, such as ethynyl, propynyl, butynyl, butadinyl, pentynyl, pentadinyl, hexynyl, hexadinyl, and isomers thereof.

[0058] In this specification, C1-3 alkylene includes, for example, methylene, ethylene, propylene or isomers thereof.

[0059] In the present specification, C2-3 alkenylene includes straight-chain or branched-chain C2-3 alkenylene, and examples thereof include vinylene, propenylene, and isomers thereof.

[0060] In the present specification, C2-3 alkynylene includes straight-chain or branched-chain C2-3 alkynylene, and examples thereof include ethynylene, propynylene, and isomers thereof.

[0061] In this specification, C3-6 alkylene includes straight or branched chain C3-6 alkylene, for example, propylene, butylene, pentylene, hexylene, or isomers thereof.

[0062] In the present specification, C3-6 alkenylene includes straight-chain or branched-chain C3-6 alkenylene, and examples thereof include propenylene, butenylene, pentenylene, hexenylene, and isomers thereof.

[0063] In the present specification, C3-6 alkynylene includes straight-chain or branched-chain C3-6 alkynylene, and examples thereof include propynylene, butynylene, pentynylene, hexynylene, and isomers thereof.

[0064] In this specification, C4-7 alkylene includes straight or branched chain C4-7 alkylene, for example, butylene, pentylene, hexylene, heptylene, or isomers thereof.

[0065] In the present specification, C4-7 alkenylene includes straight-chain or branched-chain C4-7 alkenylene, and examples thereof include butenylene, pentenylene, hexenylene, heptenylene, and isomers thereof.

[0066] In the present specification, C4-7 alkynylene includes straight or branched chain C4-7 alkynylene, for example, butynylene, pentynylene, hexynylene, heptynylene, or isomers thereof.

[0067] In this specification, the term "C1-6 haloalkyl group" refers to, for example, a straight-chain or branched-chain alkyl group substituted with one or more halogen atoms. Specific examples of the C1-6 haloalkyl group include a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a pentafluoroethyl group, a 1-fluoropropyl group, a 2-chloropropyl group, a 3-fluoropropyl group, a 3-chloropropyl group, a 4,4,4-trifluorobutyl group, a 4-bromobutyl group, a 5,5,5-trifluoropentyl group, a 6,6-trifluorohexyl group, and isomers thereof.

[0068] As used herein, the term "C2-6 haloalkenyl group" refers to, for example, a straight-chain or branched-chain alkenyl group substituted with one or more halogen atoms. Specific examples of the C2-6 haloalkenyl group include 1-fluoroethenyl, 2-fluoroethenyl, 2-chloroethenyl, 1-fluoropropenyl, 2-chloropropenyl, 3-fluoropropenyl, 3-chloropropenyl, 4-bromobutenyl, 5,5,5-trifluoropentenyl, 6,6-trifluorohexenyl, and isomers thereof.

[0069] As used herein, the term "C2-6 haloalkynyl group" refers to, for example, a straight-chain or branched-chain alkynyl group substituted with one or more halogen atoms. Specific examples of the C2-6 haloalkynyl group include 2-fluoroethynyl group, 2-chloroethynyl group, 3-fluoropropynyl group, 3-chloropropynyl group, 4-bromobutynyl group, 5,5,5-trifluoropentynyl group, 6,6-trifluorohexynyl group, and isomers thereof.

[0070] In this specification, the term "C1-6 alkoxy group" includes straight-chain or branched-chain C1-6 alkoxy groups, such as methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy groups, and isomers thereof.

[0071] In this specification, the term "C1-6 haloalkoxy group" refers to, for example, a straight-chain or branched-chain alkoxy group substituted with one or more halogen atoms. Specific examples of the C1-6 haloalkoxy group include a fluoromethoxy group, a chloromethoxy group, a bromomethoxy group, an iodomethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1-fluoroethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a pentafluoroethoxy group, a 1-fluoropropoxy group, a 2-fluoropropoxy group, a 2-chloropropoxy group, a 2-chloropropoxy group, a 3-fluoropropoxy group, a 3-chloropropoxy group, a 4,4,4-trifluorobutoxy group, a 4-bromobutoxy group, a 5,5-trifluoropentyloxy group, a 6,6-trifluorohexyloxy group, and isomers thereof.

[0072] In this specification, examples of the C5-7 carbocyclic ring include cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, and a benzene ring.

[0073] In this specification, examples of the 5- to 7-membered heterocyclic compound include pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, and pyrazolidine. , dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, tetrahydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydro Hydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydrothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxadiazine, tetrahydrothiadiazine, tetra Hydrothiadiazine, tetrahydrothiadiazole, tetrahydrothiadiazine (thiadiazolidine), dihydrothiazine, tetrahydrothiadiazine, tetrahydrothiadiazine, morpholine, thiomorpholine, oxathiane, dioxolane, dioxolane, dioxane, dithiolane, dithiane, azepine, diazepine, oxepine, thiepine, oxazepine, oxadiazepine, thiazepine, thiadiazepine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine,Examples of the dihydrooxapine include dihydrooxepine, tetrahydrooxepine, perhydrooxepine, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazepine, dihydrooxazepine, dihydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, perhydrooxadiazepine, dihydrothiazepine, dihydrothiazepine, perhydrothiazepine, dihydrothiazepine, perhydrothiazepine, dihydrothiazepine, perhydrothiazepine, dihydrothidiazepine, perhydrothiazepine, dihydrothiadiazepine, perhydrothiadiazepine, perhydrothiadiazepine, perhydrothiadiazepine, and perhydrothiadiazepine ring.

[0074] In the present specification, examples of the 5- to 10-membered heterocycle include, in addition to the 5- to 7-membered heterocycle, indole, isoindole, indolizine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, dithiananaphthalene, indazole, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, chromene, benzofurazan, benzothiadiazole, benzotriazole, indole, benzoind ... benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzoindole, benzo Phosphorus, Isoindoline, Dihydrobenzofuran, Perhydrobenzofuran, Dihydroisobenzofuran, Dihydroisobenzofuran, Perhydrobenzofuran, Dihydroisobenzothiophene, Perhydroisobenzothiophene, Dihydroindazole, Perhydroindazole, Dihydroquinoline, Tetrahydroquinoline, Perhydroquinoline, Dihydroquinoline, Dihydroquinoline, Dihydroquinoline, Dihydroquinoline, Dihydrophthalazine, Tetrahydrophthalazine, Perhydrophthalazine, Dihydronaphthyridine, Tetrahydronaphthyridine, Perhydro Hydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, dioxadane, benzodioxane, 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].3]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.

[0075] In this disclosure, L 1 is preferably a C4-7 alkylene group, more preferably a hexylene group.

[0076] In this disclosure, L 2 is preferably methylene.

[0077] In the present disclosure, X is preferably —O— or —S—, and more preferably —O—.

[0078] In the present disclosure, Ring 1 is preferably a benzene ring or a 5- to 7-membered heterocycline, more preferably a benzene ring, a thiazole ring, an oxazole ring, or a pyridazine ring, and even more preferably the following compounds: [ka]

[0079] (In the formula, * indicates L 2 and the bond position is indicated.

[0080] In this disclosure, R 1 is preferably a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a benzene ring or a 5- or 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.

[0081] In this disclosure, R L1is preferably a halogen atom, more preferably a fluorine atom.

[0082] In this disclosure, R L2 is preferably a halogen atom or a C1-6 alkyl group, more preferably a methyl group.

[0083] In this disclosure, R 1-1 is preferably a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group or a C1-6 haloalkoxy group, more preferably a halogen atom, a methyl group or a methoxy group.

[0084] In the present disclosure, n is preferably 0, 1, or 2.

[0085] In the present disclosure, the compound represented by formula (I) is preferably a compound represented by formula (I-1): [ka]

[0086] (In the formula, R L1-1 represents (1) a halogen atom or (2) a C1-6 alkyl group,

[0087] m represents an integer from 1 to 2,

[0088] Ring2 has the following ring structure: [ka]

[0089] (wherein the * symbol indicates the bonding position to the methylene),

[0090] The other symbols have the same meanings as those described above.) and more preferably, a compound represented by formula (I-2): [ka]

[0091] (In the formula, R 1-2 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkoxy group, or (4) a phenyl group, and R 1-2 (2)-(4) in the table are 1-5 R 1-1 and the other symbols have the same meanings as those defined above.

[0092] In the present disclosure, the compound represented by formula (I) is preferably 1 , L 2 , X, Ring1, R 1 , R L1 , R L2 , R 1-1 and n are each a combination of preferred definitions.

[0093] In the present disclosure, the compound represented by formula (I-1) preferably includes the ring 2, R 1 , R L1-1 , R 1-1 , m, and n are each a combination of preferred definitions.

[0094] In the present disclosure, the compound represented by formula (I-2) preferably includes the ring 2, R 1-2 , R L1-1 , R 1-1 and n are each a combination of preferred definitions.

[0095] In the present disclosure, another embodiment of the compound represented by formula (I) is most preferably an example compound described in the examples below, or a pharmaceutically acceptable salt thereof.

[0096] In this disclosure, all isomers are encompassed unless otherwise specified. For example, alkyl groups, alkoxy groups, and alkylene groups include both straight-chain and branched-chain isomers. Furthermore, isomers (E, Z, cis, trans) in double bonds, rings, and fused rings; isomers due to the presence of asymmetric carbons (R, S, α, β, enantiomers, diastereomers); optically active isomers with optical rotation (D, L, d, l); polar isomers (high polarity, low polarity) obtained by chromatographic separation; equilibrium compounds; rotational isomers; mixtures of these in any proportion; and racemic mixtures are all encompassed in this disclosure. Furthermore, all isomers due to tautomerism are also encompassed in this disclosure.

[0097] In this disclosure, unless otherwise specified, symbols that will be apparent to those skilled in the art are used. [ka]

[0098] indicates bonding to the other side of the paper (i.e., α-configuration), [ka]

[0099] indicates that the molecule is bonded to the front side of the paper (i.e., β-configuration), [ka]

[0100] represents an α-configuration, a β-configuration, or any mixture of the α-configuration and the β-configuration.

[0101] [salt] The compound of formula (I) can be converted into a salt by known methods.

[0102] The salt is a pharmaceutically acceptable salt.

[0103] The salt is preferably water-soluble.

[0104] Pharmaceutically acceptable salts include, for example, acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, or amine salts.

[0105] Acid addition salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or organic acid salts such as acetate, lactate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, or gluconate.

[0106] Examples of alkali metal salts include potassium salts and sodium salts.

[0107] Alkaline earth metal salts include, for example, calcium salts and magnesium salts.

[0108] Examples of ammonium salts include tetramethylammonium salts.

[0109] Examples of amine salts include triethylamine salts, methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts, tris(hydroxymethyl)aminomethane salts, lysine salts, arginine salts, and N-methyl-D-glucamine salts.

[0110] The compounds of the present disclosure can be converted into N-oxides by any method. N-oxides refer to compounds in which the nitrogen atom of the compound represented by general formula (I) is oxidized.

[0111] The compound represented by general formula (I) and its pharmaceutically acceptable salts may exist in a non-solvated form or in a solvated form with a pharmaceutically acceptable solvent such as water, ethanol, etc. The solvate is preferably a hydrate. The compound represented by general formula (I) and its pharmaceutically acceptable salts may be converted into a solvate.

[0112] The compound of formula (I) can form a co-crystal with a suitable co-crystal former. The co-crystal is preferably a pharmaceutically acceptable co-crystal former. A co-crystal is typically defined as a crystal formed by two or more different molecules through intermolecular interactions other than ionic bonding. A co-crystal may also be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, such as melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers include those described in WO 2006 / 007448.

[0113] In this disclosure, all references to the disclosed compounds include a compound represented by general formula (I), a pharmaceutically acceptable salt thereof, an N-oxide thereof, a solvate (e.g., hydrate) thereof, or a co-crystal thereof, or an N-oxide of a pharmaceutically acceptable salt of a compound represented by general formula (I), a solvate (e.g., hydrate) thereof, or a co-crystal thereof.

[0114] [Prodrug] A prodrug of a compound represented by general formula (I) refers to a compound that is converted into the compound represented by general formula (I) in vivo by a reaction catalyzed by an enzyme, gastric acid, or the like. Examples of prodrugs of a compound represented by general formula (I) include, when the compound represented by general formula (I) has an amino group, compounds in which the amino group has been acylated, alkylated, or phosphorylated (for example, compounds in which the amino group of a compound represented by general formula (I) has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, or tert-butylated); when the compound represented by general formula (I) has a hydroxyl group, compounds in which the hydroxyl group has been acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxyl group of a compound represented by general formula (I) has been acetylated, palmitoylated, or propanoylated). When the compound represented by general formula (I) has a carboxy group, examples thereof include compounds in which the carboxy group is esterified or amidated (for example, compounds in which the carboxy group of the compound represented by general formula (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, 1-{(ethoxycarbonyl)oxy}ethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl esterified, or methylamidated). 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 anhydrate. Furthermore, the prodrug of the compound represented by general formula (I) may be one that is converted into the compound represented by general formula (I) under physiological conditions, as described in "Drug Development," Vol. 7, "Molecular Design," pp. 163-198, Hirokawa Publishing, 1990.

[0115] Furthermore, each atom constituting the compound represented by the general formula (I) may contain its isotope (e.g., 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 I, etc.) may be substituted. [Method of producing the disclosed compound]

[0116] The compounds of the present disclosure 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 described in the Examples. Salts may be used as starting materials. The order of each reaction can be changed as appropriate depending on the protecting groups introduced and the reaction conditions.

[0117] Furthermore, a compound having an amino group, a carboxyl group, or a hydroxyl group can be produced, if necessary, by using a compound protected with a protecting group commonly used for these groups, for example, a protecting group described in T.W. Greene, Protective Groups in Organic Synthesis, Wiley, New York, 5th Edition, 2014, and performing a known deprotection reaction after an appropriate reaction step.

[0118] Examples of the protective group for a carboxyl group include methyl, ethyl, tert-butyl, trichloroethyl, benzyl (Bn), phenacyl, p-methoxybenzyl, trityl, and 2-chlorotrityl.

[0119] Examples of protecting groups for amino groups or tetrazolyl groups include benzyloxycarbonyl groups, tert-butoxycarbonyl groups, allyloxycarbonyl (Alloc) groups, 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc) groups, trifluoroacetyl groups, 9-fluorenylmethoxycarbonyl groups, benzyl (Bn) groups, p-methoxybenzyl groups, benzyloxymethyl (BOM) groups, and 2-(trimethylsilyl)ethoxymethyl (SEM) groups.

[0120] Examples of protecting groups for hydroxyl groups or hydroxamic acid 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).

[0121] The deprotection reaction is known and can be carried out by the following method. For example, (1) Deprotection reaction by alkaline hydrolysis,

[0122] (2) Deprotection reaction under acidic conditions,

[0123] (3) deprotection by hydrogenolysis,

[0124] (4) deprotection reaction of the silyl group,

[0125] (5) metal-mediated deprotection reaction,

[0126] (6) Deprotection reaction using a metal complex, etc.

[0127] To explain these methods in detail, (1) The deprotection reaction by alkaline hydrolysis is carried out, for example, in an organic solvent (e.g., methanol, tetrahydrofuran (hereinafter, THF), dioxane, etc.) using an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide, etc.), or a carbonate (e.g., sodium carbonate, potassium carbonate, etc.), or an aqueous solution thereof, or a mixture thereof, at 0 to 40°C. (2) The deprotection reaction under acidic conditions is carried out, for example, in an organic solvent (e.g., dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, THF, anisole, etc.), in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.), in the presence or absence of 2,2,2-trifluoroethanol, at 0-100°C. (3) The deprotection reaction by hydrogenolysis is carried out, for example, in a solvent (e.g., ethers (e.g., THF, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (e.g., methanol, ethanol, etc.), benzenes (e.g., benzene, toluene, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), amides (e.g., N,N-dimethylformamide (hereinafter, DMF)), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, etc.) in the presence of a catalyst (e.g., palladium-carbon, palladium black, palladium hydroxide-carbon, platinum oxide, Raney nickel, etc.) under a hydrogen atmosphere or ammonium formate at normal or elevated pressure, at 0 to 200°C. (4) The deprotection reaction of the silyl group is carried out, for example, using tetrabutylammonium fluoride in a water-miscible organic solvent (e.g., THF, acetonitrile, etc.) at 0 to 40° C. Alternatively, it is carried out, for example, in an organic acid (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), an inorganic acid (e.g., hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (e.g., hydrogen bromide / acetic acid, etc.) at −10 to 100° C. (5) The deprotection reaction using a metal is carried out, for example, in an acidic solvent (e.g., acetic acid, a buffer solution of pH 4.2 to 7.2, or a mixture of such a solution with an organic solvent such as THF) in the presence of zinc powder at 0 to 40°C, if necessary, with ultrasonication. (6) The deprotection reaction using a metal complex is carried out in, for example, an organic solvent (e.g., dichloromethane, DMF, THF, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or a mixture thereof, in the presence of a trapping 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., tetrakistriphenylphosphinepalladium(0), bis(triphenylphosphine)palladium(II) dichloride, palladium(II) acetate, tris(triphenylphosphine)rhodium(I) chloride, etc.) at 0 to 40°C.

[0128] The compounds of general formula (I) can be prepared according to reaction scheme 1. [ka]

[0129] (In the formula, A represents a leaving group (e.g., a halogen atom, an arylsulfonic acid, or an alkylsulfonic acid), and the other symbols have the same meanings as above.)

[0130] In Reaction Scheme 1, Reaction 1-1 is an alkylation reaction of an amino group. The alkylation reaction of an amino group is 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 hydrogencarbonate, 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.

[0131] The compound of formula (1b) can be prepared according to reaction scheme 2. [ka]

[0132] (In the formula, X 1 represents OH or SH, A 1 represents a halogen atom, and the other symbols have the same meanings as above.

[0133] In Reaction Scheme 2, Reaction 2-1 is an alkylation reaction of a hydroxyl group or a thiol group. The alkylation reaction of a hydroxyl group is 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.

[0134] In Reaction Scheme 2, Reaction 2-2 is a sulfonylation reaction of a hydroxyl group. The sulfonylation reaction of a hydroxyl group is known and is carried out, for example, in an organic solvent (acetonitrile, chloroform, dichloromethane, pyridine, etc.) in the presence of a sulfonylating 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.

[0135] In Reaction Scheme 2, Reaction 2-3 is a halogenation reaction of a hydroxyl group. The halogenation reaction of a hydroxyl group is known and is 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 hydrogencarbonate, potassium carbonate, etc.), an aqueous solution, or a mixture thereof, at 0°C to 100°C.

[0136] The compound of formula (3b) can be prepared according to reaction scheme 3. [ka]

[0137] In the formula, L 1-A represents (1) C3-6 alkylene, (2) C3-6 alkenylene, or (3) C3-6 alkynylene, and other symbols have the same meanings as above.

[0138] In Reaction Scheme 3, Reaction 3-1 is a reductive amination. Reductive amination is 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.

[0139] In one embodiment, a compound corresponding to the compound of formula (4g) can be prepared according to Reaction Scheme 4. [ka]

[0140] (In the formula, PG represents a protecting group, and the other symbols have the same meanings as above.)

[0141] In Reaction Scheme 4, Reaction 4-1 is a fluorination reaction. Fluorination reactions are known and are carried out, for example, in an organic solvent (e.g., THF, acetonitrile, EtOAc, chloroform, isopropyl alcohol, or a mixture thereof) in the presence of a hydrogen fluoride salt (e.g., triethylamine tris(hydrogen fluoride), hydrogen fluoride pyridine, potassium hydrogen fluoride, etc.) and an organic catalyst (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.

[0142] In Reaction Scheme 4, Reaction 4-2 is a reduction reaction of an aldehyde group, which is carried out in an organic solvent (dichloroethane, dichloromethane, DMF, THF, or a mixture thereof, etc.) in the presence of a reducing agent (e.g., sodium borohydride) at 0°C to 40°C.

[0143] In Reaction Scheme 4, Reaction 4-3 is a fluorination reaction. Fluorination reactions are 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 hydrogen fluoride salt (e.g., triethylamine tris(hydrogen fluoride), hydrogen fluoride pyridine, potassium hydrogen fluoride, etc.) at −20° C. to 70° C.

[0144] In Reaction Scheme 4, Reaction 4-4 is an alkylation reaction of a hydroxyl group, which is known and is carried out as described in Reaction 2-1 in Reaction Scheme 2.

[0145] In reaction scheme 4, reactions 4-5 are deprotection reactions of protecting groups, which are known and are carried out as described above.

[0146] In one embodiment, a compound corresponding to the compound of formula (5d) can be prepared according to Reaction Scheme 5. [ka]

[0147] (In the formula, PG represents a protecting group, and the other symbols have the same meanings as above.)

[0148] In Reaction Scheme 5, Reaction 5-1 is an ether-forming reaction. The ether-forming reaction is known and is carried out, for example, in an organic solvent (e.g., t-BuOH, HO, or a mixture thereof) in the presence of an inorganic base (e.g., sodium hydroxide) and a phase-transfer catalyst (e.g., tetrabutylammonium iodide) at 20°C to 100°C.

[0149] In Reaction Scheme 5, Reaction 5-2 is a fluorination reaction. Fluorination reactions are known and are carried out, for example, in an organic solvent (e.g., dichloromethane, THF, toluene, or a mixture thereof) in the presence of a fluorinating agent (e.g., diethylaminosulfur trifluoride, perfluorobutanesulfonyl fluoride, 2-pyridinesulfonyl fluoride, etc.), in the presence or absence of a base (e.g., triethylamine, diisopropylethylamine, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, etc.), and in the presence or absence of a hydrogen fluoride salt (e.g., triethylamine tris(hydrogen fluoride)), at −20° C. to 40° C.

[0150] In Reaction Scheme 5, Reaction 5-3 is a deprotection reaction of a protecting group, which is known and is carried out as described above.

[0151] In one embodiment, a compound corresponding to the compound of formula (6k) can be prepared according to Reaction Scheme 6. [ka]

[0152] (In the formula, PG 1 represents the protecting group for the aldehyde, and PG 2 represents a protecting group for a carboxylic acid, and the other symbols have the same meanings as above.

[0153] In Reaction Scheme 6, Reaction 6-1 is an alkylation reaction of a malonic acid diester. The alkylation reaction of a malonic acid diester is 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.

[0154] In Reaction Scheme 6, Reaction 6-2 is a fluorination reaction. Fluorination reactions are 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]octane bis(tetrafluoroborate), N-fluoro-bis[(trifluoromethyl)sulfonyl]imide, N-fluorodibenzenesulfonimide, etc.) in the presence or absence of a base (sodium hydride, lithium diisopropylamide, cesium carbonate, etc.) at 0°C to 100°C.

[0155] In Reaction Scheme 6, Reaction 6-3 is an alkylation reaction of 2-fluoromalonic acid diester, which is known and is carried out as described in Reaction 6-1.

[0156] In Reaction Scheme 6, Reaction 6-4 is a deprotection reaction of a protecting group, which is known and is carried out as described above.

[0157] In Reaction Scheme 6, Reaction 6-5 is a decarboxylation reaction. Decarboxylation reactions are known and are carried out, for example, in an organic solvent (DMF, dimethyl sulfoxide, pyridine, etc.) in the presence or absence of a base (triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium hydroxide, potassium carbonate, cesium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) in the presence or absence of 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.

[0158] In Reaction Scheme 6, Reaction 6-6 is the reduction of a carboxylic acid. The reduction of a carboxylic acid is 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 to 200°C.

[0159] In Reaction Scheme 6, Reaction 6-7 is a known alkylation reaction of a hydroxyl group, and is carried out as described in Reaction 2-1 in Reaction Scheme 2.

[0160] Reactions 6-8 in Reaction Scheme 6 are deprotection reactions of protecting groups, which are known and are carried out as described above (for example, deprotection reactions under acidic conditions).

[0161] In each reaction in the present specification, the compounds used as starting materials and represented by Formula 1a, Formula 2a, Formula 2b, Formula 2d, Formula 2e, Formula 3a, Formula 4a, Formula 4c, Formula 4e, Formula 5a, Formula 6a, Formula 6b, Formula 6e, and Formula 6i are either known compounds or can be easily produced by combining known methods, such as the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or methods in which known methods are partially modified.

[0162] Among the compounds disclosed herein, optically active compounds can be produced using optically active starting materials or reagents, or by optically resolving a racemic production intermediate and then leading to the compound disclosed herein, or by optically resolving a racemic compound disclosed herein.

[0163] This optical resolution is well known, and examples of such methods include forming a salt or complex with another optically active compound, recrystallizing it, and then isolating the target compound, or directly separating it using a chiral column.

[0164] In each reaction herein, reactions involving heating can be carried out using a water bath, oil bath, sand bath or microwave, as will be apparent to those skilled in the art.

[0165] In each reaction herein, a solid-phase-supported reagent supported on a high molecular weight polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

[0166] In each reaction in this specification, the reaction product can be purified by a conventional purification method, for example, distillation under atmospheric pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, scavenger resin, or column chromatography, washing, recrystallization, etc. Purification may be carried out for each reaction or after completion of several reactions. [toxicity]

[0167] The compounds of the present disclosure have low toxicity and can therefore be safely used as pharmaceuticals. [Application to pharmaceuticals]

[0168] The compounds of the present disclosure have GBA1 and GCS dual regulatory activity and are therefore useful as prophylactic and / or therapeutic agents for diseases associated with GBA1 and / or GCS, such as Parkinson's disease, Lewy body disease, Gaucher disease, multiple system atrophy, Fabry disease, Niemann-Pick disease type C, lysosomal storage diseases, 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 disorders, learning disabilities, movement disorders, sleep disorders, neurological disorders, CNS disorders, polycystic kidney disease, diabetes, cancer, open-angle glaucoma, endometriosis, multiple myeloma, viral diseases, inflammation, systemic lupus erythematosus, hepatitis, Guillain-Barré syndrome, diabetic nephropathy, and skin disorders.

[0169] The disease associated with GBA1 and / or GCS is preferably Parkinson's disease, Lewy body disease, or Gaucher disease.

[0170] To use the disclosed compounds for the prevention and / or treatment of the above-mentioned diseases, the active ingredient is typically formulated with a pharmaceutically acceptable carrier, such as various additives or solvents, and then administered systemically or locally, orally or parenterally. Here, a pharmaceutically acceptable carrier refers to a substance other than the active ingredient that is generally used in pharmaceutical formulations. Pharmaceutically acceptable carriers are preferably those that do not exhibit pharmacological activity at the dosage of the formulation, are harmless, and do not interfere with the therapeutic effects of the active ingredient. 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 2021 "Dictionary of Pharmaceutical Additives" (edited by the Japan Pharmaceutical Additives Association) published by Yakuji Nipposha, etc., can be selected appropriately depending on the purpose.

[0171] The disclosed compounds are administered to a mammal (preferably a human, more preferably a human patient) in a pharmaceutically effective amount.

[0172] The dosage of the disclosed compound will inevitably vary depending on age, body weight, symptoms, desired therapeutic effect, route of administration, duration of treatment, etc. Generally, it is administered orally in the range of 0.1 ng to 1000 mg per patient per dose, or parenterally in the range of 0.01 ng to 100 mg per patient per dose, or by continuous intravenous administration.

[0173] Of course, as mentioned above, the dosage varies depending on various conditions, so in some cases a smaller dosage than the above may be sufficient, and in other cases a dosage exceeding the range may be necessary.

[0174] Examples of dosage forms used for administration include oral preparations (e.g., tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral preparations (e.g., oral tablets, oral sprays, oral semisolids, mouthwashes, 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.), otic preparations (e.g., ear drops, etc.), nasal preparations (e.g., nasal drops, etc.), rectal preparations (e.g., suppositories, rectal semisolids, enteral injections, etc.), vaginal preparations (e.g., vaginal tablets, vaginal suppositories, etc.), and dermatological preparations (e.g., solid preparations for external application, liquid preparations for external application, sprays, ointments, creams, gels, patches, etc.). [Oral administration formulation]

[0175] Oral formulations include, for example, tablets, capsules, granules, powders, oral liquids, syrups, and oral jellies. Oral formulations include rapidly disintegrating formulations, in which the release of the active ingredient from the formulation is not specifically controlled, and modified-release formulations, such as enteric-coated formulations and sustained-release formulations, in which the release is specifically controlled by a specific formulation design and manufacturing method. Enteric-coated formulations are designed to release the active ingredient primarily in the small intestine rather than in the stomach, for purposes such as preventing the active ingredient from being decomposed in the stomach or reducing the irritating effect of the active ingredient on the stomach. These formulations are typically prepared by coating with an acid-insoluble enteric base. Sustained-release formulations are formulations in which the release rate, release time, and release site of the active ingredient are controlled for purposes such as reducing the frequency of administration or reducing side effects. These formulations are typically prepared by using an appropriate sustained-release agent. Among preparations for oral administration, capsules, granules, tablets, etc. may be coated with an appropriate coating agent such as a sugar, sugar alcohol, or polymer compound for the purpose of facilitating administration or preventing decomposition of the active ingredient. (1) Tablets

[0176] Tablets are solid preparations having a certain shape that are administered orally, and include those generally called tablets, such as plain tablets, film-coated tablets, sugar-coated tablets, multi-layer tablets, and dry-coated tablets, as well as oral rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets. When plain tablets are manufactured, the following method (a), (b), or (c) is usually used: (a) Add excipients, binders, disintegrants, and other additives to the active ingredient and mix until homogeneous, then granulate using water or a solution containing a binder in an appropriate manner, add lubricants, mix, and compress; (b) The active ingredient is mixed with additives such as excipients, binders, disintegrants, etc. to form a homogeneous mixture, which is then directly compressed and molded, or the active ingredient and lubricants are added to granules prepared in advance with additives, mixed together to form a homogeneous mixture, and then compressed and molded; (c) The active ingredient is mixed with additives such as excipients and binders to make it homogeneous, and the mixture is moistened with a solvent and poured into a mold to form the mixture, after which it is dried in an appropriate manner; is used.

[0177] Film-coated tablets can usually be produced by coating a plain tablet with a thin layer of an appropriate coating agent such as a polymer compound. Sugar-coated tablets can usually be produced by coating a plain tablet with a coating agent containing sugars or sugar alcohols. Multilayer tablets can be produced by stacking powder particles of different compositions in layers using an appropriate method and compressing them. Dry-coated tablets can be produced by coating an inner core tablet with an outer layer of different composition. Tablets can also be made into enteric-coated or sustained-release tablets using known appropriate methods. Orally rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that have unique functions imparted to them by appropriate selection of excipients, and can be produced in accordance with the above-mentioned tablet production methods. Furthermore, an intraorally rapidly disintegrating tablet is a tablet that can be taken by quickly dissolving or disintegrating in the mouth; a chewable tablet is a tablet that is taken by chewing; an effervescent tablet is a tablet that dissolves or disperses while rapidly effervescent in water; a dispersible tablet is a tablet that is taken by dispersing in water; and a dissolving tablet is a tablet that is taken by dissolving in water. Effervescent tablets can be produced by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives. (2) Capsules

[0178] Capsules are preparations filled into capsules or encapsulated with a capsule base, and include hard capsules, soft capsules, etc. Hard capsules can be produced by blending the active ingredient with additives such as excipients to form a homogeneous mixture, or by forming it into granules or molded products using an appropriate method, and then filling the mixture directly into a capsule or by lightly molding it. Soft capsules can be produced by encapsulating the active ingredient with additives and molding it into a specific shape using an appropriate capsule base such as gelatin whose plasticity has been increased by adding glycerin, D-sorbitol, etc. Capsules can also be made into enteric-coated capsules or sustained-release capsules using appropriate known techniques, and coloring agents, preservatives, etc. can also be added to the capsule base. (3) Granules

[0179] Granules are preparations that have been granulated into granules, and include not only those generally called granules but also effervescent granules. When manufacturing granules, the following methods (a), (b), or (c) are usually used: (a) The powdered active ingredient is mixed with an excipient, binder, disintegrant, or other additive to form a homogeneous mixture, and then granulated by a suitable method; (b) Add excipients and other additives to the active ingredient, which has been pre-formed into granules, and mix until homogeneous; (c) Add excipients and other additives to the active ingredient that has been prepared in advance into granules, mix them, and form them into granules by an appropriate method; is used.

[0180] Granules can be coated as needed, and can also be made into enteric-coated or sustained-release granules using known appropriate techniques. Effervescent granules can be produced by using appropriate acidic substances, carbonates, bicarbonates, etc. as additives. Effervescent granules refer to granules that dissolve or disperse in water while rapidly effervescent. Granules can also be made into fine granules by adjusting the particle size. (4) Powder

[0181] Powders are powdered preparations, and can usually be produced by adding excipients or other additives to the active ingredient, mixing them together, and making them homogeneous. (5) Oral liquid

[0182] Oral liquids are liquid or fluid, viscous gel-like preparations, and include not only those commonly referred to as oral liquids but also elixirs, suspensions, emulsions, lemonades, etc. Oral liquids are typically prepared by adding additives and purified water to the active ingredient, mixing to form a homogeneous solution, or emulsifying or suspending the mixture, and then filtering as necessary. Elixirs are clear, liquid oral liquids containing sweet and aromatic ethanol, typically prepared by dissolving a solid active ingredient or its extract in ethanol, purified water, flavoring agents, and sucrose, other sugars, or sweeteners, and then filtering or otherwise preparing a clear liquid. Suspensions are oral liquids in which the active ingredient is finely and homogeneously suspended, typically prepared by adding suspending agents or other additives and purified water or oil to the solid active ingredient, suspending the mixture in an appropriate manner, and homogenizing the entire mixture. An emulsion is an oral liquid preparation in which the active ingredient is finely and homogeneously emulsified, and can usually be produced by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it in an appropriate manner, and making the whole homogeneous. Meanwhile, a lemonade is a clear, liquid oral preparation with a sweet and sour taste. (6) Syrup

[0183] Syrups are viscous liquid or solid preparations containing sugars or sweeteners, including syrup preparations. Syrups are typically prepared by adding an active ingredient to a solution of sucrose, other sugars, or sweeteners, or to a simple syrup, dissolving, mixing, suspending, or emulsifying the mixture, boiling the mixture as needed, and then filtering it while hot. Syrup preparations are granular or powder preparations that become syrups upon addition of water, and are sometimes referred to as dry syrups. Syrup preparations typically use sugars or sweeteners as additives and can be prepared in accordance with the manufacturing methods for the granules or powders described above. (7) Oral jelly

[0184] Oral jellies are non-flowable, molded gel-like preparations, and can usually be produced by mixing the active ingredient with additives and a polymer gel base, gelling it using an appropriate method, and molding it into a specific shape. [Injectable preparation] (1) Injectable

[0185] Injections are solutions, suspensions, emulsions, or solid sterile preparations that are administered subcutaneously, intramuscularly, or directly into body tissues or organs such as blood vessels, and are dissolved or suspended just before use. In addition to what is generally called an injection, these include freeze-dried injections, powder injections, pre-filled syringes, cartridges, infusions, implanted injections, and sustained-release injections. When manufacturing injections, the following method (a) or (b) is usually used: (a) The active ingredient, either as is or with the addition of additives, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents to form a homogeneous solution, which is then filled into a container for injection, sealed, and sterilized; (b) The active ingredient, either as it is or with the addition of additives, is dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents to form a homogeneous solution, which is then filtered aseptically, or the homogeneous solution is prepared aseptically and filled into a container for injection and sealed; is used.

[0186] Freeze-dried injectables are typically produced by dissolving the active ingredient directly or with additives such as excipients in water for injection, sterile filtering, and filling into an injectable container followed by freeze-drying, or by freeze-drying in a dedicated container and then filling directly into a container. Powdered injectables are typically produced by sterile filtering, followed by crystallization of the powder, or by adding sterilized additives to the powder, and then filling into an injectable container. Prefilled syringes are typically produced by filling a syringe with the active ingredient directly or a solution, suspension, or emulsion prepared using the active ingredient and additives. Cartridges are injectables that are loaded into dedicated syringes and used with a drug solution. Cartridges filled with a drug solution are typically produced by filling the cartridge with the active ingredient directly or a solution, suspension, or emulsion prepared using the active ingredient and additives. Infusion solutions are injectables typically 100 mL or more that are administered intravenously. An implantable injection refers to a solid or gel-like injection that is administered subcutaneously, intramuscularly, etc. using an implantation device or by surgery, with the aim of releasing the active ingredient over a long period of time. An implantable injection can usually be produced by using a biodegradable polymer compound and forming it into pellets, microspheres, or a gel. A sustained-release injection refers to an injection that is administered intramuscularly, etc., with the aim of releasing the active ingredient over a long period of time, and can usually be produced by dissolving or suspending the active ingredient in vegetable oil, etc., or by forming it into a suspension of microspheres using a biodegradable polymer compound.

[0187] The compounds of the present disclosure are 1) complementing and / or enhancing the prophylactic and / or therapeutic effects of the compound; 2) improving the kinetics and absorption of the compound, reducing the dosage, and / or 3) The compound may be administered as a combination drug in combination with other drugs to reduce side effects of the compound.

[0188] A combination of a compound of the present disclosure and another drug may be administered in the form of a combined preparation in which both components are combined in a single preparation, or in the form of separate preparations. Administration in these separate preparations includes simultaneous administration and administration at different times. Furthermore, administration at different times may involve administering the compound of the present disclosure first and the other drug later, or administering the other drug first and the compound of the present disclosure later. The respective administration methods may be the same or different.

[0189] There are no particular limitations on the diseases for which the above-mentioned combination drug can exert a preventive and / or therapeutic effect, as long as the preventive and / or therapeutic effect of the compound of the present disclosure can be complemented and / or enhanced.

[0190] Examples of other drugs that can be used to complement and / or enhance the preventive and / or therapeutic effects of the compounds of the present disclosure on Parkinson's disease include levodopa, carbidopa, pramipexole, ropinirole, rotigotine, apomorphine, zonisamide, droxidopa, cabergoline, pergolide, tolcapone, entacapone, selegiline, rasagiline, safinamide, istradefylline, foslevodopa / foscarbidopa, benserazide, bromocriptine, talipexole, amantadine, trihexyphenidyl, and biperiden.

[0191] Examples of other drugs that can be used to complement and / or enhance the preventive and / or therapeutic effect of the compounds of the present disclosure on Lewy body diseases include donepezil hydrochloride and zonisamide.

[0192] Other drugs that can complement and / or enhance the preventive and / or therapeutic effects of the compounds of the present disclosure on Gaucher disease include, for example, imiglucerase, velaglucerase alfa, eliglustat, alglucerase, and miglustat.

[0193] Any two or more of the other drugs may be administered in combination.

[0194] Furthermore, other drugs that complement and / or enhance the preventive and / or therapeutic effects of the compounds of the present disclosure include not only those that have been discovered so far but also those that will be discovered in the future, based on the mechanisms described above.

[0195] 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.

[0196] Furthermore, the contents of all patent and non-patent literature or references explicitly cited in this specification may be incorporated herein by reference in their entirety.

[0197] The present disclosure provides, in one aspect,

[0198] [1] Formula (I): [ka]

[0199] (In the formula,

[0200] L 1 represents (1) C4-7 alkylene, (2) C4-7 alkenylene, or (3) C4-7 alkynylene;

[0201] L 1 1-5 R L1 may be substituted with

[0202] R L1 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a hydroxyl group;

[0203] Multiple R L1 may be the same or different,

[0204] L 2 represents (1) C1-3 alkylene, (2) C2-3 alkenylene, or (3) C2-3 alkynylene;

[0205] L 2 is 1-4 R L2 may be substituted with

[0206] R L2 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a hydroxyl group;

[0207] Multiple R L2 may be the same or different,

[0208] X represents (1) a bond, (2) —O—, (3) —S—, (4) —SO—, or (5) —SO—;

[0209] Ring 1 represents (1) a benzene ring, (2) a naphthalene ring, or (3) a 5- to 10-membered heterocycle;

[0210] R 1 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, (10) a C carbocycle, (11) a 5- to 7-membered heterocycle, (12) -O-(C carbocycle), or (13) -O-(5- to 7-membered heterocycle);

[0211] Multiple R 1 may be the same or different,

[0212] R 1(2)-(13) are 1-5 R 1-1 may be substituted with

[0213] R 1-1 represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, (10) a C alkylsulfonyl group, (11) a cyano group, or (12) a phenyl group;

[0214] Multiple R 1-1 can be the same or different

[0215] symbol: [ka]

[0216] indicates that the substituents are bonded in an appropriate ratio to form an α-configuration, a β-configuration, or a mixture of the α-configuration and the β-configuration,

[0217] n represents an integer of 0 to 5, or a pharmaceutically acceptable salt thereof;

[0218] [2]L 1 the compound according to the above [1] or a pharmaceutically acceptable salt thereof, wherein

[0219] [3] The compound according to the above [1] or [2], wherein X is -O-, or a pharmaceutically acceptable salt thereof.

[0220] [4]L 2 is a methylene group, or a pharmaceutically acceptable salt thereof;

[0221] [5] Ring 1 has the following ring structure: [ka]

[0222] (In the formula, * indicates L 2 The compound according to any one of the above [1] to [4] or a pharmaceutically acceptable salt thereof, wherein

[0223] [6]R L1 is (1) a halogen atom or (2) a C1-6 alkyl group, or a pharmaceutically acceptable salt thereof,

[0224] [7] The compound represented by formula (I) is a compound represented by formula (I-1): [ka]

[0225] (In the formula, R L1-1 represents (1) a halogen atom or (2) a C1-6 alkyl group,

[0226] Multiple R L1-1 may be the same or different,

[0227] m represents an integer from 1 to 2,

[0228] Ring2 represents a ring structure selected from the group consisting of the following ring structures: [ka]

[0229] (In the formula, * indicates the bond position to methylene.)

[0230] Other symbols have the same meanings as those described in the above [1].) The compound according to any one of the above [1] to [6], which is a compound represented by the formula:

[0231] [8] The compound represented by formula (I)

[0232] (1) (3S,4R,5R,6S)-1-{6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol,

[0233] (2) (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol,

[0234] (3) (3S,4R,5R,6S)-1-{(5R)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol,

[0235] (4) (3S,4R,5R,6S)-1-{(5S)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol,

[0236] (5) (3S,4R,5R,6S)-1-[(5R)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl]-3,4,5,6-azepantetrol,

[0237] (6) (3S,4R,5R,6S)-1-[(5S)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl]-3,4,5,6-azepantetrol,

[0238] (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-azepantetrol

[0239] (8) (3S,4R,5R,6S)-1-[(5S)-6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazol-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrol

[0240] (9) (3S,4R,5R,6S)-1-{(5S)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol,

[0241] (10) (3S,4R,5R,6S)-1-{(5R)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol,

[0242] (11) (3S,4R,5R,6S)-1-{(5S)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol,

[0243] (12) (3S,4R,5R,6S)-1-{(5R)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol

[0244] (13) (3S,4R,5R,6S)-1-{(5S)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[0245] (14) (3S,4R,5R,6S)-1-{(5R)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[0246] (15) (3S,4R,5R,6S)-1-[(5S)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrol, and

[0247] (16) (3S,4R,5R,6S)-1-[(5R)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrol, The compound according to any one of the above [1] to [7], or a pharmaceutically acceptable salt thereof, which is a compound selected from the group consisting of:

[0248] [9] A pharmaceutical composition comprising the compound according to any one of the above [1] to [8] or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

[0249]

[10] The pharmaceutical composition according to [9] above, which is a GBA1 chaperone modulator.

[0250]

[11] The pharmaceutical composition according to the above [9], which is a GCS inhibitor.

[0251]

[12] The pharmaceutical composition according to [9] above, which is a GBA1 and GCS dual regulator.

[0252]

[13] The pharmaceutical composition according to any one of [9] to

[12] above, which is a therapeutic and / or preventive agent for a disease associated with GBA1 and / or GCS.

[0253]

[14] The pharmaceutical composition according to

[13] 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 disease, 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, movement disorder, sleep disorder, neurological disorder, CNS disorder, polycystic kidney disease, diabetes, cancer, open-angle glaucoma, endometriosis, multiple myeloma, viral disease, inflammation, systemic lupus erythematosus, hepatitis, Guillain-Barré syndrome, diabetic nephropathy, and skin disorder.

[0254]

[15] The pharmaceutical composition according to

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

[0255]

[16] The pharmaceutical composition according to [9] above, wherein 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, velaglucerase alfa, eliglustat, alglucerase, and miglustat are co-administered.

[0256]

[17] A therapeutic and / or preventive agent for a disease associated with GBA1 and / or GCS, comprising the compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof.

[0257]

[18] A method for preventing and / or treating a disease associated with GBA1 and / or GCS, comprising administering to a patient in need of the prevention and / or treatment of a disease associated with GBA1 and / or GCS a compound according to any one of [1] to [8] above, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to [9] above.

[0258]

[19] The compound or pharmaceutically acceptable salt thereof according to any one of 1 to 8 above, for use in the prevention and / or treatment of a disease associated with GBA1 and / or GCS.

[0259]

[20] Use of the compound according to any one of [1] to [8] above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing and / or treating a disease associated with GBA1 and / or GCS. and other embodiments are provided. [Example]

[0260] The solvents in parentheses shown in the chromatographic separations and TLCs indicate the eluting or developing solvents used, and the ratios are by volume.

[0261] The solvent used in the NMR measurements is shown in parentheses.

[0262] The names of compounds used in this specification are generally determined using ACD / Name (registered trademark) from Advanced Chemistry Development, Inc., a computer program that determines names according to IUPAC rules, or are determined according to IUPAC nomenclature.

[0263] LC-MS analysis was carried out under the following conditions.

[0264] Method A: Reversed-phase LC / MS analysis was performed on 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), flow rate: 1.5 mL / min, elution gradient: 5%-95% (solvent B) in 0.7 min, 95% in 0.4 min; Column: Agilent Pursit 5 C18 20*2.0 mm; Wavelength: UV 220 nm, 254 nm; Column temperature: 50 °C; MS ionization: ESI.

[0265] Method B: Reversed-phase LC / MS analysis was performed on a Shimadzu LC20-MS2020 with an ESI source. MS parameters: Mobile phase: 0.8 mL / 4 L NH₃·H₂O aqueous solution (solvent A) and acetonitrile (solvent B), flow rate: 1.2 mL / min, elution gradient: 10%–80% (solvent B) over 2 min and 80% over 0.48 min; Column: Xbridge C18 2.1 × 50 mm, 5 μm; Wavelength: UV 220 nm and 254 nm; Column temperature: 50 °C; MS ionization: ESI.

[0266] Method C: Reversed-phase LC / MS analysis was performed on a Shimadzu LC20-MS2020 with an ESI source. MS parameters: Mobile phase: 0.8 mL / 4 L NH₃·H₂O aqueous solution (solvent A) and acetonitrile (solvent B), flow rate: 0.8 mL / min, elution gradient: 10%–80% (solvent B) over 6 min and 80% over 0.5 min; Column: Xbridge C18 2.1 × 50 mm, 5 μm; Wavelength: UV 220 nm and 254 nm; Column temperature: 50 °C; MS ionization: ESI.

[0267] Preparative HPLC was performed under the following conditions or with different solvent gradients and columns.

[0268] Prep-HPLC(HCl):

[0269] Mobile phase: 0.1% HCl aqueous solution (solvent A) / acetonitrile solution (solvent B) at a flow rate of 30 mL / min, eluting with a gradient of 25% to 55% (solvent B) for 8 min, followed by a 2 min hold at 100%; column: Phenomenex Synergi C18 150 × 30 mm × 4 μm.

[0270] Prep-HPLC(FA):

[0271] Mobile phase: 0.225% FA aqueous solution (solvent A) / acetonitrile solution (solvent B) at a flow rate of 30 mL / min, eluting with a gradient of 55% to 85% (solvent B) for 8 min, followed by a 2 min hold at 100%; column: Welch Xtimate C18 100 × 40 mm × 3 μm.

[0272] Prep-HPLC (base):

[0273] Mobile phase: 0.05% NH₃·H₂O and 10 mM NH₄HCO₃ in water (solvent A) and acetonitrile (solvent B) at a flow rate of 30 mL / min. Elute with a gradient of 30%–60% (solvent B) for 20 min, followed by a 5-min hold at 100%. Column: Xtimate C18 150 × 40 mm × 5 μm.

[0274] Prep-HPLC (neutral)

[0275] Mobile phase: 10 mM NH4HCO3 in water (solvent A) / acetonitrile (solvent B) at a flow rate of 30 mL / min, eluting with a gradient of 35%-65% (solvent B) over 9.5 min, followed by a 2 min hold at 100%; column: Phenomenex Gemini C18 75 x 40 mm x 3 μm.

[0276] The SFC analysis was carried out under the following conditions.

[0277] Preparative SFC was performed under similar conditions to the analytical method or with different mobile phases, gradients and columns.

[0278] Method A1:

[0279] Waters UPCC with PDA detector, column: Cellulose 2 150 × 4.6 mm ID, 5 μm, mobile phase: A: CO2, B: Ethanol (0.05% DEA), gradient: 5%–40% B for 5 min, 40% for 2.5 min, then 5% B for 2.5 min, flow rate: 2.5 mL / min, column temperature: 35°C, ABPR: 1500 psi.

[0280] Method A2:

[0281] Waters UPCC with PDA detector, column: Cellulose 2 100 × 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: 35 °C, ABPR: 1500 psi.

[0282] Method A3:

[0283] Waters UPCC with PDA detector, column: Cellulose 2 150 × 4.6 mm ID, 5 μm, mobile phase: A: CO2, B: methanol (0.05% DEA), mobile phase composition: 40% B, flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi.

[0284] Method B1:

[0285] Waters UPCC with PDA detector, column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm, mobile phase: 50% ethanol in CO2 (0.05% DEA), flow rate: 2.2 mL / min, column temperature: 35 °C, ABPR: 1500 psi.

[0286] Method B2:

[0287] Waters UPCC with PDA detector, Column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: Ethanol (0.05% DEA), Gradient: 5%–40% B for 4 min, 40% for 2 min, then 5% B for 2 min, Flow rate: 2.5 mL / min, Column temperature: 35°C, ABPR: 1500 psi.

[0288] Method B3:

[0289] Waters UPCC with PDA detector, column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm, mobile phase: 40% methanol in CO2 (0.05% DEA), flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi.

[0290] Method B4:

[0291] Agilent 1260 with DAD detector, column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: methanol (0.05% DEA), gradient: 5%–40% B for 5.5 min, 40% for 3 min, then 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 40°C, ABPR: 1500 psi.

[0292] Method B5:

[0293] Waters UPCC with PDA detector, Column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: Methanol (0.05% DEA), Gradient: 5%–40% B in 5 min, 40% in 2.5 min, then 5% B in 2.5 min, Flow rate: 2.5 mL / min, Column temperature: 35°C, ABPR: 1500 psi.

[0294] Method B6:

[0295] Agilent 1260 with DAD detector, column: Chiralpak AD-3 150 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: methanol (0.05% DEA), mobile phase composition: 40% B, flow rate: 2.5 mL / min, column temperature: 40 °C, ABPR: 1500 psi.

[0296] Method B7:

[0297] Agilent 1260 with DAD detector, column: Chiralpak AD-3 50 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: methanol (0.05% DEA), mobile phase composition: 40% B, flow rate: 4 mL / min, column temperature: 35 °C, ABPR: 1500 psi.

[0298] Method B8:

[0299] Waters UPCC with PDA detector, column: Chiralpak AS-3 150 × 4.6 mm ID, 3 μm, mobile phase: 40% isopropanol in CO2 (0.05% DEA), flow rate: 2.5 mL / min, column temperature: 35 °C, ABPR: 1500 psi.

[0300] Method D1:

[0301] Waters UPCC with PDA detector, Column: Chiralcel OD-3 150 × 4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: Ethanol (0.05% DEA), Gradient: 5%–40% B for 4 min, 40% for 2 min, then 5% B for 2 min, Flow rate: 2.5 mL / min, Column temperature: 35°C, ABPR: 1500 psi.

[0302] Method E1:

[0303] Waters UPCC with PDA detector, column: Chiralcel OJ-3 100 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%–40% B for 4 min, 40% for 0.5 min, then 5% B for 1.5 min, hold 5%–40% B for 4 min, hold 40% for 0.5 min, then hold 5% B for 1.5 min, flow rate: 2.8 mL / min, column temperature: 35°C, ABPR: 1500 psi.

[0304] Method F1:

[0305] Waters UPCC with PDA detector, column: Chiralpak IG-3 100 × 4.6 mm ID, 3 μm, mobile phase: 40% ethanol in CO2 (0.05% DEA), flow rate: 2.8 mL / min, column temperature: 35 °C, ABPR: 1500 psi.

[0306] Method F2:

[0307] Waters UPCC with PDA detector, column: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm, mobile phase: 40% ethanol in CO2 (0.05% DEA), flow rate: 4 mL / min, column temperature: 35 °C, ABPR: 1500 psi.

[0308] Method F3:

[0309] Agilent 1260 with DAD detector, Column: Chiralpak IG-3 100 × 4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: Ethanol (0.05% DEA), Gradient: 5%–40% B in 4 min, 40% in 2.5 min, then 5% B in 1.5 min, Flow rate: 2.8 mL / min, Column temperature: 35 °C, ABPR: 1500 psi.

[0310] Method F4:

[0311] Waters UPCC with PDA detector, Column: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: Methanol (0.05% DEA), Gradient: 5%-40% B in 2 min, 40% in 1.2 min, then 5% B in 0.8 min, Flow rate: 4 mL / min, Column temperature: 35 °C, ABPR: 1500 psi.

[0312] Method F5:

[0313] Agilent 1260 with DAD detector, column: Chiralpak IG-3 100 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: methanol (0.05% DEA), gradient: 5%–40% B for 4 min, 40% for 3 min, then 5% B for 1 min, flow rate: 2.5 mL / min, column temperature: 40°C, ABPR: 1500 psi.

[0314] Method F6:

[0315] Waters UPCC with PDA detector, column: Chiralpak IG-3 50 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: isopropanol (0.05% DEA), mobile phase composition: 40% B, flow rate: 4 mL / min, column temperature: 35 °C, ABPR: 1500 psi.

[0316] Method G1:

[0317] Agilent 1260 with DAD detector, column: cellulose-4, 100 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%-40% B for 4 min, 40% for 2.5 min, then 5% B for 1.5 min, flow rate: 2.8 mL / min, column temperature: 40 °C, back pressure: 100 bar.

[0318] Method G2:

[0319] Agilent 1260 with DAD detector, column: cellulose-4, 100 × 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.

[0320] Method H1:

[0321] Agilent 1260 with DAD detector, column: ChiralPak AY-3 150 × 4.6 mm ID, 3 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%-40% B for 5.5 min, 40% for 3 min, then 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 40 °C, ABPR: 100 bar.

[0322] Method J1:

[0323] Agilent 1260 with DAD detector, column: Chiralcel OJ-H 150 × 4.6 mm ID, 5 μm, mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: 5%–40% B for 4.5 min, then 5% B for 1.5 min, flow rate: 2.5 mL / min, column temperature: 40°C, ABPR: 1500 psi.

[0324] The abbreviations used in the description of 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 azodicarboxylate; DAST is N,N-diethylaminosulfur trifluoride; DCM is dichloromethane; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; EtOAc is ethyl acetate; PE is petroleum ether; THF is tetrahydrofuran; DMP is Dess-Martin 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.

[0325] Reference Example 1: 6-Iodohexyl 4-methylbenzyl ether

[0326] To a mixture of (4-methylphenyl)methanol (CAS number: 589-18-4, 0.16 mL) and t-BuOK (207 mg) in THF (5 mL) was added 1,6-diiodohexane (CAS number: 629-09-4, 0.61 mL) at 25 °C. The reaction mixture was stirred at 40 °C for 14 h. After dilution with DCM, the mixture was concentrated to dryness. The crude product was purified by silica gel flash column (PE-15% EtOAc in PE) to give the title compound (103 mg).

[0327] 1H-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.

[0328] Example 1: (3S,4R,5R,6S)-1-{6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol [ka]

[0329] 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 and mixed at 25°C. The reaction was stirred at 80°C for 16 hours. The residue was purified by prep-HPLC (basic) to obtain the title compound (67 mg).

[0330] LCMS retention time: 1.622 min (method B); MS (ESI, Pos.): m / z 368.2 (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.

[0331] Example 2-60:

[0332] Examples 2-60 were synthesized in the same manner as in Reference Example 1 and Example 1, except that the corresponding alcohol compounds were used instead of (4-methylphenyl)methanol.

[0333] Example 2: (3S,4R,5R,6S)-1-[6-(4-biphenylylmethoxy)hexyl]-3,4,5,6-azepantetrol

[0334] LCMS retention time: 1.835 min (method B); MS(ESI, Pos.): m / z 430.3(M+H)+;

[0335] 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.

[0336] Example 3: (3S,4R,5R,6S)-1-{6-[(3-phenyl-2-propyn-1-yl)oxy]hexyl}-3,4,5,6-azepantetrol hydrochloride (1:1)

[0337] LCMS retention time: 0.67 minutes (Method A); MS(ESI, Pos.): m / z 378.1(M+H)+;

[0338] 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.

[0339] Example 4: (3S,4R,5R,6S)-1-(6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0340] LCMS retention time: 0.692 minutes (Method A); MS(ESI, Pos.): m / z 455.2(M+H)+;

[0341] 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.

[0342] Example 5: (3S,4R,5R,6S)-1-{6-[(2-phenyl-1,3-thiazol-4-yl)methoxy]hexyl}-3,4,5,6-azepantetrol hydrochloride (1:1)

[0343] LCMS retention time: 0.688 minutes (Method A); MS(ESI, Pos.): m / z 437.1(M+H)+;

[0344] 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.

[0345] Example 6: (3S,4R,5R,6S)-1-[6-({2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methoxy)hexyl]-3,4,5,6-azepantetrol hydrochloride (1:1)

[0346] LCMS retention time: 0.751 minutes (Method A); MS(ESI, Pos.): m / z 505.1(M+H)+;

[0347] 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.

[0348] Example 7: (3S,4R,5R,6S)-1-[6-({2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methoxy)hexyl]-3,4,5,6-azepantetrol hydrochloride (1:1)

[0349] LCMS retention time: 0.75 minutes (Method A); MS(ESI, Pos.): m / z 505.1(M+H)+;

[0350] 1 H-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.

[0351] Example 8: (3S,4R,5R,6S)-1-(6-{[2-(3-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0352] LCMS retention time: 0.698 minutes (Method A); MS(ESI, Pos.): m / z 455.1(M+H)+;

[0353] 1H-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.

[0354] Example 9: (3S,4R,5R,6S)-1-(6-{[2-(2-methylphenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0355] LCMS retention time: 0.701 minutes (Method A); MS(ESI, Pos.): m / z 451.1(M+H)+;

[0356] 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.

[0357] Example 10: (3S,4R,5R,6S)-1-(6-{[2-(2-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0358] LCMS retention time: 0.704 minutes (Method A); MS(ESI, Pos.): m / z 455.1(M+H)+;

[0359] 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.

[0360] Example 11: (3S,4R,5R,6S)-1-{6-[(5-phenyl-2-pyrazinyl)methoxy]hexyl}-3,4,5,6-azepantetrol

[0361] LCMS retention time: 0.676 minutes (Method A); MS(ESI, Pos.): m / z 432.1(M+H)+;

[0362] 1H-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.

[0363] Example 12: (3S,4R,5R,6S)-1-(6-{[2-(4-fluorophenyl)-1,3-thiazol-5-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0364] LCMS retention time: 0.739 minutes (Method A); MS(ESI, Pos.): m / z 455.2(M+H)+;

[0365] 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.

[0366] Example 13: (3S,4R,5R,6S)-1-(6-{[4-(4-fluorophenyl)-1,3-thiazol-2-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0367] LCMS retention time: 0.755 minutes (Method A); MS(ESI, Pos.): m / z 455.2(M+H)+;

[0368] 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.

[0369] Example 14: (3S,4R,5R,6S)-1-(6-{[2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0370] LCMS retention time: 0.731 minutes (Method A); MS(ESI, Pos.): m / z 439.2(M+H)+;

[0371] 1H-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.

[0372] Example 15: (3S,4R,5R,6S)-1-(6-{[2-(4-fluorophenyl)-5-methyl-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0373] LCMS retention time: 0.712 minutes (Method A); MS(ESI, Pos.): m / z469(M+H)+;

[0374] 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.

[0375] Example 16: (3S,4R,5R,6S)-1-{6-[(3'-fluoro-4-biphenylyl)methoxy]hexyl}-3,4,5,6-azepantetrol

[0376] LCMS retention time: 0.744 minutes (Method A); MS(ESI, Pos.): m / z 448.1(M+H)+;

[0377] 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.

[0378] Example 17: (3S,4R,5R,6S)-1-(6-{[3'-(trifluoromethyl)-4-biphenylyl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0379] LCMS retention time: 0.767 minutes (Method A); MS(ESI, Pos.): m / z 498.1(M+H)+;

[0380] 1H-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.

[0381] Example 18: (3S,4R,5R,6S)-1-(6-{[4'-(trifluoromethyl)-4-biphenylyl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0382] LCMS retention time: 0.785 minutes (Method A); MS(ESI, Pos.): m / z 498.1(M+H)+;

[0383] 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.

[0384] Example 19: (3S,4R,5R,6S)-1-(6-{[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0385] LCMS retention time: 0.72 minutes (Method A); MS(ESI, Pos.): m / z471(M+H)+;

[0386] 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.

[0387] Example 20: (3S,4R,5R,6S)-1-(6-{[2-(3,4-difluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0388] LCMS retention time: 0.707 minutes (Method A); MS(ESI, Pos.): m / z 473.1(M+H)+;

[0389] 1H-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.

[0390] Example 21: (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

change

[0391] LCMS retention time: 0.709 minutes (Method A); MS(ESI, Pos.): m / z 473.1(M+H)+;

[0392] 1 H-NMR(CD3OD): δ7.69-7.50, 7.15-7.02, 4.67, 3.68-3.53, 3.46-3.37, 2.90-2.76, 2.58-2.44, 1.70-1.60, 1.56-1.30.

[0393] Example 22: (3S,4R,5R,6S)-1-(6-{[2-(4-methylphenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0394] LCMS retention time: 0.71 minutes (Method A); MS(ESI, Pos.): m / z 451.1(M+H)+;

[0395] 1 H-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.

[0396] Example 23: (3S,4R,5R,6S)-1-(6-{[2-(4-methoxyphenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0397] LCMS retention time: 0.749 minutes (Method A); MS(ESI, Pos.): m / z 467.1(M+H)+;

[0398] 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.

[0399] Example 24: (3S,4R,5R,6S)-1-(6-{[2-(3,4,5-trifluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0400] LCMS retention time: 0.724 minutes (Method A); MS(ESI, Pos.): m / z491(M+H)+;

[0401] 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.

[0402] Example 25: (3S,4R,5R,6S)-1-(6-{[2-(3-chloro-4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0403] LCMS retention time: 0.725 minutes (Method A); MS(ESI, Pos.): m / z489(M+H)+;

[0404] 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.

[0405] Example 26: (3S,4R,5R,6S)-1-[6-({2-[4-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}methoxy)hexyl]-3,4,5,6-azepantetrol

[0406] LCMS retention time: 0.746 minutes (Method A); MS(ESI, Pos.): m / z521.1(M+H)+;

[0407] 1H-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.

[0408] Example 27: (3S,4R,5R,6S)-1-(6-{[2-(3-methoxyphenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0409] LCMS retention time: 0.696 minutes (Method A); MS(ESI, Pos.): m / z 467.1(M+H)+;

[0410] 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.

[0411] Example 28: (3S,4R,5R,6S)-1-[6-(3-biphenylylmethoxy)hexyl]-3,4,5,6-azepantetrol

[0412] LCMS retention time: 0.726 minutes (Method A); MS(ESI, Pos.): m / z 430.1(M+H)+;

[0413] 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.

[0414] Example 29: (3S,4R,5R,6S)-1-(6-{[4-(1,3-thiazol-4-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0415] LCMS retention time: 0.669 minutes (Method A); MS(ESI, Pos.): m / z 437.1(M+H)+;

[0416] 1H-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.

[0417] Example 30: (3S,4R,5R,6S)-1-[6-({2-[3-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}methoxy)hexyl]-3,4,5,6-azepantetrol

[0418] LCMS retention time: 0.721 minutes (Method A); MS(ESI, Pos.): m / z521.1(M+H)+;

[0419] 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.

[0420] Example 31: 3-{4-[({6-[(3S,4R,5R,6S)-3,4,5,6-tetrahydroxy-1-azepanyl]hexyl}oxy)methyl]-1,3-thiazol-2-yl}benzonitrile

[0421] LCMS retention time: 0.678 minutes (Method A); MS(ESI, Pos.): m / z 462.1(M+H)+;

[0422] 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.

[0423] Example 32: 4-{4-[({6-[(3S,4R,5R,6S)-3,4,5,6-tetrahydroxy-1-azepanyl]hexyl}oxy)methyl]-1,3-thiazol-2-yl}benzonitrile

[0424] LCMS retention time: 0.673 minutes (Method A); MS(ESI, Pos.): m / z 462.2(M+H)+;

[0425] 1H-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.

[0426] Example 33: (3S,4R,5R,6S)-1-(6-{[2-(4-fluoro-3-methoxyphenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0427] LCMS retention time: 0.703 minutes (Method A); MS(ESI, Pos.): m / z 485.1(M+H)+;

[0428] 1 H-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.

[0429] Example 34: (3S,4R,5R,6S)-1-[6-({2-[4-(methylsulfonyl)phenyl]-1,3-thiazol-4-yl}methoxy)hexyl]-3,4,5,6-azepantetrol

[0430] LCMS retention time: 0.656 minutes (Method A); MS(ESI, Pos.): m / z515(M+H)+;

[0431] 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.

[0432] Example 35: (3S,4R,5R,6S)-1-(6-{[6-(3-fluoro-5-methoxyphenyl)-3-pyridinyl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0433] LCMS hold time: 1.031 minutes (D method); MS(ESI, Pos.): m / z 479.2(M+H)+;

[0434] 1H-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.

[0435] Example 36: (3S,4R,5R,6S)-1-(6-{[5-(3-fluoro-5-methoxyphenyl)-2-pyridinyl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0436] LCMS retention time: 0.665 minutes (Method A); MS(ESI, Pos.): m / z 479.1(M+H)+;

[0437] 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.

[0438] Example 37: (3S,4R,5R,6S)-1-(6-{[2-(3-chloro-5-methoxyphenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0439] LCMS retention time: 1.808 minutes (Method B); MS(ESI, Pos.): m / z 501.2(M+H)+;

[0440] 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.

[0441] Example 38: (3S,4R,5R,6S)-1-{6-[(2-cyclohexyl-1,3-thiazol-4-yl)methoxy]hexyl}-3,4,5,6-azepantetrol

[0442] LCMS retention time: 0.715 minutes (Method A); MS(ESI, Pos.): m / z443(M+H)+;

[0443] 1H-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.

[0444] Example 39: (3S,4R,5R,6S)-1-{6-[(2-propyl-1,3-thiazol-4-yl)methoxy]hexyl}-3,4,5,6-azepantetrol

[0445] LCMS retention time: 0.655 minutes (Method A); MS(ESI, Pos.): m / z403(M+H)+;

[0446] 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.

[0447] Example 40: (3S,4R,5R,6S)-1-(6-{[2-(2,4-difluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0448] LCMS retention time: 0.723 minutes (Method A); MS(ESI, Pos.): m / z 473.1(M+H)+;

[0449] 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.

[0450] Example 41: (3S,4R,5R,6S)-1-(6-{[2-(2,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0451] LCMS retention time: 0.764 minutes (Method A); MS(ESI, Pos.): m / z 473.2(M+H)+;

[0452] 1H-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.

[0453] Example 42: (3S,4R,5R,6S)-1-(6-{[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0454] LCMS retention time: 0.689 minutes (Method A); MS(ESI, Pos.): m / z 473.1(M+H)+;

[0455] 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.

[0456] Example 43: (3S,4R,5R,6S)-1-(6-{[2-(2,3,4-trifluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0457] LCMS retention time: 0.78 minutes (Method A); MS(ESI, Pos.): m / z 491.2(M+H)+;

[0458] 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.

[0459] Example 44: (3S,4R,5R,6S)-1-(6-{[2-(2,4,6-trifluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0460] LCMS retention time: 0.749 minutes (Method A); MS(ESI, Pos.): m / z 491.2(M+H)+;

[0461] 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.

[0462] Example 45: (3S,4R,5R,6S)-1-[6-({2-[(E)-2-phenylvinyl]-1,3-thiazol-4-yl}methoxy)hexyl]-3,4,5,6-azepantetrol

[0463] LCMS retention time: 1.706 minutes (Method B); MS(ESI, Pos.): m / z 463.2(M+H)+;

[0464] 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.

[0465] Example 46: (3S,4R,5R,6S)-1-[6-(2-naphthylmethoxy)hexyl]-3,4,5,6-azepantetrol

[0466] LCMS retention time: 1.729 minutes (Method B); MS(ESI, Pos.): m / z 404.3(M+H)+;

[0467] 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.

[0468] Example 47: (3S,4R,5R,6S)-1-[6-(2-biphenylylmethoxy)hexyl]-3,4,5,6-azepantetrol

[0469] LCMS retention time: 1.828 minutes (Method B); MS(ESI, Pos.): m / z 430.3(M+H)+;

[0470] 1H-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.

[0471] Example 48: (3S,4R,5R,6S)-1-{6-[(3',5'-difluoro-2-biphenylyl)methoxy]hexyl}-3,4,5,6-azepantetrol

[0472] LCMS retention time: 1.89 minutes (Method B); MS(ESI, Pos.): m / z 466.3(M+H)+;

[0473] 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.

[0474] Example 49: (3S,4R,5R,6S)-1-{6-[(3,4-dipropylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[0475] LCMS retention time: 2.148 minutes (Method B); MS(ESI, Pos.): m / z 438.4(M+H)+;

[0476] 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.

[0477] Example 50: (3S,4R,5R,6S)-1-(6-{[2-(3-methylbutyl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol formate (1:1)

[0478] LCMS retention time: 0.756 minutes (Method A); MS(ESI, Pos.): m / z 424.2(M+H)+;

[0479] 1H-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.

[0480] Example 51: (3S,4R,5R,6S)-1-{6-[(4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[0481] LCMS retention time: 1.854 minutes (Method B); MS(ESI, Pos.): m / z 396.4(M+H)+;

[0482] 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.

[0483] Example 52: (3S,4R,5R,6S)-1-(6-{[4-(1-cyclohexen-1-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol

[0484] LCMS retention time: 0.781 minutes (Method A); MS(ESI, Pos.):m / z456.2(M+Na)+;

[0485] 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.

[0486] Example 53: (3S,4R,5R,6S)-1-(6-{[3-(1-cyclohexen-1-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol

[0487] LCMS retention time: 1.996 minutes (Method B); MS(ESI, Pos.): m / z 434.4(M+H)+;

[0488] 1H-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.

[0489] Example 54: (3S,4R,5R,6S)-1-{6-[(3-cyclohexylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[0490] LCMS retention time: 0.865 minutes (Method A); MS(ESI, Pos.): m / z 436.3(M+H)+;

[0491] 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.

[0492] Example 55: (3S,4R,5R,6S)-1-(6-{[2-(1-cyclohexen-1-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol

[0493] LCMS retention time: 0.75 minutes (Method A); MS(ESI, Pos.): m / z 434.2(M+H)+;

[0494] 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.

[0495] Example 56: (3S,4R,5R,6S)-1-{6-[(2-cyclohexylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[0496] LCMS retention time: 0.758 minutes (Method A); MS(ESI, Pos.): m / z 436.2(M+H)+;

[0497] 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.

[0498] Example 57: (3S,4R,5R,6S)-1-{6-[(4-cyclohexylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[0499] LCMS retention time: 2.08 minutes (Method B); MS(ESI, Pos.): m / z 436.4(M+H)+;

[0500] 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.

[0501] Example 58: (3S,4R,5R,6S)-1-(6-{[3-(3,5-difluorophenyl)-1,2-oxazol-5-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0502] LCMS retention time: 1.69 minutes (Method B); MS(ESI, Pos.): m / z 457.4(M+H)+;

[0503] 1 H-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.

[0504] Example 59: (3S,4R,5R,6S)-1-(6-{[5-(3,5-difluorophenyl)-1,2-oxazol-3-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[0505] LCMS retention time: 0.783 minutes (Method A); MS (ESI, Pos.): m / z 457.3 (M+H)+;

[0506] 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.

[0507] Example 60: (3S,4R,5R,6S)-1-{6-[(4-ethylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[0508] LCMS retention time: 0.708 min (method A); MS (ESI, Pos.): m / z 382.1 (M+H)+;

[0509] 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.

[0510] Reference Example 2: (3S,4R,5R,6S)-1-{6-[(4-bromobenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[0511] The title compound was synthesized in the same manner as in Reference Example 1 and Example 1, except that (4-bromophenyl)methanol (CAS number 873-75-6) was used instead of (4-methylphenyl)methanol.

[0512] LCMS retention time: 0.702 min (method A); MS(ESI, Pos.): m / z431.8, 433.8[M+H]+.

[0513] Example 61: (3S,4R,5R,6S)-1-(6-{[4-(3,6-dihydro-2H-pyran-4-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol

[0514] To a solution of the compound prepared in Reference Example 2 (150 mg) in 1,4-dioxane (2 mL) and water (0.5 mL) was added 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) at 20-25 °C. The reaction mixture was stirred at 100 °C for 16 hours to give a brown solution. The reaction mixture was concentrated to dryness. The residue was purified using a reverse-phase column (30-40% MeCN aqueous solution) to give the title compound (35 mg).

[0515] LCMS retention time: 0.69 min (method A); MS (ESI, Pos.): m / z 436.1 (M+H)+;

[0516] 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.

[0517] Examples 62-67:

[0518] Examples 62 to 67 were synthesized in the same manner as in Example 61, using the compound prepared in Reference Example 2 and the corresponding boronic acid or boronic acid ester instead of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0519] Example 62: (3S,4R,5R,6S)-1-{6-[(4'-fluoro-4-biphenylyl)methoxy]hexyl}-3,4,5,6-azepantetrol

[0520] LCMS retention time: 0.739 min (method A); MS (ESI, Pos.): m / z 448.1 (M+H)+;

[0521] 1H-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.

[0522] Example 63: 4'-[({6-[(3S,4R,5R,6S)-3,4,5,6-tetrahydroxy-1-azepanyl]hexyl}oxy)methyl]-3-biphenylcarbonitrile

[0523] LCMS retention time: 0.716 minutes (Method A); MS(ESI, Pos.): m / z 455.1(M+H)+;

[0524] 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.

[0525] Example 64: (3S,4R,5R,6S)-1-{6-[(4'-fluoro-3'-methoxy-4-biphenylyl)methoxy]hexyl}-3,4,5,6-azepantetrol

[0526] LCMS retention time: 0.729 minutes (Method A); MS(ESI, Pos.): m / z 478.1(M+H)+;

[0527] 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.

[0528] Example 65: 4'-[({6-[(3S,4R,5R,6S)-3,4,5,6-tetrahydroxy-1-azepanyl]hexyl}oxy)methyl]-4-biphenylcarbonitrile

[0529] LCMS retention time: 0.721 minutes (Method A); MS(ESI, Pos.): m / z 455.1(M+H)+;

[0530] 1H-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.

[0531] Example 66: 4'-[({6-[(3S,4R,5R,6S)-3,4,5,6-tetrahydroxy-1-azepanyl]hexyl}oxy)methyl]-2-biphenylcarbonitrile

[0532] LCMS retention time: 0.715 minutes (Method A); MS(ESI, Pos.): m / z 455.1(M+H)+;

[0533] 1 H-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.

[0534] Example 67: (3S,4R,5R,6S)-1-{6-[(3'-fluoro-5'-methoxy-4-biphenylyl)methoxy]hexyl}-3,4,5,6-azepantetrol

[0535] LCMS retention time: 0.75 minutes (Method A); MS(ESI, Pos.): m / z 478.1(M+H)+;

[0536] 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.

[0537] Example 68: (3S,4R,5R,6S)-1-(6-{[4-(tetrahydro-2H-pyran-4-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol

[0538] To a solution of the compound prepared in Example 61 (20 mg) in methanol (1 mL) was added Pd / C (5 mg, wet, 10%) and then purged with H (15 psi). The reaction was stirred at 20-25 °C for 15 hours, resulting in a black suspension. The reaction solution was filtered and concentrated to dryness. The mixture was purified by prep-HPLC (neutral) and concentrated to give the title compound (18.2 mg).

[0539] LCMS retention time: 0.689 min (method A); MS (ESI, Pos.): m / z 438.1 (M+H)+;

[0540] 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.

[0541] Reference Example 3: Methyl 4-phenoxy-2-pyrimidinecarboxylate

[0542] To a solution of 2-chloro-4-phenoxypyrimidine (CAS number: 18214-00-1, 2.0 g) in methanol (115 mL) and toluene (23 mL) was added TEA (4.04 mL) and Pd(dppf)Cl (708 mg). The mixture was heated to 150 °C under CO (3 MPa) for 15 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with H O and extracted with EtOAc. The organic phase was dried over Na SO and concentrated to dryness under reduced pressure. The residue was purified using a silica gel flash column (PE-30% EtOAc / PE) to give the title compound (1.3 g).

[0543] LCMS retention time: 0.689 min (method A); MS(ESI, Pos.):m / z230.9[M+H]+.

[0544] Reference Example 4: (4-phenoxy-2-pyrimidinyl)methanol

[0545] To a solution of the compound prepared in Reference Example 3 (500 mg) in methanol (6 mL) was added NaBH (98.6 mg) at 0°C. The mixture was stirred at 20-25°C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with H2O and saturated brine, and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to obtain the title compound (470 mg, crude product). The crude product was used directly in the next step.

[0546] Reference Example 5: 2-(Bromomethyl)-4-phenoxypyrimidine

[0547] To a solution of the compound prepared in Reference Example 4 (150 mg) and PPh3 (292 mg) in DCM (2 mL) was added CBr4 (492 mg) in DCM (1 mL) at 0-5 °C. The mixture was refluxed for 6 hours. The reaction mixture was diluted with DCM, washed with H2O, and extracted with DCM. The combined organic phase was washed with saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc = 3 / 1) to give the title compound (100 mg).

[0548] 1 H-NMR (CDCl3): δ8.61-8.53, 7.50-7.42, 7.34-7.28, 7.21-7.15, 6.69, 4.45.

[0549] Reference Example 6: 6-[(4-phenoxy-2-pyrimidinyl)methoxy]-1-hexanol

[0550] To a solution of the compound prepared in Reference Example 5 (150 mg) and t-BuOK (95 mg) in THF (4.5 mL) was added dropwise hexane-1,6-diol (CAS number 629-11-8, 0.12 mL). The mixture was stirred at 20-25°C for 16 hours. The reaction mixture was diluted with H2O and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc = 1 / 1) to give the title compound (30 mg).

[0551] LCMS retention time: 0.756 min (method A); MS(ESI, Pos.):m / z302.9[M+H]+.

[0552] Reference Example 7: 6-[(4-phenoxy-2-pyrimidinyl)methoxy]hexyl 4-methylbenzenesulfonate

[0553] To a solution of the compound prepared in Reference Example 6 (45 mg) in DCM (0.64 mL) and pyridine (0.010 mL) was added TsCl (34 mg) at 0-5°C. The mixture was stirred at 20-25°C for 5 hours. The reaction mixture was diluted with DCM, washed with H2O, and extracted with DCM. The combined organic phase was separated, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc = 3 / 1) to give the title compound (15 mg).

[0554] LCMS retention time: 0.956 min (method A); MS(ESI, Pos.):m / z457.0[M+H]+.

[0555] Example 69: (3S,4R,5R,6S)-1-{6-[(4-phenoxy-2-pyrimidinyl)methoxy]hexyl}-3,4,5,6-azepantetrol

[0556] 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) was added DIEA (0.03 mL). The resulting mixture was heated at 80-90°C for 2 hours. The mixture was purified by prep-HPLC (basic) to obtain the title compound (6.6 mg).

[0557] LCMS retention time: 0.667 min (method A); MS (ESI, Pos.): m / z 448 (M+H)+;

[0558] 1 H-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.

[0559] Reference Example 8: 1-Bromo-2-({[6-(trityloxy)hexyl]oxy}methyl)benzene

[0560] To a solution of (2-bromophenyl)methanol (CAS number: 18982-54-2, 500 mg) in DMF (5 mL) was added NaH (160 mg, 60% in oil) at 0-5°C. The mixture was stirred at 0-5°C for 0.5 h. Next, 1,1',1''-{[(6-bromohexyl)oxy]methanetriyl}tribenzene (CAS number: 113354-79-3, 2.3 g) and KI (44.3 mg) were added at 0-5°C. The reaction mixture was stirred at 20°C for 1.5 h to give a brown solution. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash column (PE-0% EtOAc / PE) to give the title compound (1.1 g).

[0561] TLC: Rf 0.5 (PE / Et0Ac=1 / 1).

[0562] Reference Example 9: 6-[(2-bromobenzyl)oxy]-1-hexanol

[0563] To a solution (12 mL) of the compound (1.1 g) prepared in Reference Example 8 in DCM was added formic acid (0.80 mL) at 20°C. The mixture was stirred at 20°C for 17 hours to give a colorless solution. The reaction mixture was poured into water and extracted with DCM. The organic phase was dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel flash column (PE-25% EtOAc / PE) to give the title compound (300 mg).

[0564] TLC: Rf 0.3 (PE / Et0Ac=3 / 1).

[0565] Reference Example 10: 6-{[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]oxy}-1-hexanol

[0566] 300 mg of the compound prepared in Reference Example 9 was dissolved in 4 mL of 1,4-dioxane, and 308 mg of KOAc, 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 at 80°C for 15 hours under a nitrogen atmosphere. The reaction mixture was filtered. The filtrate was poured into water and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated to give the title compound (300 mg).

[0567] LCMS retention time: 0.927 min (method A); MS(ESI, Pos.):m / z357.1[M+Na]+.

[0568] Reference Example 11: 6-{[2-(4,6-difluoro-2-pyridinyl)benzyl]oxy}-1-hexanol

[0569] 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) was added the compound prepared in Reference Example 10 (214 mg), K2CO3 (258 mg), and Pd(dppf)Cl2 (37.7 mg) at 20-25 °C. The reaction mixture was stirred at 80 °C for 4 hours to give a yellow suspension. The reaction mixture was filtered. The filtrate was poured into water and extracted with EtOAc. 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% EtOAc / PE) to give the title compound (190 mg).

[0570] TLC: Rf 0.3 (PE / Et0Ac=3 / 1).

[0571] Reference Example 12: 6-{[2-(4,6-difluoro-2-pyridinyl)benzyl]oxy}hexanal

[0572] To a solution of the compound prepared in Reference Example 11 (190 mg) in DCM (4 mL) was added DMP (377 mg) at 20°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched with saturated aqueous NaSO and extracted with DCM. The organic phase was dried over NaSO, filtered, and concentrated. The residue was purified by silica gel flash column (PE-10% EtOAc / PE) to give the title compound (60.0 mg).

[0573] TLC: Rf 0.50 (PE / EtOAc=3 / 1).

[0574] Example 70: (3S,4R,5R,6S)-1-(6-{[2-(4,6-difluoro-2-pyridinyl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol

[0575] To a solution of the compound prepared in Reference Example 12 (60 mg) in methanol (3 mL) were added (3S,4R,5R,6S)-azepane-3,4,5,6-tetrol hydrochloride (41 mg) and NaOAc (73 mg) at 20°C. The reaction mixture was stirred at 20°C for 0.5 hours to give a yellow solution. NaBHCN (35 mg) was then 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 give the title compound (34 mg).

[0576] LCMS retention time: 0.693 min (method A); MS(ESI, Pos.):m / z489.1(M+Na)+;

[0577] 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.

[0578] Reference Example 13: 1-[(4-ethoxy-3-fluorobenzyl)oxy]-6-[(triisopropylsilyl)oxy]-2-hexanol

[0579] To a solution of (3-ethoxy-4-fluorophenyl)methanol (CAS number: 1000207-64-6, 800 mg) in t-BuOH (5 mL) was added 15% NaOH (5 mL), triisopropyl[4-(2-oxiranyl)butoxy]silane (CAS number: 2734792-44-81, 41 g), and TBAI (758 mg) at 20-25 °C. The resulting mixture was purged with nitrogen gas three times and stirred at 90 °C for 15 h. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using a silica gel flash column (PE-15% EtOAc in PE) to give the title compound (660 mg).

[0580] TLC: Rf 0.40 (PE / EtOAc=5 / 1).

[0581] Reference Example 14: ({6-[(4-ethoxy-3-fluorobenzyl)oxy]-5-fluorohexyl}oxy)(triisopropyl)silane

[0582] To a solution (1 mL) of the compound prepared in Reference Example 13 (660 mg) in DCM was added DAST (0.26 mL) at 0° C. The mixture was stirred for 5 minutes. The mixture was quenched with saturated aqueous NaHCO3, washed with water, and extracted with DCM. The organic phase was concentrated and purified by silica gel flash column (PE-5% EtOAc, PE) to give the title compound (160 mg).

[0583] TLC: Rf 0.60 (PE / Et0Ac=10 / 1).

[0584] Reference Example 15: 6-[(4-ethoxy-3-fluorobenzyl)oxy]-5-fluoro-1-hexanol

[0585] To a solution of the compound prepared in Reference Example 14 (160 mg) in THF (2 mL) was added 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 give a yellow solution. The reaction was concentrated to dryness. The residue was directly purified using a silica gel flash column (PE-35% EtOAc, PE) to give the title compound (90 mg).

[0586] TLC: Rf 0.20 (PE / Et0Ac=2 / 1).

[0587] Reference Example 16: 6-[(4-ethoxy-3-fluorobenzyl)oxy]-5-fluorohexyl 4-methylbenzenesulfonate

[0588] To a solution of the compound prepared in Reference Example 15 (85 mg) in DCM (2 mL) was added 4-methylbenzenesulfonyl chloride (0.090 mL), TEA (0.12 mL), and DMAP (13 mg) 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 by silica gel flash column (PE-20% EtOAc, PE) to give the title compound (100 mg).

[0589] TLC: Rf 0.60 (PE / EtOAc=3 / 1).

[0590] Example 71: (3S,4R,5R,6S)-1-{(5R)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0591] Example 72: (3S,4R,5R,6S)-1-{(5S)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2) [ka]

[0592] To a solution of (3S,4R,5R,6S)-azepane-3,4,5,6-tetrol hydrochloride (68 mg) in DMSO (1.5 mL) was added DIEA (0.19 mL), KI (19 mg), and the compound prepared in Reference Example 16 (100 mg) 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 chiral SFC separation gave Isomer 1 (5.0 mg) and Isomer 2 (15 mg).

[0593] Example 71 (Isomer 1): LCMS retention time: 0.683 min (Method A); MS (ESI, Pos.): m / z 434.1 (M+H)+;

[0594] 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;

[0595] SFC retention time: 6.027 min (method A1).

[0596] Example 72 (Isomer 2): LCMS retention time: 0.688 min (Method A); MS (ESI, Pos.): m / z 434.1 (M+H)+;

[0597] 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;

[0598] SFC retention time: 6.254 min (method A1).

[0599] Examples 73-86:

[0600] Examples 73 to 86 were synthesized in the same manner as in Reference Examples 13, 14, 15, and 16, and Examples 71 and 72, using the corresponding alcohol compounds instead of (3-ethoxy-4-fluorophenyl)methanol.

[0601] Example 73: (3S,4R,5R,6S)-1-[(5R)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl]-3,4,5,6-azepantetrol (isomer 1)

[0602] LCMS retention time: 1.612 min (method B); MS (ESI, Pos.): m / z 473.1 (M+H)+;

[0603] 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;

[0604] SFC retention time: 4.734 min (method B8).

[0605] Example 74: (3S,4R,5R,6S)-1-[(5S)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl]-3,4,5,6-azepantetrol (isomer 2)

change

[0606] LCMS retention time: 1.62 minutes (Method B); MS(ESI, Pos.): m / z 473.1(M+H)+;

[0607] 1 H-NMR(CD3OD): δ8.05-7.95, 7.48, 7.27-7.19, 4.75-4.57, 4.72, 3.78-3.63, 3.45, 2.90, 2.80-2.50, 1.75-1.38;

[0608] SFC retention time: 3.393 minutes (Method B8).

[0609] Example 75: (3S,4R,5R,6S)-1-{5-fluoro-6-[(3,4,5-trifluorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 1)

[0610] LCMS retention time: 0.726 minutes (Method A); MS(ESI, Pos.): m / z 426.1(M+H)+;

[0611] 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;

[0612] SFC holding time: 1.826 minutes (method F4).

[0613] Example 76: (3S,4R,5R,6S)-1-{5-fluoro-6-[(3,4,5-trifluorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 2)

[0614] LCMS retention time: 0.741 minutes (Method A); MS(ESI, Pos.): m / z 426.1(M+H)+;

[0615] 1H-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;

[0616] SFC retention time: 1.965 minutes (Method F4).

[0617] Example 77: (3S,4R,5R,6S)-1-[6-(benzyloxy)-5-fluorohexyl]-3,4,5,6-azepantetrol (isomer 1)

[0618] LCMS retention time: 1.384 minutes (Method B); MS(ESI, Pos.): m / z 372.1(M+H)+;

[0619] 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;

[0620] SFC holding time: 6.251 minutes (Method B5).

[0621] Example 78: (3S,4R,5R,6S)-1-[6-(benzyloxy)-5-fluorohexyl]-3,4,5,6-azepantetrol (isomer 2)

[0622] LCMS retention time: 1.394 minutes (Method B); MS(ESI, Pos.): m / z 372.1(M+H)+;

[0623] 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;

[0624] SFC retention time: 6.795 minutes (Method B5).

[0625] Example 79: (3S,4R,5R,6S)-1-{5-fluoro-6-[(4-fluorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 1)

[0626] LCMS retention time: 1.448 minutes (Method B); MS(ESI, Pos.): m / z 390.1(M+H)+;

[0627] 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;

[0628] SFC retention time: 6.3 minutes (Method B4).

[0629] Example 80: (3S,4R,5R,6S)-1-{5-fluoro-6-[(4-fluorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 2)

[0630] LCMS retention time: 0.666 minutes (Method A); MS(ESI, Pos.): m / z 390(M+H)+;

[0631] 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;

[0632] SFC retention time: 6.799 minutes (Method B4).

[0633] Example 81: (3S,4R,5R,6S)-1-{6-[(2-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0634] LCMS retention time: 0.696 minutes (Method A); MS(ESI, Pos.): m / z 406.1(M+H)+;

[0635] 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;

[0636] SFC holding time: 4.572 minutes (Method G1).

[0637] Example 82: (3S,4R,5R,6S)-1-{6-[(2-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2)

[0638] LCMS retention time: 0.694 minutes (Method A); MS(ESI, Pos.): m / z406(M+H)+;

[0639] 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;

[0640] SFC retention time: 4.809 minutes (Method G1).

[0641] Example 83: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(1-propyn-1-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol (isomer 1)

[0642] LCMS retention time: 0.687 minutes (Method A); MS(ESI, Pos.): m / z 410.1(M+H)+;

[0643] 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;

[0644] SFC retention time: 4.628 minutes (Method G1).

[0645] Example 84: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(1-propyn-1-yl)benzyl]oxy}hexyl)-3,4,5,6-azepantetrol (isomer 2)

[0646] LCMS retention time: 0.693 minutes (Method A); MS(ESI, Pos.): m / z 410.1(M+H)+;

[0647] 1H-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;

[0648] SFC holding time: 4.865 minutes (Method G1).

[0649] Example 85: (3S,4R,5R,6S)-1-{6-[(2-chloro-4-methylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0650] LCMS retention time: 0.707 minutes (Method A); MS(ESI, Pos.): m / z 420.1(M+H)+;

[0651] 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;

[0652] SFC holding time: 1.855 minutes (Method G2).

[0653] Example 86: (3S,4R,5R,6S)-1-{6-[(2-chloro-4-methylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2)

[0654] LCMS retention time: 0.703 minutes (Method A); MS(ESI, Pos.): m / z 420.1(M+H)+;

[0655] 1 H-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;

[0656] SFC holding time: 2.103 minutes (Method G2).

[0657] Examples 87-98:

[0658] Examples 87 to 98 were synthesized in the same manner as in Reference Examples 13, 14, 15, and 16 and Example 69, using the corresponding alcohol compounds instead of (3-ethoxy-4-fluorophenyl)methanol.

[0659] Example 87: (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepantetrol (mixture of two isomers)

[0660] LCMS retention time: 0.711 min (method A); MS (ESI, Pos.): m / z 491.1 (M+H)+;

[0661] 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;

[0662] SFC retention time: 3.525 / 3.851 min (method B1).

[0663] Example 88: (3S,4R,5R,6S)-1-{6-[(3',5'-difluoro-2-biphenylyl)methoxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (mixture of two isomers)

[0664] LCMS retention time: 1.802 min (method B); MS (ESI, Pos.): m / z 484.4 (M+H)+;

[0665] 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;

[0666] SFC retention time: 2.082 / 2.139 min (method E1).

[0667] Example 89: (3S,4R,5R,6S)-1-(6-{[2-(3-chloro-5-fluorophenyl)-1,3-thiazol-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepantetrol (mixture of two isomers)

[0668] LCMS retention time: 1.793 min (method B); MS(ESI, Pos.): m / z 507.4(M+H)+;

[0669] 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.

[0670] Example 90: (3S,4R,5R,6S)-1-(6-{[2-(3-chloro-5-methoxyphenyl)-1,3-thiazol-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepantetrol (mixture of two isomers)

[0671] LCMS retention time: 1.779 minutes (Method B); MS(ESI, Pos.): m / z 519.4(M+H)+;

[0672] 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.

[0673] Example 91: (3S,4R,5R,6S)-1-{5-fluoro-6-[(3'-fluoro-2-biphenylyl)methoxy]hexyl}-3,4,5,6-azepantetrol hydrochloride (1:1) (mixture of two isomers)

[0674] LCMS retention time: 0.735 minutes (Method A); MS(ESI, Pos.): m / z 466.2(M+H)+;

[0675] 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;

[0676] SFC retention time: 2.298 / 2.342 minutes (Method E1).

[0677] Example 92: (3S,4R,5R,6S)-1-{6-[(3',4'-difluoro-2-biphenylyl)methoxy]-5-fluorohexyl}-3,4,5,6-azepantetrole (mixture of two isomers)

[0678] LCMS retention time: 0.743 minutes (Method A); MS(ESI, Pos.): m / z 484.1(M+H)+;

[0679] 1 H-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;

[0680] SFC retention time: 2.275 / 2.393 minutes (Method E1).

[0681] Example 93: (3S,4R,5R,6S)-1-{5-fluoro-6-[(4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (mixture of two isomers)

[0682] LCMS retention time: 1.789 minutes (Method B); MS(ESI, Pos.): m / z 414.2(M+H)+;

[0683] 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.

[0684] Example 94: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(3,4,5-trifluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrole (mixture of two isomers)

[0685] LCMS retention time: 0.718 minutes (Method A); MS(ESI, Pos.):m / z531.1(M+Na)(M+H)+;

[0686] 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;

[0687] SFC retention time: 3.254 / 3.307 minutes (Method J1).

[0688] Example 95: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(2,3,4-trifluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol (mixture of two isomers)

[0689] LCMS retention time: 0.734 minutes (Method A); MS(ESI, Pos.):m / z531.1(M+Na)(M+H)+;

[0690] 1 H-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;

[0691] SFC holding time: 2.657 / 2.747 minutes (Method E1).

[0692] Example 96: (3S,4R,5R,6S)-1-(6-{[5-(3,5-difluorophenyl)-1,2-oxazol-3-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepantetrol (mixture of two isomers)

[0693] LCMS retention time: 0.799 minutes (Method A); MS(ESI, Pos.): m / z 475.2(M+H)+;

[0694] 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.

[0695] Example 97: (3S,4R,5R,6S)-1-{5-fluoro-6-[(5-methyl-2-propyl-1,3-thiazol-4-yl)methoxy]hexyl}-3,4,5,6-azepantetrol (mixture of two isomers)

[0696] LCMS retention time: 1.531 minutes (Method B); MS(ESI, Pos.): m / z 435.2(M+H)+;

[0697] 1H-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;

[0698] SFC retention time: 3.529 / 3.618 min (method D1).

[0699] Example 98: (3S,4R,5R,6S)-1-{5-fluoro-6-[(4-isopropylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (mixture of two isomers)

[0700] LCMS retention time: 1.811 min (method B); MS (ESI, Pos.): m / z 414.2 (M+H)+;

[0701] 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;

[0702] SFC retention time: 4.438 / 4.795 min (method B2).

[0703] Reference Example 17: 2-Fluoro-6-[(triisopropylsilyl)oxy]hexanal

[0704] A solution of NFSI (90 g), DL-proline (33 g), THF (560 mL), and IPA (70 mL) was stirred at 20°C for 15 minutes. Then, a THF solution (100 mL) of 6-[(triisopropylsilyl)oxy]hexanal (CAS number: 245124-09-8, 78 g) was added. The mixture was stirred at 20°C for 16 hours. MTBE was added to the reaction mixture. After stirring at -78°C for 30 minutes, the mixture was filtered. The filtrate was washed with saturated aqueous NaHCO3 and saturated brine, dried over Na2SO4, and concentrated to give the title compound (78 g). The title compound was used in the next step without further purification.

[0705] Reference Example 18: 2-Fluoro-6-[(triisopropylsilyl)oxy]-1-hexanol

[0706] To a solution of the compound (39 g) prepared in Reference Example 17 in DCM (400 mL) and EtOH (400 mL) was added NaBH (28 g) at 0° C. The mixture was stirred at 0° C. for 0.5 hours. The reaction mixture was quenched with saturated aqueous NH Cl (500 mL) at 0° C. The mixture was vigorously stirred for 0.5 hours. The mixture was extracted with DCM and washed with saturated aqueous NaHCO (20 mL). The organic phase was concentrated to give the crude product. Two batches of the crude product were combined and purified by silica gel column chromatography (EtOAc / PE=0-4%) to give the title compound (30 g).

[0707] 1 H-NMR (CD3OD): δ4.58-4.38, 3.77-3.65, 1.84-1.62, 1.56-1.33, 109-1.04.

[0708] Reference Example 19: Methyl 5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole-4-carboxylate

[0709] The title compound was synthesized in the same manner as in Reference Example 11 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) and used in the next step without purification.

[0710] Reference Example 20: [5-(3,5-difluorophenyl)-2-methyl-1,3-oxazol-4-yl]methanol

[0711] To a solution of the compound (5.00 g) prepared in Reference Example 19 in THF (200 mL) was added a 3.5 M Red-Al toluene solution (7 mL) at 0°C. The mixture was stirred at 0°C for 15 minutes. 1 M hydrochloric acid was added to quench the reaction, and the mixture was stirred for 10 minutes. After washing with water, the mixture was extracted with EtOAc. The aqueous phase was washed with saturated brine and extracted with EtOAc. The organic phase was dried over Na2SO4. The crude product (5.00 g x 6 batches) was purified by silica gel column chromatography (PE-28% EtOAc / PE) to give the title compound (14.5 g).

[0712] TLC: Rf 0.40 (PE / EtOAc=1 / 1)

[0713] Reference Example 21: 4-(bromomethyl)-5-(3,5-difluorophenyl)-2-methyl-1,3-oxazole

[0714] The compound (12 g) prepared in Reference Example 20 was mixed with DCM (150 mL) and dissolved by heating. After cooling, DIEA (19 mL) and LiBr (14 g) were added at 0°C. The mixture was stirred at 0°C for 10 minutes. Then, MsO (12 g) 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 over NaSO and concentrated under reduced pressure. The residue was purified using a silica gel column (PE-10% EtOAc, PE) to obtain the title compound (12 g).

[0715] TLC: Rf 0.70 (PE / Et0Ac=3 / 1).

[0716] Reference Example 22: 5-(3,5-difluorophenyl)-4-[({2-fluoro-6-[(triisopropylsilyl)oxy]hexyl}oxy)methyl]-2-methyl-1,3-oxazole

[0717] To a solution of the compound (17 g) prepared in Reference Example 18 in THF (300 mL) was added NaH (4.7 g, 60% in oil) at 0°C. The mixture was stirred at 0°C for 30 minutes. The compound (17 g) prepared in Reference Example 21 was added, and the mixture was stirred at 0°C for 16 hours. After washing with water, the mixture was extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using a silica column (PE-5% EtOAc, PE) to give the title compound (22 g).

[0718] TLC: Rf 0.8 (PE / EtOAc=3 / 1)

[0719] Example 99: (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-azepantetrol (isomer 1)

[0720] Example 100: (3S,4R,5R,6S)-1-[(5S)-6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazol-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrol (isomer 2) [ka]

[0721] The title compound was synthesized in the same manner as in Reference Examples 15 and 16 and Examples 71 and 72, except that the compound prepared in Reference Example 22 was used instead of the compound prepared in Reference Example 14. Example 99 (Isomer 1): LCMS retention time: 0.681 min (Method A);

[0722] MS (ESI, Pos.): m / z 489.1 (M+H)+;

[0723] 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;

[0724] SFC retention time: 3.312 min (method A2).

[0725] Example 100 (Isomer 2): LCMS retention time: 0.688 min (Method A); MS (ESI, Pos.): m / z 489.1 (M+H)+;

[0726] 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;

[0727] SFC retention time: 4.893 min (method A2).

[0728] Reference Example 23: 1-[(4-ethylbenzyl)oxy]-6-[(triisopropylsilyl)oxy]-2-hexanol

[0729] To a solution of (4-ethylphenyl)methanol (CAS number: 768-59-2, 66 g) and triisopropyl(4-(oxiran-2-yl)butoxy)silane (158 g) in t-BuOH (150 mL) was added TBAI (31 g) and 15% NaOH (150 mL) at 20 °C. The reaction was stirred at 80 °C for 16 h. The mixture was extracted with EtOAc and washed with saturated brine. The organic phase was concentrated and purified by silica gel flash column chromatography (0-3% EtOAc in PE) to give the title compound (34 g).

[0730] 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.

[0731] Reference Example 24: 6-[(4-ethylbenzyl)oxy]-1,5-hexanediol

[0732] To a solution of the compound (60 g) prepared in Reference Example 23 in THF (400 mL) was added TBAF (152 mL) at 20°C. The reaction was stirred at 20°C for 15 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with saturated brine, dried over Na2SO4, filtered, and concentrated. The residue was purified using a silica gel flash column (Et0Ac in PE = 55-65%) to give the title compound (30 g).

[0733] 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.

[0734] Reference Example 25: 6-[(4-ethylbenzyl)oxy]-5-hydroxyhexyl 4-methylbenzenesulfonate

[0735] To a DCM solution (400 mL) of the compound prepared in Reference Example 24, 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 combined organic phase was dried over NaSO and concentrated under reduced pressure. The residue was purified by silica column chromatography (PE-35% EtOAc / PE) to give the title compound (33 g).

[0736] 1 H-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.

[0737] Reference Example 26: 6-[(4-ethylbenzyl)oxy]-5-fluorohexyl 4-methylbenzenesulfonate

[0738] To a solution of the compound (39 g) prepared in Reference Example 25 in THF (400 mL) was added PBSF (33 mL), a solution of hydrogen fluoride in triethylamine (31 mL), and a solution of TEA (80 mL) at 0°C. The reaction was stirred for 16 hours. The reaction solution was poured into water and extracted with EtOAc. The organic phase was dried over Na2SO4 and then concentrated. The residue was purified using a silica gel flash column (PE-4% EtOAc / PE) to give the title compound (12 g).

[0739] 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.

[0740] Example 101: (3S,4R,5R,6S)-1-{(5S)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0741] Example 102: (3S,4R,5R,6S)-1-{(5R)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2) [ka]

[0742] The compound (16 g) prepared in Reference Example 26 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 NaHCO and then extracted with EtOAc. The organic phase was washed with water. The organic phase was dried over NaSO and concentrated under reduced pressure to give the crude title compound (14 g). Two batches of the crude product (36 g) were purified by SFC to give Isomer 1 (14 g) and Isomer 2 (14 g).

[0743] Example 101 (Isomer 1): LCMS retention time: 0.697 min (Method A); MS (ESI, Pos.): m / z 400.1 (M+H)+;

[0744] 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;

[0745] SFC retention time: 2.827 minutes (Method B6).

[0746] Example 102 (Isomer 2): LCMS retention time: 0.691 min (Method A); MS (ESI, Pos.): m / z 400.1 (M+H)+;

[0747] 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;

[0748] SFC retention time: 3.852 min (method B6).

[0749] Examples 103-134:

[0750] Examples 103 to 134 were synthesized in the same manner as in Reference Examples 23, 24, 25, and 26, and Examples 71 and 72, using the corresponding alcohol compounds instead of (4-ethylphenyl)methanol.

[0751] Example 103: (3S,4R,5R,6S)-1-[(5R)-5-fluoro-6-{[2-(3-methoxyphenyl)-1,3-thiazol-4-yl]methoxy}hexyl]-3,4,5,6-azepantetrol (isomer 1)

[0752] LCMS retention time: 0.715 min (method A); MS (ESI, Pos.): m / z 485.1 (M+H)+;

[0753] 1H-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;

[0754] SFC holding time: 5.341 minutes (Method B7).

[0755] Example 104: (3S,4R,5R,6S)-1-[(5S)-5-fluoro-6-{[2-(3-methoxyphenyl)-1,3-thiazol-4-yl]methoxy}hexyl]-3,4,5,6-azepantetrol (isomer 2)

[0756] LCMS retention time: 0.711 minutes (Method A); MS(ESI, Pos.): m / z 485.1(M+H)+;

[0757] 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;

[0758] SFC retention time: 6.714 minutes (Method B7).

[0759] Example 105: (3S,4R,5R,6S)-1-(6-{[2-(3,4-difluorophenyl)-1,3-thiazol-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepantetrol (isomer 1)

[0760] LCMS retention time: 1.665 minutes (Method B); MS(ESI, Pos.): m / z 491.1(M+H)+;

[0761] 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;

[0762] SFC retention time: 2.95 minutes (Method E1).

[0763] Example 106: (3S,4R,5R,6S)-1-(6-{[2-(3,4-difluorophenyl)-1,3-thiazol-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepantetrol (isomer 2)

[0764] LCMS retention time: 1.658 minutes (Method B); MS(ESI, Pos.): m / z 491.1(M+H)+;

[0765] 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;

[0766] SFC retention time: 2.858 minutes (Method E1).

[0767] Example 107: (3S,4R,5R,6S)-1-{(5S)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

change

[0768] LCMS retention time: 0.694 minutes (Method A); MS(ESI, Pos.): m / z 406.1(M+H)+;

[0769] 1 H-NMR(CDCl3): δ7.36-7.29, 4.78-4.60, 4.55, 3.71, 3.63-3.51, 2.91, 2.69-2.53, 1.59-1.27;

[0770] SFC retention time: 2.686 minutes (Method F4).

[0771] Example 108: (3S,4R,5R,6S)-1-{(5R)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2)

[0772] LCMS retention time: 0.696 minutes (Method A); MS(ESI, Pos.): m / z 406.1(M+H)+;

[0773] 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;

[0774] SFC retention time: 2.973 minutes (Method F4).

[0775] Example 109: (3S,4R,5R,6S)-1-{6-[(3,4-difluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0776] LCMS retention time: 0.676 minutes (Method A); MS(ESI, Pos.):m / z430.1(M+Na)+;

[0777] 1 H-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;

[0778] SFC retention time: 2.01 minutes (Method F4).

[0779] Example 110: (3S,4R,5R,6S)-1-{6-[(3,4-difluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2)

[0780] LCMS retention time: 0.672 minutes (Method A); MS (ESI, Pos.): m / z 430(M+Na)+;

[0781] 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;

[0782] SFC retention time: 2.15 minutes (Method F4).

[0783] Example 111: (3S,4R,5R,6S)-1-{6-[(3-ethoxybenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0784] LCMS retention time: 1.536 minutes (Method B); MS(ESI, Pos.): m / z 416.2(M+H)+;

[0785] 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;

[0786] SFC holding time: 4.762 minutes (Method G1).

[0787] Example 112: (3S,4R,5R,6S)-1-{6-[(3-ethoxybenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2)

[0788] LCMS retention time: 1.534 minutes (Method B); MS(ESI, Pos.): m / z 416.1(M+H)+;

[0789] 1 H-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;

[0790] SFC retention time: 4.577 minutes (Method G1).

[0791] Example 113: (3S,4R,5R,6S)-1-{6-[(2,4-difluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0792] LCMS retention time: 1.461 minutes (Method B); MS(ESI, Pos.): m / z 408.1(M+H)+;

[0793] 1H-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;

[0794] SFC retention time: 4.784 minutes (method F5).

[0795] Example 114: (3S,4R,5R,6S)-1-{6-[(2,4-difluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2)

[0796] LCMS retention time: 1.47 minutes (Method B); MS(ESI, Pos.): m / z 408.1(M+H)+;

[0797] 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;

[0798] SFC retention time: 5.027 minutes (method F5).

[0799] Example 115: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 1)

[0800] LCMS retention time: 0.719 minutes (Method A); MS(ESI, Pos.): m / z 414.1(M+H)+;

[0801] 1 H-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;

[0802] SFC retention time: 2.744 minutes (Method E1).

[0803] Example 116: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 2)

[0804] LCMS retention time: 0.721 minutes (Method A); MS(ESI, Pos.): m / z 414.1(M+H)+;

[0805] 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;

[0806] SFC retention time: 2.997 minutes (Method E1).

[0807] Example 117: (3S,4R,5R,6S)-1-{6-[(4-ethyl-2-methylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0808] LCMS retention time: 0.725 minutes (Method A); MS(ESI, Pos.): m / z 414.1(M+H)+;

[0809] 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;

[0810] SFC retention time: 5.967 minutes (Method B4).

[0811] Example 118: (3S,4R,5R,6S)-1-{6-[(4-ethyl-2-methylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2)

[0812] LCMS retention time: 0.73 minutes (Method A); MS(ESI, Pos.): m / z 414.1(M+H)+;

[0813] 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;

[0814] SFC retention time: 6.48 minutes (Method B4).

[0815] Example 119: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(4-methylphenyl)-1,3-oxazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol (isomer 1)

[0816] LCMS retention time: 0.702 minutes (Method A); MS(ESI, Pos.):m / z475.2(M+Na)+;

[0817] 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;

[0818] SFC retention time: 4.729 minutes (Method F1).

[0819] Example 120: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(4-methylphenyl)-1,3-oxazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol (isomer 2)

[0820] LCMS retention time: 0.697 minutes (Method A); MS(ESI, Pos.):m / z475.1(M+Na)+;

[0821] 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;

[0822] SFC holding time: 6.14 minutes (Method F1).

[0823] Example 121: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol (isomer 1)

[0824] LCMS retention time: 0.677 minutes (Method A); MS(ESI, Pos.): m / z 457.1(M+H)+;

[0825] 1 H-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;

[0826] SFC retention time: 5.91 minutes (Method F3).

[0827] Example 122: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(4-fluorophenyl)-1,3-oxazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol (isomer 2)

[0828] LCMS retention time: 0.689 minutes (Method A); MS(ESI, Pos.): m / z 457.1(M+H)+;

[0829] 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;

[0830] SFC retention time: 6.763 minutes (Method F3).

[0831] Example 123: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(3-fluorophenyl)-1,3-oxazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol (isomer 1)

[0832] LCMS retention time: 0.689 minutes (Method A); MS(ESI, Pos.): m / z 457.1(M+H)+;

[0833] 1H-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;

[0834] SFC retention time: 1.704 minutes (Method F2).

[0835] Example 124: (3S,4R,5R,6S)-1-(5-fluoro-6-{[2-(3-fluorophenyl)-1,3-oxazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol (isomer 2)

[0836] LCMS retention time: 0.687 minutes (Method A); MS(ESI, Pos.): m / z 457.1(M+H)+;

[0837] 1 H-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;

[0838] SFC retention time: 2.442 minutes (Method F2).

[0839] Example 125: (3S,4R,5R,6S)-1-{6-[(4-butylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0840] LCMS retention time: 0.757 minutes (Method A); MS(ESI, Pos.): m / z 428.2(M+H)+;

[0841] 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;

[0842] SFC retention time: 0.8 minutes (Method B7).

[0843] Example 126: (3S,4R,5R,6S)-1-{6-[(4-butylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2)

[0844] LCMS retention time: 4.203 minutes (Method C); MS(ESI, Pos.): m / z 428.2(M+H)+;

[0845] 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;

[0846] SFC retention time: 1.292 minutes (Method B7).

[0847] Example 127: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-fluoro-4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 1)

[0848] LCMS retention time: 1.8 minutes (Method B); MS(ESI, Pos.): m / z 432.2(M+H)+;

[0849] 1 H-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;

[0850] SFC retention time: 3.093 minutes (Method A3).

[0851] Example 128: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-fluoro-4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 2)

[0852] LCMS retention time: 1.793 minutes (Method B); MS(ESI, Pos.): m / z 432.1(M+H)+;

[0853] 1H-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;

[0854] SFC retention time: 3.485 minutes (Method A3).

[0855] Example 129: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-methyl-4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 1)

[0856] LCMS retention time: 0.755 minutes (Method A); MS(ESI, Pos.): m / z 428.2(M+H)+;

[0857] 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;

[0858] SFC retention time: 5.982 minutes (Method B4).

[0859] Example 130: (3S,4R,5R,6S)-1-{5-fluoro-6-[(2-methyl-4-propylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 2)

[0860] LCMS retention time: 0.75 minutes (Method A); MS(ESI, Pos.): m / z 428.1(M+H)+;

[0861] 1 H-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;

[0862] SFC retention time: 6.677 minutes (Method B4).

[0863] Example 131: (3S,4R,5R,6S)-1-{6-[(2,6-difluoro-4-propylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0864] LCMS retention time: 0.749 minutes (Method A); MS(ESI, Pos.): m / z 450.1(M+H)+;

[0865] 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;

[0866] SFC retention time: 6.545 minutes (Method A3).

[0867] Example 132: (3S,4R,5R,6S)-1-{6-[(2,6-difluoro-4-propylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2)

[0868] LCMS retention time: 0.753 minutes (Method A); MS(ESI, Pos.): m / z 450.1(M+H)+;

[0869] 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;

[0870] SFC retention time: 6.945 minutes (Method A3).

[0871] Example 133: (3S,4R,5R,6S)-1-{6-[(2,4-dimethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 1)

[0872] LCMS retention time: 1.601 minutes (Method B); MS(ESI, Pos.): m / z 400.2(M+H)+;

[0873] 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;

[0874] SFC retention time: 4.069 min (Method H1).

[0875] Example 134: (3S,4R,5R,6S)-1-{6-[(2,4-dimethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol (isomer 2)

[0876] LCMS retention time: 1.597 min (method B); MS (ESI, Pos.): m / z 400.2 (M+H)+;

[0877] 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;

[0878] SFC retention time: 4.58 min (Method H1).

[0879] Reference Example 27: 1-[(4-methylbenzyl)oxy]-6-[(triisopropylsilyl)oxy]-2-hexanol

[0880] To a solution of (4-methylphenyl)methanol (50 g) in t-BuOH (250 mL) was added 15% NaOH aq (250 mL), triisopropyl(4-(oxiran-2-yl)butoxy)silane (123 g), and TBAI (66 g) at 20 °C. The reaction was stirred at 90 °C for 15 h. The mixture was poured into water and extracted with EtOAc. The organic phase was concentrated and purified by silica gel flash column (PE-5% EtOAc / PE) to give the title compound (79.5 g).

[0881] TLC: Rf 0.40 (PE / EtOAc=5 / 1).

[0882] Reference Example 28: 6-[(4-methylbenzyl)oxy]-1,5-hexanediol

[0883] To a solution of the compound prepared in Reference Example 27 (79.5 g) in THF (250 mL) was added a solution of 1 M TBAF in THF (292 mL) at 20° C. The reaction was stirred at 20° C. for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel flash column (PE-35% EtOAc / PE) to give the title compound (44.7 g).

[0884] TLC: Rf 0.20 (PE / Et0Ac=2 / 1).

[0885] Reference Example 29: 5-Hydroxy-6-[(4-methylbenzyl)oxy]hexyl 4-methylbenzenesulfonate

[0886] To a solution (400 mL) of the compound (44.7 g) prepared in Reference Example 28 in DCM, 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 by silica gel flash column chromatography (PE-20% EtOAc / PE) to give the title compound (45.4 g).

[0887] TLC: Rf 0.60 (PE / EtOAc=3 / 1).

[0888] Reference Example 30: 5-Fluoro-6-[(4-methylbenzyl)oxy]hexyl 4-methylbenzenesulfonate

[0889] To a solution of the compound (45.4 g) prepared in Reference Example 29 in THF (450 mL) was added PBSF (39.9 mL), a solution of hydrogen fluoride in triethylamine (37.7 mL), and TEA (53.1 mL) at 0°C. The reaction was stirred at 20°C for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was dried over NaSO and concentrated. The residue was purified using a silica gel flash column (PE-4% EtOAc / PE) to give the title compound (22.7 g).

[0890] TLC: Rf 0.50 (PE / Et0Ac=5 / 1).

[0891] Example 135: (3S,4R,5R,6S)-1-{(5S)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 1) [ka]

[0892] Example 136: (3S,4R,5R,6S)-1-{(5R)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol (isomer 2)

[0893] To a solution of (3S,4R,5R,6S)-azepane-3,4,5,6-tetrol hydrochloride (700 mg) in DMF (5 mL), DIEA (5.5 mL), KI (53 mg), and the compound prepared in Reference Example 30 (1.25 g) were added at 20-25°C, and the solvent was removed under reduced pressure. The reaction mixture was stirred at 80°C for 16 hours. The mixture was treated with saturated aqueous NaHCO3 and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The residue was purified using a C18 reverse-phase column (10-30% aqueous MeCN) and chiral SFC separation to give Isomer 1 (403 mg) and Isomer 2 (358 mg).

[0894] Example 135 (Isomer 1): LCMS retention time: 1.514 min (Method B); MS (ESI, Pos.): m / z 386.1 (M+H)+;

[0895] 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;

[0896] SFC retention time: 3.123 min (Method B3).

[0897] Example 136 (Isomer 2): LCMS retention time: 1.495 min (Method B); MS (ESI, Pos.): m / z 386.2 (M+H)+;

[0898] 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;

[0899] SFC retention time: 3.884 min (method B3).

[0900] Reference Example 31: Methyl 2-(3,5-difluorophenyl)-1,3-oxazole-4-carboxylate

[0901] To a solution of methyl 2-amino-3-hydroxypropanoate (CAS number: 5680-80-8, 500 mg) and 3,5-difluorobenzaldehyde (CAS number: 32085-88-4, 460 mg) in DMA (10 mL) was added KCO (888 mg) and stirred at 25 °C for 16 hours. BrCCl (1.9 g) and DBU (1.4 mL) were added at 0 °C and stirred at 25 °C for 16 hours. The mixture was purified by silica gel flash column (Et0Ac in PE = 0-40%) to give the title compound (390 mg).

[0902] TLC: Rf 0.50 (Et0Ac / PE=1 / 3).

[0903] Reference Example 32: [2-(3,5-difluorophenyl)-1,3-oxazol-4-yl]methanol

[0904] LiAlH (20 mg) was added to a solution of the compound prepared in Reference Example 31 (100 mg) in THF (3 mL) at 0°C, and the mixture was stirred at 0°C for 3 hours to give a yellow solution. The reaction mixture was quenched with water, 15% NaOH aq, and water. The mixture was dried over NaSO and filtered. The filtrate was concentrated and purified using a silica gel flash column (Et0Ac in PE = 0-50%) to give the title compound (74 mg).

[0905] TLC: Rf 0.30 (Et0Ac / PE=1 / 3).

[0906] Examples 137 and 138:

[0907] Examples 137 and 138 were synthesized in the same manner as in Reference Examples 23, 24, 25, and 26 and Examples 71 and 72, except that the corresponding alcohol prepared in Reference Example 32 was used instead of (4-ethylphenyl)methanol.

[0908] Example 137: (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-oxazol-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepantetrol (isomer 1)

[0909] LCMS retention time: 0.778 minutes (Method A); MS(ESI, Pos.): m / z 475.2(M+H)+;

[0910] 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;

[0911] SFC retention time: 2.37 minutes (Method F2).

[0912] Example 138: (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-oxazol-4-yl]methoxy}-5-fluorohexyl)-3,4,5,6-azepantetrol (isomer 2)

[0913] LCMS retention time: 0.781 minutes (Method A); MS(ESI, Pos.): m / z 475.2(M+H)+;

[0914] 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;

[0915] SFC retention time: 3.083 minutes (Method F2).

[0916] Reference Example 33: Methyl 6-(3,5-difluorophenyl)-3-pyridazinecarboxylate

[0917] To a solution of methyl 6-chloro-3-pyridazinecarboxylate (CAS number: 65202-50-8, 25 g) and (3,5-difluorophenyl)boronic acid (32 g) in DMF (250 mL) was added KPO (40 g) and Pd(dppf)Cl (1.1 g) under a nitrogen atmosphere. The mixture was stirred at 70 °C under a nitrogen atmosphere for 12 hours. The mixture was cooled to 20 °C, poured into water, and filtered. The collected solid was washed with water. The filtrate was treated with MeOH and dried under reduced pressure to give the title compound (10 g). This was used in the next step without further purification.

[0918] Reference Example 34: [6-(3,5-difluorophenyl)-3-pyridazinyl]methanol

[0919] To a solution of the compound prepared in Reference Example 33 (4.2 g) in THF (80 mL) were added CaCl (1.9 g) and NaBH (0.95 g) at 0°C. After stirring at 10°C for 0.5 hours, MeOH (4 mL) was added dropwise at 0°C. Stirring at 10°C for 2 hours gave a yellow solution. The reaction mixture was acidified with 1 M HCl and adjusted to pH 8. Water and EtOAc were added. The mixture was filtered. The filtrate was extracted with EtOAc. The organic phase was washed with saturated brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified using a silica gel flash column (0%-40% EtOAc in PE) to give the title compound (2.3 g).

[0920] TLC: Rf 0.10 (PE / Et0Ac=2 / 1).

[0921] Examples 139 and 140:

[0922] Examples 139 and 140 were synthesized in the same manner as in Reference Examples 23, 24, 25, and 26 and Examples 71 and 72, except that the corresponding alcohol prepared in Reference Example 34 was used instead of (4-ethylphenyl)methanol.

[0923] Example 139: (3S,4R,5R,6S)-1-[(5S)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrol (isomer 1) [ka]

[0924] LCMS retention time: 0.658 minutes (Method A); MS(ESI, Pos.): m / z 486.1(M+H)+;

[0925] 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;

[0926] SFC retention time: 1.838 minutes (method F6).

[0927] Example 140: (3S,4R,5R,6S)-1-[(5R)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrol (isomer 2)

[0928] LCMS retention time: 0.662 minutes (Method A); MS(ESI, Pos.): m / z 486.1(M+H)+;

[0929] 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;

[0930] SFC retention time: 3.359 minutes (method F6).

[0931] Reference Example 35: (3E)-6-(4-biphenylylmethoxy)-3-hexen-1-ol

[0932] To a solution of 4-(bromomethyl)-1,1'-biphenyl (CAS no.: 2567-29-5, 250 mg) in THF (3 mL) and HO (0.6 mL), TBAB (33 mg) was added and stirred. Aqueous sodium hydroxide (0.28 mL) and (E)-hex-3-ene-16-diol (CAS no.: 71655-17-9, 141 mg) were added at 20-25 °C and stirred at 60 °C for 15 h to give a yellow solution. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was dried over NaSO, filtered, and concentrated to dryness. The residue was purified using a silica gel flash column (PE-15% EtOAc / PE) to give the title compound (130 mg).

[0933] 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.

[0934] Example 141: (3S,4R,5R,6S)-1-[(3E)-6-(4-biphenylylmethoxy)-3-hexen-1-yl]-3,4,5,6-azepantetrol

[0935] Example 141 was synthesized in the same manner as in Reference Example 7 and Example 69, except that the corresponding alcohol prepared in Reference Example 35 was used instead of the compound prepared in Reference Example 6.

[0936] LCMS retention time: 0.725 min (method A); MS (ESI, Pos.): m / z 428.1 (M+H)+;

[0937] 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.

[0938] Examples 142-146:

[0939] Examples 142 to 146 were synthesized in the same manner as in Reference Example 7 and Example 69, except that the corresponding alcohol was used instead of the compound prepared in Reference Example 6.

[0940] Example 142: (3S,4R,5R,6S)-1-[(3E)-6-{[2-(2,3,4-trifluorophenyl)-1,3-thiazol-4-yl]methoxy}-3-hexen-1-yl]-3,4,5,6-azepantetrol

[0941] LCMS retention time: 1.705 min (method B); MS (ESI, Pos.): m / z 489.1 (M+H)+;

[0942] 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.

[0943] Example 143: (3S,4R,5R,6S)-1-{(3E)-6-[(4-propylbenzyl)oxy]-3-hexen-1-yl}-3,4,5,6-azepantetrol

[0944] LCMS retention time: 1.784 min (method B); MS (ESI, Pos.): m / z 394.4 (M+H)+;

[0945] 1 H-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.

[0946] Example 144: (3S,4R,5R,6S)-1-[(3E)-6-{[2-(3,4-difluorophenyl)-1,3-thiazol-4-yl]methoxy}-3-hexen-1-yl]-3,4,5,6-azepantetrol

[0947] LCMS retention time: 1.663 min (method B); MS (ESI, Pos.): m / z 471.1 (M+H)+;

[0948] 1H-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.

[0949] Example 145: (3S,4R,5R,6S)-1-[(3E)-6-{[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}-3-hexen-1-yl]-3,4,5,6-azepantetrol

[0950] LCMS retention time: 1.671 minutes (Method B); MS(ESI, Pos.): m / z 471.2(M+H)+;

[0951] 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.

[0952] Example 146: (3S,4R,5R,6S)-1-[(3E)-6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}-3-hexen-1-yl]-3,4,5,6-azepantetrol

[0953] LCMS retention time: 0.68 minutes (Method A); MS(ESI, Pos.): m / z 453.1(M+H)+;

[0954] 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.

[0955] Reference Example 36: 6-{[2-(2-bromo-1,3-thiazol-4-yl)-2-propanyl]oxy}-1-hexanol

[0956] To a DCM solution (3 mL) of 2-(2-bromo-1,3-thiazol-4-yl)-2-propanol (CAS number: 2228788-36-9, 180 mg) was added TsOH (167 mg) and 1,6-hexanediol (0.44 mL). The mixture was stirred at 50° C. for 16 hours. The reaction mixture was purified by silica gel column chromatography (PE-18% EtOAc / PE) to give the title compound (48 mg).

[0957] TLC: Rf 0.2 (PE / Et0Ac=3 / 1).

[0958] Reference Example 37: 6-({2-[2-(1-propyn-1-yl)-1,3-thiazol-4-yl]-2-propanyl}oxy)-1-hexanol

[0959] To a solution of the compound prepared in Reference Example 36 (48 mg) in THF (1 mL) was added TEA (0.041 mL), 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 EtOAc (10 mL) and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (PE-20% EtOAc / PE) to give the title compound (25 mg).

[0960] TLC: Rf 0.2 (PE / Et0Ac=2 / 1).

[0961] Example 147: (3S,4R,5R,6S)-1-[6-({2-[2-(1-propyn-1-yl)-1,3-thiazol-4-yl]-2-propanyl}oxy)hexyl]-3,4,5,6-azepantetrol

[0962] Example 147 was synthesized in the same manner as in Reference Example 16 and Example 69, except that the compound prepared in Reference Example 37 was used instead of the compound prepared in Reference Example 7.

[0963] LCMS retention time: 0.665 min (method A); MS (ESI, Pos.): m / z 427.1 (M+H)+;

[0964] 1H-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.

[0965] Reference Example 38: Ethyl [2-(4-chloro-3-fluorophenyl)-1,3-oxazol-4-yl]acetate

[0966] A mixture of 4-chloro-3-fluorobenzamide (CAS number: 874781-07-4, 1.0 g) and ethyl 4-chloro-3-oxobutanoate (CAS number: 638-07-3, 1.9 g) was stirred at 140 °C for 2 hours. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified using a silica gel flash column (5% EtOAc containing PE) to give the title compound (760 mg).

[0967] 1 H-NMR (CDCl3): δ7.83-7.70, 7.54-7.41, 4.27-4.18, 3.68, 1.33-1.27.

[0968] Reference Example 39: 2-[2-(4-chloro-3-fluorophenyl)-1,3-oxazol-4-yl]ethanol

[0969] To a solution of the compound prepared in Reference Example 38 (400 mg) in THF (4 mL) was added LiAlH (64 mg) at 0°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched with water and 15% NaOH aq. The mixture was stirred for 10 minutes. The suspension was diluted with EtOAc and filtered, and the collected solid was washed with EtOAc. The filtrate was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the title compound (320 mg).

[0970] Esi / ms:241.8[m+h]+.

[0971] Reference Example 40: 2-(4-chloro-3-fluorophenyl)-4-[2-(4-iodobutoxy)ethyl]-1,3-oxazole

[0972] To a solution of the compound prepared in Reference Example 39 (50 mg) in THF (0.50 mL) were added 15% NaOH (2.5 mL), 1,4-diiodobutane (CAS number: 628-21-7, 0.050 mL), and TBAI (67 mg) at 20 °C. The reaction mixture was stirred at 50 °C for 17 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep-TLC (PE / EtOAc = 5 / 1, Rf = 0.4) to give the title compound (25 mg).

[0973] TLC: Rf 0.40 (PE / EtOAc=5 / 1).

[0974] Example 148: (3S,4R,5R,6S)-1-(4-{2-[2-(4-chloro-3-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}butyl)-3,4,5,6-azepantetrol

[0975] Example 148 was synthesized in the same manner as in Example 1, except that the iodide prepared in Reference Example 40 was used instead of the compound prepared in Reference Example 1.

[0976] LCMS retention time: 0.69 min (method A); MS (ESI, Pos.): m / z 458.9 (M+H)+;

[0977] 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.

[0978] Examples 149-153:

[0979] Examples 149 to 153 were synthesized in the same manner as in Reference Example 1 and Example 1 using 1,5-diiodopentane (CAS number 628-77-3) and the corresponding alcohol compound.

[0980] Example 149: (3S,4R,5R,6S)-1-[5-(4-biphenylylmethoxy)pentyl]-3,4,5,6-azepantetrol

[0981] LCMS retention time: 1.734 min (method B); MS (ESI, Pos.): m / z 416.3 (M+H)+;

[0982] 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.

[0983] Example 150: (3S,4R,5R,6S)-1-(5-{[4-(4-fluorophenyl)-1,3-thiazol-2-yl]methoxy}pentyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[0984] LCMS retention time: 0.739 minutes (Method A); MS(ESI, Pos.): m / z 441.2(M+H)+;

[0985] 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.

[0986] Example 151: (3S,4R,5R,6S)-1-[5-(3-biphenylylmethoxy)pentyl]-3,4,5,6-azepantetrol

[0987] LCMS retention time: 0.708 minutes (Method A); MS(ESI, Pos.): m / z 416.1(M+H)+;

[0988] 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.

[0989] Example 152: (3S,4R,5R,6S)-1-(5-{[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}pentyl)-3,4,5,6-azepantetrol

[0990] LCMS retention time: 1.632 minutes (Method B); MS(ESI, Pos.): m / z 459.2(M+H)+;

[0991] 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.

[0992] Example 153: (3S,4R,5R,6S)-1-[5-(2-biphenylylmethoxy)pentyl]-3,4,5,6-azepantetrol

[0993] LCMS retention time: 1.736 min (method B); MS (ESI, Pos.): m / z 416.3 (M+H)+;

[0994] 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.

[0995] Reference Example 41: 2-[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]ethanol

[0996] The title compound was synthesized in the same manner as in Reference Example 39, using ethyl 2-(2-(3,5-difluorophenyl)thiazol-4-yl)acetate (CAS number: 1501541-90-7) instead of the compound prepared in Reference Example 38.

[0997] TLC: Rf 0.40 (PE / Et0Ac=3 / 1).

[0998] Example 154: (3S,4R,5R,6S)-1-(5-{2-[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]ethoxy}pentyl)-3,4,5,6-azepantetrol

[0999] Example 154 was synthesized in the same manner as in Reference Example 1 and Example 1 using 1,5-diiodopentane and the compound prepared in Reference Example 41.

[1000] LCMS retention time: 0.706 min (method A); MS (ESI, Pos.): m / z 473 (M+H)+;

[1001] 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.

[1002] Examples 155 and 156:

[1003] Examples 155 and 156 were prepared in the same manner as in Reference Example 1 and Example 1 using 1,7-diiodoheptane (CAS number 51526-03-5) and the corresponding alcohol compound. 6 was synthesized.

[1004] Example 155: (3S,4R,5R,6S)-1-(7-{[4-(4-fluorophenyl)-1,3-thiazol-2-yl]methoxy}heptyl)-3,4,5,6-azepantetrol

[1005] LCMS retention time: 0.781 min (Method C); MS (ESI, Pos.): m / z 469.2 (M+H)+;

[1006] 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.

[1007] Example 156: (3S,4R,5R,6S)-1-(7-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}heptyl)-3,4,5,6-azepantetrol

[1008] LCMS retention time: 0.702 min (method A); MS (ESI, Pos.): m / z 469.1 (M+H)+;

[1009] 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.

[1010] Example 157: (3S,4R,5R,6S)-1-{4-[(4'-methyl-4-biphenylyl)methoxy]butyl}-3,4,5,6-azepantetrol

[1011] Example 157 was synthesized in the same manner as in Reference Example 1 and Example 1 using 1,4-diiodobutane and the corresponding alcohol compound.

[1012] LCMS retention time: 0.723 min (method A); MS (ESI, Pos.): m / z 416.1 (M+H)+;

[1013] 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.

[1014] Reference Example 42: Methyl 4,4-difluoro-6-hydroxyhexanoate

[1015] To a solution of 5,5-difluorooxepan-2-one (CAS number: 35196-95-3, 1.7 g) in methanol (20 mL) was added MeONa (600 mg). The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.7 g). This compound was used in the next step without further purification.

[1016] Reference Example 43: Methyl 4,4-difluoro-6-[(triisopropylsilyl)oxy]hexanoate

[1017] To a mixture of the compound (0.70 g) prepared in Reference Example 42 and DMF (10 mL) were added chlorotriisopropylsilane (0.90 mL) and imidazole (520 mg). The reaction mixture was stirred at 25°C for 16 hours to give a brown mixture. The reaction mixture was diluted with water and extracted with EtOAc. 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% EtOAc / PE) to give the title compound (0.73 g).

[1018] TLC: Rf 0.4 (PE / Et0Ac=20 / 1).

[1019] Reference Example 44: 4,4-Difluoro-6-[(triisopropylsilyl)oxy]-1-hexanol

[1020] To a solution of the compound prepared in Reference Example 43 (730 mg) in THF (9 mL) was added LiAlH4 (123 mg). The mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with water and 15% NaOH aq. The mixture was diluted with THF and filtered. The collected solid was washed with THF. The filtrate was concentrated under reduced pressure to give the title compound (640 mg). This compound was used in the next step without purification.

[1021] Reference Example 45: [(3,3-difluoro-6-iodohexyl)oxy](triisopropyl)silane

[1022] To a solution of I2 (785 mg) in DCM (8 mL) were added PPh3 (811 mg), imidazole (281 mg), and the compound prepared in Reference Example 44 (640 mg). The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with DCM and then filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica column chromatography (0-6% EtOAc in PE) to obtain the title compound (360 mg).

[1023] TLC: Rf 0.7 (PE / Et0Ac=10 / 1).

[1024] Reference Example 46: 2-(3,5-difluorophenyl)-4-[({4,4-difluoro-6-[(triisopropylsilyl)oxy]hexyl}oxy)methyl]-1,3-thiazole

[1025] To a mixture of [2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methanol (CAS number: 1480594-24-8, 100 mg) and DMF (2 mL) was added NaH (35 mg, 60% in oil) at 0°C. After stirring at 0°C for 30 minutes, 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 EtOAc. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel (0-8% EtOAc containing PE) to give the title compound (110 mg).

[1026] TLC: Rf 0.7 (PE / Et0Ac=10 / 1).

[1027] Example 158: (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}-3,3-difluorohexyl)-3,4,5,6-azepantetrol

[1028] Example 158 was synthesized in the same manner as in Reference Examples 15 and 16 and Example 69, except that the compound prepared in Reference Example 46 was used instead of the compound prepared in Reference Example 14.

[1029] LCMS retention time: 0.732 min (method A); MS(ESI, Pos.):m / z531.1(M+Na)+;

[1030] 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.

[1031] Examples 159-161:

[1032] Examples 159 to 161 were synthesized in the same manner as in Reference Examples 46, 15, and 16 and Example 69, using the corresponding alcohol compounds instead of [2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methanol.

[1033] Example 159: (3S,4R,5R,6S)-1-(6-{[2-(3,4-difluorophenyl)-1,3-thiazol-4-yl]methoxy}-3,3-difluorohexyl)-3,4,5,6-azepantetrol

[1034] LCMS retention time: 1.724 minutes (Method B); MS(ESI, Pos.): m / z 509.1(M+H)+;

[1035] 1 H-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.

[1036] Example 160: (3S,4R,5R,6S)-1-(3,3-difluoro-6-{[2-(2,3,4-trifluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[1037] LCMS retention time: 1.753 minutes (Method B); MS(ESI, Pos.): m / z527.1(M+H)+;

[1038] 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.

[1039] Example 161: (3S,4R,5R,6S)-1-(3,3-difluoro-6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[1040] LCMS retention time: 1.649 minutes (Method B); MS(ESI, Pos.): m / z 491.2(M+H)+;

[1041] 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.

[1042] Reference Example 47: 4,4-Difluoro-6-[(triisopropylsilyl)oxy]hexyl benzoate

[1043] To a solution of the compound (15 g) prepared in Reference Example 44 in DCM (500 mL) were added TEA (10 mL), DMAP (590 mg), and benzoyl chloride (6.7 mL) at 0-5°C. The reaction mixture was stirred at 20°C for 1 hour to give 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 by silica gel flash column (EtOAc 0-10% PE) to give the title compound (18 g).

[1044] 1 H-NMR (CDCl3): δ8.03, 7.56, 7.44, 4.36, 3.89, 2.23-1.91, 1.12-0.99.

[1045] Reference Example 48: 4,4-Difluoro-6-hydroxyhexyl benzoate

[1046] To a solution of the compound (15 g) prepared in Reference Example 47 in THF (100 mL) was added a 1 M THF solution (54.3 mL) of TBAF at 20° C. The reaction mixture was stirred at 20° C. for 0.5 hours to give a yellow solution. The reaction mixture was concentrated to dryness. The residue was purified using a silica gel flash column (0-50% EtOAc, PE) to give the title compound (8.5 g).

[1047] 1 H-NMR (CDCl3): δ8.04, 7.57, 7.45, 4.37, 3.89, 2.24-1.99.

[1048] Reference Example 49: 6-[(4-ethylbenzyl)oxy]-4,4-difluoro-1-hexanol

[1049] To a solution of the compound prepared in Reference Example 48 (93 mg) in DMF (2 mL) was added NaH (11 mg, 60% in oil) 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 dropwise. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated. The residue was purified by flash column chromatography on silica gel (0-30% EtOAc containing PE) to give the title compound (60 mg).

[1050] 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.

[1051] Example 162: (3S,4R,5R,6S)-1-{6-[(4-ethylbenzyl)oxy]-4,4-difluorohexyl}-3,4,5,6-azepantetrol

[1052] Example 162 was synthesized in the same manner as in Reference Example 7 and Example 69, except that the compound prepared in Reference Example 49 was used instead of the compound prepared in Reference Example 6.

[1053] LCMS retention time: 1.711 min (method B); MS (ESI, Pos.): m / z 418.2 (M+H)+;

[1054] 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.

[1055] Reference Example 50: 1-{[2-(3-methoxyphenyl)-1,3-thiazol-4-yl]methoxy}-6-[(triisopropylsilyl)oxy]-2-hexanol

[1056] To a solution of (2-(3-methoxyphenyl)thiazol-4-yl)methanol (CAS number: 885280-53-5, 500 mg) in tert-butanol (5 mL) was added 15% NaOH (5 mL), TBAI (728 mg), and triisopropyl(4-(oxiran-2-yl)butoxy)silane (0.92 g) at 20 °C. The reaction mixture was stirred at 90 °C for 15 h to give a yellow solution. The reaction mixture was poured into water and extracted with EtOAc. 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% EtOAc / PE) to give the title compound (390 mg).

[1057] TLC: Rf 0.50 (PE / EtOAc=3 / 1).

[1058] Reference Example 51: 1-{[2-(3-methoxyphenyl)-1,3-thiazol-4-yl]methoxy}-6-[(triisopropylsilyl)oxy]-2-hexanone

[1059] To a solution of the compound prepared in Reference Example 50 (200 mg) in DCM (5 mL) was added DMP (259 mg) at 20°C. The reaction was stirred at 20°C for 2 hours. The reaction mixture was poured into saturated aqueous NaHCO3 solution and extracted with DCM. The organic phase was washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified using a silica gel flash column (PE-15% EtOAc in PE) to give the title compound (140 mg).

[1060] TLC: Rf 0.60 (PE / EtOAc=3 / 1).

[1061] Reference Example 52: 4-[({2,2-difluoro-6-[(triisopropylsilyl)oxy]hexyl}oxy)methyl]-2-(3-methoxyphenyl)-1,3-thiazole

[1062] To a solution of the compound prepared in Reference Example 51 (140 mg) in DCM (3 mL) was added diethylaminosulfur trifluoride (0.30 mL) at 20 °C. The reaction mixture was stirred at 35 °C for 15 hours to give a yellow solution. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash column (PE-8% EtOAc / PE) to give the title compound (80 mg).

[1063] TLC: Rf 0.80 (PE / Et0Ac=3 / 1).

[1064] Example 163: (3S,4R,5R,6S)-1-(5,5-difluoro-6-{[2-(3-methoxyphenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol

[1065] Example 163 was synthesized in the same manner as in Reference Examples 15 and 16 and Example 69, except that the compound prepared in Reference Example 52 was used instead of the compound prepared in Reference Example 14.

[1066] LCMS retention time: 0.696 min (method A); MS (ESI, Pos.): m / z 503.1 (M+H)+;

[1067] 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.

[1068] Reference Example 53: 4-[(4-biphenylylmethyl)thio]-1-butanol

[1069] To a solution of 4-(bromomethyl)biphenyl (200 mg) and 4-mercapto-1-butanol (CAS number 14970-83-3, 103 mg) in DMF (5 mL), K2CO3 (224 mg) was added and stirred at 25 °C for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic phase was washed with saturated brine, dried over Na2SO4, and concentrated. The residue was purified using a silica gel flash column (0-90% PE EtOAc) to give the title compound (200 mg).

[1070] 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.

[1071] Example 164: (3S,4R,5R,6S)-1-{4-[(4-biphenylylmethyl)thio]butyl}-3,4,5,6-azepantetrol

[1072] Example 164 was synthesized in the same manner as in Reference Example 12 and Example 70, except that the compound prepared in Reference Example 53 was used instead of the compound prepared in Reference Example 11.

[1073] LCMS retention time: 0.784 min (method A); MS (ESI, Pos.): m / z 418.1 (M+H)+;

[1074] 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.

[1075] Reference Example 54: 4-(2-bromoethyl)-2-(4-fluorophenyl)-1,3-thiazole

[1076] To a solution of 2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethanol (CAS No. 871689-11-1, 220 mg) in THF (5 mL) was added PPh3 (550 mg) and CBr4 (660 mg) at 0 °C, and the mixture was stirred at 15-20 °C for 5 hours to obtain a yellow suspension. The reaction mixture was quenched with water and extracted with EtOAc. The organic phase was concentrated to dryness. The residue was purified by silica gel flash column (Et0Ac in PE = 0-20%) and concentrated to obtain the title compound (260 mg).

[1077] TLC: Rf 0.70 (PE / Et0Ac=3 / 1).

[1078] Reference Example 55: 4-({2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethyl}thio)-1-butanol

[1079] To a solution of the compound prepared in Reference Example 54 (260 mg) in DMF (5 mL) were added K2CO3 (251 mg) and 4-mercapto-1-butanol (0.10 mL) at 20 °C. The resulting mixture was stirred at 15-20 °C for 16 hours. The reaction mixture was washed with water and extracted with EtOAc. The organic phase was concentrated and purified using a silica gel flash column (Et0Ac in PE = 10-30%) to give the title compound (290 mg).

[1080] TLC: Rf 0.20 (Et0Ac / PE=1 / 3).

[1081] Reference Example 56: 4-({2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethyl}thio)butanal

[1082] To a solution of the compound prepared in Reference Example 55 (100 mg) in DMSO (1 mL) and DCM (2 mL), TEA (0.22 mL) was added, and Py.SO3 (340 mg) was added. The mixture was stirred at 0-20°C for 18 hours at 0-20°C to obtain a white suspension. The mixture was quenched with water and extracted with EtOAc. The organic phase was concentrated and purified by silica gel flash column chromatography (EtOH in PE = 0-20%) to obtain the title compound (30 mg).

[1083] LCMS retention time: 0.898 min (method A); MS(ESI, Pos.):m / z309.9[M+H]+.

[1084] Example 165: (3S,4R,5R,6S)-1-[4-({2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]ethyl}thio)butyl]-3,4,5,6-azepantetrol hydrochloride (1:1)

[1085] Example 165 was synthesized in the same manner as in Example 70, except that the compound prepared in Reference Example 56 was used instead of the compound prepared in Reference Example 12.

[1086] LCMS retention time: 0.701 min (method A); MS (ESI, Pos.): m / z 457 (M+H)+;

[1087] 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.

[1088] Reference Example 57: S-{2-[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]ethyl} ethanethioate

[1089] To a solution of PPh3 (435 mg) in THF (2 mL) was added DIAD (0.33 mL) at 0-5°C and stirred at 0-5°C for 0.5 hours to give a white suspension. Then, at 0-5°C, a THF solution (1 mL) of thioacetic acid (CAS No.: 507-09-5, 0.12 mL) and 2-[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]ethanol (CAS No.: 1874632-93-5, 200 mg) was added. The mixture was stirred at 0-5°C for 2 hours and then at 20°C for 15 hours. The reaction mixture was concentrated to dryness. The residue was purified by preparative TLC (PE / EtOAc = 5 / 1, Rf = 0.6) to give the title compound (240 mg).

[1090] TLC: Rf 0.60 (PE / Et0Ac=5 / 1).

[1091] Reference Example 58: 5-({2-[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]ethyl}thio)-1-pentanol

[1092] To a solution of the compound prepared in Reference Example 54 (100 mg) in methanol (1 mL) was added K2CO3 (138 mg) at 20°C. The mixture was stirred at 20°C for 1 hour. 5-Bromo-1-pentanol (CAS number: 34626-51-2, 279 mg) was then added, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. 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% EtOAc, PE) to give the title compound (70 mg).

[1093] TLC: Rf 0.30 (PE / EtOAc=3 / 1).

[1094] Example 166: (3S,4R,5R,6S)-1-[5-({2-[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]ethyl}thio)pentyl]-3,4,5,6-azepantetrol

[1095] Example 166 was synthesized in the same manner as in Reference Example 12 and Example 70, except that the compound prepared in Reference Example 58 was used instead of the compound prepared in Reference Example 11.

[1096] LCMS retention time: 0.732 min (method A); MS (ESI, Pos.): m / z 489 (M+H)+;

[1097] 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.

[1098] Reference Example 59: 4-({2-[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]ethyl}thio)-1-butanol

[1099] The title compound was synthesized in the same manner as in Reference Examples 54 and 55 using the compound prepared in Reference Example 41.

[1100] LCMS retention time: 0.926 min (method A); MS(ESI, Pos.):m / z330.0[M+H]+.

[1101] Reference Example 60: 2-(3,5-difluorophenyl)-4-{2-[(4-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}butyl)thio]ethyl}-1,3-thiazole

[1102] To a mixture of the compound prepared in Reference Example 59 (120 mg) 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 give a colorless solution. The mixture was washed with water and then extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified on a silica column (PE-8% EtOAc / PE) to give the title compound (196 mg).

[1103] LCMS retention time: 1.264 min (method A); MS(ESI, Pos.):m / z444.1[M+H]+.

[1104] Reference Example 61: 2-(3,5-difluorophenyl)-4-{2-[(4-{[dimethyl(2-methyl-2-propanyl)silyl]oxy}butyl)sulfonyl]ethyl}-1,3-thiazole

[1105] To a solution of the compound prepared in Reference Example 60 (140 mg) in DCM (1.5 mL) was added mCPBA (60 mg). The mixture was stirred at 20°C for 16 hours to give a colorless solution. Then, mCPBA (60 mg) was added, and the mixture was stirred at 20°C for 3 hours to give a white suspension. The mixture was washed with water and then extracted with EtOAc. The organic phase was dried over NaSO and concentrated. The residue was purified on a silica column (PE-24% EtOAc / PE) to give the title compound (104 mg).

[1106] LCMS retention time: 1.116 min (method A); MS(ESI, Pos.):m / z476.2[M+H]+.

[1107] Reference Example 62: 4-({2-[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]ethyl}sulfonyl)-1-butanol

[1108] To a mixture of the compound prepared in Reference Example 61 (104 mg) and THF (2 mL) was added a 1 M THF solution (0.44 mL). The reaction was stirred at 20°C for 16 hours to give a yellow mixture. The mixture was concentrated under reduced pressure. The residue was purified on a silica gel column (DCM to 6% MeOH in DCM) to give the title compound (60 mg).

[1109] LCMS retention time: 0.812 min (method A); MS(ESI, Pos.):m / z362.0[M+H]+.

[1110] Example 167: (3S,4R,5R,6S)-1-[4-({2-[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]ethyl}sulfonyl)butyl]-3,4,5,6-azepantetrol

[1111] Example 167 was synthesized in the same manner as in Reference Example 7 and Example 69, except that the compound prepared in Reference Example 62 was used instead of the compound prepared in Reference Example 6.

[1112] LCMS retention time: 1.467 min (method B); MS (ESI, Pos.): m / z 507.1 (M+H)+;

[1113] 1H-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.

[1114] Reference Example 63: 2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]-2-propanol

[1115] To a mixture of ethyl 2-(4-fluorophenyl)thiazole-4-carboxylate (CAS number: 132089-35-10.50 g) in THF (10 mL) was added MeMgBr (2.7 mL) at 0 °C. Stirring under N2 at 20 °C for 16 h gave a brown mixture. The reaction mixture was quenched with saturated aqueous NH4Cl 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 by silica gel flash column (PE-40% EtOAc / PE) to give the title compound (0.45 g).

[1116] TLC: Rf 0.50 (PE / EtOAc=3 / 1).

[1117] Reference Example 64: 4-{2-[(6-bromohexyl)oxy]-2-propanyl}-2-(4-fluorophenyl)-1,3-thiazole

[1118] To a solution of the compound prepared in Reference Example 63 (150 mg) in DMF (2 mL) were added NaH (51 mg) and 1,6-dibromohexane (CAS No. 629-03-8, 0.29 mL). The mixture was stirred at 60 °C for 16 hours. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with water and saturated brine, then dried over Na2SO4, filtered, and concentrated. The residue was purified using a silica gel flash column (5% EtOAc-10% PE) to give the title compound (120 mg).

[1119] 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.

[1120] Example 168: (3S,4R,5R,6S)-1-[6-({2-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]-2-propanyl}oxy)hexyl]-3,4,5,6-azepantetrol

[1121] Example 168 was synthesized in the same manner as in Example 1, except that the compound prepared in Reference Example 64 was used instead of the compound prepared in Reference Example 1.

[1122] LCMS retention time: 0.724 min (method A); MS (ESI, Pos.): m / z 483.1 (M+H)+;

[1123] 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.

[1124] Reference Example 65: {[7-(2-biphenylylmethoxy)-5-heptyn-1-yl]oxy}(triisopropyl)silane

[1125] The title compound was synthesized in the same manner as in Reference Example 6 using 7-[(triisopropylsilyl)oxy]-2-heptyn-1-ol (CAS number: 1802596-80-0) and 2-(bromomethyl)biphenyl (CAS number: 19853-09-9).

[1126] TLC: Rf 0.75 (PE / EtOAc=5 / 1).

[1127] Example 169: (3S,4R,5R,6S)-1-[7-(2-biphenylylmethoxy)-5-heptyn-1-yl]-3,4,5,6-azepantetrol hydrochloride (1:1)

[1128] The title compound was synthesized in the same manner as in Reference Examples 15 and 16 and Example 69, except that the compound prepared in Reference Example 65 was used instead of the compound prepared in Reference Example 14.

[1129] LCMS retention time: 0.733 min (method A); MS (ESI, Pos.): m / z 440.2 (M+H)+;

[1130] 1H-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.

[1131] Examples 170 and 171:

[1132] Examples 170 and 171 were synthesized in the same manner as in Reference Examples 21, 22, 15, 16, and Examples 71 and 72, using [5-(3,5-difluorophenyl)-2-methyl-1,3-oxazol-4-yl]methanol instead of [2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methanol.

[1133] Example 170: (3S,4R,5R,6S)-1-[(5R)-6-{[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrol hydrochloride (1:1) (isomer 1)

[1134] LCMS retention time: 0.792 min (Method A); MS (ESI, Pos.): m / z 491.3 (M+H)+;

[1135] 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;

[1136] SFC retention time: 4.121 min (method A3).

[1137] Example 171: (3S,4R,5R,6S)-1-[(5S)-6-{[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrol hydrochloride (1:1) (isomer 2)

[1138] LCMS retention time: 0.694 min (method A); MS (ESI, Pos.): m / z 491.3 (M+H)+;

[1139] 1H-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;

[1140] SFC retention time: 4.535 min (method A3).

[1141] Examples 172-174:

[1142] Examples 172 to 174 were synthesized in the same manner as in Reference Example 1 and Example 1, except that the corresponding alcohol compounds were used instead of (4-methylphenyl)methanol.

[1143] Example 172: (3S,4R,5R,6S)-1-{6-[(3-ethoxy-4-fluorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[1144] LCMS retention time: 0.681 min (method A); MS (ESI, Pos.): m / z 416.1 (M+H)+;

[1145] 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.

[1146] Example 173: (3S,4R,5R,6S)-1-{6-[(4-chlorobenzyl)oxy]hexyl}-3,4,5,6-azepantetrol

[1147] LCMS retention time: 0.683 min (method A); MS (ESI, Pos.): m / z 388.1 (M+H)+;

[1148] 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.

[1149] Example 174: (3S,4R,5R,6S)-1-(6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol hydrochloride (1:1)

[1150] LCMS retention time: 0.689 min (method A); MS(ESI, Pos.):m / z493.1(M+Na)+;

[1151] 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.

[1152] Pharmacological Experiment Example 1:

[1153] 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 a substrate. Reactions were performed in acidic assay buffer (pH 5.2 McIlvaine's buffer, 0.25% sodium taurocholate, 0.1% Triton® X-100). Five μL of each test compound solution was preincubated with 10 μL of GBA enzyme (0.1 ng / μL) for 5 minutes at room temperature. The reaction was initiated 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 achieve optimal fluorescence intensity. The released 4-methylumbelliferone (4-MU) was measured using a fluorescence spectrophotometer (excitation wavelength 355 nm, emission wavelength 450 nm). The blank contained GBA, and the reaction stop solution and substrate were added sequentially. The mean value of the blank group was set as 100% inhibition, and the mean value of the untreated group was set as 0% inhibition. The inhibitory activity (IC50) of the test substance was calculated from the 4-MU production inhibition rate at each compound concentration.

[1154] From the above pharmacological experiments, it has been found that the compounds of the present disclosure have GBA1 inhibitory activity. For example, the IC50 values ​​of some compounds of the present disclosure are shown in Table 1. These data suggest that the compounds of the present disclosure may be able to bind to GBA1 and stabilize GBA1 to such an extent that they can protect GBA1 from degradation.

[1155] Pharmacological Experiment Example 2: Evaluation of human GCS enzyme inhibitory activity

[1156] This assay used HL60 cell lysate. HL60 cells were thawed and cultured in RPMI1640 medium containing 10% FBS. The cells were passaged once before use. The cells were collected in a centrifuge tube, washed three times with PBS, and then counted. 1 mL / 4 x 10 7M-PER® (Mammalian Protein Extraction Reagent) (1:100) containing protease cocktail inhibitors was added to the cells and lysed on ice for 30 minutes with mixing every 5 minutes. The cell lysate was sonicated in an ice-water bath for 15 minutes and then centrifuged at 1000 rpm at 4°C 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. 25 nanoliters of 1000x the test compound was dispensed into a 384-well assay plate by ECHO. A reaction cocktail (10 μmol / L NBD-C6 ceramide, 25 μmol / L UDP-glucose, 35 μmol / L dioleoylphosphatidylcholine, 1 mmol / L dithiothreitol, and 1 mmol / L EGTA in 100 mmol / L Tris buffer (pH 7.5)) was prepared and 15 μL was dispensed into each well. The reaction was initiated by adding 10 μL of cell lysate (1 mg / mL) to each well. The plate was incubated at 37°C for 90 minutes, and then 75 μL of a stop solution (methanol:acetonitrile (6:5) containing 200 ng / mL tolbutamide as an internal control) was added to terminate the reaction. The reaction solution was vortexed and centrifuged to obtain the supernatant for further LC / MS / MS analysis. The reaction product, NBD-C6-glucosylceramide, was analyzed using an AB Sciex triple quadrupole mass spectrometer. The inhibitory activity (IC50) of the test compound was calculated from the NBD-C6-glucosylceramide production inhibition rate at each compound concentration, when the mean value of the blank group was 100% and the mean value of the untreated group was 0%.

[1157] The above pharmacological experiments showed that the compounds of the present disclosure have strong GCS inhibitory activity. For example, the IC50 values ​​of some of the compounds of the present disclosure are shown in Table 1.

[1158] Pharmacological Experiment Example 3: Evaluation of human GBA2 enzyme inhibitory activity

[1159] Human GBA2 plasmid was prepared as follows. The complete open reading frame of GBA2 (human NM_20944.2) was amplified from human tissues using specific primers containing restriction sites and an extended Kozak sequence before the start codon. PCR products were cloned into the pGEM-T vector, and their sequences were verified. Using the added restriction sites, the appropriate fragment was subcloned into pcDNA-3.1. HEK293T cells were transiently transfected with the human GBA2 plasmid using Lipo3000 reagent. Transduced cells were homogenized in four volumes of ice-cold 25 mM potassium phosphate (pH 5.5), sonicated three times for 1 min, and centrifuged at 100,000 × g for 1 h. The supernatant was discarded, the pellet 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 assay.

[1160] 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. Reactions were performed in assay buffer (pH 5.2 Mcilvaine's buffer, 0.25% sodium taurocholate, 0.1% Triton® X-100). GBA1 was inhibited by preincubating 10 μg of the enzyme suspension with 1 mmol / L conduritol B epoxide (CBE) for 30 min at 4°C. The reaction was initiated by adding 0.5 mmol / L (final concentration) substrate solution and incubated at 37°C for 45 min. The reaction was terminated 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 using a fluorescence spectrophotometer (excitation wavelength 362 nm, emission wavelength 450 nm). The mean value of the blank group and the mean value of the untreated group were taken as 100% and 0%, respectively, and the inhibitory activity (IC50) of the test substance was calculated from the 4-MU production inhibition rate at each compound concentration.

[1161] The above pharmacological experiments showed that the compounds disclosed herein do not have strong GBA2 inhibitory activity. The compounds disclosed herein were found to be compounds with little risk of causing glycolipid accumulation due to GBA2 inhibition. For example, the IC50 values ​​of some of the compounds disclosed herein are shown in Table 1.

[1162] [Table 1]

[1163] The inhibitory activities of GBA1, GCS, and GBA2 were 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 comparative compounds. The IC50 values ​​of the comparative compounds are shown in Table 1-1 below. [ka]

[1164] [Table 1-1]

[1165] From the above results, it was found that the compounds of the present disclosure have lower GBA2 inhibitory activity than the comparative compounds.

[1166] Pharmacological Experiment Example 4: Evaluation of human GBA1 cell activity

[1167] Gaucher cell line (Coriell Institute, Cat. GM00372) carrying the N307S β-glucocerebrosidase mutation was cultured and expanded in EMEM containing 15% FBS. The cells were passaged at least twice and were usable up to passage 20. 1.25 × 10 cells were plated in a 96-well plate. 4Cells were seeded at a density of 1000 cells / well. After overnight culture, 50 μL of cell culture medium was discarded, and 50 μL of diluted compound (supplemented with 0.3% DMSO) was added. On day 6, cells were washed once with HBSS and incubated in HBSS for 3 hours. Cells were then lysed with 30 μL of assay buffer (Mclvaine's buffer, pH 5.2, supplemented with 0.25% sodium taurocholate, 0.5% Triton® X-100, and protease cocktail inhibitors) for 5 minutes at 4°C on a shaker. For the GBA enzyme assay, 5 μL of 4-MUG (6 mmol / L) was added to 15 μL of cell lysate and incubated in a 384-well plate for 60 minutes. After incubation, 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, emission wavelength 450 nm). For protein quantification, 4 μL of cell lysate was mixed with 36 μL of Pierce BCA Reagent for 30 minutes. Protein was detected according to the manufacturer's instructions. Enzyme activity in the cell lysate was normalized to protein concentration. A blank contained substrate and assay buffer, and a stop solution was added. Enzyme activity in DMSO-treated cells served as a negative control, and the results were expressed as the percentage change in enzyme activity in cells treated with each compound. For example, the percentage change in intracellular enzyme activity is shown in Table 2 below.

[1168] The above pharmacological experiments demonstrated that the compounds of the present disclosure have potent GBA1 chaperone activity.

[1169] [Table 2]

[1170] Pharmacological Experiment Example 5: Evaluation of sphingolipid-lowering effect

[1171] Gaucher cell line (Coriell Institute, Cat. GM00372) carrying the N307S β-glucocerebrosidase mutation was cultured and expanded in EMEM containing 15% FBS. After thawing, the cell line was passaged at least twice. The cell density was 1 x 10 5Cells were seeded onto a 6 cm dish at 1000 x 1000 cells / dish. After overnight incubation, the cell medium was discarded and 4 mL of test compound solution (containing 0.1% DMSO) was added. The cells were treated with the compound for 6 days. On the 6th day, the cells were washed twice with PBS. Then, 1 mL of 20 mmol / L acetic acid / ethanol was added and the cells were collected using a cell scraper. This procedure was repeated to obtain 2 mL of cell extract. Ten microliters 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)) were added to the mixture, which was then vortexed. Then, 1 mL of chloroform was added. The mixture was sonicated on ice for 10 minutes, vortexed again, and centrifuged at 2,130 × g for 3 minutes at 4°C. The supernatant was collected and evaporated to dryness using a centrifugal concentrator. After drying, the mixture was dissolved in 0.2 mL of a chloroform / methanol mixture (2:1, v / v) and sphingolipids were measured by SFC / MS / MS.

[1172] Pharmacological Experiment Example 6: Assessment of cognitive impairment in mice.

[1173] Evaluation of the pharmacological activity of a test compound includes improvement of cognitive impairment in mice. For example, improvement of cognitive impairment by a compound can be evaluated by the following method.

[1174] Mice (male C57BL / 6 mice, 16-23 months old (Charles River Japan)) were used. The test substance and its vehicle were orally administered once daily for two weeks. Subsequently, cognitive function was assessed by a novel object recognition (NOR) test using a plastic box (460mm x 300mm x 450mm) equipped with a video camera as the experimental apparatus. The evaluation was performed in a dark room, with the light intensity adjusted to approximately 20 lux near the experimental apparatus. To allow the animals to acclimate to the evaluation environment, the mice were moved to the evaluation room at least one hour before the start of the test. This test was conducted over a three-day period. On the first day, the mice were placed in a cage and allowed to move freely for 10 minutes to allow them to acclimate to the experimental apparatus. This step was repeated twice, with a four-hour interval between each. On the second day, two identical objects (familiar objects) were placed on top of the cage, and the mice were given the same 10-minute acquisition trial. The two objects were spaced apart on a line parallel to the long sides of one cage. The distance between the object and the inner walls of the two adjacent surfaces is 10 cm. In the third 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 allowed to behave in the same way for 10 minutes. The trial begins 24 hours after the acquisition trial (acceptable range: 23-25 ​​hours). The exploration time for each object is measured from the video images recorded in the test trial. The total exploration time and novel object recognition rate are calculated from the exploration times for the familiar and novel objects using the following formulas.

[1175] Total exploration time (seconds) = exploration time for familiar objects + exploration time for novel objects

[1176] Recognition rate (%) = 100 × (exploration time for novel objects / total exploration time)

[1177] [Formulation example]

[1178] Formulation example

[1179] The following ingredients are mixed by a conventional method and then compressed into tablets to obtain approximately 10,000 tablets, each containing 10 mg of active ingredient.

[1180] (3S,4R,5R,6S)-1-{6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol ......100g

[1181] Carboxymethylcellulose calcium (disintegrant) ......20g

[1182] Magnesium stearate (lubricant) ......10g

[1183] Crystalline cellulose ......870g

[1184] [Industrial Applicability]

[1185] Since the compound of the present disclosure has dual GBA1 and GCS regulating activity, pharmaceuticals containing the compound of the present disclosure as an active ingredient are useful as agents for preventing and / or treating diseases associated with GBA1 and / or GCS.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, L １ represents (1) C4-7 alkylene, (2) C4-7 alkenylene, or (3) C4-7 alkynylene; L １ is 1-5 R Ｌ１ may be substituted with R Ｌ１ represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a hydroxyl group; Multiple R Ｌ１ may be the same or different, L ２ represents (1) C1-3 alkylene, (2) C2-3 alkenylene, or (3) C2-3 alkynylene; L ２ is 1-4 R Ｌ２ may be substituted with R Ｌ２ represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, or (10) a hydroxyl group; Multiple R Ｌ２ may be the same or different, X is (1) a bond, (2) —O—, (3) —S—, (4) —SO—, or (5) —SO ２ represents -, Ring 1 represents (1) a benzene ring, (2) a naphthalene ring, or (3) a 5- to 10-membered heterocycle; R １ represents (1) a halogen atom, (2) a C alkyl group, (3) a C alkenyl group, (4) a C alkynyl group, (5) a C alkoxy group, (6) a C haloalkyl group, (7) a C haloalkenyl group, (8) a C haloalkynyl group, (9) a C haloalkoxy group, (10) a C carbocycle, (11) a 5- to 7-membered heterocycle, (12) —O—(C carbocycle), or (13) —O—(5- to 7-membered heterocycle); Multiple R １ may be the same or different, R １ (2)-(13) are R １－１ may be substituted with 1-5 of R １－１ 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 may be the same or different, symbol: 【Chemistry 2】 indicates that the substituents are bonded in an appropriate ratio to form an α-configuration, a β-configuration, or a mixture of the α-configuration and the β-configuration, and n is an integer of 0 to 5, or a pharmaceutically acceptable salt thereof.

2. L １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a hexylene group.

3. 3. The compound according to claim 1 or 2, wherein X is -O-, or a pharmaceutically acceptable salt thereof.

4. L ２ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is a methylene group.

5. Ring 1 is the following ring structure: 【Transformation 3】 (In the formula, * indicates L ２ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the ring structure is selected from the group consisting of:

6. R Ｌ１ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein is (1) a halogen atom, or (2) a C1-6 alkyl group.

7. The compound represented by formula (I) is represented by formula (I-1): 【Chemistry 4】 (In the formula, R Ｌ１－１ represents (1) a halogen atom, or (2) a C1-6 alkyl group, Multiple R Ｌ１－１ may be the same or different, m represents an integer of 1 to 2; Ring 2 has the following ring structure: 【Transformation 5】 (wherein * indicates the bonding position to the methylene), and other symbols have the same meanings as the symbols in claim 1.) or a pharmaceutically acceptable salt thereof.

8. The compound of formula (I) (1) (3S,4R,5R,6S)-1-{6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol, (2) (3S,4R,5R,6S)-1-(6-{[2-(3,5-difluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl)-3,4,5,6-azepantetrol, (3) (3S,4R,5R,6S)-1-{(5R)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol, (4) (3S,4R,5R,6S)-1-{(5S)-6-[(3-ethoxy-4-fluorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol, (5) (3S,4R,5R,6S)-1-[(5R)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl]-3,4,5,6-azepantetrol, (6) (3S,4R,5R,6S)-1-[(5S)-5-fluoro-6-{[2-(4-fluorophenyl)-1,3-thiazol-4-yl]methoxy}hexyl]-3,4,5,6-azepantetrol, (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-azepantetrol, (8) (3S,4R,5R,6S)-1-[(5S)-6-{[5-(3,5-difluorophenyl)-2-methyl-1,3-oxazol-4-yl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrol, (9) (3S,4R,5R,6S)-1-{(5S)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol, (10) (3S,4R,5R,6S)-1-{(5R)-6-[(4-ethylbenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol, (11) (3S,4R,5R,6S)-1-{(5S)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol, (12) (3S,4R,5R,6S)-1-{(5R)-6-[(4-chlorobenzyl)oxy]-5-fluorohexyl}-3,4,5,6-azepantetrol, (13) (3S,4R,5R,6S)-1-{(5S)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol, (14) (3S,4R,5R,6S)-1-{(5R)-5-fluoro-6-[(4-methylbenzyl)oxy]hexyl}-3,4,5,6-azepantetrol, (15) (3S,4R,5R,6S)-1-[(5S)-6-{[6-(3,5-difluorophenyl)-3-pyridazinyl]methoxy}-5-fluorohexyl]-3,4,5,6-azepantetrol, and (16) The compound according to any one of claims 1 to 7, which is 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-azepantetrol, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, as an active ingredient, and further comprising a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9, which is a GBA1 chaperone modulator.

11. The pharmaceutical composition of claim 9, which is a GCS inhibitor.

12. The pharmaceutical composition of claim 9, which is a GBA1 and GCS dual regulator.

13. The pharmaceutical composition according to any one of claims 9 to 12, which is an agent for treating and / or preventing diseases associated with GBA1 and / or GCS.

14. 14. The pharmaceutical composition of claim 13, 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 disease, 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, movement disorder, sleep disorder, neurological disorder, CNS disorder, polycystic kidney disease, diabetes, cancer, open-angle glaucoma, endometriosis, multiple myeloma, viral disease, inflammation, systemic lupus erythematosus, hepatitis, Guillain-Barré syndrome, diabetic nephropathy, and skin disorders.

15. The pharmaceutical composition according to claim 13, wherein the disease associated with GBA1 and / or GCS is selected from the group consisting of Parkinson's disease, Lewy body disease, and Gaucher disease.

16. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition 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, velaglucerase alfa, eliglustat, alglucerase, and miglustat.

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

18. A method for preventing and / or treating a disease associated with GBA1 and / or GCS, comprising administering a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 to a patient in need of such prevention and / or treatment.

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

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

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