Cyclohexene derivative and pharmaceutical composition containing same

Abstract

The present invention provides a compound of chemical formula 1 or a pharmaceutically acceptable salt thereof. The compound of chemical formula 1 or a pharmaceutically acceptable salt thereof is a novel cyclohexene derivative which can serve as a pharmacological chaperone for increasing the activity of human mutant β-galactosidase and can be used for treating or preventing GM1 gangliosidosis.

Description

Cyclohexene derivatives and pharmaceutical compositions containing the same

[0001] The present invention relates to cyclohexene derivatives and pharmaceutical compositions comprising the same. Specifically, the present invention relates to cyclohexene derivatives that increase the activity of mutant human β-galactosidase and pharmaceutical compositions comprising the same. More specifically, the present invention relates to cyclohexene derivatives that can act as pharmacological protectors for mutated β-galactosidase by increasing the activity of mutant human β-galactosidase and can be utilized for the treatment or prevention of GM1 gangliosidosis, and pharmaceutical compositions comprising the same.

[0002] This application claims the benefit of priority to Republic of Korea Patent Application No. 10-2023-0148808, dated November 1, 2023, and Republic of Korea Patent Application No. 10-2024-0149654, dated October 29, 2024, the entire contents of which are incorporated herein by reference.

[0003] Lysosomal storage disease (LSD) is a rare, inherited metabolic disorder caused by genetic mutations in enzymes that degrade substrates within lysosomes. This deficiency leads to the accumulation of substrates within the cell. Normal enzymes are synthesized in the endoplasmic reticulum (ER), folded into the correct three-dimensional structure, and then transported to the appropriate intracellular organelle to perform their functions. However, abnormal proteins synthesized due to genetic mutations fail to fold properly, fail to be transported to their destination, and can be eliminated from the cell. Consequently, the protein's intrinsic activity is reduced, leading to various disease manifestations.

[0004] GM1 gangliosidosis is a lysosomal storage disorder of glycosphingolipids caused by mutations in the biallelic genes of GLB1, resulting in deficiency of the enzyme β-galactosidase activity translated by GLB1, and accumulation of substrates metabolized by the enzyme in the lysosome. β-Galactosidase is involved in the metabolic process of degrading β-linked galactose from various oligosaccharides, glycans, and oligosphingolipids in the lysosome. Therefore, the defective enzyme activity caused by the mutant β-galactosidase leads to accumulation of various substrates in the body's organ tissues, resulting in systemic clinical symptoms such as organ hypertrophy, muscle weakness, joint stiffness, skeletal deformities, and cherry spots in the macula. In particular, because it is involved in the metabolism of GM1 ganglioside, which is abundant in neural tissue, a decrease in the activity of this enzyme causes serious brain lesions due to the accumulation of GM1 ganglioside in neural tissue, which is accompanied by neurodegeneration such as decreased motor ability, cognitive and developmental disorders.

[0005] GM1 gangliosidosis disease is classified into three types (type 1 (infantile), type 2 (late infantile and adolescent), and type 3 (adult)) based on the age of onset of clinical symptoms, but in reality, there is a continuum of disease onset and severity, which is partly related to the residual activity of the mutated enzyme. The most serious clinical symptoms in all forms of GM1 ganglioside disease are neurological symptoms, including neurocognitive decline, developmental delay, and motor dysfunction. Types 1 and 2 disease are characterized by severe neurocognitive decline and developmental delay and are associated with early death. Type 2 disease also exhibits slower neurodegeneration and a longer survival than type 1, but ultimately leads to death before adulthood.

[0006] Most patients with GM1 gangliosidosis die before adulthood, yet there are currently no approved medications or therapies to treat them. Because GM1 gangliosidosis is a disease characterized by severe neurological symptoms in addition to systemic symptoms, effective treatment requires brain-penetrating drugs that can improve neurological symptoms and delay progression. Furthermore, the development of treatments to extend patient survival is urgently needed.

[0007] Pharmacological chaperone therapy (PCT) has been proposed as a drug development approach to restore enzyme activity caused by misfolding due to a mutated gene. This approach involves small molecules binding to the mutated protein, aiding its folding and increasing its stability, thereby enabling its transport to the target organelle, thus enabling the enzyme to function.

[0008] The present inventor completed the present invention after studying a substance that can act as a pharmacological protector for mutated β-galactosidase that is effectively delivered to the brain as well as surrounding organs.

[0009] [Prior Art Literature]

[0010] [Non-patent literature]

[0011] (Non-patent Document 1) “Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics”, EMBO Mol Med 1, 268-279

[0012] The present invention aims to provide a novel cyclohexene derivative and a pharmaceutical composition comprising the same, which increases the activity of human mutant β-galactosidase and is brain-penetrating, and can be used for the treatment and prevention of GM1-gangliosidosis accompanied by brain lesions and neurodegenerative symptoms.

[0013] According to the first aspect of the present invention,

[0014] The present invention provides a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0015] [Chemical Formula 1]

[0016]

[0017] In one specific example of the present invention, X is halogen.

[0018] In one specific example of the present invention, R1 and R2 are each independently hydrogen or C 1-4 It's alkyl.

[0019] In one specific example of the present invention, L is a direct bond, C 1-7 Alkylene, C 1-7 Halogenated alkylene, C 1-7 Alkenylene, C 3-7 Cycloalkylene or a combination thereof.

[0020] In one specific example of the present invention, R3 is hydrogen, halogen, hydroxy, cyano, nitro, amino, mercapto, carbamoyl, C 1-7 Alkyl, C 1-7 Halogenated alkyl, C 2-7 Alkenyl, C 2-7 alkynyl, C 1-7 Alkoxy, C 1-7 Halogenated alkoxy, C 1-4　 Alkoxy-C 1-4　 Alkoxy, C 3-10 Cycloalkyl-C 1-4 Alkoxy, C 6-10 Aryl-C 1-4 Alkoxy, C 2-7 Alkenyloxy, C 2-7 alkynyloxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkanonyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Selected from the group consisting of arylsulfonamidyl, 5-10 membered heteroarylsulfonamidyl and non-aromatic condensed rings.

[0021] In one specific embodiment of the present invention, the non-aromatic condensed ring is C 6-10 C to aryl or 5-10 membered heteroaryl 3-7 Cycloalkyl, C 3-7 It is a polycyclic ring in which cycloalkenyl or 3-7 membered heterocycloalkyl is condensed.

[0022] In one specific example of the present invention, in R3, C 6-10 Aryl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkanonyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Arylsulfonamidyl, 5-10 membered heteroarylsulfonamidyl and non-aromatic condensed rings are each independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4　 Alkoxy-C 1-4　 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl, C 3-7 Cycloalkenyl, C 3-7 Cycloalkyloxy, 3-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, mono- or di-C 1-4Alkylamino and mono- or di-C 6-10 It may be substituted with a substituent selected from the group consisting of arylamino.

[0023] In one specific example of the present invention, the substituent may be substituted with a halogen.

[0024] In one specific example of the present invention, two C among the substituents 1-4 Alkyl groups can be linked to each other by direct bonds, -CH2-, -O-, -S- or -NH- to form rings.

[0025] In one specific example of the present invention, X is fluorine.

[0026] In one specific example of the present invention, R1 and R2 are hydrogen.

[0027] In one specific example of the present invention, L is C 1-7 It is alkylene.

[0028] In one specific example of the present invention, R3 is C 3-10 Cycloalkyl-C 1-4 Alkoxy, C 6-10 Aryl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 Selected from the group consisting of aryl and 5-10 membered heteroaryl.

[0029] In one specific embodiment of the present invention, R3 is selected from the group consisting of cyclopentyl, cyclohexyl, adamantyl, cyclopentyloxy, cyclohexyloxy, adamantyloxy, cyclopentenyl, cyclohexenyl, cyclopentenyloxy, cyclohexenyloxy, tetrahydropyranyl, phenyl, phenyloxy, and phenylmethoxy.

[0030] In one specific example of the present invention, in R3, C6-10 Aryl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkanonyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy and non-aromatic condensed rings are each independently halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 It may be substituted with a substituent selected from the group consisting of halogenated alkoxy.

[0031] In one specific example of the present invention, R3 is cyclopentyl, cyclohexyl, phenyl or phenyloxy, and in R3, cyclopentyl, cyclohexyl, phenyl and phenyloxy may each be independently substituted with a substituent selected from the group consisting of halogen, methyl, ethyl, propyl, halogenated methyl, halogenated ethyl and halogenated propyl.

[0032] In one specific example of the present invention, the compound of Chemical Formula 1 has a three-dimensional structure of Chemical Formula 2:

[0033] [Chemical Formula 2]

[0034]

[0035] In one specific example of the present invention, the compound or a pharmaceutically acceptable salt thereof is Compound 1 to 89 below.

[0036]

[0037] According to the second aspect of the present invention,

[0038] The present invention provides a pharmaceutical composition for treating or preventing GM1-gangliosidosis, comprising the above-described compound as an active ingredient and a pharmaceutically acceptable carrier.

[0039] A cyclohexene derivative according to one embodiment of the present invention, when administered to cells derived from patients with GM1 gangliosidosis having a genetic mutation, provides a high level of increased activity of the mutant enzyme without exhibiting toxicity. Furthermore, when administered in vivo, it is distributed at high concentrations not only in peripheral organs but also in brain tissue, and degrades substrates accumulated throughout the body, including the brain. To evaluate its potential as a therapeutic agent, it was administered to genetically engineered GM1 disease animals and its effects were tested. As a result, even a short-term administration of just one week showed a very high level of increased activity of the mutant enzyme not only in peripheral organ tissues but also in brain tissue, along with a significant decrease in GM1 ganglioside in the brain tissue. This indicates that a cyclohexene derivative according to one embodiment of the present invention acts as a pharmacological protector that restores the activity of the mutant β-galactosidase, and is useful as a therapeutic agent for glycolipid metabolism disorders, including GM1 gangliosidosis accompanied by brain lesions and neurodegenerative symptoms.

[0040] Figure 1 is a graph showing the results of cerebral permeability evaluation by in vivo administration of a cyclohexene derivative according to one specific example of the present invention according to Experimental Example 3.

[0041] FIG. 2 is a graph showing the results (increased mutant protein activity) in liver tissue of genetically modified GM1 disease mice, relating to the evaluation of efficacy by in vivo administration of a cyclohexene derivative according to one specific example of the present invention according to Experimental Example 4.

[0042] FIG. 3 is a graph showing the results (increased mutant protein activity) in brain tissue of a genetically modified GM1 disease mouse, in accordance with Experimental Example 4, regarding the evaluation of efficacy by in vivo administration of a cyclohexene derivative according to one specific example of the present invention.

[0043] FIG. 4 is a graph showing the results (reduction in GM1-ganglioside accumulation) in brain tissue of mice with genetically modified GM1 disease, relating to the evaluation of efficacy by in vivo administration of a cyclohexene derivative according to one specific example of the present invention according to Experimental Example 4.

[0044] The specific embodiments provided in accordance with the present invention can all be achieved by the following description. It should be understood that the following description describes preferred embodiments of the present invention and that the present invention is not necessarily limited thereto.

[0045]

[0046] The present invention relates to the development of a substance capable of acting as a pharmacological protector for mutated β-galactosidase, and provides an effective method for treating or preventing GM1 gangliosidosis disease. Furthermore, the invention presents the characteristics of a brain-penetrating drug for improving neurodegenerative and neurological symptoms, which are considered the most serious symptoms in GM1 gangliosidosis disease.

[0047] The cyclohexene derivative according to one specific example of the present invention can be applied to diseases caused by double allelic mutations of GLB1 encoding β-galactosidase, and thus can be applied to a treatment for MorquioB (MPSIV) disease, which is a disease caused by the same gene mutation, and has the potential to be applied to a treatment for Krabbe disease, which is a deficiency in the activity of galactocerebrosidase enzyme that takes β-galactose as a degradation substrate, and a treatment for ceramide lactoside lipidosis.

[0048] Cyclohexene derivatives according to one specific example of the present invention exhibit a very high activity restoration of mutant human β-galactosidase, and in particular, exhibit excellent blood-brain barrier penetration properties, thereby showing a very high level of mutant enzyme activity increase and reduction of GM1-ganglioside accumulation not only in surrounding organ tissues but also in brain tissues. Therefore, the cyclohexene derivatives can act as pharmacological protectors restoring the activity of mutant β-galactosidase, and can be useful as therapeutic agents for glycolipid metabolism disorders, including GM1-gangliosidosis diseases accompanied by brain lesions and neurodegenerative symptoms.

[0049]

[0050] The present invention provides a cyclohexene derivative and a pharmaceutical composition comprising the same, which can act as a pharmacological protector for mutated β-galactosidase by increasing the activity of β-galactosidase and can be used for the treatment or prevention of GM1 gangliosidosis. The pharmaceutical composition comprises a cyclohexene derivative as an active ingredient and, in addition, a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is not particularly limited as long as it is a substance commonly used in the relevant technical field.

[0051] In defining a cyclohexene derivative according to one specific example of the present invention, the terms used in the present specification may be defined as follows.

[0052] The term “C” as used herein n1-n2 " means that the functional group has n1 to n2 carbon atoms.

[0053] The term “alkyl” as used herein refers to a straight or branched chain saturated hydrocarbon containing one radical, wherein one radical determines a bonding position as a functional group, and the bonding position is not particularly limited. Examples of the term “alkyl” include, but are not necessarily limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, and hexyl.

[0054] The term “alkylene” as used herein refers to a straight-chain or branched-chain saturated hydrocarbon containing two radicals, each of which serves as a functional group and determines a bonding position, and the bonding position is not particularly limited. Examples of the term “alkylene” include, but are not necessarily limited to, methylene and ethylene.

[0055] The term "alkenyl" as used herein refers to a straight-chain or branched-chain hydrocarbon containing one radical and having one or more carbon-carbon double bonds, wherein one radical serves as a functional group and determines the bonding position, and the bonding position is not particularly limited. Examples of the term "alkenyl" include, but are not necessarily limited to, ethenyl and propenyl.

[0056] As used herein, “alkenylene” refers to a straight or branched chain hydrocarbon having two radicals and at least one carbon-carbon double bond, each of which serves as a functional group to determine a bonding position, and the bonding position is not particularly limited. Examples of the term “alkenylene” include, but are not necessarily limited to, ethenylene, propenylene, and the like.

[0057] The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon group containing one radical and having one or more carbon-carbon triple bonds, wherein one radical serves as a functional group and determines the bonding position, and the bonding position is not particularly limited. Examples of the term "alkynyl" include, but are not necessarily limited to, acetylenyl and 1-propynyl.

[0058] The term “halogen” as used herein means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0059] The term “halogenated alkyl” as used herein means alkyl in which one or more hydrogens are replaced by halogen.

[0060] The term “cycloalkyl” as used herein refers to a saturated hydrocarbon having one or more rings and containing one radical, wherein one radical serves as a functional group and determines the bonding position, and the bonding position is not particularly limited. Examples of the term “cycloalkyl” include, but are not necessarily limited to, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like.

[0061] The term “cycloalkylene” as used herein refers to a saturated hydrocarbon having two radicals and one or more rings, each of which serves as a functional group to determine a bonding position, and the bonding position is not particularly limited. Examples of the term “cycloalkylene” include, but are not necessarily limited to, cyclopentylene, cyclohexylene, and cycloheptylene.

[0062] The term “cycloalkenyl” as used herein refers to a hydrocarbon containing one radical, having one or more rings, and having one or more carbon-carbon double bonds within the ring, wherein one radical serves as a functional group and determines a bonding position, and the bonding position is not particularly limited. Examples of the term “cycloalkenyl” include, but are not necessarily limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0063] The term “cycloalkanonyl” as used herein means a cycloalkyl in which one carbon atom forming the ring is replaced by a -C(O)- group.

[0064] The term “n1-n2 membered” as used herein means a group in which the sum of the number of carbon atoms and the number of heteroatoms is n1 to n2. While heteroatoms broadly refer to elements other than carbon, the term “n1-n2 membered” as used herein is used in front of a cyclic functional group to refer to the number of elements constituting the ring.

[0065] The term “heterocycloalkyl” as used herein refers to a saturated hydrocarbon containing one radical, having one or more rings, and having one or more heteroatoms within the ring, wherein one radical serves as a functional group and determines a bonding position, and the bonding position is not particularly limited. The heteroatom can form a ring, and examples thereof include O, N, S, etc. Examples of the term “heterocycloalkyl” include, but are not necessarily limited to, piperidinyl and tetrahydropyranyl.

[0066] The term "aryl" as used herein refers to an aromatic ring hydrocarbon having one or more rings and containing one radical, wherein one radical serves as a functional group and determines the bonding position, and the bonding position is not particularly limited. Examples of the term "aryl" include, but are not necessarily limited to, phenyl and naphthyl.

[0067] The term “heteroaryl” as used herein refers to an aromatic ring hydrocarbon having one radical, one or more rings, and one or more heteroatoms in the ring, wherein one radical serves as a functional group and determines a bonding position, and the bonding position is not particularly limited. The heteroatom can form a ring, and examples thereof include O, N, S, etc. Examples of the term “heteroaryl” include, but are not necessarily limited to, pyrrolyl and furanyl.

[0068] The term "alkoxy" as used herein means R a The above-mentioned alkyl -OR a Refers to a functional group of the form. Examples of the term “alkoxy” include, but are not necessarily limited to, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.

[0069] The term “halogenated alkoxy” as used herein means an alkoxy in which one or more hydrogens are replaced by a halogen.

[0070] The term “alkoxy-alkoxy” as used herein means R a is alkylene, and R b The above-mentioned alkyl -OR a -OR b Refers to a functional group of the form. Examples of the term “alkoxy-alkoxy” include, but are not necessarily limited to, methoxy-methoxy, methoxy-ethoxy, and ethoxy-ethoxy.

[0071] The term “cycloalkyl-alkoxy” as used herein means R a is alkylene, and R b -OR, the cycloalkyl group described above a -R bRefers to a functional group of the form. Examples of the term “cycloalkyl-alkoxy” include, but are not necessarily limited to, cyclopentyl-methoxy, cyclopentyl-ethoxy, cyclohexyl-methoxy, and cyclohexyl-ethoxy.

[0072] The term “aryl-alkoxy” as used herein refers to R a is alkylene, and R b The above-mentioned aryl -OR a -R b Refers to a functional group of the form. Examples of the term “aryl-alkoxy” include, but are not necessarily limited to, phenyl-methoxy and phenyl-ethoxy.

[0073] The term “alkenyloxy” as used herein refers to R a -OR, the alkenyl group described above a It refers to a functional group of the form. Examples of the term “alkenyloxy” include, but are not necessarily limited to, ethenyloxy and propenyloxy.

[0074] The term “alkynyloxy” as used herein refers to R a -OR, the alkynyl group described above a It refers to a functional group of the form. Examples of the term “alkynyloxy” include, but are not necessarily limited to, ethynyloxy and propynyloxy.

[0075] The term “cycloalkyloxy” as used herein means R a -OR, the cycloalkyl group described above a It refers to a functional group of the form. Examples of the term “cycloalkyloxy” include, but are not necessarily limited to, cyclopentyloxy and cyclohexyloxy.

[0076] The term “cycloalkenyloxy” as used herein refers to R a -OR, the cycloalkenyl group described above a It refers to a functional group of the form. Examples of the term “cycloalkenyloxy” include, but are not necessarily limited to, cyclopentenyloxy and cyclohexenyloxy.

[0077] The term “heterocycloalkyloxy” as used herein means R a -OR, the heterocycloalkyl described above a Refers to a functional group of the form. Examples of the term “heterocycloalkyloxy” include, but are not necessarily limited to, piperidinyloxy and tetrahydropyranyloxy.

[0078] The term “aryloxy” as used herein refers to R a The above-mentioned aryl -OR a Refers to a functional group of the form. Examples of the term “aryloxy” include, but are not necessarily limited to, phenyloxy and naphthyloxy.

[0079] The term “heteroaryloxy” as used herein refers to R a -OR, the heteroaryl group described above a It refers to a functional group of the form. Examples of the term “heteroaryloxy” include, but are not necessarily limited to, pyrrolyloxy and furanyloxy.

[0080] The term “arylsulfonamidyl” as used herein refers to R a The aryl -NHSO2R described above a It refers to a functional group of the form. Examples of the term “arylsulfonamidyl” include, but are not necessarily limited to, phenylsulfonamidyl and naphthylsulfonamidyl.

[0081] The term “heteroarylsulfonamidyl” as used herein refers to R a The heteroaryl described above - NHSO2R a It refers to a functional group of the form. Examples of the term “heteroaryloxy” include, but are not necessarily limited to, pyrrolylsulfonamidyl and furanylsulfonamidyl.

[0082] The term “non-aromatic condensed ring” as used herein refers to C 6-10 C to aryl or 5-10 membered heteroaryl 3-7 Cycloalkyl, C 5-7It refers to a polycyclic ring in which a cycloalkenyl or a 3-7 membered heterocycloalkyl is condensed. Examples of the term “non-aromatic condensed ring” include, but are not necessarily limited to, benzofuranyl and indenyl.

[0083] The term “mercapto” as used herein refers to a functional group of the form -SH.

[0084] The term “hydroxy” as used herein refers to a functional group of the form -OH.

[0085] The term "amino" as used herein refers to a functional group of the form -NH2. The amino may have one or more hydrogens substituted with the above-described alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. For example, if one hydrogen in the amino is replaced with an alkyl, it is called a mono-alkylamino, and if two hydrogens in the amino are replaced with alkyl, it is called a di-alkylamino.

[0086] The term “cyano” as used herein refers to a functional group of the form -CN.

[0087] The term “carbamoyl” as used herein refers to a functional group of the form -C(O)NH2, wherein one or more hydrogens may be substituted with alkyl or the like.

[0088] The term “nitro” as used herein refers to a functional group of the form -NO2.

[0089] For the functional groups described above, even if not indicated separately, halogen, hydroxy, cyano, nitro, amino, mercapto, carbamoyl, C 1-4 By substituting alkyl, etc., it can be easily changed within the scope understandable to a person skilled in the art.

[0090] The present invention is also understood to encompass pharmaceutically acceptable salts of the compounds according to the present invention. Examples of such salts include acid addition salts, such as hydrochloric acid, trifluoroacetic acid, formic acid, citric acid, fumaric acid, monosodium fumarate, p-toluenesulfonic acid, stearic acid, disodium citrate, tartaric acid, malic acid, lactic acid, succinic acid, and salicylic acid addition salts; and salts with alkaline earth metals, such as sodium, potassium, and magnesium salts.

[0091]

[0092] According to one specific example of the present invention, the cyclohexene derivative is a compound of chemical formula 1:

[0093] [Chemical Formula 1]

[0094]

[0095] Hereinafter, X, R1, R2, and R3 described in the above chemical formula 1 will be described in detail.

[0096] The above X is a functional group linked to a methyl group substituted on cyclohexyl. According to one specific example of the present invention, the X is a halogen. The halogen in the X is fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), specifically, fluorine (F), chlorine (Cl), or bromine (Br), more specifically, fluorine (F) or chlorine (Cl), and even more specifically, fluorine (F).

[0097] The above R1 is a functional group directly connected to the double bond of cyclohexyl. In addition, R2 is a functional group connected to the nitrogen substituted on cyclohexyl. According to one specific example of the present invention, the above R1 and R2 are each independently hydrogen or C 1-4 It is alkyl. In the above R1 and R2, alkyl is C 1-4 Alkyl, C 1-3 Alkyl, C 1-2It may be alkyl, etc. According to one specific example of the present invention, at least one of R1 and R2 is hydrogen, and specifically, both R1 and R2 are hydrogen.

[0098] The above L is a linker connecting N and R3. According to one specific example of the present invention, L is a direct bond, C 1-7 Alkylene, C 1-7 Halogenated alkylene, C 1-7 Alkenylene, C 3-7 Cycloalkylene or a combination thereof. Here, the combination means, for example, a combination of alkylene and cycloalkylene, and the combination can be repeatedly expanded. Examples of the combination include, but are not necessarily limited to, methylene-cyclohexylene, ethylene-cyclohexylene, methylene-cyclohexylene-methylene, ethylene-cyclohexylene-ethylene, etc. According to one specific embodiment of the present invention, L is C 1-7 Alkylene, C 3-7 Cycloalkylene or C 1-7 Alkylene- C 3-7 Cycloalkylene, specifically C 1-7 Alkylene or C 1-7 Alkylene- C 3-7 Cycloalkylene, more specifically C 1-7 It is alkylene. In the above L, alkylene is C 1-7 Alkylene, C 1-6 Alkylene, C 1-5 Alkylene, C 1-4 Alkylene, C 1-3 Alkylene, C 1-2 It may be alkylene, etc.

[0099] The above R3 is a functional group connected to L. According to one specific example of the present invention, the above R3 is hydrogen, halogen, hydroxy, cyano, nitro, amino, mercapto, carbamoyl, C 1-7 Alkyl, C 1-7 Halogenated alkyl, C 2-7 Alkenyl, C 2-7 alkynyl, C 1-7 Alkoxy, C 1-7 Halogenated alkoxy, C1-4　 Alkoxy-C 1-4　 Alkoxy, C 3-10 Cycloalkyl-C 1-4 Alkoxy, C 6-10 Aryl-C 1-4 Alkoxy, C 2-7 Alkenyloxy, C 2-7 alkynyloxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkanonyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Arylsulfonamidyl, 5-10 membered heteroarylsulfonamidyl and non-aromatic condensed ring selected from the group consisting of C 6-10 C to aryl or 5-10 membered heteroaryl 3-7 Cycloalkyl, C 3-7 It is a polycyclic ring in which cycloalkenyl or 3-7 membered heterocycloalkyl is condensed.

[0100] According to one specific example of the present invention, R3 is C 3-10 Cycloalkyl-C 1-4 Alkoxy, C 6-10 Aryl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10Selected from the group consisting of aryl and 5-10 membered heteroaryl, and specifically selected from the group consisting of cyclopentyl, cyclohexyl, adamantyl, cyclopentyloxy, cyclohexyloxy, adamantyloxy, cyclopentenyl, cyclohexenyl, cyclopentenyloxy, cyclohexenyloxy, tetrahydropyranyl, phenyl, phenyloxy and phenylmethoxy.

[0101] C in the above R3 6-10 Aryl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Functional groups containing rings such as arylsulfonamidyl, 5-10 membered heteroarylsulfonamidyl and non-aromatic condensed rings may be substituted with specific substituents.

[0102] According to one specific example of the present invention, in the R3, C 6-10 Aryl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkanonyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Arylsulfonamidyl, 5-10 membered heteroarylsulfonamidyl and non-aromatic condensed rings are each independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4　 Alkoxy-C 1-4　Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl, C 3-7 Cycloalkenyl, C 3-7 Cycloalkyloxy, 3-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, mono- or di-C 1-4 Alkylamino and mono- or di-C 6-10 It may be substituted with a substituent selected from the group consisting of arylamino.

[0103] According to one specific example of the present invention, the substituent may be substituted with a halogen.

[0104] According to one specific example of the present invention, in the R3, C 6-10 Aryl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkanonyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Arylsulfonamidyl, 5-10 membered heteroarylsulfonamidyl and non-aromatic condensed rings are each independently halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 It may be substituted with a substituent selected from the group consisting of halogenated alkoxy.

[0105] According to one specific example of the present invention, R3 is cyclopentyl, cyclohexyl, phenyl or phenyloxy, and in R3, cyclopentyl, cyclohexyl, phenyl and phenyloxy may each be independently substituted with a substituent selected from the group consisting of halogen, methyl, ethyl, propyl, halogenated methyl, halogenated ethyl and halogenated propyl.

[0106] Two C among the above substituents 1-4 Alkyl groups can be linked to each other by direct bonds, -CH2-, -O-, -S-, or -NH- to form rings. Substituents substituted on the same or adjacent atoms, as well as those substituted on atoms that are somewhat distant from each other, can be linked to form rings as long as the positions of the substituents are close together.

[0107] For the functional groups described above, even if not indicated separately, halogen, hydroxy, cyano, nitro, amino, mercapto, carbamoyl, C 1-4 By substituting alkyl, etc., it can be easily changed within the scope understandable to a person skilled in the art.

[0108] The above cyclohexene derivative may be in the form of a pharmaceutically acceptable salt of the compound of formula 1. The salt is formed by adding an acid to the compound of formula 1, and may be a sulfonate, a carboxylate, or a hydrochloride. For example, the salt may be hydrochloric acid, trifluoroacetic acid, formic acid, p-toluenesulfonic acid, succinic acid, or the like.

[0109] The three-dimensional structure of the above cyclohexene derivative is not particularly limited, but a compound having a three-dimensional structure represented by the following chemical formula 2 may be preferred. According to one specific example of the present invention, the cyclohexene derivative has a three-dimensional structure such as, for example, compounds 1 to 89 below.

[0110] [Chemical Formula 2]

[0111]

[0112] According to one specific example of the present invention, the cyclohexene derivatives are compounds 1 to 89 of Table 1 below.

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131] The above compounds 1 to 89 are named as follows and are manufactured according to the manufacturing method described below. 1 H NMR, 19 The structure was confirmed by F NMR and LCMS results.

[0132]

[0133] Compound 1:

[0134] (1S,2S,3S,6R)-6-((cyclohexylmethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0135] 1 H NMR (400 MHz, DMSO-d6) δ 0.81-0.94 (m, 2H), 1.10-1.25 (m, 3H), 1.27-1.37 (m, 1H), 1.57-1.77 (m, 5H), 2.27-2.34 (m, 1H), 2.42-2.46 (m, 1H), 2.87-2.95 (m, 1H), 3.32-3.37 (m, 1H), 3.48-3.59 (m, 1H), 3.98-4.06 (m, 1H), 4.50-5.20 (m, 5H), 5.70-5.71 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.12 (t, J = 47 Hz); LCMS (M+H) + : 274.18.

[0136]

[0137] 화합물 2:

[0138] (1S,2S,3S,6R)-6-((cyclohexylmethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol 4-methylbenzenesulfonate

[0139] 1H NMR (400 MHz, DMSO-d6) δ 0.90-1.00 (m, 2H), 1.10-1.30 (m, 3H), 1.60-1.80 (m, 6H), 2.29 (s, 3H), 2.78-2.81 (m, 2H), 3.40-3.42 (m, 1H), 3.60-3.70 (m, 1H), 3.80-3.88 (m, 1H), 4.02-4.08 (m, 1H), 4.85-5.60 (m, 5H), 5.70-5.75 (m, 1H), 7.11 (d, J = 7.6 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 8.54 (brs, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -223.13 (t, J = 44 Hz); LCMS (M-H) - : 272.02.

[0140]

[0141] 화합물 3:

[0142] (1S,2S,3S,6R)-6-((cyclohexylmethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol formate

[0143] 1 H NMR (400 MHz, DMSO-d6)δ 0.82-0.93 (m, 2H), 1.10-1.24 (m, 3H), 1.30-1.42 (m, 1H), 1.60-1.80 (m, 5H), 2.32-2.39 (m, 1H), 2.50-2.55 (m, 1H), 3.00-3.10 (m, 1H), 3.30-3.32 (m, 1H), 3.55-3.62 (m, 1H), 4.00-4.05 (m, 1H), 4.50-5.10 (m, 5H), 5.70-5.72 (m, 1H), 8.19 (s, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -215.30 (t, J = 47 Hz); LCMS (M+H) + : 274.15.

[0144]

[0145] 화합물 4:

[0146] (1S,2S,3S,6R)-6-((cyclohexylmethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol hydrochloride

[0147] 1 H NMR (400 MHz, MeOD-d4) δ 1.00-1.12 (m, 2H), 1.18-1.40 (m, 3H), 1.55-1.90 (m, 6H), 2.94 (d, J = 6.8 Hz, 2H), 3.57 (dd, J = 9.6, 4.0 Hz, 1H), 3.72-3.78 (m, 1H), 3.93-3.96 (m, 1H), 4.22 (d, J = 3.6 Hz, 1H), 4.80-5.20 (m, 2H), 5.78-5.83 (m, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -218.23 (brs); LCMS (M+H) + : 274.14.

[0148]

[0149] 화합물 5:

[0150] (1S,2S,3S,6R)-6-((5-(4-fluoro-2,6-dimethylphenoxy)pentyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0151] 1H NMR (400 MHz, MeOD-d4)δ 1.50-1.70 (m, 4H), 1.80-1.90 (m, 2H), 2.24 (s, 6H), 2.60-2.64 (m, 1H), 2.78-2.83 (m, 1H), 3.16-3.20 (m, 1H), 3.46-3.49 (m, 1H), 3.70-3.77 (m, 3H), 4.19-4.20 (m, 1H), 4.76-5.07(m, 2H), 5.84-5.85 (m, 1H), 6.72 (d, J = 9.2 Hz, 2H); 19 F NMR (376 MHz, MeOD-d4) δ -122.38 (t, J = 8.6 Hz), -219.02 (brs);LCMS (M+H) + : 386.27.

[0152]

[0153] 화합물 6:

[0154] (1S,2S,3S,6R)-6-((5-(4-fluoro-2,6-dimethylphenoxy)pentyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol 2,2,2-trifluoroacetate

[0155] 1 H NMR (400 MHz, MeOD-d4) δ 1.60-1.78 (m, 4H), 1.80-1.90 (m, 2H), 2.24 (s, 6H), 2.78-2.88 (m, 1H), 2.90-3.00 (m, 1H), 3.35-3.40 (m, 1H), 3.48-3.52 (m, 1H), 3.76 (t, J = 6.4 Hz, 2H), 3.81-3.84 (m, 1H), 4.21 (d, J = 4.4 Hz, 1H), 4.80-5.10 (m, 2H), 5.82-5.87 (m, 1H), 6.72 (d, J = 8.8 Hz, 2H); 19F NMR (376 MHz, MeOD-d4) δ -76.95, -122.30 (t, J = 8.6 Hz), -220.57 (brs); LCMS (M+H) + : 386.23.

[0156]

[0157] 화합물 7:

[0158] (1S,2S,3S,6R)-6-((2-cyclohexylethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0159] 1 H NMR (400 MHz, MeOD-d4) δ 0.89-1.01 (m, 2H), 1.15-1.50 (m, 6H), 1.62-1.80 (m, 5H), 2.58-2.65 (m, 1H), 2.75-2.84 (m, 1H), 3.12-3.20 (m, 1H), 3.44-3.50 (m, 1H), 3.70-3.77 (m, 1H), 4.19 (d, J = 4.0 Hz 1H), 4.60-5.10 (m, 2H), 5.82-5.85 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.19 (t, J = 46 Hz);LCMS (M+H) + : 288.14.

[0160]

[0161] 화합물 8:

[0162] (1S,2S,3S,6R)-6-((3-cyclohexylpropyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0163] 1H NMR (400 MHz, MeOD-d4) δ 0.85-0.96 (m, 2H), 1.17-1.40 (m, 6H), 1.50-1.58 (m, 2H), 1.60-1.80 (m, 5H), 2.50-2.62 (m, 1H), 2.70-2.80 (m, 1H), 3.12-3.20 (m, 1H), 3.44-3.51 (m, 1H), 3.69-3.76 (m, 1H), 4.18 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.81-5.84 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.14 (brs); LCMS (M+H) + : 302.18.

[0164]

[0165] 화합물 9:

[0166] (1S,2S,3S,6R)-6-((5-((4-fluorobenzyl)oxy)pentyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0167] 1 H NMR (400 MHz, MeOD-d4) δ 1.42-1.51 (m, 2H), 1.62-1.69 (m, 4H), 2.85-3.02 (m, 2H), 3.30-3.35 (m, 1H), 3.45-3.55 (m, 4H), 3.80-3.90 (m, 1H), 4.21 (d, J = 4.0 Hz, 1H), 4.47 (s, 2H), 4.80-5.10 (m, 2H), 5.80-5.83 (m, 1H), 7.06 (t, J = 8.8 Hz, 2H), 7.33-7.36 (m, 2H); 19 F NMR (376 MHz, MeOD-d4) δ -116.30, -220.92 (brs); LCMS (M+H) + : 372.13.

[0168]

[0169] 화합물 10:

[0170] (1S,2S,3S,6R)-6-((5-(4-chloro-2,6-dimethylphenoxy)pentyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0171] 1 H NMR (400 MHz, MeOD-d4) δ 1.54-1.70 (m, 4H), 1.80-1.91 (m, 3H), 2.23 (s, 6H), 2.66-2.76 (m, 1H), 2.82-2.88 (m, 1H), 3.20-3.26 (m, 1H), 3.44-3.53 (m, 1H), 3.71-3.81 (m, 3H), 4.16-4.22 (m, 1H), 4.70-5.10 (m, 2H), 5.81-5.88 (m, 1H), 6.96-7.02 (m, 2H); 19 F NMR (376 MHz, MeOD-d4) δ -219.63 (brs); LCMS (M+H) + : 402.13.

[0172]

[0173] 화합물 11:

[0174] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((5-(4-fluorophenoxy)pentyl)amino)cyclohex-4-ene-1,2,3-triol

[0175] 1 H NMR (400 MHz, DMSO-d6) δ 1.37-1.44 (m, 4H), 1.65-1.78 (m, 3H), 2.40-2.45 (m, 1H), 2.60-2.70 (m, 1H), 2.90-2.98 (m, 1H), 3.10-3.20 (m, 1H), 3.50-3.60 (m, 1H), 3.92 (t, J = 6.8 Hz, 2H), 4.00-4.05 (m, 1H), 4.71-5.02 (m, 5H), 5.70-5.73 (m, 1H), 6.90-6.96 (m, 2H), 7.05-7.13 (m, 2H); 19F NMR (376 MHz, DMSO-d6) δ -124.34 (t, J = 8.3 Hz), -214.65 (t, J = 47 Hz); LCMS (M+H) + : 358.13.

[0176]

[0177] 화합물 12:

[0178] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((5-(4-fluorophenoxy)pentyl)amino)cyclohex-4-ene-1,2,3-triol formate

[0179] 1 H NMR (400 MHz, MeOD-d4) δ 1.52-1.62 (m, 2H), 1.65-1.85 (m, 4H), 2.88-3.00 (m, 1H), 3.01-3.08 (m, 1H), 3.47-3.55 (m, 2H), 3.83-3.90 (m, 1H), 3.95 (t, J = 6.0 Hz, 2H), 4.21 (d, J = 4.0 Hz, 1H), 4.80-5.10 (m, 2H), 5.82-5.84 (m, 1H), 6.85-6.90 (m, 2H), 6.95-7.01 (m, 2H), 8.53 (brs, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -124.23, -215.05 (t, J = 51 Hz); LCMS (M+H) + : 358.19.

[0180]

[0181] 화합물 13:

[0182] (1S,2S,3S,6R)-6-((5-(4-bromo-2,6-dimethylphenoxy)pentyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0183] 1H NMR (400 MHz, MeOD-d4) δ 1.51-1.70 (m, 4H), 1.79-1.90 (m, 2H), 2.20 (s, 6H), 2.60-2.71 (m, 1H), 2.80-2.88 (m, 1H), 3.10-3.20 (m, 1H), 3.45-3.51 (m, 1H), 3.70-3.80 (m, 3H), 4.19 (d, J = 4.0 Hz, 1H), 4.65-5.10 (m, 2H), 5.84-5.85 (m, 1H), 7.13-7.15 (m, 2H); 19 F NMR (376 MHz, MeOD-d4) δ -219.09 (t, J = 44 Hz); LCMS (M+H) + : 446.32.

[0184]

[0185] 화합물 14:

[0186] (1S,2S,3S,6R)-6-((6-(4-fluoro-2,6-dimethylphenoxy)hexyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0187] 1 H NMR (400 MHz, MeOD-d4) δ 1.42-1.51 (m, 2H), 1.52-1.63 (m, 4H), 1.75-1.86 (m, 2H), 2.24 (s, 6H), 2.60-2.68 (m, 1H), 2.77-2.83 (m, 1H), 3.15-3.22 (m, 1H), 3.46-3.49 (m, 1H), 3.71-3.79 (m, 3H), 4. 20 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.83-5.87 (m, 1H), 6.72 (d, J = 8.8 Hz, 2H); LCMS (M+H) + : 400.15.

[0188]

[0189] 화합물 15:

[0190] (1S,2S,3S,6R)-6-((4-chlorophenethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0191] 1 H NMR (400 MHz, DMSO-d6) δ 2.65-2.78 (m, 3H), 2.80-2.90 (m, 1H), 2.95-3.10 (m, 1H), 3.15-3.20 (m, 1H), 3.50-3.55 (m, 1H), 4.00-4.05 (m, 1H), 4.50-5.10 (m, 5H), 5.69-5.74 (m, 1H), 7.24-7.34 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) δ -214.33 (t, J = 47 Hz); LCMS (M+H) + : 316.12.

[0192]

[0193] 화합물 16:

[0194] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((4-methylphenethyl)amino)cyclohex-4-ene-1,2,3-triol

[0195] 1 H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.60-2.74 (m, 3H), 2.80-2.90 (m, 1H), 2.95-3.03 (m, 1H), 3.28-3.29 (m, 1H), 3.50-3.57 (m, 1H), 3.98-4.03 (m, 1H), 4.71-5.03 (m, 5H), 5.70-5.75 (m, 1H), 7.06-7.11 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) δ -214.33 (t, J = 48 Hz); LCMS (M+H) + : 296.24.

[0196]

[0197] 화합물 17:

[0198] (1S,2S,3S,6R)-6-((2-(((3R,5S,7R)-3,5-dimethyladamantan-1-yl)oxy)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0199] 1 H NMR (400 MHz, DMSO-d6)δ 0.83 (s, 6H), 1.08 (s, 2H), 1.20-1.39 (m, 9H), 1.46-1.55 (m, 2H), 2.10-2.18 (m, 1H), 2.54-2.60 (m, 1H), 2.64-2.76 (m, 1H), 2.88-2.97 (m, 1H), 3.26-3.30 (m, 1H), 3.37-3.44 (m, 2H), 3.46-3.53 (m, 1H), 3.96-4.04 (m, 1H), 4.68-5.05 (m, 5H), 5.69-5.76 (m, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -214.49 (t, J = 45 Hz); LCMS (M+H) + : 384.46.

[0200]

[0201] 화합물 18:

[0202] (1S,2S,3S,6R)-6-((2-((3R,5R,7R)-adamantan-1-yl)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0203] 1H NMR (400 MHz, MeOD-d4) δ 1.25-1.37 (m, 2H), 1.50-1.60 (m, 6H), 1.62-1.68 (m, 3H), 1.70-1.86 (m, 3H), 1.90-1.97 (m, 3H), 2.51-2.62 (m, 1H), 2.70-2.82 (m, 1H), 3.10-3.18 (m, 1H), 3.45-3.50 (m, 1H), 3.58-3.65 (m, 1H), 4.20 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.82-5.83 (m, 1H); LCMS (M+H) + : 340.35.

[0204]

[0205] 화합물 19:

[0206] (1S,2S,3S,6R)-6-((1-((1S,3S)-adamantan-1-yl)propan-2-yl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0207] 1 H NMR (400 MHz, MeOD-d4) δ 1.10-1.25 (m, 4H), 1.28-1.42 (m, 2H), 1.50-1.65 (m, 6H), 1.66-1.80 (m, 6H), 1.90-1.95 (m, 3H), 3.05-3.20 (m, 2H), 3.49-3.70 (m, 2H), 4.21-4.22 (m, 1H), 4.70-5.10 (m, 2H), 5.80-5.92 (m, 1H); LCMS (M+H) + : 354.42.

[0208]

[0209] 화합물 20:

[0210] (1S,2S,3S,6R)-6-(benzylamino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0211] 1H NMR (400 MHz, DMSO-d6) δ 2.95-3.03 (m, 1H), 3.20-3.25 (m, 1H), 3.58-3.72 (m, 2H), 3.80-3.87 (m, 1H), 4.00-4.05 (m, 1H), 4.50-5.05 (m, 5H), 5.80-5.82 (m, 1H), 7.19-7.23 (m, 1H), 7.28-7.39 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) δ -214.53 (t, J = 44 Hz); LCMS (M+H) + : 268.4.

[0212]

[0213] 화합물 21:

[0214] (1S,2S,3S,6R)-6-((5-((4-fluoro-2,6-dimethylbenzyl)oxy)pentyl)amino)-4-fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0215] 1 H NMR (500 MHz, DMSO-d6) δ 1.30-1.43 (m, 4H), 1.48-1.53 (m, 2H), 1.60-1.80 (brs, 1H), 2.32 (s, 6H), 2.40-2.42 (m, 1H), 2.55-2.64 (m, 1H), 2.91 (t, J = 13.0 Hz, 1H), 3.25-3.30 (m, 1H), 3.42 (t, J = 6.5 Hz, 2H), 3.50-3.54 (m, 1H), 3.99-4.02 (m, 1H), 4.39 (s, 2H), 4.60-5.05 (m, 5H), 5.69-5.73 (m, 1H), 6.85 (d, J = 8.0 Hz, 2H); 19 F NMR (376 MHz, DMSO-d6) δ -115.71 (t, J = 8.3 Hz), -214.53 (t, J = 45 Hz); LCMS (M+H) + : 400.18.

[0216]

[0217] 화합물 22:

[0218] (1S,2S,3S,6R)-6-((4-(4-fluoro-2,6-dimethylphenoxy)butyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0219] 1 H NMR (400 MHz, DMSO-d6) δ 1.52-1.65 (m, 2H), 1.70-1.80 (m, 2H), 2.21 (s, 6H), 2.55-2.60 (m, 1H), 2.63-2.75 (m, 1H), 2.90-2.96 (m, 1H), 3.28-3.30 (m, 1H), 3.50-3.60 (m, 1H), 3.69 (t, J = 5.0 Hz, 2H), 4.00-4.05 (m, 1H), 4.50-5.10 (m, 5H), 5.72-5.76 (m, 1H), 6.85 (d, J = 9.0 Hz, 2H); 19 F NMR (470 MHz, DMSO-d6) δ -120.25 (t, J = 8.9 Hz), -214.61 (t, J = 48 Hz); LCMS (M+H) + : 372.25.

[0220]

[0221] 화합물 23:

[0222] (1S,2S,3S,6R)-4-(fluoromethyl)-6-(phenethylamino)cyclohex-4-ene-1,2,3-triol

[0223] 1 H NMR (400 MHz, DMSO-d6) δ 2.68-2.78 (m, 3H), 2.80-2.90 (m, 1H), 2.95-3.00 (m, 1H), 3.20-3.30 (m, 1H), 3.48-3.58 (m, 1H), 4.00-4.05 (m, 1H), 4.50-5.01 (m, 5H), 5.70-5.75 (m, 1H), 7.10-7.30 (m, 5H);19 F NMR (376 MHz, DMSO-d6) δ -214.32(t, J = 47 Hz);LCMS (M+H) + : 282.12.

[0224]

[0225] 화합물 24:

[0226] (1S,2S,3S,6R)-6-((2-cyclopentylethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0227] 1 H NMR (400 MHz, MeOD-d4) δ 1.10-1.21 (m, 2H), 1.50-1.71 (m, 6H), 1.73-1.90 (m, 3H), 2.54-2.68 (m, 1H), 2.78-2.86 (m, 1H), 3.11-3.22 (m, 1H), 3.45-3.50 (m, 1H), 3.70-3.75 (m, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.60-5.10 (m, 2H), 5.82-5.84 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.28 (t, J = 49 Hz); LCMS (M+H) + : 274.14.

[0228]

[0229] 화합물 25:

[0230] (1S,2S,3S,6R)-6-((3-cyclopentylpropyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0231] 1H NMR (400 MHz, MeOD-d4) δ 1.00-1.20 (m, 2H), 1.25-1.70 (m, 8H), 1.75-1.85 (m, 3H), 2.50-2.60 (m, 1H), 2.70-2.80 (m, 1H), 3.05-3.15 (m, 1H), 3.40-3.50 (m, 1H), 3.65-3.75 (m, 1H), 4.15-4.25 (m, 1H), 4.70-5.10 (m, 2H), 5.72-5.73 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.14 (t, J = 51 Hz); LCMS (M+H) + : 288.57.

[0232]

[0233] 화합물 26:

[0234] (1S,2S,3S,6R)-4-(fluoromethyl)-6-(((4-(trifluoromethyl)cyclohexyl)methyl)amino)cyclohex-4-ene-1,2,3-triol

[0235] 1 H NMR (400 MHz, DMSO-d6) δ 0.90-0.98 (m, 2H), 1.18-1.33 (m, 3H), 1.75-1.95 (m, 4H), 2.11-2.21 (m, 1H), 2.29-2.33 (m, 1H), 2.44-2.49 (m, 1H), 2.92-2.98 (m, 1H), 3.28-3.29 (m, 1H), 3.50-3.54 (m, 1H), 3.98-4.02 (m, 1H), 4.63-5.02 (m, 5H), 5.68-5.72 (m, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -214.62 (t, J = 48 Hz); LCMS (M+H) + : 342.21.

[0236]

[0237] 화합물 27:

[0238] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((3-(tetrahydro-2H-pyran-4-yl)propyl)amino)cyclohex-4-ene-1,2,3-triol

[0239] 1 H NMR (500 MHz, DMSO-d6) δ 1.09-1.15 (m, 2H), 1.20-1.24 (m, 2H), 1.37-1.44 (m, 3H), 1.50-1.60 (m, 2H), 1.90 (brs, 1H), 2.41-2.46 (m, 1H), 2.53-2.60 (m, 1H), 2.85-2.95 (m, 1H), 3.21-3.29 (m, 3H), 3.50-3.54 (m, 1H), 3.78-3.83 (m, 2H), 3.95-4.05 (m, 1H), 4.70-5.05 (m, 5H), 5.70-5.73 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.22 (t, J = 44 Hz); LCMS (M+H) + : 304.26.

[0240]

[0241] 화합물 28:

[0242] (1S,2S,3S,6R)-6-(((4,4-difluorocyclohexyl)methyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0243] 1 H NMR (400 MHz, MeOD-d4) δ 1.22-1.36 (m, 2H), 1.65-1.91 (m, 6H), 2.02-2.09 (m, 2H), 2.62-2.67 (m, 1H), 2.73-2.78 (m, 1H), 3.45-3.52 (m, 1H), 3.76-3.81 (m, 1H), 4.20 (d, J = 4.00 Hz, 1H), 4.70-5.10 (m, 2H), 5.81-5.82 (m, 1H); 19F NMR (376 MHz, MeOD-d4) δ -93.05 (d, J = 237 Hz), -103.65 (d J = 243 Hz), -220.15 (brs); LCMS (M+H) + : 310.18.

[0244]

[0245] 화합물 29:

[0246] (1S,2S,3S,6R)-6-(((4,4-difluorocyclohexyl)methyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol formate

[0247] 1 H NMR (400 MHz, MeOD-d4) δ 1.28-1.35 (m, 2H), 1.76-1.93 (m, 6H), 2.05-2.09 (m, 2H), 2.86-2.91 (m, 2H), 3.52-3.56 (m, 1H), 3.86-3.89 (m, 1H), 4.22 (d, J = 4.00 Hz, 1H), 4.70-5.10 (m, 2H), 5.80-5.83 (m, 1H), 8.46 (s, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -89.12 (d, J = 229 Hz), -99.40 (d, J = 227 Hz), -214.61 (t, J = 48 Hz); LCMS (M+H) + : 310.13.

[0248]

[0249] 화합물 30:

[0250] (1S,2S,3S,6R)-6-((2-(4,4-difluorocyclohexyl)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0251] 1H NMR (400 MHz, MeOD-d4) δ 1.23-1.34 (m, 2H), 1.48-1.59 (m, 3H), 1.66-1.86 (m, 4H), 2.00-2.06 (m, 2H), 2.77-2.81 (m, 1H), 2.90-2.97 (m, 1H), 3.35-3.39 (m, 1H), 3.48-3.52 (m, 1H), 3.78-3.82 (m, 1H), 4.20 (d, J = 4.00 Hz, 1H), 4.70-5.10 (m, 2H), 5.80-5.83 (m, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -89.74 (d, J = 232 Hz), -98.73 to -99.46 (m), -216.02 (brs); LCMS (M+H) + : 324.51.

[0252]

[0253] 화합물 31:

[0254] (1S,2S,3S,6R)-6-((5-(4-chlorophenoxy)pentyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0255] 1 H NMR (400 MHz, DMSO-d6)δ 1.38 -1.50 (m, 4H), 1.63-1.75 (m, 2H), 2.41-2.43 (m, 2H), 2.61 -2.70 (m, 1H), 2.90-3.00 (m, 1H), 3.49-3.60 (m, 1H), 3.95 (t, J = 6.4 Hz, 2H), 3.98-4.03 (m, 1H), 4.59-4.99 (m, 5H), 5.65-5.80 (m, 1H), 6.92-6.97 (m, 2H), 7.26-7.35 (m, 2H); 19 F NMR (376 MHz, DMSO-d6)δ-214.67 (brs); LCMS(M+H) + : 374.45.

[0256]

[0257] 화합물 32:

[0258] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((4-isobutoxyphenethyl)amino)cyclohex-4-ene-1,2,3-triol

[0259] 1 H NMR (400 MHz, MeOD-d4) δ 1.02 (d, J = 6.4 Hz, 6H), 2.03 (sept, 1H), 2.71-2.85 (m, 3H), 2.93-3.04 (m, 1H), 3.10-3.20 (m, 1H), 3.42 -3.48 (m, 1H), 3.65-3.75 (m, 3H), 4.18 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.80-5.85 (m, 1H), 6.80-6.86 (m, 2H), 7.09-7.16 (m, 2H); 19 F NMR (376 MHz, DMSO-d6)δ-214.56 (t, J = 45 Hz); LCMS (M+H) + : 354.40.

[0260]

[0261] 화합물 33:

[0262] (1S,2S,3S,6R)-6-((2-(cyclopent-3-en-1-yl)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0263] 1H NMR (500 MHz, MeOD-d4) δ 1.62-1.67 (m, 2H), 1.98-2.03 (m, 2H), 2.28-2.31 (m, 1H), 2.48-2.54 (m, 2H), 2.61-2.68 (m, 1H), 2.81-2.83 (m, 1H), 3.20-3.23 (m, 1H), 3.49 (dd, J = 10, 4.0 Hz, 1H), 3.73-3.76 (m, 1H), 4.20 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.65-5.68 (m, 2H), 5.83-5.84 (m, 1H); 19 F NMR (470 MHz, MeOD-d4) δ -219.47 (brs); LCMS (M+H) + : 272.43.

[0264]

[0265] 화합물 34:

[0266] (1S,2S,3S,6R)-6-((4-(4-chlorophenoxy)butyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0267] 1 H NMR (400 MHz, MeOD-d4) δ 1.70-1.74 (m, 2H), 1.82-1.85 (m, 2H), 2.68-2.73 (m, 1H), 2.82-2.90 (m, 1H), 3.15-3.25 (m, 1H), 3.48 (dd, J = 10, 4.0 Hz, 1H), 3.72-3.75 (m, 1H), 3.99 (t, J = 6.0 Hz, 2H), 4.20 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.80-5.85 (m, 1H), 6.88-6.90 (m, 2H), 7.22-7.24 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) δ -214.67 (brs); LCMS (M+H) + : 360.12.

[0268]

[0269] 화합물 35:

[0270] (1S,2S,3S,6R)-6-((2-(4,4-dimethylcyclohexyl)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0271] 1 H NMR (400 MHz, MeOD-d4) δ 1.88 (s, 3H), 1.89 (s, 3H), 1.13-1.29 (m, 5H), 1.37-1.47 (m, 4H), 1.55-1.58 (m, 2H), 2.56-2.61 (m, 1H), 2.74-2.79 (m, 1H), 3.12-3.14 (m, 1H), 3.45-3.48 (m, 1H), 3.68-3.73 (m, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.90-5.06 (m, 2H), 5.82-5.83 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -218.88 (t, J = 46 Hz); LCMS (M+H) + : 316.24.

[0272]

[0273] 화합물 36:

[0274] (1S,2S,3S,6R)-6-(((4-((4-chlorobenzyl)oxy)cyclohexyl)methyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0275] 1H NMR (400 MHz, MeOD-d4) δ 0.92-1.05 (m, 2H), 1.22-1.32 (m, 2H), 1.43-1.49 (m, 1H), 1.85-1.90 (m, 2H), 2.10-2.13 (m, 2H), 2.43 (dd, J = 12, 6.4 Hz, 1H), 2.59 (dd, J = 12, 6.8 Hz, 1H), 3.12-3.14 (m, 1H), 3.31-3.37 (m, 1H), 3.47 (dd, J = 10, 8.0 Hz, 1H), 3.69-3.73 (m, 1H), 4.19 (d, J = 4.4 Hz, 1H), 4.54 (s, 2H), 4.70-5.10 (m, 2H), 5.81-5.82 (m, 1H), 7.32 (m, 4H); 19 F NMR (376 MHz, MeOD-d4) δ -219.09 (t, J = 46 Hz); LCMS (M+H) + : 414.21.

[0276]

[0277] 화합물 37:

[0278] (1S,2S,3S,6R)-6-((3-(cyclopent-3-en-1-yl)propyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0279] 1 H NMR (400 MHz, MeOD-d4) δ 1.42-1.47 (m, 2H), 1.53-1.59 (m, 2H), 1.95-2.00 (m, 2H), 2.23-2.27 (m, 1H), 2.46-2.51 (m, 2H), 2.59-2.62 (m, 1H), 2.75-2.80 (m, 1H), 3.15-3.20 (m, 1H), 3.48 (dd, J = 10, 4.0 Hz, 1H), 3.70-3.75 (m, 1H), 4.20 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.60-5.70 (m, 2H), 5.82-5.84 (m, 1H);19 F NMR (376 MHz, MeOD-d4) δ -219.29 (t, J = 45 Hz); LCMS (M+H) + : 286.22.

[0280]

[0281] 화합물 38:

[0282] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((2-(4-(trifluoromethyl)cyclohexyl)ethyl)amino)cyclohex-4-ene-1,2,3-triol

[0283] 1 H NMR (400 MHz, MeOD-d4) δ 0.95-1.10 (m, 1H), 1.26-1.37 (m, 2H), 1.39-1.49 (m, 1H), 1.53-1.74 (m, 7H), 1.84-1.96 (m, 2H), 2.02-2.19 (m, 1H), 2.56-2.65 (m, 1H), 2.72-2.84 (m, 1H), 3.11-3.20 (m, 1H), 3.44-3.52 (m, 1H), 3.67-3.76 (m, 1H), 4.20 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.80-5.86 (m, 1H); 19 F NMR (376 MHz, DMSO-d6)δ-75.41 (brs), -219.10 (brs); LCMS (M+H) + : 356.12.

[0284]

[0285] 화합물 39:

[0286] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((4-(trifluoromethoxy)phenethyl)amino)cyclohex-4-ene-1,2,3-triol

[0287] 1H NMR (400 MHz, MeOD-d4) δ 2.82-2.94 (m, 3H), 2.99-3.09 (m, 1H), 3.18-3.25 (m, 1H), 3.46 (dd, J = 10, 4.0 Hz, 1H), 3.72 (dd, J = 10, 8.0, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.80-5.86 (m, 1H), 7.16-7.23 (m, 2H), 7.31-7.37 (m, 2H); 19 F NMR (376 MHz, DMSO-d6)δ-56.80, -214.70 (brs); LCMS (M+H) + : 366.10.

[0288]

[0289] 화합물 40:

[0290] (1S,2S,3S,6R)-6-((4-ethylphenethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0291] 1 H NMR (400 MHz, MeOD-d4) δ 1.20 (t, J = 7.6 Hz, 3H), 2.60 (q, J = 7.6 Hz, 2H), 2.78-2.84 (m, 2H), 2.86-2.95 (m, 1H), 3.02-3.10 (m, 1H), 3.21-3.29 (m, 1H), 3.47 (dd, J = 10, 4.0 Hz, 1H), 3.73 (dd, J = 10, 8.0, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.81-5.84 (m, 1H), 7.11-7.17 (m, 4H); 19 F NMR (376 MHz, DMSO-d6)δ-214.89 (brs); LCMS (M+H) + : 310.13.

[0292]

[0293] 화합물 41:

[0294] (1S,2S,3S,6R)-6-(((4,4-dimethylcyclohexyl)methyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0295] 1 H NMR (400 MHz, DMSO-d6) δ 0.85 (s, 3H), 0.88 (s, 3H), 1.04-1.16 (m, 4H), 1.20-1.25 (m, 1H), 1.32-1.35 (m, 2H), 1.53-1.57 (m, 2H), 2.32-2.35 (m, 1H), 2.47-2.49 (m, 1H), 2.90-3.00 (m, 1H), 3.34-3.38 (m, 1H), 3.52-3.55 (m, 1H), 3.95-4.05 (m, 1H), 4.71-5.02 (m, 5H), 5.70-5.73 (m, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -214.62 (t, J = 50 Hz); LCMS (M+H) + : 302.19.

[0296]

[0297] 화합물 42:

[0298] (1S,2S,3S,6R)-6-((3-(4-chlorophenyl)propyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0299] 1 H NMR (400 MHz, MeOD-d4) δ 1.78-1.86 (m, 2H), 2.57-2.68 (m, 3H), 2.72-2.82 (m, 1H), 3.11-3.19 (m, 1H), 3.45-3.51 (m, 1H), 3.68-3.72 (m, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.70-5.15 (m, 2H), 5.79-5.80 (m, 1H), 7.18-7.21 (m, 2H), 7.24-7.27 (m, 2H); 19F NMR (376 MHz, MeOD-d4) δ -219.15 (brs); LCMS(M+H) + : 330.13.

[0300]

[0301] 화합물 43:

[0302] (1S,2S,3S,6R)-6-((3-chlorophenethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0303] 1 H NMR (400 MHz, MeOD-d4) δ 2.86-2.87 (m, 3H), 2.96-3.04 (m, 1H), 3.14-3.18 (m, 1H), 3.43-3.47 (m, 1H), 3.67-3.71 (m, 1H), 4.17 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.82-5.83 (m, 1H), 7.16-7.21 (m, 2H), 7.25-7.27 (m, 2H); 19 F NMR (376 MHz, MeOD-d4)δ-218.95 (t, J = 47 Hz); LCMS (M+H) + : 316.09.

[0304]

[0305] 화합물 44:

[0306] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((4-(4-(trifluoromethoxy)phenoxy)butyl)amino)cyclohex-4-ene-1,2,3-triol

[0307] 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.57 (m, 2H), 1.66-1.80 (m, 2H), 2.53-2.55 (m, 1H), 2.64-2.71 (m, 1H), 2.91-3.00 (m, 1H), 3.32-3.36 (m, 1H), 3.49-3.59 (m, 1H), 3.95-4.05 (m, 3H), 4.62-5.04 (m, 5H), 5.72-5.76 (m, 1H), 7.02 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H); 19 F NMR (376 MHz, MeOD-d4)δ-60.04, -218.99 (t, J = 48 Hz); LCMS(M+H) + : 410.17.

[0308]

[0309] 화합물 45:

[0310] (1S,2S,3S,6R)-6-((2-(4-chlorophenoxy)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0311] 1 H NMR (400 MHz, MeOD-d4) δ 2.92-3.01 (m, 1H), 3.09-3.15 (m, 1H), 3.17-3.21 (m, 1H), 3.46-3.49 (m, 1H), 3.70-3.74 (m, 1H), 4.04-4.12 (m, 2H), 4.19 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.86-5.87 (m, 1H), 6.92-6.94 (m, 2H), 7.23-7.26 (m, 2H); 19 F NMR (376 MHz, DMSO-d6)δ -214.54 (t, J = 43 Hz); LCMS (M+H) + : 332.10.

[0312]

[0313] 화합물 46:

[0314] (1S,2S,3S,6R)-6-((2-(3,4-dimethylcyclopent-3-en-1-yl)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0315] 1 H NMR (400 MHz, MeOD-d4) δ 1.58-1.66 (m, 8H), 1.96-2.01 (m, 2H), 2.18-2.25 (m, 1H), 2.42-2.47 (m, 2H), 2.68-2.75 (m, 1H), 2.83-2.89 (m, 1H), 3.27-3.29 (m, 1H), 3.50 (dd, J = 10, 4.0 Hz, 1H), 3.76-3.80 (m, 1H), 4.20 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.82-5.83 (m, 1H); 19 F NMR (470 MHz, DMSO-d6) δ -215.68 (brs); LCMS (M+H) + : 300.17.

[0316]

[0317] 화합물 47:

[0318] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((4-methoxyphenethyl)amino)cyclohex-4-ene-1,2,3-triol

[0319] 1 H NMR (400 MHz, MeOD-d4) δ 2.65-2.80 (m, 2H), 3.00-3.20 (m, 2H), 3.30-3.40 (m, 1H), 3.50-3.60 (m, 4H), 3.70-3.80 (m, 1H), 4.02 (d, J = 3.6 Hz, 1H), 4.70-4.90 (m, 2H), 5.60-5.65 (m, 1H), 6.69 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H); LCMS (M+H) + : 312.15.

[0320]

[0321] 화합물 48:

[0322] (1S,2S,3S,6R)-6-((3,4-dichlorophenethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0323] 1 H NMR (400 MHz, MeOD-d4) δ 2.80-2.88 (m, 2H), 2.90-2.98 (m, 1H), 3.00-3.10 (m, 1H), 3.45-3.50 (m, 1H), 3.70-3.80 (m, 1H), 4.20 (d, J = 4.0 Hz, 1H), 4.55-4.60 (m, 1H), 4.70-5.10 (m, 2H), 5.75-5.80 (m, 1H), 7.15-7.20 (m, 1H), 7.40-7.50 (m, 2H); LCMS (M+H) + : 350.06.

[0324]

[0325] 화합물 49:

[0326] (1S,2S,3S,6R)-6-((4-chlorophenethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol hydrochloride

[0327] 1 H NMR (400 MHz, MeOD-d4) δ 2.90-3.10 (m, 2H), 3.25-3.40 (m, 2H), 3.00-3.10 (m, 1H), 3.58 (dd, J = 9.2, 4.4 Hz, 1H), 3.75-3.85 (m, 1H), 3.98 (dd, J = 9.2, 8.0 Hz, 1H), 4.23 (d, J = 4.0 Hz, 1H), 4.80-5.20 (m, 2H), 5.80-5.85 (m, 1H), 7.25-7.30 (m, 2H), 7.31-7.40 (m, 2H); LCMS (M+H) +: 316.10.

[0328]

[0329] 화합물 50:

[0330] (1S,2S,3S,6R)-6-((4-chlorophenethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol formate

[0331] 1 H NMR (400 MHz, MeOD-d4) δ 2.97 (t, J = 8.0 Hz, 2H), 3.15-3.40 (m, 2H), 3.55 (dd, J = 9.6, 4.0 Hz, 1H), 3.60-3.70 (m, 1H), 3.45-3.50 (m, 1H), 3.90 (dd, J = 9.6, 8.0 Hz, 1H), 4.22 (d, J = 4.0 Hz, 1H), 4.80-5.10 (m, 2H), 5.80-5.85 (m, 1H), 7.25-7.30 (m, 2H), 7.31-7.40 (m, 2H), 8.45 (s, 1H); LCMS (M+H) + : 316.10.

[0332]

[0333] 화합물 51:

[0334] (1S,2S,3S,6R)-4-(fluoromethyl)-6-(((4-(trifluoromethyl)cyclohexyl)methyl)amino)cyclohex-4-ene-1,2,3-triol hydrochloride

[0335] 1H NMR (400 MHz, MeOD-d4) δ 1.05-1.20 (m, 2H), 1.21-1.45 (m, 4H), 1.60-1.75 (m, 1H), 1.90-2.05 (m, 4H), 2.10-2.30 (m, 1H), 2.95-3.02 (d, J = 6.8 Hz, 1H), 3.45-3.50 (m, 1H), 3.55-3.65 (m, 1H), 3.70-3.80 (m, 1H), 3.90-4.00 (m, 1H), 4.22 (d, J = 4.0 Hz, 1H), 4.55-4.60 (m, 1H), 4.90-5.20 (m, 2H), 5.30-5.35 (m, 1H); LCMS (M+H) + : 342.16.

[0336]

[0337] 화합물 52:

[0338] (1S,2S,3S,6R)-4-(fluoromethyl)-6-(((4-methylcyclohexyl)methyl)amino)cyclohex-4-ene-1,2,3-triol

[0339] 1 H NMR (400 MHz, MeOD-d4) δ 0.85-0.95 (m, 3H), 1.25-1.85 (m, 10H), 2.40-2.72 (m, 2H), 3.10-3.20 (m, 1H), 3.45-3.50 (m, 1H), 3.68-3.78 (m, 1H), 4.15-4.20 (m, 1H), 4.70-5.10 (m, 2H), 5.80-5.84 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.07 (t, J = 48 Hz); LCMS (M+H) + : 288.15.

[0340]

[0341] 화합물 53:

[0342] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((spiro[2.5]octan-6-ylmethyl)amino)cyclohex-4-ene-1,2,3-triol

[0343] 1 H NMR (400 MHz, MeOD-d4) δ 0.16-0.22 (m, 2H), 0.23-0.30 (m, 2H), 0.85-0.97 (m, 1H), 1.10-1.21 (m, 2H), 1.47-1.60 (m, 1H), 1.68-1.81 (m, 4H), 2.48 (dd, J = 12, 6.4 Hz, 1H), 2.65 (dd, J = 12, 7.2 Hz, 1H), 3.10-3.20 (m, 1H), 3.48 (dd, J = 10, 4.0 Hz, 1H), 3.73 (dd, J = 10, 8.0 Hz, 1H), 4.10 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.80-5.83 (m, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -214.68 (brs); LCMS (M+H) + : 300.17.

[0344]

[0345] 화합물 54:

[0346] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((4-isopropylphenethyl)amino)cyclohex-4-ene-1,2,3-triol

[0347] 1H NMR (400 MHz, MeOD-d4) δ 1.22 (d, J = 6.8 Hz, 6H), 2.75–2.90 (m, 4H), 2.94–3.04 (m, 1H), 3.11–3.19 (m, 1H), 3.45 (dd, J = 10, 4.4 Hz, 1H), 3.69 (dd, J =10, 8.0 Hz, 1H), 4.18 (d, J = 4.4 Hz, 1H), 4.71–5.07 (m, 2H), 5.80–5.82 (m, 1H), 7.15 (s, 4H); 19 F NMR (376 MHz, MeOD-d4) δ-218.98 (t, J = 48 Hz); LCMS (M+H) + : 324.20.

[0348]

[0349] 화합물 55:

[0350] (1S,2S,3S,6R)-6-((4-bromophenethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0351] 1 H NMR (400 MHz, MeOD-d4) δ 2.74–2.88 (m, 3H), 2.94–3.05 (m, 1H), 3.10–3.19 (m, 1H), 3.45 (dd, J = 10, 4.0 Hz, 1H), 3.68 (dd, J = 10, 8.0 Hz, 1H), 4.18 (d, J = 4.4 Hz, 1H), 4.72–5.03 (m, 2H), 5.80–5.83 (m, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H); 19 F NMR (376 MHz, MeOD-d4) δ-219.02 (t, J = 48 Hz); LCMS (M+H) + : 360.05.

[0352]

[0353] 화합물 56:

[0354] (1S,2S,3S,6R)-6-(((1-ethylcyclohexyl)methyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0355] 1 H NMR (400 MHz, MeOD-d4) δ 0.81 (t, J = 7.6 Hz, 3H), 1.25-1.53 (m, 14H), 2.37 (d, J = 12 Hz, 1H), 2.61 (d, J = 12 Hz, 1H), 3.10-3.18 (m, 1H), 3.48 (dd, J = 10, 4.4 Hz, 1H), 3.75 (dd, J = 10, 8.0 Hz, 1H), 4.20 (d, J = 4.4 Hz, 1H), 4.73-5.10 (m, 2H), 5.80-5.85 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -218.91 (brs); LCMS (M+H) + : 302.19.

[0356]

[0357] 화합물 57:

[0358] (1S,2S,3S,6R)-4-(fluoromethyl)-6-(((1-methylcyclohexyl)methyl)amino)cyclohex-4-ene-1,2,3-triol

[0359] 1 H NMR (400 MHz, MeOD-d4) δ 0.94 (s, 3H), 1.24-1.41 (m, 5H), 1.42-1.55 (m, 5H), 2.34 (d, J = 12 Hz, 1H), 2.57 (d, J = 12 Hz, 1H), 3.10-3.20 (m, 1H), 3.45-3.50 (m, 1H), 3.72-3.78 (m, 1H), 4.20 (d, J = 4.4 Hz, 1H), 4.73-5.10 (m, 2H), 5.80-5.82 (m, 1H); 19F NMR (376 MHz, DMSO-d6) δ -214.55 (t, J = 47 Hz); LCMS (M+H) + : 288.19.

[0360]

[0361] 화합물 58:

[0362] (1S,2S,3S,6R)-6-(((S)-1-cyclohexylethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0363] 1 H NMR (400 MHz, MeOD-d4) δ 0.99-1.36 (m, 9H), 1.42-1.53 (m, 1H), 1.64-1.83 (m, 4H), 2.79-2.89 (m, 1H), 3.20-3.25 (m, 1H), 3.54 (dd, J = 9.6, 4.4 Hz, 1H), 3.69 (dd, J = 9.2, 7.6 Hz, 1H), 4.21 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.80-5.82 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.51 (brs); LCMS (M+H) + : 288.19.

[0364]

[0365] 화합물 59:

[0366] (1S,2S,3S,6R)-6-(((R)-1-cyclohexylethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0367] 1H NMR (400 MHz, MeOD-d4) δ 1.00-1.55 (m, 10H), 1.63-1.88 (m, 4H), 2.73-2.87 (m, 1H), 3.20-3.26 (m, 1H), 3.53 (dd, J = 9.6, 4.4 Hz, 1H), 3.63-3.76 (m, 1H), 4.21 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.80-5.85 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -218.87 (brs); LCMS (M+H) + : 288.23.

[0368]

[0369] 화합물 60:

[0370] (1S,2S,3S,6R)-6-(((1-(4-chlorophenyl)cyclopropyl)methyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0371] 1 H NMR (400 MHz, MeOD-d4) δ 0.80-0.90 (m, 4H), 2.78 (d, J = 12 Hz, 1H), 2.91 (d, J = 12 Hz, 1H), 3.05-3.15 (m, 1H), 3.41 (dd, J = 10, 4.4 Hz, 1H), 3.63 (dd, J = 10, 8.0 Hz, 1H), 4.16 (d, J = 4.4 Hz, 1H), 4.70-5.05 (m, 2H), 5.70-5.75 (m, 2H), 7.28 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H); 19 F NMR (376 MHz, MeOD-d4) δ -218.94 (t, J = 46 Hz); LCMS (M+H) + : 342.19.

[0372]

[0373] 화합물 61:

[0374] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((4-(4-fluorophenoxy)butyl)amino)cyclohex-4-ene-1,2,3-triol

[0375] 1 H NMR (400 MHz, MeOD-d4) δ 1.69-1.88 (m, 4H), 2.72-2.83 (m, 1H), 2.87-2.97 (m, 1H), 3.24-3.29 (m, 1H), 3.50 (dd, J = 10, 4.4 Hz, 1H), 3.78 (dd, J = 10, 8.0 Hz, 1H), 3.98 (t, J = 6.0 Hz, 2H), 4.20 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.82-5.86 (m, 1H), 6.84-6.92 (m, 2H), 6.93-7.02 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) δ -124.28, -215.20 (brs); LCMS (M+H) + : 344.12.

[0376]

[0377] 화합물 62:

[0378] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((4-(4-(trifluoromethyl)phenoxy)butyl)amino)cyclohex-4-ene-1,2,3-triol

[0379] 1H NMR (400 MHz, MeOD-d4) δ 1.68-1.76 (m, 2H), 1.83-1.90 (m, 2H), 2.65-2.72 (m, 1H), 2.82-2.89 (m, 1H), 3.13-3.20 (m, 1H), 3.48 (dd, J = 10, 4.4 Hz, 1H), 3.74 (dd, J = 9.6, 8.4 Hz, 1H), 4.08 (t, J = 6.2 Hz, 2H), 4.20 (d, J = 4.4 Hz, 1H), 4.85-5.06 (m, 2H), 5.80-5.84 (m, 1H), 7.05 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H); 19 F NMR (376 MHz, DMSO-d6) δ -59.74, -214.54 (brs); LCMS (M+H) + : 394.12.

[0380]

[0381] 화합물 63:

[0382] (1S,2S,3S,6R)-6-((3-(4,4-difluorocyclohexyl)propyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0383] 1 H NMR (400 MHz, MeOD-d4) δ 1.18-1.50 (m, 5H), 1.51-1.60 (m, 2H), 1.62-1.82 (m, 4H), 1.95-2.05 (m, 2H), 2.58-2.62 (m, 1H), 2.72-2.81 (m, 1H), 3.12-3.20 (m, 1H), 3.48 (dd, J = 10, 4.0 Hz, 1H), 3.73 (dd, J = 10, 8.4 Hz, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.80-5.85 (m, 1H); 19F NMR (376 MHz, DMSO-d6) δ -89.13 (d, J = 232 Hz), -99.48 (d, J = 232 Hz), -214.61 (brs); LCMS (M+H) + : 338.15.

[0384]

[0385] 화합물 64:

[0386] (1S,2S,3S,6R)-4-(fluoromethyl)-6-(((1-hydroxycyclohexyl)methyl)amino)cyclohex-4-ene-1,2,3-triol

[0387] 1 H NMR (400 MHz, DMSO-d6) δ 1.36-1.62 (m, 6H), 1.67-1.81 (m, 1H), 1.83-2.07 (m, 3H), 2.58-2.70 (m, 1H), 3.15-3.21 (m, 1H), 3.37-3.40 (m, 1H), 3.48-3.58 (m, 1H), 3.60-3.72 (m, 1H), 4.00-4.02 (m, 1H), 4.67-5.18 (m, 5H), 5.51-5.83 (m, 2H); 19 F NMR (376 MHz, DMSO-d6) δ -214.58 (brs); LCMS (M+H) + : 290.29. (regioisomeric mixture)

[0388]

[0389] 화합물 65:

[0390] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((3-(4-(trifluoromethyl)cyclohexyl)propyl)amino)cyclohex-4-ene-1,2,3-triol

[0391] 1H NMR (400 MHz, MeOD-d4) δ 0.91-1.05 (m, 1H), 1.20-1.40 (m, 4H), 1.46-1.71 (m, 6H), 1.82-1.97 (m, 2H), 1.99-2.22 (m, 1H), 2.50-2.65 (m, 1H), 2.70-2.80 (m, 1H), 3.10-3.20 (m, 1H), 3.42-3.51 (m, 1H), 3.66-3.77 (m, 1H), 4.20 (d, J = 4.0 Hz, 1H), 4.77-5.03 (m, 2H), 5.78-5.88 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -75.73 to -76.94 (m), -219.30 (brs); LCMS (M+H) + : 370.17. (regioisomeric mixture)

[0392]

[0393] 화합물 66:

[0394] (1S,2S,3S,6R)-6-((2-(4'-chloro-[1,1'-biphenyl]-4-yl)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0395] 1 H NMR (400 MHz, MeOD-d4) δ 2.82-2.89 (m, 3H), 3.00-3.10 (m, 1H), 3.12-3.20 (m, 1H), 3.46 (dd, J = 10, 4 Hz, 1H), 3.70 (dd, J = 9.6, 8.0 Hz, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.80-5.85 (m, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H); 19F NMR (376 MHz, MeOD-d4) δ -219.04 (t, J = 47 Hz); LCMS (M+H) + : 392.19.

[0396]

[0397] 화합물 67:

[0398] (1S,2S,3S,6R)-6-((2,4-dichlorophenethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0399] 1 H NMR (400 MHz, MeOD-d4) δ 2.85-2.99 (m, 4H), 3.10-3.20 (m, 1H), 3.46 (dd, J = 10, 4.0 Hz, 1H), 3.69 (dd, J = 10, 8.0 Hz , 1H), 4.19 (d, J = 4.4 Hz, 1H), 4.76-5.05 (m, 2H), 5.82-5.83 (m, 1H), 7.26 (dd, J = 8.0, 2.0 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1 H), 7.43 (d, J = 2.0 Hz, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -218.96 (t, J = 48 Hz); LCMS (M+H) + : 350.17.

[0400]

[0401] 화합물 68:

[0402] (1S,2S,3S,6R)-6-((4-chloro-2,6-dimethylphenethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0403] 1H NMR (400 MHz, MeOD-d4) δ 2.33 (s, 6H), 2.69-2.79 (m, 1H), 2.85-2.89 (m, 3H), 3.30-3.35 (m, 1H), 3.48 (dd, J = 10, 4.0 Hz, 1H), 3.78 (dd, J = 9.6, 8.0 Hz, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.82-5.86 (m, 1H), 7.01 (s, 2H); 19 F NMR (376 MHz, MeOD-d4) δ -219.97 (brs); LCMS (M+H) + : 344.39.

[0404]

[0405] 화합물 69:

[0406] (1S,2S,3S,6R)-6-((2-cycloheptylethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0407] 1 H NMR (400 MHz, MeOD-d4) δ 1.20-1.35 (m, 2H), 1.40-1.85 (m, 13H), 3.00-3.20 (m, 2H), 3.58 (d, J = 10, 4.0 Hz, 1H) 3.65-3.75 (m, 1H), 3.92-3.96 (m, 1H), 4.24 (d, J = 4.0 Hz, 1H), 4.90-5.20 (m, 2H), 5.80-5.90 (m, 1H); LCMS (M+H) + : 312.2.

[0408]

[0409] 화합물 70:

[0410] (1S,2S,3S,6R)-4-(fluoromethyl)-6-(((4-hydroxycyclohexyl)methyl)amino)cyclohex-4-ene-1,2,3-triol

[0411] 1H NMR (400 MHz, DMSO-d6) δ 1.32-1.35 (m, 6H), 1.48-1.60 (m, 2H), 2.29-2.35 (m, 1H), 2.45-2.52 (m, 1H), 2.92 (t, J = 7.6 Hz, 1H), 3.51-3.56 (m, 1H), 3.71 (brs, 1H), 4.01 (brs, 1H), 4.22 (d, J = 3.2 Hz, 1H) 4.45-5.10 (m, 5H), 5.70-5.73 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.03 (t, J = 46 Hz); LCMS (M+H) + : 290.35.

[0412]

[0413] 화합물 71:

[0414] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((spiro[3.5]nonan-7-ylmethyl)amino)cyclohex-4-ene-1,2,3-triol

[0415] 1 H NMR (400 MHz, MeOD-d4) δ 0.94-1.12 (m, 2H), 1.21-1.37 (m, 2H), 1.40-1.53 (m, 1H), 1.60-1.91 (m, 10H), 1.90-2.10 (m, 1H), 2.60 (dd, J = 12, 6.8 Hz, 1H), 2.71 (dd, J = 12, 7.2 Hz, 1H), 3.34-3.41 (m, 1H), 3.51 (dd, J = 9.6, 4.0 Hz, 1H), 3.81 (dd, J = 9.6, 8.4 Hz, 1H), 4.20 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.80-5.83 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -220.73 (t, J = 51 Hz); LCMS (M+H) + : 314.30.

[0416]

[0417] 화합물 72:

[0418] (1S,2S,3S,6R)-4-(fluoromethyl)-6-(((4-(isopropoxymethyl)cyclohexyl)methyl)amino)cyclohex-4-ene-1,2,3-triol

[0419] 1 H NMR (400 MHz, MeOD-d4) δ 0.96-1.04 (m, 4H), 1.12-1.14 (m, 6H), 1.40-1.60 (m, 3H), 1.62-1.80 (m, 1H), 1.80-1.90 (m, 4H), 2.45-2.49 (m, 1H), 2.60-2.65 (m, 1H), 3.15-3.20 (m, 1H), 3.25 (d, J = 6.4 Hz, 2H), 3.48 (dd, J = 10, 4.0 Hz, 1H), 3.52 (sept, J = 6.0 Hz, 1H), 3.71-3.76 (m, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.80-5.85 (m, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -214.55 (t, J = 48 Hz); LCMS (M+H) + : 346.44.

[0420]

[0421] 화합물 73:

[0422] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((2-(spiro[2.5]octan-6-yl)ethyl)amino)cyclohex-4-ene-1,2,3-triol

[0423] 1H NMR (400 MHz, MeOD-d4) δ 0.16-0.20 (m, 2H), 0.23-0.27 (m, 2H), 0.90 (d, J = 13 Hz, 2H), 1.10-1.20 (m, 2H), 1.30-1.40 (m, 1H), 1.45-1.50 (m, 2H), 1.65-1.80 (m, 4H), 2.60-2.70 (m, 1H), 2.80-2.90 (m, 1H), 3.10-3.20 (m, 1H), 3.48 (dd, J = 10, 4.0 Hz, 1H), 3.73 (dd, J = 10, 8.4 Hz, 1H), 4.20 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.80-5.85 (m, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -214.40 to -214.66 (m); LCMS (M+H) + : 314.34.

[0424]

[0425] 화합물 74:

[0426] (1S,2S,3S,6R)-6-(((1-fluorocyclohexyl)methyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0427] 1 H NMR (400 MHz, MeOD-d4) δ 1.26-1.39 (m, 1H), 1.41-1.67 (m, 7H), 1.80-1.92 (m, 2H), 2.68 (dd, J = 20, 13 Hz, 1H), 2.86 (dd, J = 21, 13 Hz, 1H), 3.17 (t, J = 7.6 Hz, 1H), 3.47 (dd, J = 10, 4.0 Hz, 1H), 3.72 (dd, J = 10, 8.2 Hz, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.81 (m, 1H); 19F NMR (376 MHz, MeOD-d4) δ -162.28, -218.87 (t, J = 46 Hz); LCMS (M+H) + : 292.42.

[0428]

[0429] 화합물 75:

[0430] (1S,2S,3S,6R)-6-((bicyclo[2.2.1]heptan-2-ylmethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0431] 1 H NMR (400 MHz, MeOD-d4) δ 1.04-1.63 (m, 8H), 1.67-1.79 (m, 1H), 1.96-2.34 (m, 2H), 2.59-3.14 (m, 2H), 3.48-3.58 (m, 2H), 3.82-3.93 (m, 1H), 4.21 (d, J = 4.0 Hz, 1H), 4.89-5.10 (m, 2H), 5.81 (m, 1H); 19 F NMR (376 MHz, DMSO-d6) δ -214.73 (t, J = 48 Hz); LCMS (M+H) + : 286.40.

[0432]

[0433] 화합물 76:

[0434] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((2-(1-methylcyclohexyl)ethyl)amino)cyclohex-4-ene-1,2,3-triol

[0435] 1H NMR (400 MHz, MeOD-d4) δ 0.92 (s, 3H), 1.21-1.58 (m, 12H), 2.50-2.62 (m, 1H), 2.70-2.81 (m, 1H), 3.09-3.18 (m, 1H), 3.47 (dd, J = 10, 4.0 Hz, 1H), 3.71 (dd, J = 10, 8.0 Hz, 1H), 4.20 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.83 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -218.98 (t, J = 46 Hz); LCMS (M+H) + : 302.30.

[0436]

[0437] 화합물 77:

[0438] (1S,2S,3S,6R)-6-((2-(1-ethylcyclohexyl)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0439] 1 H NMR (400 MHz, MeOD-d4) δ 0.81 (t, J = 7.6 Hz, 3H), 1.19-1.37 (m, 6H), 1.37-1.58 (m, 8H), 2.43-2.58 (m, 1H), 2.65-2.80 (m, 1H), 3.10-3.15 (m, 1H), 3.47 (dd, J = 10, 4.0 Hz, 1H), 3.71 (dd, J = 10, 8.0 Hz, 1H), 4.19 (d, J = 4.0 Hz, 1H), 4.75-5.10 (m, 2H), 5.82 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.07 (t, J = 47 Hz); LCMS (M+H) + : 316.34.

[0440]

[0441] 화합물 78:

[0442] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((4-(trifluoromethyl)phenethyl)amino)cyclohex-4-ene-1,2,3-triol

[0443] 1 H NMR (400 MHz, MeOD-d4) δ 2.80-2.95 (m, 3H), 3.00-3.10 (m, 1H), 3.15 (t, J = 6.0 Hz, 1H), 3.45 (dd, J = 8.0, 3.4 Hz, 1H), 3. 68 (dd, J = 8.0, 6.8 Hz, 1H), 4.18 (d, J = 3.2 Hz, 1H), 4.70-5.10 (m, 2H), 5.75-5.90 (m, 1H), 7.44 (d, J = 6.4 Hz, 2H), 7.58 (d, J = 6.4 Hz, 2H); LCMS (M+H) + : 350.1

[0444]

[0445] 화합물 79:

[0446] (1S,2S,3S,6R)-6-(((R)-2-(4-chlorophenyl)-2-fluoroethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0447] 1 H NMR (400 MHz, MeOD-d4) δ 2.83-2.95 (m, 1H), 3.08-3.29 (m, 2H), 3.43-3.47 (m, 1H), 4.18-4.19 (m, 1H), 4.70-5.10 (m, 2H), 5.49-5.53 (m, 1H), 5.81 (brs, 1H), 7.36-7.45 (m, 4H); 19 F NMR (376 MHz, MeOD-d4) δ -183.51 to -183.76 (m), -218.65 내지 -218.91 (m); LCMS (M+H) + : 334.33.

[0448]

[0449] 화합물 80:

[0450] (1S,2S,3S,6R)-6-((2-(5-chloropyridin-2-yl)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0451] 1 H NMR (400 MHz, MeOD-d4) δ 2.84-2.88 (m, 3H), 2.90-3.07 (m, 2H), 3.41 (dd, J = 10, 4.0 Hz, 1H), 3.59 (dd, J = 10, 8.0 Hz, 1H), 4.09 (d, J = 4.0 Hz, 1H), 4.65-5.00 (m, 2H), 5.70-5.72 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 8.4, 2.8 Hz, 1H), 8.36 (dd, J = 2.4, 0.4 Hz, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -218.97 (t, J = 46 Hz); LCMS (M+H) + : 317.28.

[0452]

[0453] 화합물 81:

[0454] (1S,2S,3S,6R)-6-((2-(4-chloronaphthalen-1-yl)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0455] 1H NMR (400 MHz, MeOD-d4) δ 2.90-3.00 (m, 1H), 3.08-3.14 (m, 1H), 3.14-3.20 (m, 1H), 3.27 (s, 2H), 3.44 (dd, J = 10, 4.0 Hz, 1H), 3.69 (dd, J = 10, 8.0 Hz, 1H), 4.18 (d, J = 4.0 Hz, 1H), 4.70-5.05 (m, 2H), 5.80-5.83 (m, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.59-7.66 (m, 2H), 8.16-8.21 (m, 1H), 8.25-8.31 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -218.94 (t, J = 48 Hz); LCMS (M+H) + : 366.35.

[0456]

[0457] 화합물 82:

[0458] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((2-(naphthalen-1-yl)ethyl)amino)cyclohex-4-ene-1,2,3-triol

[0459] 1 H NMR (400 MHz, MeOD-d4) δ 2.90-3.00 (m, 1H), 3.08-3.21 (m, 2H), 3.31 (s, 2H), 3.45 (dd, J = 10, 4.0 Hz, 1H), 3.70 (dd, J = 10, 8.0 Hz, 1H), 4.18 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.80-5.85 (m, 1H), 7.36-7.42 (m, 2H), 7.44-7.55 (m, 2H), 7.71-7.76 (m, 1H), 7.86 (dd, J = 8.0, 0.8 Hz, 1H), 8.09-8.14 (m, 1H); 19F NMR (376 MHz, MeOD-d4) δ -218.95 (t, J = 46 Hz); LCMS (M+H) + : 332.07.

[0460]

[0461] 화합물 83:

[0462] 5-(dimethylamino)-N-(4-(((1R,4S,5S,6S)-3-(fluoromethyl)-4,5,6-trihydroxycyclohex-2-en-1-yl)amino)butyl)naphthalene-1-sulfonamide

[0463] White solid; 1 H NMR (400 MHz, MeOD-d4) δ 1.35-1.44 (m, 4H), 2.35-2.45 (m, 1H), 2.53-2.62 (m, 1H), 2.82-2.90 (m, 8H), 3.00-3.05 (m, 1H), 3.44 (dd, J = 10, 4.0 Hz, 1H), 3.64 (dd, J = 10, 8.0 Hz, 1H), 4.18 (d, J = 4.0 Hz, 1H), 4.70-5.10 (m, 2H), 5.70-5.75 (m, 1H), 7.27 (dd, J = 7.6, 0.8 Hz, 1H), 7.55-7.61 (m, 2H), 8.19 (dd, J = 7.2, 1.2 Hz, 1H), 8.33-8.37 (m, 1H), 8.55-8.58 (m, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -218.95 (t, J = 47 Hz); LCMS (M+H) + : 482.22.

[0464]

[0465] 화합물 84:

[0466] (1S,2S,3S,6R)-6-((2-(6-chloronaphthalen-2-yl)ethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0467] 1 H NMR (400 MHz, MeOD-d4) δ 2.90-3.05 (m, 3H), 3.10-3.20 (m, 2H), 3.45 (dd, J = 10, 4.0 Hz, 1H), 3.69 (dd, J = 10, 8.0 Hz, 1H), 4.18 (d, J = 4.4 Hz, 1H), 4.70-5.10 (m, 2H), 5.82-5.84 (m, 1H), 7.38 (m, 2H), 7.71-7.85 (m, 4H); 19 F NMR (376 MHz, DMSO-d6) δ -214.34 내지 -214.614 (m); LCMS (M+H) + : 366.32.

[0468]

[0469] 화합물 85:

[0470] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((3-(4-methylpiperidin-1-yl)propyl)amino)cyclohex-4-ene-1,2,3-triol

[0471] 1 H NMR (400 MHz, DMSO-d6) δ 0.86-0.88 (m, 3H), 1.06-1.14 (m, 2H), 1.27-1.30 (m, 1H), 1.49-1.55 (m, 5H), 1.77-1.89 (m, 2H), 2.25-2.31 (m, 2H), 2.45-2.31 (m, 1H), 2.64-2.61 (m, 1H), 2.77-2.91 (m, 3H), 3.32-3.61 (m, 2H), 4.00 (brs, 1H), 4.72-5.00 (m, 5H), 5.71 (s, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.06 ; LCMS (M+H) + : 317.50.

[0472]

[0473] 화합물 86:

[0474] (1S,2S,3S,6R)-6-(((4-((4-chlorophenoxy)methyl)cyclohexyl)methyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0475] 1 H NMR (500 MHz, DMSO-d6) δ 0.86-1.07 (m, 2H), 1.35-1.69 (m, 7H), 1.78-1.95 (m, 3H), 2.43-2.48 (m, 1H), 2.50-2.56 (m, 1H), 2.89-2.95 (m, 1H), 3.33-3.37 (m, 1H), 3.50-3.57 (m, 1H), 3.76 (d, J = 6.5 Hz, 1H), 3.86 (d, J = 7.0 Hz, 1H), 4.00-4.05 (m, 1H), 4.66-5.02 (m, 5H), 5.68-5.72 (m, 1H), 6.92-6.98 (m, 2H), 7.28-7.32 (m, 2H); 19 F NMR (470 MHz, DMSO-d6) δ -214.54 (t, J = 47 Hz); LCMS (M+H) + : 414.38.

[0476]

[0477] 화합물 87:

[0478] (1S,2S,3S,6R)-6-((4-chloro-3-methylphenethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol

[0479] 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.62-2.74 (m, 3H), 2.81-2.89 (m, 1H), 2.90-3.00 (m, 1H), 3.27-3.31 (m, 1H), 3.50-3.55 (m, 1H), 3.95-4.05 (m, 1H), 4.68-5.02 (m, 5H), 5.70-5.73 (m, 1H), 7.07 (dd, J = 8.4, 2.0 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -219.19 (t, J = 47 Hz); LCMS (M+H) + : 330.40.

[0480]

[0481] 화합물 88:

[0482] (1S,2S,3S,6R)-4-(fluoromethyl)-6-((2-(indolin-6-yl)ethyl)amino)cyclohex-4-ene-1,2,3-triol

[0483] 1 H NMR (400 MHz, DMSO-d6) δ 2.50-2.55 (m, 2H), 2.60-2.69 (m, 1H), 2.76-2.87 (m, 3H), 2.91-2.99 (m, 1H), 3.28-3.30 (m, 1H), 3.36-3.40 (m, 2H), 3.49-3.52 (m, 1H), 3.98-4.02 (m, 1H), 4.65-5.02 (m, 5H), 5.35 (brs, 1H), 5.70-5.74 (m, 1H), 6.32-6.37 (m, 2H), 6.89 (d, J = 7.4 Hz, 1H); 19 F NMR (376 MHz, MeOD-d4) δ -214.45 (t, J = 48 Hz); LCMS (M+H) + : 323.40.

[0484]

[0485] Compound 89:

[0486] (1S,2S,3S,6R)-6-((cyclohexylmethyl)amino)-4-(fluoromethyl)cyclohex-4-ene-1,2,3-triol succinate

[0487] 1 H NMR (400 MHz, DMSO-d6) δ 0.80-0.95 (m, 2H), 1.00-1.25 (m, 3H), 1.28-1.49 (m, 1H), 1.60-1.80 (m, 4H), 2.36 (s, 4H), 2.35-2.45 (m, 1H), 2.50-2.60 (m, 1H), 3.10-3.20 (m, 1H), 3.30-3.32 (m, 1H), 3.60-3.65 (m, 1H), 4.00-4.05 (m, 1H), 4.50-5.10 (m, 5H), 5.70-5.75 (m, 1H); LCMS (M+H) + : 274.1.

[0488]

[0489] Hereinafter, preferred examples are presented to help understand the present invention, but the following examples are provided only to make it easier to understand the present invention and the present invention is not limited thereto.

[0490]

[0491] Example

[0492]

[0493] Preparation of the compound:

[0494] Below, specific manufacturing methods for compounds 1 to 89 of Table 1 are described.

[0495]

[0496] Compounds 1 to 89 according to one specific example of the present invention are basically prepared according to the following reaction schemes 1 and 2.

[0497]

[0498] [Reaction Formula 1]

[0499]

[0500]

[0501] (Step 1: Synthesis of compound Int-1)

[0502] To a stirred mixture of (+)-proto-quercitol (1.0 equiv.) in methanol, pyridinium p-toluenesulfonate (0.2 equiv.) was added little by little at 4°C, and the reaction mixture was stirred at 4°C for 24 h. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was neutralized by the addition of triethylamine and then concentrated under reduced pressure. The crude compound was purified by column chromatography using silica gel (100-200 mesh) and eluted with 20% ethyl acetate in petroleum (pet) ether to give compound Int-1.

[0503]

[0504] (Step 2: Synthesis of compound Int-2)

[0505] Benzoyl chloride (8.0 eq) was added dropwise to a stirred mixture of compound Int-1 (1.0 eq) in pyridine at 0°C, and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was diluted with sodium bicarbonate solution, stirred for 30 min, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography using silica gel (100-200 mesh) and eluted with 10% ethyl acetate in petroleum (pet) ether to obtain compound Int-2.

[0506]

[0507] (Step 3: Synthesis of compound Int-3)

[0508] To a stirred mixture of methyltriphenylphosphonium bromide (6.0 equiv) in tetrahydrofuran was added n-butyllithium (4.0 equiv) at -78°C, and the mixture was stirred in an ice bath for 1 h. A solution of compound Int-2 (1.0 equiv) in tetrahydrofuran was slowly added at -78°C, and the temperature of the reaction mixture was increased to 0°C and stirred for 4 h. The progress of the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and eluted with 10% ethyl acetate in petroleum (pet) ether to obtain compound Int-3.

[0509]

[0510] (Step 4: Synthesis of compound Int-4)

[0511] To a stirred mixture of compound Int-3 (1.0 eq) in tetrachloromethane, sodium bicarbonate (1.2 eq) was added at room temperature and stirred for 5 minutes. A solution of bromine (1.2 eq) in tetrachloromethane was added dropwise to the reaction mixture at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion of the reaction, the reaction mixture was diluted with sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by column chromatography using silica gel (100-200 mesh) and eluted with 5% ethyl acetate in petroleum (pet) ether to obtain compound Int-4.

[0512]

[0513] (Step 5: Synthesis of Compound A)

[0514] To a stirred mixture of compound Int-4 (1.0 equiv.) in N,N-dimethylformamide was added sodium benzoate (1.2 equiv.) at room temperature, and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reaction mixture was diluted with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography using silica gel (100-200 mesh) and eluted with 5% ethyl acetate in petroleum (pet) ether to obtain compound A.

[0515]

[0516] [Reaction Formula 2]

[0517]

[0518]

[0519] (Step 1: Synthesis of Compound C)

[0520] To a stirred solution of compound A (1.0 eq) and compound B (2.5 eq) dissolved in acetonitrile, K2CO3 (3.0 eq) was added at room temperature. The reaction mixture was stirred at 70°C for 16 h. The progress of the reaction was monitored by thin layer chromatography (TLC). After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate (twice). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate (anhydrous Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and eluted with 10% ethyl acetate in petroleum (pet) ether to obtain compound C.

[0521]

[0522] (Step 2: Synthesis of Compound D)

[0523] To a stirred solution of compound C (1.0 eq) dissolved in methanol, sodium methoxide (2.2 eq) was added, and the mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (twice). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound D.

[0524]

[0525] (Step 3: Synthesis of compound E)

[0526] Diethylaminosulfur trifluoride (DAST) (1.0 eq) was added to a stirred solution of compound D (1.0 eq) in dichloromethane (DCM) at 0°C. The reaction mixture was stirred at room temperature for 2 h, and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was added aqueous NaHCO3 solution and extracted with DCM (twice). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain compound E. The crude mixture was used as is in the next step.

[0527]

[0528] (Step 4: Synthesis of the target compound)

[0529] A concentrated HCl solution (3.0 eq) was added to a stirred solution of compound E (1.0 eq) dissolved in methanol at room temperature. The reaction mixture was stirred at the same temperature for 1 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized and concentrated under reduced pressure to obtain a crude material. The crude material was purified by Prep. HPLC to obtain the target compounds, which form the basic structures of compounds 1 to 89.

[0530]

[0531] The above target compound forms various salts according to the following reaction formulas 3 to 7.

[0532]

[0533] [Reaction Formula 3]

[0534]

[0535]

[0536] (Formation of p-toluenesulfonate)

[0537] p-Toluenesulfonic acid monohydrate (1.0 equivalent) was added to a stirred solution of the target compound (1.0 equivalent) dissolved in water at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The resulting reaction mixture was then directly freeze-dried to obtain p-toluenesulfonate.

[0538]

[0539] [Reaction Formula 4]

[0540]

[0541]

[0542] (Formation of formate)

[0543] Formic acid (1.0 equivalent) was added to a stirred solution of the target compound (1.0 equivalent) dissolved in water at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The resulting reaction mixture was then directly freeze-dried to obtain the formate salt.

[0544]

[0545] [Reaction Formula 5]

[0546]

[0547]

[0548] (Formation of hydrochloride)

[0549] To a stirred solution of the target compound (1.0 equivalent) dissolved in acetonitrile, 4 M HCl (1.0 equivalent) dissolved in methanol was added at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The resulting reaction mixture was then directly freeze-dried to obtain the hydrochloride salt.

[0550]

[0551] [Reaction Formula 6]

[0552]

[0553]

[0554] (Formation of trifluoroacetate)

[0555] Trifluoroacetic acid (1.0 equivalent) was added to a stirred solution of the target compound (1.0 equivalent) dissolved in methanol at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The resulting reaction mixture was then directly freeze-dried to obtain the trifluoroacetic acid salt.

[0556]

[0557] [Reaction Formula 7]

[0558]

[0559]

[0560] (Formation of succinate)

[0561] Succinic acid (1.0 equivalent) was added to a stirred solution of the target compound (1.0 equivalent) dissolved in methanol at room temperature, and the reaction mixture was stirred at the same temperature for 1 hour. The resulting reaction mixture was then directly freeze-dried to obtain the succinate.

[0562]

[0563] Experimental example

[0564]

[0565] Experiments on the effects of compounds:

[0566]

[0567] Experimental Example 1: Experimental study on increased β-galactosidase activity in patient-derived fibroblasts carrying the R201C mutation.

[0568] The cell line used in Experimental Example 1 was an immortalized patient-derived fibroblast cell line containing a mutation in which the 201st arginine of the enzyme is changed to cysteine ​​(R201C), which is known to be a mutant type that appears in patients with type 2 GM1 gangliosidosis. The immortalized patient-derived fibroblast cell line containing the mutant human β-galactosidase (R201C) was cultured in a culture medium (10% FBS DMEM) with or without the test substance for 4 days. The cells were washed with phosphate-buffered saline and scraped into sterile water containing 0.1% Triton X-100. The solution was centrifuged (6000 rpm, 15 minutes, 4°C), and the supernatant, excluding the insoluble fraction, was used. A 0.1 M citric acid buffer (pH 4.5) was used as a buffer, and a fluorescent substrate (4-methylunveripheryl-β-D-galactopyranoside, manufactured by Sigma) and the above enzyme source were mixed. The solution was reacted at 37°C for 30 minutes in the presence or absence of the test substance, and the reaction was terminated with 0.2 M glycine-sodium hydroxide buffer (pH 10.7). The fluorescence was measured using a Fluorescence Plate Reader (excitation 340 nm, emission 460 nm; Infinite F500; TECAN Japan, Kawasaki, Japan). The enzyme activity without the substance was set to 100%, and the change caused by the addition was relatively calculated. The degree of recovery of increased human β-galactosidase activity measured according to the above-described method by treating the cell line with compounds 1 to 89 according to an embodiment of the present invention is shown in Table 2 below. According to Table 2 below, when compounds 1 to 89 according to one specific example of the present invention were treated on a fibroblast cell line derived from a patient with R201C, β-galactosidase activity increased to a high level.

[0569]

[0570] Increased activity of compound β-galactosidase * Increased activity of compound β-galactosidase * 2μM20μM2μM20μM15.5810.13463.996.9325.278.39474.116.1635.1110.0648ND8.1545.3410.62494.357.4655.375.98504.788.37 62.354.85515.129.7474.748.14524.718.5284.667.49535.059.9692.776.34543.935.42103.17ND552.944.91113.397.09563.955 .51122.414.39574.125.97131.35ND581.653.37142.414.33590.981.54155.1810.01601.031.55164.336.41614.377.66171.562. 62623.966.38181.662.46634.116.79190.97ND641.474.46201.483.43654.295.62211.913.81662.46ND223.955.29673.356.23233 .885.01683.915.76244.647.25695.87.05254.407.02701.462.67265.408.93713.855.60274.115.57724.478.43284.597.86736.668.11294.949.54742.875.14305.7510.73752.745.81312.294.45763.77.21324.135.67772.14.71334.487.29786.157.63344.04 7.17791.141.89354.42ND801.583.52362.814.96814.126.18374.035.77822.726.26384.678.48833.016.39393.627.58844.329. 62402.425.99851.131.34414.076.62868.69ND424.668.51874.228.04432.784.66881.743.07441.342.61896.3711.88452.354.11

[0571] *The fold increase in activity when compound is added based on the activity of the mutant enzyme without compound, ND: Not Determined

[0572]

[0573] Experimental Example 2: Experimental study on increased β-galactosidase activity in patient-derived fibroblasts carrying type 1 mutations (R208C, R59H, and G190D).

[0574] For representative compounds (compounds 5, 7, 9, 11, 15, 24, 25, 26, 28, 29, 30, 31, 33, 34, 38, 42, 46, 48, 52, 61, 63, 69, 72, 73, 76, 84, 87, 89), an increase in β-galactosidase activity was confirmed in fibroblasts derived from patients carrying the type 1 mutation. The cell line used in the following experiments was an immortalized patient-derived fibroblast cell line, which contains a mutation in which the 208th arginine of the enzyme is changed to cysteine ​​(R208C), a mutation in which the 59th arginine of the enzyme is changed to histidine (R59H), and a mutation in which the 190th glycine of the enzyme is changed to aspartic acid (G190D), which are known to be mutation types that appear in patients with type 1 GM1 gangliosidosis. Table 3 shows the activity of representative compounds to increase mutant human β-galactosidase activity. Representative compounds showed excellent enzyme activity restoration for the tested type 1 mutants. The reactivity for the type 1 mutant strains listed in Table 3 below is an example of the reactivity for restoration of mutant enzyme activity when treated with representative compounds, and does not mean that compounds not listed in the table have no reactivity for the type 1 mutant strains.

[0575]

[0576] compound reactivity *R208CR59HG190D5·ND++7++ND++9·++11ND++15++ND+24+ND+25+ND+26+++++28+++++29++··30+++31·ND+33++++34 ++··38+··42+··46+ND++48+ND+52++··61+ND+63+ND++69+ND+++72+ND+++73+ND+++76+ND+84NDND+87+ND+89++++

[0577] * +: 1.3x to 2x, ++: 2x to 5x, +++: 5x or more, ND: Not Determined, ·: Not Tested

[0578]

[0579] Experimental Example 3: Evaluation of Cerebral Penetration by In Vivo Administration

[0580] In order to evaluate the degree of brain penetration in vivo of representative compounds (compounds 1, 2, 3, 5, 7, 15, 16, 24, 25, 26, 28, 49, 50, and 51), the compounds were orally administered to C57BL / 6J mice, and the ratio of the drug in the brain tissue to the plasma was evaluated after 1 hour, and the results are shown in Fig. 1. Specifically, the test substances were orally administered to 7-9 week-old C57BL / 6J wild-type mice, and blood and brain tissues were collected from the mice sacrificed 1 hour after administration. Blood samples were centrifuged (3200 g, 10 min, 4 °C) and immediately processed into plasma. The precipitate containing the internal standard was immediately added to the plasma, mixed well, and then centrifuged (12000 g, 15 min, 4 °C). The supernatant was transferred to a pre-labeled polypropylene microcentrifuge tube and rapidly frozen on dry ice. The sample was stored below -70°C until LC-MS / MS analysis. Brain tissue was homogenized using homogenization buffer (MeOH / 15 mM PBS (1:2, v:v)) at a ratio of 1:9 (1 g tissue to 9 mL buffer, dilution ratio 10). The tissue homogenate was stored at -70±10°C until LC-MS / MS analysis. Drug concentrations in plasma and brain tissue were measured by LC-MS / MS.

[0581] The blood-brain barrier (BBB) ​​is a gateway that protects the brain by preventing foreign substances from entering the brain tissue. It is not only a dense structure surrounded by brain capillary endothelial cells and glial cells, but also has an excretion mechanism of an efflux pump within the endothelial cells, making it difficult for general drugs or metabolites to penetrate the BBB. As a result of evaluating brain permeability in vivo, as shown in Fig. 1, most of the representative compounds according to one specific example of the present invention exhibited excellent brain permeation and distribution characteristics, ranging from 20% to 120% compared to plasma. This means that they can be effective drugs for the treatment of brain lesions due to diseases.

[0582]

[0583] Experimental Example 4: Evaluation of efficacy through in vivo administration

[0584] To evaluate the in vivo efficacy of representative compounds (compounds 3 and 15), the compounds were orally administered to C57BL / 6J mice containing GM1 disease-associated mutations for 1 week, and the organs were removed. The increased activity of the mutant protein in the liver and brain tissues was measured, and the results are shown in Fig. 2 (liver tissue results) and Fig. 3 (brain tissue results). In addition, the decrease in GM1-ganglioside accumulation in the brain tissues was measured (the amount of GM1-ganglioside detected compared to the non-administered group, %), and the results are shown in Fig. 4. Specifically, the in vivo efficacy of the compounds was evaluated using 6-7 week-old C57BL / 6J mice transformed to harbor a human β-galactosidase mutation (R201C). The test substance was orally administered once (QD) or twice (BID) daily for 7 days, and on the 8th day, the animals were sacrificed, and plasma, liver tissue, and brain tissue were obtained and frozen. The activity of the mutant β-galactosidase was measured from the lysates of the frozen plasma, liver tissue, and brain tissue. The frozen tissue was sonicated in distilled water, centrifuged (8000 rpm, 15 min, 4°C), and the supernatant after excluding the insoluble fraction was used. 0.1 M citric acid buffer (pH 4.5) was used as a buffer, and the fluorescent substrate (4-methylunveripheryl-β-D-galactopyranoside, manufactured by Sigma) and the above enzyme source were mixed. The solution was reacted at 37°C for 30 min in the presence or absence of the test substance, and the reaction was terminated with 0.2 M glycine-sodium hydroxide buffer (pH 10.7). The fluorescence was measured using a Fluorescence Plate Reader (excitation 340 nm, emission 460 nm; Infinite F500; TECAN Japan, Kawasaki, Japan). The protein concentration was measured using a Protein Assay Rapid Kit (WAKO, Tokyo, Japan), and the activity of the mutant β-galactosidase was corrected for the measured protein concentration.

[0585] For immunohistochemistry, monoclonal anti-GM1 antibody (clone GMB16) and monoclonal anti-GA1 antibody (clone AG-1) were purchased from Seikagaku Corporation (Tokyo).

[0586] Brain tissue sections were permeabilized with 0.25% Triton X-100 in PBS for 15 min at room temperature, blocked with 1% BSA in PBS for 1 h at room temperature, and then incubated with primary antibodies overnight at 4°C. Anti-GM1 was diluted 1:50 in 0.1% BSA in PBS before use, and anti-GA1 was diluted 1:25.

[0587] Sections were washed three times for 5 min each in 1% BSA in PBS at room temperature. They were then incubated with FITC-conjugated anti-mouse IgM (diluted 1:50 in 0.1% BSA in PBS), washed three times for 5 min each in PBS, and mounted on slide glass.

[0588] In all groups administered low doses of 30 mg / kg or less of the representative compound, a significant increase in activity was observed in liver tissues, ranging from 4.5 to 11.28 times, and in brain tissues, from 1.4 to 4.1 times, compared to the untreated group. Furthermore, the accumulation of GM1 ganglioside in brain tissues was confirmed to be reduced by 51.9 to 71.1% depending on the dose and frequency of administration. This suggests that GM1-galactosidase disease can be effectively treated by restoring deficient enzyme activity in brain lesions and surrounding tissues.

[0589]

[0590] Although the present invention has been described with reference to the specific embodiments described above, it should be understood that those skilled in the art can make various modifications and variations to the present invention, which are also within the scope of the present invention defined by the appended claims.

Claims

1. A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, The above X is a halogen, The above R1 and R2 are each independently hydrogen or C 1-4 It is alkyl, The above L is a direct bond, C 1-7 Alkylene, C 1-7 Halogenated alkylene, C 1-7 Alkenylene, C 3-7 Cycloalkylene or a combination thereof, The above R3 is hydrogen, halogen, hydroxy, cyano, nitro, amino, mercapto, carbamoyl, C 1-7 Alkyl, C 1-7 Halogenated alkyl, C 2-7 Alkenyl, C 2-7 alkynyl, C 1-7 Alkoxy, C 1-7 Halogenated alkoxy, C 1-4　 Alkoxy-C 1-4　 Alkoxy, C 3-10 Cycloalkyl-C 1-4 Alkoxy, C 6-10 Aryl-C 1-4 Alkoxy, C 2-7 Alkenyloxy, C 2-7 alkynyloxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkanonyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Selected from the group consisting of arylsulfonamidyl, 5-10 membered heteroarylsulfonamidyl and non-aromatic condensed rings, The above non-aromatic condensed ring is C 6-10 C to aryl or 5-10 membered heteroaryl 3-7 Cycloalkyl, C 3-7 A polycyclic ring in which cycloalkenyl or 3-7 membered heterocycloalkyl is condensed, C in the above R3 6-10 Aryl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkanonyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy, C 6-10 Arylsulfonamidyl, 5-10 membered heteroarylsulfonamidyl and non-aromatic condensed rings are each independently selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4　 Alkoxy-C 1-4　 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkenyl, C 3-7 Cycloalkenyl, C 3-7 Cycloalkyloxy, 3-7 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, mono- or di-C 1-4 Alkylamino and mono- or di-C 6-10 It may be substituted with a substituent selected from the group consisting of arylamino, The above substituents may be substituted with halogen, Two C among the above substituents 1-4 Alkyl groups can be linked to each other by direct bonds, -CH2-, -O-, -S- or -NH- to form rings.

2. In claim 1, A compound or a pharmaceutically acceptable salt thereof, wherein X is fluorine.

3. In claim 1, A compound or a pharmaceutically acceptable salt thereof, characterized in that the above R1 and R2 are hydrogen.

4. In claim 1, The above L is C 1-7 A compound or a pharmaceutically acceptable salt thereof, characterized in that it is an alkylene.

5. In claim 1, The above R3 is C 3-10 Cycloalkyl-C 1-4 Alkoxy, C 6-10 Aryl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 A compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of aryl and 5-10 membered heteroaryl.

6. In claim 5, A compound or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of cyclopentyl, cyclohexyl, adamantyl, cyclopentyloxy, cyclohexyloxy, adamantyloxy, cyclopentenyl, cyclohexenyl, cyclopentenyloxy, cyclohexenyloxy, tetrahydropyranyl, phenyl, phenyloxy and phenylmethoxy.

7. In claim 1, C in the above R3 6-10 Aryl-C 1-4 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkenyl, C 3-10 Cycloalkanonyl, 3-10 membered heterocycloalkyl, C 3-10 Cycloalkyloxy, C 3-10 Cycloalkenyloxy, 3-10 membered heterocycloalkyloxy, C 6-10 Aryl, 5-10 membered heteroaryl, C 6-10 Aryloxy, 5-10 membered heteroaryloxy and non-aromatic condensed rings are each independently halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 A compound or a pharmaceutically acceptable salt thereof, characterized in that it can be substituted with a substituent selected from the group consisting of halogenated alkoxy.

8. In claim 6, wherein R3 is cyclopentyl, cyclohexyl, phenyl or phenyloxy, A compound or a pharmaceutically acceptable salt thereof, characterized in that in the above R3, cyclopentyl, cyclohexyl, phenyl and phenyloxy can each be independently substituted with a substituent selected from the group consisting of halogen, methyl, ethyl, propyl, halogenated methyl, halogenated ethyl and halogenated propyl.

9. In claim 1, A compound of the above chemical formula 1, characterized in that it has a three-dimensional structure of the following chemical formula 2, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] 10. In claim 1, A compound or a pharmaceutically acceptable salt thereof, characterized in that the compound or a pharmaceutically acceptable salt thereof is one of the following compounds 1 to 89:

11. A pharmaceutical composition for treating or preventing GM1-gangliosidosis, comprising a compound according to claim 1 as an active ingredient and a pharmaceutically acceptable carrier.

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