5-(hydroxymethyl)furfural derivative, preparation method therefor, and use thereof

Abstract

The present invention relates to a 5-(hydroxymethyl)furfural (5-HMF) derivative and use thereof. The compound of the present invention induces accumulation of β-catenin in the cytoplasm so as to activate the Wnt / β-catenin signaling pathway, and thus can be effectively used in the prevention or treatment of hair loss.

Description

5-(hydroxymethyl)furfural derivatives, methods for preparing the same, and uses of the same

[0001] The present invention relates to 5-(hydroxymethyl)furfural (5-HMF) derivatives, methods for preparing the same, and uses thereof. In particular, the present invention relates to the ligand-independent regulation of the activity of the Wnt / β-catenin signaling pathway through GSK3β inhibition and AKT activation. Specifically, the present invention relates to a compound of a novel structure that activates the Wnt / β-catenin signaling pathway and medicinal uses thereof.

[0002] Although hair loss is a complex disease involving various signaling pathways and genes, new hair loss treatments targeting novel signaling pathways are being developed to specifically treat various types of hair loss. In particular, to treat severe patients with follicle loss and to address the side effects and low efficacy issues of existing hair loss treatments, the Wnt / β-catenin signaling pathway, PI3K / AKT signaling pathway, Shh signaling pathway, prostaglandin signaling pathway, and TGF-β / BMP signaling pathway, which play key roles in follicle regeneration and follicle stem cell activation, are receiving attention (Mol Pharm. 2023;20(11):5396-5415).

[0003] Among these, the Wnt / β-catenin signaling pathway is considered one of the major targets for drug development because it can influence the mechanisms of action of various diseases through processes such as cell proliferation, differentiation, motility, survival, and apoptosis, as well as the regulation of embryonic and adult stem cell activity. In particular, activation of the Wnt / β-catenin signaling pathway is essential for hair growth and is known to promote the activation of hair follicle stem cells and the proliferation of dermal papilla cells (Cosmetics 2023, 10(4), 106). The activation of this Wnt / β-catenin signaling pathway can be determined by the degree of accumulation of β-catenin in the cytoplasm.

[0004] Meanwhile, GSK3β and AKT belong to the serine / threonine protein kinase group, and it has been revealed that they are involved in various cellular processes, such as cell proliferation, stem cell maintenance, and apoptosis, and regulate various signaling pathways. In particular, GSK3β is a component of the Wnt / β-catenin signaling pathway and functions as a major regulator of Wnt activation (Pharmacol Ther. 2019 Apr; 196:79-90). Since β-catenin is degraded in the proteasome when phosphorylated by GSK3β, inhibition of GSK3β induces the stabilization of β-catenin and the activation of the Wnt / β-catenin signaling pathway. Activation by phosphorylation of AKT can inhibit the degradation of β-catenin through the phosphorylation of the Ser9 residue of GSK3β, or induce the stabilization of β-catenin and nuclear accumulation by directly phosphorylating the Ser552 residue of β-catenin (Cell. 2012;149(6):1245-1256).

[0005] To date, there are no commercially available hair loss treatments targeting the Wnt / β-catenin signaling pathway, and since existing drugs have limitations in hair follicle regeneration, there is a growing need to develop novel small molecule compounds capable of inducing new hair follicle regeneration by activating this pathway.

[0006] The object of the present invention is to provide a 5-(hydroxymethyl)furfural derivative compound of a novel structure, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0007] Specifically, the present invention provides a novel compound that overcomes the limitations of the existing Wnt ligand-dependent method, promotes the transition from the resting phase to the growth phase during the hair growth cycle, and induces the proliferation of dermal papilla cells.

[0008] Another objective of the present invention is to provide a method for manufacturing the above compound.

[0009] Another objective of the present invention is to provide a use for the said compound. Specifically, the present invention provides a pharmaceutical composition for the prevention or treatment of hair loss comprising the said compound as an active ingredient.

[0010] Another objective of the present invention is to provide a method for the prevention or treatment of hair loss using the said compound, or a method for the prevention or treatment of hair loss comprising the step of administering the said compound.

[0011] To achieve the above objective, the inventors completed the present invention by confirming, through their research efforts, that a compound represented by Chemical Formula I mentioned below activates the Wnt / β-catenin signaling pathway.

[0012] 5-HMF derivative

[0013] The present invention provides a compound represented by the following formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0014] [Chemical Formula I]

[0015]

[0016] In the above chemical formula I,

[0017] L X is -O-, -NH-, *-(CH2)nC(=O)-O-, *-(CH2)nC(=O)-NH-, *-(CH2)n-CH=CH-C(=O)-O-, or *-(5-6-membered heterocycloalkyl)-, where * is R X Indicates a point attached to, where n is 0, 1, 2, 3, or 4, and the *-(5-6-membered heterocycloalkyl)- comprises one or more N, O, or S within the ring;

[0018] R X is -H, -C 1-6 Alkyl, -C 1-6Hydroxyalkyl, -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl), wherein the -(4-6-membered heterocycloalkyl), -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) comprises one or more N, O, or S within the ring, and the -(5-10-membered heteroaryl) may comprise C (=O) within the ring, and one or more hydrogens of the -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) ring are R U1 It can be replaced with;

[0019] L Y is a single bond, -(C=O)-O-(CH2)m-**, -(C=O)-NH-(CH2)m-**, -CH=CH-C(=O)-(CH2)m-**, where ** indicates a point attached to ring Y, and m is 0, 1, 2, 3, or 4;

[0020] Ring Y is -phenyl or -(9-10-membered heteroaryl), wherein the -(9-10-membered heteroaryl) comprises one or more N, O, or S within the ring, and one or more hydrogens of the -phenyl or -(9-10-membered heteroaryl) ring are R U2 It can be replaced with;

[0021] R U1 and R U2 -C each independently 1-6 Alkyl, -NR a R b , -OR c , -SR c , -(3-6-membered cycloalkyl), -phenyl, -CN, -NO2, -C 1-6 haloalkyl, or -halo, wherein one or more hydrogens of the -(3-6-membered cycloalkyl) or -phenyl ring are -C 1-6 alkyl or -C 1-6It can be substituted with an alkoxy;

[0022] R a and R b -H or -C, respectively, independently 1-6 It is alkyl;

[0023] R c -H or -C 1-6 It is an alkyl.

[0024] According to a specific embodiment of the present invention, L X is -O-, *-(CH2)nC(=O)-O-, *-(CH2)nC(=O)-NH-, *-CH=CH-C(=O)-O-, or *-(5-6-membered heterocycloalkyl)-, where * is R X Indicates a point attached to, where n is 0, 1, or 2, and the *-(5-6-membered heterocycloalkyl)- comprises one or more N, O, or S within the ring;

[0025] R X is -H, -C 1-4 It is an alkyl, -(5-6-membered cycloalkyl), -phenyl, or -(5-10-membered heteroaryl), wherein the -(5-10-membered heteroaryl) comprises one or more N, O, or S within the ring, and the -(5-10-membered heteroaryl) may comprise C (=O) within the ring, and one or more hydrogens of the -(5-6-membered cycloalkyl), -phenyl, or -(5-10-membered heteroaryl) ring are R U1 It can be replaced with;

[0026] R U1 is -C 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -(5-6 member cycloalkyl), -phenyl, -CN, -NO2, -C 1-4 haloalkyl, or -halo, wherein one or more hydrogens of the -(5-6-membered cycloalkyl) or -phenyl ring are -C 1-4alkyl or -C 1-4 It can be substituted with an alkoxy.

[0027] According to a specific embodiment of the present invention, L Y is a single bond, -(C=O)-NH-(CH2)m-**, -CH=CH-C(=O)-(CH2)m-**, where ** indicates a point attached to ring Y, and m is 0, 1, 2, 3, or 4;

[0028] Ring Y is -phenyl or -(9-10-membered heteroaryl), wherein the -(9-10-membered heteroaryl) comprises one or more N, O, or S within the ring, and one or more hydrogens of the -phenyl or -(9-10-membered heteroaryl) ring are R U2 It can be replaced with;

[0029] R U2 is -C 1-4 Alkyl, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -(5-6 member cycloalkyl), -phenyl, -NO2, -C 1-4 haloalkyl, or -halo, wherein one or more hydrogens of the -(5-6-membered cycloalkyl) or -phenyl ring are -C 1-4 alkyl or -C 1-4 It can be substituted with an alkoxy.

[0030] According to a specific embodiment of the present invention, the compound represented by the formula I may be a compound represented by the following formula Ia or formula Ib.

[0031] Specifically, the present invention provides a compound represented by the following formula Ia, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0032] [Chemical Formula Ia]

[0033]

[0034] In the above chemical formula Ia,

[0035] L Xis -O-, -NH-, *-(CH2)nC(=O)-O-, *-(CH2)nC(=O)-NH-, *-(CH2)n-CH=CH-C(=O)-O-, or *-(5-6-membered heterocycloalkyl)-, where * is R X Indicates a point attached to, where n is 0, 1, 2, 3, or 4, and the *-(5-6-membered heterocycloalkyl)- comprises one or more N, O, or S within the ring;

[0036] R X is -H, -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl), wherein the -(4-6-membered heterocycloalkyl), -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) comprises one or more N, O, or S within the ring, and the -(5-10-membered heteroaryl) may comprise C (=O) within the ring, and one or more hydrogens of the -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) ring are R U1 It can be replaced with;

[0037] L Y is a single bond, -(C=O)-O-(CH2)m-**, -(C=O)-NH-(CH2)m-**, -CH=CH-C(=O)-(CH2)m-**, where ** indicates a point attached to ring Y, and m is 0, 1, 2, 3, or 4;

[0038] R U1 and R U2 -C each independently 1-6 Alkyl, -NR a R b , -OR c , -SR c, -(3-6-membered cycloalkyl), -phenyl, -CN, -NO2, -C 1-6 haloalkyl, or -halo, wherein one or more hydrogens of the -(3-6-membered cycloalkyl) or -phenyl ring are -C 1-6 alkyl or -C 1-6 It can be substituted with an alkoxy;

[0039] R a and R b -H or -C, respectively, independently 1-6 It is alkyl;

[0040] R c -H or -C 1-6 It is alkyl;

[0041] y is 0, 1, 2, or 3.

[0042] In addition, the present invention provides a compound represented by the following formula Ib, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0043] [Chemical Formula Ib]

[0044]

[0045] In the above chemical formula Ib,

[0046] L X is -O-, -NH-, *-(CH2)nC(=O)-O-, *-(CH2)nC(=O)-NH-, *-(CH2)n-CH=CH-C(=O)-O-, or *-(5-6-membered heterocycloalkyl)-, where * is R X Indicates a point attached to, where n is 0, 1, 2, 3, or 4, and the *-(5-6-membered heterocycloalkyl)- comprises one or more N, O, or S within the ring;

[0047] R X is -H, -C 1-6 Alkyl, -C 1-6Hydroxyalkyl, -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl), wherein the -(4-6-membered heterocycloalkyl), -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) comprises one or more N, O, or S within the ring, and the -(5-10-membered heteroaryl) may comprise C (=O) within the ring, and one or more hydrogens of the -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) ring are R U1 It can be replaced with;

[0048] R U1 and R U2 -C each independently 1-6 Alkyl, -NR a R b , -OR c , -SR c , -(3-6-membered cycloalkyl), -phenyl, -CN, -NO2, -C 1-6 haloalkyl, or -halo, wherein one or more hydrogens of the -(3-6-membered cycloalkyl) or -phenyl ring are -C 1-6 alkyl or -C 1-6 It can be substituted with an alkoxy;

[0049] R a and R b -H or -C, respectively, independently 1-6 It is alkyl;

[0050] R c -H or -C 1-6 It is alkyl;

[0051] y is 0, 1, 2, or 3.

[0052] According to a specific embodiment of the present invention, the compound represented by the chemical formula I may be selected from the group consisting of compounds listed in Tables 1 to 9 below.

[0053] In the present invention, "alkyl" may mean a straight-chain or branched-chain acyclic, cyclic, or saturated hydrocarbon combined with such acyclic hydrocarbon, unless otherwise specified. For example, "C 1-6 "alkyl" may mean an alkyl containing 1 to 6 carbon atoms. Examples of non-cyclic alkyls may include, but are not limited to, methyl, ethyl,n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylpentyl. In this specification, a residue obtained by removing one hydrogen atom from the "alkyl" is referred to as "alkylene." Cyclic alkyls may be used interchangeably with "cycloalkyl" in this specification and may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0054] In the present invention, "alkenyl" and "alkynyl" may refer to straight-chain or branched-chain acyclic, cyclic, or combined unsaturated hydrocarbons. For example, "C 1-6 "Alkenyl" may refer to an unsaturated hydrocarbon having 1 to 6 carbon atoms having one or more double bonds, and "C 1-6 "Alkynyl" may mean an unsaturated hydrocarbon having 1 to 6 carbon atoms having one or more triple bonds.

[0055] In the present invention, "alkoxy" may mean an alkyl ether group -(R'-OR"), where R' is a single bond and C 1-6 It can be selected from the group consisting of alkyls, and R" is C 1-6 It may be an alkyl. Here, the alkyl is as defined above. For example, "C 1-6 "Alkoxy" is C 1-6 Alkoxy containing an alkyl group, i.e., -(OC 1-6 alkyl) or -(C 1-6 Alkyl-OC 1-6It may mean alkyl, and examples of alkoxy may include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy, but are not limited thereto.

[0056] In the present invention, "halo" may be F, Cl, Br, or I.

[0057] In the present invention, "haloalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with one or more halos as defined herein. Examples of said haloalkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl independently substituted with one or more halogens, e.g., F, Cl, Br, or I.

[0058] In the present invention, "hydroxyalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with a hydroxy (-OH), and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl independently substituted with -OH, but is not limited thereto.

[0059] In the present invention, "alkylamino" or "aminoalkyl" may mean -(NR'R"), where R' and R' are each independently hydrogen, C 1-6 It may be selected from the group consisting of alkyl groups and N protecting groups (e.g., Boc), and the selected R' and R" may each be independently substituted or unsubstituted. Additionally, "C 0-6 "Alkylamino" refers to an amino (-NH2) or C that does not contain an alkyl group. 1-6Amino containing an alkyl group, i.e., -NH(C 1-6 alkyl) or -N(C 1-6 It may mean alkyl)2 and may include, but is not limited to, dimethylamino, diethylamino, methylethylamino, methylpropylamino, and ethylpropylamino.

[0060] In the present invention, "cyanoalkyl" may mean a straight-chain or branched-chain alkyl (hydrocarbon) having a carbon atom substituted with cyano(-CN).

[0061] In the present invention, "alkylsulfonyl" may mean -(R'-S(=O)2-R"), where R' is a single bond and C 1-6 It can be selected from the group consisting of alkyl groups, and R" is hydroxyl and C 1-6 It can be selected from the group consisting of alkyl groups. The selected R' and R" may each be independently substituted or unsubstituted. In addition, "C 0-6 "Alkylsulfonyl" refers to a sulfonic acid group (-S(=O)2OH) or C that does not contain an alkyl group. 1-6 A sulfonyl group containing an alkyl group, i.e., -S(=O)2-(C 1-6 alkyl) or -(C 1-6 Alkyl)-S(=O)2-(C 1-6 It may mean alkyl, and may include methylsulfonyl, (methylsulfonyl)methyl, (methylsulfonyl)ethyl, ethylsulfonyl, (ethylsulfonyl)methyl, and (ethylsulfonyl)ethyl, but is not limited thereto.

[0062] In the present invention, "alkyl carbonyl" may mean -(R'-C(=O)-R"), where R' is a single bond and C 1-6 It can be selected from the group consisting of alkyls, and R" is hydrogen and C 1-6 It can be selected from the group consisting of alkyl groups. The selected R' and R" may each be independently substituted or unsubstituted. In addition, "C 0-6"Alkyl carbonyl" refers to an aldehyde group (-C(=O)H) or C that does not contain an alkyl group. 1-6 A ketone group containing an alkyl group, i.e., -C(=O)-(C 1-6 alkyl) or -(C 1-6 Alkyl)-C(=O)-(C 1-6 It can mean alkyl.

[0063] In the present invention, "cycloalkyl" may mean a hydrocarbon ring that does not contain heteroatoms (N, O, P, P(=O), or S, etc.) within the ring, and may be saturated or partially unsaturated. Here, if unsaturated, it may be referred to as a cycloalkene. Unless otherwise noted, a cycloalkyl may be a single ring or a polycyclic ring such as a spiro ring, a bridged ring, or a fused ring.

[0064] In the present invention, "heterocycloalkyl" may mean a ring containing one or more selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. Here, if unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise noted, a heterocycloalkyl may be a single ring or a multi-ring such as a spiro ring, a bridged ring, or a fused ring. Additionally, "4-7-membered heterocycloalkyl" may mean a heterocycloalkyl comprising 4 to 7 atoms forming a ring. Examples of heterocycloalkyls include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomopoline, thiomopoline-S-oxide, thiomopoline-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, tetrahydrofuran, tetrahydrothiophene, quinuclidein, tropane, 2-azaspiro[3.3]heptane, (1r,5s)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1r,4r)-2-oxa-5-azabicyclo[2.2.2]octane, etc. may be included, but are not limited thereto.

[0065] In the present invention, "heterobicycloalkyl" may refer to a multi-ring such as a spiro ring, a bridged ring, or a fused ring containing one or more selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. Here, if unsaturated, it may be referred to as a heterobicycloalkene. Examples of heterobicycloalkyl may include, but are not limited to, quinuclidein, tropane, 2-azaspiro[3.3]heptane, (1r,5s)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1r,4r)-2-oxa-5-azabicyclo[2.2.2]octane.

[0066] In the present invention, "arene" may refer to an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming carbon atoms of the arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaternbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluorantene, chrysene, etc. In this specification, a residue obtained by removing one hydrogen atom from the "arene" is referred to as "aryl".

[0067] In the present invention, "heteroarene" may be a ring comprising one or more of O, N, P, Si, and S as heteroelements. The number of ring-forming atoms of the heteroarene may be 3 or more and 30 or less, 3 or more and 20 or less, or 3 or more and 15 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a two-ring or three-ring structure. Examples of heteroalenes include thiophene, purine, pyrrole, pyrazol, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, pyridin-2-one, pyridin-3-one, pyridin-4-one, bipyridyl, triazine, acryl, pyridazine, pyrazine, quinoline, quinazolin, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole. Examples include, but are not limited to, benzoxazole, benzimidazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isooxazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilol, and dibenzofuran. In one embodiment of the present invention, the heteroarene may also include a bicyclic heterocycloarene comprising an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In this specification, a residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as "heteroaryl".

[0068] In the present invention, "hydroalene" or "hydroaryl" is a saturated form of one or more double bonds in an aromatic hydrocarbon ring.

[0069] In the present invention, "heterohydroarene" may mean a polycyclic ring (2 to 4 rings) containing 1 to 5 heteroatoms selected from N, O, and S as ring-forming atoms, at least one of the polycyclic rings may be a saturated or partially unsaturated ring, and at least one other may have an aromatic ring. In this specification, a residue obtained by removing one hydrogen atom from the "heterohydroarene" is referred to as "heterohydroaryl".

[0070] In the present invention, the "ring" may be a single ring or multiple rings. The multiple rings may be a spiro ring, a bridged ring, or a fused ring.

[0071] In the present invention, "stereoisomer" refers to a compound having the same chemical formula or molecular formula but differing stereochemically. In this specification, stereoisomers include optical isomers, enantiomers, diastereomers, cis / trans isomers, rotamers, and atropisomers, and each of these isomers, racemies, and mixtures thereof are also included within the scope of the present invention. For example, the compound represented by Formula I of the present invention may include the stereoisomers of Formula I because its stereochemical structure is not specified. Unless otherwise noted, solid line bonds connected to an asymmetric carbon atom ( ) is a wedge-shaped solid line combination representing an absolute arrangement of three-dimensional centers ( ) or wedge-shaped dotted line connection ( It may include ).

[0072] The compound represented by Formula I of the present invention may exist in the form of a "pharmaceutically acceptable salt." Accordingly, the category of compounds of the present invention includes pharmaceutically acceptable salts of the compound represented by Formula I. The term "pharmaceutically acceptable salt" of the present invention refers to any organic acid or inorganic acid addition salt of said compound, wherein the side effects caused by said salt do not impair the beneficial efficacy of the compound represented by Formula I, at a concentration having an effective action that is relatively non-toxic and harmless to the patient.

[0073] In particular, the above pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, the acid addition salt may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromide, hydroiodide, nitrous acid, phosphoric acid, etc., non-toxic organic acids such as aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.

[0074] These types of pharmaceutically acceptable salts may include sulfates, sulfites, nitrates, phosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maliates, benzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, glycolates, malates, tartrates, mandelates, etc.

[0075] The above acid addition salt can be prepared by conventional methods, for example, by dissolving a derivative of Formula I in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or an inorganic acid, filtering and drying the resulting precipitate, or by vacuum distilling the solvent and excess acid, drying, and crystallizing under an organic solvent.

[0076] In addition, the above pharmaceutically acceptable salt may be a salt obtained using a base or a metal salt. As an example of a metal salt, an alkali metal or alkaline earth metal salt may be obtained by dissolving a compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. Sodium, potassium, or calcium salts may be pharmaceutically suitable as alkali metal salts. In addition, the corresponding salt may be obtained by reacting the alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate) and may be prepared through a method of salt preparation known in the art.

[0077] Method for preparing 5-HMF derivatives

[0078] The present invention provides a method for preparing a compound represented by the formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0079] A preferred method for preparing the compound represented by Formula I of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof is the same as Reaction Schemes 1 to 6, and includes methods for preparation modified to a degree obvious to those skilled in the art.

[0080] [Reaction Equation 1]

[0081]

[0082] The synthesis of an A-type 5-HMF derivative belonging to chemical formula Ia was carried out as shown in reaction scheme 1 above. Specifically, an ester compound (1) was obtained by protecting the hydroxyl group of 5-HMF with acetic anhydride (Ac2O) under pyridine solvent. Subsequently, an A-1 type compound (3) was synthesized by a Pinnick-type oxidative amidation reaction using sodium hypochlorite, sodium dihydrogen phosphate, and 2,3-dimethyl-2-butene under ethyl acetate (EA) solvent on compound (1) and compound (2) containing various substituents. Subsequently, an A-2 type compound (4) was obtained by hydrolyzing compound (3) with lithium hydroxide. Subsequently, the compound (4) and various acid compounds (5) were subjected to an esterification reaction in anhydrous dichloromethane (DCM) solvent in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl) and 4-(dimethylamino)pyridine (DMAP) to obtain an A-3 type compound (6).

[0083] [Reaction Equation 2]

[0084]

[0085] The synthesis of a B-type 5-HMF derivative belonging to chemical formula Ia was carried out as shown in reaction scheme 2 above. Specifically, a B-1 type compound (8) was obtained by performing an aldol reaction by reacting compound (1) and compound (7) with various substituents introduced in methanol (MeOH) solvent with an excess amount of potassium hydroxide. Subsequently, a B-2 type compound (9) was synthesized by acetylating compound (8) with acetyl chloride (AcCl).

[0086] [Reaction Equation 3]

[0087]

[0088] The synthesis of C-2 and C-3 type 5-HMF derivatives belonging to chemical formula Ia was carried out as shown in reaction scheme 3 above. Specifically, compound (10) was obtained by performing an Appel reaction with carbon tetrabromide and triphenylphosphine on 5-HMF in anhydrous DCM solvent. Subsequently, compound (10) and compound (11) were combined by a Finkelstein reaction using potassium carbonate and sodium iodide in dimethylformamide (DMF) solvent to synthesize compound (12). A C-2 type compound (13) was obtained by applying the same synthesis method as for A-1 type compound (3), except that compound (1) was changed to compound (12). Meanwhile, a C-3 type compound (14) was obtained by carrying out the reaction under the same synthesis conditions as for B-1 type compound (8), except that compound (12) was used instead of compound (1).

[0089] [Reaction Equation 4]

[0090]

[0091] The synthesis of a C-4 type 5-HMF derivative belonging to chemical formula Ia was carried out as shown in reaction scheme 4 above. Specifically, for the A-2 type compound (4), the alcohol group was converted to an azide group using diphenylphosphoryl azide (DPPA) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a tetrahydrofuran (THF) solvent. Subsequently, an amine compound (15) was obtained through a reduction reaction using zinc (Zn) and acetic acid (AcOH). Meanwhile, compound (16) was reacted with a small amount of perchloric acid added in an AcOH / Ac2O (v / v = 2:1) solvent to obtain an acetyl-protected compound (17). Subsequently, compound (15) and compound (17) were combined by an amide coupling reaction using EDC·HCl and DMAP to obtain compound (18). Finally, a C-4 type compound (19) was synthesized by removing the acetyl group of compound (18) using potassium carbonate and an excess amount of Amberlite IR-120 ion exchange resin in MeOH solvent.

[0092] [Reaction Equation 5]

[0093]

[0094] The synthesis of the D-1 type 5-HMF derivative belonging to chemical formula Ib was carried out as shown in Reaction Scheme 5 above. Specifically, compound (1) and compound (20) with various substituents introduced were reacted in MeOH solvent, and then compound (21) containing a benzoxazole ring was obtained through an oxidation reaction using 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ). Subsequently, compound (22) was synthesized by applying the same method as the hydrolysis reaction presented in Reaction Scheme 1 to compound (21). Compound (23) was synthesized by applying the same Appel reaction conditions used in Reaction Scheme 3 to compound (22). Meanwhile, compound (24) was obtained by using a nucleophilic aromatic substitution reaction with 1-Boc-piperazine and potassium carbonate in dimethyl sulfoxide (DMSO) solvent to obtain compound (25). Next, compound (26) was synthesized by removing the amine protecting group of compound (25) using trifluoroacetic acid (TFA). Subsequently, compound (27) was obtained by applying the same conditions as the Finkelstein reaction presented in Reaction Scheme 3 to compounds (23) and (26). Finally, the nitro group of compound (27) was reduced using zinc (Zn) and ammonium chloride to obtain D-1 type compound (28).

[0095] [Reaction Equation 6]

[0096]

[0097] The synthesis of D-2 and D-3 type 5-HMF derivatives belonging to chemical formula Ib was carried out as shown in reaction scheme 6 above. Specifically, the alcohol group of compound (22) was converted to an amine group by applying the same method as the conditions presented in reaction scheme 4 to obtain compound (29). Subsequently, compound (29) was reacted with compound (30) or compound (32) under amide coupling conditions using propylphosphonic anhydride (T3P) and triethylamine (TEA) in DMF solvent to synthesize D-2 type compound (32) or D-3 type compound (33).

[0098] Uses of 5-HMF derivatives

[0099] The present invention provides the use of a compound represented by the following formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0100] [Chemical Formula I]

[0101]

[0102] The above chemical formula I is as defined above.

[0103] A compound represented by Formula I of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can activate the Wnt / β-catenin signaling pathway.

[0104] The activation of the Wnt / β-catenin signaling pathway can be regulated by the amount of β-catenin in the cytoplasm; if the Frizzled receptor and LRP5 / 6 co-receptors do not recognize external signals (i.e., Wnt) at the cell membrane, a destruction complex composed of cytoplasmic proteins such as APC, AXIN, CK1, and GSK3β can degrade β-catenin. When Wnt proteins bind to the receptor complex on the cell membrane, the downstream protein Dishelved (Dvl) is phosphorylated, inhibiting the function of the destruction complex and leading to the accumulation of stabilized β-catenin in the cytoplasm. The accumulated β-catenin translocates to the nucleus and forms a complex with TCF / LEF transcription factors, promoting gene expression related to cell proliferation, survival, differentiation, and migration. On the other hand, when the Wnt / β-catenin signaling pathway is inhibited, the Frizzled receptor and LRP5 / 6 co-receptors are separated from each other and exist on the cell membrane, and β-catenin is degraded by CK1 and GSK3β of the destruction complex in the cytoplasm, thereby inhibiting target gene expression.

[0105] According to one embodiment of the present invention, the compound represented by Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof can induce activation by inhibiting the degradation of β-catenin. Specifically, the compound can significantly activate the Wnt / β-catenin signaling pathway by inhibiting the degradation of β-catenin in the cytoplasm, thereby inducing accumulation and promoting its translocation to the nucleus, and thus can promote or induce cell proliferation and / or differentiation of dermal papilla cells. Accordingly, the compound represented by Formula I of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof can be used as a β-catenin activator.

[0106] In addition, according to one embodiment of the present invention, the compound represented by Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof can inhibit GSK3β. Specifically, the compound can inhibit the activity of GSK3β by inducing phosphorylation of GSK3β in dermal papilla cells, and thus can accumulate β-catenin in the cytoplasm, thereby activating signaling pathways associated with the proliferation of dermal papilla cells. Therefore, the compound represented by Formula I, its stereoisomer, or a pharmaceutically acceptable salt thereof can be used as a GSK3β inhibitor.

[0107] In addition, according to one embodiment of the present invention, a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can activate AKT. Specifically, the compound can induce phosphorylation of AKT in dermal papilla cells, thereby inhibiting the degradation of β-catenin or causing it to accumulate in the cytoplasm, and thus can activate signaling pathways associated with the proliferation of dermal papilla cells. Therefore, a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can be used as an AKT activator.

[0108] Accordingly, the compound represented by Formula I of the present invention, its stereoisomers, or pharmaceutically acceptable salts thereof may induce β-catenin accumulation through a ligand-independent mechanism, such as AKT activation or GSK3β inhibition, independently of the Wnt ligand.

[0109] According to one embodiment of the present invention, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound represented by the formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0110] In addition, according to one embodiment of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of hair loss, comprising as an active ingredient a compound represented by the formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0111] The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicinal effects in addition to the compound represented by the formula I, its stereoisomer, or its pharmaceutically acceptable salt.

[0112] The pharmaceutical composition of the present invention can be used for clinical administration and can be prepared to be administered in various oral and parenteral formulations.

[0113] In addition, according to one embodiment of the present invention, the present invention provides a use of a compound represented by the formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of hair loss.

[0114] In addition, according to one embodiment of the present invention, a method for preventing or treating hair loss is provided, comprising the step of administering a therapeutically effective amount of a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be a mammal, including humans.

[0115] In addition, according to one embodiment of the present invention, the present invention provides a method for preventing or treating hair loss comprising the step of administering a therapeutically effective amount of a compound represented by the formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0116] In addition, according to one embodiment of the present invention, the present invention provides a method for activating the Wnt / β-catenin signaling pathway, comprising the step of administering a therapeutically effective amount of a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

[0117] The term "therapeutically effective amount" as used in the present invention refers to an amount of the compound represented by Formula I above that is effective for the prevention or treatment of hair loss. Specifically, "therapeutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined based on factors including individual type and severity, age, gender, type of disease, drug activity, sensitivity to the drug, time of administration, route of administration and elimination rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual treatment or in combination with other treatments, and may be administered sequentially or simultaneously with commercially available treatments. It may also be administered as a single or multiple doses. It is important to administer an amount that obtains maximum effect with a minimum amount without side effects by considering all of the above factors, and this can be easily determined by a person skilled in the art. The dosage of the pharmaceutical composition of the present invention may be determined by an expert based on various factors such as the patient's condition, age, gender, and complications. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used even at doses greater than the determined dosage.

[0118] As used in the present invention, "prevention" refers to any act of suppressing or delaying the occurrence, spread, and recurrence of the said disease through the administration of the said compound, and "treatment" refers to any act of improving or beneficially altering the symptoms of the said disease through the administration of the said compound.

[0119] In addition, according to one embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable additive.

[0120] Examples of additives used in the above pharmaceutical composition may include sweeteners, binders, solvents, solubilizing aids, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, etc. For example, the additives may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, tragacanth gum, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[0121] The above pharmaceutical composition may be formulated into various formulations for oral administration (e.g., tablets, pills, powders, capsules, syrups, or emulsions) or parenteral administration (e.g., intramuscular, intravenous, or subcutaneous injection).

[0122] For example, the above pharmaceutical composition may be formulated as an oral administration preparation, and the additives used therein may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. Specifically, solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms may be formulated by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose, gelatin, etc., with the above composition. In addition, in addition to simple excipients, lubricants such as magnesium stearate and talc may be used. In addition, liquid formulations for oral administration may include suspensions, emulsions, syrups, etc., and may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.

[0123] In addition, preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As bases for suppositories, Witepsol, Macrogol, Tween 61, cacao oil, laurin oil, glycerogelatin, etc. may be used. Meanwhile, injectable preparations may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0124] In addition, it can be manufactured as a complex formulation with other active agents to have a synergistic effect of the active ingredients.

[0125] The matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they contradict one another.

[0126] The compound of the present invention induces the accumulation of β-catenin in the cytoplasm even in the absence of Wnt ligands, thereby significantly activating the Wnt / β-catenin signaling pathway, and simultaneously induces GSK3β inhibition and AKT activation, exhibiting mutually complementary hair growth-promoting effects, so it can be usefully used for the prevention or treatment of hair loss.

[0127] In addition, the compound of the present invention experimentally demonstrated a significant hair regeneration effect not only upon topical application but also upon oral administration.

[0128] Figures 1a to 1c show the results of evaluating the proliferation rate of normal hair papilla cells of the compound.

[0129] Figures 2a and 2b show the results of evaluating the proliferation rate of damaged dermal papilla cells of the compound.

[0130] Figure 3 shows the results of the evaluation of the mechanism of action of the compound through Western blot analysis.

[0131] The present invention will be explained in detail below through examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

[0132] Example: Preparation of the compound of the present invention

[0133] <Reagents, Purification, and Analysis Conditions>

[0134] The reagents used in this example were purchased from companies such as Sigma-Aldrich, TCI, Alfa Aesar, Aladdin, Avention, and Combi-Blocks, and were used without additional purification. The progress of all reactions was monitored using thin-layer chromatography (TLC), and the silica product coated on the glass plate was Merck's Silica Gel 60 F. 254UV light in the 254 and 365 nm ultraviolet (UV) regions was used for TLC verification during the monitoring process, and chromogenic reagents such as ninhydrin, p-anisaldehyde, and bromocresol green were used when color development of specific functional groups was required.

[0135] Purification was performed using extraction, trituration, and flash column chromatography, and Merck silica gel (particle size: 230-400 mesh) was used as the stationary phase for flash column chromatography. For the purified compounds, Bruker Avance-DXR 400 MHz spectrometers and Jeol JNM-ECZR 500 MHz spectrometers were used 1 H NMR and 13 1 / 3C NMR spectra were obtained, and HRMS data were acquired using a Thermo Scientific Q-Exactive instrument. Tetramethylsilane (TMS) was used as the internal reference material for NMR, and chemical shifts (δ) values ​​were expressed in ppm. Coupling constants (J) were expressed in hertz (Hz), and signal multiplicities were expressed as s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), dd (doublet of doublet), m (multiplet), etc.

[0136] Example 1. Synthesis of (5-(phenylcarbamoyl)furan-2-yl)methyl acetate (Compound 1)

[0137] [Step 1] Synthesis of (5-formylfuran-2-yl)methyl acetate

[0138] 5-(hydroxymethyl)furfural (4 g, 31.7 mmol, 1.0 eq) was dissolved in acetonitrile, and acetic anhydride (4.94 mL, 52.3 mmol, 1.7 eq) and pyridine (0.64 mL, 7.92 mmol, 0.25 eq) were added at 0 °C. The mixture was stirred at room temperature for 2 hours, after which the reaction was terminated. After removing the solvent under reduced pressure, the reaction mixture was purified by flash column chromatography (ethyl acetate:n-hexane = 1:3) to obtain the title compound (4.79 g, 87%) as a light brown solid.

[0139] 1 H NMR (500 MHz, CDCl3) δ 9.63 (s, 1H), 7.20 (d,J= 3.5 Hz, 1H), 6.58 (d,J= 3.5 Hz, 1H), 5.11 (s, 2H), 2.10 (s, 3H).

[0140] [Step 2] Synthesis of (5-(phenylcarbamoyl)furan-2-yl)methyl acetate

[0141] (5-formylfuran-2-yl)methyl acetate (0.08 mL, 0.60 mmol, 1.0 eq), aniline (0.08 mL, 0.89 mmol, 1.5 eq), and 2,3-dimethyl-2-butene (0.32 mL, 2.97 mmol, 5.0 eq) obtained in Step 1 were dissolved in ethyl acetate and reacted for 2 hours. Subsequently, NaClO2 (0.168 g, 1.86 mmol, 3.1 eq) and NaH2PO4 (0.146 g, 2.08 mmol, 3.5 eq) were added, and the mixture was stirred at 40 °C for 17 hours. After the reaction was complete, the mixture was extracted with ethyl acetate and water, and the organic layer was dried with anhydrous MgSO4. After removing the solvent under reduced pressure, it was purified by flash column chromatography (ethyl acetate:n-hexane = 1:4). Finally, a white solid title compound (0.10 g, 68%) was obtained through trituration using dichloromethane and n-hexane.

[0142] 1 H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.69 (dd,J= 8.4, 0.8 Hz, 2H), 7.34-7.27 (m, 3H), 7.09-7.04 (m, 1H), 6.69 (d,J= 3.4 Hz, 1H), 5.08 (s, 2H), 2.04 (s, 3H).

[0143] Examples 2 to 4, 6, 7, 10, 12, 16, 17, 19, 21 and 23 to 25

[0144] Examples of compounds 2 to 4, 6, 7, 10, 12, 16, 17, 19, 21, 23 to 25 of the present invention were synthesized in a manner similar to Example 1.

[0145] The structure, NMR and MS analysis results, and properties (yield) of the compounds synthesized in each example are summarized in Table 1 below.

[0146] [Table 1]

[0147]

[0148]

[0149]

[0150] Example 5. Synthesis of N-(4-fluorophenyl)-5-(hydroxymethyl)furan-2-carboxamide (Compound 5)

[0151] Compound 4 (0.094 g, 0.34 mmol, 1.0 eq) was dissolved in tetrahydrofuran / methanol / water (v / v / v = 1:1:1), and then LiOH (0.145 g, 6.03 mmol, 18 eq) was added and stirred for 10 minutes. After the reaction was complete, the solvent was removed under reduced pressure, and a saturated ammonium chloride solution was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was dried with anhydrous MgSO4 and the solvent was removed under reduced pressure. Subsequently, the title compound (0.06 g, 78%) as a light brown solid was obtained by trituration using dichloromethane, n-hexane, and isopropyl ether.

[0152] 1 H NMR (500 MHz, DMSO-d6) δ 10.12 (s, 1H), 7.77-7.67 (m, 2H), 7.23 (d,J= 3.4 Hz, 1H), 7.19-7.08 (m, 2H), 6.47 (d,J= 3.4 Hz, 1H), 5.40 (t,J= 5.8 Hz, 1H), 4.46 (d,J= 5.8 Hz, 2H).

[0153] Examples 8, 9, 11, 13, 18, 20, 22, and 26

[0154] Examples of compounds 8, 9, 11, 13, 18, 20, 22, and 26 of the present invention were synthesized in a manner similar to Example 5.

[0155] The structure, NMR and MS analysis results, and properties (yield) of the compounds synthesized in each example are summarized in Table 2 below.

[0156] [Table 2]

[0157]

[0158]

[0159] Example 14. Synthesis of (E)-(5-(p-tolylcarbamoyl)furan-2-yl)methyl 3-(benzo[d][1,3]dioxol-6-yl)acrylate (Compound 14)

[0160] Compound 13 (0.17 g, 0.74 mmol, 1.0 eq), (E)-3-(benzo[d][1,3]dioxol-6-yl)acrylic acid (0.212 g, 1.10 mmol, 1.5 eq), and 4-(dimethylamino)pyridine (0.045 g, 0.37 mmol, 0.5 eq) were dissolved in anhydrous dichloromethane, and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.169 g, 0.88 mmol, 1.2 eq) was added at 0 °C and stirred at room temperature for 18 hours. After the reaction was complete, the mixture was extracted with dichloromethane and water, and the organic layer was dried with anhydrous MgSO4. After removing the solvent under reduced pressure, it was purified by flash column chromatography (ethyl acetate:n-hexane = 1:2). Subsequently, a white solid title compound (0.20 g, 68%) was obtained through trituration using dichloromethane and petroleum ether.

[0161] Examples 15, 38, and 43

[0162] Example compounds 15, 38, and 43 of the present invention were synthesized in a manner similar to Example 14.

[0163] The structure, NMR and MS analysis results, and properties (yield) of the compounds synthesized in each example are summarized in Table 3 below.

[0164] [Table 3]

[0165]

[0166]

[0167] Example 27. Synthesis of (E)-3-(5-(hydroxymethyl)furan-2-yl)-1-(3-nitrophenyl)prop-2-en-1-one (Compound 27)

[0168] (5-formylfuran-2-yl)methyl acetate (0.295 g, 1.78 mmol, 1.0 eq) obtained in Step 1 of Example 1 was dissolved in methanol, and then an excess amount of 50 wt% KOH solution was added and stirred at room temperature for 5 minutes. Subsequently, 1-(3-nitrophenyl)ethanol (0.301 g, 1.82 mmol, 1.1 eq) was added and stirred for an additional 8 hours. After the reaction was complete, 2 N HCl solution was added to adjust the pH to neutral, and the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate and water, and the separated organic layer was dried with anhydrous MgSO4. After removing the solvent under reduced pressure, it was purified by flash column chromatography (ethyl acetate:n-hexane = 1:2). Finally, a yellow solid title compound (0.25 g, 51%) was obtained through trituration using dichloromethane and petroleum ether.

[0169] Examples 28, 29, 31 to 33, 35, 37, 42 and 45

[0170] Examples of compounds 28, 29, 31 to 33, 35, 37, 42 and 45 of the present invention were synthesized in a manner similar to Example 27.

[0171] The structure, NMR and MS analysis results, and properties (yield) of the compounds synthesized in each example are summarized in Table 4 below.

[0172] [Table 4]

[0173]

[0174]

[0175]

[0176] Example 30. Synthesis of (5-((E)-3-(2-hydroxy-5-methoxyphenyl)-3-oxoprop-1-enyl)furan-2-yl)methyl acetate (Compound 30)

[0177] Compound 29 (0.147 g, 0.54 mmol, 1.0 eq) was dissolved in dichloromethane, and then acetyl chloride (0.04 mL, 0.59 mmol, 1.1 eq) and pyridine (0.07 mL, 0.80 mmol, 1.5 eq) were added at 0 °C and stirred at room temperature for 1 hour. After the reaction was complete, the mixture was extracted with dichloromethane and water, and the separated organic layer was dried with anhydrous MgSO4. After removing the solvent under reduced pressure, the mixture was purified by flash column chromatography (ethyl acetate:n-hexane = 1:5). Subsequently, the title compound (0.06 g, 67%) as an orange solid was obtained through trituration using dichloromethane and petroleum ether.

[0178] Examples 34 and 36

[0179] Examples of compounds 34 and 36 of the present invention were synthesized in a manner similar to Example 30.

[0180] The structure, NMR and MS analysis results, and properties (yield) of the compounds synthesized in each example are summarized in Table 5 below.

[0181] [Table 5]

[0182]

[0183] Example 39. Synthesis of 5-((benzo[d][1,3]dioxol-6-yloxy)methyl)-Np-tolylfuran-2-carboxamide (Compound 39)

[0184] [Step 1] Synthesis of 5-(bromomethyl)furan-2-carbaldehyde

[0185] 5-(hydroxymethyl)furfural (2 g, 15.9 mmol, 1.0 eq), carbon tetrabromide (6.31 g, 19.0 mmol, 1.2 eq), and triphenylphosphine (5.82 g, 20.6 mmol, 1.3 eq) were dissolved in anhydrous dichloromethane and stirred at 0 °C for 4 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the solution was purified by flash column chromatography (ethyl acetate:n-hexane = 1:4) to obtain the black liquid title compound (1.72 g, 57%).

[0186] 1 H NMR (500 MHz, CDCl3) δ 9.62 (s, 1H), 7.19 (d,J= 3.6 Hz, 1H), 6.58 (d,J= 3.6 Hz, 1H), 4.48 (s, 2H).

[0187] [Step 2] Synthesis of 5-((benzo[d][1,3]dioxol-5-yloxy)methyl)furan-2-carbaldehyde

[0188] 5-(bromomethyl)furan-2-carbaldehyde (0.3 g, 1.59 mmol, 1.0 eq), benzo[d][1,3]dioxol-5-ol (0.219 g, 1.59 mmol, 1.0 eq), potassium carbonate (1.097 g, 7.94 mmol, 5.0 eq), and sodium iodide (0.238 g, 1.59 mmol, 1.0 eq) obtained in Step 1 were dissolved in dimethylformamide and reacted for 4 hours. After the reaction was complete, a saturated ammonium chloride solution was added to the residue and extracted with ethyl acetate, and the separated organic layer was dried with anhydrous MgSO4. After removing the solvent under reduced pressure, the mixture was purified by flash column chromatography (ethyl acetate:n-hexane = 1:3). Subsequently, a white solid title compound (0.21 g, 52%) was obtained through trituration using dichloromethane, acetone, petroleum ether, and n-hexane.

[0189] 1H NMR (500 MHz, DMSO-d6) δ 9.55 (s, 1H), 7.49 (d,J= 3.5 Hz, 1H), 6.80 (d,J= 3.5 Hz, 1H), 6.79 (d,J= 8.5 Hz, 1H), 6.71 (d,J= 2.5 Hz, 1H), 6.43 (dd,J= 8.5, 2.5 Hz, 1H), 5.93 (s, 2H), 5.07 (s, 2H).

[0190] [Step 3] Synthesis of 5-((benzo[d][1,3]dioxol-6-yloxy)methyl)-Np-tolylfuran-2-carboxamide

[0191] The title compound (0.03 g, 23%), an orange solid, was synthesized in the same manner as in Step 2 of Example 1, except that the 5-((benzo[d][1,3]dioxol-5-yloxy)methyl)furan-2-carbaldehyde obtained in Step 2 was used.

[0192] Examples 40, 41, 44, and 46

[0193] Example compounds 40, 41, 44, and 46 of the present invention were synthesized in a manner similar to Example 39.

[0194] The structure, NMR and MS analysis results, and properties (yield) of the compounds synthesized in each example are summarized in Table 6 below.

[0195] [Table 6]

[0196]

[0197]

[0198] Example 47. Synthesis of N-(4-fluorobenzyl)-5-(((1R,3S,4R,5S)-1,3,4,5-tetrahydroxycyclohexane-1-carboxamide)methyl)furan-2-carboxamide (Compound 47)

[0199] [Step 1] Synthesis of 5-(aminomethyl)-N-(4-fluorobenzyl)furan-2-carboxamide

[0200] Compound 26 (0.275 g, 1.10 mmol, 1.0 eq) was dissolved in tetrahydrofuran, and then diphenylphosphoryl azide (0.35 mL, 1.65 mmol, 1.5 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL, 1.93 mmol, 1.8 eq) were slowly added at 0 °C and stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the separated organic layer was extracted with ethyl acetate and water and dried with anhydrous MgSO4. The residue obtained by vacuum concentration was then dissolved in ethanol / water (v / v= 5:1), followed by the addition of Zn (0.186 g, 2.84 mmol, 2.6 eq) and acetic acid (0.21 mL, 3.72 mmol, 3.4 eq) and stirring at 70 °C. After the reaction was complete, the resulting solid was filtered, and a 10 wt% NaOH solution was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous MgSO4 and the solvent was removed under vacuum; subsequently, the unrefined white solid title compound (0.18 g, 68%) was obtained through trituration using dichloromethane and petroleum ether.

[0201] 1 H NMR (500 MHz, DMSO-d6) δ 8.74 (t,J= 6.0 Hz, 1H), 7.33-7.25 (m, 2H), 7.10 (t,J= 8.8 Hz, 2H), 6.98 (d,J= 3.2 Hz, 1H), 6.31 (d,J= 3.2 Hz, 1H), 4.35 (d,J= 6.0 Hz, 2H), 3.67 (s, 2H), 2.00 (s, 2H).

[0202] [Step 2] Synthesis of (1R,3S,4R,5S)-1,3,4,5-tetraacetoxycyclohexane-1-carboxylic acid

[0203] D-(-)-quinic acid (1 g, 5.20 mmol, 1.0 eq) was dissolved in acetic acid / acetic anhydride (v / v= 2:1), and then a small amount of perchloric acid was added and stirred for 12 hours. After the reaction was complete, the mixture was extracted with chloroform and water, and the separated organic layer was dried with anhydrous MgSO4. The residue was concentrated under reduced pressure to obtain the title compound (1.23 g, 66%), which is an unpurified, transparent, foamy solid.

[0204] 1 H NMR (500 MHz, DMSO-d6) δ 13.17 (s, 1H), 5.32 (ddd,J= 3.8 Hz, 1H), 5.22 (ddd,J= 10.0, 8.3, 4.3 Hz, 1H), 5.04 (dd,J= 10.0, 3.8 Hz, 1H), 2.44-2.40 (m, 1H), 2.38 (dd,J= 15.8, 3.8 Hz, 1H), 2.30 (ddd,J= 13.2, 4.3, 2.3 Hz, 1H), 2.03 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H), 1.95-1.92 (m, 1H), 1.92 (s, 3H).

[0205] [Step 3] Synthesis of (1S,2R,3S,5R)-5-(((5-((4-fluorobenzyl)carbamoyl)furan-2-yl)methyl)carbamoyl)cyclohexane-1,2,3,5-tetrayl tetraacetate

[0206] A white solid title compound (0.20 g, 44%) was obtained by synthesizing in the same manner as in Example 14, except that 5-(aminomethyl)-N-(4-fluorobenzyl)furan-2-carboxamide obtained in Step 1 and (1R,3S,4R,5S)-1,3,4,5-tetraacetoxycyclohexane-1-carboxylic acid obtained in Step 2 were used.

[0207] 1H NMR (400 MHz, DMSO-d6) δ 8.76 (t,J= 6.1 Hz, 1H), 8.59 (t,J= 5.8 Hz, 1H), 7.35-7.30 (m, 2H), 7.14 (t,J= 8.9 Hz, 2H), 7.05 (d,J= 3.4 Hz, 1H), 6.25 (d,J= 3.4 Hz, 1H), 5.39 (ddd,J= 3.8, 3.4, 3.2 Hz, 1H), 5.30 (ddd,J= 10.3, 8.6, 4.5 Hz, 1H), 5.05 (dd,J= 10.3, 3.8 Hz, 1H), 4.39 (d,J= 6.1 Hz, 2H), 4.27 (d,J= 5.8 Hz, 2H), 2.62-2.54 (m, 1H), 2.46 (dd,J= 16.1, 3.4 Hz, 1H), 2.43-2.35 (m, 1H), 2.10 (s, 3H), 2.05 (s, 3H), 1.99 (s, 3H), 1.97-1.89 (m, 1H), 1.95 (s, 3H).

[0208] [Step 4] Synthesis of N-(4-fluorobenzyl)-5-(((1R,3S,4R,5S)-1,3,4,5-tetrahydroxycyclohexane-1-carboxamide)methyl)furan-2-carboxamide

[0209] (1S,2R,3S,5R)-5-(((5-((4-fluorobenzyl)carbamoyl)furan-2-yl)methyl)carbamoyl)cyclohexane-1,2,3,5-tetrayl tetraacetate (0.12 g, 0.20 mmol, 1.0 eq) obtained in Step 3 and potassium carbonate (0.112 g, 0.81 mmol, 4.0 eq) were dissolved in methanol and stirred at room temperature for 1 hour. Subsequently, an excess amount of Amberlite IR-120 ion exchange resin was added and stirred for an additional 1 hour. After the reaction was complete, the reaction mixture was filtered, and the resulting filtrate was dried with anhydrous MgSO4. After removing the solvent under reduced pressure, the solid insoluble in ethyl acetate, diethyl ether, and petroleum ether was filtered again to obtain the white solid title compound (0.06 g, 65%).

[0210] Examples 48 to 50

[0211] Examples of compounds 48 to 50 of the present invention were synthesized in a manner similar to Example 47.

[0212] The structure, NMR and MS analysis results, and properties (yield) of the compounds synthesized in each example are summarized in Table 7 below.

[0213] [Table 7]

[0214]

[0215]

[0216] Example 51. Synthesis of 4-(4-((5-(5-chlorobenzo[d]oxazole-2-yl)furan-2-yl)methyl)piperazine-1-yl)benzeneamine (Compound 51)

[0217] [Step 1a] Synthesis of (5-(5-chlorobenzo[d]oxazole-2-yl)furan-2-yl)methyl acetate

[0218] (5-formylfuran-2-yl)methyl acetate (0.3 g, 1.79 mmol, 1.0 eq) and 2-amino-4-chlorophenol (0.256 g, 1.79 mmol, 1.0 eq) obtained in Example 1 were dissolved in methanol and stirred at 45 °C for 12 hours. Afterward, the solvent was removed under reduced pressure, and the resulting residue was dissolved in dichloromethane. Then, 2,3-dichloro-5,6-dicyano-p-benzoquinone (0.446 g, 1.96 mmol, 1.1 eq) was added and stirred at room temperature for an additional 2 hours. After the reaction was complete, the mixture was extracted with a solution of dichloromethane and sodium bicarbonate, and the separated organic layer was dried with anhydrous MgSO4. The residue obtained by reduced pressure concentration was purified by flash column chromatography (ethyl acetate:n-hexane = 1:5), and then a white solid title compound (0.19 g, 36%) was obtained through trituration using dichloromethane, n-hexane, and petroleum ether.

[0219] 1 H NMR (400 MHz, CDCl3) δ 7.73 (d,J= 2.0 Hz, 1H), 7.49 (d,J= 8.6 Hz, 1H), 7.34 (dd,J= 8.6, 2.0 Hz, 1H), 7.26 (d,J= 3.5 Hz, 1H), 6.63 (d,J= 3.5 Hz, 1H), 5.17 (s, 2H), 2.11 (s, 3H).

[0220] [Step 1b] Synthesis of (5-(5-chlorobenzo[d]oxazole-2-yl)furan-2-yl)methanol

[0221] A light brown solid title compound (0.57 g, 95%) was obtained by synthesizing in the same manner as in Example 5, except that the (5-(5-chlorobenzo[d]oxazole-2-yl)furan-2-yl)methyl acetate obtained in Step 1a was used.

[0222] 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (d,J= 2.1 Hz, 1H), 7.81 (d,J= 8.7 Hz, 1H), 7.47 (dd,J= 8.7, 2.1 Hz, 1H), 7.45 (d,J= 3.5 Hz, 1H), 6.65 (d,J= 3.5 Hz, 1H), 5.55 (t,J= 4.2 Hz, 1H), 4.55 (d,J= 4.2 Hz, 2H).

[0223] [Step 1c] Synthesis of 2-(5-(bromomethyl)furan-2-yl)-5-chlorobenzo[d]oxazole

[0224] A white solid title compound (0.25 g, quant.) was obtained by synthesizing in the same manner as in Step 1 of Example 39, except that the (5-(5-chlorobenzo[d]oxazole-2-yl)furan-2-yl)methanol obtained in Step 1b was used.

[0225] 1H NMR (400 MHz, CDCl3) δ 7.73 (d,J= 2.0 Hz, 1H), 7.49 (d,J= 8.8 Hz, 1H), 7.34 (dd,J= 8.8, 2.0 Hz, 1H), 7.24 (d,J= 3.5 Hz, 1H), 6.62 (d,J= 3.5 Hz, 1H), 4.58 (s, 2H).

[0226] [Step 2a] Synthesis of tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate

[0227] Potassium carbonate (1.96 g, 14.2 mmol, 2.0 eq) and 1-Boc-piperazine (1.58 g, 8.50 mmol, 1.2 eq) were dissolved in dimethyl sulfoxide, and then 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol, 1.0 eq) was added and stirred at 100 °C for 12 hours. After the reaction was complete, the mixture was extracted with ethyl acetate and brine, and the separated organic layer was dried with anhydrous MgSO4. The residue obtained by vacuum concentration was triturated with dichloromethane, n-hexane, and petroleum ether to obtain the yellow solid title compound (2.05 g, 94%).

[0228] 1 H NMR (400 MHz, CDCl3) δ 8.14 (d,J= 9.4 Hz, 2H), 6.82 (d,J= 9.4 Hz, 2H), 3.61 (t,J= 6.5 Hz, 4H), 3.42 (t,J= 6.5 Hz, 4H), 1.49 (s, 9H).

[0229] [Step 2b] Synthesis of 4-(4-nitrophenyl)pyrerazine-1-ium 2,2,2-trifluoroacetate

[0230] The tert-butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (2 g, 6.51 mmol, 1.0 eq) obtained in Step 2a was dissolved in dichloromethane, and then trifluoroacetic acid (4.77 mL, 52.1 mmol, 8.0 eq) was added and stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed under reduced pressure, and the yellow solid title compound (2.09 g, 99%) was obtained by trituration using methanol and diethyl ether.

[0231] 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 2H), 8.15-8.08 (m, 2H), 7.13-7.08 (m, 2H), 3.66 (t,J= 6.5 Hz, 4H), 3.24 (t,J= 6.5 Hz, 4H).

[0232] [Step 3] Synthesis of 5-chloro-2-(5-((4-(4-nitrophenyl)piperazine-1-yl)methyl)furan-2-yl)benzo[d]oxazole

[0233] The yellow solid title compound (0.29 g, 84%) was obtained by synthesizing in the same manner as Step 2 of Example 39, except that 2-(5-(bromomethyl)furan-2-yl)-5-chlorobenzo[d]oxazole obtained in Step 1c and 4-(4-nitrophenyl)pyrerazine-1-ium 2,2,2-trifluoroacetate obtained in Step 2b were used.

[0234] 1 H NMR (400 MHz, CDCl3) δ 8.12 (d,J= 9.4 Hz, 2H), 7.72 (d,J= 2.0 Hz, 1H), 7.47 (d,J= 8.6 Hz, 1H), 7.32 (dd,J= 8.6, 2.0 Hz, 1H), 7.26 (d,J= 3.4 Hz, 1H), 6.81 (d,J= 9.4 Hz, 2H), 6.50 (d,J= 3.4 Hz, 1H), 3.77 (s, 2H), 3.46 (t,J= 5.2 Hz, 4H), 2.72 (t,J= 5.2 Hz, 4H).

[0235] [Step 4] Synthesis of 4-(4-((5-(5-chlorobenzo[d]oxazole-2-yl)furan-2-yl)methyl)piperazine-1-yl)benzenamine

[0236] 5-chloro-2-(5-((4-(4-nitrophenyl)piperazine-1-yl)methyl)furan-2-yl)benzo[d]oxazole (0.06 g, 0.14 mmol, 1.0 eq), Zn (0.072 g, 1.10 mmol, 8.0 eq), and ammonium chloride (0.010 g, 0.19 mmol, 1.4 eq) obtained in Step 3 were dissolved in ethanol / water (v / v= 5:1) and stirred at room temperature for 2 hours. After the reaction was complete, the mixed solution was filtered, and a 10 wt% NaOH solution was added to the filtrate and extracted with ethyl acetate. The separated organic layer was dried with anhydrous MgSO4 and the solvent was removed under reduced pressure. Subsequently, it was purified by flash column chromatography (dichloromethane:methanol:NH4Cl = 50:1:0.1), and finally, a yellow solid title compound (0.03 g, 45%) was obtained through trituration using dichloromethane, methanol, petroleum ether, and n-hexane.

[0237] Examples 53 to 55

[0238] Examples of compounds 53 to 55 of the present invention were synthesized in a manner similar to Example 51.

[0239] The structure, NMR and MS analysis results, and properties (yield) of the compounds synthesized in each example are summarized in Table 8 below.

[0240] [Table 8]

[0241]

[0242]

[0243] Example 52. Synthesis of N-((5-(benzo[d]oxazole-2-yl)furan-2-yl)methyl)-2-oxo-2H-chromene-3-carboxamide (Compound 52)

[0244] [Step 1] Synthesis of (5-(benzo[d]oxazole-2-yl)furan-2-yl)methane-aluminum acetate

[0245] A white solid title compound (0.12 g, 45%) was obtained by synthesizing in the same manner as in Step 1 of Example 47, except that the (5-(5-chlorobenzo[d]oxazole-2-yl)furan-2-yl)methanol obtained in Step 1b of Example 51 was used.

[0246] 1 H NMR (400 MHz, DMSO-d6) δ 7.79-7.71 (m, 2H), 7.44-7.36 (m, 3H), 6.60 (d, J= 3.5 Hz, 1H), 3.85 (s, 2H), 2.68 (s, 3H), 1.81 (s, 3H).

[0247] [Step 2] Synthesis of N-((5-(benzo[d]oxazole-2-yl)furan-2-yl)methyl)-2-oxo-2H-chromene-3-carboxamide

[0248] 2-oxo-2H-cremen-3-carboxylic acid (0.093 g, 0.49 mmol, 1.2 eq) was dissolved in anhydrous dimethylformamide, and then triethylamine (0.26 mL, 1.84 mmol, 4.5 eq), propylphosphonic anhydride (0.16 mL, 0.53 mmol, 1.3 eq), and Compound 29 (0.112 g, 0.41 mmol, 1.0 eq) were added and stirred at room temperature for 12 hours. After the reaction was complete, the mixture was extracted with ethyl acetate and brine, and the separated organic layer was dried with anhydrous MgSO4. The solvent was removed under reduced pressure, and the white solid title compound (0.06 g, 35%) was obtained by trituration using dichloromethane, methanol, and petroleum ether.

[0249] Examples 56 to 58

[0250] Examples of compounds 56 to 58 of the present invention were synthesized in a manner similar to Example 52.

[0251] The structure, NMR and MS analysis results, and properties (yield) of the compounds synthesized in each example are summarized in Table 9 below.

[0252] [Table 9]

[0253]

[0254]

[0255] Experimental Example: Evaluation of the efficacy of the compound of the present invention

[0256] Statistical analysis

[0257] The experimental results obtained in this experiment were expressed as mean ± standard error (mean ± SEM), and statistical analysis was performed using GraphPad Prism 8.0.2. For comparisons between groups, one-way ANOVA or two-way ANOVA was applied, and Dunnett's post-hoc test was used to evaluate the significance between groups. A p-value of less than 0.05 was considered statistically significant.

[0258]

[0259] Experimental Example 1. Evaluation of cell proliferation effects on normal and damaged dermal papilla cells

[0260] Dermal papilla cells are specialized fibroblasts located at the base of the hair follicle that play a key role in hair growth and follicle regeneration by regulating the hair growth cycle and follicle stem cell activation through various signaling mechanisms, including cell proliferation. Therefore, in this experimental example, a Cell Counting Kit-8 (CCK-8) assay was performed using immortalized rat vibrissa dermal papilla cells (DPCs) to evaluate the cell proliferation effect of the compound of the present invention in normal dermal papilla cells and dexamethasone (Dex)-damaged dermal papilla cells, respectively. Dex is known to inhibit dermal papilla cell proliferation and reduce the expression of growth factors essential for hair growth. Accordingly, in this experimental example, the survival rate of dermal papilla cells according to Dex concentration was evaluated in advance, and treatment with 5 μM Dex, which showed a survival rate of approximately 65.2 ± 2.67%, was selected as the standard condition for the damaged dermal papilla cell model. In addition, 10 μM Minoxidil (MNX) was used as a positive control.

[0261] Experimental method

[0262] (1) All samples were dissolved in 10% DMSO to prepare a 100 mM stock solution, and the DMSO concentration to which the cells were exposed at the final treatment was set to 0.002% or less. DPCs were seeded into 96-well plates at a density of 2,000 cells / well and cultured for 24 hours at 37°C and 5% CO2 in Dulbecco's modified eagle medium (DMEM) containing 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin.

[0263] (2-1) Normal dermal papilla cell model: The compound was diluted in serum-free medium to final concentrations of 0.1, 1, 10, and 20 μM, respectively. After culturing the cells for an additional 72 hours, Cell Counting Kit-8 (CCK-8) solution was added at a ratio of 1 / 10 of the medium volume per well and incubated in an incubator for 1 hour.

[0264] (2-2) Dexamethasone-damaged dermal papilla cell model: The compound was diluted in serum-free medium to final concentrations of 0.1, 1, 10, and 20 μM, respectively. Subsequently, 5 μM of dexamethasone was added to each experimental group to induce cell damage, followed by incubation for 72 hours. Afterward, Cell Counting Kit-8 (CCK-8) solution was added at a ratio of 1 / 10 of the medium volume per well, and the cells were incubated in an incubator for 1 hour.

[0265] (3) After the reaction was complete, absorbance was measured at 450 nm using a microplate reader and Gen5 software, and cell proliferation rate was calculated as the cell proliferation rate (%) relative to the vehicle treatment group. All experiments were repeated in several independent batches, and the results normalized relative to the vehicle control group (100%) for each batch were presented (ND: not measured).

[0266] Experimental results

[0267] The results of the cell proliferation evaluation for each example compound in normal dermal papilla cells and dexamethasone-damaged dermal papilla cells, respectively, are shown in Table 10, Figure 1, and Figure 2 below.

[0268] [Table 10]

[0269]

[0270]

[0271] As shown in Table 10, Figures 1 and 2 above, the compounds of the present invention exhibited superior cell proliferation rates compared to the vehicle control group and / or the Dex treatment group when treated with normal dermal papilla cells and / or damaged dermal papilla cells under specific concentration conditions. In addition, it was confirmed that the compounds of the present invention exhibited equivalent or superior proliferative effects in normal dermal papilla cells and / or damaged dermal papilla cells when compared to the positive control, minoxidil.

[0272]

[0273] Experimental Example 2. Evaluation of Wnt / β-catenin signaling pathway activation

[0274] The activation of the Wnt / β-catenin signaling pathway can be determined by the degree of β-catenin accumulation in the cytoplasm. GSK3β is a key component of the degradation complex and regulates the degradation of β-catenin. When the Ser9 residue of GSK3β is phosphorylated, GSK3β activity is inhibited, which prevents the degradation of β-catenin and stabilizes it. Subsequently, β-catenin accumulates in the cytoplasm, which can activate the Wnt / β-catenin signaling pathway. Therefore, in this experimental example, the phosphorylation level of the Ser9 residue of GSK3β and the degree of β-catenin accumulation were evaluated using Western blot after treating dermal papilla cells with 20 μM of the compound. The experiment was performed under starvation conditions containing 0.1% FBS and 1% penicillin / streptomycin; 20 μM of 5-HMF was used as a comparative example, and 20 μM of minoxidil was used as a positive control.

[0275] Experimental method

[0276] (1) DPCs were seeded in a 60 mm dish at a density of 15,000 cells and cultured for 24 hours. The next day, the medium was replaced with starvation medium containing 0.1% FBS and 1% penicillin / streptomycin, and after 1 hour of culture, 20 μM of compound and 20 μM of minoxidil were treated, respectively.

[0277] (2) After 24 hours of sample treatment, 35 μL of lysis buffer was added to elute the protein, and the quantified protein was separated by SDS-PAGE. The separated protein was transferred to a PVDF membrane (15 V, 500 mA) and reacted with primary antibodies against β-catenin, p-GSK3β, and β-actin. Afterward, the PVDF membrane was washed three times with tween / tris-buffered saline (T / TBS) and reacted with secondary antibodies at room temperature for 2 hours. After washing three times again with T / TBS, the chemiluminescence signal expressed was detected on the film by treating with ECL (Electrochemiluminescence) solution.

[0278] Experimental results

[0279] Western blot results confirmed that the compound of the present invention effectively inhibits the activity of GSK3β by inducing phosphorylation of the Ser9 residue of GSK3β. Consequently, β-catenin is stabilized without being degraded, and high protein levels of β-catenin were observed. Therefore, it was confirmed that the compound of the present invention has the effect of inducing the accumulation of β-catenin as a GSK3β inhibitor.

[0280]

[0281] Experimental Example 3. Evaluation of mechanism of action in dermal papilla cells

[0282] To elucidate the mechanism by which the compound of the present invention affects the survival and proliferation of dermal papilla cells, Western blot analysis was performed focusing on AKT activation and the Wnt / β-catenin signaling pathway, which are critically involved in β-catenin accumulation and transcriptional activation. β-catenin accumulation is regulated by multiple pathways, including GSK3β inhibition and AKT activation, in addition to signals mediated by Wnt ligands.

[0283] Experimental method

[0284] (1) DPCs were seeded into a 6-well plate at a density of 50,000 cells / well and cultured for 2 hours under serum-free conditions. Subsequently, 4 μM of compound, 4 μM of 5-HMF, 10 μM of minoxidil, and 50 μM of dexamethasone were treated, respectively.

[0285] (2) After 1 hour and 48 hours of treatment, 35 μL of lysis buffer was added to elute the protein, and the quantified protein was separated by SDS-PAGE. The separated protein was transferred to a PVDF membrane (15 V, 500 mA) and blocked in 5% blocking buffer for 1 hour. After reacting with primary antibodies against AKT, p-AKT, β-catenin, p-β-catenin, Wnt3a, and β-actin, the PVDF membrane was washed 3 times with T / TBS. After reacting with a secondary antibody at room temperature for 2 hours and washing again 3 times with T / TBS, the expressed chemiluminescence signal was detected on the film by treating with ECL solution. Quantitative analysis was performed using FusionCapt software.

[0286] Experimental results

[0287] Figure 3 shows the Western blot results for compounds 17, 26, 34, 57, and 58 of the present invention, which showed excellent proliferative effects in normal and damaged dermal papilla cells, and analyzed p-AKT / AKT, p-β-catenin / β-catenin ratio and Wnt3a expression.

[0288] First, an analysis of AKT activation revealed that under normal conditions, minoxidil, compounds 57, and 58 exhibited a higher p-AKT / AKT ratio compared to the control group, confirming a tendency to induce AKT activation. Upon Dex treatment, AKT phosphorylation decreased compared to the normal control group, but minoxidil and compound 58 restored the reduced AKT phosphorylation to levels above normal. Accordingly, it was confirmed that AKT activation acts as the central mechanism for the inhibitory and proliferative effects of the compounds of the present invention on Dex-induced cell death.

[0289] Next, the p-β-catenin / β-catenin ratio was measured and analyzed to assess changes in β-catenin signaling. Phosphorylation of Ser33 residues associated with β-catenin degradation was confirmed; in the initial stages of Wnt / β-catenin signaling pathway activity, phosphorylated β-catenin can temporarily accumulate within the degradation complex and reach a saturation state before degradation occurs. Under normal conditions, all compound-treated groups showed a tendency for the p-β-catenin / β-catenin ratio to increase compared to the control group, with the most distinct increases observed in compounds 17, 26, 57, and 58. Upon Dex treatment, the p-β-catenin / β-catenin ratio of the normal control group decreased, but compound 58 restored the phosphorylation level of β-catenin to a level higher than that under normal conditions. This indicates the potential for the compounds of the present invention to induce dermal papilla cell proliferation and hair regeneration through the regulation of β-catenin activity.

[0290] Finally, analysis of Wnt3a expression showed that under normal conditions, compounds 17 and 26 increased Wnt3a expression compared to the control group, and upon Dex treatment, all compounds partially restored Wnt3a expression compared to the Dex-alone group and 5-HMF. In particular, compound 17 showed the most potent Wnt3a regulatory effect. However, the fact that the pattern of change in Wnt3a expression levels did not necessarily coincide with the pattern of change in the p-β-catenin / β-catenin ratio suggests that the compounds of the present invention may exhibit β-catenin-mediated hair growth effects through ligand-independent mechanisms, such as AKT activation or GSK3β inhibition, independent of Wnt ligands.

[0291] In summary, the compound of the present invention is considered a potent candidate substance for inducing hair growth efficacy through the regulation of AKT activation and β-catenin activity. Furthermore, it has been reported that AKT activation inhibits GSK3β activity by increasing the phosphorylation of the Ser9 residue of GSK3β, and conversely, GSK3β inhibition can induce AKT activation. These results suggest that the compound of the present invention can be usefully utilized as an AKT activator and / or GSK3β inhibitor.

[0292]

[0293] Experimental Example 4. Evaluation of Hair Regeneration Effect and Systemic Toxicity Using C57BL / 6 Mice

[0294] To evaluate the hair regeneration effect of the compound of the present invention, an in vivo test was conducted using C57BL / 6 mice that exhibit distinct skin color changes according to the hair growth cycle. During the growth phase, when melanin synthesis and secretion are active, the skin appears black; during the regression phase, when melanin synthesis decreases, it appears gray; and during the resting phase, when melanin synthesis does not occur, it appears pink.

[0295] Experimental method

[0296] (1) 6-week-old male C57BL / 6 mice were given an adaptation period of 7 days after receiving them, and then had their back hair completely removed using an electric clipper and depilatory cream 24 hours before the first administration. After a recovery period of 2 days, their body weight was measured and the application and administration of the sample began.

[0297] (2) The control group was treated with acetone / olive oil (v / v= 1:1), and the experimental group was treated with acetone / olive oil (v / v= 4:1). The compound was prepared at a concentration of 1% and applied to the back, or the compound was suspended in triple-distilled water and administered orally at a dose of 10 mg / kg. A solution containing 5% minoxidil in acetone / olive oil (v / v= 4:1) was used as a positive control. Treatment was carried out for a total of 12 days, and photographs of the back were taken at 3-day intervals. On the last day of the study, mice were anesthetized with CO2 gas and sacrificed. Blood was collected from the vena cava, and serum was separated after centrifugation. Additionally, skin tissue, kidneys, spleen, liver, brain, and heart were excised, weighed, and the potential for systemic toxicity was evaluated. Quantitative analysis of hair growth was performed using ImageJ software by determining the areas of black (threshold 0-75), gray (threshold 76-150), and pink (threshold 151-255) regions based on changes in skin tone within the same area, and evaluating the ratio (%) of each color area to the total area. For visual simplification, the vehicle control group was abbreviated as 'Normal', minoxidil as 'Minox', and the oral administration group as 'PO'.

[0298] Experimental results

[0299] As a result of the hair regeneration evaluation, the 1% topical application group of the compound of the present invention was confirmed to have a statistically significant hair growth effect compared to the normal control group, and in particular, showed biological activity equivalent to that of the positive control group, the 5% topical application group of minoxidil.

[0300] Next, as a result of the systemic toxicity evaluation, the compound of the present invention showed less change in mouse body weight compared to minoxidil 5%, regardless of the route of administration, and no significant weight changes were observed, particularly in major organs such as the kidneys, spleen, heart, brain, and thymus. Therefore, the compound of the present invention has lower drug toxicity compared to minoxidil and is more suitable for long-term administration.

[0301]

[0302] Experimental Example 5. Skin Tissue Evaluation

[0303] C57BL / 6 mice, in which the hair regeneration effect was evaluated in Experimental Example 4, were sacrificed, and skin tissue from the back was excised and stained with H&E. The follicle density, growth phase follicle ratio, dermal thickness, subcutaneous layer thickness, and follicle depth were analyzed using an automated microscope.

[0304] Experimental method

[0305] (1) After the experiment as described in Experimental Example 4 was completed, mice were sacrificed and skin tissue from the back was excised. The tissue was fixed in 10% neutral buffered formalin for more than 24 hours and then cut into sections about 4-5 μM thick. The obtained sections were stained with hematoxylin-eosin (H&E) according to standard protocols.

[0306] (2) Stained sections were photographed using an automated microscope (ImageXpress® Pico, Molecular Devices, USA) at the same magnification and conditions. Quantitative analysis of the captured images was performed using QuPath-0.6.0 software. The analysis items included follicle density, growth follicle ratio, dermal thickness, subcutaneous thickness, and follicle depth. Follicle density was calculated based on the number of follicles per length of the epidermis, and the growth follicle ratio was calculated as the ratio of growth follicles identified based on follicle shape and bulb position relative to the total number of follicles. Dermal thickness was measured from the epidermal-dermal boundary to the upper subcutaneous tissue, and subcutaneous thickness was measured from the lower dermis to the base of the subcutaneous fat layer. Follicle depth was defined as the vertical distance from the epidermis to the growth follicle. All quantitative analyses were performed on 3 mice per group, and measurements were taken at 3-4 sites per mouse. Thickness-related indicators (dermal thickness, subcutaneous thickness, and follicle depth) were measured once at the same anatomical location with high representativeness per section, and follicle density and the ratio of growing follicles were calculated by analyzing multiple fields of view within the same section to obtain average values.

[0307] Experimental results

[0308] As a result of the histological analysis evaluation, the vehicle control group showed that most hair follicles were located in the upper dermis and exhibited a morphology corresponding to the resting or early growth phase. Additionally, it displayed structural characteristics of low hair follicle activity, such as generally thin epidermal and dermal thickness, low cell density, and weak pigmentation.

[0309] In contrast, a distinct growth phase pattern was observed in the minoxidil 5% topical application group and all experimental groups. In particular, in the case of the 1% topical application group of the compound of the present invention, typical late-stage growth phase characteristics were observed as the hair bulbs penetrated deep into the subcutaneous tissue and cell density and pigmentation increased, showing a growth phase ratio equivalent to or higher than that of the minoxidil 5% topical application group.

[0310] Consequently, the compound of the present invention exhibited a hair follicle growth phase promoting effect similar to or greater than that of minoxidil and was evaluated as a promising candidate for hair growth promotion in both topical and oral formulations.

[0311]

[0312] Although the present invention has been described in detail through preferred embodiments and experimental examples, the scope of the invention is not limited to the compounds of specific embodiments and should be interpreted according to the appended claims. Furthermore, those skilled in the art will understand that many modifications and variations are possible without departing from the scope of the invention.

Claims

1. A compound represented by the following chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula I] In the above chemical formula I, L X is -O-, -NH-, *-(CH2)nC(=O)-O-, *-(CH2)nC(=O)-NH-, *-(CH2)n-CH=CH-C(=O)-O-, or *-(5-6-membered heterocycloalkyl)-, where * is R X Indicates a point attached to, where n is 0, 1, 2, 3, or 4, and the *-(5-6-membered heterocycloalkyl)- comprises one or more N, O, or S within the ring; R X is -H, -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl), wherein the -(4-6-membered heterocycloalkyl), -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) comprises one or more N, O, or S within the ring, and the -(5-10-membered heteroaryl) may comprise C (=O) within the ring, and one or more hydrogens of the -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) ring are R U1 It can be replaced with; L Y is a single bond, -(C=O)-O-(CH2)m-**, -(C=O)-NH-(CH2)m-**, -CH=CH-C(=O)-(CH2)m-**, where ** indicates a point attached to ring Y, and m is 0, 1, 2, 3, or 4; Ring Y is -phenyl or -(9-10-membered heteroaryl), wherein the -(9-10-membered heteroaryl) comprises one or more N, O, or S within the ring, and one or more hydrogens of the -phenyl or -(9-10-membered heteroaryl) ring are R U2 It can be replaced with; R U1 and R U2 -C each independently 1-6 Alkyl, -NR a R b , -OR c , -SR c , -(3-6-membered cycloalkyl), -phenyl, -CN, -NO2, -C 1-6 haloalkyl, or -halo, wherein one or more hydrogens of the -(3-6-membered cycloalkyl) or -phenyl ring are -C 1-6 alkyl or -C 1-6 It can be substituted with an alkoxy; R a and R b -H or -C, respectively, independently 1-6 It is alkyl; R c -H or -C 1-6 It is an alkyl.

2. In Paragraph 1, L X is -O-, *-(CH2)nC(=O)-O-, *-(CH2)nC(=O)-NH-, *-CH=CH-C(=O)-O-, or *-(5-6-membered heterocycloalkyl)-, where * is R X Indicates a point attached to, where n is 0, 1, or 2, and the *-(5-6-membered heterocycloalkyl)- comprises one or more N, O, or S within the ring; R X is -H, -C 1-4 It is an alkyl, -(5-6-membered cycloalkyl), -phenyl, or -(5-10-membered heteroaryl), wherein the -(5-10-membered heteroaryl) comprises one or more N, O, or S within the ring, and the -(5-10-membered heteroaryl) may comprise C (=O) within the ring, and one or more hydrogens of the -(5-6-membered cycloalkyl), -phenyl, or -(5-10-membered heteroaryl) ring are R U1 It can be replaced with; R U1 is -C 1-4 Alkyl, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 Alkyl)2, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -(5-6 member cycloalkyl), -phenyl, -CN, -NO2, -C 1-4 haloalkyl, or -halo, wherein one or more hydrogens of the -(5-6-membered cycloalkyl) or -phenyl ring are -C 1-4 alkyl or -C 1-4 That which can be substituted with an alkoxy, A compound represented by chemical formula I, its stereoisomers, or pharmaceutically acceptable salts thereof.

3. In Paragraph 1, L Y is a single bond, -(C=O)-NH-(CH2)m-**, -CH=CH-C(=O)-(CH2)m-**, where ** indicates a point attached to ring Y, and m is 0, 1, 2, 3, or 4; Ring Y is -phenyl or -(9-10-membered heteroaryl), wherein the -(9-10-membered heteroaryl) comprises one or more N, O, or S within the ring, and one or more hydrogens of the -phenyl or -(9-10-membered heteroaryl) ring are R U2 It can be replaced with; R U2 is -C 1-4 Alkyl, -OH, -OC 1-4 Alkyl, -SH, -SC 1-4 Alkyl, -(5-6 member cycloalkyl), -phenyl, -NO2, -C 1-4 haloalkyl, or -halo, wherein one or more hydrogens of the -(5-6-membered cycloalkyl) or -phenyl ring are -C 1-4 alkyl or -C 1-4 That which can be substituted with an alkoxy, A compound represented by chemical formula I, its stereoisomers, or pharmaceutically acceptable salts thereof.

4. A compound represented by the following chemical formula Ia, its stereoisomers, or pharmaceutically acceptable salts thereof: [Chemical Formula Ia] In the above chemical formula Ia, L X is -O-, -NH-, *-(CH2)nC(=O)-O-, *-(CH2)nC(=O)-NH-, *-(CH2)n-CH=CH-C(=O)-O-, or *-(5-6-membered heterocycloalkyl)-, where * is R X Indicates a point attached to, where n is 0, 1, 2, 3, or 4, and the *-(5-6-membered heterocycloalkyl)- comprises one or more N, O, or S within the ring; R X is -H, -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl), wherein the -(4-6-membered heterocycloalkyl), -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) comprises one or more N, O, or S within the ring, and the -(5-10-membered heteroaryl) may comprise C (=O) within the ring, and one or more hydrogens of the -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) ring are R U1 It can be replaced with; L Y is a single bond, -(C=O)-O-(CH2)m-**, -(C=O)-NH-(CH2)m-**, -CH=CH-C(=O)-(CH2)m-**, where ** indicates a point attached to ring Y, and m is 0, 1, 2, 3, or 4; R U1 and R U2 -C each independently 1-6 Alkyl, -NR a R b , -OR c , -SR c , -(3-6-membered cycloalkyl), -phenyl, -CN, -NO2, -C 1-6 haloalkyl, or -halo, wherein one or more hydrogens of the -(3-6-membered cycloalkyl) or -phenyl ring are -C 1-6 alkyl or -C 1-6 It can be substituted with an alkoxy; R a and R b -H or -C, respectively, independently 1-6 It is alkyl; R c -H or -C 1-6 It is alkyl; y is 0, 1, 2, or 3.

5. Compounds represented by the following chemical formula Ib, stereoisomers thereof, or pharmaceutically acceptable salts thereof: [Chemical Formula Ib] In the above chemical formula Ib, L X is -O-, -NH-, *-(CH2)nC(=O)-O-, *-(CH2)nC(=O)-NH-, *-(CH2)n-CH=CH-C(=O)-O-, or *-(5-6-membered heterocycloalkyl)-, where * is R X Indicates a point attached to, where n is 0, 1, 2, 3, or 4, and the *-(5-6-membered heterocycloalkyl)- comprises one or more N, O, or S within the ring; R X is -H, -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl), wherein the -(4-6-membered heterocycloalkyl), -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) comprises one or more N, O, or S within the ring, and the -(5-10-membered heteroaryl) may comprise C (=O) within the ring, and one or more hydrogens of the -(3-6-membered cycloalkyl), -(4-6-membered heterocycloalkyl), -phenyl, -(5-10-membered heteroaryl), or -(9-10-membered heterohydroaryl) ring are R U1 It can be replaced with; R U1 and R U2 -C each independently 1-6 Alkyl, -NR a R b , -OR c , -SR c , -(3-6-membered cycloalkyl), -phenyl, -CN, -NO2, -C 1-6 haloalkyl, or -halo, wherein one or more hydrogens of the -(3-6-membered cycloalkyl) or -phenyl ring are -C 1-6 alkyl or -C 1-6 It can be substituted with an alkoxy; R a and R b -H or -C, respectively, independently 1-6 It is alkyl; R c -H or -C 1-6 It is alkyl; y is 0, 1, 2, or 3.

6. A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, any one selected from the group consisting of the following compounds: .

7. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and comprising a pharmaceutically acceptable additive.

8. A pharmaceutical composition for the prevention or treatment of hair loss, comprising as an active ingredient a compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition according to claim 8, wherein the compound, its stereoisomer, or its pharmaceutically acceptable salt induces activation by inhibiting the degradation of β-catenin.

10. A pharmaceutical composition according to claim 8, wherein the compound, its stereoisomer, or its pharmaceutically acceptable salt inhibits GSK3β.

11. A pharmaceutical composition according to claim 8, wherein the compound, its stereoisomer, or its pharmaceutically acceptable salt is an AKT-activating compound.

12. Use of a compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for the prevention or treatment of hair loss.

13. A method for preventing or treating hair loss, comprising the step of administering a therapeutically effective amount of a compound according to any one of claims 1 to 6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

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