SIK inhibitor and method of use thereof

Abstract

In one aspect, compounds capable of inhibiting salt-inducible kinase (SIK) and methods of using the compounds to treat diseases or disorders are provided.

Description

[Background technology]

[0001] Many treatments for skin disorders are recognized as having drawbacks, including various side effects and limited effectiveness. Drugs that increase skin pigmentation can have many beneficial dermatological effects, ranging from improving inflammatory skin disorders and providing sun protection to purely cosmetic uses. Therefore, it would be desirable to have new treatments for dermatological disorders and defects.

[0002] Cross-reference of related applications This application relates to U.S. Patent Application No. 63 / 081,089, filed on 21 September 2020, claiming priority thereto, the full disclosure of which is incorporated herein by reference. [Overview of the project] [Means for solving the problem]

[0003] In one embodiment, the present inventors provide compounds that inhibit salt-inducible kinases for treating or preventing a target dermatological disorder and skin-related disorder.

[0004] In a preferred embodiment, the following compound of formula (I): [ka] (In the formula, W is either S or O, Y 1 is N or CR A And, Y 2 is N or CR B And, Ring A is a monocyclic or polycyclic carbonalicyclic group, a monocyclic or polycyclic heteroalicyclic group, a monocyclic or polycyclic carbonalicyclic aryl group, or a monocyclic or polycyclic heteroaryl group. Each R is the same or different substituted or unsubstituted alkyl, halogen, hydroxyl, cyano, amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfone, or substituted or unsubstituted alkylamine. z is an integer ranging from 0 (ring A has no nonhydrogen ring substituents) to an integer value allowed by the valence of ring A. R A and R B These are independently H, halogen, -OH, -NH2, -CN, or substituted or unsubstituted alkyl groups. R 1 These are substituted or unsubstituted monocyclic or polycyclic carbon-alicyclic groups, substituted or unsubstituted monocyclic or polycyclic heteroalicyclic groups, substituted or unsubstituted monocyclic or polycyclic carbon-aryl groups, or substituted or unsubstituted monocyclic or polycyclic heteroaryl groups. R 4 (is H or a substituted or unsubstituted alkyl group.) and its pharmaceutically acceptable salts are provided.

[0005] In certain embodiments, ring A is a monocyclic or polycyclic carbocyclic aryl or polycyclic heteroaryl group. For example, ring A may be optionally substituted phenyl, optionally substituted naphthyl, optionally substituted anthracenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, or optionally substituted prinyl. In certain embodiments, ring A is phenyl, naphthyl, or anthracenyl, and z is an integer from 0 to 10. In certain preferred embodiments, ring A is optionally substituted phenyl.

[0006] In certain preferred embodiments, ring A is a monocyclic or polycyclic carbon-alicyclic group or a monocyclic or polycyclic heteroalicyclic group. In certain preferred embodiments, ring A is a polycyclic carbon-alicyclic group or a polycyclic heteroalicyclic group. In certain preferred embodiments, ring A is a polycyclic carbon-alicyclic group.

[0007] In certain preferred embodiments, R 1 is a monocyclic or polycyclic carbocyclic alicyclic group or a monocyclic or polycyclic heteroalicyclic group. In certain preferred embodiments, R 1 is a polycyclic carbocyclic alicyclic group or a polycyclic heteroalicyclic group. In certain preferred embodiments, R 1 is a polycyclic carbocyclic alicyclic group.

[0008] In certain embodiments, R 1 is a monocyclic or polycyclic carbocyclic aryl or a polycyclic heteroaryl group. For example, R 1 can be optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted anthracenyl, optionally substituted pyridyl, optionally substituted pyrimidyl, or optionally substituted purinyl. In certain aspects, R 1 is not a monocyclic group such as phenyl or other monocyclic carbocyclic aryl or monocyclic carbocyclic alicyclic group.

[0009] In certain embodiments of Formula (I), z is an integer from 0 to 20, more typically z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, or in certain embodiments z is 0, 1, 2, 3, 4, 5 or 6, or in certain embodiments z is 0, 1, 2 or 3.

[0010] In certain embodiments of Formula I, R is substituted or unsubstituted alkyl or halogen, for example F, Cl, Br or I, particularly Cl. In certain embodiments of Formula I, R is substituted or unsubstituted alkoxy such as methoxy or ethoxy.

[0011] In certain aspects, one or more R groups are substituted or unsubstituted alkyl and do not contain any unsaturated carbon-carbon bonds. In certain aspects, one or more R groups are C 1-6R is a substituted alkyl, such as an unsubstituted alkyl, and does not contain any unsaturated carbon-carbon bonds. In other embodiments, R is a substituted or unsubstituted alkyl and may contain one or more unsaturated carbon-carbon bonds (thus such R may be called a substituted or unsubstituted alkenyl having 2 to 6 or 8 carbon atoms, or a substituted or unsubstituted alkynyl having 2 to 6 or 8 carbon atoms).

[0012] In a preferred embodiment, the compound of the following formula (II): [ka] (In the formula, W is either S or O, Y 1 is N or CR A And, Y 2 is N or CR B And, R A and R B These are independently H, halogen, -OH, -NH2, -CN, or substituted or unsubstituted alkyl groups. R 1 is a substituted or unsubstituted polycyclic carbon-alicyclic group or a substituted or unsubstituted polycyclic heteroalicyclic group, R 2 and R 3 Each of these is independently H, a substituted or unsubstituted alkyl, a halogen, a hydroxyl, a cyano, an amino, a substituted or unsubstituted alkoxy, a substituted or unsubstituted alkylthio, a substituted or unsubstituted alkylsulfone, or a substituted or unsubstituted alkylamine. R 4 (is H or a substituted or unsubstituted alkyl group.) and its pharmaceutically acceptable salts are provided.

[0013] Preferred compounds of formula (I) or (II) include those of formula (III) below: [ka] (In formula (III), W, R1 , R 2 , R 3 and R 4 These include the same compounds as defined above for formula (II), and their pharmaceutically acceptable salts.

[0014] In a further embodiment, the compound of the following formula (IV): [ka] (In formula (IV), R 1 , R 2 , R 3 and R 4 The following are provided: (where each is the same as defined above for formula (II)) and their pharmaceutically acceptable salts.

[0015] In a particular embodiment, in any of formulas (II), (III), or (IV), R 2 and R 3 Each of them is independently H, a substituted or unsubstituted C1-C6 alkyl, or a halogen, and R 4 is H or a substituted or unsubstituted C1-C6 alkyl group. In certain embodiments, R 2 and R 3 At least one of them is a substituted or unsubstituted C1-C4 alkyl, for example an optionally substituted methyl, or a halogen, for example -F, -Cl, -Br, or -I. In certain embodiments of formula (II), (III), or (IV), R 2 and R 3 Both are other than H, and in certain preferred embodiments, they may be substituted or unsubstituted C1-C4 alkyl groups, for example optionally substituted methyl groups, or halogens, for example -F, -Cl, -Br, or -I, in particular -Cl.

[0016] In certain embodiments, in any of formulas (II), (III), or (IV), R 2 , R 3 and R 4These are the same or different, and each is an unsubstituted C1-C4 alkyl group. In a particular embodiment, R 2 , R 3 and R 4 One or more of them are unsubstituted methyl groups. In a particular embodiment, R 2 , R 3 and R 4 At least two of them are unsubstituted methyl groups. In a particular embodiment, R 2 , R 3 and R 4 Each of them is an unsubstituted methyl group.

[0017] In certain embodiments, in any of formulas (II), (III), or (IV), R 2 and R 3 Each of these is independently an unsubstituted C1-C4 alkyl or halogen. In a particular embodiment, R 2 and R 3 At least one of them is an unsubstituted methyl group. In a particular embodiment, R 2 and R 3 At least one of them is a halogen. In a particular embodiment, R 2 and R 3 At least one of them is -Cl. In a particular embodiment, R 2 and R 3 At least one of them is -Br. In a particular embodiment, R 2 and R 3 At least one of them is -F. In a particular embodiment, R 2 and R 3 At least one of them is -I.

[0018] In certain embodiments, preferred compounds have the structure of formula (V): [ka] (In formula (V), R 1 This includes the same as that defined in formula (I) or (II) above, and its pharmaceutically acceptable salts.

[0019] In certain embodiments, the preferred compound of formula (I), (II), (III), (IV), or (V) above is R 1 This includes polycyclic carbon-alicyclic groups that have been optionally substituted.

[0020] In any one preferred embodiment of the above formula, R 1 It includes a bicyclic carbon-alicyclic group. In another preferred embodiment, R 1 It contains a tricyclic carbon-alicyclic group.

[0021] More specifically, in one embodiment, R 1 A compound of formula (VI), defined as any of the compounds of formulas (I), (II), (III), (IV), and / or (V) above, having the structure of formula (VIa) below, is preferred: [ka] (In formula (VIa), m is an integer between 0 and 5. n is an integer between 0 and 3. o is an integer between 0 and 3. p is an integer between 0 and 5. Each R 5 These are the same or different non-hydrogen substituents such as hydroxyl, halo, optionally substituted alkyl, or optionally substituted heteroalkyl. g is 0(R 5 (If no group exists) or a positive integer such as 1 to 10, more typically g is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments of formula (VIa), at least one of n and o is a positive integer, and if n or o is 0, no direct bond is formed between two adjacent carbon atoms, and if m or p is 0, a direct bond is formed between two adjacent carbon atoms. In certain embodiments, g is 0, i.e., the carbo-alicyclic ring has a ring nitrogen (not shown in formula (VIa) above, but R to the ring nitrogen of compounds of formula (I), (II), (III), (IV), (V) or (VI)). 1The compound ring nitrogen, which is a bond, has no other non-hydrogen substituents other than the bond with (recognized as being indicated by the tilde in formula VIa). In certain embodiments, g is 0, 1, 2 or 3, or g is 0, 1 or 2.

[0022] In certain embodiments of equations (VI) and (VIa), at least one of n and o is an integer of 1 or more.

[0023] In certain additional embodiments of the above formulas, including formulas (VI) and (VIa), R 1 This could be an adamantil replaced by an optional substitution.

[0024] In further embodiments of the above formulas, including formulas (VI) and (VIa), R 1 This could be norbornil substituted with an optional choice.

[0025] In further embodiments of the above formulas, including formulas (VI) and (VIa), R 1 This can be bicyclo[2,2,2]octanyl substituted with any choice.

[0026] In additional embodiments of the above formulas, including formulas (VI) and (VIa), R 1 This can be bicyclo[3,3,1]nonanyl substituted with any choice.

[0027] In the relevant embodiments, in any of formulas (I), (II), (III), (IV), (V), and / or (VI), R 1 This may include parts selected from the following: [ka] (In the formula, in those structures, each R 6 C is substituted with hydroxyl, halo, or any other C. 1-6 C is substituted with alkyl or of any choice. 1-6 Heteroalkyl groups, for example, C, which are optionally substituted. 1-6may be the same or different non-hydrogen substituents such as alkoxy, and g is 0(R 6 when no group is present) or a positive integer such as 1 to 10, more typically 1, 2, 3, 4, 5 or 6). In certain embodiments, g is 0, that is, the indicated carbocyclic alicyclic ring does not have any non-hydrogen substituents other than the bond to the ring nitrogen. As will be understood, the wavy line in the above structure indicates a bond to the ring nitrogen of the compound of formula (I), (II), (III), (IV), (V) and / or (VI).

[0028] In certain preferred embodiments, g is 0 in the above structure. In such embodiments, in the compound of formula (I), (II), (III), (IV), (V) and / or (VI), R 1 may comprise a moiety selected from the following.

Chemical Formula

Chemical Formula

[0029] In additional embodiments, preferred compounds include any of the following structures:

Chemical Formula

Chemical Formula

[0030] In an additional embodiment, preferred compounds include any of the following structures:

Chemical Structure

Chemical Structure

Chemical Structure

[0031] In an additional embodiment, the compound of the above formula (I), (II), (III), (IV), (V) and / or (VI) includes those wherein R 1 is an optionally substituted polycyclic heteroalicyclic group. For example, a suitable R 1 group may comprise a moiety containing optionally substituted thionorbornyl or optionally substituted oxonorbornyl.

[0032] In further embodiments, pharmaceutical compositions are provided comprising any one compound of formulas (I), (II), (III), (IV), (V), and / or (VI). The composition may preferably comprise one or more pharmaceutically acceptable carriers. In preferred embodiments, the composition may be formulated for a skin pigmentation-related condition or otherwise adapted, for example, the composition may be adapted for topical administration such as an ointment, gel, or lotion, or for oral administration as a tablet or capsule.

[0033] A preferred embodiment provides a method for increasing pigmentation of a target tissue, comprising administering to the target a compound of any one of the above formulas (I), (II), (III), (IV), (V), and / or (VI) in an amount sufficient to increase melanin production, thereby increasing pigmentation of the target tissue.

[0034] In other preferred embodiments, methods are provided for treating subjects suffering from or susceptible to inflammatory dermatology, including any of the following: erythematous telangiectatic rosacea (subtype 1 rosacea), papular pustular rosacea (subtype 2 rosacea), cystic rosacea (subtype 3 rosacea), and / or ocular rosacea (subtype 4 rosacea).

[0035] In another preferred embodiment, a method is provided for increasing cellular DNA stability in the skin tissue of a subject requiring such stability, comprising administering to the subject an amount sufficient to reduce apoptosis and / or thymine dimer formation in the cellular DNA of the skin tissue, thereby increasing the cellular DNA stability in the skin tissue of the subject.

[0036] In further embodiments, kits are provided for use in treating or preventing diseases or disorders, including hyperpigmentation disorders, uneven skin tone, hypopigmentation, vitiligo, inflammatory skin diseases including rosacea, or other skin-related disorders or conditions. A kit of the present invention may preferably comprise: 1) one or more compounds of formula (I), (II), (III), (IV), (V), or (VI); and 2) instructions for using one or more compounds to treat or prevent diseases or disorders, including hypopigmentation, vitiligo, inflammatory skin diseases including rosacea, or other skin-related disorders or conditions. Preferably, the kit comprises a therapeutically effective amount of one or more compounds of formula (I), (II), (III), (IV), (V), or (VI). The instructions may preferably be in written form, including a product label.

[0037] Methods for treating various skin conditions for cosmetic purposes and other reasons can be carried out using the systems described herein. While such methods can be performed by physicians, it is understood that non-physicians, such as cosmetic physicians and other suitably trained personnel, may treat various skin conditions using the systems described herein, with or without the supervision of a physician.

[0038] Other aspects of the present invention are disclosed below.

[0039] The following detailed description is given as an example, but is not intended to limit the invention to any particular embodiment described herein and should be understood in conjunction with the accompanying drawings incorporated herein by reference. [Brief explanation of the drawing]

[0040] [Figure 1] This figure shows the melanin content in Fontana-Masson stained sections of vehicle (PEG / ethanol / Transcutol®) and SLT-008, 3 mM. [Figure 2]This figure shows the effect of SLT-008 on melanin synthesis compared to excipient E2-treated strip batch SE2J11. Black: control, red: UV control, purple: 0.5% SLT-008, and blue: 0.9% SLT-008. [Figure 3] This figure shows the melanin content determined from Fontana-Masson reagent stained sections using a vehicle (anhydrous ethanol) and SLT-008 (0.9%). [Figure 4] This figure shows tissue samples containing different doses of SLT-008 (0.3 μg / ml, 0.01 μg / ml, 0.0033 μg / ml), fixed with 4% formaldehyde, dehydrated, and embedded in paraffin. 6 μm epidermal sections were stained with eosin and hematoxylin (H / E). Specific media were mounted on glass slides and examined using a Leica DM2000 microscope connected to a digital camera (Zeiss). [Figure 5] This figure shows the release of lactate dehydrogenase (LDH) after applying SLT-008 to melanin-reconstructed epidermis for 10 days. [Figure 6] This figure shows the melanin content in Fontana-Masson reagent-stained sections. Epidermal pigmentation is indicated by the dendritic morphology of functional melanocytes and the formation of melanosomes organized as supranuclear melanin caps on top of keratinocyte nuclei. Figure 6A shows untreated control, vehicle (DMSO 0.05%) and two positive controls, forskolin (3.33 μM) or IBMX (150 μM) versus DMSO 0.05%. Figure 6B shows SLT-008 at 0.3 μg / ml, 0.011 μg / ml, and 0.0033 μg / ml versus DMSO 0.005%. [Figure 7]This figure shows the melanin content determined from Fontana-Masson reagent-stained sections (% relative to 0.05% DMSO for IBMX and FSK; %) relative to 0.005% DMSO for SLT-008 treatment). IBMX administered at 150 μM and forskolin administered at 3.33 μM were used as pigmentation-promoting controls. The results are shown in the figure. SLT-008 administered at 0.3 μg / ml recorded a melanin content of 129 + / - 5.7. SLT-008 administered at 0.011 μg / ml recorded a melanin content of 125.6 + / - 15.4. [Figure 8] This figure shows the melanin content obtained by chemical extraction after applying SLT-008 at concentrations of 1.0 μg / ml, 0.1 μg / ml, and 0.3 μg / ml. [Figure 9] This figure shows the percentage of surfaces positive for TUNEL staining, which is associated with apoptotic cells in the epidermis, for all samples. [Figure 10] This figure shows the percentage of surfaces that tested positive for thymine dimer in the epidermis for all samples. [Figure 11] This figure shows the percentage of surfaces positive for TUNEL staining, which is associated with apoptotic cells in the epidermis, for all samples. [Modes for carrying out the invention]

[0041] As will be discussed, the present inventors hereby provide novel compounds and methods comprising compounds of formulas (I), (II), (III), (IV), (V), and (VI). Specifically preferred compounds include the following compounds and pharmaceutically acceptable salts of these compounds: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and pharmaceutically acceptable salts of the above compounds are included. Particularly preferred compounds are [ka] and its pharmaceutically acceptable salts.

[0042] definition The abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the field of chemistry.

[0043] The term "carbo-alicyclic" means, unless otherwise specified, a cyclic version of "alkyl" which may contain one or more intracyclic carbon-carbon double bonds, but is not aromatic. However, in preferred embodiments, carbo-alicyclic compounds do not contain any intracyclic carbon-carbon multiple bonds. The carbo-alicyclic portion contains a monocyclic or polycyclic group, such as a bicyclic, tricyclic, or other polycyclic cycloalkyl ring system. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A bicyclic cycloalkyl ring system is a bridged monocyclic ring or a fused bicyclic ring. A bridged monocyclic ring contains a monocyclic cycloalkyl ring, where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of 1 to 3 additional carbon atoms (i.e., form (CH2)). wA bridging group (wherein w is 1, 2, or 3). Representative examples of bicyclic systems include, but are not limited to, adamantyl, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In addition, condensed bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring condensed to any of phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocyclil, or monocyclic heteroaryl. In certain embodiments, the bridging or condensed bicyclic carbon-alicyclic moiety is bonded to the parent molecule via any carbon atom contained within the monocyclic alicyclic ring. In certain embodiments, the condensed bicyclic carbon-alicyclic moiety is a 5- or 6-membered monocyclic cycloalkyl ring condensed to either a phenyl ring or a 5- or 6-membered monocyclic cycloalkyl ring.

[0044] As used herein, the terms “heteroalicyclic” or “heterocyclic” mean monocyclic, bicyclic, or polycyclic heterocycles. A heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6, or 7-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, P, and S, and the ring is saturated or unsaturated but not aromatic. A 3 or 4-membered ring contains one heteroatom selected from the group consisting of O, N, P, and S. A 5-membered ring may contain 0 or 1 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, P, and S. A 6 or 7-membered ring contains 0, 1, or 2 double bonds and 1, 2, or 3 heteroatoms selected from the group consisting of O, N, P, and S. A heterocyclyl monocyclic heterocycle is bonded to its parent molecule through any carbon or nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include azetidinyl, azepanyl, azilidinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolinyl, isoxazolinyl, isoxazolinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, and This includes, but is not limited to, xazolidinyl, piperadinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianil. Heterocyclic bicyclic heterocycles are monocyclic heterocycles condensed with phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycles are bonded to the parent molecule through any carbon or nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclils include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) condensed into either (i) one ring system selected from the group consisting of bicyclic aryls, bicyclic heteroaryls, bicyclic cycloalkyls, bicyclic cycloalkenyls, and bicyclic heterocyclyls, or (ii) two other ring systems independently selected from the group consisting of phenyls, bicyclic aryls, monocyclic or bicyclic heteroaryls, monocyclic or bicyclic cycloalkyls, monocyclic or bicyclic cycloalkenyls, and monocyclic or bicyclic heterocyclyls. The polycyclic heterocyclyl is bonded to the parent molecule through any carbon or nitrogen atom contained within the base ring. Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazine-10-yl, 9,10-dihydroacridine-9-yl, 9,10-dihydroacridine-10-yl, 10H-phenoxazine-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepine-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinoline-2-yl, 12H-benzo[b]phenoxazine-12-yl, and dodecahydro-1H-carbazole-9-yl.

[0045] The term "alkyl" means a straight (i.e., unbranched) or branched carbon chain (or carbons) or combination thereof, either by itself or as part of another substituent, which may be fully saturated, monovalent, or polyunsaturated, and which may contain monovalent, divalent, and polyvalent radicals, unless otherwise specified. Alkyl refers to a specified number of carbons (e.g., C1-C1). 10Alkyl groups may contain 1 to 10 carbon atoms. Alkyl groups are non-cyclized chains. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups are those that have one or more double or triple bonds. Examples of unsaturated alkyl groups (which may also be called alkenyls) include, but are not limited to, vinyl, 2-propenyl, clotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkoxy groups are alkyl groups bonded to the rest of the molecule via an oxygen linker (-O-). The alkyl group may be an alkenyl group. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be completely saturated. In accordance with the following discussion of “alkenyls”, an alkenyl may contain one or more double bonds, plus two or more double bonds and / or one or more triple bonds. In accordance with the following discussion of “alkynyls”, an alkynyl may contain one or more triple bonds, plus two or more triple bonds and / or one or more double bonds. In certain embodiments, the alkyl group preferably has 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1, 2, 3, 4, 5, or 6 carbon atoms.

[0046] As used herein, the term “carbocyclic aryl” refers to an aromatic group in which each aromatic ring atom is carbon, and includes, for example, phenyl, naphthyl, anthracenyl, acenaphthyl, biphenyl, indene, indan, 1,2-dihydronaphthalene, and 1,2,3,4-tetrahydronaphthalene.

[0047] As used herein, the term “heteroaromatic group” refers to an aromatic group in which at least one aromatic ring atom is not carbon (and may be, for example, N, O, or S). Heteroaromatic groups include, for example, pyridyl, furanyl, pyrrole, thiophene, furan, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, franzanine, oxadiazole, thiadiazole, dithiazole, terazole, pyran, thiopyran, diazine, oxazine, thiazine, dioxin, ditin, and triazine.

[0048] "alkoxy" is the formula -OR a It refers to the radical of, in the formula, R a As discussed above, the alkyl group preferably has 1 to 10 carbon atoms, or 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of alkoxy groups include, but are not limited to, -O-methyl (methoxy), -O-ethyl (ethoxy), -O-propyl (propoxy), and -O-isopropyl (isopropoxy).

[0049] "Alkylthio" is represented by formula -SR a It refers to the radical of, in the formula, R a This is the above-defined alkyl radical containing 1 to 12 carbon atoms, at least 1 to 10 carbon atoms, at least 1 to 8 carbon atoms, at least 1 to 6 carbon atoms, or at least 1 to 4 carbon atoms.

[0050] "Sulfone" refers to the -S(O)2- group, in which hexavalent sulfur is bonded to each of two oxygen atoms through a double bond, and further bonded to two carbon atoms through a single covalent bond.

[0051] "Alkyl sulfone" refers to an alkyl group, for example, of the formula -S(O)2(C 1-6 This refers to a sulfone group bonded to an alkyl radical.

[0052] In certain embodiments, "alkenyl" is defined as having at least one double bond and 2 to 12 carbon atoms (C2-C2). 12 Alkenyls are unsaturated alkyl groups having 2 to 8 carbon atoms (C2-C8 alkenyls) or 2 to 6 carbon atoms (C2-C6 alkenyls) that are bonded to the rest of the molecule by a single bond, such as ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0053] In certain embodiments, "alkynyl" is defined as having at least one triple bond and 2 to 12 carbon atoms (C2-C2). 12 Alkynyl), 2 to 10 carbon atoms (C2-C 10 Alkynyl refers to an unsaturated alkyl group having 2 to 8 carbon atoms (C2-C8 alkynyl) or 2 to 6 carbon atoms (C2-C6 alkynyl) that is bonded to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0054] As used herein, "amino" refers to -NH2 unless otherwise specified.

[0055] As used herein, “alkylamino” refers to the -NR'(R”) radical unless otherwise specified, where R' and R'' may be hydrogen or a substituted or unsubstituted alkyl as defined herein. In some embodiments, the alkylamino is a C1-C6 alkyl-amino such as methylamino, ethylamino, n-, iso-propylamino or n-, iso-, tert-butylamino or methylamino-N-oxide.

[0056] sign [ka] The symbol indicates the bonding point of the chemical part to the rest of the molecule or chemical formula.

[0057] Substitution R of any of the above formulas (I), (II), (III), (V), or (V) 1 , R 2 , R3 , R 4 , R 5 or R 6 The "substituted" groups include hydroxyl, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 member heteroalkyl, 2-6 member heteroalkyl, or 2-4 member heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 member heterocycloalkyl, 3-6 member heterocycloalkyl, or 5-6 member heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Ariel, C 10 This refers to a group that is substituted with one or more non-hydrogen substituents, such as aryl or phenyl groups, or unsubstituted heteroaryl groups (e.g., 5-10 membered heteroaryls, 5-9 membered heteroaryls, or 5-6 membered heteroaryls), which may be further optionally substituted.

[0058] As used herein, “salt-inducible kinases” or “SIKs” include, for example, a family of serine / threonine kinases that can play a role in signal transduction by controlling the phosphorylation and intracellular localization of transcriptional regulators (e.g., histone deacetylases (HDACs) and cAMP-regulating transcriptional coactivators (CRTCs)). SIKs can regulate gene expression in response to extracellular cues that increase intracellular levels of cAMP (e.g., dietary salt intake in the adrenal glands). Exemplary SIKs may include, but are not limited to, SIK1 (UniPro ID: P57059, Q60670, Q9R1U5), SIK2 (UniPro ID: Q9H0K1, Q8CFH6, or Q9IA88), SIK1B (UniPro ID: A0A0B4J2F2), and others.

[0059] Terms such as “inhibition,” “to inhibit,” and “to inhibit” in relation to protein-inhibitor interactions mean that the inhibitor adversely affects (e.g., reduces) the activity or function of a protein compared to the activity or function of the protein in the absence of the inhibitor. In embodiments, inhibition means that the inhibitor adversely affects (e.g., reduces) the concentration or level of a protein compared to the concentration or level of the protein in the absence of the inhibitor. In embodiments, inhibition refers to the alleviation of a disease or the symptoms of a disease. In embodiments, inhibition refers to a decrease in the activity of a particular protein target. Thus, inhibition includes blocking at least some, partial or complete, a stimulus, reducing, preventing or delaying activation, or inactivating, desensitizing, or downregulating signaling or enzymatic activity or the amount of a protein. In embodiments, inhibition refers to a decrease in the activity of a target protein resulting from a direct interaction (e.g., the inhibitor binding to the target protein). In embodiments, inhibition refers to a decrease in the activity of a target protein from an indirect interaction (e.g., the inhibitor binding to a protein that activates the target protein, thereby preventing the activation of the target protein). An "SIK inhibitor" is a compound that adversely affects (e.g., reduces) the activity or function of SIK compared to the activity or function of SIK in the absence of the inhibitor.

[0060] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” refer to substances that can replaceably and detectably reduce the expression or activity of a given gene or protein. Antagonists can reduce expression or activity by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more compared to a control in the absence of the antagonist. In certain cases, the expression or activity may be 1.5, 2, 3, 4, 5, or 10 times or less of the expression or activity in the absence of the antagonist.

[0061] As used herein, the terms “a” or “an” mean one or more. In addition, as used herein, the phrase “substituted with a[n]” means that the specified group may be substituted with one or more or all of the nominated substituents.

[0062] As used herein, the term “about” means a range of values ​​that includes a specified value, which a person skilled in the art would reasonably consider to be similar to the specified value. In embodiments, about means within a standard deviation using generally acceptable measurements in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0063] The term “pharmaceutically acceptable salt” means that, depending on the specific substituents found in the compounds described herein, salts of the active compound prepared with a relatively non-toxic acid or base may be obtained. Where a compound of the disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base in either a neat or suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. Where a compound of the disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid in either a neat or suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, and those derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, and methanesulfonic acid. For example, salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid are also included (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds in this disclosure contain both basic and acidic functional groups that enable the conversion of the compound into either a base addition salt or an acid addition salt.

[0064] Accordingly, compounds comprising any of the formulas (I), (II), (III), (IV), (V), or (VI) of the present disclosure may exist as salts with pharmaceutically acceptable acids, etc. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobroms, phosphates, sulfates, methanesulfons, nitrates, maleates, acetates, citrates, fumarates, propions, tartrates (e.g., (+)-tartrate, (-)-tartrate, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts may be prepared by methods known to those skilled in the art.

[0065] The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional methods. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0066] In addition to salt forms, this disclosure provides compounds in prodrug forms. Prodrugs of the compounds described herein are those compounds that readily undergo chemical transformation under physiological conditions to provide the compounds of this disclosure. Prodrugs of the compounds described herein can be converted in vivo after administration. Furthermore, prodrugs can be converted to the compounds of this disclosure by chemical or biochemical methods in an ex vivo environment, for example, by contact with a suitable enzyme or chemical reagent.

[0067] Certain compounds in this disclosure may exist in solvated forms, including non-solvated and hydrated forms. Generally, solvated forms are equivalent to non-solvated forms and are included within the scope of this disclosure. Certain compounds in this disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent to the uses envisioned by this disclosure and are intended to be within the scope of this disclosure.

[0068] "Pharmacopoeia-acceptable excipients" and "pharmacopoeia-acceptable carriers" refer to substances that can be included in the compositions of the present disclosure without causing significant adverse toxic effects to the patient, and which assist in the administration of active agents to a subject and their absorption by the subject. Non-limiting examples of pharmacopoeia-acceptable excipients include water, NaCl, ordinary saline, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and colorants. Such preparations may be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or aromatics that do not react adversely with the compounds of the present disclosure. Those skilled in the art will recognize that other pharmaceutical excipients may be useful in the present disclosure.

[0069] The term "administer" means oral administration, suppository administration, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intrafocal, intrathecal, intranasal, or subcutaneous administration to a subject, or implantation of a sustained-release device, such as a mini osmotic pump. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palate, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriole, intradermal, subcutaneous, intraperitoneal, ventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous injection, and transdermal patches. In embodiments, administration does not include the administration of any activator other than those listed.

[0070] "Co-administered" means that the compositions described herein are administered at the same time as, immediately before or immediately after, the administration of one or more additional therapies. The compounds provided herein may be administered alone or co-administered to a patient. Co-administration means administering compounds individually or in combination (two or more compounds) simultaneously or sequentially. Thus, preparations may also be combined with other active substances (e.g., to reduce metabolic degradation) if necessary. The compounds and compositions of the present invention may preferably be delivered transdermally, by topical routes, or may be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. In one embodiment, a compound having any one structure of formula (I), (II), (III), (IV), (V), or (VI) is co-administered with a sunscreen.

[0071] The terms “disease” or “condition” refer to a condition or health state of a patient or subject that can be treated with the compounds or methods provided herein. In one embodiment, “disease” or “condition” is an inflammatory disease or condition.

[0072] As used herein, “to treat” or “treatment” (and as well understood in the art) also broadly includes any approach to obtain a beneficial or desired outcome in the condition of interest, including clinical outcomes. Beneficial or desired clinical outcomes may include relief or improvement of one or more symptoms or conditions, reduction of the severity of the disease, stabilization of the disease condition (i.e., no worsening), prevention of disease transmission or spread, delay or slowing of disease progression, improvement or relief of the disease condition, reduction of disease recurrence, and remission, whether partial or total, detectable or undetectable. In other words, as used herein, “treatment” includes any cure, improvement, or prevention of disease. Treatment may prevent the onset of disease, suppress the spread of disease, alleviate symptoms of disease (e.g., eye pain, seeing halos around lights, conjunctivitis, very high intraocular pressure), completely or partially eliminate the underlying cause of disease, shorten the duration of disease, or a combination of these.

[0073] "Patient" or "subject requiring it" refers to an organism that is suffering from or prone to a disease or condition that can be treated by the administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans and other mammals. In preferred embodiments, the patient or subject is human.

[0074] An “effective dose” is the amount of a compound sufficient to accomplish its stated purpose in the absence of the compound (e.g., to achieve the effect it is administered, to treat a disease, to decrease or increase enzyme activity, to reduce a signaling pathway, or to reduce one or more symptoms of a disease or condition). An example of an “effective dose” is an amount sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease, and may also be called a “therapeutic effective dose.” “Reduction” of one or more symptoms (and the grammatical equivalents of this phrase) means a reduction in the severity or frequency of symptoms, or the elimination of symptoms. The “preventive effective dose” of a drug is the amount of the drug, when administered to a subject, that, when administered, produces the intended preventive effect, e.g., to prevent or delay the onset (or recurrence) of injury, disease, condition or state, or to reduce the likelihood of the onset (or recurrence) of injury, disease, condition or state, or their symptoms. Complete preventive effect does not necessarily result from a single dose, but may only occur after a series of doses. Therefore, a preventive effective dose may be administered in one or more doses. As used herein, “activity reduction amount” refers to the amount of antagonist required to reduce the activity of an enzyme in the absence of the antagonist. As used herein, “functional disruption amount” refers to the amount of antagonist required to disrupt the function of an enzyme or protein in the absence of the antagonist. The exact amount depends on the therapeutic purpose and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0075] For any compound described herein, the therapeutically effective dose can first be determined by in vitro analysis, such as a cell culture assay. The target concentration is the concentration of the active compound that can achieve the method described herein, measured using the method described herein or known in the art.

[0076] As is well known in the art, therapeutically effective doses for use in humans can also be determined from animal models. For example, doses for humans can be formulated to achieve concentrations known to be safe or effective in animals. Doses in humans can be adjusted, as described above, by monitoring the efficacy of the compound and adjusting the dose upward or downward. Adjusting the dose to achieve maximum efficacy in humans based on the above and other methods is well within the capabilities of those skilled in the art.

[0077] As used herein, the term “therapeutic dose” refers to the amount of therapeutic agent sufficient to improve the above-mentioned disorder. For example, for a given parameter, a therapeutic dose represents an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic effectiveness can also be expressed as a “-times” increase or decrease. For example, a therapeutic dose may have at least 1.2 times, 1.5 times, 2 times, or 5 times or more the effect compared to the control.

[0078] In one embodiment, “increase” refers to a melanin production amount that is at least about 0.05 times greater than the reference level (e.g., a subject with normal melanin production or a subject with a melanin production disorder) (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 1, 5, 10, 25, 50, 100, 1000, 10,000 times or more). “Increased” in reference to melanin production also means at least about 5% greater than the reference level (e.g., a subject with normal melanin production or a subject with a melanin production disorder) (e.g., 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, or 100% or more). The amount can be measured according to methods known in the art for determining the amount of melanin.

[0079] In one embodiment, “increased” also refers to an amount of DNA stability that is at least about 0.05 times greater than the level of DNA stability compared to a reference level (e.g., untreated subject) (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 1, 5, 10, 25, 50, 100, 1000, 10,000 or more). “Increased” in reference to the amount of DNA stability also means at least about 5% greater than the amount of DNA stability compared to a reference level (e.g., untreated subject) (e.g., 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99 or 100% or more). The amount can be measured according to methods known in the art for determining DNA damage (e.g., TUNEL assay and thymidine dimer detection).

[0080] Dosage may vary depending on the patient and the requirements of the compound used. In the context of this disclosure, the dose administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose is also determined by the presence, nature, and severity of any adverse side effects. Determining the appropriate dose for a particular situation is within the scope of the practitioner's skill. Generally, treatment is initiated with a dose lower than the optimal dose of the compound. The dose is then gradually increased until the optimal effect is achieved under the circumstances. Dosage and dosing intervals can be individually adjusted to provide an effective level of the compound for the specific clinical indication being treated. This provides a treatment regimen that is appropriate to the severity of the individual's disease state.

[0081] As can be considered, pharmaceutical compositions are also provided that contain one or more of the compounds of the present formula, comprising one or more compounds of formula (I), (II), (III), (IV), (V), or (VI) and pharmaceutically acceptable excipients. The pharmaceutical compositions may contain one or more compounds of formula (I), (II), (III), (IV), (V), or (VI) in a therapeutically effective amount (e.g., a therapeutically effective amount).

[0082] In addition, the pharmaceutical compositions of the present invention may be manufactured with additional pharmaceutically acceptable carriers for each formulation. The types of carriers that can be used in the present invention are not particularly limited, and any carrier that is conventionally used in the industrial field and is pharmaceutically acceptable may be used.

[0083] Saline solution, sterile water, IV fluid, buffered saline, albumin injection, dextrose solution, maltodextrin solution, glycerol, and ethanol are non-limiting examples of usable carriers. These carriers may be used alone or in combination of two or more. The carriers may include carriers that do not exist in nature. Other conventionally used additives such as antioxidants and / or buffers may be used as needed.

[0084] The pharmaceutical composition may preferably be in the form of a spray or liquid cleanser, or other formulation for topical application, such as a lotion, cream, ointment, paste, gel, foam, or any other physical form as a carrier commonly known for topical administration. Such thickened topical formulations are particularly advantageous because the formulation adheres to the area of ​​skin on which the material is placed, and thus allows for the introduction of one or more localized high concentrations of the compound into a specific area. For example, paraffinic and lanolinic creams are commonly known in the art. Other thickeners, such as polymeric thickeners, may also be used. The formulation may also contain one or more of water, preservatives, active surfactants, emulsifiers, antioxidants, or solvents.

[0085] Pharmaceutical compositions can be formulated for various other routes of administration, such as nasal, oral, parenteral, intramuscular, intra-articular, intravenous, subcutaneous, or transdermal administration. Suitable pharmaceutical compositions can be formulated, for example, with diluents, dispersants, surfactants, binders, lubricants for preparing injectable solutions such as aqueous solutions, or as suspensions, emulsions, and as pills, capsules, granules, or tablets.

[0086] As can be considered, kits are also provided. For example, one or more compounds of any one of formulas (I), (II), (III), (IV), (V), or (VI) can be suitably packaged in a labeled suitable container for use as a therapy for treating subjects suffering from, for example, pigmentation disorders, uneven skin tone, hypopigmentation, inflammatory skin diseases including rosacea, vitiligo, or other skin-related disorders or diseases. In addition, the product or kit may further include, for example, packaging materials, instructions for use, delivery devices, and devices for treating or monitoring the specified condition.

[0087] The kit may also include a legend (e.g., a printed label or insert or other medium (e.g., an audio or videotape) describing the use of the product). The legend may be associated with the container (e.g., affixed to the container) and may describe how the composition therein should be administered (e.g., frequency and route of administration), the labeling therefor, and other uses. The composition may be ready for administration (e.g., present in units appropriate to the dose) and may include one or more additional pharmaceutically acceptable adjuvants, carriers or other diluents and / or additional therapeutic agents. Alternatively, the composition may be provided in a concentrated form, for example, with diluents and instructions for dilution.

[0088] As considered, a method is provided for treating diseases or disorders associated with salt-inducible kinase (SIK), such as inflammatory diseases or disorders, by administering a compound or a pharmaceutical composition containing the compound to a subject. Preferably, the compound may have one of the structures of formula (I), (II), (III), (IV), (V), or (VI). The method may preferably involve administering an effective amount (e.g., a therapeutically effective amount) of the compound. In a preferred embodiment, the method is for treating or preventing hyperpigmentation disorders, skin tone heterogeneity, hypopigmentation, inflammatory skin diseases including rosacea, vitiligo, or other skin-related diseases or disorders, and is suitable for subjects suffering from or susceptible to such diseases or disorders. As considered, the subject may preferably be a male or female human.

[0089] The subjects are individuals who have or are susceptible to vitiligo, a disorder characterized by the appearance of white patches on the skin associated with pigment deficiencies.

[0090] Subjects may have or be susceptible to one of the following: erythematous telangiectatic rosacea (subtype 1 rosacea), papular pustular rosacea (subtype 2 rosacea), cystic rosacea (subtype 3 rosacea), and / or ocular rosacea (subtype 4 rosacea). In some embodiments, the treatment method may further include the step of identifying and selecting subjects with rosacea, including specific subtypes of rosacea or other skin-related diseases or disorders. Subjects with erythematous telangiectatic rosacea (subtype 1 rosacea) may exhibit redness and flushing of the skin and visible blood vessels. Subjects with papular pustular rosacea (subtype 2 rosacea) may exhibit redness, swelling, and acne-like rashes. Subjects with cystic rosacea (subtype 3) may exhibit thickening of the face or other skin, and the skin may exhibit an uneven texture. Subjects suffering from ocular rosacea (subtype 4) may exhibit conjunctivitis and watery eyes, rough eyes, dry eyes, itchy eyes, and decreased vision. The identified and selected subjects may then be treated with the therapeutic compounds or compositions disclosed herein.

[0091] In some embodiments, a treatment method may provide a method for increasing skin pigmentation and / or reducing the risk of skin cancer in a subject requiring it. This disclosure provides a method for increasing skin pigmentation for cosmetic purposes. In certain embodiments, provided herein is a method for increasing the appearance of darkening of the skin in a subject requiring it, using a compound described (e.g., via topical administration of the compound described).

[0092] In certain embodiments, the Disclosure provides a method for increasing the appearance of skin pigmentation in a subject, comprising the step of topically administering a compound having the structure of any one of formulas (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutically acceptable composition thereof, to the skin in a subject.

[0093] In certain embodiments, the Disclosure provides a method for treating polymorphic photoerectomy (e.g., photosensitivity). The Disclosure provides a method for inducing eumelanin synthesis. The Disclosure provides a method for inducing melanosome maturation, transport, and localization.

[0094] In certain embodiments, a method is provided for reversibly increasing skin pigmentation and / or reducing the risk of skin cancer in a subject requiring such treatment, comprising topically administering an effective amount of a compound having the structure of any one of formulas (I), (II), (III), (IV), (V), or (VI), or a pharmaceutical composition thereof, to the skin of the subject. In certain embodiments, a method is provided for increasing skin pigmentation and / or reducing the risk of skin cancer by topically administering the compounds described herein to the skin of a subject on a body part. In certain embodiments, the body part is the face of the subject. In certain embodiments, the body part is the neck of the subject. In certain embodiments, the body part is the chest of the subject. In certain embodiments, the body part is the back of the subject. In certain embodiments, the skin of the body part is the skin of the arm of the subject. In certain embodiments, the skin of the body part is the skin of the leg of the subject. In certain embodiments, the skin is on the torso of the subject.

[0095] In certain embodiments, the present invention relates to cosmetic and / or dermatological uses of compounds or pharmaceutical compositions thereof having the structure of any one of formulas (I), (II), (III), (IV), (V), or (VI) for coloring and / or coloring skin and / or body hair and / or scalp hair. The uses are particularly suited to improving the appearance of white hair (hair carcinoma or natural whitening) in humans, which may be a defect and disorder of pigmentation, for example, a visible manifestation of the aging process (senile dwarfism) or may be associated with a genetic predisposition. Pigmentation of scalp and body hair requires the presence of melanocytes in the bulbous portion of the hair follicle, where hair follicle is recognized to be associated with a decrease in the amount of melanin in the hair shaft. Maintaining a certain coloration of the scalp of hair is a considerable desire, and therefore it is desirable to be able to counteract the appearance of these visible signs of aging, i.e., to maintain or re-establish the coloration of body hair and / or scalp hair.

[0096] Preferred compounds can be suitably prepared according to the following scheme 1: [ka] The variation of the ring A (formula (I)) group of the compounds of formulas (I) to (VI) above can be provided by using an appropriate amine (other than the above 2,6-dimethylphenylamine) in the step of obtaining the above compound 3, such as 2-methyl-6-methoxyphenylamine, 2-methyl-6-ethoxyphenylamine, 2-methyl-6-hydroxyphenylamine, 2-methyl-6-chlorophenylamine, 2,6-di(trifluoromethyl)phenylamine, 2,4-dimethylphenylamine, and 2-(-SO2CH3)-6-methylphenylamine. Various R 1 -NH2 compounds are used to create desired R such as adamantylamine. 1 This can be incorporated into the compound in step 4.

[0097] The following non-restrictive examples are illustrative.

[0098] Examples 1-4: Compound Synthesis

[0099] Example 1: Synthesis of Compound 7 Part 1: Synthesis of N-((2,4-dichloropyrimidine-5-yl)methyl)-2,6-dimethylaniline (Compound 3, Scheme 2) [ka]

[0100] 2,4-Dichloro-5-(chloromethyl)pyrimidine (1) (40 g) was added all at once to a solution of sodium iodide (30.6 g) in acetone (244 mL), and the mixture was stirred until a clear solution was obtained (intermediate (2) was not isolated). The mixture was stirred under reflux under a nitrogen atmosphere at room temperature for 15 minutes, and then at 60°C for 45 minutes. The mixture was cooled and diluted with acetone (366 mL). Then, 2-6-dimethylaniline (24.9 g) and potassium carbonate (83.9 g) were added, and the mixture was heated to 55°C under reflux and a nitrogen atmosphere.

[0101] The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution and brine, separated, dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to obtain a crude solid. The solid was triturated with ethyl acetate, cooled to 0°C, and filtered to obtain N-((2,4-dichloropyrimidine-5-yl)methyl)-2,6-dimethylaniline(3) (46.8g) as a white solid. Part 2: Synthesis of N-((3s,5s,7s)-adamantan-1-yl)-2-chloro-5-(((2,6-dimethylphenyl)amino)methyl)pyrimidine-4-amine (Compound 4, Scheme 3) [ka]

[0102] N-((2,4-dichloropyrimidine-5-yl)methyl)-2,6-dimethylaniline (3) (10 g) was dissolved in THF (106 mL). Then, di-isopropylethylamine (24.6 mL) and 1-adamantamine (10.7 g) were added to the mixture and refluxed with stirring for 48 hours. The mixture was stirred overnight in a sealed tube at 80°C. Ethyl acetate was added and washed with water (x3). The separated organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude solid was purified by flash column chromatography using silica gel (heptane / ethyl acetate (85:15)). The desired fraction was collected and evaporated under reduced pressure to obtain N-((3s,5s,7s)-adamantan-1-yl)-2-chloro-5-(((2,6-dimethylphenyl)amino)methyl)pyrimidine-4-amine (4) (7.49 g) as a white solid.

[0103] Part 3. Synthesis of ((4-(((3s,5s,7s)-adamantan-1-yl)amino)-2-chloropyrimidine-5-yl)methyl)(2,6-dimethylphenyl)carbamate chloride (compound 5, scheme 3) Triphosgene (7.9 g) was added to a solution of N-((3s,5s,7s)-adamantan-1-yl)-2-chloro-5-(((2,6-dimethylphenyl)amino)methyl)pyrimidine-4-amine (4) (7.09 g) dissolved in CH2Cl2 (212 mL), and the mixture was stirred for 1 hour. A solution of sodium hydroxide (14.3 g) and tetrabutylammonium hydroxide (40% in water) (1.5 g) in water (212 mL) was added dropwise to the reaction mixture at 0°C, and the mixture was stirred overnight. The organic and aqueous layers were separated, the organic phase was dried over anhydrous MgSO4, filtered, and removed under reduced pressure. The product was diluted with CH2Cl2 and washed with saturated NaHCO3 (×2) and water. The organic layer was separated, dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography using silica gel eluted with CH2Cl2. The desired fraction was collected and evaporated under reduced pressure to obtain ((4-(((3s,5s,7s)-adamantan-1-yl)amino)-2-chloropyrimidine-5-yl)methyl)(2,6-dimethylphenyl)carbamate chloride (5) (7.9 g) as a white solid.

[0104] Part 4.1 Synthesis of ((3s,5s,7s)-adamantan-1-yl)-7-chloro-3-(2,6-dimethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one (Compound 6, Scheme 4) [ka] Cs2CO3 (8.4g) was added under nitrogen to a solution of ((4-(((3s,5s,7s)-adamantan-1-yl)amino)-2-chloropyrimidine-5-yl)methyl)(2,6-dimethylphenyl)carbamilcloride (7.9g) (compound 5) in dry DMF. The mixture was stirred overnight at room temperature. The mixture was then diluted with CH2Cl2 and washed with water (x2) and brine. The organic layer was separated, dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure to obtain 1-((3s,5s,7s)-adamantan-1-yl)-7-chloro-3-(2,6-dimethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one (7.0g) (compound 6), which was used in the next step without purification.

[0105] Part 5.1 Synthesis of 1-((3s,5s,7s)-adamantan-1-yl)-3-(2,6-dimethylphenyl)-7-((4-(4-methylpiperazine-1-yl)phenyl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one (Compound 7, Scheme 4) 4-(4-methylpiperazin-1-yl)aniline (5.5 g) and trifluoroacetic acid (6.3 mL) were added to a solution of 1-((3s,5s,7s)-adamantan-1-yl)-7-chloro-3-(2,6-dimethylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one (6) (7.2 g) and N-methylpyrrolidone (6.2 mL) in isopropanol (94 mL). The mixture was stirred overnight in a sealed tube at 110°C. Ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate and brine. The separated organic layer was dried over anhydrous MgSO4, filtered, and the solvent was removed under reduced pressure. The crude mixture was purified by flash column chromatography of silica gel eluted on a CH2Cl2:MeOH (100:0~70:30) gradient. The desired fraction was collected and the solvent was removed under reduced pressure. The desired compound (7) was recrystallized from CH2Cl2-acetonitrile and filtered to obtain 1-((3s,5s,7s)-adamantan-1-yl)-3-(2,6-dimethylphenyl)-7-((4-(4-methylpiperazine-1-yl)phenyl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one (6.14 g) as a white solid. This compound (7) may be referred to herein as SLT-008.

[0106] Analysis: LCMS (rt2.647 min, m / z578.4). Melting temperature: 283.5℃ 1 H NMR(400MHz,CDCl3)δ7.96(s,1H),7.51-7.44(m,2H),7.15-7.04(m,3H),6.94(d,J=9.0Hz,2H),6.88(s,1H),4.18(s,2H),3.25-3.19 (m,4H),2.67(s,4H),2.55(d,J=1.8Hz,6H),2.42(s,3H),2.16(s,J=6.0Hz,6H),2.12(d,J=4.2Hz,3H),1.70(dd,J=27.8,12.0Hz,6H).

[0107] Examples 2-4: The compounds of Examples 2 to 4 below are prepared by following the procedure of Example 1 above, with the appropriate amine compound of Scheme 1 above (i.e., the amine that produces the compounds corresponding to compounds 3 and 4 of Scheme 1 above) substituted. Example 2: [ka] Example 3: [ka] Example 4: [ka]

[0108] Example 5: Salt-induced kinase inhibition The salt-inducible kinase (SIK) inhibitor SLT-008 (compound 7) can be optimized as a topical agent capable of inducing skin pigmentation.

[0109] SIK1(h) is mixed with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μM AMARAASAAALARRR, 10 mM magnesium acetate, and [γ- 33 The reaction was incubated with [P]-ATP (45 μM). The reaction was initiated by adding a Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. Then, 10 μL of the reaction mixture was spotted onto a P30 filter mat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol before drying and scintillation counting.

[0110] SIK2(h) is mixed with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μM KKKVSRSGLYRSPSMPENLNRPR, 10 mM magnesium acetate, and [γ- 33The reaction was incubated with P-ATP (45 μM). The reaction was initiated by adding a Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. Then, 10 μL of the reaction mixture was spotted onto a P30 filter mat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol before drying and scintillation counting.

[0111] SIK3(h) is mixed with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 100 μM KKKVSRSGLYRSPSMPENLNRPR, 10 mM magnesium acetate, and [γ- 33 The reaction was incubated with P-ATP (45 μM). The reaction was initiated by adding a Mg / ATP mixture. After incubation at room temperature for 40 minutes, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. Then, 10 μL of the reaction mixture was spotted onto a P30 filter mat and washed four times for 4 minutes in 0.425% phosphoric acid and once in methanol before drying and scintillation counting.

[0112] IC50 was calculated to be greater than 5, 8, and 20 nanomoles for SIK1, SIK2, and SIK3, respectively.

[0113] Table 1: Estimated IC 50 value [Table 1]

[0114] Examples 6-10: In vitro and ex vivo skin tissue models demonstrate the pigmentation efficacy of SLT-008 (SLT-008 is indicated herein as compound 7 of Scheme 4 above, 1-((3s,5s,7s)-adamantan-1-yl)-3-(2,6-dimethylphenyl)-7-((4-(4-methylpiperazine-1-yl)phenyl)amino)-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-one).

[0115] Example 6: Topical application of SLT-008 induces melanin pigmentation. Primary human epidermal keratinocytes (hEKs) were seeded in a suitable carrier matrix and co-cultured with human epidermal melanocytes. SLT-8 was solubilized in 0.3 mM, 1 mM, and 3 mM PEG / ethanol / Transcutol® and applied topically to the surface of the model using a mesh, which was removed after 4 hours. The test compound was applied once daily for 4 days. Untreated and vehicle-treated models served only as controls. A UV-irradiated model was used as a positive control. Fontana-Masson staining was performed to visualize the pigmentation effect. Fontana-Masson staining is routinely used to visualize argentaphin substances such as melanin, argentaphin granules, and some neurosecretory granules. Melanin is a non-lipid, non-hematogenous pigment. It is the brown-black pigment normally present in hair, skin, retina, iris, and certain parts of the central nervous system. Argentaphin granules are found in carcinoid tumors. Argentafin cell granules or melanin stain black. The nucleus stains pink-red. The cytoplasm stains pale pink. At 1 mM, specifically 3 mM, a single topical application of SLT-008 induced melanin pigment dots at the zona pellucida level. At 3 mM, a single topical application also induced melanin translocation to keratinocytes, and nuclear capping was observed (Figure 1).

[0116] Example 7: SLT-008 pigment deposition activity on human living skin explants The pigmentation activity of two concentrations of SLT-008 was evaluated on skin using human in vivo skin explants with stripping.

[0117] Human skin explants with an average diameter of 11 mm (±1 mm) were prepared by abdominoplasty from a 35-year-old Caucasian woman with phototype III. The explants were kept alive in BEM culture medium (BIO-EC explant medium) at 37°C, high humidity, and a 5%-CO2 atmosphere. This study was performed using human skin tissue obtained from surgical residues in accordance with the Declaration of Helsinki and Article L.1243-4 of the French Public Health Act.

[0118] On day 0, the explants of batch "S" were peeled five times using Scotch 3M to remove some of the stratum corneum and promote penetration of the test product. Excipients and the tested product were applied at a rate of 2 μl (2 mg / cm³) per explant. 2 It was applied topically based on the formula and spread using a small spatula on day 0 (D0, after peeling), D1, D4, D6, and D8.

[0119] Control explants T received no treatment other than culture medium replacement. The culture medium was halved on D0, D1, D4, D6, and D8 (1 ml per well). On D0, D1, D4, D5, D6, D7, and D8, the medium (TUV) of the irradiated explants was replaced with HBSS (Hanks equilibrium saline solution; 1 ml per explant). Then, using the UV simulator Vibert Lourmat RMX 3W, the "TUV" batch of explants was irradiated with a UVA dose of 2.25 J / cm2, equivalent to 0.5 MED (minimum erythematous dose) for phototype II donors. At the end of UV irradiation, these explants were returned to 2 mL of BEM medium. It was determined that UVA (TUVJ11 vs. TJ11) irradiation did not induce any modification of cell viability. Treatment with 0.5% and 0.9% SLT-008 compared to the stripped batch also did not result in any modification of cell viability. UVA (TUVJ11 vs. TJ11) irradiation induced increased melanin synthesis in the basal layer of the epidermis.

[0120] A 0.9% dose of SLT-008 induced a significant (p<0.1) increase in melanin in 36% of patients (Figure 2). Pigmentation activity was also detected by Fontana-Masson staining (Figure 3).

[0121] Example 8: Dosage determination and whole-body exposure to SLT-008 We conducted a study to determine three non-toxic concentrations of SLT-008 that do not cause systemic cytotoxicity to normal human epidermal melanocytes (NHEMs-MP; Thermo Fisher Scientific, C1025C) in culture media of reconstituted epidermis.

[0122] Preliminary dose-determining studies were performed using cultures of NHEM grown in M254 medium (Thermo Fisher Scientific, M254500) supplemented with human melanocyte growth supplement (HMGS; Thermo Fisher Scientific, S0025) and antibiotic (gentamicin, Thermo Fisher Scientific, 15710049). Cells were maintained in a humidified incubator at 37°C in a 5% CO2 atmosphere.

[0123] NHEM cells were triple-seed in 24-well plates 24 hours prior to the initiation of treatment with five concentrations of the test compound (n=3). DMSO 0.003%, used for solubilizing the test compound, was tested concurrently. A total of six repeated applications to the culture medium were performed over 10 days (from day 1 to day 11 after seeding, with the medium refreshed on days 4, 5, 6, 7, and 8). SDS 0.008% was used as a cytotoxicity-positive control. At the end of treatment, cell viability was evaluated by the MTS assay (3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl-2H-tetrazolium).

[0124] Next, hematoxylin / eosin (H / E) staining of tissue sections was used to assess the absence of toxicity at three doses in the reconstituted melanized epidermis.

[0125] At the end of treatment with the test compound, three tissue samples per dose (n=3) were fixed with 4% formaldehyde, dehydrated, and embedded in paraffin. 6 μm sections of epidermis were stained with eosin and hematoxylin (H / E). Specific media were mounted on glass slides and examined using a Leica DM2000 microscope connected to a digital camera (Zeiss).

[0126] Analysis revealed no morphological changes after treatment with three selected doses of SLT-008 (Figure 4).

[0127] Example 9: LDH release assay To ensure that the selected dose was not cytotoxic to melanized reconstructed human epidermis, quantification of lactate dehydrogenase (LDH) release from melanized tissue was performed during and at the end of treatment with SLT-008. LDH release in the culture model was evaluated 5 and 10 days after treatment with the Cytotoxicity Detection Kit PLUS (Roche-04744926001) according to the manufacturer's instructions. Briefly, the culture supernatant was collected and mixed with the LDH detection reaction in a 96-well plate for 30 minutes, after which the optical density at 490 nm was measured using a spectrophotometer (GloMax-Promega) at a reference wavelength of 600 nm. This was performed on three cultures (n=3). Overall, 10 days of application of SLT-008 to melanized reconstructed epidermis did not induce any significant changes in tissue integrity. After 10 days of treatment with a dose of 0.3 μg / ml of SLT-008, a slight but significant increase in LDH release from tissues was observed, but it did not reach the established cytotoxic level. Therefore, the effect of these concentrations on tissue pigmentation was studied (Figure 5).

[0128] Example 10: Melanin content Based on the results of dose determination studies, SLT-008 at doses of 0.3 μg / ml, 0.01 μg / ml, and 0.0033 μg / ml was selected for further application to culture media of reconstituted melanized human epidermis. Pigmentation effect studies were performed on epidermis reconstituted with NHEK (normal human epidermal keratinocytes, Lonza 00192906) and NHEM-MP melanocytes isolated from the foreskin of three neonatal Caucasian donors.

[0129] Tissues were cultured at the gas-liquid interface in Epilife medium (Fisher Scientific, MEPI500CA) containing specific supplements (particularly human keratinocyte growth factor, Fisher Scientific S0015 or S001K) and antibiotics (gentamicin, Fisher Scientific, 15710049). They were maintained at 37°C in a humid atmosphere of 5% CO2.

[0130] Melanocytes were co-cultured with reconstituted epidermis and cultured at a gas-liquid interface for 14 days in a humid atmosphere at 37°C and 5% CO2. SLT-008 was applied to the culture medium at three concentrations over 10 days from day 4 to day 14 after placement at the air / liquid interface, with five medium refreshes (days 7, 8, 9, 10, and 11) (n=6). The concentration of BPE (bovine pituitary extract) in the culture medium was adjusted during treatment to allow epidermal pigmentation. 0.005% DMSO, used for solubilization of the compound, was used as a reference control. The experiment was validated using 150 μM IBMX and 3.33 μM forskolin as pigmentation-promoting reference compounds. An additional 0.05% DMSO control corresponding to the solvent of the reference compound was also added to the experiment.

[0131] Morphological analysis was performed at the end of the treatment period (day 14). Epidermal pigmentation was quantified after soluble extraction and then quantified by Fontana-Masson staining of tissue sections. 6 μm epidermal sections embedded in paraffin were prepared and stained with Fontana-Masson reagent. Fontana-Masson staining specifically stains melanin in the epidermis. In addition to melanin, counterstaining with hemalam / eosin was also performed to visualize the epidermis. Tissue section staining was performed three times consecutively for each test compound in one set. To compare the effect of SLT-008, slides containing epidermal sections treated with 0.005% DMSO were placed in each set for Fontana-Masson staining.

[0132] Melanin deposition on 6 μm paraffin sections of each epidermis was stained with Fontana-Masson reagent (VWR-VWRK641295, VWRK641311; Clinipas-641215). Specific culture media were mounted on glass slides and examined using a Leica DM2000 microscope equipped with a digital camera (Zeiss).

[0133] For melanin quantification, three photographs of each epidermis were taken and analyzed using Leica QWin3 software. Two measurement values were obtained. The first corresponds to the overall intensity of staining, and reflects lighter or darker melanin. The second represents the labeled surface on the photograph, thus the area occupied by melanin in the epidermis. These measurements were obtained by examining all cell layers of the epidermis excluding the stratum corneum.

[0134] Analysis of melanin content was then observed. The analysis was performed from 9 photographs per dose (3 photographs per epidermis and 3 epidermises per condition, for a total of 9 photographs). Figure 6A shows an untreated control, vehicle (0.05% DMSO) and two positive controls, showing the complete epidermal pigmentation indicated by the dendritic morphology of functional melanocytes and the formation of melanosomes organized as supranuclear melanin caps above keratinocyte nuclei (Figure 6). Pigmentation was increased by forskolin (3.33 μM) or IBMX (150 μM) compared to 0.05% DMSO. Forskolin and IBMX are known as epidermal inducers of melanin production, and are used herein as positive controls to confirm in vitro functional pigmentation. As shown in Figure 6B, pigmentation was significantly increased by SLT-008 at 0.3 μg / ml compared to 0.005% DMSO. This increase is observed both in the presence of melanosomes, dendrites and melanin capping.

[0135] Melanin content was determined from Fontana-Masson reagent stained sections (as a percentage relative to 0.005% DMSO). Statistical analysis (Student's t-test) was used to compare the effect of 0.005% SLT-008 versus DMSO, and the effect of 0.05% IBMX and forskolin versus DMSO, where 0.01 < p-value < 0.05 was considered significant (*), 0.001 < p-value < 0.01 was considered highly significant (**), and p-value < 0.001 was considered extremely significant (***). The compound SLT-008 at 0.3 μg / ml induced a significant increase in melanin content compared to the respective 0.005% DMSO control (Figure 7).

[0136] In this embodiment, the experiment was repeated using the same method as described above. At the end of these processes, the tissue (n=3) was removed from the insert and immersed in a soluble extract solution (Perkin Elmer-NJTSRN8010060), and heated at 80°C for 1 hour. The optical density of the supernatant was measured at 490 nm using a spectrophotometer (GloMax-Promega), and the melanin content was determined by comparing it with the standard curve for synthetic melanin (Sigma-M8631).

[0137] Treatment with forskolin (positive control) significantly increased melanin production in the epidermis compared to its solvent control (0.03% DMSO). DMSO used as a solvent at 0.03% and 0.01% did not alter melanin content levels, demonstrating its passive effect on pigmentation. SLT-008 increased melanin content at 1 and 0.1 μg / ml, and further increased it at 0.3 μg / ml, due to a dose-effect relationship (Figure 8). Based on these studies, systemic application of SLT-008 increased melanin content in reconstructed epidermal tissue models in vitro, as observed by both Fontana-Masson staining and chemical extraction quantification.

[0138] Example 11: Stripping-induced apoptosis DNA protection study The objective of this study was to perform complementary immunostaining for TUNEL (an apoptotic cell marker).

[0139] Table 2: Batches analyzed in UVA controlled irradiation studies: [Table 2]

[0140] Table 3: Experiment Schedule [Table 3]

[0141] Histological preparation: 5 μm thick sections were prepared using a Leica RM 2125 Minot microtome and mounted on Superfrost® histological glass slides. Microscopic observation was performed using a Leica DMLB, Olympus BX43, or BX63 microscope. Photographs were digitized using a Numeric DP72 or DP74 Olympus camera with CellSens software.

[0142] TUNEL assay: DNA damage was assessed in formol-fixed paraffin-embedded skin sections using an in situ cell death detection kit (Roche, reference 11 684 817 910) with the TUNEL reagent diluted 1:2 in PBS and left at room temperature for 1 hour, followed by VIP (Vector, reference SK-4600). Staining was semi-quantified by image analysis.

[0143] Image analysis method: Image analysis was performed on all images in the selected batch using CellSens software. Comparison of stained surfaces.

[0144] Compare the percentage of stained surface (Surf%) relative to the treated condition with the untreated condition => S vs T; SP vs S.

[0145] Figure 9 shows the percentage of surface area occupied by TUNEL staining associated with apoptotic cells in the epidermis. 0.9% SLT-008 in anhydrous ethanol significantly reduced the number of apoptotic cells by 97% after tape stripping, thereby demonstrating DNA protection.

[0146] Example 12: UVB DNA protection research The objective of this study was to evaluate the effectiveness of product DNA protection using living human skin explants.

[0147] Table 4: DNA protection activity (UVB) [Table 4]

[0148] Sixty-three human skin explants with an average diameter of 11 mm (±1 mm) were prepared using abdoplasty from a 51-year-old Caucasian woman with a II-III phototype (according to the Fitzpatrick skin color classification). The explants were kept alive in BEM culture medium (BIO-EC explant medium) at 37°C and 5% humidity in a CO2 atmosphere.

[0149] Table 5. Explant distribution [Table 5]

[0150] DNA protection activity (UVB): Excipients and test products P1 and P2 were administered at a concentration of 2 μl (2 mg / cm³) per explant. 2 The solution was applied topically and spread using a small spatula on days 0 (D0), D2, D4, and D6. On D4, the excipient and products P1 and P2 were applied twice (before and immediately after UV-B irradiation). The control explant (T) received no treatment other than the refreshment of the culture medium. The culture medium was half refreshed on D2, D3, and D6 (1 ml per well).

[0151] DNA protection activity (UVB): At D4, the culture medium (UVB) of irradiated explants was replaced with HBSS (Hanks equilibrium salt solution; 1 ml per explant). Then, using the UV simulator Vibert Lourmat RMX 3W, 0.3 J / cm² of UVB corresponding to 2MED on skin with phototypes II-III was measured. 2 The explants were irradiated with the specified dose. At the end of UV irradiation, the UVB-treated explants were returned to 2 mL of BEM medium.

[0152] Sampling: On D0, three explants were collected from T0 and cut into two parts. Half were fixed in buffered formalin solution, and the other half were frozen at -80°C. On D5, D6, D7, and D10, three explants were collected from the relevant batches and processed in the same manner as on D0. Processing, irradiation, and sampling days were scheduled to workdays according to the arrangement described in the study plan.

[0153] Histological preparation: After fixing in buffered formalin for 24 hours, the samples were dehydrated using a Leica PEARL dehydration automat and impregnated in paraffin. The samples were embedded using a Leica EG 1160 embedding station. 5 μm thick sections were prepared using a Leica RM 2125 Minot microtome and mounted on Superfrost® histological glass slides. Microscopic observations were performed using a Leica DMLB, Olympus BX43, or BX63 microscope. Photographs were digitized using a Numeric DP72 or DP74 Olympus camera with CellSens software.

[0154] Thymine Dimer Immunostaining: Ultraviolet light is absorbed by the double bonds between thymine and cytosine bases in DNA. This added energy opens the bond, allowing it to react with an adjacent base. If the adjacent group is another thymine or cytosine base, the adjacent group can form a cyclobutane ring that links the two bases. These cyclobutane dimers are constrained and form covalent crosslinks in the DNA. This causes problems when cells need to replicate their DNA. DNA polymerase has trouble reading the dimers because they do not fit smoothly into the active site. Thymine dimer immunostaining was performed on FFPE skin sections using a monoclonal anti-thymine dimer antibody (Kamiya, reference MC-062, clone KTM53) diluted 1:1600 in 0.05% PBS-BSA 0.3%-Tween20. The samples were incubated at room temperature for 1 hour using the Vectastain Kit Vector Amplification System avidin / biotin, and revealed by VIP, a substrate of peroxidase (Vector Laboratories, reference SK-4600) that gives a purple signal when oxidized. Staining was semi-quantified by image analysis using CellSens software.

[0155] No thymine dimers were observed in the unirradiated batch. Figure 10 shows the percentage of the epidermal surface occupied by thymine dimers for all batches. On day 5, thymine dimers accounted for 26.5% of the epidermal surface in UVBJ5. The effect of product application on thymine dimer formation was compared with UVBJ5. Excipients induced a significant increase of 32%, P1 induced a non-significant increase of 1%, and P2 induced a significant decrease of 35%. The effect of product application on thymine dimer formation was also compared with EUVBJ5. P1 induced a significant decrease of 24%, and P2 induced a significant decrease of 51%.

[0156] TUNEL assay: Damaged DNA (apoptotic cells) was stained with an in situ detection kit for cell death (Merck, reference no. 11 684 817 910) using TUNEL reagent diluted 1:2 in PBS for 1 hour at room temperature. The POD converter was diluted 1:4 in PBS and then revealed by VIP (Vector Laboratories, reference SK-4600). Staining was semi-quantified by image analysis using CellSens software. For each explant sample, the percentage of the region of interest covered by staining (stained surface percentage) was determined by image analysis. Stained surface percentage (Surf%) relative to treatment was compared to untreated conditions => P vs T. The same comparison was made for irradiated batches with and without treatment => e.g., PUVA vs UVA.

[0157] Figure 11 shows the percentage of the epidermal surface occupied by apoptotic cells for all samples. On day 5, TJ5 apoptotic cells accounted for 5.2% of the epidermal surface. UVB irradiation (UVBJ5 vs. TJ5) induced a significant 142% increase in apoptotic cell formation in the epidermis. The effects of product application on apoptotic cell formation were compared with UVBJ5. Excipients induced a significant 78% increase, P1 induced a non-significant 13% increase, and P2 induced a non-significant 18% increase.

[0158] The effect of product application on apoptotic cell formation was compared with that of EUVBJ5. P1 induced a significant reduction of 36%, and P2 induced a significant reduction of 34%.

[0159] In conclusion, (SLT-008 0.1% solution) exhibits good DNA protective activity by reducing the levels of thymine dimer and apoptotic cell formation by 24% and 51%, respectively, upon UVB irradiation (vs. EUVBJ5). P2 (SLT-008 0.5% solution) also exhibits good DNA protective activity by reducing the levels of thymine dimer and apoptotic cell formation by 36% and 34%, respectively, upon UVB irradiation (vs. EUVBJ5).

[0160] The examples and embodiments described herein are for illustrative purposes only, and it will be understood that various modifications or changes will be suggested in light thereof and should be incorporated into the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety for all purposes.

Claims

1. Compounds of the following formula (I): 【Chemistry 1】 (In the formula, W is either S or O, Y １ is N or CR Ａ And, Y ２ is N or CR Ｂ And, Ring A is a monocyclic or polycyclic carbonalicyclic group, a monocyclic or polycyclic or heteroalicyclic group, a monocyclic or polycyclic carbonalicyclic aryl group, or a monocyclic or polycyclic carbonalihexeroaryl group. Each R is the same or different substituted or unsubstituted alkyl, halogen, hydroxyl, cyano, amino, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfone, or substituted or unsubstituted alkylamine. z is an integer from 0 to a value allowed by the valence of ring A, R Ａ and R Ｂ These are independently H, halogen, -OH, and -NH ２ , -CN, or substituted or unsubstituted alkyl, R １ This is a substituted or unsubstituted polycyclic carbon-alicyclic group, or a substituted or unsubstituted polycyclic heteroalicyclic group. R ４ is H, or substituted or unsubstituted alkyl, The "substituted" portion when the aforementioned group is substituted is hydroxyl, halogen, -CCl3, -CBr3, -CF3, -CI3, CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3, -OCF3, -OCBr3, -OCI3, -OCCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -N3, (a group selected from C1-C8 alkyl, 2-8 membered heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl, or 5-10 membered heteroaryl) and its pharmaceutically acceptable salts.

2. The compound according to claim 1, wherein each R is the same or different substituted or unsubstituted alkyl or halogen.

3. The compound according to claim 1, wherein each R is the same or different substituted or unsubstituted alkyl or chloro.

4. The compound according to claim 1, wherein each R is the same or different substituted or unsubstituted alkyl group.

5. The compound according to any one of claims 1 to 4, wherein ring A is a monocyclic or polycyclic carbon-alicyclic group or a monocyclic or polycyclic heteroalicyclic group.

6. The aforementioned compound is given by the following formula (II): 【Chemistry 2】 (In the formula, W is either S or O, Y １ is N or CR Ａ And, Y ２ is N or CR Ｂ And, R Ａ and R Ｂ These are independently H, halogen, -OH, and -NH ２ , -CN, or substituted or unsubstituted alkyl, R １ These are substituted or unsubstituted polycyclic carbon-alicyclic groups or heteroalicyclic groups, R ２ and R ３ Each of these is independently H, a substituted or unsubstituted alkyl, a halogen, a hydroxyl, a cyano, an amino, a substituted or unsubstituted alkoxy, a substituted or unsubstituted alkylthio, a substituted or unsubstituted alkylsulfone, or a substituted or unsubstituted alkylamine. R ４ The compound according to claim 1, wherein ( is H or a substituted or unsubstituted alkyl) and a pharmaceutically acceptable salt thereof.

7. The aforementioned compound is given by the following formula (III): 【Transformation 3】 (In formula (III), W is either S or O, R １ These are substituted or unsubstituted polycyclic carbon-alicyclic or heteroalicyclic groups, R ２ and R ３ Each of these is independently H, a substituted or unsubstituted alkyl, a halogen, a hydroxyl, a cyano, an amino, a substituted or unsubstituted alkoxy, a substituted or unsubstituted alkylthio, a substituted or unsubstituted alkylsulfone, or a substituted or unsubstituted alkylamine. R ４ (This is H or a substituted or unsubstituted alkyl group.) The compound according to claim 1, which is a pharmaceutically acceptable salt thereof.

8. The aforementioned compound is given by the following formula (IV): 【Chemistry 4】 (In formula (IV), R １ These are substituted or unsubstituted polycyclic carbon-alicyclic or heteroalicyclic groups, R ２ and R ３ Each of these is independently H, a substituted or unsubstituted alkyl, a halogen, a hydroxyl, a cyano, an amino, a substituted or unsubstituted alkoxy, a substituted or unsubstituted alkylthio, a substituted or unsubstituted alkylsulfone, or a substituted or unsubstituted alkylamine. R ４ The compound according to claim 1, wherein ( is H or a substituted or unsubstituted alkyl) and a pharmaceutically acceptable salt thereof.

9. The aforementioned compound is given by the following formula (V): 【Transformation 5】 (In formula (V), R １ The compound according to claim 1, wherein is a substituted or unsubstituted polycyclic carbon-alicyclic or heteroalicyclic group) and a pharmaceutically acceptable salt thereof.

10. R １ The compound according to any one of claims 1 to 9, wherein the polycyclic carbon-alicyclic group is optionally substituted.

11. R １ The compound according to any one of claims 1 to 10, wherein the compound is optionally substituted with adamantyl, optionally substituted with norbornyl, optionally substituted with cyclo[2,2,2]octanyl, or optionally substituted with bicyclo[3,3,1]nonanyl.

12. R １ The compound according to any one of claims 1 to 9, wherein the polycyclic heteroalicyclic group is optionally substituted.

13. The following compounds: 【Transformation 7】 or a pharmaceutically acceptable salt thereof.

14. The following compounds: 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and one or more pharmaceutically acceptable carriers.

16. The pharmaceutical composition according to claim 15 for treating subjects who are suffering from or are susceptible to skin-related disorders or diseases.

17. The pharmaceutical composition according to claim 15 for treating a person suffering from or susceptible to rosacea.

18. A pharmaceutical composition for increasing pigmentation in a target tissue, comprising administering to the target a sufficient amount of the composition to increase melanin production, thereby increasing pigmentation in the target tissue, according to claim 15.

19. A pharmaceutical composition for increasing cellular DNA stability in the skin tissue of a subject requiring such stability, wherein the composition is administered to the subject in an amount sufficient to reduce apoptosis and / or thymine dimer formation in the cellular DNA of the skin tissue, thereby increasing the cellular DNA stability in the skin tissue of the subject, according to claim 15.

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