Photoprotective compositions containing marassia-derived compounds and / or chemical analogs thereof

Abstract

The present invention relates to compounds, compositions and methods for modulating skin pigmentation and treating or preventing UV-induced skin injury, erythema, skin aging, sunburn and hyperpigmentation in a subject. The compounds, compositions, and methods of the invention generally relate to malassezia derived compounds, including malassezia and indirubin, and / or chemical analogs thereof. Other applications of the compounds and compositions disclosed herein include, but are not limited to, ameliorating hyperpigmentation caused by hyperpigmentation conditions, inducing apoptosis of melanocytes, inducing apoptosis of melanocytes, and inducing apoptosis of melanocytes. And modulate aromatic hydrocarbon receptor (AhR) activity, melanogenesis, melanin production, melanosome biosynthesis, melanosome transfer, melanocyte activity, and melanin concentration.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application is a divisional application of the Chinese invention patent application with application number 201980039661.6, application date April 12, 2019, and invention name “Photoprotective composition containing compounds derived from Malassezia and / or chemical analogs thereof”. The original application is a national phase application with international application number PCT / US2019 / 027181, which claims U.S. Provisional Application No. 62 / 656,769 filed on April 12, 2018. The present invention claims the benefit of U.S. Provisional Application No. 62 / 668,007, filed May 7, 2018, U.S. Provisional Application No. 62 / 685,800, filed June 15, 2018, U.S. Provisional Application No. 62 / 686,912, filed June 19, 2018, U.S. Provisional Application No. 62 / 722,412, filed August 24, 2018, and U.S. Provisional Application No. 62 / 742,657, filed October 8, 2018. The entire contents of the foregoing applications are incorporated herein by reference. Field of the Invention

[0003] The present invention relates to compounds produced or derived from Malassezia yeast, and chemical analogs thereof. The compounds of the present invention and compositions containing the compounds have photoprotective properties and other beneficial properties. The present disclosure also encompasses methods of using the compounds and compositions of the present invention. Background Art

[0004] Individuals around the world use skin-lightening agents to achieve a variety of cosmetic goals, including anti-aging effects, sun damage management, and meeting certain cultural beauty standards. Many commercially available skin-lightening products, while effective to varying degrees, contain harmful ingredients, some of which have been linked to cancer. Consequently, there is a need for new skin-lightening agents and formulations that offer improved safety and / or efficacy levels compared to currently marketed skin-lightening agents.

[0005] Malassezia is a genus of lipophilic yeasts commonly found in the normal flora of human skin. Malassezia is responsible for many skin diseases, including tinea versicolor (pityriasis versicolor), seborrheic dermatitis, and atopic dermatitis.

[0006] The natural habitat of Malassezia furfur (M. furfur) is the epidermis. However, exposure to UV light destroys the organism in its natural habitat. Therefore, UV filters may be necessary for the organism's survival. Two such UV-filtering indoles produced by the organism have been identified: pityriacitrin and pityrialactone. Pityriacitrin, originally described by Mayser et al. (2002), is synthesized by M. furfur. It is a stable, yellow, lipophilic compound that absorbs broadly across the UVA, UVB, and UVC spectra. Similar compounds have been isolated from Paracoccus and patented as UV protectants (Zhang et al., 2018).

[0007] Gambichler et al. (2007) investigated the UV protection of pityrostegrin in humans using in vitro and in vivo assays. Pityrostegrin cream and vehicle were spectrophotometrically measured in the 290 to 400 nm wavelength range. UV transmittance and sun protection factor (SPF) of the different cream formulations were evaluated. The authors used colorimetry to assess erythema and pigmentation after irradiation of cream-protected and unprotected skin of healthy subjects. UVB and UVA transmittance decreased with increasing pityrostegrin concentration. Increasing pityrostegrin concentrations of 1.25%, 2.5%, and 5% were associated with slight increases in SPF of 1.4, 1.5, and 1.7, respectively. In vivo testing confirmed the effectiveness of the in vitro SPF determination for the 5% pityrostegrin cream. Overall, the UV protection effect of pityrostegrin was very weak, suggesting that pityrostegrin may be a weak cofactor in the development of hypopigmentation in pityriasis versicolor lesions after sun exposure.

[0008] The UV filtering effects of furfural were also investigated against the human skin microbiome (Machowinski et al., 2006). The authors determined that furfural provided UV protection against avirulent Candida albicans and Staphylococci within the tested range. The UV protection properties of furfural have also been confirmed in a yeast model (Mayser et al., 2003). Furfural appears to be responsible for the yellow fluorescence of tinea versicolor under Wood's light examination.

[0009] Tinea versicolor is a noncontagious skin disease characterized by localized altered pigmentation caused by an overgrowth of Malassezia species. Malassezia yeasts have two metabolic pathways for synthesizing melanin and tryptophan-derived indole pigments. Malassezin and indirubin are tryptophan metabolites of Malassezia species, which may contribute to the depigmentation characteristic of Malassezia overgrowth.

[0010] The invention disclosed herein utilizes compounds produced or derived from the yeast Malassezia species, including malassezia, indirubin, and chemical analogs thereof, as the basis for safe and effective skin lightening and darkening compositions. Also disclosed herein are photoprotective compositions comprising malassezia, indirubin, and chemical analogs thereof. Summary of the Invention

[0011] One embodiment of the present invention is a compound for skin lightening, wherein the compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0012] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes, wherein the compound is a chemical analog of a compound produced by Malassezia yeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0013] Another embodiment of the present invention is a compound for modulating melanocyte activity, wherein the compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0014] Another embodiment of the present invention is a compound for agonizing the aryl hydrocarbon receptor (AhR), which is a chemical analog of a compound produced by Malassezia yeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0015] Another embodiment of the present invention is a compound for improving hyperpigmentation caused by a hyperpigmentation disorder. The compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0016] Another embodiment of the present invention is a compound for regulating melanin production, wherein the compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0017] Another embodiment of the present invention is a compound for modulating melanosome biosynthesis, wherein the compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0018] Another embodiment of the present invention is a compound for regulating melanosome transfer, wherein the compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0019] Another embodiment of the present invention is a composition comprising Malassezia yeast and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

[0020] Another embodiment of the present invention is a composition comprising a compound isolated or isolatable from a yeast of the genus Malassezia and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

[0021] Another embodiment of the present invention is a composition comprising any of the compounds disclosed herein (including analogs), and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier.

[0022] Another embodiment of the present invention is a method for lightening the skin of a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0023] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0024] Another embodiment of the present invention is a method of modulating melanocyte activity in a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0025] Another embodiment of the present invention is a method of agonizing the aryl hydrocarbon receptor (AhR) in a subject. The method comprises contacting the subject with any one of the compounds or compositions disclosed herein.

[0026] Another embodiment of the present invention is a method of improving hyperpigmentation caused by a hyperpigmentation disorder in a subject in need thereof. The method comprises contacting the subject with any one of the compounds or compositions disclosed herein.

[0027] Another embodiment of the present invention is a method of regulating melanin production in a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0028] Another embodiment of the present invention is a method of modulating melanosome biogenesis in a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0029] Another embodiment of the present invention is a method of modulating melanosome transfer in a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0030] Another embodiment of the present invention is a compound having the structure of formula (II):

[0031]

[0032] in:

[0033] R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl, and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 is methyl; or a crystalline form, a hydrate, or a cosmetically or pharmaceutically acceptable salt thereof.

[0034] Another embodiment of the present invention is a compound having the structure of formula (III):

[0035]

[0036] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl, and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 is methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0037] Another embodiment of the present invention is a compound for lightening the skin. The compound has the structure of formula (II):

[0038]

[0039] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0040] Another embodiment of the present invention is a compound for lightening the skin. The compound has the structure of formula (III):

[0041]

[0042] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0043] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound has a structure of formula (II):

[0044]

[0045] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0046] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound has a structure of formula (III):

[0047]

[0048] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0049] Another embodiment of the present invention is a compound for agonizing the aryl hydrocarbon receptor (AhR). The compound has the structure of formula (II):

[0050]

[0051] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0052] Another embodiment of the present invention is a compound for agonizing the aryl hydrocarbon receptor (AhR). The compound has the structure of formula (III):

[0053]

[0054] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0055] Another embodiment of the present invention is a composition comprising a compound having the structure of formula (II):

[0056]

[0057] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, a hydrate or a cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

[0058] Another embodiment of the present invention is a composition comprising a compound having the structure of formula (III):

[0059]

[0060] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, a hydrate or a cosmetically or pharmaceutically acceptable salt thereof, and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

[0061] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises: contacting the subject with a compound having the structure of formula (II) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0062]

[0063] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl.

[0064] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises: contacting the subject with a compound having the structure of formula (III) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0065]

[0066] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl.

[0067] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises: contacting the subject with a compound having the structure of formula (II) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0068]

[0069] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl.

[0070] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises: contacting the subject with a compound having the structure of formula (III) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0071]

[0072] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl.

[0073] Another embodiment of the present invention is a method for agonizing the aryl hydrocarbon receptor (AhR) in a subject. The method comprises contacting the subject with a compound having the structure of formula (II) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0074]

[0075] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl.

[0076] Another embodiment of the present invention is a method for agonizing the aryl hydrocarbon receptor (AhR) in a subject. The method comprises contacting the subject with a compound having the structure of formula (III) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0077]

[0078] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl.

[0079] One embodiment of the present invention is a compound having the following structure:

[0080]

[0081] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 A group consisting of: a is hydrogen, then Y is CR5R6, and R 13 With R 14 are all hydrogen, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 At least one of them is R 16 ; or R5 is selected from hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0082] Another embodiment of the present invention is a compound having the following structure:

[0083]

[0084] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 At least one of the following is not hydrogen; or a crystalline form, a hydrate, or a cosmetically or pharmaceutically acceptable salt thereof.

[0085] Another embodiment of the present invention is a compound for lightening the skin. The compound has the following structure:

[0086]

[0087] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0088] Another embodiment of the present invention is a compound for lightening the skin. The compound has the following structure:

[0089]

[0090] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0091] Another embodiment of the present invention is a compound for lightening skin. The compound is selected from the group consisting of:

[0092]

[0093] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound has the following structure:

[0094]

[0095] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0096] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound has the following structure:

[0097]

[0098] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0099] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound is selected from the group consisting of:

[0100]

[0101] Another embodiment of the present invention is a compound for modulating the activity of the aryl hydrocarbon receptor (AhR). The compound has the following structure:

[0102]

[0103] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0104] Another embodiment of the present invention is a compound for modulating the activity of the aryl hydrocarbon receptor (AhR). The compound has the following structure:

[0105]

[0106] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0107] Another embodiment of the present invention is a compound for modulating the activity of the aryl hydrocarbon receptor (AhR). The compound is selected from the group consisting of:

[0108]

[0109] Another embodiment of the present invention is a compound for regulating melanin production. The compound has the following structure:

[0110]

[0111] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0112] Another embodiment of the present invention is a compound for regulating melanin production. The compound has the following structure:

[0113]

[0114] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0115] Another embodiment of the present invention is a compound for regulating melanin production. The compound is selected from the group consisting of:

[0116]

[0117] Another embodiment of the present invention is a compound for regulating melanin concentration. The compound has the following structure:

[0118]

[0119] Where: X is selected from NR14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0120] Another embodiment of the present invention is a compound for regulating melanin concentration. The compound has the following structure:

[0121]

[0122] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0123] Another embodiment of the present invention is a compound for regulating melanin concentration. The compound is selected from the group consisting of:

[0124]

[0125] Another embodiment of the present invention is a composition comprising a compound having the following structure:

[0126]

[0127] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0128] Another embodiment of the present invention is a composition comprising a compound having the following structure:

[0129]

[0130] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0131] Another embodiment of the present invention is a composition comprising a compound selected from the group consisting of:

[0132]

[0133] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0134]

[0135] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[0136] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0137]

[0138] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl.

[0139] Another embodiment of the present invention is a method of lightening the skin of a subject. The method comprises contacting the subject with a compound selected from the group consisting of:

[0140]

[0141] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0142]

[0143] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[0144] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0145]

[0146] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13, OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl.

[0147] Another embodiment of the present invention is a method of inducing apoptosis in melanocytes of a subject. The method comprises contacting the subject with a compound selected from the group consisting of:

[0148]

[0149] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0150]

[0151] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[0152] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0153]

[0154] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl.

[0155] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:

[0156]

[0157] Another embodiment of the present invention is a method for regulating melanin production in a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0158]

[0159] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[0160] Another embodiment of the present invention is a method for regulating melanin production in a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0161]

[0162] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl.

[0163] Another embodiment of the present invention is a method of regulating melanin production in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:

[0164]

[0165] Another embodiment of the present invention is a method for regulating melanin concentration in a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0166]

[0167] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[0168] Another embodiment of the present invention is a method for regulating melanin concentration in a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0169]

[0170] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl.

[0171] Another embodiment of the present invention is a method of regulating melanin concentration in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:

[0172]

[0173]

[0174] One embodiment of the present invention is a compound for lightening skin. The compound has the following structure:

[0175]

[0176] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0177] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound has the following structure:

[0178]

[0179] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0180] Another embodiment of the present invention is a compound for modulating the activity of the aryl hydrocarbon receptor (AhR). The compound has the following structure:

[0181]

[0182] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0183] Another embodiment of the present invention is a compound for regulating melanin production. The compound has the following structure:

[0184]

[0185] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0186] Another embodiment of the present invention is a compound for regulating melanin concentration. The compound has the following structure:

[0187]

[0188] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0189] Another embodiment of the present invention is a composition comprising a compound having the following structure:

[0190]

[0191] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0192] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises contacting the subject with a compound having the following structure, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0193]

[0194] Another embodiment of the present invention is a method of inducing apoptosis in melanocytes of a subject. The method comprises contacting the subject with a compound having the following structure, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0195]

[0196] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound having the following structure, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0197]

[0198] Another embodiment of the present invention is a method of regulating melanin production in a subject. The method comprises contacting the subject with a compound having the following structure, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0199]

[0200] Another embodiment of the present invention is a method for regulating melanin concentration in a subject. The method comprises contacting the subject with a compound having the following structure, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0201]

[0202] Another embodiment of the present invention is a composition. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0203] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises giving the subject a sample of Table 5 or Figure 130 contact with one or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0204] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises: Figure 130 contact with one or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0205] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises administering to the subject a combination of Table 5 or Figure 130 contact with one or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0206] Another embodiment of the present invention is a method for regulating melanin production in a subject. The method comprises subjecting the subject to Table 5 or Figure 130 contact with one or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0207] Another embodiment of the present invention is a method for regulating the melanin concentration of a subject. The method comprises subjecting the subject to the following conditions: Figure 130 contact with one or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0208] Another embodiment of the present invention is a composition. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0209] Another embodiment of the present invention is a composition for lightening the skin. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0210] Another embodiment of the present invention is a composition for inducing apoptosis in melanocytes. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0211] Another embodiment of the present invention is a composition for modulating the activity of aryl hydrocarbon receptor (AhR). The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0212] Another embodiment of the present invention is a composition for regulating melanin production. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0213] Another embodiment of the present invention is a composition for regulating melanin concentration. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0214] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises contacting the subject with a composition comprising Table 5 or Figure 130 One or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0215] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises contacting the subject with a composition comprising Table 5 or Figure 130 One or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0216] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a composition comprising Table 5 or Figure 130 One or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0217] Another embodiment of the present invention is a method for regulating melanin production in a subject. The method comprises contacting the subject with a composition comprising Table 5 or Figure 130 One or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0218] Another embodiment of the present invention is a method for regulating the melanin concentration of a subject. The method comprises contacting the subject with a composition comprising Table 5 or Figure 130 One or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0219] Another embodiment of the present invention is a composition comprising Malassezia yeast and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

[0220] Another embodiment of the present invention is a composition comprising a compound having the following structure:

[0221]

[0222] in:

[0223] X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 the groups formed;

[0224] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt,

[0225] and cosmetically or pharmaceutically acceptable vehicles, diluents or carriers.

[0226] Another embodiment of the present invention is a composition comprising a compound having the following structure:

[0227]

[0228] in:

[0229] R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl;

[0230] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt,

[0231] and cosmetically or pharmaceutically acceptable vehicles, diluents or carriers.

[0232] Another embodiment of the present invention is a composition. The composition comprises Table 5 or Figure 130 The compounds listed in, or their chemical analogs, crystalline forms, hydrates or cosmetically or pharmaceutically acceptable salts,

[0233] and cosmetically or pharmaceutically acceptable vehicles, diluents or carriers.

[0234] Another embodiment of the present invention is a method for treating or preventing UV-induced skin damage in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[0235] Another embodiment of the present invention is a method of treating or preventing UV-induced erythema in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[0236] Another embodiment of the present invention is a method for treating or preventing UV-induced skin aging in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[0237] Another embodiment of the present invention is a method of treating or preventing sunburn in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[0238] Another embodiment of the present invention is a method of treating or preventing UV-induced hyperpigmentation in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[0239] Another embodiment of the present invention is a method of lightening the skin of a subject, comprising contacting the subject with any of the compositions disclosed herein.

[0240] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject, comprising contacting the subject with any one of the compositions disclosed herein.

[0241] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[0242] Another embodiment of the present invention is a method of regulating melanin production in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[0243] Another embodiment of the present invention is a method for regulating melanin concentration in a subject, comprising contacting the subject with any of the compositions disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0244] This patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0245] Figure 1A A diagram of the layers of the skin. The illustration shows the cellular composition of the epidermis and dermis. Figure 1B is a schematic diagram showing the potential mechanism of action of hypopigmentation contributing agents.

[0246] Figure 2 is a set of synthetic processes for malassezia and malassezia derivatives: Figure 2A : malassezia and indolo[3,2-b]carbazole; Figure 2B : Compounds I and IV; Figure 2C : Compound II.

[0247] Figure 3A is a table showing the effects of certain compounds of the present invention on the annexin V-induced EC in MeWo and WM115 cells. 50 Figures 3B-3M are line graphs showing the percentage of MeWo (Figures 3B-3G) or WM115 (Figures 3H-3M) cells labeled with Annexin V after exposure to various concentrations of the listed compounds.

[0248] Figures 4A-4D Figures 4E-4J are graphs showing the relative Annexin V levels (%) in MeWo and WM115 cells after exposure to various concentrations of the listed compounds for 6, 24, 48, and 72 hours. Figures 4A-4D results. Figure 4K and 4L is a histogram showing the expression of Annexin V-labeled MeWo ( Figure 4K ) and WM115( Figure 4L ) cells.

[0249] Figures 5A-5K are micrographs showing the morphology of MeWo cells after treatment with different concentrations of CV-8684, CV-8685, CV-8688, DMSO, and staurosporine for 6 hours.

[0250] Figures 6A-6K are micrographs showing the morphology of MeWo cells after treatment with different concentrations of CV-8684, CV-8685, CV-8688, DMSO, and staurosporine for 24 hours.

[0251] Figures 7A-7K are micrographs showing the morphology of MeWo cells after treatment with different concentrations of CV-8684, CV-8685, CV-8688, DMSO, and staurosporine for 48 hours.

[0252] Figures 8A-8K are micrographs showing the morphology of MeWo cells after treatment with different concentrations of CV-8684, CV-8685, CV-8688, DMSO, and staurosporine for 72 hours.

[0253] Figures 9A-9K are micrographs showing the morphology of WM115 cells after treatment with different concentrations of CV-8684, CV-8685, CV-8688, DMSO, and staurosporine for 6 hours.

[0254] Figures 10A-10K are micrographs showing the morphology of WM115 cells after treatment with different concentrations of CV-8684, CV-8685, CV-8688, DMSO, and staurosporine for 24 hours.

[0255] Figures 11A-11K are micrographs showing the morphology of WM115 cells after treatment with different concentrations of CV-8684, CV-8685, CV-8688, DMSO, and staurosporine for 48 hours.

[0256] Figures 12A-12K are micrographs showing the morphology of WM115 cells after treatment with different concentrations of CV-8684, CV-8685, CV-8688, DMSO, and staurosporine for 72 hours.

[0257] Figures 13A-13D is a graph showing the effect of different concentrations of CV-8684 ( Figure 13A )、CV-8685( Figure 13B )、CV-8688( Figure 13C ) or staurosporine ( Figure 13D) The percentage of MeWo and WM115 viable cells remaining after 6, 24, 48 and 72 hours of treatment. Figures 13E-13J show the cell viability. Figures 13A-13D A histogram of the results. Figure 13K is a summary table comparing the percentage of viable MeWo and WM115 cells after 24, 48, and 72 hours of exposure to the listed concentrations of malassezia, indolocarbazole, Compound II, and staurosporine.

[0258] Figures 14A-14D is a graph showing the effect of different concentrations of CV-8684 ( Figure 14A )、CV-8685( Figure 14B )、CV-8688( Figure 14C ) or staurosporine ( Figure 14D Figures 14E-14J show the levels of lactate dehydrogenase ("LDH") released from MeWo and WM115 cells after 6, 24, 48 and 72 hours of treatment. Figures 14A-14D A histogram of the results. Figure 14K and 14L is a histogram showing the MeWo( Figure 14K ) and WM115( Figure 14L ) Lactate dehydrogenase levels in cells after 24 h exposure to the listed concentrations of malassezia, carbazole, Compound II, and staurosporine.

[0259] Figures 15A-15E showed that after exposure to different concentrations of omeprazole ( Figure 15A )、CV-8684( Figure 15B )、CV-8685( Figure 15C )、CV-8686( Figure 15D ) and CV-8688( Figure 15E ) Raw data and line graph of aryl hydrocarbon receptor ("AhR") activation in HepG2 cells stably transfected with an AhR-responsive luciferase reporter plasmid. Figure 15F The EC of each test compound is shown 50 value.

[0260] Figures 16A-16K are MelanoDerm TMPhotographs of matrices on day 0 or day 7 after exposure to: no treatment ( FIG. 16A ), sterile deionized water ( FIG. 16B ), 1% kojic acid ( FIG. 16C ), 0.2% DMSO ( FIG. 16D ), 0.05% DMSO ( FIG. 16E ), 200 μM CV-8684 ( FIG. 16F ), 50 μM CV-8684 ( FIG. 16G ), 200 μM CV-8686 ( FIG. 16H ), 50 μM CV-8686 ( FIG. 16I ), 200 μM CV-8688 ( FIG. 16J ), and 50 μM CV-8688 ( FIG. 16K ).

[0261] Figures 17A-17K are MelanoDerm TM Micrographs at 15x magnification of matrices on day 0 or day 7 after exposure to: no treatment ( FIG. 17A ), sterile deionized water ( FIG. 17B ), 1% kojic acid ( FIG. 17C ), 0.2% DMSO ( FIG. 17D ), 0.05% DMSO ( FIG. 17E ), 200 μM CV-8684 ( FIG. 17F ), 50 μM CV-8684 ( FIG. 17G ), 200 μM CV-8686 ( FIG. 17H ), 50 μM CV-8686 ( FIG. 17I ), 200 μM CV-8688 ( FIG. 17J ), and 50 μM CV-8688 ( FIG. 17K ).

[0262] Figures 18A-18F Figure 18A shows photos of zebrafish exposed to no treatment (Figure 18A), DMSO (Figure 18B), phenylthiourea ("PTU") (Figure 18C), and 2.5 μM (Figure 18D), 5 μM (Figure 18E), and 10 μM (Figure 18F) of Compound II. Red arrows indicate normal melanocytes.

[0263] Figures 19A-19F Figure 19 is a photograph of zebrafish exposed to the following: no treatment (Figure 19A), DMSO (Figure 19B), phenylthiourea ("PTU") (Figure 19C), and 0.3 μM (Figure 19D), 1 μM (Figure 19E), and 3 μM (Figure 19F) of Compound II. Red arrows indicate normal melanocytes. Yellow arrows indicate abnormal small melanocytes.

[0264] Figure 20 is a table showing the number and percentage of zebrafish with reduced skin pigmentation after exposure to the listed conditions. The last six rows show the effects of different concentrations of Compound II.

[0265] Figures 21A-21EFigures are of zebrafish treated with: no treatment (Figure 21A), DMSO (Figure 21B), PTU (Figure 21C), 0.5 μM (Figure 21D), and 1.5 μM (Figure 21E). The bottom panel includes areas where the color schemes are inverted.

[0266] Figure 22A and 22B is a histogram showing the density of pigmentation as per Figures 21A-21E Colored pixels / mm of the zebrafish embryo image shown 3 ( Figure 22A ) and total pixels ( Figure 22B ) measured.

[0267] Figures 23A-23C is DMSO ( Figure 23A ), RPMI medium ( Figure 23B ) and DMEM( Figure 23C ) in the mass spectrum of CV-8684. Figures 23D-23F is DMSO ( Figure 23D ), RPMI medium ( Figure 23E ) and DMEM( Figure 23F ) in the mass spectrum of CV-8686. Figures 23G-23I is DMSO ( Figure 23G ), RPMI medium ( Figure 23H ) and DMEM( Figure 23I ) in the mass spectrum of CV-8688. Figure 23J is a table showing the percentage of test compound remaining in the listed solvents after a 2-hour incubation.

[0268] Figure 24 A-24S shows the synthetic process of the malassezia derivatives of the present invention: Figure 24 A: Compound C (CV-8802); Figure 24 B: Compound K (CV-8803); Figure 24 C: Compound A (CV-8804); Figure 24 D: Compound E (AB12508); Figure 24 E: Compound A5 (CV-8819); Figure 24 F: Compound H (AB12509); Figure 24 G: Compound B (CV-8877); Figure 24 H: compound B10; Figure 24 I: Compound AB11644; Figure 24 J: O52 (AB12976); Figure 24 K: Malassezia indole A (AB17011); Figure 24 L: furfural (AB17014); Figure 24M:AB17151; Figure 24 N: Compound VI (AB17225); Figure 24 O: Malassezia lactis (AB17227); Figure 24 P:AB12507; Figure 24 Q: Compound V (AB17219); Figure 24 R: Compound VIII (AB17220), and Figure 24 S: Compound VII (AB17221).

[0269] Figure 25 A-25D shows a data table containing the data at 6 hours after exposure to the indicated treatments ( Figure 25 A) 24th hour Figure 25 B) 48th hour Figure 25 C) and 72 hours ( Figure 25 D) The percentage of Annexin V-positive cells at 4 hr.

[0270] Figure 26 A-26D shows a data table containing the data at 6 hours after exposure to the indicated treatments ( Figure 26 A) 24th hour Figure 26 B) 48th hour Figure 26 C) and 72 hours ( Figure 26 Fold induction of caspase 3 / 7 at 4 hr (D).

[0271] Figure 27 A-27B shows the MeWo( Figure 27 A) and WM115( Figure 27 B) Percentage of remaining cell viability after exposure of cells to AB12508 (Compound E).

[0272] Figure 28 A-28B shows MeWo( Figure 28 A) and WM115( Figure 28 B) Percentage of remaining cell viability after exposure of cells to an unknown composition.

[0273] Figure 29 A-29B shows MeWo( Figure 29 A) and WM115( Figure 29 B) Percentage of remaining cell viability after exposure of cells to CV-8803 (Compound K).

[0274] Figure 30 A-30B shows the MeWo( Figure 30 A) and WM115( Figure 30B) Percentage of remaining cell viability after exposure of cells to CV-8804 (Compound A).

[0275] Figure 31 A-31B shows the MeWo( Figure 31 A) and WM115( Figure 31 B) Percentage of remaining cell viability after exposure of cells to CV-8684 (malassezia).

[0276] Figure 32 A-32B shows MeWo( Figure 32 A) and WM115( Figure 32 B) Percentage of remaining cell viability after exposure of cells to CV-8685 (indolo[3,2-b]carbazole).

[0277] Figure 33 A-33B shows the MeWo( Figure 33 A) and WM115( Figure 33 B) Percentage of remaining cell viability after exposure of cells to CV-8686 (Compound I).

[0278] Figure 34 A-34B shows the MeWo( Figure 34 A) and WM115( Figure 34 B) Percentage of remaining cell viability after exposure of cells to CV-8688 (Compound II).

[0279] Figure 35 A-35B shows MeWo( Figure 35 A) and WM115( Figure 35 B) Percentage of cells remaining viable after exposure to staurosporine.

[0280] Figure 36 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of omeprazole. Figure 36 B shows Figure 36 A is a line graph of the data, and the inset shows the measured EC50.

[0281] Figure 37 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8684 (malassezia). Figure 37 B shows Figure 37 A is a line graph of the data, and the inset shows the measured EC50.

[0282] Figure 38A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8685 (indolo[3,2-b]carbazole). Figure 38 B shows Figure 38 A is a line graph of the data, and the inset shows the measured EC50.

[0283] Figure 39 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8686 (Compound I). Figure 39 B shows Figure 39 A is a line graph of the data, and the inset shows the measured EC50.

[0284] Figure 40 A shows AhR activity readouts from the HepG2-AhR-luciferase assay after exposure to different concentrations of an unknown composition. Figure 40 B shows Figure 40 A is a line graph of the data, and the inset shows the measured EC50.

[0285] Figure 41 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8803 (Compound K). Figure 41 B shows Figure 41 A is a line graph of the data, and the inset shows the measured EC50.

[0286] Figure 42 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8804 (Compound A). Figure 42 B shows Figure 42 A is a line graph of the data, and the inset shows the measured EC50.

[0287] Figure 43 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of AB12508 (Compound E). Figure 43 B shows Figure 43 A is a line graph of the data, and the inset shows the measured EC50.

[0288] Figure 44 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8688 (Compound II). Figure 44 B shows Figure 44 A is a line graph of the data, and the inset shows the measured EC50.

[0289] Figure 45 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of omeprazole. Figure 45 B shows Figure 45 A line chart of data.

[0290] Figure 46 A shows AhR activity readouts from the HepG2-AhR-luciferase assay after exposure to different concentrations of an unknown composition. Figure 46 B shows Figure 46 A line chart of data.

[0291] Figure 47 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of 2,3,7,8-tetrachlorodibenzodioxine (TCDD). Figure 47 B shows Figure 47 A line chart of data.

[0292] Figure 48 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8819 (Compound A5). Figure 48 B shows Figure 48 A line chart of data.

[0293] Figure 49 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8684 (malassezia). Figure 49 B shows Figure 49 A line chart of data.

[0294] Figure 50 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of AB12508 (Compound E). Figure 50 B shows Figure 50 A line chart of data.

[0295] Figure 51 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8686 (Compound I). Figure 51 B shows Figure 51 A line chart of data.

[0296] Figure 52 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of AB12509 (Compound H). Figure 52B shows Figure 52 A line chart of data.

[0297] Figure 53 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8688 (Compound II). Figure 53 B shows Figure 53 A line chart of data.

[0298] Figure 54 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8877 (Compound B). Figure 54 B shows Figure 54 A line chart of data.

[0299] Figure 55 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8685 (indolo[3,2-b]carbazole). Figure 55 B shows Figure 55 A line chart of data.

[0300] Figure 56 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of Compound B10. Figure 56 B shows Figure 56 A line chart of data.

[0301] Figure 57 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of CV-8687 (Compound IV). Figure 57 B shows Figure 57 A line chart of data.

[0302] Figure 58 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of omeprazole. Figure 58 B shows Figure 58 A line chart of data.

[0303] Figure 59 A shows AhR activity readouts from the HepG2-AhR-luciferase assay after exposure to different concentrations of TCDD. Figure 59 B shows Figure 59 A line chart of data.

[0304] Figure 60A shows AhR activity readout from HepG2-AhR-luciferase assay after exposure to different concentrations of malassezia progenitor. Figure 60 B shows Figure 60 A line chart of data.

[0305] Figure 61 A shows AhR activity readouts from the HepG2-AhR-luciferase assay after exposure to different concentrations of AB11644. Figure 61 B shows Figure 61 A line chart of data.

[0306] Figure 62 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of 3-methylcholanthrene (3-MC). Figure 62 B shows Figure 62 A line chart of data.

[0307] Figure 63 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of AB12976(052). Figure 63 B shows Figure 63 A line chart of data.

[0308] Figure 64 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of AB17011 (Malassezia indole A). Figure 64 B shows Figure 64 A line chart of data.

[0309] Figure 65 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of AB17014 (furfuryl). Figure 65 B shows Figure 65 A line chart of data.

[0310] Figure 66 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of AB17151. Figure 66 B shows Figure 66 A line chart of data.

[0311] Figure 67 A shows AhR activity readout from the HepG2-AhR-luciferase assay after exposure to different concentrations of AB17225. Figure 67 B shows Figure 67 A line chart of data.

[0312] Figure 68 is a table showing the TM MTT viability data determined for substrates treated with varying concentrations of the indicated compounds.

[0313] Figure 69 is a table showing the TM Melanin concentration data determined for substrates treated with varying concentrations of the indicated compounds.

[0314] Figure 70 MelanoDerm exposed to CV-8686 (Compound I) and AB11644 is shown. TM Representative macrophotographic images of samples taken on the indicated days, where the samples were exposed to the indicated treatments.

[0315] Figure 71 MelanoDerm exposed to CV-8686 (Compound I) and AB11644 is shown. TM Representative microscopic (15X) photographic images of samples taken on the indicated days, wherein the samples were exposed to the indicated treatments.

[0316] Figure 72 MelanoDerm exposed to CV-8686 (Compound I) and kojic acid TM Representative microscopic (15X) photographic images of samples taken on the indicated days, wherein the samples were exposed to the indicated treatments.

[0317] Figure 73 MelanoDerm exposed to CV-8686 (Compound I) and kojic acid TM Representative macrophotographic images of samples taken on the indicated days, where the samples were exposed to the indicated treatments.

[0318] Figure 74 MelanoDerm exposed to CV-8686 (Compound I) and kojic acid TM Representative macrophotographic images of samples taken on the indicated days, where the samples were exposed to the indicated treatments.

[0319] Figure 75 is a table showing the TM Mean tissue viability and melanin concentration data determined for substrates treated with various concentrations of the indicated compounds. Where sponsor logo is blank, samples are of unknown composition.

[0320] Figure 76MelanoDerm exposed to the indicated treatments is shown TM Representative macrophotographic images of samples taken on the indicated dates.

[0321] Figure 77 MelanoDerm exposed to the indicated treatments is shown TM Representative macrophotographic images of samples taken 7 days after treatment. Where the compound name is blank, the sample is of unknown composition.

[0322] Figure 78 MelanoDerm exposed to the indicated treatments is shown TM Representative microscopic (15X) photographic images of samples taken on the indicated dates.

[0323] Figure 79 MelanoDerm exposed to the indicated treatments is shown TM Representative microscopic (15X) photographic images of samples taken on the indicated dates. Where compound name is blank, the sample is of unknown composition.

[0324] Figures 80-87 MelanoDerm exposed to the indicated treatments is shown TM Representative macrophotographic images of samples taken on day 7. Figure 85 In the case where the compound name is blank, the sample is of unknown composition.

[0325] Figure 88 is a table showing the TM Mean tissue viability and melanin concentration data determined for substrates treated with varying concentrations of the indicated compounds.

[0326] Figure 89 A-89X shows a histogram of the percentage of survival and percentage change of melanin in B16 melanocytes after the indicated treatments. Figure 89 In M-89N, when the compound name is blank, the sample is of unknown composition.

[0327] Figure 90 A, 90C and 90E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to staurosporine ( Figure 90 A), MeWo cells ( Figure 90 C) and WM115 cells ( Figure 90 E) percentage. Figure 90B, 90D and 90F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to staurosporine ( Figure 90 B) MeWo cells ( Figure 90 D) and WM115 cells ( Figure 90 F) percentage.

[0328] Figure 91 A, 91C and 91E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to Compound H (AB12509) ( Figure 91 A), MeWo cells ( Figure 91 C) and WM115 cells ( Figure 91 E) percentage. Figure 91 B, 91D and 91F show data tables containing propidium iodide (PI) positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to compound H (AB12509) ( Figure 91 B) MeWo cells ( Figure 91 D) and WM115 cells ( Figure 91 F) percentage.

[0329] Figure 92 A, 92C and 92E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to malassezia (CV-8684) ( Figure 92 A), MeWo cells ( Figure 92 C) and WM115 cells ( Figure 92 E) percentage. Figure 92 B, 92D and 92F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to malassezia (CV-8684) ( Figure 92 B) MeWo cells ( Figure 92 D) and WM115 cells ( Figure 92 F) percentage.

[0330] Figure 93 A, 93C and 93E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to Compound B (CV-8877) ( Figure 93 A), MeWo cells ( Figure 93 C) and WM115 cells ( Figure 93 E) percentage. Figure 93B, 93D and 93F show data tables containing propidium iodide (PI) positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to compound B (CV-8877) ( Figure 93 B) MeWo cells ( Figure 93 D) and WM115 cells ( Figure 93 F) percentage.

[0331] Figure 94 A, 94C and 94E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to Compound I (CV-8686) ( Figure 94 A), MeWo cells ( Figure 94 C) and WM115 cells ( Figure 94 E) percentage. Figure 94 B, 94D and 94F show data tables containing propidium iodide (PI) positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to Compound I (CV-8686) ( Figure 94 B) MeWo cells ( Figure 94 D) and WM115 cells ( Figure 94 F) percentage.

[0332] Figure 95 A, 95C and 95E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to compound B10 ( Figure 95 A), MeWo cells ( Figure 95 C) and WM115 cells ( Figure 95 E) percentage. Figure 95 B, 95D and 95F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to compound B10 ( Figure 95 B) MeWo cells ( Figure 95 D) and WM115 cells ( Figure 95 F) percentage.

[0333] Figure 96 A, 96C and 96E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to Compound II (CV-8688) ( Figure 96 A), MeWo cells ( Figure 96 C) and WM115 cells ( Figure 96 E) percentage. Figure 96B, 96D and 96F show data tables containing propidium iodide (PI) positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to Compound II (CV-8688) ( Figure 96 B) MeWo cells ( Figure 96 D) and WM115 cells ( Figure 96 F) percentage.

[0334] Figure 97 Figures 97A, 97C, and 97E show data tables containing Annexin V-positive B16F1 cells at 6, 24, 48, and 72 hours after exposure to malassezia pro- Figure 97 A), MeWo cells ( Figure 97 C) and WM115 cells ( Figure 97 E) percentage. Figure 97 B, 97D and 97F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to malassezia pro- Figure 97 B) MeWo cells ( Figure 97 D) and WM115 cells ( Figure 97 F) percentage.

[0335] Figure 98 Figures 98A, 98C, and 98E show data tables containing Annexin V-positive B16F1 cells at 6, 24, 48, and 72 hours after exposure to indolo[3,2-b]carbazole (CV-8685). Figure 98 A), MeWo cells ( Figure 98 C) and WM115 cells ( Figure 98 E) percentage. Figure 98 B, 98D and 98F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to indolo[3,2-b]carbazole (CV-8685) ( Figure 98 B) MeWo cells ( Figure 98 D) and WM115 cells ( Figure 98 F) percentage.

[0336] Figure 99 Figures A, 99C, and 99E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48, and 72 hours after exposure to AB17151. Figure 99 A), MeWo cells ( Figure 99 C) and WM115 cells ( Figure 99 E) percentage. Figure 99 B, 99D and 99F show data tables containing propidium iodide (PI) positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to AB17151 ( Figure 99 B) MeWo cells ( Figure 99 D) and WM115 cells ( Figure 99 F) percentage.

[0337] Figure 100 A, 100C and 100E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to Compound IV (CV-8687) ( Figure 100 A), MeWo cells ( Figure 100 C) and WM115 cells ( Figure 100 E) percentage. Figure 100 B, 100D and 100F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to compound IV (CV-8687) ( Figure 100 B) MeWo cells ( Figure 100 D) and WM115 cells ( Figure 100 F) percentage.

[0338] Figure 101 A, 101C and 101E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to AB17011 ( Figure 101 A), MeWo cells ( Figure 101 C) and WM115 cells ( Figure 101 E) percentage. Figure 101 B, 101D and 101F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to AB17011 ( Figure 101 B) MeWo cells ( Figure 101 D) and WM115 cells ( Figure 101 F) percentage.

[0339] Figure 102 A, 102C and 102E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to AB11644 ( Figure 102 A), MeWo cells ( Figure 102 C) and WM115 cells ( Figure 102 E) percentage. Figure 102 B, 102D and 102F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to AB11644 ( Figure 102 B) MeWo cells ( Figure 102 D) and WM115 cells ( Figure 102 F) percentage.

[0340] Figure 103 A, 103C and 103E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to AB17014 ( Figure 103 A), MeWo cells ( Figure 103 C) and WM115 cells ( Figure 103 E) percentage. Figure 103 B, 103D and 103F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to AB17014 ( Figure 103 B) MeWo cells ( Figure 103 D) and WM115 cells ( Figure 103 F) percentage.

[0341] Figure 104 A, 104C and 104E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to an unknown composition ( Figure 104 A), MeWo cells ( Figure 104 C) and WM115 cells ( Figure 104 E) percentage. Figure 104 B, 104D and 104F show data tables containing propidium iodide (PI) positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to an unknown composition ( Figure 104 B) MeWo cells ( Figure 104 D) and WM115 cells ( Figure 104 F) percentage.

[0342] Figure 105 A, 105C and 105E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to AB17225 ( Figure 105 A), MeWo cells ( Figure 105 C) and WM115 cells ( Figure 105 E) percentage. Figure 105B, 105D and 105F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to AB17225 ( Figure 105 B) MeWo cells ( Figure 105 D) and WM115 cells ( Figure 105 F) percentage.

[0343] Figure 106 A, 106C and 106E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to Compound A5 (CV-8819) ( Figure 106 A), MeWo cells ( Figure 106 C) and WM115 cells ( Figure 106 E) percentage. Figure 106 B, 106D and 106F show data tables containing propidium iodide (PI) positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to compound A5 (CV-8819) ( Figure 106 B) MeWo cells ( Figure 106 D) and WM115 cells ( Figure 106 F) percentage.

[0344] Figure 107 A, 107C, and 107E show data tables containing Annexin V-positive B16F1 cells at 6, 24, 48, and 72 hours after exposure to AB12976 ( Figure 107 A), MeWo cells ( Figure 107 C) and WM115 cells ( Figure 107 E) percentage. Figure 107 B, 107D and 107F show data tables containing propidium iodide (PI)-positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to AB12976 ( Figure 107 B) MeWo cells ( Figure 107 D) and WM115 cells ( Figure 107 F) percentage.

[0345] Figure 108 A, 108C and 108E show data tables containing Annexin V positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to Compound E (AB12508) ( Figure 108 A), MeWo cells ( Figure 108 C) and WM115 cells ( Figure 108 E) percentage. Figure 108B, 108D and 108F show data tables containing propidium iodide (PI) positive B16F1 cells at 6, 24, 48 and 72 hours after exposure to Compound E (AB12508) ( Figure 108 B) MeWo cells ( Figure 108 D) and WM115 cells ( Figure 108 F) percentage.

[0346] Figure 109 A, 109B, and 109C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to staurosporine for B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0347] Figure 110 A, 110B, and 110C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to malassezia (CV-8684) in B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0348] Figure 111 A, 111B, and 111C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to Compound I (CV-8686) in B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0349] Figure 112 A, 112B, and 112C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to Compound II (CV-8688) in B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0350] Figure 113 A, 113B, and 113C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to indolo[3,2-b]carbazole (CV-8685) in B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0351] Figure 114A, 114B, and 114C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to Compound IV (CV-8687) in B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0352] Figure 115 A, 115B, and 115C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to AB11644 for B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0353] Figure 116 A, 116B, and 116C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control for B16F1 cells, MeWo cells, and WM115 cells at 6, 24, 48, and 72 hours, respectively, following exposure to an unknown composition.

[0354] Figure 117 A, 117B, and 117C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to Compound A5 (CV-8819) in B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0355] Figure 118 Figures A, 118B, and 118C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to Compound E (AB12508) in B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0356] Figure 119 Figures A, 119B, and 119C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to Compound H (AB12509) in B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0357] Figure 120 A, 120B, and 120C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to Compound B (CV-8877) in B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0358] Figure 121 Figures 12A, 121B, and 121C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to compound B10 for B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0359] Figure 122 A, 122B, and 122C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to malassezia progenitor in B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0360] Figure 123 A, 123B, and 123C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to AB17151 for B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0361] Figure 124 Figures 124A, 124B, and 124C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to AB17011 for B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0362] Figure 125 Figures 125A, 125B, and 125C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to AB17014 for B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0363] Figure 126 Figures 126A, 126B, and 126C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to AB17225 for B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0364] Figure 127 A, 127B, and 127C show data tables containing the percentage of caspase 3 / 7 induction compared to vehicle control at 6, 24, 48, and 72 hours after exposure to AB12976 for B16F1 cells, MeWo cells, and WM115 cells, respectively.

[0365] Figures 128-129is a table showing the results of MelanoDerm treated with different concentrations of the indicated test substances. TM Mean tissue viability and melanin concentration data determined from independent experiments for the substrate.

[0366] Figure 130 Compounds produced by Malassezia sp. are shown.

[0367] Figures 131-132 is a table showing the results of MelanoDerm treated with different concentrations of the test substances / test compositions shown. TM Mean tissue viability and melanin concentration data determined from independent experiments for the substrate.

[0368] Figure 133 A-133B shows AB17590( Figure 133 A) and AB17653, AB17654, AB17655, AB17656, AB17657, and AB17658 ( Figure 133 B) Synthesis process.

[0369] Figure 134 Schematic diagram showing a skin treatment template for patients with skin type IV. The values ​​represent the UV dose (mJ / cm 2 ).

[0370] Figure 135 is a table showing the Dualight scale for skin types I-VI.

[0371] Figure 136 is a table showing the Mexameter MX 16 measurements of melanin and erythema on day 8 following day 7 irradiation.

[0372] Figure 137 is a table showing the Mexameter MX 16 measurements of melanin and erythema taken on day 15 following day 14 irradiation.

[0373] Figure 138 is a table showing a numerical erythema scale associated with varying degrees of erythema.

[0374] Figure 139 is a photograph showing a subject's skin 24 hours after irradiation with different levels of UV according to the skin treatment template shown in Figure 7. 24 hours after irradiation, the minimum erythema dose ("MED") was 120 mJ UVB.

[0375] Figure 140is a photograph showing the subject's skin test site on Day 7.

[0376] Figure 141 is a photograph showing a subject's skin test site on day 8 (24 hours after 120 mJ UVB irradiation).

[0377] Figure 142 is a photograph showing a test site on a subject's skin after an additional week of malassezia therapy on day 14. The treated area was given 120 mJ UVB.

[0378] Figure 143 The figure is a photograph showing the subject's skin test site on day 15 (24 hours after 120 mJ UVB exposure). Erythema was recorded for the vehicle site on days 7 and 9. Minimal to mild erythema was also recorded for the 1% malassezia-treated site on days 14, 10, and 8, with minimal erythema occurring on days 1 and 3. DETAILED DESCRIPTION

[0379] One embodiment of the present invention is a compound for skin lightening, wherein the compound is a chemical analog of a compound produced by Malassezia yeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0380] In one aspect of this embodiment, the compound produced by the Malassezia yeast has the structure of Formula (I):

[0381]

[0382] In another aspect of this embodiment, the compound is a chemical analog of malassezia.

[0383] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes, wherein the compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0384] In one aspect of this embodiment, the compound produced by the Malassezia yeast has the structure of Formula (I):

[0385]

[0386] In another aspect of this embodiment, the compound is a chemical analog of malassezia.

[0387] Another embodiment of the present invention is a compound for modulating melanocyte activity, wherein the compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0388] In one aspect of this embodiment, the compound produced by the Malassezia yeast has the structure of Formula (I):

[0389]

[0390] In another aspect of this embodiment, the compound is a chemical analog of malassezia.

[0391] Another embodiment of the present invention is a compound for agonizing the aryl hydrocarbon receptor (AhR), which is a chemical analog of a compound produced by Malassezia yeast, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0392] In one aspect of this embodiment, the compound produced by the Malassezia yeast has the structure of Formula (I):

[0393]

[0394] In another aspect of this embodiment, the compound is a chemical analog of malassezia.

[0395] Another embodiment of the present invention is a compound for improving hyperpigmentation caused by a hyperpigmentation disorder. The compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0396] In one aspect of this embodiment, the compound produced by the Malassezia yeast has the structure of Formula (I):

[0397]

[0398] In another aspect of this embodiment, the compound is a chemical analog of malassezia.

[0399] Another embodiment of the present invention is a compound for regulating melanin production, wherein the compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0400] In one aspect of this embodiment, the compound produced by the Malassezia yeast has the structure of Formula (I):

[0401]

[0402] In another aspect of this embodiment, the compound is a chemical analog of malassezia.

[0403] Another embodiment of the present invention is a compound for regulating melanosome biosynthesis, wherein the compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0404] In one aspect of this embodiment, the compound produced by the Malassezia yeast has the structure of Formula (I):

[0405]

[0406] In another aspect of this embodiment, the compound is a chemical analog of malassezia.

[0407] Another embodiment of the present invention is a compound for regulating melanosome transfer, wherein the compound is a chemical analog of a compound produced by a yeast of the genus Malassezia, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof.

[0408] In one aspect of this embodiment, the compound produced by the Malassezia yeast has the structure of Formula (I):

[0409]

[0410] In another aspect of this embodiment, the compound is a chemical analog of malassezia.

[0411] Another embodiment of the present invention is a composition comprising Malassezia yeast and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

[0412] Another embodiment of the present invention is a composition comprising a compound isolated or isolatable from a yeast of the genus Malassezia and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

[0413] Another embodiment of the present invention is a composition comprising any of the compounds disclosed herein (including analogs), and a cosmetically or pharmaceutically acceptable vehicle, diluent, or carrier.

[0414] Another embodiment of the present invention is a method of lightening the skin of a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0415] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0416] Another embodiment of the present invention is a method of modulating melanocyte activity in a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0417] Another embodiment of the present invention is a method of agonizing the aryl hydrocarbon receptor (AhR), comprising contacting a subject with any of the compounds or compositions disclosed herein.

[0418] Another embodiment of the present invention is a method of improving hyperpigmentation caused by a hyperpigmentation disorder in a subject in need thereof. The method comprises contacting the subject with any one of the compounds or compositions disclosed herein.

[0419] Another embodiment of the present invention is a method of regulating melanin production in a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0420] Another embodiment of the present invention is a method of modulating melanosome biogenesis in a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0421] Another embodiment of the present invention is a method of modulating melanosome transfer in a subject, comprising contacting the subject with any one of the compounds or compositions disclosed herein.

[0422] Another embodiment of the present invention is a compound having the structure of formula (II):

[0423]

[0424] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl, and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 is methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0425] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0426]

[0427] Another embodiment of the present invention is a compound having the structure of formula (III):

[0428]

[0429] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl, and at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 is methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0430] In one aspect of this embodiment, the compound is:

[0431]

[0432] Another embodiment of the present invention is a compound for lightening the skin. The compound has the structure of formula (II):

[0433]

[0434] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0435] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0436]

[0437] Another embodiment of the present invention is a compound for lightening the skin. The compound has the structure of formula (III):

[0438]

[0439] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0440] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0441]

[0442] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound has a structure of formula (II):

[0443]

[0444] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0445] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0446]

[0447] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound has a structure of formula (III):

[0448]

[0449] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0450] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0451]

[0452] Another embodiment of the present invention is a compound for agonizing aryl hydrocarbon receptor (AhR). The compound has the structure of formula (II):

[0453]

[0454] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0455] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0456]

[0457] Another embodiment of the present invention is a compound for agonizing aryl hydrocarbon receptor (AhR). The compound has the structure of formula (III):

[0458]

[0459] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0460] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0461]

[0462] Another embodiment of the present invention is a composition. The composition comprises a compound having a structure of formula (II)

[0463]

[0464] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof; and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

[0465] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0466]

[0467] Another embodiment of the present invention is a composition comprising a compound having the structure of formula (III):

[0468]

[0469] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl; or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof; and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

[0470] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0471]

[0472] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises: contacting the subject with a compound having the structure of formula (II) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0473]

[0474] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl.

[0475] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0476]

[0477] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises: contacting the subject with a compound having the structure of formula (III) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0478]

[0479] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl.

[0480] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0481]

[0482] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises: contacting the subject with a compound having the structure of formula (II) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0483]

[0484] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl.

[0485] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0486]

[0487]

[0488] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises: contacting the subject with a compound having the structure of formula (III) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0489]

[0490] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl.

[0491] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0492]

[0493] Another embodiment of the present invention is a method for agonizing the aryl hydrocarbon receptor (AhR) in a subject. The method comprises contacting the subject with a compound having the structure of formula (II) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0494]

[0495] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and methyl.

[0496] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0497]

[0498] Another embodiment of the present invention is a method for agonizing the aryl hydrocarbon receptor (AhR) in a subject. The method comprises contacting the subject with a compound having the structure of formula (III) or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0499]

[0500] wherein: R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are independently selected from the group consisting of hydrogen and methyl.

[0501] In one aspect of this embodiment, the compound is selected from the group consisting of:

[0502]

[0503] One embodiment of the present invention is a compound having the following structure:

[0504]

[0505] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 A group consisting of: a is hydrogen, then Y is CR5R6, and R 13 With R 14 are all hydrogen, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 At least one of them is R 16 ; or R5 is selected from hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0506] In one aspect of this embodiment, the compound has the structure:

[0507]

[0508] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0509] In another aspect of this embodiment, X is NH.

[0510] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0511] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0512] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[0513] R2 is preferably C 1-4 alkyl.

[0514] R2 is more preferably methyl.

[0515] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0516] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0517] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0518] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0519] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0520] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0521]

[0522]

[0523] Another embodiment of the present invention is a compound having the following structure:

[0524]

[0525] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 At least one of the following is not hydrogen; or a crystalline form, a hydrate, or a cosmetically or pharmaceutically acceptable salt thereof.

[0526] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0527]

[0528] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0529] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0530] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0531] In another aspect of this embodiment, R5 and R 10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0532] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0533] Preferably, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0534] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0535]

[0536] Another embodiment of the present invention is a compound for lightening the skin. The compound has the following structure:

[0537]

[0538] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0539] In one aspect of this embodiment, the compound has the structure:

[0540]

[0541] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0542] In another aspect of this embodiment, X is NH.

[0543] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0544] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0545] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[0546] R2 is preferably C 1-4 alkyl.

[0547] R2 is more preferably methyl.

[0548] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0549] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C1-4 alkyl.

[0550] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0551] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0552] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0553] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0554]

[0555]

[0556] In another aspect of this embodiment, if R a is hydrogen, then Y is CR5R6, and R 13 and R 14 are all hydrogen, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 At least one of them is R 16 ; Or, R5 is selected from hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl.

[0557] Another embodiment of the present invention is a compound for lightening the skin. The compound has the following formula:

[0558]

[0559] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0560] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0561]

[0562] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0563] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0564] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0565] In another aspect of this embodiment, R5 and R 10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0566] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4alkyl, while the remaining groups are hydrogen.

[0567] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0568] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0569]

[0570]

[0571] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 At least one of them is not hydrogen.

[0572] Another embodiment of the present invention is a compound for lightening skin. The compound is selected from the group consisting of:

[0573]

[0574] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound has the following structure:

[0575]

[0576] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0577] In one aspect of this embodiment, the compound has the structure:

[0578]

[0579] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0580] In another aspect of this embodiment, X is NH.

[0581] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0582] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0583] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[0584] R2 is preferably C 1-4 alkyl.

[0585] R2 is more preferably methyl.

[0586] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0587] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0588] R12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0589] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0590] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0591] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0592]

[0593]

[0594] In another aspect of this embodiment, if R a is hydrogen, then Y is CR5R6, and R 13 and R 14 are all hydrogen, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 At least one of them is R 16 ; Or, R5 is selected from hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl.

[0595] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes, namely a compound having the following formula:

[0596]

[0597] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0598] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0599]

[0600] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0601] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0602] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0603] In another aspect of this embodiment, R5 and R 10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0604] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0605] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0606] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0607]

[0608]

[0609] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 At least one of them is not hydrogen.

[0610] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound is selected from the group consisting of:

[0611]

[0612]

[0613] Another embodiment of the present invention is a compound for modulating the activity of the aryl hydrocarbon receptor (AhR). The compound has the following structure:

[0614]

[0615] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0616] In one aspect of this embodiment, the compound has the structure:

[0617]

[0618] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0619] In another aspect of this embodiment, X is NH.

[0620] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0621] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0622] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[0623] R2 is preferably C 1-4 alkyl.

[0624] R2 is more preferably methyl.

[0625] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0626] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C1-4 alkyl.

[0627] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0628] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0629] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0630] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0631]

[0632]

[0633] In another aspect of this embodiment, if R a is hydrogen, then Y is CR5R6, and R 13 and R 14 are all hydrogen, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 At least one of them is R 16 ; Or, R5 is selected from hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl.

[0634] Another embodiment of the present invention is a compound for modulating the activity of the aryl hydrocarbon receptor (AhR). The compound has the following formula:

[0635]

[0636] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0637] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0638]

[0639] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0640] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0641] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0642] In another aspect of this embodiment, R5 and R 10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0643] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0644] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0645] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0646]

[0647] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 At least one of them is not hydrogen.

[0648] Another embodiment of the present invention is a compound for modulating the activity of the aryl hydrocarbon receptor (AhR). The compound is selected from the group consisting of:

[0649]

[0650] Another embodiment of the present invention is a compound for regulating melanin production. The compound has the following structure:

[0651]

[0652] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -CORa and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0653] In one aspect of this embodiment, the compound has the structure:

[0654]

[0655] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0656] In another aspect of this embodiment, X is NH.

[0657] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0658] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0659] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[0660] R2 is preferably C 1-4 alkyl.

[0661] R2 is more preferably methyl.

[0662] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0663] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0664] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0665] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0666] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0667] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0668]

[0669] In another aspect of this embodiment, if R a is hydrogen, then Y is CR5R6, and R 13 and R 14 are all hydrogen, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 At least one of them is R 16 ; Or, R5 is selected from hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl.

[0670] Another embodiment of the present invention is a compound for regulating melanin production. The compound has the following formula:

[0671]

[0672] Among them: R1, R4, R5, R6, R9 and R 10are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0673] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0674]

[0675] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0676] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0677] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0678] In another aspect of this embodiment, R5 and R 10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0679] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0680] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0681] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0682]

[0683] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 At least one of them is not hydrogen.

[0684] Another embodiment of the present invention is a compound for regulating melanin production. The compound is selected from the group consisting of:

[0685]

[0686] Another embodiment of the present invention is a compound for regulating melanin concentration. The compound has the following structure:

[0687]

[0688] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0689] In one aspect of this embodiment, the compound has the structure:

[0690]

[0691] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0692] In another aspect of this embodiment, X is NH.

[0693] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0694] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0695] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[0696] R2 is preferably C 1-4 alkyl.

[0697] R2 is more preferably methyl.

[0698] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0699] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0700] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0701] R12 More preferably, it is CHO, CH2OH or CO2CH3.

[0702] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0703] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0704]

[0705] In another aspect of this embodiment, if R a is hydrogen, then Y is CR5R6, and R 13 and R 14 are all hydrogen, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 At least one of them is R 16 ; Or, R5 is selected from hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl.

[0706] Another embodiment of the present invention is a compound for regulating melanin concentration. The compound has the following formula:

[0707]

[0708] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0709] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0710]

[0711] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0712] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0713] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0714] In another aspect of this embodiment, R5 and R 10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0715] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0716] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0717] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0718]

[0719] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 At least one of them is not hydrogen.

[0720] Another embodiment of the present invention is a compound for regulating melanin concentration. The compound is selected from the group consisting of:

[0721]

[0722] Another embodiment of the present invention is a composition comprising a compound having the following structure:

[0723]

[0724] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 or a crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt thereof.

[0725] In one aspect of this embodiment, the compound has the structure:

[0726]

[0727] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0728] In another aspect of this embodiment, X is NH.

[0729] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0730] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0731] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[0732] R2 is preferably C 1-4 alkyl.

[0733] R2 is more preferably methyl.

[0734] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0735] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0736] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0737] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0738] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0739] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0740]

[0741]

[0742] Another embodiment of the present invention is a composition comprising a compound having the formula:

[0743]

[0744] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 or its crystalline form, hydrate or cosmetically or pharmaceutically acceptable salt.

[0745] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0746]

[0747] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0748] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0749] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0750] In another aspect of this embodiment, R5 and R 10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0751] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0752] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0753] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0754]

[0755] Another embodiment of the present invention is a composition comprising a compound selected from the group consisting of:

[0756]

[0757] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0758]

[0759] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 A group consisting of; and each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[0760] In one aspect of this embodiment, the compound has the structure:

[0761]

[0762] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0763] In another aspect of this embodiment, X is NH.

[0764] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0765] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0766] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R11 At least one of them is C 1-4 alkyl.

[0767] R2 is preferably C 1-4 alkyl.

[0768] R2 is more preferably methyl.

[0769] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0770] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0771] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0772] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0773] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0774] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0775]

[0776]

[0777] Another embodiment of the present invention is a method of lightening the skin of a subject. The method comprises contacting the subject with a compound having the formula:

[0778]

[0779] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl.

[0780] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0781]

[0782] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0783] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0784] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0785] In another aspect of this embodiment, R5 and R 10One of them is C 1-4 alkyl, and the other is hydrogen.

[0786] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0787] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0788] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0789]

[0790] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises contacting the subject with a compound selected from the group consisting of:

[0791]

[0792] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0793]

[0794] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[0795] In one aspect of this embodiment, the compound has the structure:

[0796]

[0797] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0798] In another aspect of this embodiment, X is NH.

[0799] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0800] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0801] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[0802] R2 is preferably C 1-4 alkyl.

[0803] R2 is more preferably methyl.

[0804] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0805] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0806] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0807] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0808] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0809] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0810]

[0811]

[0812] Another embodiment of the present invention is a method of inducing apoptosis in melanocytes of a subject. The method comprises contacting the subject with a compound having the formula:

[0813]

[0814] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl.

[0815] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0816]

[0817] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0818] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0819] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0820] In another aspect of this embodiment, R5 and R 10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0821] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0822] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0823] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0824]

[0825]

[0826] Another embodiment of the present invention is a method of inducing apoptosis in melanocytes of a subject. The method comprises contacting the subject with a compound selected from the group consisting of:

[0827]

[0828] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0829]

[0830] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[0831] In one aspect of this embodiment, the compound has the structure:

[0832]

[0833] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0834] In another aspect of this embodiment, X is NH.

[0835] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0836] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0837] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[0838] R2 is preferably C 1-4 alkyl.

[0839] R2 is more preferably methyl.

[0840] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0841] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0842] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0843] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0844] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0845] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0846]

[0847]

[0848] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound having the formula:

[0849]

[0850] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl.

[0851] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0852]

[0853] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0854] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0855] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0856] In another aspect of this embodiment, R5 and R 10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0857] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0858] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0859] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0860]

[0861]

[0862] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:

[0863]

[0864] Another embodiment of the present invention is a method for regulating melanin production in a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0865]

[0866] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[0867] In one aspect of this embodiment, the compound has the structure:

[0868]

[0869] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0870] In another aspect of this embodiment, X is NH.

[0871] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0872] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0873] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R10 and R 11 At least one of them is C 1-4 alkyl.

[0874] R2 is preferably C 1-4 alkyl.

[0875] R2 is more preferably methyl.

[0876] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0877] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0878] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0879] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0880] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0881] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0882]

[0883]

[0884] Another embodiment of the present invention is a method of regulating melanin production in a subject. The method comprises contacting the subject with a compound having the formula:

[0885]

[0886] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl.

[0887] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0888]

[0889] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0890] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0891] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0892] In another aspect of this embodiment, R5 and R10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0893] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0894] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0895] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0896]

[0897]

[0898] Another embodiment of the present invention is a method of regulating melanin production in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:

[0899]

[0900] Another embodiment of the present invention is a method for regulating melanin concentration in a subject. The method comprises contacting the subject with a compound having the following structure, or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof:

[0901]

[0902] Where: X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[0903] In one aspect of this embodiment, the compound has the structure:

[0904]

[0905] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0906] In another aspect of this embodiment, X is NH.

[0907] In another aspect of this embodiment, Y is CR5R6; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[0908] CR5R6 is preferably CH2, CHCH3, CHOCH3, C=O or CH(C3H5).

[0909] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[0910] R2 is preferably C 1-4 alkyl.

[0911] R2 is more preferably methyl.

[0912] In another aspect of this embodiment, R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[0913] In another aspect of this embodiment, R 12 Yes-COR a or C 1-4 hydroxyalkyl; and Ra is hydrogen or C 1-4 alkyl.

[0914] R 12 Preferably, CHO, CH2OH or C(=O)-O-(C 1-4 alkyl).

[0915] R 12 More preferably, it is CHO, CH2OH or CO2CH3.

[0916] In another aspect of this embodiment, X is NH; Y is CR5R6; R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of R2 is hydrogen or C 1-4 Alkyl; R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 alkyl); or R5 and R6 are combined to form an oxo (=O) group; R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[0917] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0918]

[0919]

[0920] Another embodiment of the present invention is a method for regulating melanin concentration in a subject. The method comprises contacting the subject with a compound having the formula:

[0921]

[0922] Among them: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl.

[0923] In one aspect of this embodiment, the compound has a structure according to Formula (II),

[0924]

[0925] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[0926] In another aspect of this embodiment, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[0927] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One or both of them are C 1-4 alkyl, while the remaining groups are hydrogen.

[0928] In another aspect of this embodiment, R5 and R 10 One of them is C 1-4 alkyl, and the other is hydrogen.

[0929] In another aspect of this embodiment, one of R1, R2, R3, R4, R6, R7, R8 and R9 is C 1-4 alkyl, while the remaining groups are hydrogen.

[0930] In another aspect of this embodiment, R 11 and R 12 are each hydrogen; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[0931] In another aspect of this embodiment, the compound is selected from the group consisting of:

[0932]

[0933]

[0934] Another embodiment of the present invention is a method for regulating melanin concentration in a subject. The method comprises contacting the subject with a compound selected from the group consisting of:

[0935]

[0936] One embodiment of the present invention is a compound for lightening skin. The compound has the following structure:

[0937]

[0938] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0939] Another embodiment of the present invention is a compound for inducing apoptosis in melanocytes. The compound has the following structure:

[0940]

[0941] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0942] Another embodiment of the present invention is a compound for modulating the activity of the aryl hydrocarbon receptor (AhR). The compound has the following structure:

[0943]

[0944] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0945] Another embodiment of the present invention is a compound for regulating melanin production. The compound has the following structure:

[0946]

[0947] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0948] Another embodiment of the present invention is a compound for regulating melanin concentration. The compound has the following structure:

[0949]

[0950] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0951] Another embodiment of the present invention is a composition comprising a compound having the following structure:

[0952]

[0953] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0954] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises contacting the subject with a compound having the following structure, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0955]

[0956] Another embodiment of the present invention is a method of inducing apoptosis in melanocytes of a subject. The method comprises contacting the subject with a compound having the following structure, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0957]

[0958] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a compound having the following structure, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0959]

[0960] Another embodiment of the present invention is a method of regulating melanin production in a subject. The method comprises contacting the subject with a compound having the following structure, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0961]

[0962] Another embodiment of the present invention is a method for regulating melanin concentration in a subject. The method comprises contacting the subject with a compound having the following structure, or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0963]

[0964] Another embodiment of the present invention is a composition. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0965] In one aspect of this embodiment, the composition comprises a first compound having the formula:

[0966]

[0967] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof; and a second compound having the following structure:

[0968]

[0969] or a chemical analogue, crystalline form, hydrate or pharmaceutically or cosmetically acceptable salt thereof.

[0970] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises giving the subject a sample of Table 5 or Figure 130 contact with one or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0971] In one aspect of this embodiment, the subject is contacted with a first compound having the formula: or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0972]

[0973] and contacting with a second compound having the following structure, or a chemical analogue, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0974]

[0975] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises: Figure 130 contact with one or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0976] In one aspect of this embodiment, the subject is contacted with a first compound having the formula: or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0977]

[0978] and contacting with a second compound having the following structure, or a chemical analogue, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0979]

[0980] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises administering to the subject a combination of Table 5 or Figure 130 contact with one or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0981] In one aspect of this embodiment, the subject is contacted with a first compound having the formula: or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0982]

[0983] and contacting with a second compound having the following structure, or a chemical analogue, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0984]

[0985] Another embodiment of the present invention is a method for regulating melanin production in a subject. The method comprises subjecting the subject to Table 5 or Figure 130 contact with one or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0986] In one aspect of this embodiment, the subject is contacted with a first compound having the formula: or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0987]

[0988] and contacting with a second compound having the following structure, or a chemical analogue, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0989]

[0990] Another embodiment of the present invention is a method for regulating the melanin concentration of a subject. The method comprises subjecting the subject to the following conditions: Figure 130 contact with one or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0991] In one aspect of this embodiment, the subject is contacted with a first compound having the formula: or a chemical analog, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0992]

[0993] and contacting with a second compound having the following structure, or a chemical analogue, crystalline form, hydrate, or pharmaceutically or cosmetically acceptable salt thereof:

[0994]

[0995] Another embodiment of the present invention is a composition. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0996] Another embodiment of the present invention is a composition for lightening the skin. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0997] Another embodiment of the present invention is a composition for inducing apoptosis in melanocytes. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0998] Another embodiment of the present invention is a composition for modulating the activity of aryl hydrocarbon receptor (AhR). The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[0999] Another embodiment of the present invention is a composition for regulating melanin production. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[1000] Another embodiment of the present invention is a composition for regulating melanin concentration. The composition comprises Table 5 or Figure 130 One or more compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[1001] Another embodiment of the present invention is a method for lightening the skin of a subject. The method comprises contacting the subject with a composition comprising Table 5 or Figure 130 One or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[1002] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject. The method comprises contacting the subject with a composition comprising Table 5 or Figure 130 One or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[1003] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject. The method comprises contacting the subject with a composition comprising Table 5 or Figure 130 One or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[1004] Another embodiment of the present invention is a method for regulating melanin production in a subject. The method comprises contacting the subject with a composition comprising Table 5 or Figure 130 One or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[1005] Another embodiment of the present invention is a method for regulating the melanin concentration of a subject. The method comprises contacting the subject with a composition comprising Table 5 or Figure 130 One or more compounds listed in or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[1006] In a preferred embodiment, the composition of the present invention comprises the compounds listed in Table 7.

[1007] In other preferred embodiments, the compositions of the present invention comprise the compounds listed in Table 8.

[1008] In other preferred embodiments, the compositions of the present invention comprise the compounds listed in Table 9.

[1009] In other preferred embodiments, the compositions of the present invention comprise the compounds listed in Table 10.

[1010] In other preferred embodiments, the compositions of the present invention comprise the compounds listed in Table 11.

[1011] In other preferred embodiments, the methods of the present invention comprise contacting a subject with a composition comprising a compound listed in Table 7.

[1012] In other preferred embodiments, the methods of the present invention comprise contacting a subject with a composition comprising a compound listed in Table 8.

[1013] In other preferred embodiments, the methods of the present invention comprise contacting a subject with a composition comprising a compound listed in Table 9.

[1014] In other preferred embodiments, the methods of the present invention comprise contacting a subject with a composition comprising a compound listed in Table 10.

[1015] In other preferred embodiments, the methods of the present invention comprise contacting a subject with a composition comprising a compound listed in Table 11.

[1016] Another embodiment of the present invention is a composition comprising Malassezia yeast and a cosmetically or pharmaceutically acceptable vehicle, diluent or carrier.

[1017] Another embodiment of the present invention is a composition comprising a compound having the following structure:

[1018]

[1019] in:

[1020] X is selected from NR 14 and O; Y is a covalent bond, CR5R6, O or NR 15 ;R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 independently selected from hydrogen, halogen, CN, hydroxyl, R 16 OR 16 Group composed of R 13 、R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 A group consisting of cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups composed of each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 the groups formed;

[1021] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt,

[1022] and cosmetically or pharmaceutically acceptable vehicles, diluents or carriers.

[1023] Another embodiment of the present invention is a composition comprising a compound having the following structure:

[1024]

[1025] in:

[1026] R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5-membered or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5-membered or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ; and each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl or C 2-9 Alkynyl;

[1027] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt,

[1028] and cosmetically or pharmaceutically acceptable vehicles, diluents or carriers.

[1029] Another embodiment of the present invention is a composition. The composition comprises Table 5 or Figure 130 The compounds listed in, or their chemical analogs, crystalline forms, hydrates or cosmetically or pharmaceutically acceptable salts,

[1030] and cosmetically or pharmaceutically acceptable vehicles, diluents or carriers.

[1031] In a preferred embodiment, any of the compositions of the present invention prevents UV-induced erythema in a subject.

[1032] In a preferred embodiment, any of the compositions of the present invention reduces epidermal melanin in a subject.

[1033] In preferred embodiments, any of the compositions of the present invention provides photoprotection or UV protection to a subject.

[1034] In preferred embodiments, any of the compositions of the present invention filters, absorbs or reflects UV.

[1035] In preferred embodiments, any of the compositions of the present invention prevents hyperpigmentation and / or promotes hypopigmentation.

[1036] In a preferred embodiment, any of the compositions of the present invention is a sunscreen, photoprotectant and / or UV protectant.

[1037] Another embodiment of the present invention is a method for treating or preventing UV-induced skin damage in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[1038] Another embodiment of the present invention is a method of treating or preventing UV-induced erythema in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[1039] Another embodiment of the present invention is a method for treating or preventing UV-induced skin aging in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[1040] Another embodiment of the present invention is a method of treating or preventing sunburn in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[1041] Another embodiment of the present invention is a method of treating or preventing UV-induced hyperpigmentation in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[1042] Another embodiment of the present invention is a method of lightening the skin of a subject, comprising contacting the subject with any of the compositions disclosed herein.

[1043] Another embodiment of the present invention is a method for inducing apoptosis in melanocytes of a subject, comprising contacting the subject with any one of the compositions disclosed herein.

[1044] Another embodiment of the present invention is a method of modulating aryl hydrocarbon receptor (AhR) activity in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[1045] Another embodiment of the present invention is a method of regulating melanin production in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[1046] Another embodiment of the present invention is a method for regulating melanin concentration in a subject, comprising contacting the subject with any of the compositions disclosed herein.

[1047] definition

[1048] As used herein, the term "compound" refers to two or more atoms connected by one or more chemical bonds. In the present invention, chemical bonds include, but are not limited to, covalent bonds, ionic bonds, hydrogen bonds, and van der Waals interactions. Covalent bonds in the present invention include single bonds, double bonds, and triple bonds. Compounds of the present invention include, but are not limited to, organic molecules.

[1049] The organic compounds / molecules of the present invention include straight chain, branched chain and cyclic hydrocarbons with or without functional groups. x-y ", when used in conjunction with a chemical moiety such as an alkyl, alkenyl, alkynyl, or alkoxy group, is intended to include groups containing from x to y carbons in the chain. For example, the term "C x-y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups containing x to y carbon atoms in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. The term "C x-y Alkenyl" and "C x-y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group similar in length and possible substitution to the alkyl groups described above, but containing at least one double bond and triple bond, respectively.

[1050] As used herein, the term "aliphatic" refers to a group consisting of carbon and hydrogen atoms and not containing aromatic rings. Thus, aliphatic groups include alkyl, alkenyl, alkynyl, and carbocyclyl groups.

[1051] As used herein, the term "alkyl" refers to non-cyclic straight-chain and branched hydrocarbon groups, such as "C1-C 20"Alkyl" refers to an alkyl group having 1 to 20 carbon atoms. The alkyl group can be straight or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and the like. Other alkyl groups will be apparent to those skilled in the art in view of this disclosure. The alkyl group can be unsubstituted or substituted with one or more substituents as described herein. For example, the alkyl group can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected) of the following substituents: ) is substituted with: halogen, -CO2R', -COOH, -CN, -OH, -OR', -NH2, -NHR', -N(R')2, -SR', or -S02R', wherein each instance of R' is independently C1-C3 alkyl. In an embodiment, the alkyl group is unsubstituted. In an embodiment, the alkyl group is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein). For example, the term "hydroxyalkyl" refers to an alkyl group as described herein that includes a hydroxy (-OH) substituent, including groups such as -CH2OH.

[1052] As used herein, "alkenyl" refers to any straight or branched hydrocarbon chain having one or more unsaturated carbon-carbon double bonds, which may exist at any stable point along the chain, such as "C2-C 20 "Alkenyl" refers to an alkenyl group having 2-20 carbon atoms. For example, alkenyl includes prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl, hex-5-enyl, 2,3-dimethylbut-2-enyl, and the like. In an embodiment, the alkenyl group contains 1, 2, or 3 carbon-carbon double bonds. In an embodiment, the alkenyl group contains a single carbon-carbon double bond. In an embodiment, multiple double bonds (e.g., 2 or 3) are conjugated. The alkenyl group can be unsubstituted or substituted with one or more substituents as described herein. For example, For example, alkenyl groups can be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -C0R', -CN, -OH, -OR', -NH2, -NHR', -N(R')2, -SR', or -S0R', wherein each instance of R' is independently C1-C3 alkyl. In an embodiment, alkenyl groups are unsubstituted. In an embodiment, alkenyl groups are substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein).

[1053] As used herein, "alkynyl" refers to any hydrocarbon chain having a straight or branched configuration with one or more carbon-carbon triple bonds at any stable point along the chain, e.g., "C2-C 20"Alkynyl" refers to an alkynyl group having 2-20 carbon atoms. Examples of alkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylpent-4-ynyl, hex-2-ynyl, hex-5-ynyl, and the like. In an embodiment, the alkynyl group comprises one carbon-carbon triple bond. The alkynyl group may be unsubstituted or substituted with one or more substituents as described herein. For example, the alkynyl group may be substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents) of halogen, -C0R', -CN, -OH, -OR', -NH2, -NHR', -N(R')2, -SR', or -S0R', wherein each instance of R' is independently C1-C3 alkyl. In an embodiment, the alkynyl group is unsubstituted. In an embodiment, the alkynyl group is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein).

[1054] As used herein, the term "cycloalkyl" refers to a non-aromatic saturated ring group, such as "C3-C 10 In an embodiment, the cycloalkyl group is a monocyclic ring. In an embodiment, the cycloalkyl group is polycyclic (e.g., bicyclic or tricyclic). In a polycyclic cycloalkyl group, the individual rings may be fused, bridged, or spirocyclic. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[3.2.1]octyl, octahydropentenyl, and spiro[4.5]decyl, and the like. The term "cycloalkyl" may be used interchangeably with the term "carbocycle". Cycloalkyl groups may be unsubstituted or substituted with one or more substituents as described herein. For example In one embodiment, the cycloalkyl group is substituted with one or more of the following (e.g., 1, 2, 3, 4, 5, or 6 independently selected substituents): halogen, -C0R', -CN, -OH, -OR', -NH2, -NHR', -N(R')2, -SR', or -S0R', wherein each instance of R' is independently C1-C3 alkyl. In one embodiment, the cycloalkyl group is unsubstituted. In one embodiment, the cycloalkyl group is substituted (e.g., with 1, 2, 3, 4, 5, or 6 substituents as described herein).

[1055] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[1056] As used herein, "aromatic compounds," "aromatics," or compounds containing "aromatic rings" are aryl or heteroaryl compounds. As used herein, the term "aryl" includes substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is carbon. The ring is preferably a 3- to 8-membered ring, more preferably a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more rings, wherein two or more carbon atoms are shared by two adjacent rings, wherein at least one ring is an aromatic ring, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Aryl includes benzene, naphthalene, phenanthrene, phenol, aniline, and the like. The term "heteroaryl" includes substituted or unsubstituted aromatic monocyclic ring structures, preferably 3- to 8-membered rings, more preferably 5- to 7-membered rings, even more preferably 5- to 6-membered rings, whose ring structure includes at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The term "heteroaryl" also includes polycyclic ring systems with two or more rings, wherein two or more carbon atoms are shared by two adjacent rings, wherein at least one ring is an aromatic ring, for example, the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclic radicals. Heteroaryl groups include, for example, pyrrole, furan, thiophene, indole, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, etc. Certain compounds of the present invention preferably include at least one (preferably two) indole group and at least one aldehyde group.

[1057] The term "substituted" refers to a portion in which a hydrogen atom on one or more carbon atoms of the main chain is replaced by at least one substituent. It should be understood that "substituted" or "substituted" includes the following implicit restrictions: such substitution complies with the allowed valences of the substituted atom and the substituent, and the substitution produces a stable compound, such as a compound that does not spontaneously undergo transformation (e.g., rearrangement, cyclization, elimination, etc.). For appropriate organic compounds, the permissible substituents may be one or more and may be the same or different.

[1058] As used herein, the term "heterocycle" or "heterocyclic" refers to a monocyclic, bicyclic, or tricyclic ring system containing at least one heteroatom. Heteroatoms include, but are not limited to, oxygen, nitrogen, and sulfur.

[1059] Monocyclic heterocycles consist, for example, of 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered rings containing at least one heteroatom. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridine, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.

[1060] As non-limiting examples, a bicyclic heterocycle is a monocyclic heterocycle fused to a distal aryl ring, or a monocyclic heterocycle fused to a distal cycloalkyl ring, or a monocyclic heterocycle fused to a distal cycloalkenyl ring, or a monocyclic heterocycle fused to a distal monocyclic heterocycle, or a monocyclic heterocycle fused to a distal monocyclic heteroaryl ring. Representative examples of bicyclic heterocycles include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolanyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, 2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl.

[1061] As non-limiting examples, a tricyclic heterocycle is a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a cycloalkyl group, or a bicyclic heterocycle fused to a cycloalkenyl group, or a bicyclic heterocycle fused to another monocyclic heterocycle. Representative examples of tricyclic heterocycles include, but are not limited to, 2,3,4,4a,9,9a-hexahydro-1H-carbazolyl, 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furanyl, and 5a,6,7,8,9,9a-hexahydrodibenzo[b,d]thienyl.

[1062] As non-limiting examples, the heterocycles of the present invention can be substituted with substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxyalkynyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxy-NH=C(alkyl)-, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy, carboxyl, carboxylalkyl, cyano, cyanoalkyl, cycloalkyl, carbonyl, cycloalkylalkyl, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, hydroxycycloalkyl, mercapto, nitro, oxo, and phenyl.

[1063] As used herein, "regulating skin pigmentation" and grammatical variations thereof generally refers to the skin lightening as well as the skin darkening effects of the compounds and compositions of the present invention.

[1064] As used herein, "skin lightening" and its grammatical variations generally refer to any actual or perceived reduction in skin pigmentation. Skin lightening methods have been used to reduce pigmentation in hyperpigmented areas of the skin due to age, sun exposure, or hyperpigmentation conditions. The compounds and compositions of the present invention, when applied to, for example, the skin of a subject, can reduce pigmentation, making the skin appear lighter or whiter than before the application. Skin pigmentation can be assessed in many ways, including, but not limited to, visual assessment using, for example, the von Luschan color scale, the Fitzpatrick skin typing test (Fitzpatrick et al., 1988), and the Taylor hyperpigmentation scale (Taylor et al., 2005), and reflectance spectrophotometry (Zonios et al., 2001). For example, the Fitzpatrick skin typing test includes six types of skin (I-VI), and a change from type VI skin to type V or lower is "lightened" as used herein. As discussed further below, skin lightening can be attributed to a variety of phenomena including, but not limited to, modulation of melanocyte activity, induction of apoptosis in melanocytes, or modulation of aryl hydrocarbon receptor (AhR) activity, melanogenesis, melanosome biogenesis, melanosome transfer, or melanin concentration.

[1065] Likewise, as used herein, "skin darkening" and its grammatical variations generally refer to any actual or perceived increase in skin pigmentation. Skin darkening methods have been used to increase pigmentation in hypopigmented areas of the skin, such as those caused by hypopigmentation conditions. Application of the compounds and compositions of the present invention to, for example, the skin of a subject can increase pigmentation, such that the skin appears darker than before such application.

[1066] Certain compounds of the present invention are produced, derived, isolated, or isolatable from Malassezia yeast. Malassezia yeasts are yeasts of the genus Malassezia and include, but are not limited to, Malassezia globosa, Malassezia restricta, Malassezia furfur, Malassezia sympodialis, Malassezia slooffiae, Malassezia obtusa, Malassezia pachydermatis, Malassezia dermatis, Malassezia japonica, Malassezia nana, Malassezia yamatoensis, Malassezia equine, Malassezia caprae, and Malassezia cuniculi. (Guého et al., 1996; Gaitanis et al., 2013). Malassezia yeasts are part of the normal human skin flora and generally do not cause disease. However, Malassezia yeasts can cause a number of diseases, including (but not limited to) pityriasis versicolor (hyperpigmentation and hypopigmentation varieties), seborrheic dermatitis, dandruff, atopic dermatitis, Malassezia folliculitis, psoriasis, and confluent and reticulopapillomatosis (Gaitanis et al., 2013).

[1067] As used herein, the term "chemical analogue" refers to a compound that is structurally related to a parent compound and contains different functional groups or substituents. For example, the parent compounds of the present invention include malassecin and indirubin, and chemical analogues of malassecin and indirubin contain certain functional groups and substituents that differ from malassecin and indirubin, respectively. The chemical analogues of the present invention may have significant advantages over a given parent compound, including pharmacokinetic profiles suitable for cosmetic or pharmaceutical use. In some embodiments, chemical analogues are produced from the parent molecule via one or more chemical reactions. In other embodiments, the chemical analogues of the present invention can be produced using alternative synthetic processes that do not begin with the parent compound.

[1068] A compound of the invention is produced by Malassezia yeast if the yeast synthesizes, secretes, accumulates, or otherwise produces the compound during its life cycle under appropriate growth conditions. Malassezia yeast secrete different compounds depending on the growth medium supplements (Nazzaro-Porro et al., 1978). The present invention encompasses any compound produced by Malassezia yeast under any growth conditions, but preferred compounds include, for example, malassezia, indirubin, and chemical analogs thereof.

[1069] If a compound of the invention is present on or in a Malassezia yeast at any time during the yeast's life cycle, the compound is derived from a Malassezia yeast.

[1070] Malassezia is an example of a compound produced by the Malassezia yeast of the present invention. Malassezia, also known as 2-(1H-indol-3-ylmethyl)-1H-indole-3-carbaldehyde, is a tryptophan metabolite originally isolated from Malassezia furfur. Malassezia is a known agonist of the aryl hydrocarbon receptor (AhR), a receptor involved in cell growth, differentiation, and gene expression (Wille et al., 2001). Malassezia also induces apoptosis in primary human melanocytes. et al., 2005). Recently, Winston-McPherson and colleagues, who had examined the AhR agonist activity of the analogs, synthesized some chemical analogs of malassezia (Winston-McPherson et al., 2014).

[1071] Indirubin is another example of a compound produced by the Malassezia yeast of the present invention. Indirubin is a metabolite isolated from Malassezia furfur. Indirubin is a known agonist of the aryl hydrocarbon receptor (AhR), a receptor involved in cell growth, differentiation, and gene expression.

[1072] As used herein, the term "melanocyte" refers to the dendritic cells of the epidermis, which normally synthesize tyrosinase and synthesize the pigment melanin in melanosomes. The melanocytes of the present invention exhibit upregulation of certain genes, including but not limited to one or more of the following: tyrosinase (oculocutaneous albinism IA), microphthalmia-associated transcription factor, alpha-2-macroglobulin, tyrosinase-related protein 1, solute transporter family 16, GS3955 protein, v-kit Hardy-Zuckerman 4 feline sarcoma, ocular albinism 1, Rag D protein, glycogen protein 2, G protein-coupled receptor, family C oculocutaneous albinism II, esophageal cancer deleted gene 1, melanin A, SRY-box 10, adenosine triphosphatase, class V type 10C matrix metalloproteinase 1, latent transforming growth factor beta b, ATP binding cassette, subfamily C, hydroxyprostaglandin dehydrogenase 15, transmembrane 7 superfamily member 1, glutaminyl peptide cyclotransferase, and other genes identified by Lee and colleagues. (Lee et al., 2013).

[1073] As many other cell types, melanocytes undergo programmed cell death or apoptosis. The apoptosis pathway of melanocytes is known to those skilled in the art (Wang et al., 2014), and apoptosis pathways have generally been reviewed by Elmore (Elmore, 2007). The compound or composition of the present invention "induce" melanocytes to undergo apoptosis, such as promoting certain pro-apoptotic signal transduction pathways to activate or promoting certain anti-apoptotic pathways to be suppressed in melanocytes. It is envisioned that the compound or composition of the present invention can directly activate / inhibit apoptosis-related pathways, which is achieved by directly interacting with the signal transduction molecules in the path or by indirectly interacting with the molecules in the path (via directly interacting with one or more intermediate molecules that are generally inactive in the path).

[1074] Melanocyte activity can be modulated in a number of ways encompassed by the present invention, including, but not limited to, inducing apoptosis in melanocytes or altering melanocyte gene expression, cell motility, cell growth, melanin production, melanosome biogenesis, or melanosome transfer.

[1075] As used herein, the terms "modulate" and "modulating" and grammatical variations thereof refer to the adjustment of a biological activity or phenomenon to a desired level. It is contemplated that "modulation" of the present invention includes adjustments that increase or decrease the level of a biological activity or phenomenon.

[1076] As used herein, the terms "agonist," "agonist," and grammatical variations thereof refer to a molecule that triggers (e.g., initiates or promotes), partially or completely enhances, stimulates, or activates one or more biological activities. Agonists of the present invention can interact with and activate a receptor, thereby inducing a physiological or pharmacological response characteristic of the receptor. Agonists of the present invention include naturally occurring substances as well as synthetic substances.

[1077] As used herein, the terms "antagonist," "antagonist," and grammatical variations thereof refer to molecules that partially or completely suppress, inhibit, or inactivate one or more biological activities. Antagonists of the present invention can competitively bind to the same site on a receptor as an agonist, but do not activate the intracellular response elicited by the active form of the receptor. Antagonists of the present invention can inhibit the intracellular response of an agonist or partial agonist.

[1078] The aryl hydrocarbon receptor (AhR) of the present invention is any aryl hydrocarbon receptor as described herein that is naturally present in a subject. Aryl hydrocarbon receptors are known to those skilled in the art (Noakes, 2015). Agonists of the aryl hydrocarbon receptor include, but are not limited to, tryptophan-related compounds such as kynurenine, kynurenic acid, cinnabarinic acid, and 6-formylindolo[3,2-b]carbazole (FICZ). Malasseziacin is also known as an aryl hydrocarbon receptor agonist (Wille et al., 2001).

[1079] As used herein, the compounds, compositions, and methods of the present invention can be used to improve hyperpigmentation caused by a hyperpigmentation disorder, for example, by reducing the level of hyperpigmentation in the area affected by the hyperpigmentation disorder, slowing further hyperpigmentation, or preventing the onset of further hyperpigmentation. However, because every subject may not respond to a particular dosing regimen, therapy, or method, improving hyperpigmentation caused by a hyperpigmentation disorder does not require achieving a desired physiological response or outcome in every subject or subject population. Thus, a given subject or subject population may not respond or respond insufficiently to administration, but other individuals or subject populations may respond and, as a result, experience improvement in their hyperpigmentation disorder.

[1080] As used herein, the term "hyperpigmentation" is a condition in which the skin color is, actual or perceived, too dark. Skin damage can be actual, such as due to age, excessive sun exposure, or a disease or condition that causes dark skin areas. Dark skin areas can take the form of spots, blemishes, or relatively large dark-colored areas. Skin damage can also be perceived, such as by an individual who has a skin color that is too dark. An individual may have a cosmetic desire to lighten their skin color.

[1081] Hyperpigmentation disorders are disorders in which hyperpigmentation is the primary symptom and those in which hyperpigmentation occurs as a secondary symptom. Hyperpigmentation disorders of the present invention include, but are not limited to, congenital hyperpigmentation disorders and acquired hyperpigmentation disorders. Congenital hyperpigmentation disorders of the present invention include, but are not limited to, disorders involving epidermal hyperpigmentation (nevus cell nevus, Spitz nevus, and lentigo), dermal hyperpigmentation (blue nevus, nevus Ohta, dermal melanosis, nevus Ito, and Mongolian spot), freckles, reticular acral hyperpigmentation, Spitz hyperpigmentation / acral hyperpigmentation, and maculopathy (maculopathy generalis, LEOPARD syndrome, hereditary patterned maculopathy, Carney complex, Peutz-Jeghers syndrome, Laugier-Hunziker-Baran syndrome, and lentigo). syndrome) and Cronkhite-Canada syndrome. (Yamaguchi et al., 2014). Acquired hyperpigmentation disorders of the present invention include, but are not limited to, age lentigo / age spots, melasma / chloasma, Riehl's melanosis, lip melanin, penile / vulvovaginal melanosis, erythromelanosis follicularis faciei, and erythromelanosis follicularis faciei. Kitamura), UV-induced hyperpigmentation (tanning and actinic petaloid hyperpigmentation), post-inflammatory hyperpigmentation (frictional melanosis and gray dermatosis), chemical / drug-induced hyperpigmentation (polychlorinated biphenyls, arsenic, 5-FU, bleomycin, cyclophosphamide, methotrexate, chlorpromazine, phenytoin, tetracycline, and chloroquine), pigmented demarcation lines, and deposition of foreign materials (e.g., carotene, silver, gold, mercury, bismuth, and tattoos).Hyperpigmentation associated with systemic disorders includes metabolic / enzyme disorders (hemochromatosis, Wilson's disease, Gaucher's disease, Niemann-Pick's disease, amyloidosis, ochronosis, acanthosis nigricans, and porphyriacutanea tarda), endocrine disorders (Addison's disease, Cushing syndrome, and hyperthyroidism), nutritional disorders (pellagra, vitamin B12 deficiency, folate deficiency, vagabond's disease, and prurigo pigmentosa), mastocytosis, collagen disorders, liver dysfunction, and renal dysfunction. Hyperpigmentation can also be associated with infectious diseases (measles, syphilis, and Malassezia furfur) and syndromes (von Recklinghausen's disease, Sotos syndrome, POEMS syndrome, Naegeli syndrome, Cantu syndrome, McCune-Albright syndrome, Watson syndrome, and Bloom syndrome) (Yamaguchi et al., 2014).

[1082] Melanin is the naturally occurring pigment that gives color to skin and hair. Figure 1A Melanin is produced by organelles called melanosomes in melanocytes through a process called melanogenesis. The compounds or compositions of the present invention regulate melanin production (also known as melanogenesis) in a subject by, for example, regulating melanosome biogenesis and directly or indirectly inhibiting melanin synthesis at the enzymatic level.

[1083] Melanosome biogenesis occurs through four stages: Stage I is characterized by premelanosomes, which are essentially unpigmented vesicles. In Stage II, premelanosomes develop striations, onto which melanin is deposited in Stage III. Stage IV produces mature melanosomes rich in melanin. The compounds and compositions of the present invention modulate melanosome biogenesis by inhibiting or attenuating biological processes that normally promote any or all of these stages (Wasmeier et al., 2008).

[1084] Melanin synthesis primarily involves three enzymes: tyrosinase, tyrosinase-related protein-1, and dopachrome tautomerase. Other factors that influence the intracellular trafficking of these enzymes include (but are not limited to) BLOC-1, OA1, and SLC45A2. The compounds and compositions of the present invention can modulate melanin production by, for example, inhibiting or attenuating the activity of any of these enzymes or factors (Yamaguchi et al., 2014).

[1085] Once melanosomes have formed and melanin has been synthesized, the melanosomes need to be transferred from the epidermal melanocytes to the keratinocytes of the skin and hair. Melanosomes are produced near the nucleus of the melanocytes and transported along microtubules and actin filaments to the periphery of the melanocytes. The compounds and compositions of the present invention modulate melanosome transfer by interfering with any of the biological processes that cause melanosomes to be transported from the perinuclear region to the periphery of the melanocytes and into adjacent keratinocytes. A schematic diagram of melanin synthesis, melanin transport, and apoptosis of melanocytes is shown in Figure 1B middle.

[1086] Melanin concentration can be modulated by, for example, increasing or decreasing melanin production in a subject or promoting melanin degradation or elimination in a subject.

[1087] The compounds isolated from the Malassezia yeast of the present invention must have been present in the Malassezia yeast or produced by the Malassezia yeast prior to isolation. Thus, the compounds isolated from the Malassezia yeast are derived from actual yeast cells. Standard protocols for extracting compounds from cellular materials are known to those skilled in the art.

[1088] Compounds that can be isolated from Malassezia yeast are not necessarily derived from actual yeast cells. Synthesis reactions can be used instead to generate compounds produced in yeast without involving actual yeast cells. Organic synthesis reactions are well known to those skilled in the art and can be used in this regard.

[1089] As used herein, the term "epidermal melanin" refers to melanin produced in, transported to, or otherwise present in the epidermis.

[1090] As used herein, the term "reduce" and its grammatical variations mean to cause a decrease in the level of a specified biological phenomenon or species. For example, the compounds and compositions of the present invention reduce epidermal melanin in a subject, meaning that the compounds and compositions of the present invention induce a decrease in epidermal melanin levels in the subject. The term "reduce" and its grammatical variations can refer to, for example, a decrease in the level of a specified phenomenon or species by at least 5%, 10%, 25%, 50%, 75%, or 100%.

[1091] As used herein, the term "contacting" and its grammatical variations refer to bringing two or more materials into close proximity so that they can interact. Thus, for illustrative purposes only, a compound of the present invention can contact a melanocyte by, for example, interacting with a receptor on the surface of the melanocyte. Similarly, a composition of the present invention can contact a human subject by, for example, applying directly to the subject's skin.

[1092] As used herein, "subject" refers to mammalian cells, tissues, organisms, or populations thereof. The subject of the present invention is preferably a human, including human cells, tissues, and humans, but also includes primates, farm animals, livestock, laboratory animals, and the like. Some examples of agricultural animals include cows, pigs, horses, goats, and the like. Some examples of livestock include dogs, cats, and the like. Some examples of laboratory animals include primates, rats, mice, rabbits, guinea pigs, and the like.

[1093] As used herein, a subject "in need of" improvement of hyperpigmentation due to a hyperpigmentation disorder includes a subject having a real or perceived need for improvement.

[1094] As used herein, the term "treat," "treating," and "treatment" and grammatical variations thereof refer to a regimen, therapy, method, or treatment of an individual subject in the hope of obtaining a physiological response or outcome in the subject (e.g., a patient). Specifically, the methods and compositions of the present invention can be used to slow the development of disease symptoms, or delay the onset of a disease or condition, or interrupt the progression of disease development. However, because each treated subject may be unresponsive to a particular treatment regimen, therapy, method, or treatment, treatment does not require that a desired physiological response or outcome be achieved in each subject or subject population (e.g., a patient population). Therefore, a designated subject or subject population (e.g., a patient population) may not respond or respond insufficiently to treatment.

[1095] As used herein, the terms "prevent," "preventing," and "prevention" and grammatical variations thereof mean that the compounds of the present invention are useful when administered to a patient who, at the time of administration, has not been diagnosed as possibly suffering from a condition or disease, but who would generally be expected to develop the condition or disease or be at increased risk of the condition or disease. For example, the compounds and compositions of the present invention slow the development of symptoms of the condition or disease, delay the onset of the condition or disease, or prevent the condition or disease from developing in the individual in the first place. Prevention also includes administering the compounds of the present invention to individuals who are considered susceptible to the condition or disease due to age, family history, genetic or chromosomal abnormalities, and / or the presence of one or more biological markers for the condition or disease.

[1096] As used herein, the term "facilitate" and grammatical variations thereof means to allow, enhance, permit, assist, promote, encourage, induce, or otherwise assist in producing.

[1097] As used herein, the term "produce" and its grammatical variations means to cause a specified result to occur, occur, or exist. As a non-limiting example, the compounds and compositions of the present invention produce a photoprotective or UV protective effect on a subject.

[1098] As used herein, the term "erythema" refers to redness of the skin. Erythema may be caused by dilation and / or irritation of superficial capillaries. The term "UV-induced erythema" refers to redness of the skin caused by exposure to UV. As used herein, "sunburn" and its grammatical variations refer to UV-induced erythema caused by exposure to sunlight or artificial UV sources (e.g., tanning beds).

[1099] As used herein, the term "hyperpigmentation" generally refers to pigmentation in one area of ​​skin that is greater than that in adjacent areas of the skin (e.g., pigmented spots, age spots, moles, etc.). Hyperpigmentation herein includes, but is not limited to, localized hyperpigmentation caused by excessive melanocyte activity, other localized hyperpigmentation caused by benign melanocyte hyperactivity and proliferation, disease-related hyperpigmentation, and accidental hyperpigmentation, such as hyperpigmentation due to photosensitivity, genetic makeup, chemical ingestion, or other exposures (e.g., UV exposure), age, and post-lesional scarring. As used herein, "UV-induced hyperpigmentation" refers to any hyperpigmentation caused by exposure to natural or artificial UV.

[1100] As used herein, the term "hypopigmentation" generally refers to a condition in which the pigmentation in one area of ​​skin is less than that in an adjacent area of ​​skin. Hypopigmentation of the present invention includes, but is not limited to, vitiligo, depigmentation, pityriasis alba, focal hypopigmentation, post-inflammatory hypopigmentation, mottling, albinism, tinea versicolor, photosensitivity, albinism, hypomelaninosis, atopic dermatitis, psoriasis, and the like.

[1101] As used herein, "UV-induced skin damage" refers to skin damage caused by exposure to UV (including UVA, UVB and UVC). UV-induced skin damage of the present invention includes (but is not limited to) wrinkles, hyperpigmentation, dysplasia, actinic keratosis and skin cancer.

[1102] As used herein, "UV-induced skin aging" refers to skin aging caused by exposure to UV rays, including UVA, UVB, and UVC. UV-induced skin aging of the present invention manifests itself as, for example, wrinkles, fine lines, age spots, moles, dryness, thinness, or decreased skin elasticity, uneven skin tone, and other reductions in skin brightness, texture, elasticity, firmness, sagging, and clarity caused in whole or in part by UV exposure.

[1103] As used herein, the term "photoprotective" and its grammatical variations, when used to describe the effects of the compounds and compositions of the present invention, means that the compounds and compositions described herein prevent and / or reduce damage caused by light, especially sunlight. Similarly, the "photoprotectants" of the present invention are those compounds and compositions described herein that prevent and / or reduce damage caused by light, especially sunlight.

[1104] As used herein, the term "UV protection" and its grammatical variations, when used to describe the effects of the compounds and compositions of the present invention, means that the compounds and compositions described herein prevent and / or reduce damage caused by ultraviolet ("UV") light. Similarly, the "UV protectants" of the present invention are those compounds and compositions described herein that prevent and / or reduce damage caused by UV. Ultraviolet light of the present invention includes, for example, UVA (320-240 nm), UVB (290-320 nm), and UVC (200-290 nm).

[1105] As used herein, the term "light filter" and grammatical variations thereof means blocking, reflecting, absorbing or scattering UV. "Sunscreens" of the present invention include all compounds and compositions of the present invention that block, reflect, absorb or scatter UV.

[1106] As used herein, the term "absorb" and its grammatical variations means absorbing UV or converting UV into heat. As a non-limiting example, the compounds and compositions of the present invention are capable of absorbing UV and as a result radiating heat energy to their surroundings.

[1107] As used herein, the term "reflect" and its grammatical variations, when used in the context of UVs, means projecting or bouncing UVs back rather than absorbing UVs.

[1108] As used herein, the term "composition" refers to an entity comprising one or more compounds of the present invention, as well as any entity resulting directly or indirectly from the combination of one or more compounds of the present invention with other ingredients. The compositions of the present invention can be used, for example, as in vitro or in vivo research reagents. The compositions of the present invention can also be applied directly to the skin of human or non-human subjects to achieve cosmetic or medicinal effects. In addition, the compositions of the present invention comprise one or more of Table 5 or Figure 130The compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts.

[1109] The compositions of the present invention can be administered in any desired effective manner for in vitro and in vivo applications: for oral ingestion, or for parenteral or other administration, any suitable route of administration can be used, for example, intraperitoneally, subcutaneously, topically, intradermally, by inhalation, intrapulmonary, rectal, vaginal, sublingually, intramuscularly, intravenously, intraarterially, intrathecally, or intralymphatically. Furthermore, the compositions of the present invention can be administered in combination with other compositions. If desired, the compositions of the present invention can be encapsulated or otherwise protected against gastric or other secretions.

[1110] The compositions of the present invention comprise one or more active ingredients and one or more carriers that are cosmetically or pharmaceutically acceptable and optionally a mixture of one or more other compounds, ingredients and / or materials. Regardless of the selected route of administration, the compounds and compositions of the present invention are formulated into cosmetically or pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[1111] Cosmetically or pharmaceutically acceptable vehicles, diluents, and carriers are well known in the art and include materials suitable for contact with human and non-human tissues without undue toxicity, incompatibility, instability, irritation, allergic response, and the like. Cosmetically or pharmaceutically acceptable vehicles, diluents, and carriers include any substantially non-toxic substances conventionally used, for example, for topical, oral, peritoneal, or subcutaneous administration of cosmetics or pharmaceuticals, wherein the compounds and compositions of the present invention remain stable and bioavailable when applied, ingested, injected, or otherwise administered to a human or non-human subject. Cosmetically or pharmaceutically acceptable carriers suitable for topical application are known to those skilled in the art and include cosmetically or pharmaceutically acceptable liquids, creams, oils, lotions, ointments, gels, or solids, such as conventional cosmetic night creams, foundations, sunscreens, sunscreens, hand creams, foundations and primers, facial masks, and the like. Carriers suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable carriers for a selected dosage form and method of administration can be determined using ordinary skill in the art.

[1112] The compositions of the present invention can contain other traditional ingredients in cosmetics, including fragrances, estrogens, vitamins A, C and E, alpha-hydroxy or alpha-keto acids (such as pyruvic acid, lactic acid or glycolic acid), lanolin, petrolatum, aloe vera, methylparaben or propylparaben, pigments, and the like. Non-limiting cosmetically or pharmaceutically acceptable vehicles, diluents and carriers of the present invention include sugars (e.g., lactose, sucrose, mannitol and sorbitol), starches, cellulose preparations, calcium phosphates (e.g., dicalcium phosphate, tricalcium phosphate and dibasic calcium phosphate), sodium citrate, water, aqueous solutions (e.g., saline, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, lactated Ringer's injection), alcohols (e.g., ethanol, propylene alcohol and benzyl alcohol), polyols (e.g., glycerol, propylene glycol and polyethylene glycol), organic esters (e.g., ethyl oleate and triglycerides), biodegradable polymers (e.g., polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides)), elastomeric matrices, liposomes, microspheres, oils (e.g., corn, germ, olive, castor, sesame, cottonseed and peanut), cocoa butter, waxes (e.g., suppository wax), paraffin, silicones, talc, salicylates and the like.

[1113] The compositions of the present invention may optionally contain additional ingredients and / or materials commonly used in cosmetic compositions. These ingredients and materials are well known in the art and include, for example, (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, hydroxypropylmethylcellulose, sucrose, and acacia; (3) humectants, such as glycerol; (4) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, cross-linked sodium carboxymethylcellulose, and sodium carbonate; (5) dissolution retardants, such as paraffin wax; (6) absorption enhancers, such as quaternized mixtures; (7) wetting agents such as cetyl alcohol and glyceryl monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate; (10) suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth; (11) buffers; (12) excipients such as lactose, milk sugar, polyethylene glycol, animal and vegetable fats, oils, waxes, paraffins, cocoa butter, starch, tragacanth, cellulose derivatives, polyethylene glycol , silicone, bentonite, silicic acid, talc, salicylates, zinc oxide, aluminum hydroxide, calcium silicate and polyamide powder; (13) inert diluents, such as water or other solvents; (14) preservatives; (15) surfactants; (16) dispersants; (17) controlled release or absorption delaying agents, such as hydroxypropyl methylcellulose, other polymer matrices, biodegradable polymers, liposomes, microspheres, aluminum monostearate, gelatin and waxes; (18) opacifiers; (19) adjuvants; (20) wetting agents; (21) emulsifiers and suspending agents; (22) solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, ethyl esters, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically, cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuran alcohol, polyethylene glycol, and fatty acid esters of sorbitan; (23) propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane; (24) antioxidants; (25) agents that render the formulation isotonic with the blood of the intended recipient, such as sugars and sodium chloride; (26) thickening agents; (27) coating materials, such as lecithin; and (28) sweeteners, flavorings, colorings, aromas, and preservatives. Each such ingredient or material must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Ingredients and materials suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable ingredients and materials for a selected dosage form and method of administration can be determined using ordinary skill in the art.

[1114] Compositions of the present invention suitable for oral administration can be in the form of capsules, cachets, pills, tablets, powders, granules, solutions or suspensions in aqueous or non-aqueous liquids, oil-in-water or water-in-oil liquid emulsions, elixirs or syrups, tablets, boluses, elixirs, or pastes. These formulations can be prepared by methods known in the art, for example, by conventional pan coating, mixing, granulation, or lyophilization techniques.

[1115] Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.) can be prepared, for example, by mixing the active ingredient with one or more cosmetically or pharmaceutically acceptable carriers and, optionally, one or more fillers, extenders, binders, humectants, disintegrants, dissolution retardants, absorption promoters, wetting agents, absorbents, lubricants, and / or colorants. Similar types of solid compositions can be used as fillers in soft-filled and hard-filled gelatin capsules using suitable excipients. Tablets can be prepared by compression or molding, optionally using one or more auxiliary ingredients. Compressed tablets can be prepared using suitable binders, lubricants, inert diluents, preservatives, disintegrants, surfactants, or dispersants. Molded tablets can be prepared by molding in a suitable machine. Tablets and other solid dosage forms, such as capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well-known in the field of cosmetic formulations. They can also be formulated to provide a slow or controlled release of the active ingredient therein. Sterilization can be performed, for example, by filtration through a bacteria-retaining filter. These compositions may also optionally contain opacifying agents and may be of a composition such that they release the active ingredient only or preferentially in a certain part of the gastrointestinal tract, optionally in a delayed manner. The active ingredient may also be in microencapsulated form.

[1116] Liquid dosage forms for oral administration include cosmetically or pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. The liquid dosage form may contain suitable inert diluents commonly used in the art. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, coloring agents, aromatics, and preservatives. Suspensions may contain suspending agents.

[1117] The compositions of the present invention for rectal or vaginal administration can be provided as suppositories, which can be prepared by mixing one or more active ingredients with one or more suitable non-irritating carriers that are solid at room temperature but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Compositions of the present invention suitable for vaginal administration also include vaginal suppositories, tampons, creams, gels, pastes, foams or spray formulations containing appropriate such cosmetically or pharmaceutically acceptable carriers known in the art.

[1118] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, drops, emulsions, suspensions, aerosols and inhalants. Any desired conventional vehicles, adjuvants and optionally other active ingredients may be added to the formulation.

[1119] Preferred adjuvants are from the group comprising preservatives, antioxidants, stabilizers, solubilizers, vitamins, colorants, odor improvers, film formers, thickeners and humectants.

[1120] Solutions and emulsions can contain traditional vehicles such as solvents, cosolvents and emulsifiers, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil), glycerol fatty acid esters, polyethylene glycol and fatty acid esters of sorbitan, or mixtures of these substances.

[1121] Emulsions can exist in different forms. Thus, they can be, for example, water-in-oil (W / O) or oil-in-water (O / W) emulsions or microemulsions, or multiple emulsions, for example water-in-oil-in-water (W / O / W) emulsions.

[1122] The composition according to the invention may also be in the form of an emulsifier-free dispersed preparation, which may be, for example, an aqueous dispersion or a Pickering emulsion.

[1123] The suspension may contain a conventional vehicle, for example a liquid diluent such as water, ethanol or propylene glycol, a suspending medium (e.g. ethoxylated isostearyl alcohol, polyoxyethylene sorbitan esters and polyoxyethylene sorbitan esters), microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or a mixture of these substances.

[1124] Pastes, ointments, gels and creams may contain traditional vehicles, such as animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures of these substances.

[1125] Facial and body oils may contain conventional vehicles such as synthetic oils, eg, fatty acid esters, fatty alcohols, silicone oils, natural oils (eg, vegetable oils and oily plant extracts), paraffin oil, lanolin oil, or mixtures of these.

[1126] Sprays may contain conventional propellants, such as chlorofluorocarbons, propane / butane or dimethyl ether.

[1127] The compositions of the present invention suitable for parenteral administration comprise one or more compounds and one or more cosmetically or pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders, which can be reconstituted into sterile injectable solutions or dispersions before use. These solutions can contain antioxidants, buffers, solutes that make the formulation isotonic for the blood of the intended recipient, or suspending agents or thickening agents. Suitable fluidity can be maintained, for example, by using coating materials, by maintaining the required particle size in the case of dispersions, and by using surfactants. These compositions can also contain suitable adjuvants, such as wetting agents, emulsifiers, and dispersants. Including an isotonic agent is also expected. In addition, extended absorption of the injectable cosmetic form can be achieved by including an absorption delaying agent.

[1128] In some cases, in order to prolong the duration of action, it is desirable to slow the absorption of the drug following subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of the poorly water-soluble crystalline or amorphous material.

[1129] The absorption rate of the active agent / drug depends on its dissolution rate, which in turn can depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenteral compositions can be achieved by dissolving or suspending the active composition in an oil vehicle. Injectable depot forms are prepared by forming a microencapsulation matrix of the active ingredient in a biodegradable polymer. Depending on the ratio of active ingredient to polymer and the properties of the specific polymer used, the rate of release of the active ingredient can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable material can be sterilized, for example, by filtering through a bacteria-retaining filter.

[1130] The compositions of the present invention can be provided in unit dose or multi-dose sealed containers (e.g., ampoules and vials) and can be stored in a lyophilized condition, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Ready-to-use injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[1131] In the present invention, the term "crystalline form" refers to the crystal structure of a compound. A compound may exist in one or more crystalline forms, which may have different structural, physical, pharmacological or chemical characteristics. Different crystalline forms can be obtained by utilizing variations in nucleation, growth kinetics, coalescence and fracture. When the phase transition energy barrier is overcome, nucleation is caused, thereby allowing particles to form from a supersaturated solution. Crystal growth is the enlargement of crystal particles caused by the deposition of a compound on an existing crystal surface. The relative rates of nucleation and growth determine the size distribution of the crystals formed. For nucleation and growth, the thermodynamic driving force is supersaturation, which is defined as a deviation from thermodynamic equilibrium. Coalescence is the formation of larger particles, which is achieved by two or more particles (e.g., crystals) sticking together and forming a larger crystalline structure.

[1132] As used herein, the term "hydrate" refers to a compound in solid or semisolid form that contains water in a molecular complex. The water is generally present in a stoichiometric amount relative to the compound.

[1133] As used herein, "cosmetically or pharmaceutically acceptable salts" refers to derivatives of the compounds disclosed herein, wherein the compounds are modified by preparing acid or basic salts thereof. Examples of cosmetically or pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); alkali or organic salts of acidic residues (e.g., carboxylic acids); and the like. For example, such salts include salts of ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxy-ethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2',2"-nitrilotri(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-ethyl Amido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclohexylaminesulfonic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, gentisic acid, D-glucoheptanoic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, Glycine, glycolic acid, caproic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, and undecylenic acid. Other cosmetically or pharmaceutically acceptable salts can be formed using metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like.

[1134] The cosmetically or pharmaceutically acceptable salts of the present invention can be synthesized from the compounds disclosed herein containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile or a mixture thereof.

[1135] It is contemplated that the compounds and compositions of the present invention may be included in cosmetic or pharmaceutical compositions for in vitro and in vivo applications.

[1136] It is contemplated that the compounds and compositions of the present invention (comprising one or more of Table 5 or Figure 130 The compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts) can be co-administered to a subject to achieve the purpose of skin pigmentation regulation of the present invention.

[1137] It is also envisioned that the compositions of the present invention may comprise one or more of Table 5 or Figure 130 The compounds listed in, or their chemical analogs, crystalline forms, hydrates or pharmaceutically or cosmetically acceptable salts. For example, the composition of the present invention may comprise a combination of indirubin or its chemical analogs and malassezia or its chemical analogs.

[1138] Additionally, it is contemplated that the compounds of the present invention include compounds produced by Malassezia, or chemical analogs, crystalline forms, hydrates, or pharmaceutically or cosmetically acceptable salts thereof. Additionally, it is contemplated that the compositions and methods of the present invention may include one or more compounds produced by Malassezia, or chemical analogs, crystalline forms, hydrates, or pharmaceutically or cosmetically acceptable salts thereof. For example, compounds produced or derived from Malassezia include, but are not limited to: Figure 130 The compound shown in .

[1139] It is further contemplated that the methods of the present invention may comprise co-administering two or more compounds and / or compositions of the present invention to achieve the goals of skin pigmentation regulation as described herein.

[1140] Co-administered compounds and compositions of the invention may, for example, be contacted with the subject substantially simultaneously or sequentially.

[1141] Compositions of the present invention comprising one or more Malassezia derived compounds or chemical analogs thereof can exhibit synergistic effects relative to the individual constituent compounds according to various efficacy criteria including, but not limited to, mean tissue viability, melanin concentration, skin lightening, skin darkening, induction of melanocyte apoptosis and modulation of aryl hydrocarbon (AhR) activity, melanogenesis, or melanin concentration.

[1142] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in the specification and claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise.

[1143] For numerical ranges recited herein, each intervening number therebetween is expressly contemplated with equal precision. For example, when the range is 6-9, in addition to 6 and 9, the numbers 7 and 8 are also contemplated; and when the range is 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly contemplated.

[1144] The embodiments of various aspects provided by the present invention are also described in any of the following paragraphs.

[1145] Embodiment 1. A compound having the structure of the following formula:

[1146]

[1147] in:

[1148] X is selected from NR 14 and O's group;

[1149] Y is a covalent bond, CR5R6, O or NR 15 ;

[1150] R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ;

[1151] R 13 、R 14 and R 15 are independently hydrogen or R 16 ;

[1152] R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 Cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl;

[1153] R 12 Selected from hydrogen, -COR a and R 16 the groups formed;

[1154] Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and

[1155] R aSelected from hydrogen, hydroxyl and OR 16 the groups formed;

[1156] in:

[1157] If R a is hydrogen, then Y is CR5R6, and R 13 With R 14 All are hydrogen,

[1158] R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 At least one of them is R 16 ;or

[1159] R5 is selected from the group consisting of: hydroxyl, OR 16 、R 16 and C 3-6 Cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl;

[1160] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1161] Embodiment 2. The compound according to embodiment 1, which has the following structure:

[1162]

[1163] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1164] Embodiment 3. The compound according to embodiment 1,

[1165] in:

[1166] Y is CR5R6;

[1167] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[1168] Embodiment 4. The compound according to embodiment 1, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[1169] Embodiment 5. The compound according to embodiment 1, wherein R1, R2, R3, R4, R7, R8, R9, R 10and R 11 Each of them is hydrogen.

[1170] Embodiment 6. The compound according to embodiment 1, wherein R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[1171] Embodiment 7. The compound according to embodiment 1,

[1172] in:

[1173] X is NH;

[1174] Y is CR5R6;

[1175] R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of them is hydrogen;

[1176] R2 is hydrogen or C 1-4 alkyl;

[1177] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group;

[1178] R 12 Yes-COR a or C 1-4 hydroxyalkyl; and

[1179] R a is hydrogen or C 1-4 alkyl.

[1180] Embodiment 8. The compound of embodiment 1, wherein the compound is selected from the group consisting of:

[1181]

[1182]

[1183] Embodiment 9. A compound having the following structure:

[1184]

[1185] in:

[1186] R1, R4, R5, R6, R9 and R10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO;

[1187] R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R2 and R3 are combined to form a 5- or 6-membered heterocyclic group;

[1188] R7 and R8 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5- or 6-membered heterocyclic group;

[1189] R 11 With R 12 are independently hydrogen or R 13 ;

[1190] Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and

[1191] R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 At least one of them is not hydrogen;

[1192] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1193] Embodiment 10. The compound according to Embodiment 9, which has a structure according to Formula (II):

[1194]

[1195] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1196] Embodiment 11. The compound according to embodiment 9, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[1197] Embodiment 12. The compound of embodiment 9, wherein:

[1198] R11 and R 12 are each hydrogen; and

[1199] R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[1200] Embodiment 13. The compound of embodiment 9, wherein the compound is selected from the group consisting of:

[1201]

[1202]

[1203] Embodiment 14. A composition comprising a compound having the structure of:

[1204]

[1205] in:

[1206] X is selected from NR 14 and O's group;

[1207] Y is a covalent bond, CR5R6, O or NR 15 ;

[1208] R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ;

[1209] R 13 、R 14 and R 15 are independently hydrogen or R 16 ;

[1210] R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 Cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl;

[1211] R 12 Selected from hydrogen, -COR a and R 16 the groups formed;

[1212] Each R 16 are independently formyl, C1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and

[1213] R a Selected from hydrogen, hydroxyl and OR 16 the groups formed;

[1214] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1215] Embodiment 15. The composition according to embodiment 14, having the following structure:

[1216]

[1217] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1218] Embodiment 16. The composition according to embodiment 14,

[1219] in:

[1220] Y is CR5R6;

[1221] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[1222] Embodiment 17. The composition according to embodiment 14, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[1223] Embodiment 18. The composition of embodiment 14, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[1224] Embodiment 19. The composition according to embodiment 14, wherein R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[1225] Embodiment 20. The composition according to embodiment 14,

[1226] in:

[1227] X is NH;

[1228] Y is CR5R6;

[1229] R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of them is hydrogen;

[1230] R2 is hydrogen or C 1-4 alkyl;

[1231] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 Alkyl); or a combination of R5 and R6

[1232] Formation of an oxo (=O) group;

[1233] R 12 Yes-COR a or C 1-4 hydroxyalkyl; and

[1234] R a is hydrogen or C 1-4 alkyl.

[1235] Embodiment 21. The composition of embodiment 14, wherein the compound is selected from the group consisting of:

[1236]

[1237]

[1238] Embodiment 22. A composition comprising a compound having the formula:

[1239]

[1240] in:

[1241] R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO;

[1242] R2 and R3 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13and -CHO, or R2 and R3 are combined to form a 5- or 6-membered heterocyclic group;

[1243] R7 and R8 are independently selected from the group consisting of hydrogen, hydroxy, halogen, CN, R 13 , OR 13 , OCOR 13 and -CHO, or R7 and R8 are combined to form a 5- or 6-membered heterocyclic group;

[1244] R 11 and R 12 are independently hydrogen or R 13 ;and

[1245] Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 Alkynyl;

[1246] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1247] Embodiment 23. The composition of embodiment 22, having a structure according to formula (II):

[1248]

[1249] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1250] Embodiment 24. The composition of embodiment 22, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 independently selected from hydrogen and C 1-4 A group consisting of alkyl groups.

[1251] Embodiment 25. The composition of embodiment 22, wherein:

[1252] R 11 and R 12 are each hydrogen; and

[1253] R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 One, two, three or four of the groups are methyl and the remaining groups are hydrogen.

[1254] Embodiment 26. The composition of embodiment 22, wherein the compound is selected from the group consisting of:

[1255]

[1256]

[1257] Embodiment 27. A composition comprising a compound selected from the group consisting of:

[1258]

[1259]

[1260] Embodiment 28. A method of lightening the skin of a subject, the method comprising contacting the subject with a compound or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[1261]

[1262] in:

[1263] X is selected from NR 14 and O's group;

[1264] Y is a covalent bond, CR5R6, O or NR 15 ;

[1265] R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ;

[1266] R 13 、R 14 and R 15 are independently hydrogen or R 16 ;

[1267] R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 Cycloalkyl, or

[1268] R5 and R6 combine to form an oxo (=O) group or C 3-6 Cycloalkyl;

[1269] R 12 Selected from hydrogen, -COR a and R 16 the groups formed;

[1270] Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9alkynyl; and

[1271] R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[1272] Embodiment 29. The method of embodiment 28, having the following structure:

[1273]

[1274] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1275] Embodiment 30. The method according to embodiment 28,

[1276] in:

[1277] Y is CR5R6;

[1278] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[1279] Embodiment 31. The method according to embodiment 28, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[1280] Embodiment 32. The method according to embodiment 28, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[1281] Embodiment 33. The method according to embodiment 28, wherein R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[1282] Embodiment 34. The method according to embodiment 28,

[1283] in:

[1284] X is NH;

[1285] Y is CR5R6;

[1286] R1, R3, R4, R7, R8, R9, R10 、R 11 and R 13 Each of them is hydrogen;

[1287] R2 is hydrogen or C 1-4 alkyl;

[1288] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 Alkyl); or a combination of R5 and R6

[1289] Formation of an oxo (=O) group;

[1290] R 12 Yes-COR a or C 1-4 hydroxyalkyl; and

[1291] R a is hydrogen or C 1-4 alkyl.

[1292] Embodiment 35. The method of embodiment 28, wherein the compound is selected from the group consisting of:

[1293]

[1294]

[1295] Embodiment 36. A method of inducing apoptosis in melanocytes of a subject, the method comprising contacting the subject with a compound or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[1296]

[1297] in:

[1298] X is selected from NR 14 and O's group;

[1299] Y is a covalent bond, CR5R6, O or NR 15 ;

[1300] R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ;

[1301] R 13 、R 14 and R15 are independently hydrogen or R 16 ;

[1302] R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 Cycloalkyl, or

[1303] R5 and R6 combine to form an oxo (=O) group or C 3-6 Cycloalkyl;

[1304] R 12 Selected from hydrogen, -COR a and R 16 the groups formed;

[1305] Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and

[1306] R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[1307] Embodiment 37. The method according to embodiment 36, which has the following structure:

[1308]

[1309] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1310] Embodiment 38. The method according to embodiment 36,

[1311] in:

[1312] Y is CR5R6;

[1313] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[1314] Embodiment 39. The method according to embodiment 36, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[1315] Embodiment 40. The method according to embodiment 36, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[1316] Embodiment 41. The method according to embodiment 36, wherein R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[1317] Embodiment 42. The method according to embodiment 36,

[1318] in:

[1319] X is NH;

[1320] Y is CR5R6;

[1321] R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of them is hydrogen;

[1322] R2 is hydrogen or C 1-4 alkyl;

[1323] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 Alkyl); or a combination of R5 and R6

[1324] Formation of an oxo (=O) group;

[1325] R 12 Yes-COR a or C 1-4 hydroxyalkyl; and

[1326] R a is hydrogen or C 1-4 alkyl.

[1327] Embodiment 43. The method of embodiment 36, wherein the compound is selected from the group consisting of:

[1328]

[1329]

[1330]

[1331] Embodiment 44. A method of modulating aryl hydrocarbon receptor (AhR) activity in a subject, the method comprising contacting the subject with a compound having the formula:

[1332]

[1333] in:

[1334] X is selected from NR 14 and O's group;

[1335] Y is a covalent bond, CR5R6, O or NR 15 ;

[1336] R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ;

[1337] R 13 、R 14 and R 15 are independently hydrogen or R 16 ;

[1338] R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 Cycloalkyl, or

[1339] R5 and R6 combine to form an oxo (=O) group or C 3-6 Cycloalkyl;

[1340] R 12 Selected from hydrogen, -COR a and R 16 the groups formed;

[1341] Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and

[1342] R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[1343] Embodiment 45. The method of embodiment 44, having the following structure:

[1344]

[1345] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1346] Embodiment 46. The method according to embodiment 44,

[1347] in:

[1348] Y is CR5R6;

[1349] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[1350] Embodiment 47. The method according to embodiment 44, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[1351] Embodiment 48. The method according to embodiment 44, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[1352] Embodiment 49. The method according to embodiment 44, wherein R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[1353] Embodiment 50. The method according to embodiment 44,

[1354] in:

[1355] X is NH;

[1356] Y is CR5R6;

[1357] R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of them is hydrogen;

[1358] R2 is hydrogen or C 1-4 alkyl;

[1359] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6Cycloalkyl or O-(C 1-4 Alkyl); or a combination of R5 and R6

[1360] Formation of an oxo (=O) group;

[1361] R 12 Yes-COR a or C 1-4 hydroxyalkyl; and

[1362] R a is hydrogen or C 1-4 alkyl.

[1363] Embodiment 51. The method of embodiment 44, wherein the compound is selected from the group consisting of:

[1364]

[1365]

[1366] Embodiment 52. A method of regulating melanin production in a subject, the method comprising contacting the subject with a compound or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[1367]

[1368] in:

[1369] X is selected from NR 14 and O's group;

[1370] Y is a covalent bond, CR5R6, O or NR 15 ;

[1371] R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ;

[1372] R 13 、R 14 and R 15 are independently hydrogen or R 16 ;

[1373] R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 Cycloalkyl, or

[1374] R5 and R6 combine to form an oxo (=O) group or C 3-6 Cycloalkyl;

[1375] R 12 Selected from hydrogen, -COR a and R 16 the groups formed;

[1376] Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and

[1377] R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[1378] Embodiment 53. The method according to embodiment 52, which has the following structure:

[1379]

[1380] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1381] Embodiment 54. The method according to embodiment 52,

[1382] in:

[1383] Y is CR5R6;

[1384] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[1385] Embodiment 55. The method according to embodiment 52, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[1386] Embodiment 56. The method according to embodiment 52, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[1387] Embodiment 57. The method according to embodiment 52, wherein R 12 Yes-COR a or C 1-4 hydroxyalkyl; and Ra is hydrogen or C 1-4 alkyl.

[1388] Embodiment 58. The method according to embodiment 52,

[1389] in:

[1390] X is NH;

[1391] Y is CR5R6;

[1392] R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of them is hydrogen;

[1393] R2 is hydrogen or C 1-4 alkyl;

[1394] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 Alkyl); or a combination of R5 and R6

[1395] Formation of an oxo (=O) group;

[1396] R 12 Yes-COR a or C 1-4 hydroxyalkyl; and

[1397] R a is hydrogen or C 1-4 alkyl.

[1398] Embodiment 59. The method of embodiment 52, wherein the compound is selected from the group consisting of:

[1399]

[1400]

[1401]

[1402] Embodiment 60. A method of regulating melanin concentration in a subject, the method comprising contacting the subject with a compound or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[1403]

[1404] in:

[1405] X is selected from NR 14and O's group;

[1406] Y is a covalent bond, CR5R6, O or NR 15 ;

[1407] R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ;

[1408] R 13 、R 14 and R 15 are independently hydrogen or R 16 ;

[1409] R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 、R 16 and C 3-6 Cycloalkyl, or

[1410] R5 and R6 combine to form an oxo (=O) group or C 3-6 Cycloalkyl;

[1411] R 12 Selected from hydrogen, -COR a and R 16 the groups formed;

[1412] Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and

[1413] R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

[1414] Embodiment 61. The method of embodiment 60, having the following structure:

[1415]

[1416] or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

[1417] Embodiment 62. The method according to embodiment 60,

[1418] in:

[1419] Y is CR5R6;

[1420] R5 is hydrogen, and R6 is hydrogen, C1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 or R5 and R6 are combined to form an oxo (=O) group.

[1421] Embodiment 63. The method according to embodiment 60, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 At least one of them is C 1-4 alkyl.

[1422] Embodiment 64. The method according to embodiment 60, wherein R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 Each of them is hydrogen.

[1423] Embodiment 65. The method according to embodiment 60, wherein R 12 Yes-COR a or C 1-4 hydroxyalkyl; and R a is hydrogen or C 1-4 alkyl.

[1424] Embodiment 66. The method according to embodiment 60,

[1425] in:

[1426] X is NH;

[1427] Y is CR5R6;

[1428] R1, R3, R4, R7, R8, R9, R 10 、R 11 and R 13 Each of them is hydrogen;

[1429] R2 is hydrogen or C 1-4 alkyl;

[1430] R5 is hydrogen, and R6 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or O-(C 1-4 Alkyl); or a combination of R5 and R6

[1431] Formation of an oxo (=O) group;

[1432] R 12 Yes-COR a or C 1-4 hydroxyalkyl; and

[1433] R a is hydrogen or C 1-4alkyl.

[1434] Embodiment 67. The method of embodiment 60, wherein the compound is selected from the group consisting of:

[1435]

[1436]

[1437] The following examples are provided to further illustrate the method of the present invention. These examples are illustrative only and are not intended to limit the scope of the present invention in any way.

[1438] Example

[1439] Example 1

[1440] Materials and methods

[1441] Isolation of compounds produced by Malassezia spp.

[1442] Malasseziain was isolated using, for example, the procedure outlined by Wille et al. (2001). A brief summary of the protocol follows.

[1443] culture medium

[1444] A culture medium consisting of Tween 80 (30 mL), cycloheximide (0.5 g), chloramphenicol (0.05 g), agar (20 g) and a volume of water sufficient to obtain 1000 mL of the mixture was sterilized and mixed with 0.3% sterile-filtered L-tryptophan (0.3 g% concentration) at 50° C. 10 mL portions were poured into 10 cm Petri dishes and the pH was adjusted to 5.5 using 0.1 M HCl.

[1445] Cultivation of Malassezia furfur and isolation of compounds produced by Malassezia furfur

[1446] Malassezia furfur was spread on the above medium and incubated at 30°C for 14 days. The contents of the petri dish were purified and extracted with ethyl acetate for 12 hours. The extract was filtered on glass wool, evaporated to dryness, and dissolved in methanol. The extract was then fractionated by Sephadex LH-20 chromatography using methanol as eluent. Further separation was achieved by preparative thin-layer chromatography using toluene:ethyl formate:formic acid (10:5:3). The main band was divided between water and ethyl acetate. The fractions were analyzed for target activity. The compound was isolated from the target fraction by HPLC.

[1447] Synthesis of Malasseziain and its chemical analogs

[1448] Malasseziain was synthesized according to the protocol described by Wille et al. (2001). Chemical analogs of malassezia were synthesized according to novel synthetic protocols and those described by Winston-McPherson et al. (2014).

[1449] Screening program

[1450] Effective skin lightening compounds were evaluated using screening protocols and novel screening methods known to those skilled in the art. For example, malassezia and its chemical analogs were evaluated by tyrosinase bioassay as described above. Other screening protocols involving in vitro cell and in vivo tissue models were used, including aryl hydrocarbon receptor (AhR) binding assays.

[1451] Tyrosinase bioassay

[1452] Tyrosinase bioassays were performed as described by Wille et al. (2001). Briefly, L-DOPA was mixed with tyrosinase. Extinction, indicating dopaquinone formation, was measured over 1 minute. Using fractions such as those discussed above, these fractions were dissolved in DMSO and added directly to the tyrosinase reaction, with pure DMSO used as a control. Tyrosinase inhibitory activity was measured as a decrease in extinction relative to the control increase.

[1453] Aryl hydrocarbon receptor binding assay

[1454] AhR binding assays were performed according to protocols such as those described by Song et al. (2002). Briefly, human and murine AhRs were expressed in vitro using, for example, the TnT fast-coupled reticulocyte lysate system reaction (Promega, Madison, WI). Receptor-ligand binding was investigated using sucrose gradient-based velocity sedimentation as described by Karchner et al. (1999).

[1455] EROD analysis

[1456] The compounds, compositions and formulations of the present invention were also evaluated using the ethoxyresorufin-O-deethylase (EROD) assay known to those skilled in the art (Donato et al., 1993; Whyte et al., 2000; Wille et al., 2001).

[1457] Apoptosis analysis of melanocytes

[1458] Candidate compounds were evaluated for their apoptosis-inducing activity on melanocytes. Human epidermal melanocytes were cultured in medium 254 supplemented with human melanocyte growth supplement (HMGS) (Thermo-Fisher Scientific, Waltham, MA) or dermal cell basal medium (ATCC, Manassas, VA). Other components of human melanocyte growth medium can include, but are not limited to, insulin (5 μg / ml), ascorbic acid (50 μg / ml), L-glutamine (6 mM), epinephrine (1.0 μM), and calcium chloride (0.2 mM). Human melanocyte cultures were maintained at 37° C., 5% CO 2 .

[1459] Candidate compounds were diluted in DMSO and mixed directly into melanocyte cultures. An equal volume of pure DMSO was used as a control. Cytotoxicity assays known to those skilled in the art were performed according to the manufacturer's instructions. Cytotoxicity assays used in the present invention include, but are not limited to, CellTox®. TM Green light cytotoxicity assay, Apo-ONE fluorescent cysteine ​​protease assay, ApoTox-Glo TM Analysis and cysteine ​​proteases- Analysis (Promega, Madison, WI). Standard FACS or microscopy analysis known to those skilled in the art (including et al. (2005) for fluorescence detection.

[1460] Other means of assessing apoptosis were used, including FACS analysis for Annexin V and Western blotting for caspase-9 expression. Western blotting was performed according to methods known to those skilled in the art.

[1461] Mouse xenograft analysis

[1462] A mouse xenograft model of human skin was generated according to protocols known in the art. (Black et al., 1985; Manning et al., 1973; Reed et al., 1973; Plenat et al., 1992; Scott et al., 1998; Otulakowski et al., 1994). Once the mouse xenograft model was established, it was exposed to the compounds of the invention, and changes in pigmentation were observed compared to controls. Changes in skin pigmentation were assessed using a variety of pigmentation scales known to those skilled in the art, including but not limited to the Fitzpatrick skin typing test and the Taylor hyperpigmentation scale. (Taylor et al., 2005).

[1463] Human Analysis

[1464] The compounds, compositions and formulations of the present invention are applied to humans, for example, on human skin, and compared to a control. Changes in skin pigmentation are assessed using a variety of pigmentation scales known to those skilled in the art, including but not limited to the Fitzpatrick Skin Type Test and the Taylor Hyperpigmentation Scale.

[1465] Example 2

[1466] Biochemical targets of malassezia and its analogs

[1467] It is expected that the compounds and compositions of the present invention will exhibit, for example, tyrosinase inhibition and AhR agonist activity similar to that of malassezia. It is expected that the compounds and compositions of the present invention will exhibit, for example, stronger tyrosinase inhibition and stronger AhR agonism than malassezia. Likewise, it is expected that certain compounds and compositions of the present invention will be less effective tyrosinase inhibitors and AhR agonists than malassezia. Such compounds, compositions, and formulations may have more favorable toxicity profiles than more potent compounds.

[1468] Example 3

[1469] In vitro efficacy

[1470] It is expected that the compounds and compositions of the present invention will induce apoptosis in melanocytes and modulate melanocyte activity, melanin production, melanosome biogenesis, and / or melanosome transfer at least as potently as malassezia. It is also contemplated that certain compounds and compositions of the present invention may not affect these biological processes as potently as malassezia. Such compounds and compositions may have a more favorable toxicity profile than more potent substances.

[1471] Example 4

[1472] In vivo effects

[1473] The compounds and compositions of the present invention are expected to be at least as effective as malassezia for lightening skin and improving hyperpigmentation caused by hyperpigmentation disorders. It is also expected that the compounds and compositions of the present invention will exhibit favorable pharmacokinetic characteristics, such as with respect to half-life and absorption. Certain compounds will exhibit longer half-lives, while others will exhibit shorter half-lives. Similarly, certain compounds will exhibit different absorption profiles, with some taking longer to be fully absorbed, while others take less time to be fully absorbed.

[1474] Example 5

[1475] Synthesis of Malasseziain and Malasseziain Derivatives

[1476] according to Figure 2A Malasseziain ("CV-8684") and its cyclized derivative indolo[3,2-b]carbazole ("CV-8685") were synthesized according to the scheme shown in FIG.

[1477] Synthesis of tert-butyl (2-iodo-phenyl)carbamate, compound 1

[1478] At 0 ° C, to a solution of 2-iodoaniline (25.0 g, 0.114 mol) in tetrahydrofuran (250 mL), LiHMDS (251.0 mL, 1 M in THF, 0.251 mol) was slowly added over 40 minutes while maintaining the internal temperature below 5 ° C. After stirring at 0 ° C for 30 minutes, a solution of BOC anhydride (27.0 g, 0.125 mol) in THF (50 mL) was slowly added over 40 minutes while maintaining the internal temperature below 5 ° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 hour. Saturated NH4Cl (250 mL) was added to quench the reaction. The organic layer was separated and washed with water (150 mL). The combined aqueous layer was extracted with ethyl acetate (2 × 150 mL) and the layers were separated. The ethyl acetate layer was combined with the original organic layer and concentrated in vacuo to give a brown oil. The crude compound was purified by column chromatography (0-5% ethyl acetate / hexane). Compound 1 (29.0 g, 80%) was obtained as a light yellow liquid.

[1479] Synthesis of compound 2

[1480] At ambient temperature, copper iodide (0.95g, 10% mol) and PdCl(PPh) (1.75g, 5% mol) are added to a degassed solution of compound 1 (16.0g, 0.05mol) and propargyl methyl ether (4.25g, 0.06mol) in triethylamine (200mL). After stirring for 2 hours at ambient temperature, the reaction is complete (using 10% ethyl acetate / hexane, monitored by TLC). The reaction mixture is diluted with ethyl acetate (300mL), and the reaction mixture is washed with water, saturated NaCl and dried over NaSO. The solvent is filtered and concentrated in vacuo to obtain a brown oil. The crude compound is purified by column chromatography (10% ethyl acetate / hexane). Compound 2 (13.0g, 99%) is obtained as a light yellow liquid.

[1481] Synthesis of compound 3

[1482] In the oven-dried flask, add dioxane (120mL) containing PtCl (0.26g, 0.001mol), Na CO (1.6g, 0.015mol), indole (2.32g, 0.02mol) and compound 2 (2.6g, 0.01mol). The flask is degassed with nitrogen, sealed and heated to 100°C overnight. After the reaction is complete (using 10% ethyl acetate / hexane, monitored by TLC), the solvent is evaporated under reduced pressure. The reaction mixture is diluted with ethyl acetate (200mL), and the reaction mixture is washed with water, saturated NaCl and through Na SO Drying. Filter the solvent and carry out vacuum concentration to obtain a brown oil.

[1483] This reaction was repeated using different batches of compound 2 (2.6 g, 0.01 mol). The two batches of crude compound were combined and purified by column chromatography (10% ethyl acetate / hexane). Compound 3 (3.8 g, 55%) was obtained as a light brown solid.

[1484] Synthesis of compound 4

[1485] At ambient temperature, potassium carbonate (4.6g, 0.0329mol) is added into the solution of compound 3 (3.8g, 0.0109mol) in methanol (150mL) and water (50mL) mixture.Gained suspension is heated to reflux overnight.After the completion of the reaction (using 20% ​​ethyl acetate / hexane, monitored by TLC), the reaction mixture is cooled to ambient temperature, and the solvent is concentrated in vacuo.Residue is dissolved in ethyl acetate (200mL) and washed with water and salt water, then dried (sodium sulfate), filtered, and the solvent is concentrated in vacuo to obtain a brown solid.Crude compound is purified by column chromatography (20% ethyl acetate / hexane).Compound 4 (2.2g, 81%) is obtained as an orange solid.

[1486] Synthetic compound - Malassezia (CV-8684)

[1487] At 0 DEG C, under argon, dimethylformamide (20mL) is added to a dry 100mL double-necked round-bottom flask. POCl (0.75g, 0.0048mol) is slowly added over 10 minutes while maintaining an internal temperature below 5 DEG C. After stirring at 0 DEG C for 30 minutes, a solution of compound 4 (1.0g, 0.004mol) in dimethylformamide (5mL) is slowly added over 10 minutes while maintaining an internal temperature below 5 DEG C. The resulting mixture is stirred overnight at ambient temperature. After the reaction is complete (using 20% ​​ethyl acetate / hexane, monitored by TLC), the reaction mixture is poured into saturated sodium bicarbonate aqueous solution (150mL) and stirred for 1 hour. The resulting mixture is extracted with ethyl acetate (2 × 100mL). The organic layers are combined, washed with water, saturated NaCl, and dried over NaSO. The solvent is filtered and concentrated in vacuo to obtain a brown solid. The crude compound is purified by column chromatography (0-20% ethyl acetate / hexane). The compound malassezia (CV-8684) was obtained as a light pink solid (0.82 g, 74%).

[1488] HPLC purity: 97.8% (area %). 1 H-NMR, 13 C spectrum is consistent with the structure. ESI-MS: C 18 H 15 N2O(M+H) + Calculated value: 275, measured value: 275.2

[1489] Synthetic compound indolo[3,2-b]carbazole (CV-8685)

[1490] At ambient temperature, concentrated HCl (0.25 mL) was added to a solution of malassezia (0.75 g) in tetrahydrofuran (120 mL). The resulting mixture was heated to reflux overnight. After completion of the reaction (using 40% ethyl acetate / hexane, monitored by TLC), the reaction mixture was cooled to ambient temperature and stirred for 1 hour. The solid was filtered, washed with tetrahydrofuran (20 mL), and dried to give indolo[3,2-b]carbazole CV-8685) (0.55 g, 78%) as a light yellow solid.

[1491] HPLC purity: 96.22% (area %). 1 H-NMR, 13 C spectrum is consistent with the structure. ESI-MS: C 18 H 13 N2(M+H) + Calculated value: 257, measured value: 257.5.

[1492] according to Figure 2BCompound I ("CV-8686") and Compound IV ("CV-8687") were synthesized according to the scheme shown in FIG.

[1493] Synthesis of compound 5

[1494] In the flask of oven dry, add dioxane (250mL) solution containing PtCl (1.0g, 0.0038mol), Na CO (6.1g, 0.057mol), 6-methylindole (10.0g, 0.076mol) and compound 2 (10.0g, 0.038mol). Flask is degassed with nitrogen, sealed and heated to 100 ℃ and spend the night. After the reaction is complete (using 10% ethyl acetate / hexane, monitored by TLC), solvent is evaporated under reduced pressure. With ethyl acetate (400mL) diluted reaction mixture, water, saturated NaCl washing reaction mixture, through Na SO Drying. Filter solvent, and carry out vacuum concentration to obtain brown oil. Crude compound is purified by column chromatography (10% ethyl acetate / hexane). Obtain compound 5 (6.5g, 47%) as light brown solid.

[1495] Synthesis of compound 6

[1496] At ambient temperature, potassium carbonate (7.4g, 0.054mol) is added into a solution of compound 5 (6.5g, 0.018mol) in a mixture of methanol (150mL) and water (50mL). The gained suspension is heated to reflux overnight. After the completion of the reaction (using 20% ​​ethyl acetate / hexane, monitored by TLC), the reaction mixture is cooled to ambient temperature, and the solvent is concentrated in vacuo. Residue is dissolved in ethyl acetate (200mL) and washed with water and salt water, then dried (sodium sulfate), filtered, and the solvent is concentrated in vacuo to obtain a brown solid. The crude compound is purified by column chromatography (20% ethyl acetate / hexane). Compound 6 (3.3g, 72%) is obtained as an orange solid.

[1497] Synthetic compound - Compound I (CV-8686)

[1498] At 0 DEG C, under argon, dimethylformamide (20mL) is added to a dry 100mL double-necked round-bottom flask. POCl (0.6g, 0.0038mol) is slowly added over 10 minutes while maintaining an internal temperature below 5 DEG C. After stirring at 0 DEG C for 30 minutes, a solution of compound 6 (1.0g, 0.0038mol) in dimethylformamide (5mL) is slowly added over 10 minutes while maintaining an internal temperature below 5 DEG C. The resulting mixture is stirred overnight at ambient temperature. After the reaction is complete (using 20% ​​ethyl acetate / hexane, monitored by TLC), the reaction mixture is poured into saturated sodium bicarbonate aqueous solution (150mL) and stirred for 1 hour. The resulting mixture is extracted with ethyl acetate (2 × 100mL). The organic layers are combined, washed with water, saturated NaCl, and dried over NaSO. The solvent is filtered and concentrated in vacuo to obtain a brown solid. The crude compound is purified by column chromatography (0-20% ethyl acetate / hexane). Compound I (CV-8686) (0.84 g, 75%) was obtained as a light pink solid.

[1499] HPLC purity: 97.01% (area %). 1 H-NMR, 13 C spectrum is consistent with the structure. ESI-MS: C 19 H 17 N2(M+H) + Calculated value: 289, measured value: 289.1

[1500] Synthetic compound - Compound IV (CV-8687)

[1501] At ambient temperature, concentrated HCl (0.3mL) is added to a solution of compound I (1.0g) in tetrahydrofuran (125mL). The resulting mixture is heated to reflux overnight. After the completion of the reaction (using 40% ethyl acetate / hexane, monitored by TLC), the reaction mixture is cooled to ambient temperature and stirred for 1 hour. The solid is filtered, washed with tetrahydrofuran (20mL), dried, and compound IV (CV-8687) as a light yellow solid (0.84g, 89%) is obtained.

[1502] HPLC purity: 98.4% (area %). 1 H-NMR, 13 C spectrum is consistent with the structure. ESI-MS: C 19 H 15 N2(M+H) + Calculated value: 271, measured value: 271.3.

[1503] according to Figure 2C Compound II ("CV-8688") was synthesized according to the scheme shown in .

[1504] Synthesis of compound 7

[1505] At ambient temperature, copper iodide (0.53g, 10%mol) and PdCl(PPh) (1.0g, 5%mol) are added to a degassed solution of compound 1 (9.0g, 0.03mol) and 3-methoxy-1-butyne (2.8g, 0.035mol) in triethylamine (150mL). After stirring for 2 hours at ambient temperature, the reaction was completed (using 10% ethyl acetate / hexane, monitored by TLC). The reaction mixture was diluted with ethyl acetate (300mL), washed with water, saturated NaCl, and dried over NaSO. The solvent was filtered and concentrated in vacuo to obtain a brown oil. The crude compound was purified by column chromatography (10% ethyl acetate / hexane). Compound 7 (7.0g, 90%) was obtained as a light yellow liquid.

[1506] Synthesis of compound 8

[1507] In the flask of oven dry, add dioxane (250mL) solution containing PtCl (0.68g, 0.0025mol), Na CO (4.0g, 0.038mol), indole (6.0g, 0.05mol) and compound 7 (10.0g, 0.025mol). Flask is degassed with nitrogen, sealed and heated to 100 ℃ and spend the night. After the reaction is complete (using 10% ethyl acetate / hexane, monitored by TLC), solvent is evaporated under reduced pressure. With ethyl acetate (400mL) diluted reaction mixture, water, saturated NaCl washing reaction mixture, through Na SO Drying. Filter solvent, and carry out vacuum concentration to obtain brown oil. Crude compound is purified by column chromatography (10% ethyl acetate / hexane). Obtain compound 8 (3.5g, 77%) as light brown solid.

[1508] Synthesis of compound 9

[1509] At ambient temperature, potassium carbonate (3.8g, 0.027mol) is added to a solution of compound 8 (3.3g, 0.0091mol) in a mixture of methanol (75mL) and water (25mL). The resulting suspension is heated to reflux overnight. After the completion of the reaction (using 20% ​​ethyl acetate / hexane, monitored by TLC), the reaction mixture is cooled to ambient temperature, and the solvent is concentrated in vacuo. Residue is dissolved in ethyl acetate (200mL), washed with water and salt water, then dried (sodium sulfate), filtered, and the solvent is concentrated in vacuo to obtain a brown solid. The crude compound is purified by column chromatography (20% ethyl acetate / hexane). Compound 9 (2.1g, 88%) is obtained as an orange solid.

[1510] Synthetic compound - Compound II (CV-8688)

[1511] At 0 ° C, under argon, dimethylformamide (20 mL) is added to a dry 100 mL double-necked round-bottom flask. POCl (0.76 g, 0.005 mol) is slowly added over 10 minutes while maintaining an internal temperature below 5 ° C. After stirring at 0 ° C for 30 minutes, a solution of compound 9 (1.3 g, 0.005 mol) in dimethylformamide (5 mL) is slowly added over 10 minutes while maintaining an internal temperature below 5 ° C. The resulting mixture is stirred overnight at ambient temperature. After the reaction is complete (using 20% ​​ethyl acetate / hexane, monitored by TLC), the reaction mixture is poured into a saturated aqueous sodium bicarbonate solution (150 mL) and stirred for 1 hour. The resulting mixture is extracted with ethyl acetate (2 × 100 mL). The organic layers are combined, washed with water, saturated NaCl, and dried over Na2SO4. The solvent is filtered and concentrated in vacuo to give a brown solid. The crude compound is crystallized in chloroform (25 mL). Compound II (CV-8688) (0.81 g, 53%) was obtained as a light pink solid.

[1512] HPLC purity: 98.94% (area %). 1 H-NMR, 13 C spectrum is consistent with the structure. ESI-MS: C 19 H 17 N2O(M+H) + Calculated value: 289, measured value: 289.0.

[1513] Example 6

[1514] Cell morphology

[1515] Typical cell morphologies after different treatments are shown in Figure 2. Figures 5A-5K 、 6A-6K , 7A-7K, 8A-8K, 9A-9K, 10A-10K, 11A-11K, and 12A-12K. At 6 hours of treatment, 100 μM of CV-8684 and CV-8688, as well as staurosporine, significantly affected the morphology of both cell lines. CV-8685 appeared to affect WM115 only at 100 μM.

[1516] Example 7

[1517] Apoptosis-inducing activity of malassezia and malassezia derivatives-preliminary Annexin V analysis

[1518] Materials and reagents

[1519] Annexin V-FITC assay kit was purchased from Beyotime Biotechnology, RPMI 1640 medium and Dulbecco's modified Eagle's medium ("DMEM") were purchased from Gibco, fetal bovine serum ("FBS") was purchased from Invitrogen, stabilized antibiotic-antimycotic solution (100x) was purchased from Sigma, and 0.25% trypsin-EDTA (1X), phenol red were purchased from Invitrogen.

[1520] Cell culture

[1521] MeWo( HTB-65 TM ) and WM115( CRL-1675) cells were purchased from ATCC (Manassas, VA) and maintained in: for MeWo: DMEM supplemented with 10% FBS; for WM115: RPMI 1640 supplemented with 10% FBS (10% FBS, 1% stabilized antibiotic-antimycotic solution).

[1522] Research Overview

[1523] During the intermediate stages of apoptosis, phosphatidylserine ("PS") translocates from the interior of the cell to the outer layer of the cell membrane, exposing PS to the extracellular environment where it can be detected. Highly fluorescent Annexin V conjugates provide a rapid and reliable assay for studying PS externalization.

[1524] During the first set of studies, MeWo and WM115 cells were treated with 10 doses of test compounds starting at 100 μM in 3-fold dilutions. Staurosporine was used as a positive control. After 6 hours of treatment, apoptosis was assessed using the Annexin V assay. The test compounds evaluated were CV-8684, CV-8685, CV-8686, CV-8687, and CV-8688.

[1525] Analytical procedures

[1526] For cell seeding, cells were harvested and used Cell count was determined using a cell counter. Cells were subsequently diluted to the desired density using culture medium. 40 μL of cell suspension per well was added to the desired number of wells in a 384-well culture plate (Corning 3712-clear bottom culture plate). The final cell density was 6,000 cells / well. After inoculation, the culture plate was incubated overnight at 37°C and 5% CO2.

[1527] To prepare the compound source plates, each test compound was dissolved in DMSO to a 10 mM stock solution.TM A liquid handler (TECAN) performed 3-fold serial dilutions to generate ten concentrations of test compound. 0.1% DMSO was used as a vehicle (negative) control. The compound source plate was then rotated at 1,000 RPM for 1 minute at room temperature and agitated for 2 minutes using a plate shaker.

[1528] For compound treatment, 40 nL of compound was transferred from the compound source plate to a 384-well plate using a liquid handler Echo 550 (LabCyte, Inc.) After 6 hours of incubation, the plate was removed from the incubator for detection.

[1529] For the initial Annexin V assay, the culture plates were removed from the incubator and allowed to equilibrate at room temperature for 15 minutes. The culture medium was then removed. 20 μL of premixed Annexin V-FITC and Hoechst 33342 dye working solution was added to each well. The cells were then incubated at room temperature for 20 minutes. The culture plates were sealed and centrifuged at 1,000 RPM for 1 minute to remove air bubbles. The plates were then read using an Acumen eX3 plate reader. Relative activity was calculated according to the following formula: Activity (%) = 100% × (Counts) 膜联蛋白V / count 总细胞 ), and EC was calculated using GraphPad Prism (v.5.01). 50 .

[1530] result

[1531] In the initial screening described above, CV-8688 significantly increased Annexin V staining in MeWo cells, and EC 50 The positive control, staurosporine, significantly increased Annexin V staining in both cell lines. Figure 3A -3M).

[1532] Example 8

[1533] Apoptosis-inducing activity of malassezia and malassezia derivatives using Annexin V assay Other assessments

[1534] Research Overview

[1535] To further investigate the effects of test compounds on apoptosis, multiple readouts covering different stages of apoptosis were performed on both MeWo and WM115 cells. Both cell types were treated with three doses of test compound (100 μM, 10 μM, and 1 μM). Staurosporine was used as a positive control. After the desired treatment period (6, 24, 48, or 72 hours), apoptosis was assessed by measuring the percentage of cells that exhibited Annexin V binding after exposure to the test compound. The test compounds evaluated were CV-8684, CV-8685, and CV-8688.

[1536] Analytical procedures

[1537] Cell seeding was performed as described above with the following exceptions: the final cell density for the 6-hour and 24-hour assays was 4,000 cells / well, while 2,000 cells / well were used for the 48-hour and 72-hour assays. 384-well clear-bottom culture plates (Corning 3712) and solid white-bottom culture plates (Corning 3570) were prepared for each time point. The culture plates were incubated as described above.

[1538] To prepare the compound source plates, each test compound was dissolved in DMSO to a 10 mM stock solution. Two additional concentrations were generated by 10-fold dilution to 1 mM and 0.1 mM. Staurosporine was used as a positive control, while 1% DMSO was used as a vehicle (negative) control. The compound source plates were rotated at 1,000 RPM for 1 minute at room temperature and agitated on a plate shaker for 2 minutes.

[1539] An Echo 550 liquid handler was used to transfer 400 nL of test compound from the compound source plate to a 384-well plate. After 6, 24, 48, and 72 hours, the plates were removed from the incubator and assayed.

[1540] For Annexin V analysis, the culture plates were removed from the incubator and equilibrated at room temperature for 15 minutes. The culture medium was removed and the cells were washed twice with PBS. 20 μL of premixed Annexin V-FITC working solution was added to each well. The cells were incubated at room temperature for 20 minutes. The plates were read using an Acumen eX3 reader to count the number of FITC-positive cells. Relative activity was calculated according to the following for...

Claims

1. A compound having the structure of the following formula: in: X is selected from NR 14 and O formed a group; Y is a covalent bond, CR5R6, O or NR 15 ; R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ; R 13 , R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 , R 16 and C 3-6 Cycloalkyl, or R5 and R6 combine to form an oxo (=O) group or a C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups formed; Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups formed; in: If R a is hydrogen, then Y is CR5R6, and R 13 With R 14 All are hydrogen, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 and R 11 At least one of them is R 16 ;or R5 is selected from the group consisting of: hydroxyl, OR 16 , R 16 and C 3-6 Cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

2. A compound having the following structure: in: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 ,OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 ,OCOR 13 and -CHO, or R2 and R3 are combined to form a 5- or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 ,OCOR 13 and -CHO, or R7 and R8 are combined to form a 5- or 6-membered heterocyclic group; R 11 With R 12 are independently hydrogen or R 13 ; Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R 10 At least one of them is not hydrogen; or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

3. A composition comprising a compound having the structure of the following formula: in: X is selected from NR 14 and O formed a group; Y is a covalent bond, CR5R6, O or NR 15 ; R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ; R 13 , R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 , R 16 and C 3-6 Cycloalkyl, or R5 and R6 combine to form an oxo (=O) group or a C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups formed; Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups formed; or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

4. A composition comprising a compound having the formula: in: R1, R4, R5, R6, R9 and R 10 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 ,OCOR 13 and -CHO; R2 and R3 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 ,OCOR 13 and -CHO, or R2 and R3 are combined to form a 5- or 6-membered heterocyclic group; R7 and R8 are independently selected from the group consisting of hydrogen, hydroxyl, halogen, CN, R 13 , OR 13 ,OCOR 13 and -CHO, or R7 and R8 are combined to form a 5- or 6-membered heterocyclic group; R 11 and R 12 are independently hydrogen or R 13 ;and Each R 13 Independently C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 Alkynyl; or its crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt.

5. A composition comprising a compound selected from the group consisting of:

6. A method of lightening the skin of a subject, the method comprising contacting the subject with a compound or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, wherein the compound has the following structure: in: X is selected from NR 14 and O formed a group; Y is a covalent bond, CR5R6, O or NR 15 ; R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ; R 13 , R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 , R 16 and C 3-6 Cycloalkyl, or R5 and R6 combine to form an oxo (=O) group or a C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups formed; Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

7. A method of inducing apoptosis in melanocytes of a subject, the method comprising contacting the subject with a compound or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, wherein the compound has the following structure: in: X is selected from NR 14 and O formed a group; Y is a covalent bond, CR5R6, O or NR 15 ; R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ; R 13 , R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 , R 16 and C 3-6 Cycloalkyl, or R5 and R6 combine to form an oxo (=O) group or a C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups formed; Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

8. A method of modulating aryl hydrocarbon receptor (AhR) activity in a subject, the method comprising contacting the subject with a compound or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, wherein the compound has the following structure: in: X is selected from NR 14 and O formed a group; Y is a covalent bond, CR5R6, O or NR 15 ; R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ; R 13 , R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 , R 16 and C 3-6 Cycloalkyl, or R5 and R6 combine to form an oxo (=O) group or a C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups formed; Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

9. A method of regulating melanin production in a subject, the method comprising contacting the subject with a compound or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, wherein the compound has the following structure: in: X is selected from NR 14 and O formed a group; Y is a covalent bond, CR5R6, O or NR 15 ; R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ; R 13 , R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 , R 16 and C 3-6 Cycloalkyl, or R5 and R6 combine to form an oxo (=O) group or a C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups formed; Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

10. A method of regulating melanin concentration in a subject, the method comprising contacting the subject with a compound or a crystalline form, hydrate, or cosmetically or pharmaceutically acceptable salt thereof, wherein the compound has the following structure: in: X is selected from NR 14 and O formed a group; Y is a covalent bond, CR5R6, O or NR 15 ; R1, R2, R3, R4, R7, R8, R9, R 10 and R 11 are independently selected from the group consisting of hydrogen, halogen, CN, hydroxyl, R 16 OR 16 ; R 13 , R 14 and R 15 are independently hydrogen or R 16 ; R5 and R6 are independently selected from the group consisting of hydrogen, hydroxyl, OR 16 , R 16 and C 3-6 Cycloalkyl, or R5 and R6 are combined to form an oxo (=O) group or C 3-6 Cycloalkyl; R 12 Selected from hydrogen, -COR a and R 16 Groups formed; Each R 16 are independently formyl, C 1-9 Alkyl, C 2-9 Alkenyl, or C 2-9 alkynyl; and R a Selected from hydrogen, hydroxyl and OR 16 Groups composed of.

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