Compositions and methods for treating hyperpigmentation

Abstract

Provided are compositions and methods for decreasing hyperpigmentation of a subject in need thereof. In some embodiments, the methods comprise administering a composition comprising a compound having a structure of Formulas (I) or (II), or a salt thereof.

Description

P-660558-PCCOMPOSITIONS AND METHODS FOR TREATING HYPERPIGMENTATIONBACKGROUND

[0001] Hyperpigmentation, a common skin condition marked by an excess production of melanin, presents significant treatment challenges due to the side effects and limitations of existing methods. Despite being primarily a cosmetic concern, hyperpigmentation can potentially impact an individual's quality of life and self-esteem. The present disclosure addresses this critical need.SUMMARY

[0002] Provided herein is a method of decreasing hyperpigmentation on skin of a subject in need thereof, the method comprising administering to the subject a composition comprising a compound having a structure of Formula (I):Formula (I); or a salt thereof, wherein:X is CRnor N, wherein R11is selected from hydrogen, deuterium, and C1-3 alkyl;Y is selected from O, NR11, and S;Z is CR11or N;R1is selected from the group consisting of hydrogen, deuterium, -OH, -CN, -NO2, -NH2, C1-10 alkyl, Ci-10 haloalkyl, and C3-12 carbocycle, wherein the C1-10 alkyl and C3-12 carbocycle are optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, CM alkyl, -S-C1-3 alkyl, C2-4 alkenyl, and C2-4 alkynyl;P-660558-PCR2is selected from hydrogen, deuterium, -OH, -CN, -NO2, -NH2, C1-10 alkyl, and -C1-10 haloalkyl;R3is selected from the group consisting of hydrogen, deuterium, -OH, -CN, -NO2, and C1-10 alkyl; andR4is selected from C1-10 alkyl, C3-12 carbocycle, and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R41, wherein R41is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -NO2, -CN, -OR42, -SR42, and -N(R42)2, wherein R42is selected from hydrogen, deuterium, and C1-3 alkyl.

[0003] In some embodiments, X is CR11. In some embodiments, R11is hydrogen. In some embodiments, R11is C1-3 alkyl. In some embodiments, R11is Ci alkyl.

[0004] In some embodiments, X is N.

[0005] In some embodiments, Y is O. In some embodiments, Y is S.

[0006] In some embodiments, Z is CR11. In some embodiments, R11is hydrogen.

[0007] In some embodiments, Z is N.

[0008] In some embodiments, R1is hydrogen. In some embodiments, R1is -OH. In some embodiments, R1is C3-12 carbocycle. In some embodiments, R1is phenyl. In some embodiments, the phenyl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, -NO2, and CM alkyl.

[0009] In some embodiments, R2is hydrogen. In some embodiments, R2is C1-10 alkyl.

[0010] In some embodiments, R3is hydrogen. In some embodiments, R3is Ci-10 alkyl.

[0011] In some embodiments, R4is Ci-10 alkyl. In some embodiments, R4is C4 alkyl. In some embodiments, R4is tert-butyl. In some embodiments, R4is iso-butyl.

[0012] In some embodiments, R4is C5-12 carbocycle optionally substituted with one or more R41. In some embodiments, R4is phenyl. In some embodiments, the phenyl is substituted with one or more R41. In some embodiments, R41is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-e alkynyl, -NO2, -CN, and -OR42. In some embodiments, R41is C1-6 alkyl. In some embodiments, R41is C3 alkyl. In some embodiments, R41is isopropyl. In some embodiments, R4is. In some embodiments, R41is -OR42. In someP-660558-PC embodiments, R42is hydrogen. In some embodiments, R42is C1-3 alkyl. In some embodiments,R42is Ci alkyl. In some embodiments, R41is -OCH3. In some embodiments, R4is O-~._

[0013] In some embodiments, R4is selected from 5- to 12-membered heterocycle. In some embodiments, R4is selected from 5-membered heterocycle. In some embodiments, R4is selected from 5-membered heteroaryl group. In some embodiments, R4is selected from,embodiments, R4isin some embodiments, R4isIn some embodiments, the compound having a structure of Formula (I) is selected from:P-660558-PC

[0014] Provided herein is a method of decreasing hyperpigmentation on skin of a subject in need thereof, the method comprising administering to the subject a composition comprising a compound having a structure of Formula (II):Formula (II); or a salt thereof, wherein:A is selected from O, S, and NRla, wherein Rlais selected from hydrogen, deuterium, and Ci-6 alkyl;R5is selected from hydrogen, deuterium, Ci-io alkyl, Ci-iohaloalkyl, and C3-12 carbocycle, wherein the C1-10 alkyl and C3-12 carbocycle are optionally substituted with one or more substituents independently selected from halogen, deuterium, hydroxy, -NO2, CM alkyl, C1-6 aminoalkyl, -S-C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 hydroxyalkynyl, and C1-3 cyanoalkyl;R6is selected from hydrogen, deuterium, -OH, -CN, -NO2, C1-10 alkyl, Ci-io haloalkyl, - N(R61)2, -C(O)N(R61)2, -CH2N(R61)C(O)R62, -CH2N(R61)C(O)N(R62)2, -N(R61)C(O)R62, - N(R61)C(O)N(R62)2, and -N(R61)C(O)OR62,P-660558-PC wherein R61is independently selected at each occurrence from hydrogen, deuterium, Ci-io alkyl, Ci-io haloalkyl, and 5- to 12-membered heterocycle, wherein the Ci-io alkyl and 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected at each occurrence from Ci-6 alkyl, C2-6 alkenyl, C2-ealkynyl, - NO2, -CN, and -ORla, wherein R62is independently selected at each occurrence from hydrogen, deuterium, C1-10 alkyl, and 5- to 12-membered heterocycle, wherein the C1-10 alkyl and 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected at each occurrence from C1-6 alkyl, -NO2, -CN, and -ORla, wherein Rlais selected from hydrogen, deuterium, and C1-3 alkyl;R7is selected from hydrogen, deuterium, halogen, C3-12 carbocycle, and 3- to 12- membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, -OH, - OCH3, -OCH2CH3, -C(0)0CH3, -C(O)OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; andR8is selected from hydrogen, deuterium, halogen, C3-12 carbocycle, and 3- to 12- membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, -OH, - 0CH3, -OCH2CH3, -C(O)OCH3, or -C(O)OCH2CH3.

[0015] In some embodiments, A is S or NRla. In some embodiments, A is S. In some embodiments, A is NRla. In some embodiments, Rlais hydrogen.

[0016] In some embodiments, R5is hydrogen.

[0017] In some embodiments, R5is C1-10 alkyl. In some embodiments, R5is C4 alkyl.

[0018] In some embodiments, R5is C3-12 carbocycle. In some embodiments, R5is Ce carbocycle. In some embodiments, R5is phenyl.

[0019] In some embodiments, R6is hydrogen.

[0020] In some embodiments, R6is C1-10 alkyl.

[0021] In some embodiments, R6is -N(R61)2.

[0022] In some embodiments, R6is -CH2N(R61)C(O)R62. In some embodiments, R61is hydrogen.

[0023] In some embodiments, R62is selected from 5- to 12-membered heterocycle.P-660558-PC

[0024] In some embodiments, R62is selected from 5-membered heterocycle. In some embodiments, R62is selected from 5-membered heteroaryl group. In some embodiments, R62is

[0025] In some embodiments, R7is hydrogen.

[0026] In some embodiments, R7is selected from 3- to 12-membered heterocycle. In some embodiments, R7is selected from optionally substituted 8-membered heterocycle. In someeach of which is optionally substituted. In some embodiments, R7optionally substituted. In some embodiments, R7is optionally substitutedembodiments, R7is optionally substitutedIn some embodiments, R7is optionally substituted by -OH. In some embodiments,someP-660558-PC embodiments, R7is optionally substituted by -OCH3. In some embodiments, R7isIn some embodiments, R7is optionally substituted by -C(O)OCH2CH3. In some embodiments,

[0027] In some embodiments, R8is hydrogen. In some embodiments, R8is C3-12 carbocycle. In some embodiments, R8is Ce carbocycle. In some embodiments, R8is phenyl.

[0028] In some embodiments, the compound having a structure of Formula (II) is selected from:

[0029] In some embodiments, the administration of the composition comprises administering the composition to a skin of the subject. In some embodiments, an area of the skin is selected from scalp, face, under or around an eye, around a mouth or a nose, a neck, a hand, penile region,P-660558-PC around joint, a wrist, an ankle, an eyelid, on or behind a knee, on or behind an elbow, a foot, a leg, or an area of skin experiencing friction through contact, or a combination thereof.

[0030] In some embodiments, the composition is a cosmetic composition or a pharmaceutical composition.

[0031] In some embodiments, the composition further comprises an additive comprising a cosmetically acceptable carrier, an excipient, an adjuvant, a diluent, or a combination thereof.

[0032] In some embodiments, the composition is formulated as a toner, a cream, an emulsion, a lotion, an ointment, a paste, a gel, a suspension, a serum, an oil, an edible supplement, a direct injection, a beverage, a transdermal patch, a topical patch, a moisturizer, a face mask, a shampoo, a foam, a cleanser, a mousse, a liquid, a powder, an aerosol, a spray, a balm, a pigmentcontaining cosmetic, a foundation, a primer, a concealer, a sunscreen, or a combination thereof.

[0033] In some embodiments, the composition is formulated by delivery vehicles selected from an aqueous phase solution, an oil phase solution, water-in-oil emulsion, oil-in-water emulsion, water-in-oil-in-water emulsion, oil-in-water-in-oil emulsion, water-in-silicone emulsion, silicone-in-water emulsion, encapsulation, a liposome, a vesicle, an ethosome, a polymersome, an exosome, a transfersome, a niosome, a complex, a cyclodextrin, a lipid nanoparticle, a nanoparticle, a microparticle, a macroparticle, solid powder, or a combination thereof.

[0034] In some embodiments, the administration of the composition decreases hyperpigmentation selected from melasma, sunspots, solar lentigos, age spots, liver spots, Cafe au lait spot, post-inflammatory hyperpigmentation, uneven skin tone, drug-induced hyperpigmentation, and a combination thereof.

[0035] In some embodiments, the administration of the composition decreases melanocyte viability. In some embodiments, the administration of the composition results in skin brightening or whitening. In some embodiments, the administration of the composition reduces the abundance of melanocytes, decreases the viability of melanocytes, controls proliferation of new melanocytes, suppresses melanocytes, or a combination thereof. In some embodiments, the administration of the composition results in the inhibition of melanosome transfer, inhibition of melanin production, regulation of the melanocyte environment, or a combination thereof. In some embodiments, the administration of the composition aids in reducing oxidative stress, preventing oxidative stress, or a combination thereof. In some embodiments, the administrationP-660558-PC of the composition facilitates pigment removal, brightens within the dermal layer, reduces of skin hyperpigmentation, balances skin tone irregularities, or a combination thereof. In some embodiments, the administration of the composition improves skin barrier function, inhibits melanogenesis, regulates melanocyte viability, reduces melanocyte quantity, or a combination thereof. In some embodiments, the administration of the composition aids in fading age spots, dark spots, or treats post-acne scars or marks. In some embodiments, the administration of the composition cleanses the skin of dirt, oil, germs, dead skin cells, or any other impurities. In some embodiments, the administration of the composition increases skin moisture. In some embodiments, the administration of the composition reduces skin roughness or fine lines. In some embodiments, the administration of the composition protects the skin from ultraviolet damage.

[0036] In some embodiments, the composition is administered one to three times a day. In some embodiments, the composition is administered two times a day. In some embodiments, the composition is administered three times a day. In some embodiments, the composition is administered for at least two consecutive days. In some embodiments, the composition is administered for at least five consecutive days. In some embodiments, the composition is administered for at least seven consecutive days. In some embodiments, the composition is administered at least for about 15 days, about 30 days, about 60 days, about 90 days, about 6 months, or a year.

[0037] Provided herein is a kit for use in performing the method described herein. In some embodiments, the kit further comprises an applicator. In some embodiments, the applicator comprises a brush, a comb, a cotton swab, a spatula, a spoon, a dropper, a spray nozzle, a squeeze bottle, a pump bottle, a tube, an applicator wand, a sponger, a foam blender, a silicone applicator, a rollerball, a powder puff, a tottle, a microneedling device, a microneedling stamp, a microneedling roller, a microneedling pen, a microneedling patch, dissolvable microneedles, a transdermal patch, a hydrocolloid patch, or a combination thereof. In some embodiments, the kit further comprises written instructions for using the kit.

[0038] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the presentP-660558-PC disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure.Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.INCORPORATION BY REFERENCE

[0039] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0041] FIG. 1A-FIG. IF display the results of measurement of cellular proliferation in human melanocytes, in accordance with one or more embodiments of the present disclosure. They demonstrate that the compounds disclosed herein can reduce cellular proliferation in melanocytes. Cellular viability changes, resulting from the treatment with the example compounds (Table 1), were assessed using a CellTiter-Glo™ assay (Promega). A dosedependent reduction in normalized viability was observed across the example compounds (open circle). The data presented signifies the mean ± standard deviation (s.d.), collected from a total of three experimental replicates. For comparative analysis, Hydroquinone (HQ) (closed circle), a recognized compound known for reducing the quantity of viable melanocytes, was included as a benchmark.

[0042] FIG. 2A shows a standard curve of representative luminescence versus melanin concentration (mg / ml), in accordance with one or more embodiments of the present disclosure.P-660558-PCThe linear portions of the melanin standard curves were employed to convert luminescence into melanin concentration in the experimental samples.

[0043] FIG. 2B displays relative melanin content (%) for the example compounds (Table 1) from a luminescence-based melanin content assay, in accordance with one or more embodiments of the present disclosure. The bar graphs depict the average, and a dose-dependent decrease in normalized viability was observed across the compounds under the investigation. The data represents the mean ± standard deviation (s.d.) gathered from a minimum of three experimental replicates (represented by circles).

[0044] FIG. 3A-FIG. 3D display relative viability (%) of diverse healthy, non-melanocyte human cell types, including keratinocytes (3 A), fibroblasts (3B), follicle dermal papilla cells (3C), and microvascular endothelial cells (3D) vs concentration of the example compounds, in accordance with one or more embodiments of the present disclosure. A CellTiter-Glo™ assay (Promega) was deployed to measure the viability of various primary human skin and non-skin cells when exposed to increasing concentrations of the example compounds. Hydroquinone (HQ), a compound known for its melanocytotoxic properties, was used as a benchmark. The data depicted represents the mean ± standard deviation (s.d.) of n=3 technical replicates, and is representative of at least two experimental replicates.

[0045] FIG. 4 provides KeratinoSense assay results of the example compounds, in accordance with one or more embodiments of the present disclosure. The HEK-KeratinoSens cell line (BPS Biosciences) was utilized to assess potential skin sensitization. This cell line has the firefly luciferase gene inserted under the control of the ARE-response pathway. Therefore, treatment with the compounds leading to the activation of the ARE-NRF2 pathway displays high luminescence values and has positive KeratinoSens assay scores when compared to a control. Hydroquinone (HQ), a known melanocytotoxic and skin-sensitizing agent, was used as a benchmark. The data represents the mean ± standard deviation (s.d.) of n=3 technical replicates.

[0046] FIG. 5 provides NHEM-As cell viability assay results of Compound 712A.

[0047] FIG. 6 provides NHEM-Af melanin content assay results of Compound 712A.P-660558-PCDETAILED DESCRIPTION

[0048] Hyperpigmentation is a common skin condition characterized by the darkening of an area of the skin or nails due to an excess of melanin. Melanin is the pigment that gives skin, hair, and eyes their color. When the skin produces more melanin than usual, it can lead to conditions such as freckles, age spots, Melasma, and other forms of hyperpigmentation. This condition can occur in small patches, cover large areas, or affect the entire body, presenting in various forms and degrees of severity. The causes of hyperpigmentation are varied, with factors including excessive sun exposure, hormonal fluctuations such as those caused by pregnancy or medication, inflammation, skin injuries or trauma, and certain diseases or conditions. Additionally, individuals with darker skin tones are more prone to hyperpigmentation due to higher levels of melanin in their skin.

[0049] Treatment of hyperpigmentation can be complex and often includes the use of topical treatments such as creams, lotions, and serums. These products often contain active ingredients designed to inhibit the production of melanin. One such treatment is hydroquinone, which has been the standard in the treatment of hyperpigmentation for many years. However, the use of hydroquinone has been associated with potential adverse effects. Overuse can lead to skin discoloration, and it has been linked to more severe health issues in some studies. As a result, hydroquinone has been banned or restricted in several countries, including those in the European Union, Japan, and Australia. Other compounds like kojic acid, azelaic acid, and certain retinoids have been used as alternative treatments for hyperpigmentation. While they can be effective, they may also cause skin irritation, sensitivity, and other undesirable side effects. This is particularly true when they are used over a long period or in high concentrations. Therefore, safer and more effective alternatives are needed for the treatment of hyperpigmentation.

[0050] The present disclosure aims to address this gap in the field of dermatology. It pertains to specific compounds or salts thereof, their compositions, and their use as a potential treatment for hyperpigmentation. The disclosed compounds or salts thereof have been found to effectively modulate melanin production and the proliferation rate in melanocytes, making them viable candidates for treating hyperpigmentation. The safety, stability, and efficacy of the disclosed compounds or salts thereof may give them a significant advantage over currently usedP-660558-PC treatments. These characteristics make the composition comprising the compounds or salts thereof promising candidates for the development of topical formulations, including creams, lotions, and serums, for the treatment of hyperpigmentation and other related skin disorders. The present disclosure also encompasses methods of treatment using the composition comprising these compounds or salts thereof. These methods could potentially offer improved results and fewer side effects compared to currently available treatments.

[0051] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.DEFINITIONS

[0052] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0053] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure.Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.P-660558-PC

[0054] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0055] The term “Cx-y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “Ci-ealkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.

[0056] The terms “Cx.yalkenyl” and “Cx.yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.

[0057] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0058] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., Cb-Cs alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., Ci-Ce alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like.

[0059] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., Ch-Cs alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., Ci-Ce alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.P-660558-PC

[0060] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, w-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., Ci-Cs alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., Ci-Cs alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., Cj-Cx alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene).

[0061] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group may be through any two carbons within the chain. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-C10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., Ch-Cx alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2 alkenylene). In other embodiments, an alkenylene comprisesP-660558-PC five to eight carbon atoms (i.e., Cs-Cs alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene).

[0062] The term “aryl” refers to an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

[0063] The term “cycloalkyl” refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyl may include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, spiro bicycles, and 5- to 12-membered bridged rings. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0064] “Carbocycle” refers to a saturated, unsaturated or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom.

[0065] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond.P-660558-PCExamples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbomyl ( / .<?., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0066] The term “halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0067] The term “haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1 -chloromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the haloalkyl radical is optionally further substituted as described herein.

[0068] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro bicycles, and 5- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. A bicyclic heterocycle further includes spiro bicyclic rings e.g., 5 to 12-membered spiro bicycles.

[0069] The term "heteroaryl" refers to a radical derived from a 5 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) n-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl,P-660558-PC benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, and thiophenyl (i.e. thienyl).

[0070] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0071] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazino (=N-NH2), -Rbb-0Raa, -Rbb-OC(O)-Raa, -Rbb-OC(O)-ORaa, - Rbb-OC(O)-N(Raa)2, -Rbb-N(Raa)2, -Rbb-C(O)Raa, -Rbb-C(O)ORaa, -Rbb-C(O)N(Raa)2, - Rbb-O-Rcc-C(O)N(Raa)2, -Rbb-N(Raa)C(O)ORaa, -Rbb-N(Raa)C(O)Raa, -Rbb-N(Raa)S(O)tRaa(where t is 1 or 2), -Rbb-S(O)tRaa(where t is 1 or 2), -Rbb-S(O)tORaa(where t is 1 or 2), and - Rbb-S(O)tN(Raa)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), -Rbb-0Raa, -Rbb-OC(O)-Raa, -Rbb-OC(O)-ORaa, -P-660558-PC alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Raa, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-0H), hydrazine (=N-NH2), - Rbb-0Raa, -Rbb-0C(0)-Raa, -Rbb-0C(0)-0Raa, -Rbb-0C(0)-N(Raa)2, -Rbb-N(Raa)2, -Rbb-C(0)Raa, - Rbb-C(0)0Raa, -Rbb-C(0)N(Raa)2, -Rbb-0-Rcc-C(0)N(Raa)2, -Rbb-N(Raa)C(0)0Raa, - Rbb-N(Raa)C(0)Raa, -Rbb-N(Raa)S(0)tRaa(where t is 1 or 2), -Rbb-S(O)tRaa(where t is 1 or 2), - Rbb-S(O)tORaa(where t is 1 or 2) and -Rbb-S(O)tN(Raa)2(where t is 1 or 2); and wherein each Rbbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rccis a straight or branched alkylene, alkenylene or alkynylene chain.

[0072] Double bonds to oxygen atoms, such as oxo groups, are represented herein as both “=O” and “(O)” Double bonds to nitrogen atoms are represented as both “=NR” and “(NR)”. Double bonds to sulfur atoms are represented as both “=S” and “(S)”.

[0073] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0074] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol andP-660558-PC polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0075] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0076] In certain embodiments, the term “cosmetically acceptable salt” means any salt that is cosmetically tolerated if used appropriately for a cosmetic treatment especially if used on or applied to humans and / or mammals. In certain embodiments, these salts include, but are not restricted to the salts used to form base addition salts, either inorganic, such as for example and in a non-limiting sense, lithium, sodium, potassium, calcium, magnesium or aluminium, among others, or organic such as for example and in a non-limiting sense, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine, or piperazine among others; or acid addition salts, either organic, such as for example and in a non-limiting sense,P-660558-PC acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate or gluconate among others, or inorganic, such as for example and in a non-limiting sense, chloride, sulfate, borate, or carbonate among others.

[0077] A “cosmetically effective amount” as used herein refers to the amount of a compound sufficient to improve the outward physical appearance of a subject. It is to be understood that a “cosmetically effective” amount can vary from subject to subject, due to numerous factors including for example age, weight, and general condition of the subject.

[0078] The phrase “cosmetically acceptable excipient” or “cosmetically acceptable carrier” as used herein comprises as a cosmetic cream base, an oil-in-water emulsion, a water-in-oil emulsion, a silicone-in-water emulsion, a water-in-silicone emulsion, a gel, or the like. The skilled artisan will understand that the appropriate carriers typically will contain ingredients, such as those typically found in the cosmetic and cosmeceutical fields: oils, waxes or other standard fatty substances, or conventional gelling agents and / or thickeners; emulsifiers; moisturizing agents; emollients; sunscreens; hydrophilic or lipophilic active agents; agents for combatting free radicals; preservatives; basifying or acidifying agents; fragrances; surfactants; fillers; natural products or extracts of natural product, such as aloe or green tea extract; vitamins; or coloring materials.

[0079] A term “nutraceutical” as used herein refers to any compounds or chemicals that are capable of having beneficial dietary or healing effects when consumed by humans or animals.

[0080] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0081] The terms “subject,” “individual,” or “patient” are often used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, andP-660558-PC protozoa. The subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.

[0082] The term “hyperpigmentation,” as referred to in the present disclosure, is a dermatological condition characterized by the darkening of patches of skin caused by an excess production of melanin, the pigment responsible for skin, hair, and eye color. This overproduction can be triggered by various factors such as sun exposure, hormonal changes, inflammation, and skin injuries or diseases. The condition can occur in small patches, cover large areas, or in some cases, affect the entire body. Hyperpigmentation presents in several forms, including freckles, age spots, Melasma, and other related skin conditions.

[0083] The term “zn vivo” is used to describe an event that takes place in a subject’s body.

[0084] The term “ex vivo” is used to describe an event that takes place outside of a subject’s body. An ex vivo assay is not performed on a subject. Rather, it is performed upon a sample separate from a subject. An example of an ex vivo assay performed on a sample is an “in vitro” assay.

[0085] The term “in vitro” is used to describe an event that takes places contained in a container for holding laboratory reagent such that it is separated from the biological source from which the material is obtained. In vitro assays can encompass cell-based assays in which living or dead cells are employed. In vitro assays can also encompass a cell-free assay in which no intact cells are employed.

[0086] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[0087] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the seventy of one or more symptoms of the disorder or condition relative to the untreated control sample.P-660558-PC

[0088] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[0089] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0090] “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0091] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.COMPOUNDS

[0092] The present disclosure provides compounds or a salt thereof, designed with the intention of treating hyperpigmentation of a subject in need. These compounds may have a structure ofP-660558-PCFormula (I) or Formula (II) or a salt thereof. The compounds or salts thereof disclosed herein may be utilized in the compositions and methods disclosed herein.

[0093] In certain aspects, disclosed herein is a compound having a structure of Formula (I):Formula (I); or a salt thereof, wherein:X is CR11or N;Y is selected from O, NR11, and S;Z is CR11or N, wherein R11is selected from hydrogen, deuterium, and C1-3 alkyl;R1is selected from the group consisting of hydrogen, deuterium, -OH, -CN, -NO2, -NH2, C1-10 alkyl, Ci-io haloalkyl, and C3-12 carbocycle, wherein the C1-10 alkyl and C3-12 carbocycle are optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, C1-4 alkyl, -S-C1-3 alkyl, C2-4 alkenyl, and C2-4 alkynyl;R2is selected from hydrogen, deuterium, -OH, -CN, -NO2, -NH2, C1-10 alkyl, and -C1-10 haloalky 1;R3is selected from the group consisting of hydrogen, deuterium, -OH, -CN, -NO2, and C1-10 alkyl; andR4is selected from C1-10 alkyl, C3-12 carbocycle, and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R41, wherein R41is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -NO2, -CN, -OR42, -SR42, and -N(R42)2, wherein R42is selected from hydrogen, deuterium, and C1-3 alkyl.

[0094] In some embodiments, the compound has a structure of Formula (I):P-660558-PCFormula (I); or a salt thereof, wherein:X is CR11or N;Y is selected from O, NR11, and S;Z is CR11or N;R1is selected from the group consisting of hydrogen, deuterium, -OH, -CN, -NO2, -NH2, C1-10 alkyl, Ci-io haloalkyl, and C3-12 carbocycle;R2is selected from hydrogen, deuterium, -OH, -CN, -NO2, -NH2, C1-10 alkyl, and -C1-10 haloalky 1;R3is selected from the group consisting of hydrogen, deuterium, -OH, -CN, -NO2, and C1-10 alkyl; andR4is selected from C1-10 alkyl, C3-12 carbocycle, and 5- to 12-membered heterocycle.

[0095] In some embodiments, X is CR11or N. In some embodiments, X is N. In some embodiments, X is CR11. In some embodiments, R11is selected from hydrogen, deuterium, and C1-3 alkyl. In some embodiments, R11is hydrogen. In some embodiments, R11is deuterium. In some embodiments, R11is C1-3 alkyl. In some embodiments, R11is Ci alkyl. In some embodiments, R11is C2 alkyl. In some embodiments, R11is C3 alkyl.

[0096] In some embodiments, Y is selected from O, NR11, and S. In some embodiments, Y is O. In some embodiments, Y is NR11. In some embodiments, R11is selected from hydrogen, deuterium, and C1-3 alkyl. In some embodiments, R11is hydrogen. In some embodiments, R11is deuterium. In some embodiments, R11is C1-3 alkyl. In some embodiments, R11is Ci alkyl. In some embodiments, R11is C2 alkyl. In some embodiments, R11is C3 alkyl. In some embodiments, Y is S.

[0097] In some embodiments, Z is CR11or N. In some embodiments, Z is N. In some embodiments, Z is CR11. In some embodiments, R11is selected from hydrogen, deuterium, andP-660558-PCCi-3 alkyl. In some embodiments, R11is hydrogen. In some embodiments, R11is deuterium. In some embodiments, R11is C1-3 alkyl. In some embodiments, R11is Ci alkyl. In some embodiments, R11is C2 alkyl. In some embodiments, R11is C3 alkyl.

[0098] In some embodiments, R1is selected from the group consisting of hydrogen, deuterium, - OH, -CN, -NO2, -NH2, Ci-10 alkyl, Ci-io haloalkyl, and C3-12 carbocycle. In some embodiments, R1is hydrogen. In some embodiments, R1is deuterium. In some embodiments, R1is -OH. In some embodiments, R1is -CN. In some embodiments, R1is -NO2. In some embodiments, R1is - NH2. In some embodiments, R1is C1-10 alkyl. In some embodiments, R1is C1-6 alkyl. In some embodiments, R1is Ci alkyl. In some embodiments, R1is C2 alkyl. In some embodiments, R1is C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CH3)2. In some embodiments, R1is C4 alkyl. In some embodiments, C4 alkyl is CH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, R1is C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In some embodiments, R1is Ce alkyl. In some embodiments, Ce alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2. In some embodiments, R1is Ci-io haloalkyl. In some embodiments, R1is C3-12 carbocycle. In some embodiments, R1is Ce carbocycle. In some embodiments, R1is Cs carbocycle. In some embodiments, R1is C10 carbocycle. In some embodiments, R1is phenyl.

[0099] In some embodiments, the C1-10 alkyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, C1-4 alkyl, -S-C1-3 alkyl, C2-4 alkenyl, and C2-4 alkynyl. In some embodiments, the C1-10 alkyl is optionally substituted with one or more halogen. In some embodiments, the C1-10 alkyl is optionally substituted with one or more hydroxy. In some embodiments, the C1-10 alkyl is optionally substituted with one or more -NO2. In some embodiments, the C1-10 alkyl is optionally substituted with one or more C1-4 alkyl. In some embodiments, the C1-10 alkyl is optionally substituted with one or more -S-C1-3 alkyl. In some embodiments, the C1-10 alkyl is optionally substituted with one or more C2-4 alkenyl. In some embodiments, the C1-10 alkyl is optionally substituted with one or more C2-4 alkynyl.

[0100] In some embodiments, the C3-12 carbocycle is optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, C1-4 alkyl, -S-C1-3 alkyl, C2-4 alkenyl, and C2-4 alkynyl. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more halogen. In some embodiments, the C3-12 carbocycle is optionally substitutedP-660558-PC with one or more hydroxy. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more -NO2. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more C alkyl. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more -S-C1-3 alkyl. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more C2-4 alkenyl. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more C2-4 alkynyl.

[0101] In some embodiments, the phenyl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, =0, -NO2, CM alkyl, -S-C1-3 alkyl, C2-4 alkenyl, and C2-4 alkynyl. In some embodiments, the phenyl is optionally substituted with one or more halogen. In some embodiments, the phenyl is optionally substituted with one or more hydroxy. In some embodiments, the phenyl is optionally substituted with one or more =0. In some embodiments, the phenyl is optionally substituted with one or more -NO2. In some embodiments, the phenyl is optionally substituted with one or more CM alkyl. In some embodiments, the phenyl is optionally substituted with one or more -S-C1-3 alkyl. In some embodiments, the phenyl is optionally substituted with one or more C2-4 alkenyl. In some embodiments, the phenyl is optionally substituted with one or more C2-4 alkynyl.

[0102] In some embodiments, R2is selected from hydrogen, deuterium, -OH, -CN, -NO2, -NH2, Ci-10 alkyl, and -Ci-io haloalkyl. In some embodiments, R2is hydrogen. In some embodiments, R2is deuterium. In some embodiments, R2is -OH. In some embodiments, R2is -CN. In some embodiments, R2is -NO2. In some embodiments, R2is -NH2. In some embodiments, R2is C1-10 alkyl. In some embodiments, R2is C1-6 alkyl. In some embodiments, R2is Ci alkyl. In some embodiments, R2is C2 alkyl. In some embodiments, R2is C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CHs)2. In some embodiments, R2is C4 alkyl. In some embodiments, C4 alkyl is CH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, R2is C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In some embodiments, R2is C& alkyl. In some embodiments, C& alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2. In some embodiments, R2is -Ci-io haloalkyl.

[0103] In some embodiments, R3is selected from the group consisting of hydrogen, deuterium, - OH, -CN, -NO2, and C1-10 alkyl. In some embodiments, R3is hydrogen. In some embodiments, R3is deuterium. In some embodiments, R3is -OH. In some embodiments, R3is -CN. In someP-660558-PC embodiments, R3is -NO2. In some embodiments, R3is C1-10 alkyl. In some embodiments, R3is C1-6 alkyl. In some embodiments, R3is Ci alkyl. In some embodiments, R3is C2 alkyl. In some embodiments, R3is C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CH3)2. In some embodiments, R3is C4 alkyl. In some embodiments, C4 alkyl is CH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, R3is C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In some embodiments, R3is C& alkyl. In some embodiments, C6alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2.

[0104] In some embodiments, R4is selected from C1-10 alkyl, C3-12 carbocycle, and 5- to 12- membered heterocycle. In some embodiments, R4is Ci-10 alkyl. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is Ci alkyl. In some embodiments, R4is C2 alkyl. In some embodiments, R4is C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CH3)2. In some embodiments, R4is C4 alkyl. In some embodiments, C4 alkyl is CH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, C4 alkyl is tert-butyl. In some embodiments, C4 alkyl is iso-butyl. In some embodiments, R4is C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In some embodiments, R4is C& alkyl. In some embodiments, C6alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2.

[0105] In some embodiments, R4is C3-12 carbocycle. In some embodiments, R4is optionally substituted C3-12 carbocycle. In some embodiments, R4is C3-12 carbocycle optionally substituted with one or more R41. In some embodiments, R4is G> carbocycle optionally substituted with one or more R41. In some embodiments, R4is Cs carbocycle optionally substituted with one or more R41. In some embodiments, R4is C10 carbocycle optionally substituted with one or more R41. In some embodiments, R4is phenyl optionally substituted with one or more R41.

[0106] In some embodiments, the C3-12 carbocycle is optionally substituted with one or more R41. In some embodiments, R41is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -NO2, -CN, -OR42, -SR42, and -N(R42)2. In some embodiments, R41is independently C1-6 alkyl. In some embodiments, R41is independently C1-3 alkyl. In some embodiments, R11is independently C2 alkyl. In some embodiments, R41is independently C3 alkyl. In some embodiments, R41is independently isopropyl. In some embodiments, R41is independently C2-6 alkenyl. In some embodiments, R41is independently C2-6 alkynyl. In some embodiments, R41is independently -NO2. In some embodiments, R41is independently -CN. InP-660558-PC some embodiments, R41is independently -OR42. In some embodiments, R41is -SR42. In some embodiments, R41is independently -N(R42)2.

[0107] In some embodiments, R42is selected from hydrogen, deuterium, and C1-3 alkyl. In some embodiments, R42is hydrogen. In some embodiments, R42is deuterium. In some embodiments, R42is C1-3 alkyl. In some embodiments, R42is Ci alkyl. In some embodiments, R42is C2 alkyl. In some embodiments, R42is C3 alkyl.

[0108] In some embodiments, R4is C3-12 carbocycle. In some embodiments, R4is optionally substituted C3-12 carbocycle. In some embodiments, R4is C3-12 carbocycle optionally substituted with one or more R41. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more C1-6 alkyl. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more C2-6 alkenyl. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more C2-6 alkynyl. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more -NO2. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more -CN. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more -OR42. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more -SR42. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more -N(R42)2.

[0109] In some embodiments, R4is Ce carbocycle. In some embodiments, R4is Cs carbocycle. In some embodiments, R4is C10 carbocycle. In some embodiments, R4is phenyl. In some embodiments, phenyl is optionally substituted with one or more C1-6 alkyl. In some embodiments, phenyl is optionally substituted with one or more C2-6 alkenyl. In some embodiments, phenyl is optionally substituted with one or more C2-6 alkynyl. In some embodiments, phenyl is optionally substituted with one or more -NO2. In some embodiments, phenyl is optionally substituted with one or more -CN. In some embodiments, phenyl is optionally substituted with one or more -OR42. In some embodiments, phenyl is optionally substituted with one or more -SR42. In some embodiments, phenyl is optionally substituted with one or more -N(R42)2.

[0110] In some embodiments, the C3-12 carbocycle is optionally substituted with one or more R41. In some embodiments, R41is independently C1-3 alkyl. In some embodiments, R41isP-660558-PC independently C3 alkyl. In some embodiments, R41is independently isopropyl. In some embodiments, R4is. In some embodiments,

[0111] In some embodiments, R4is C3-12 carbocycle. In some embodiments, R4is optionally substituted C3-12 carbocycle. In some embodiments, R4is C3-12 carbocycle optionally substituted with one or more R41. In some embodiments, the C3-12 carbocycle is optionally substituted with one or more R41. In some embodiments, R4is Ce carbocycle. In some embodiments, R4is Cs carbocycle. In some embodiments, R4is C10 carbocycle.

[0112] In some embodiments, R4is phenyl optionally substituted with one or more R41. In some embodiments, R41is independently -OR42. In some embodiments, R42is selected from hydrogen, deuterium, and C1-3 alkyl. In some embodiments, R42is hydrogen. In some embodiments, R42is deuterium. In some embodiments, R42is C1-3 alkyl. In some embodiments, R42is Ci alkyl. In some embodiments, R42is C2 alkyl. In some embodiments, R42is C3 alkyl. In some embodiments, R41is independently -OH. In some embodiments, R41is independently -OCH3. In some embodiments, R4is. In some embodiments, R4is

[0113] In some embodiments, R4is 5- to 12-membered heterocycle optionally substituted with one or more R41. In some embodiments, R4is 5-membered heterocycle optionally substituted with one or more R41. In some embodiments, R4is 6-membered heterocycle optionally substituted with one or more R41. In some embodiments, R4is 8-membered heterocycle optionally substituted with one or more R41. In some embodiments, R4is 10-membered heterocycle optionally substituted with one or more R41. In some embodiments, R4is 12- membered heterocycle optionally substituted with one or more R41.

[0114] In some embodiments, R4is selected from 5-membered heterocycle optionally substituted with one or more R41. In some embodiments, R4is selected from 5-membered heteroaryl group optionally substituted with one or more R41. In some embodiments, R4is selected fromP-660558-PCembodiments, R4is optionally substitutedIn some embodiments, R4is optionally substitutedIn some embodiments, R4is optionally substitutedsome embodiments, R4is optionally substitutedIn some embodiments, R4is optionally in some embodiments, R4is. In some embodiments, R4is

[0115] In some embodiments, the compound having a structure of Formula (I) is selected from:P-660558-PC

[0116] In some embodiments, the compound having a structure of Formula (I) is.

[0118] In some embodiments, the compound having a structure of Formula (I) isor a salt thereof.

[0119] In some embodiments, the compound having a structure of Formula (I) isP-660558-PC.

[0121] In some embodiments, the compound having a structure of Formula (I) is.

[0123] In some embodiments, the compound having a structure of Formula (I) isor a salt thereof.

[0124] In some embodiments, the compound having a structure of Formula (I) isP-660558-PC or a salt thereof. ents, the compound having a structure of Formula (I) isor a salt thereof.

[0126] In some embodiments, the compound having a structure of Formula (I) isor a salt thereof.

[0127] In certain aspects, disclosed herein is a compound having a structure of Formula (II):Formula (II); or a salt thereof, wherein:A is selected from O, S, and NRla, wherein Rlais selected from hydrogen, deuterium, and Ci-6 alkyl;R5is selected from hydrogen, deuterium, Ci-io alkyl, Ci-io haloalkyl, and C3-12 carbocycle, wherein the C1-10 haloalkyl and C3-12 carbocycle are optionally substituted with one or more substituents independently selected from halogen, deuterium, hydroxy, -NO2, CM alkyl, CM aminoalkyl, -S-C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 hydroxyalkynyl, and C1-3 cyanoalkyl;P-660558-PCR6is selected from hydrogen, deuterium, -OH, -CN, -NO2, C1-10 alkyl, C1-10 haloalkyl, -N(R61)2, - C(O)N(R61)2, -CH2N(R61)C(O)R62, -CH2N(R61)C(O)N(R62)2, -N(R61)C(O)R62, - N(R61)C(O)N(R62)2, and -N(R61)C(O)OR62, wherein R61is independently selected at each occurrence from hydrogen, deuterium, C1-10 alkyl, Ci-10 haloalkyl, and 5- to 12-membered heterocycle, wherein the C1-10 alkyl and 5- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-ealkynyl, - NO2, -CN, and -ORla, wherein R62is independently selected at each occurrence from hydrogen, deuterium, C1-10 alkyl, and 5- to 12-membered heterocycle, wherein the C1-10 alkyl and 5- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected at each occurrence from C1-6 alkyl, -NO2, -CN, and -ORla, wherein Rlais selected from hydrogen, deuterium, and C1-3 alkyl;R7is selected from hydrogen, deuterium, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, -OH, -OCH3, -OCH2CH3, -C(0)0CH3, -C(O)OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; andR8is selected from hydrogen, deuterium, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, -OH, -OCH3, -OCH2CH3, - C(O)OCH3, or -C(O)OCH2CH3.

[0128] In some embodiments, the compound has a structure of Formula (II):Formula (II); or a salt thereof, wherein:A is selected from O, S, and NRla;R5is selected from hydrogen, deuterium, C1-10 alkyl, C1-10 haloalkyl, and C3-12 carbocycle;P-660558-PCR6is selected from hydrogen, deuterium, -OH, -CN, -NO2, C1-10 alkyl, C1-10 haloalkyl, -N(R61)2, - C(O)N(R61)2, -CH2N(R61)C(O)R62, -CH2N(R61)C(O)N(R62)2, -N(R61)C(O)R62, - N(R61)C(O)N(R62)2, and -N(R61)C(O)OR62;R7is selected from hydrogen, deuterium, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle; andR8is selected from hydrogen, deuterium, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0129] In some embodiments, A is selected from O, S, and NRla. In some embodiments, A is O. In some embodiments, A is S. In some embodiments, A is NRla. In some embodiments, Rlais selected from hydrogen, deuterium, and Ci-6 alkyl. In some embodiments, Rlais hydrogen. In some embodiments, Rlais deuterium. In some embodiments, Rlais Ci-6 alkyl. In some embodiments, Rlais Ci alkyl. In some embodiments, Rlais C2 alkyl. In some embodiments, Rlais C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CHs)2. In some embodiments, Rlais C4 alkyl. In some embodiments, C4 alkyl is CH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, Rlais C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In some embodiments, Rlais Ce alkyl. In some embodiments, Ce alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2.

[0130] In some embodiments, R5is selected from hydrogen, deuterium, C1-10 alkyl, C1-10 haloalkyl, and C3-12 carbocycle. In some embodiments, R5is hydrogen. In some embodiments, R5is deuterium. In some embodiments, R5is C1-10 alkyl. In some embodiments, R5is Ci alkyl. In some embodiments, R5is C2 alkyl. In some embodiments, R5is C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CHs)2. In some embodiments, C3 alkyl is CH2CH2CH3. In some embodiments, C3 alkyl is CH(CHs)2. In some embodiments, R5is C4 alkyl. In some embodiments, C4 alkyl is CH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, C4 alkyl is CH2CH2CH2CH3. In some embodiments, C4 alkyl is CH2CH(CH3)2. In some embodiments, R5is C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3. In some embodiments, C5 alkyl is (CH2)2CH(CH3)2. In some embodiments, R5is Ce alkyl. In some embodiments, Ce alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2. In some embodiments, Ce alkyl isP-660558-PCCH2CH2CH2CH2CH2CH3. In some embodiments, Ce alkyl is (CH2)3CH(CH3)2. In some embodiments, R5is C 1-10 haloalky 1.

[0131] In some embodiments, R5is C3-12 carbocycle. In some embodiments, R5is Ce carbocycle. In some embodiments, R5is Cs carbocycle. In some embodiments, R5is C10 carbocycle. In some embodiments, R5is phenyl.

[0132] In some embodiments, the C1-10 alkyl is optionally substituted with one or more substituents independently selected from halogen, deuterium, hydroxy, -NO2, CM alkyl, CM aminoalkyl, -S-C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 hydroxyalkynyl, and C1-3 cyanoalkyl. In some embodiments, the C1-10 alkyl is optionally and independently substituted with one or more halogen. In some embodiments, the C1-10 alkyl is optionally and independently substituted with one or more deuterium. In some embodiments, the C1-10 alkyl is optionally and independently substituted with one or more hydroxy. In some embodiments, the C1-10 alkyl is optionally and independently substituted with one or more -NO2. In some embodiments, the C1-10 alkyl is optionally and independently substituted with one or more CM alkyl. In some embodiments, the Ci-10 alkyl is optionally and independently substituted with one or more CM aminoalkyl. In some embodiments, the C1-10 alkyl is optionally and independently substituted with one or more -S-C1-3 alkyl. In some embodiments, the C1-10 alkyl is optionally and independently substituted with one or more C2-4 alkenyl. In some embodiments, the C1-10 alkyl is optionally and independently substituted with one or more C2-4 alkynyl. In some embodiments, the C1-10 alkyl is optionally and independently substituted with one or more C2-4 hydroxyalkynyl. In some embodiments, the C1-10 alkyl is optionally and independently substituted with one or more C1-3 cyanoalkyl.

[0133] In some embodiments, the C3-12 carbocycle is optionally substituted with one or more substituents independently selected from halogen, deuterium, hydroxy, -NO2, CM alkyl, CM aminoalkyl, -S-C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 hydroxyalkynyl, and C1-3 cyanoalkyl. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or more halogen. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or more deuterium. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or more hydroxy. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or more -NO2. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or moreP-660558-PCCi-4 alkyl. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or more C1-6 aminoalkyl. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or more -S-C1-3 alkyl. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or more C2-4 alkenyl. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or more C2-4 alkynyl. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or more C2-4 hydroxyalkynyl. In some embodiments, the C3-12 carbocycle is optionally and independently substituted with one or more C1-3 cyanoalkyl.

[0134] In some embodiments, the phenyl is optionally substituted with one or more substituents independently selected from halogen, deuterium, hydroxy, -NO2, C1-4 alkyl, C1-6 aminoalkyl, -S- C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 hydroxyalkynyl, and C1-3 cyanoalkyl. In some embodiments, the phenyl is optionally and independently substituted with one or more halogen. In some embodiments, the phenyl is optionally and independently substituted with one or more deuterium. In some embodiments, the phenyl is optionally and independently substituted with one or more hydroxy. In some embodiments, the phenyl is optionally and independently substituted with one or more -NO2. In some embodiments, the phenyl is optionally and independently substituted with one or more C1-4 alkyl. In some embodiments, the phenyl is optionally and independently substituted with one or more C1-6 aminoalkyl. In some embodiments, the phenyl is optionally and independently substituted with one or more -S-C1-3 alkyl. In some embodiments, the phenyl is optionally and independently substituted with one or more C2-4 alkenyl. In some embodiments, the phenyl is optionally and independently substituted with one or more C2-4 alkynyl. In some embodiments, the phenyl is optionally and independently substituted with one or more C2-4 hydroxyalkynyl. In some embodiments, the phenyl is optionally and independently substituted with one or more C1-3 cyanoalkyl.

[0135] In some embodiments, R6is selected from hydrogen, deuterium, -OH, -CN, -NO2, C1-10 alkyl, Ci-iohaloalkyl, -N(R61)2, -C(O)N(R61)2, -CH2N(R61)C(O)R62, -CH2N(R61)C(O)N(R62)2, - N(R61)C(O)R62, - N(R61)C(O)N(R62)2, -N(R61)C(O)OR62. In some embodiments, R6is hydrogen. In some embodiments, R6is deuterium. In some embodiments, R6is -OH. In some embodiments, R6is -CN. In some embodiments, R6is -NO2. In some embodiments, R6is C1-10 alkyl. In some embodiments, R6is C1-6 alkyl. In some embodiments, R6is Ci alkyl. In some embodiments, R6isP-660558-PCCi alkyl. In some embodiments, R6is C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CH3)2. In some embodiments, C3 alkyl is CH2CH2CH3. In some embodiments, C3 alkyl is CH(CH3)2. In some embodiments, R6is C4 alkyl. In some embodiments, C4 alkyl is CH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, C4 alkyl is CH2CH2CH2CH3. In some embodiments, C4 alkyl is CH2CH(CH3)2. In some embodiments, R6is C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3. In some embodiments, C5 alkyl is (CH2)2CH(CH3)2. In some embodiments, R6is G> alkyl. In some embodiments, G, alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2. In some embodiments, Ce alkyl is CH2CH2CH2CH2CH2CH3. In some embodiments, Ce alkyl is (CH2)3CH(CH3)2. In some embodiments, R6is Ci-io haloalkyl. In some embodiments, R6is -N(R61)2. In some embodiments, R6is -C(O)N(R61)2. In some embodiments, R6is -CH2N(R61)C(O)R62. In some embodiments, R6is -CH2N(R61)C(O)N(R62)2. In some embodiments, R6is -N(R61)C(O)R62. In some embodiments, R6is - N(R61)C(O)N(R62)2. In some embodiments, R6is -N(R61)C(O)OR62.

[0136] In some embodiments, R61is independently selected at each occurrence from hydrogen, deuterium, C1-10 alkyl, C1-10 haloalkyl, and 5- to 12-membered heterocycle. In some embodiments, R61is independently hydrogen. In some embodiments, R61is independently deuterium. In some embodiments, R61is independently C1-10 alkyl. In some embodiments, R61is independently C1-10 haloalkyl. In some embodiments, R61is independently 5- to 12-membered heterocycle. In some embodiments, R61is independently 5-membered heterocycle. In some embodiments, R61is independently 6-membered heterocycle. In some embodiments, R61isindependently 8-membered heterocycle. In some embodiments, R61is selected from HP-660558-PC

[0137] In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected at each occurrence from Ci-6 alkyl, C2-6 alkenyl, C2-e alkynyl, -NO2, -CN, and -ORla. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more C1-6 alkyl. In some embodiments, the one or more substituents are Ci alkyl. In some embodiments, the one or more substituents are C2 alkyl. In some embodiments, the one or more substituents are C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CH3)2. In some embodiments, C3 alkyl is CH2CH2CH3. In some embodiments, C3 alkyl is CH(CH3)2. In some embodiments, the one or more substituents are C4 alkyl. In some embodiments, C4 alkyl is CH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, C4 alkyl is CH2CH2CH2CH3. In some embodiments, C4 alkyl is CH2CH(CH3)2. In some embodiments, the one or more substituents are C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3. In some embodiments, C5 alkyl is (CH2)2CH(CH3)2. In some embodiments, the one or more substituents are G> alkyl. In some embodiments, G, alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2. In some embodiments, Ce alkyl is CH2CH2CH2CH2CH2CH3. In some embodiments, Ce alkyl is (CH2)3CH(CH3)2. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more C2-6 alkenyl. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more C2-6 alkynyl. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more -NO2. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more -CN. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more -ORla.

[0138] In some embodiments, the C1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -NO2, -CN, and -ORla. In some embodiments, the C1-10 alkyl is optionally substituted with one or more C1-6 alkyl. In some embodiments, the one or more substituents are Ci alkyl. In some embodiments, the one or more substituents are C2 alkyl. In some embodiments, the one or more substituents are C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CH3)2. In some embodiments, C3 alkyl is CH2CH2CH3. In some embodiments, C3 alkyl is CH(CH3)2. In some embodiments, the one or more substituents are C4 alkyl. In some embodiments, C4 alkyl isP-660558-PCCH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, C4 alkyl is CH2CH2CH2CH3. In some embodiments, C4 alkyl is CH2CH(CH3)2. In some embodiments, the one or more substituents are C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3. In some embodiments, C5 alkyl is (CH2)2CH(CH3)2. In some embodiments, the one or more substituents are Ce alkyl. In some embodiments, Ce alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2. In some embodiments, Ce alkyl is CH2CH2CH2CH2CH2CH3. In some embodiments, Ce alkyl is (CH2)3CH(CH3)2. In some embodiments, the C1-10 alkyl is optionally substituted with one or more C2-6 alkenyl. In some embodiments, the C1-10 alkyl is optionally substituted with one or more C2-6 alkynyl. In some embodiments, the C1-10 alkyl is optionally substituted with one or more -NO2. In some embodiments, the C1-10 alkyl is optionally substituted with one or more -CN. In some embodiments, the C1-10 alkyl is optionally substituted with one or more -ORla.

[0139] In some embodiments, R62is independently selected at each occurrence from hydrogen, deuterium, C1-10 alkyl, and 5- to 12-membered heterocycle. In some embodiments, R62is independently hydrogen. In some embodiments, R62is independently deuterium. In some embodiments, R62is independently C1-10 alkyl. In some embodiments, R62is independently 5- to 12-membered heterocycle. In some embodiments, R62is independently 5 -membered heterocycle. In some embodiments, R62is independently 6-membered heterocycle. In some embodiments, R62is independently 8-membered heterocycle. In some embodiments, R62is selected from H, , some embodiments, R62is,

[0140] In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2 -6 alkynyl, -NO2, -CN, and -ORla. In some embodiments, the 5- to 12-membered heterocycle isP-660558-PC optionally substituted with one or more Ci-6 alkyl. In some embodiments, the one or more substituents are Ci alkyl. In some embodiments, the one or more substituents are C2 alkyl. In some embodiments, the one or more substituents are C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CH3)2. In some embodiments, C3 alkyl is CH2CH2CH3. In some embodiments, C3 alkyl is CH(CH3)2. In some embodiments, the one or more substituents are C4 alkyl. In some embodiments, C4 alkyl is CH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, C4 alkyl is CH2CH2CH2CH3. In some embodiments, C4 alkyl is CH2CH(CH3)2. In some embodiments, the one or more substituents are C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3. In some embodiments, C5 alkyl is (CH2)2CH(CH3)2. In some embodiments, the one or more substituents are G> alkyl. In some embodiments, G, alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2. In some embodiments, Ce alkyl is CH2CH2CH2CH2CH2CH3. In some embodiments, Ce alkyl is (CH2)3CH(CH3)2. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more C2-6 alkenyl. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more C2-6 alkynyl. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more -NO2. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more -CN. In some embodiments, the 5- to 12-membered heterocycle is optionally substituted with one or more -ORla.

[0141] In some embodiments, the C1-10 alkyl is optionally substituted with one or more substituents independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -NO2, -CN, and -ORla. In some embodiments, the C1-10 alkyl is optionally substituted with one or more C1-6 alkyl. In some embodiments, the one or more substituents are Ci alkyl. In some embodiments, the one or more substituents are C2 alkyl. In some embodiments, the one or more substituents are C3 alkyl. In some embodiments, C3 alkyl is CH2CH2CH3 or CH(CH3)2. In some embodiments, C3 alkyl is CH2CH2CH3. In some embodiments, C3 alkyl is CH(CH3)2. In some embodiments, the one or more substituents are C4 alkyl. In some embodiments, C4 alkyl is CH2CH2CH2CH3 or CH2CH(CH3)2. In some embodiments, C4 alkyl is CH2CH2CH2CH3. In some embodiments, C4 alkyl is CH2CH(CH3)2. In some embodiments, the one or more substituents are C5 alkyl. In some embodiments, C5 alkyl is CH2CH2CH2CH2CH3 or (CH2)2CH(CH3)2. In someP-660558-PC embodiments, C5 alkyl is CH2CH2CH2CH2CH3. In some embodiments, C5 alkyl is (CH2)2CH(CH3)2. In some embodiments, the one or more substituents are Ce alkyl. In some embodiments, Ce alkyl is CH2CH2CH2CH2CH2CH3 or (CH2)3CH(CH3)2. In some embodiments, Ce alkyl is CH2CH2CH2CH2CH2CH3. In some embodiments, Ce alkyl is (CH2)3CH(CH3)2. In some embodiments, the C1-10 alkyl is optionally substituted with one or more C2-6 alkenyl. In some embodiments, the C1-10 alkyl is optionally substituted with one or more C2-6 alkynyl. In some embodiments, the C1-10 alkyl is optionally substituted with one or more -NO2. In some embodiments, the C1-10 alkyl is optionally substituted with one or more -CN. In some embodiments, the C1-10 alkyl is optionally substituted with one or more -ORla.

[0142] In some embodiments, Rlais selected from hydrogen, deuterium, and C1-3 alkyl. In some embodiments, Rlais hydrogen. In some embodiments, Rlais deuterium. In some embodiments, Rlais C1-3 alkyl. In some embodiments, Rlais Ci alkyl. In some embodiments, Rlais C2 alkyl. In some embodiments, Rlais C3 alkyl.

[0143] In some embodiments, R6is -CH2N(R61)C(O)R62. In some embodiments, R61is hydrogen. In some embodiments, R62is selected from 5 -membered heterocycle. In some embodiments, R62is,

[0144] In some embodiments, R7is selected from hydrogen, deuterium, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12- membered heterocycle are optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, -OH, -0CH3, -OCH2CH3, -C(O)OCH3, -C(O)OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle. In some embodiments, R7is hydrogen. In some embodiments, R7isP-660558-PC deuterium. In some embodiments, R7is halogen. In some embodiments, R7is F. In some embodiments, R7is Cl. In some embodiments, R7is C3-12 carbocycle.

[0145] In some embodiments, R7is optionally substituted C5-12 carbocycle. In some embodiments, R7is C5-12 carbocycle optionally substituted with one or more substituents. In some embodiments, the C5-12 carbocycle is optionally substituted with one or more substituents. In some embodiments, R7is G> carbocycle optionally substituted with one or more substituents. In some embodiments, R7is Cs carbocycle optionally substituted with one or more substituents. In some embodiments, R7is C10 carbocycle optionally substituted with one or more substituents. In some embodiments, R7is phenyl optionally substituted with one or more substituents. In some embodiments, the one or more substituents are independently selected at each occurrence from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, -OH, -OCH3, -OCH2CH3, -C(O)OCH3, - C(O)OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle. In some embodiments, R7is Ce carbocycle optionally substituted with one or more halogen. In some embodiments, R7is Ce carbocycle optionally substituted with one or more -CN. In some embodiments, R7is Ce carbocycle optionally substituted with one or more -NO2. In some embodiments, R7is Ce carbocycle optionally substituted with one or more -NH2. In some embodiments, R7is Ce carbocycle optionally substituted with one or more -NHCH3. In some embodiments, R7is Ce carbocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R7is Ce carbocycle optionally substituted with one or more -OH. In some embodiments, R7is Ce carbocycle optionally substituted with one or more -OCH3. In some embodiments, R7is Ce carbocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R7is Ce carbocycle optionally substituted with one or more -C(O)OCH3. In some embodiments, R7is Ce carbocycle optionally substituted with one or more -C(O)OCH2CH3. In some embodiments, R7is Ce carbocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R7is Ce carbocycle optionally substituted with one or more 3- to 6-membered heterocycle. In some embodiments, R7is Cs carbocycle optionally substituted with one or more halogen. In some embodiments, R7is Cs carbocycle optionally substituted with one or more -CN. In some embodiments, R7is Cs carbocycle optionally substituted with one or more -NO2. In some embodiments, R7is Cs carbocycle optionally substituted with one or more -NH2. In some embodiments, R7is Cs carbocycle optionally substituted with one or more -NHCH3. In someP-660558-PC embodiments, R7is Cs carbocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R7is Cs carbocycle optionally substituted with one or more -OH. In some embodiments, R7is Cs carbocycle optionally substituted with one or more -OCH3. In some embodiments, R7is Cs carbocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R7is Cs carbocycle optionally substituted with one or more -C(O)OCH3. In some embodiments, R7is Cs carbocycle optionally substituted with one or more -C(O)OCH2CH3. In some embodiments, R7is Cs carbocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R7is Cs carbocycle optionally substituted with one or more 3- to 6- membered heterocycle.

[0146] In some embodiments, R7is 3- to 12-membered heterocycle. In some embodiments, R7is optionally substituted 3- to 12-membered heterocycle. In some embodiments, R7is 3- to 12- membered heterocycle optionally substituted with one or more substituents. In some embodiments, the 3- to 12-membered heterocycle is optionally substituted with one or more substituents. In some embodiments, R7is 3-membered heterocycle optionally substituted with one or more substituents. In some embodiments, R7is 5-membered heterocycle optionally substituted with one or more substituents. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more substituents. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more substituents. In some embodiments, R7is 10- membered heterocycle optionally substituted with one or more substituents. In some embodiments, R7is 12-membered heterocycle optionally substituted with one or more substituents. In some embodiments, the one or more substituents are independently selected at each occurrence from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, -OH, -OCH3, - OCH2CH3, -C(O)OCH3, -C(O)OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle. In some embodiments, R7is 5 -membered heterocycle optionally substituted with one or more halogen. In some embodiments, R7is 5-membered heterocycle optionally substituted with one or more -CN. In some embodiments, R7is 5-membered heterocycle optionally substituted with one or more -NO2. In some embodiments, R7is 5-membered heterocycle optionally substituted with one or more -NH2. In some embodiments, R7is 5-membered heterocycle optionally substituted with one or more -NHCH3. In some embodiments, R7is 5 -membered heterocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R7is 5-membered heterocycleP-660558-PC optionally substituted with one or more -OH. In some embodiments, R7is 5-membered heterocycle optionally substituted with one or more -OCH3. In some embodiments, R7is 5- membered heterocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R7is 5-membered heterocycle optionally substituted with one or more - C(O)OCH3. In some embodiments, R7is 5-membered heterocycle optionally substituted with one or more -C(O)OCH2CH3. In some embodiments, R7is 5-membered heterocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R7is 5-membered heterocycle optionally substituted with one or more 3- to 6-membered heterocycle. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more halogen. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more -CN. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more - NO2. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more -NH2. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more -NHCH3. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more -OH. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more -OCH3. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R7is 6- membered heterocycle optionally substituted with one or more -C(O)OCH3. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more - C(O)OCH2CH3. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R7is 6-membered heterocycle optionally substituted with one or more 3- to 6-membered heterocycle. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more halogen. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more -CN. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more -NO2. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more - NH2. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more -NHCH3. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R7is 8-membered heterocycle optionallyP-660558-PC substituted with one or more -OH. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more -OCH3. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R7is 6- membered heterocycle optionally substituted with one or more -C(O)OCH3. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more - C(O)OCH2CH3. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R7is 8-membered heterocycle optionally substituted with one or more 3- to 6-membered heterocycle. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more halogen. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more -CN. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more - NO2. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more -NH2. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more -NHCH3. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more -OH. In some embodiments, R7is 10- membered heterocycle optionally substituted with one or more -OCH3. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more - C(O)OCH3. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more -C(O)OCH2CH3. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R7is 10-membered heterocycle optionally substituted with one or more 3- to 6-membered heterocycle.

[0147] In some embodiments, R7is 8-membered heterocycle optionally substituted with one orP-660558-PCIn some embodiments, R7is selected fromhich is optionally substituted. In some embodiments, R7is optionallysubstituted H In some embodiments, R7is optionally substitutedN , some embodiments, R7is optionally substitutedH. In some embodiments, R7is optionally substituted

[0148] In some embodiments, R7is optionally substituted by -OH. In some embodiments, R7is substituted by -OH. In some embodiments,some embodiments, R7is

[0149] In some embodiments, R7is optionally substituted by -OCH3. In some embodiments, R7is substituted by -OCH3. In some embodiments,some embodiments, R7P-660558-PC

[0150] In some embodiments, R7is optionally substituted by -C(O)OCH2CH3. In some

[0151] In some embodiments, R8is selected from hydrogen, deuterium, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12- membered heterocycle are optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, - NHCH2CH3, -OH, -0CH3, -OCH2CH3, -C(O)OCH3, -C(O)OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle. In some embodiments, R8is hydrogen. In some embodiments, R8is deuterium. In some embodiments, R8is halogen. In some embodiments, R8is F. In some embodiments, R8is Cl. In some embodiments, R8is C3-12 carbocycle. In some embodiments, R8is phenyl.

[0152] In some embodiments, R8is optionally substituted C5-12 carbocycle. In some embodiments, R8is C5-12 carbocycle optionally substituted with one or more substituents. In some embodiments, the C5-12 carbocycle is optionally substituted with one or more substituents.P-660558-PCIn some embodiments, R8is G> carbocycle optionally substituted with one or more substituents. In some embodiments, R8is Cs carbocycle optionally substituted with one or more substituents. In some embodiments, R8is Cio carbocycle optionally substituted with one or more substituents. In some embodiments, R8is phenyl optionally substituted with one or more substituents. In some embodiments, the one or more substituents are independently selected at each occurrence from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, -OH, -OCH3, -OCH2CH3, -C(O)OCH3, - C(O)OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle. In some embodiments, R8is Ce carbocycle optionally substituted with one or more halogen. In some embodiments, R8is Ce carbocycle optionally substituted with one or more -CN. In some embodiments, R8is Ce carbocycle optionally substituted with one or more -NO2. In some embodiments, R8is Ce carbocycle optionally substituted with one or more -NH2. In some embodiments, R8is Ce carbocycle optionally substituted with one or more -NHCH3. In some embodiments, R8is Ce carbocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R8is Ce carbocycle optionally substituted with one or more -OH. In some embodiments, R8is Ce carbocycle optionally substituted with one or more -OCH3. In some embodiments, R8is Ce carbocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R8is Ce carbocycle optionally substituted with one or more -C(O)OCH3. In some embodiments, R8is Ce carbocycle optionally substituted with one or more -C(O)OCH2CH3. In some embodiments, R8is Ce carbocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R8is Ce carbocycle optionally substituted with one or more 3- to 6-membered heterocycle. In some embodiments, R8is Cs carbocycle optionally substituted with one or more halogen. In some embodiments, R8is Cs carbocycle optionally substituted with one or more -CN. In some embodiments, R8is Cs carbocycle optionally substituted with one or more -NO2. In some embodiments, R8is Cs carbocycle optionally substituted with one or more -NH2. In some embodiments, R8is Cs carbocycle optionally substituted with one or more -NHCH3. In some embodiments, R8is Cs carbocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R8is Cs carbocycle optionally substituted with one or more -OH. In some embodiments, R8is Cs carbocycle optionally substituted with one or more -OCH3. In some embodiments, R8is Cs carbocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R8is Cs carbocycle optionally substituted with one or more -C(O)OCH3. In someP-660558-PC embodiments, R8is Cs carbocycle optionally substituted with one or more -C(O)OCH2CH3. In some embodiments, R8is Cs carbocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R8is Cs carbocycle optionally substituted with one or more 3- to 6- membered heterocycle.

[0153] In some embodiments, R8is 3- to 12-membered heterocycle. In some embodiments, R8is optionally substituted 3- to 12-membered heterocycle. In some embodiments, R8is 3- to 12- membered heterocycle optionally substituted with one or more substituents. In some embodiments, the 3- to 12-membered heterocycle is optionally substituted with one or more substituents. In some embodiments, R8is 3-membered heterocycle optionally substituted with one or more substituents. In some embodiments, R8is 5-membered heterocycle optionally substituted with one or more substituents. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more substituents. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more substituents. In some embodiments, R8is 10- membered heterocycle optionally substituted with one or more substituents. In some embodiments, R8is 12-membered heterocycle optionally substituted with one or more substituents. In some embodiments, the one or more substituents are independently selected at each occurrence from halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, -OH, -OCH3, - OCH2CH3, -C(O)OCH3, -C(O)OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle. In some embodiments, R8is 5 -membered heterocycle optionally substituted with one or more halogen. In some embodiments, R8is 5-membered heterocycle optionally substituted with one or more -CN. In some embodiments, R8is 5-membered heterocycle optionally substituted with one or more -NO2. In some embodiments, R8is 5-membered heterocycle optionally substituted with one or more -NH2. In some embodiments, R8is 5-membered heterocycle optionally substituted with one or more -NHCH3. In some embodiments, R8is 5 -membered heterocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R8is 5-membered heterocycle optionally substituted with one or more -OH. In some embodiments, R8is 5-membered heterocycle optionally substituted with one or more -OCH3. In some embodiments, R8is 5- membered heterocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R8is 5-membered heterocycle optionally substituted with one or more - C(O)OCH3. In some embodiments, R8is 5-membered heterocycle optionally substituted withP-660558-PC one or more -C(O)OCH2CH3. In some embodiments, R8is 5-membered heterocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R8is 5-membered heterocycle optionally substituted with one or more 3- to 6-membered heterocycle. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more halogen. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more -CN. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more - NO2. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more -NH2. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more -NHCH3. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more -OH. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more -OCH3. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R8is 6- membered heterocycle optionally substituted with one or more -C(O)OCH3. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more - C(O)OCH2CH3. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R8is 6-membered heterocycle optionally substituted with one or more 3- to 6-membered heterocycle. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more halogen. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more -CN. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more -NO2. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more - NH2. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more -NHCH3. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more -OH. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more -OCH3. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R8is 6- membered heterocycle optionally substituted with one or more -C(O)OCH3. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more -P-660558-PCC(O)OCH2CH3. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R8is 8-membered heterocycle optionally substituted with one or more 3- to 6-membered heterocycle. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more halogen. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more -CN. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more - NO2. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more -NH2. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more -NHCH3. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more -NHCH2CH3. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more -OH. In some embodiments, R8is 10- membered heterocycle optionally substituted with one or more -OCH3. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more -OCH2CH3. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more - C(O)OCH3. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more -C(O)OCH2CH3. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more C3-12 carbocycle. In some embodiments, R8is 10-membered heterocycle optionally substituted with one or more 3- to 6-membered heterocycle.

[0154] In some embodiments, the compound having a structure of Formula (II) is selected from:P-660558-PCthereof.

[0155] In some embodiments, the compound having a structure of Formula (II) isor a salt thereof.

[0156] In some embodiments, the compound having a structure of Formula (II) is

[0157] In some embodiments, the compound having a structure of Formula (II) isor a salt thereof.

[0158] In some embodiments, the compound having a structure of Formula (II) isP-660558-PC

[0159] In some embodiments, the compound having a structure of Formula (II) isor a salt thereof.

[0160] In some embodiments, the compound having a structure of Formula (II) isor a salt thereof.

[0161] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0162] Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds described herein. The compounds of the present disclosure that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0163] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions” , John Wiley and Sons,P-660558-PCInc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0164] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0165] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).COMPOSITIONS

[0166] In certain aspects, the present disclosure provides a composition formulated to reduce hyperpigmentation in a subject requiring such treatment. This composition comprises a compound with either the structure of Formula (I) or Formula (II), or a corresponding salt thereof.

[0167] In some embodiments, the composition may be categorized as a cosmetic composition. In some embodiments, the composition may be categorized as a pharmaceutical composition. In some embodiments, the composition may be available without a prescription. In some embodiments, the composition may be available with a prescription.

[0168] The composition may further comprise at least one additive selected from the group consisting of a carrier, an excipient, an adjuvant, and a diluent. Various formulations for the composition may include, but not limited to a toner, cream, emulsion, lotion, ointment, paste, gel, suspension, serum, oil, edible supplement, direct injection, beverage, transdermal patch,P-660558-PC topical patch, moisturizer, face mask, shampoo, foam, cleanser, mousse, liquid, powder, aerosol, spray, balm, pigment-containing cosmetic, foundation, primer, concealer, sunscreen, or a combination thereof.

[0169] In some embodiments, the composition may be a pharmaceutical composition. The pharmaceutical composition may further comprise at least one additive selected from the group consisting of a pharmaceutically acceptable carrier, an excipient, an adjuvant, and a diluent.

[0170] In some embodiments, the composition may be a cosmetic composition. The cosmetic composition may further comprise at least one additive selected from the group consisting of a cosmetically acceptable carrier, an excipient, an adjuvant, and a diluent. In some embodiments, the additives may include, but not limited to water, glycerin, hydroxy ethyl acrylate / sodium acryloyldimethyl taurate copolymer, di caprylyl carbonate, caprylic / capric triglycerides, glyceryl stearate and polyethylene glycol (PEG)- 100, glyceryl stearate SE (self-emulsifying), pentylene glycol, caprylyl glycol, propanediol, ethylhexylglycerin, and dimethyl isosorbide.

[0171] In some embodiments, the composition may be a nutraceutical composition. The nutraceutical composition may further comprise at least one additive selected from the group consisting of a nutraceutically acceptable carrier, a nutritional source, a filler, an emulsifier, a preservative, a flavoring agent, and a coloring agent.

[0172] In some embodiments, the composition may be formulated by delivery vehicles selected from an aqueous phase solution, an oil phase solution, water-in-oil emulsion, oil-in-water emulsion, water-in-oil-in-water emulsion, oil-in-water-in-oil emulsion, water-in-silicone emulsion, silicone-in-water emulsion, encapsulation, a liposome, a vesicle, an ethosome, a polymersome, an exosome, a transfersome, a niosome, a complex, a cyclodextrin, a lipid nanoparticle, a nanoparticle, a microparticle, a macroparticle, solid powder, or a combination thereof.

[0173] In some embodiments, a weight % of the compound in the composition ranges from about 0.0001 % to about 10 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is about 0.0001, about 0.0005,P-660558-PC about 0.001, about 0.005, about 0.01, about 0.02, about 0.03, about 0.04, about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.0001 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.0005 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.001 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.005 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.01 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.02 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.03 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.04 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.05 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.06 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.07 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.08 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.09 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.1 % by weight relative to a total weight of the composition. In some embodiments, a weight % of theP-660558-PC compound in the composition is at least about 0.2 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.3 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.4 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.5 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.6 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.7 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.8 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 0.9 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at least about 1 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.0001 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.0005 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.001 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.005 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.01 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.02 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.03 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.04 % by weight relative to a total weight of the composition. InP-660558-PC some embodiments, a weight % of the compound in the composition is at most about 0.05 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.06 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.07 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.08 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.09 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.1 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.2 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.3 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.4 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.5 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.6 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.7 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.8 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 0.9 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition is at most about 1 % by weight relative to a total weight of the composition. In some embodiments, a weight % of the compound in the composition ranges from about 0.0001 to 10, 0.0005 to 9, 0.001 to 8, 0.005 to 7, 0.01 to 6, 0.02 to 5, 0.03 to 4, 0.04 to 3, 0.05 to 2, 0.06 to 1, 0.07 to 0.9, 0.08 to 0.8, 0.09 to 0.7, 0.1 to 0.6, 0.2 to 0.5, or 0.3 to 0.4 % by weight relative to a total weight of the composition. In some embodiments, the weight % of the compound in the composition ranges from about 0.0001 % to about 1.0 % by weight relative to a total weight of the composition. In some embodiments, the weight % of the compound in the compositionP-660558-PC ranges from about 0.001 % to about 2.0 % by weight relative to a total weight of the composition.

[0174] In some embodiments, the composition comprises one or more compounds or salts thereof disclosed herein. In some embodiments, the composition comprises one compound or salt thereof disclosed herein. In some embodiments, the composition comprises two compounds or salts thereof disclosed herein. In some embodiments, the composition comprises three compounds or salts thereof disclosed herein.METHODS

[0175] The compounds or compositions described herein may be useful for reducing hyperpigmentation of a subject who require such treatment. The methods outlined herein for reducing hyperpigmentation involve the administration of the disclosed compounds or compositions to the subject. In certain aspects, disclosed herein is a method for reducing hyperpigmentation of a subject in need thereof, the method comprising administering the compound disclosed herein or the composition comprising the compound described herein.

[0176] Melanocytes are specialized cells in the skin that produce melanin, the pigment responsible for skin, hair, and eye color. They are located at the basal layer of the skin's epidermis and in other parts of the body like the eye, inner ear, bones, and heart. Melanocytes play a crucial role in the body's natural defense against harmful ultraviolet (UV) radiation by absorbing and dispersing the energy from UV rays, protecting the skin cells from DNA damage. Dysregulation of melanocytes can lead to conditions such as albinism, vitiligo, and melanoma.

[0177] In one embodiment, the method may not affect the non-melanocytes. In one embodiment, the present disclosure provides a method for selectively affecting melanocytes in a subject, without adversely affecting the population of non-melanocytes. This method comprises administering the subject the compound disclosed herein. The composition comprising a compound of Formula (I) or Formula (II) has been designed to target melanocytes, thereby minimizing any potential impacts on the non-melanocytes. This selective activity ensures the preservation of the overall health and functionality of other cells in the subject, while exerting the desired impact on melanocytes.P-660558-PC

[0178] In some embodiments, the method involves administering the composition topically to the subject's skin. The potential areas for application are diverse, and include, but are not limited to, the scalp, face, under or around the eyes, around the mouth or nose, neck, hands, penile region, areas around joints, wrists, ankles, eyelids, behind or on the knee, behind or on the elbow, feet, legs, or any areas of skin experiencing friction through contact. It could also involve a combination of these areas, ensuring versatility in its potential usage and effectiveness.

[0179] The skin condition, disorder, or disease discussed in this disclosure may involve several symptoms or manifestations related to a subject's hyperpigmentation. This may include various forms of hyperpigmentation such as melasma, sunspots, solar lentigos, age spots, liver spots, Cafe au lait spot, post-inflammatory hyperpigmentation, uneven skin tone, drug-induced hyperpigmentation, or a combination thereof. In some embodiments, any method detailed herein may be applied to subjects who have been previously diagnosed with a skin condition, disorder, or disease. In other embodiments, the methods detailed can be used for subjects who have not received a formal diagnosis of a skin condition, disorder, or disease.

[0180] In some embodiments, the composition is administered one to three times a day. In some embodiments, the composition is administered once a day. In some embodiments, the composition is administered two times a day. In some embodiments, the composition is administered three times a day. In some embodiments, the composition is administered every other day. In some embodiments, the composition is administered for at least two consecutive days. In some embodiments, the composition is administered for at least three consecutive days. In some embodiments, the composition is administered for at least four consecutive days. In some embodiments, the composition is administered for at least five consecutive days. In some embodiments, the composition is administered for at least seven consecutive days.

[0181] In some embodiments, the composition is administered at least for 2 days, 3 days, 5 days, 7 days, 10 days, 15 days, 20 days, 30 days, 50 days, 60 days, 80 days, 90 days, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, a year, 2 years, or 3 years. In some embodiments, the composition is administered at most for 2 days, 3 days, 5 days, 7 days, 10 days, 15 days, 20 days, 30 days, 50 days, 60 days, 80 days, 90 days, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, a year, 2 years, or 3 years. In some embodiments, the composition is administered from about 2 days to 3 years, from 3 days to 2P-660558-PC years, from 5 days to a year, from 7 days to 11 months, from 10 days to 10 months, from 15 days to 9 months, from 20 days to 8 months, from 30 days to 7 months, from 50 days to 6 months, from 60 days to 5 months, from 80 days to 4 months, or from 90 days to 3 years.

[0182] In various embodiments, the administration of the composition might have a range of potential effects. This could include decreasing melanocyte viability, resulting in skin brightening or whitening, or reducing the quantity of melanocytes. It might also decrease the viability of melanocytes, control the proliferation of new melanocytes, suppress melanocytes, or it could lead to a combination of these outcomes.

[0183] In certain embodiments, the administration of the composition may help to inhibit the transfer of melanosomes, inhibit the production of melanin, regulate the melanocyte environment, or achieve both. Additionally, it could assist in reducing oxidative stress, preventing oxidative stress, or a combination thereof.

[0184] In some embodiments, the administration of the composition might facilitate pigment removal, induce brightening within the dermal layer, or reduce skin hyperpigmentation, balance skin tone irregularities, or it could accomplish a combination of these effects.

[0185] In some embodiments, the administration of the composition may enhance skin barrier function, inhibit melanogenesis, regulate melanocyte viability, reduce melanocyte quantity, or it might achieve a combination of these effects.

[0186] In some embodiments, the administration of the composition might help to fade age spots or dark spots, treat post-acne scars or marks, cleanse the skin of dirt, oil, germs, dead skin cells, or other impurities, enhance skin moisture, reduce skin roughness or fine lines, or protect the skin from ultraviolet damage.

[0187] In some embodiments, the administration of the composition herein may decrease hyperpigmentation. The decrease may be by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments, the decrease may be less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, less than 90%, or less than 95%. The decrease may be by about 5%, about 10%, aboutP-660558-PC15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and sub ranges in between. The decrease may be by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0188] In some embodiments, the administration of the composition herein may decrease melanocyte viability. The decrease may be by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments, the decrease may be less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, less than 90%, or less than 95%. The decrease may be by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and sub ranges in between. The decrease may be by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0189] In some embodiments, the administration of the composition herein may decrease melanin. The decrease may be by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. In some embodiments, the decrease may be less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, less than 90%, or less than 95%. The decrease may be by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%, including all values and sub ranges in between. The decrease may be byP-660558-PC5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.KITS

[0190] This disclosure also provides a kit comprising the composition disclosed herein.

[0191] In some embodiments, the kit further comprises an applicator. In some embodiments, the applicator includes but is not limited to, a brush, a comb, a cotton swab, a spatula, a spoon, a dropper, a spray nozzle, a squeeze bottle, a pump bottle, a tube, an applicator wand, a sponger, a foam blender, a silicone applicator, a rollerball, a powder puff, a tottle, a microneedling device, a microneedling stamp, a microneedling roller, a microneedling pen, a microneedling patch, dissolvable microneedles, a transdermal patch, a hydrocolloid patch, or a combination thereof. In some embodiments, the kit further comprises written instructions for the method disclosed herein.EXAMPLES

[0192] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.Example 1: Assay for measurement of cellular proliferation in human melanocytes

[0193] The potential of the example compounds or salts thereof, disclosed in the present disclosure (refer to Table 1), to modulate the proliferation speed of regular human epidermal melanocytes (PromoCell) was examined employing a cell viability assay like CellTiter-Glo® (Promega). The cells were cultured in a specially designed media that promotes optimal cell growth, which in this case was PromoCell Melanocyte Growth Medium, supplemented with 1% penicillin-streptomycin. The compound or salt under investigation (Table 1) was introduced to the cultures at eight diverse concentrations, ranging from 30 to 0.2 pg / mL. Following a 24-hour incubation period, luminescent signals were monitored in a microplate reader after an additional 10-minute incubation with the CellTiter-Glo reagent. The relative shift in cell proliferation was calculated using the following formula:(SampleLUM - VehicleLUM) / VehicleLUM x 100P-660558-PC

[0194] Negative scores correspond to a decrease in melanocyte proliferation, while positive scores suggest an increase in melanocyte proliferation. Scores near 0 indicate no change in proliferation. The presented data represents the mean ± standard deviation (s.d.) collected from three experimental replicates. Hydroquinone (HQ), a compound known to reduce the number of viable melanocytes, was included for benchmark comparison. A dose-dependent decrease in normalized viability was observed across the tested compounds as depicted in FIG 1 A-FIG. IF. FIG. 1A-FIG. IF demonstrate that the example compounds can reduce cellular proliferation in melanocytes.TABLE 1. Example CompoundsP-660558-PCExample 2: Assay for measurement of melanin content in a mouse melanoma cell line

[0195] The capability of the example compounds or salts thereof, as described in the present disclosure (refer to Table 1), to modulate melanin production in B16-F10 mouse melanoma cells (sourced from ATCC) was assessed using a luminescent assay developed in-house. In summary, the B16-F10 cells were cultured in DMEM, supplemented with 10% FBS and 1% penicillinstreptomycin, until reaching confluence in multi-well plates. The compound or salt under investigation was then introduced to the cultures at a final concentration of 10 pg / mL, spanning a period of 2 to 4 days. Upon completion of the incubation period, a reagent comprising fixed concentrations of firefly luciferase, luciferin, and ATP was added to provide a constant luminescent signal to all wells before a reading was taken using a microplate reader. Given the ability of melanin to absorb light, the final luminescent signal read by the plate reader is inversely related to the melanin concentration present in the sample. For each experiment, a logscale regression analysis of a melanin standard curve was utilized to convert the luminescence signal in each sample to a melanin concentration. The relative percentage increase in melanin content was calculated with the following equation:(SampleMelanin Cone. - V ehicleMelanin Conc.) / V ehicleMelanin Cone. X 100P-660558-PC

[0196] Negative scores signify a decrease in melanin production, while positive scores indicate an increase. Scores in proximity to 0 suggest no change in the melanin production rate.

[0197] FIG. 2A displays a standard curve of representative luminescence versus melanin concentration (mg / ml), showing the inverse relationship between melanin concentration and luminescence, which underscores melanin's capability to absorb light from the luminescent reagent. The linear portions of the melanin standard curves were employed to convert luminescence into melanin concentration in the experimental samples.

[0198] FIG. 2B demonstrates that the example compounds can reduce melanin content in Bl 6- F10 mouse melanoma cells (sourced from ATCC). A luminescence-based melanin content assay was utilized to evaluate changes in melanin content in the mouse melanoma cells post treatment with the example compounds at a 10 pg / mL concentration. The bar graphs depict the average, and a dose-dependent decrease in normalized viability was observed across the lead molecules. The data represents the mean ± standard deviation (s.d.) gathered from a minimum of three experimental replicates (represented by circles). Data summarized in Table 2 using the following key:Mean: A represents -100 to -70, B represents -70 to -40, and C represents -40 or higher. Standard deviation (std): X represents 0 to 10, Y represents 10 to 20 and Z represents 20 or higher.TABLE 2. Melanocyte viability change (%) and Melanin change (%)P-660558-PCExample 3: Toxicology / Safety

[0199] Assay for measurement of cytotoxicity against various human cell types

[0200] The capacity of the example compounds or salts thereof, as detailed in the present disclosure, to maintain the viability of diverse healthy, non-melanocyte human cell types was evaluated using the aforementioned cell viability assay, specifically, the Promega CellTiter- Glo® Luminescent Cell Viability Assay. The human cell types examined consisted of human epidermal keratinocytes, fibroblasts, follicle dermal papilla cells, and microvascular endothelial cells. The compound or salt under the investigation was administered at eight different concentrations, ranging from 30 to 0.2 pg / mL.

[0201] All cell types were cultured on tissue culture-treated plastic, utilizing their respective optimal growth media (such as fibroblast growth media from Promocell), which was supplemented with 1% Penicillin / Streptomycin. The relative change in cell viability was calculated using the following equation:(SampleLUM - VehicleLUM) / VehicleLUM x 100

[0202] Negative scores are indicative of a decrease in cell viability, while positive scores suggest an increase in cell viability. Scores around 0 denote no significant change in viability. FIG. 3A- FIG. 3D demonstrated that the example compounds are non-toxic to primary skin and non-skin cells.

[0203] Assay for measurement of skin sensitization potential

[0204] The potential of the example compounds or salts thereof, as described in the present disclosure, to stimulate skin sensitization was tested using a HEK-KeratinoSens (BPS Biosciences) cell line. This cell line is uniquely engineered to express luciferase upon the activation of the cellular stress Nrf2-ARE pathway. The compound or salt under the investigation was introduced at eight separate concentrations, ranging between 30 to 0.2 pg / mL. The HEK- KeratinoSens cells were cultured using DMEM 4.5 g / L glucose, supplemented with 10% FBS and 1% Penicillin / Streptomycin.P-660558-PC

[0205] The increase in the luciferase gene post treatment with the compounds was measured using a luminescence detection kit, which included Bright-Glo™ (Promega). The relative change in skin sensitization induction was calculated using the subsequent formula:(SampleLUM - VehicleLUM) / VehicleLUM x 100

[0206] Positive scores are indicative of a potential to cause skin sensitization. Scores that are close to 0 signify no significant change in skin sensitization potential. FIG. 4 demonstrates that the example compounds do not exhibit a potential for skin sensitization.

[0207] FIG. 5 provides NHEM-As cell viability assay results of Compound 712A.Example 4: Assay for measurement of melanin content in human epidermal melanocytes

[0208] As previously outlined, the capacity of a compound or salt thereof, disclosed in the present disclosure, to regulate melanin production is assessed using a tailor-made luminescencebased assay. Primary human melanocytes (obtained from PromoCell) is cultured in the optimal melanocyte growth media (also from PromoCell) supplemented with 1% Penicillin / Streptomycin and 1 pM forskolin.

[0209] The compounds or salts disclosed in the present disclosure are introduced to the melanocyte cultures at eight distinct concentrations, ranging from 30 to 0.2 pg / mL, and incubated for a duration of 2 to 4 days. Following the incubation, a reagent comprising constant concentrations of firefly luciferase, luciferin, and ATP is added to provide a steady luminescent signal to all wells prior to reading with a microplate reader.

[0210] For each experiment, a log-scale regression analysis of a melanin standard curve is used to transform the luminescence signal in each sample into a melanin concentration. The relative percentage increase in melanin content is calculated using the following formula:(SampleMelanin Cone. - VehicleMelanin Conc.) / Vehld eMelanin Cone. X 100

[0211] Negative scores indicate a decrease in melanin production, whereas positive scores imply an increase. Scores in proximity to 0 suggest no significant change in melanin production.

[0212] Given that primary human melanocytes cultures more accurately mirror human in vivo physiology, the results of these experiments offer direct insights into the potential effects of lead molecules on melanin production in human skin. The scores obtained from these experiments areP-660558-PC utilized to generate dose-response curves and to calculate the half-maximal inhibitory concentration (IC50) values for each of the lead molecules.

[0213] FIG. 6 provides NHEM-Af melanin content assay results of Compound 712A.Example 5: Compositions

[0214] Formulations containing compounds disclosed in the present disclosure are developed and include options such as a cosmetic skin topical, serum, cream, cleanser, or moisturizer.

[0215] An example of a composition intended for direct skin application as a topical serum is presented in Table 3. Table 3 represents example ranges of percent weights of each ingredient. For instance, A refers to values equal to or larger than about 0.05% and less than about 1%, B represents values equal to or larger than about 1% and less than about 5%, C refers to values equal to or larger than about 5% and less than about 25%, and D represents values equal to or larger than about 25%.TABLE 3. Example of compositionP-660558-PCExample 6: Delivery

[0216] The compounds disclosed herein or a salt thereof can be carried in various delivery vehicles including, but not limited to, an aqueous phase solution, an oil phase solution, water-in- oil or oil-in-water emulsions, more complex emulsions such as water-in-oil-in-water or oil-in- water-in-oil, water-in-silicone or silicone-in-water emulsions, encapsulations, liposomes, vesicles, ethosomes, polymersomes, exosomes, transfersomes, niosomes, complexes, cyclodextrins, lipid nanoparticles, different size particles such as nanoparticles, microparticles, or macroparticles, solid powders, salts, or any combination of these.

[0217] Additional delivery vehicles could include hydrogels, aerosols, foams, creams, lotions, ointments, transdermal patches, subcutaneous implants, intradermal injections, and dissolvable microneedles.

[0218] The testing methods may involve topical application of vehicles containing the disclosed compound or its salts onto skin samples and / or synthetic membranes. This is followed by an analytical assessment of release and penetration rates over time.Example 7: Solubility

[0219] The solubility of the compounds was evaluated under equilibrium conditions in saturated solvent systems, using a standard shake-test methodology, and assessed via Ultra High Performance Liquid Chromatography with Ultraviolet detection (UHPLC-UV). The compounds were dissolved to their saturation limits under ambient conditions, subsequently filtered, and examined in triplicate against established calibration curves.Example 8: Stability

[0220] Stability of compounds from the present disclosure in final formulations are confirmed in cosmetic skin primer formulations, as well as other formulations. Extended shelf-life testing is performed on solid raw materials, under open air and UV-irradiated room temperature conditions (using dark, refrigerated samples as a baseline).P-660558-PCExample 9: Topical efficacy studies

[0221] The efficacy of a compound or salt thereof, disclosed in the present disclosure, when used topically, is evaluated in forthcoming human observational studies. The studies, spanning a duration of up to 12 weeks, aim to analyze the effects of a skin-brightening topical formula that includes selected compounds on the skin of human subjects.

[0222] The study engage a diverse array of participants who exhibit signs of skin discoloration, such as dark spots, age spots, melasma, or solar lentigos. The study design is randomized and incorporate a placebo control. A pool of at least 100 adult participants is randomly assigned to receive either a formula containing one of the selected compounds, a control composition, or a placebo.

[0223] The primary objective of this study is to observe any improvements in the appearance of skin hyperpigmentation and general brightening, among other skin conditions. This is achieved by means of a self-perception survey, third-party evaluation, clinical assessment, objective measurement tools, or a combination of these methods.Example 10: Toxicology / safety

[0224] In silico safety / toxicology studies

[0225] The in silico safety / toxicology profiles of all compounds is determined by screening chemical structures against a series of computational models. These includes the carcinogenicity (genotoxic and non-genotoxic), reproductive and developmental toxicity (DART scheme), DNA mutation alerts, estrogen receptor binding, skin and respiratory sensitization models from the QSAR Toolbox.

[0226] Assay for cytotoxicity against additional human cell types

[0227] The ability of a compound or salt thereof, disclosed the present disclosure, to not alter the viability of various human cell types is tested using the same aforementioned cell viability assay, the Promega CellTiter-Glo® Luminescent Cell Viability Assay. Additional human cell types include human renal, skeletal muscle, and smooth muscle cells. The compound or salt was added at different concentrations spanning at least a 1-log range. All cell types were cultured on tissue culture-treated plastic using optimal growth medium for each respective cell type.P-660558-PC

[0228] Assay for induction of apoptosis in human non-tumorigenic HepG2 cells

[0229] The ability of a compound or salt of the present disclosure to induce apoptosis in human HepG2 cells will be tested by measuring caspase activity using readily available kits, such as Promega Caspase-Gio® 3 / 7. The compound or salt will be added at eight concentrations spanning a 1-log range. The cells were cultured in DMEM supplemented with 10% FBS and 1% penicillin-streptomycin.

[0230] In vitro safety / toxicology studies

[0231] Research includes mechanism-oriented studies, such as metabolism and transport studies, which focus on the potential of a compound or salt from the present disclosure to stimulate or inhibit passive / active transport. This is carried out using the Caco-2 cell line, a recognized compound transport assay. These studies also evaluate whether it can inhibit or enhance cytochrome P450, alongside other ADME (Absorption, Distribution, Metabolism, and Excretion) studies and / or genotoxicity studies, such as micronuclei formation.

[0232] In vitro carcinogenicity studies

[0233] The safety / toxicology profiles of a compound or salt from the present disclosure is evaluated through a series of supplementary in vitro genotoxicity assays. This includes the SOS- chromotest, which assesses bacterial genotoxicity, and the TK.6 micronucleus assay, which determines chromosomal damage and forward mutations.

[0234] Skin and ocular sensitization studies

[0235] The skin sensitization profiles of a compound or salt thereof, disclosed in in this disclosure, is assessed using the widely accepted method of repeat insult patch testing on a minimum of 100 human volunteers. Furthermore, ocular sensitization is evaluated through the standard Hens Egg Test on the Chorioallantoic Membrane (HET-CAM) test, a reliable technique for assessing potential eye irritation.

[0236] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicingP-660558-PC the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

P-660558-PCCLAIMSWHAT IS CLAIMED IS:

1. A method of decreasing hyperpigmentation on skin of a subject in need thereof, the method comprising administering to the subject a composition comprising a compound having a structure of Formula (I):Formula (I); or a salt thereof, wherein:X is CRnor N, wherein R11is selected from hydrogen, deuterium, and C1-3 alkyl;Y is selected from O, NR11, and S;Z is CR11or N;R1is selected from the group consisting of hydrogen, deuterium, -OH, -CN, -NO2, -NH2, C1-10 alkyl, Ci-10 haloalkyl, and C3-12 carbocycle, wherein the C1-10 alkyl and C3-12 carbocycle are optionally substituted with one or more substituents independently selected from halogen, hydroxy, -NO2, CM alkyl, -S-C1-3 alkyl, C2-4 alkenyl, and C2-4 alkynyl;R2is selected from hydrogen, deuterium, -OH, -CN, -NO2, -NH2, C1-10 alkyl, and -C1-10 haloalkyl;R3is selected from the group consisting of hydrogen, deuterium, -OH, -CN, -NO2, and C1-10 alkyl; andR4is selected from C1-10 alkyl, C3-12 carbocycle, and 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R41, wherein R41is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl,C2-6 alkynyl, -NO2, -CN, -OR42, -SR42, and -N(R42)2, wherein R42is selected from hydrogen, deuterium, and C1-3 alkyl.

2. The compound of claim 1, wherein X is CR11.P-660558-PC3. The compound of claim 2, wherein R11is hydrogen.

4. The compound of claim 2, wherein R11is C1-3 alkyl.

5. The compound of claim 4, wherein R11is Ci alkyl.

6. The compound of claim 1 , wherein X is N.

7. The compound of any one of claims 1 to 6, wherein Y is O.

8. The compound of any one of claims 1 to 6, wherein Y is S.

9. The compound of any one of claims 1 to 8, wherein Z is CR11.

10. The compound of claim 9, wherein R11is hydrogen.

11. The compound of any one of claims 1 to 8, wherein Z is N.

12. The compound of any one of claims 1 to 11, wherein R1is hydrogen.

13. The compound of any one of claims 1 to 11, wherein R1is -OH.

14. The compound of any one of claims 1 to 11, wherein R1is C3-12 carbocycle.

15. The compound of claim 14, wherein R1is phenyl.

16. The compound of claim 15, wherein the phenyl is optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, -NO2, and CM alkyl.

17. The compound of any one of claims 1 to 16, wherein R2is hydrogen.

18. The compound of any one of claims 1 to 16, wherein R2is C1-10 alkyl.

19. The compound of any one of claims 1 to 18, wherein R3is hydrogen.

20. The compound of any one of claims 1 to 18, wherein R3is Ci-10 alkyl.

21. The compound of any one of claims 1 to 20, wherein R4is Ci-10 alkyl.

22. The compound of claim 21, wherein R4is C4 alkyl.

23. The compound of claim 22, wherein R4is tert-butyl.

24. The compound of claim 22, wherein R4is iso-butyl.

25. The compound of any one of claims 1 to 20, wherein R4is C5-12 carbocycle optionally substituted with one or more R41.

26. The compound of claim 25, wherein R4is phenyl.

27. The compound of claim 26, wherein the phenyl is substituted with one or more R41.

28. The compound of claim 27, wherein R41is independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, -NO2, -CN, and -OR42.

29. The compound of claim 28, wherein R41is Ci-6 alkyl.P-660558-PC30. The compound of claim 28, wherein R41is C3 alkyl.

31. The compound of claim 28, wherein R41is isopropyl.

32. The compound of claim 25, wherein R4is33. The compound of claim 28, wherein R41is -OR42.

34. The compound of claim 33, wherein R42is hydrogen.

35. The compound of claim 33, wherein R42is C1-3 alkyl.

36. The compound of claim 35, wherein R42is Ci alkyl.

37. The compound of claim 36, wherein R41is -OCH3.

38. The compound of claim 25, wherein R4is39. The compound of any one of claims 1 to 20, wherein R4is selected from 5- to 12- membered heterocycle.

40. The compound of any one of claims 1 to 20, wherein R4is selected from 5-membered heterocycle.

41. The compound of claim 40, wherein R4is selected from 5-membered heteroaryl group.

43. The compound of any one of claims 39 to 42, wherein R4is selected from HP-660558-PC44. The compound of any one of claims 39 to 43, wherein45. The compound of any one of claims 39 to 43, wherein R4isThe compound of any one of claims 39 to 43, wherein R4is47. The compound of any one of claims 1 to 46, wherein the compound having a structure ofFormula (I) is selected from:P-660558-PC48. A method of decreasing hyperpigmentation on skin of a subject in need thereof, the method comprising administering to the subject a composition comprising a compound having a structure of Formula (II):Formula (II); or a salt thereof, wherein:A is selected from O, S, and NRla, wherein Rlais selected from hydrogen, deuterium, and Ci-6 alkyl;R5is selected from hydrogen, deuterium, Ci-io alkyl, Ci-io haloalkyl, and C3-12 carbocycle, wherein the C1-10 alkyl and C3-12 carbocycle are optionally substituted with one or more substituents independently selected from halogen, deuterium, hydroxy, -NO2, CM alkyl, CM aminoalkyl, -S-C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C2-4 hydroxyalkynyl, and C1-3 cyanoalkyl;R6is selected from hydrogen, deuterium, -OH, -CN, -NO2, C1-10 alkyl, C1-10 haloalkyl, -N(R61)2, - C(O)N(R61)2, -CH2N(R61)C(O)R62, -CH2N(R61)C(O)N(R62)2, -N(R61)C(O)R62, - N(R61)C(O)N(R62)2, and - N(R61)C(O)OR62, wherein R61is independently selected at each occurrence from hydrogen, deuterium, C1-10 alkyl, Ci-10 haloalkyl, and 5- to 12-membered heterocycle, wherein the C1-10 alkyl and 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected at each occurrence from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, - NO2, -CN, and -ORla, wherein R62is independently selected at each occurrence from hydrogen, deuterium, C1-10 alkyl, and 5- to 12-membered heterocycle, wherein the C1-10 alkyl and 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected at each occurrence from C1-6 alkyl, -NO2, -CN, and -ORla, wherein Rlais selected from hydrogen, deuterium, and C1-3 alkyl;R7is selected from hydrogen, deuterium, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are optionallyP-660558-PC substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, -OH, -OCH3, -OCH2CH3, - C(O)OCH3, -C(O)OCH2CH3, C3-12 carbocycle, or 3- to 6-membered heterocycle; and R8is selected from hydrogen, deuterium, halogen, C3-12 carbocycle, and 3- to 12-membered heterocycle, wherein the C3-12 carbocycle and 3- to 12-membered heterocycle are optionally substituted by halogen, -CN, -NO2, -NH2, -NHCH3, -NHCH2CH3, -OH, -OCH3, -OCH2CH3, - C(O)OCH3, or -C(O)OCH2CH3.

49. The method of claim 48, wherein A is S or NRla.

50. The method of claim 48 or 49, wherein A is S.

51. The method of claim 48 or 49, wherein A is NRla.

52. The method of any one of claims 48 to 51, wherein Rlais hydrogen.

53. The method of any one of claims 48 to 52, wherein R5is hydrogen.

54. The method of any one of claims 48 to 52, wherein R5is C1-10 alkyl.

55. The method of claim 54, wherein R5is C4 alkyl.

56. The method of any one of claims 48 to 52, wherein R5is C3-12 carbocycle.

57. The method of claim 56, wherein R5is C& carbocycle.

58. The method of claim 57, wherein R5is phenyl.

59. The method of any one of claims 48 to 58, wherein R6is hydrogen.

60. The method of any one of claims 48 to 58, wherein R6is C1-10 alkyl.

61. The method of any one of claims 48 to 58, wherein R6is -N(R61)2.

62. The method of any one of claims 48 to 58, wherein R6is -CH2N(R61)C(O)R62.

63. The method of claim 61 or 62, wherein R61is hydrogen.

64. The method of claim 62 or 63, wherein R62is selected from 5- to 12-membered heterocycle.

65. The method of claim 64, wherein R62is selected from 5-membered heterocycle.

66. The compound of claim 65, wherein R62is selected from 5-membered heteroaryl group.P-660558-PC67. The compound of claim 65 or 66, wherein R62is selected fromThe compound of claim 65 or 66, wherein R62is69. The compound of claim 65 or 66, wherein R62is70. The method of any one of claims 62 to 69, wherein71. The method of any one of claims 48 to 70, wherein R7is hydrogen.

72. The method of any one of claims 48 to 70, wherein R7is selected from 3- to 12- membered heterocycle.

73. The method of claim 72, wherein R7is selected from optionally substituted 8-membered heterocycle.

74. The method of claim 73, wherein R7is selected from,each of which is optionally substituted.

75. The method of claim 74, wherein R7is selected fromP-660558-PC76. The method of claim 75, wherein R7is optionally substituted H77. The method of claim 75, wherein R7is optionally substituted78. The method of claim 76, wherein R7is optionally substituted by -OH.

79. The method of claim 78, wherein80. The method of claim 77, wherein R7is optionally substituted by -OCH3.

81. The method of claim 80, wherein R7is.

82. The method of claim 77, wherein R7is optionally substituted by -C(O)OCH2CH3.

83. The method of claim 82, wherein84. The method of any one of claims 48 to 83, wherein R8is hydrogen.

85. The method of any one of claims 48 to 83, wherein R8is C3-12 carbocycle.

86. The method of claim 85, wherein R8is Ce carbocycle.

87. The method of claim 86, wherein R8is phenyl.

88. The method of any one of claims 47 to 87, wherein the compound having a structure ofFormula (II) is selected from:P-660558-PC89. The method of any one of claims 1 to 88, wherein the administration of the composition comprises administering the composition to a skin of the subject.

90. The method of any one of claims 1 to 89, wherein an area of the skin is selected from scalp, face, under or around an eye, around a mouth or a nose, a neck, a hand, penile region, around joint, a wrist, an ankle, an eyelid, on or behind a knee, on or behind an elbow, a foot, a leg, or an area of skin experiencing friction through contact, or a combination thereof.

91. The method of any one of claims 1 to 90, wherein the composition is a cosmetic composition or a pharmaceutical composition.

92. The method of any one of claims 1 to 91, wherein the composition further comprises an additive comprising a cosmetically acceptable carrier, an excipient, an adjuvant, a diluent, or a combination thereof.

93. The method of any one of claims 1 to 92, wherein the composition is formulated as a toner, a cream, an emulsion, a lotion, an ointment, a paste, a gel, a suspension, a serum, an oil, an edible supplement, a direct injection, a beverage, a transdermal patch, a topical patch, aP-660558-PC moisturizer, a face mask, a shampoo, a foam, a cleanser, a mousse, a liquid, a powder, an aerosol, a spray, a balm, a pigment-containing cosmetic, a foundation, a primer, a concealer, a sunscreen, or a combination thereof.

94. The method of any one of claims 1 to 92, wherein the composition is formulated by delivery vehicles selected from an aqueous phase solution, an oil phase solution, water-in-oil emulsion, oil-in-water emulsion, water-in-oil-in-water emulsion, oil-in-water-in-oil emulsion, water-in-silicone emulsion, silicone-in-water emulsion, encapsulation, a liposome, a vesicle, an ethosome, a polymersome, an exosome, a transfersome, a niosome, a complex, a cyclodextrin, a lipid nanoparticle, a nanoparticle, a microparticle, a macroparticle, solid powder, or a combination thereof.

95. The method of any one of claims 1 to 94, wherein the administration of the composition decreases hyperpigmentation selected from melasma, sunspots, solar lentigos, age spots, liver spots, Cafe au lait spot, post-inflammatory hyperpigmentation, uneven skin tone, drug-induced hyperpigmentation, and a combination thereof.

96. The method of any one of claims 1 to 95, wherein the administration of the composition decreases melanocyte viability.

97. The method of any one of claims 1 to 96, wherein the administration of the composition results in skin brightening or whitening.

98. The method of any one of claims 1 to 97, wherein the administration of the composition reduces the abundance of melanocytes, decreases the viability of melanocytes, controls proliferation of new melanocytes, suppresses melanocytes, or a combination thereof.

99. The method of any one of claims 1 to 98, wherein the administration of the composition results in the inhibition of melanosome transfer, inhibition of melanin production, regulation of the melanocyte environment, or a combination thereof.

100. The method of any one of claims 1 to 99, wherein the administration of the composition aids in reducing oxidative stress, preventing oxidative stress, or a combination thereof.

101. The method of any one of claims 1 to 100, wherein the administration of the composition facilitates pigment removal, brightens within the dermal layer, reduces of skin hyperpigmentation, balances skin tone irregularities, or a combination thereof.P-660558-PC102. The method of any one of claims 1 to 101, wherein the administration of the composition improves skin barrier function, inhibits melanogenesis, regulates melanocyte viability, reduces melanocyte quantity, or a combination thereof.

103. The method of any one of claims 1 to 102, wherein the administration of the composition aids in fading age spots, dark spots, or treats post-acne scars or marks.

104. The method of any one of claims 1 to 103, wherein the administration of the composition cleanses the skin of dirt, oil, germs, dead skin cells, or any other impurities.

105. The method of any one of claims 1 to 104, wherein the administration of the composition increases skin moisture.

106. The method of any one of claims 1 to 105, wherein the administration of the composition reduces skin roughness or fine lines.

107. The method of any one of claims 1 to 106, wherein the administration of the composition protects the skin from ultraviolet damage.

108. The method of any one of claims 1 to 107, wherein the composition is administered one to three times a day.

109. The method of any one of claims 1 to 107, wherein the composition is administered two times a day.

110. The method of any one of claims 1 to 107, wherein the composition is administered three times a day.

111. The method of any one of claims 1 to 110, wherein the composition is administered for at least two consecutive days.

112. The method of any one of claims 1 to 10, wherein the composition is administered for at least five consecutive days.

113. The method of any one of claims 1 to 110, wherein the composition is administered for at least seven consecutive days.

114. The method of any one of claims 1 to 110, wherein the composition is administered at least for about 15 days, about 30 days, about 60 days, about 90 days, about 6 months, or a year.

115. A kit for use in performing the method of any one of claims 1 to 114.

116. The kit of claim 115, further comprising an applicator.P-660558-PC117. The kit of claims 116, wherein the applicator comprises a brush, a comb, a cotton swab, a spatula, a spoon, a dropper, a spray nozzle, a squeeze bottle, a pump bottle, a tube, an applicator wand, a sponger, a foam blender, a silicone applicator, a rollerball, a powder puff, a tottle, a microneedling device, a microneedling stamp, a microneedling roller, a microneedling pen, a microneedling patch, dissolvable microneedles, a transdermal patch, a hydrocolloid patch, or a combination thereof.

118. The kit of any one of claims 115 to 117, further comprising written instructions for using the kit.

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