Compositions and methods for reducing skin aging effects

Abstract

Provided are compounds, compositions and methods for reducing properties associated with skin aging in cells of a subject in need thereof. In some embodiments, the methods comprise administering a composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof.

Description

P-660561 -PCCOMPOSITIONS AND METHODS FOR REDUCING SKIN AGING EFFECTSBACKGROUND

[0001] Skin aging, a natural biological process, is characterized by a progressive decline in physiological integrity. This leads to visible changes such as wrinkles, loss of elasticity, and uneven pigmentation, driven primarily by cellular degradation and an accumulation of molecular damage over time. Despite significant advancements in research, there remains a substantial need for more effective and reliable means to reduce properties associated with skin aging in cells. The present disclosure addresses this critical need.SUMMARY

[0002] The present disclosure provides a compound having a structure of Formula (I):O Formula (I),or a pharmaceutically acceptable salt thereof or solvate thereof,wherein:Y is -O-, -S-, or -N(R11)-,R11is hydrogen, deuterium, or C1-5 alkyl;X is hydrogen, C1-5 alkyl, -C(O)R12, -C(O)OR12, C(O)N(R12)2, -(CH2)nC(O)R12, - (CH2)nC(O)OR12, --(CH2)nC(O)N(R12)2, C5-12 carbocycle, or 5- to 12-membered heterocycle, the C5-12 carbocycle and 5- to 12-membered heterocycle each being independently optionally substituted with one or more R15;each R12is independently hydrogen, deuterium, C1-5 alkyl, C2-6 alkenyl, or C2-6alkynyl, each C1-5 alkyl, C2-6 alkenyl, and C2-6 alkynyl being independently optionally substituted with one or more substituents selected from the group consisting ofP-660561 -PChalogen, -NO2, -CN, -OH, -SH, -NH2, C3-12 carbocycle, and 3- to 12-membered heterocycle;n is between 1-5; andeach R15is independently hydrogen, deuterium, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, =0, -NO2, -CN, -OH, -SH, or -NH2.

[0003] In some embodiments, Y is -O-. In some embodiments, Y is -S-. In some embodiments, Y is -N(R11)-.

[0004] In some embodiments, R11is hydrogen. In some embodiments, R11is C1-5 alkyl. In some embodiments, R11is -CH3.

[0005] In some embodiments, X is C1-5 alkyl. In some embodiments, X is -CH2CH3. In some embodiments, X is — (CH2)nC(O)R12. In some embodiments, X is — (CH2)nC(O)N(R12)2. In some embodiments X is -CH2C(O)R12. In some embodiments X is -CH2C(O)N(R12)2. In some embodiments, each R12is independently optionally substituted C1-5 alkyl. In some embodiments, each R12is methyl.

[0006] In some embodiments, X is optionally substituted 5- to 12-membered heterocycle. In some embodiments, X is optionally substituted 5 -membered heterocycle. In some embodiments, the 5-membered heterocycle is or comprises 5 -membered heterocyclyl. In some embodiments, the 5-membered heterocycle is or comprises 5 -membered heteroaryl. In some embodiments, X isselected from, and

[0007] In some embodiments, R15is halogen. In some embodiments, R15is -Cl. In some embodiments, R15is =0. In some embodiments, R15is -CH3. In some embodiments, X isP-660561 -PC

[0009] The present disclosure provides a compound having a structure of Formula (II):P-660561 -PCor a pharmaceutically acceptable salt thereof or solvate thereof,wherein:A is -O-, -S-, or -N(Rla)-,Rlais hydrogen, deuterium, or C1-5 alkyl;R21is C1-C5 alkyl, C5-12 carbocycle or 5- to 12-membered heterocycle, the C5-12 carbocycle and 5- to 12-membered heterocycle each being independently substituted with one or more R21a,each R21ais independently halogen, -NO2, -CN, -OR21b, -SR21b, -N(R21b)2, -C(O)R21b, - C(O)OR21b, -OC(O)N(R21b)2, -NR21bC(O)R21b, - NR21bC(O)OR21b, - NR21bC(O)N(R21b)2, or -C(O)N(R21b)2,each R21bis independently hydrogen, deuterium, or C1-5 alkyl; andR22is O or S.

[0010] In some embodiments, A is -O-. In some embodiments, A is -S-. In some embodiments, A is -N(Rla)-.

[0011] In some embodiments, Rlais H. In some embodiments, Rlais C1-5 alkyl. In some embodiments, Rlais -CH3.

[0012] In some embodiments, R21is an optionally substituted C5-12 carbocycle. In some embodiments, R21is an optionally substituted C6carbocycle. In some embodiments, R21is C1-C5 alkyl. In some embodiments, R21is an optionally substituted phenyl. In some embodiments, R21is an optionally substituted 5- to 12-membered heterocycle. In some embodiments, R21is an optionally substituted 6-membered heterocycle. In some embodiments, R21is selected from, triazole, and. In some embodiments, R21is C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is halogen. In some embodiments, R21is C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is -F or -Cl. In some embodiments, R21is C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is independently -OR21bor -N(R21b)2.P-660561 -PC

[0013] In some embodiments, each R21bis independently C1-5 alkyl. In some embodiments, each R21bis independently -CH3 or -CH2CH3.

[0015] In some embodiments, R22is O. In some embodiments, R22is S.P-660561 -PCo-7

[0017] The present disclosure provides a compound having a structure of Formula (III):Y1r51Formula (III),or a pharmaceutically acceptable salt thereof or solvate thereof;,wherein:Y1is O and Y2is O, Y1is O and Y2is S, or Y1is S and Y2is O;R51is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12- membered heterocycle, each of the C5-12 carbocycle, and 5- to 12-membered heterocycle bring optionally substituted with one or more R51a,each R51ais independently hydrogen, deuterium, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, =0, -NO2, -CN, -OH, -SH, or -NH2; andR52is hydrogen, deuterium, optionally substituted C1-5 alkyl, optionally substituted C1-5 haloalkyl, -(CH2)m1OR52a, -(CH2)m2O (CH2)m3OR52a, -(CH2)m4N(R52a)(R52b), (CH2)m5C(O)OR52a, -(CH2)m6C(O)R52a, -C(O)N(R52a)2, or -N(R52a)C(O)R,each R52aand R52bis independently hydrogen, deuterium, or optionally substituted C1-5 alkyl; andeach ml, m2, m3, m4, m5 and m6 is independently selected at each occurrence from 1, 2, 3, 4, and 5.

[0018] In some embodiments, Y1is O and Y2is O. In some embodiments, Y1is S and Y2is O.P-660561 -PC

[0019] In some embodiments, R51is hydrogen. In some embodiments, R51is C1-5 alkyl. In some embodiments, R51is -CH2CH3. In some embodiments, R51is C5-12 carbocycle. In some embodiments, R51is C6carbocycle. In some embodiments, R51is phenyl.

[0020] In some embodiments, R52is hydrogen. In some embodiments, R52is optionally substituted -C1-5 alkyl. In some embodiments, R52is optionally substituted propyl. In someembodiments, R52is optionally substituted methyl. In some embodiments, R52isIn some embodiments, R52is -(CH2)m1OR52a. In some embodiments, R52ais optionally substituted ethyl. In some embodiments, R52ais optionally substituted methyl. In some embodiments, R52aisF\F\optionally substituted propyl. In some embodiments, R52aisF. In some embodiments, ml is 2. In some embodiments, ml is 3. In some embodiments, ml is 4. In some embodiments, R52is -(CH2)3OCH2CH3. In some embodiments, R52is -(CH2)4OCH2CH3. In someFxF embodiments, R52is -(CPh^OCIR. In some embodiments, R52isF. In some embodiments, R52is -(CH2)m4N(R52a)(R52b). In some embodiments, R52ais -CH3. In some embodiments, R52bis -CH3. In some embodiments, m4 is 3.O

[0021] In some embodiments, the compound is selected from:HP-660561 -PC

[0022] In some embodiments, the compoundis or a salt or solvate thereof.

[0023] The present disclosure provides a compound having a structure of Formula (IV):Formula (IV),or a pharmaceutically acceptable salt thereof or solvate thereof,wherein:Z is -O-, -S-, or -N(RZ)-,P-660561 -PCRzis hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12- membered heterocycle, each of the C5-12 carbocycle, and 5- to 12-membered heterocycle being optionally substituted with one or more Rza,each Rzais independently selected from the group consisting of C 1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -NO2, -CN, -OH, -SH, and -NH2;R61is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12- membered heterocycle, each C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, and 5- to 12- membered heterocycle being optionally substituted with one or more R61a,each R61ais independently selected from the group consisting of -OH, -SH, -NH2, C5-12 carbocycle, and 5- to 12-membered heterocycle;each R62and R63is independently hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, -NO2, - CN, -OH, -SH, or -NH2; andR64is hydrogen, deuterium, C1-5 alkyl, or C1-5 haloalkyl.

[0024] In some embodiments, Z is -O-. In some embodiments, Z is -S-. In some embodiments, Z is -N(RZ)-. In some embodiments, Rzis hydrogen. In some embodiments, Rzis C1-5 alkyl. In some embodiments, Rzis -CH2CH3. In some embodiments, Rzis 5- to 12-membered heterocycle.In some embodiments, Rzis 5-membered heterocycle. In some embodiments, Rzis ^0 O

[0025] In some embodiments, R61is C1-5 alkyl. In some embodiments, R61is -CH3. In some embodiments, R61is -CH2Ph. In some embodiments, R61is -CH2OH. In some embodiments, R61is -CH2NH2. In some embodiments, R61ais alkyl substituted with 5- to 12-membered heterocycle. In some embodiments, R61ais alkyl substituted with 5 -membered heterocycle. Insome embodiments, R61is' — '. In some embodiments, R61is C5-12 carbocycle. In some embodiments, R61is C6carbocycle. In some embodiments, R61is phenyl.

[0026] In some embodiments, R62is hydrogen. In some embodiments, R62is C1-5 alkyl. In some embodiments, R62is -CH3. In some embodiments, R62is -NH2.

[0027] In some embodiments, R63is hydrogen. In some embodiments, R63is -CH3.P-660561 -PC

[0028] In some embodiments, R64is hydrogen. In some embodiments, R64is C1-5 alkyl. In some embodiments, R64is -CH3.HO O

[0029] In some embodiments, the compound is selected fromH,

[0030] The present disclosure also provides a compound having a structure of Formula (V):or pharmaceutically acceptable salt thereof or solvate thereof,wherein:Xais -O- or -S-;R71is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, -C(R71a)2N(R71a)2, - C(R71a)(R71b)N(R71a)(R71b), -C(R71a)2C(O)N(R71a)2, -C(R71a)2C(O)N(R71b)2, - C(R71a)(R71b)C(O)N(R71a)(R71b), -CFFPh, C5-12 carbocycle, or 5- to 12-membered heterocycle;each R71aand R71bis independently hydrogen, deuterium, C1-5 alkyl, or C1-5 haloalkyl, each R72, R74, and R75is independently hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, - NO2, -CN, -OH, -SH, or -NH2; andP-660561 -PCR73is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12- membered heterocycle, each of the C5-12 carbocycle and 5- to 12-membered heterocycle is optionally substituted with one or more C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -NO2, -CN, -OH, -SH, and -NH2.

[0031] In some embodiments, Xais -O-. In some embodiments, Xais -S-.

[0032] In some embodiments, R71is C1-5 alkyl. In some embodiments, R71is C3 alkyl. In some embodiments, R71is -CH(CH3)CH3. In some embodiments, R71is -CH2Ph. In some embodiments, R71is -C(R71a)2N(R71a)2. In some embodiments, R71ais hydrogen. In some embodiments, R71is -C(R71a)2C(O)N(R71b)2. In some embodiments, R71ais hydrogen. In some embodiments, R71bis -CH3. In some embodiments, R71is C5-12 carbocycle. In some embodiments, R71is C6carbocycle. In some embodiments, R71is phenyl.

[0033] In some embodiments, R72is hydrogen or -OH.

[0034] In some embodiments, R74is hydrogen, C1-5 alkyl, or -NH2. In some embodiments, R74is hydrogen. In some embodiments, R74is NH2.

[0035] In some embodiments, R75is hydrogen or C1-5 alkyl. In some embodiments, R75is hydrogen. In some embodiments, R75is -CH3.

[0036] In some embodiments, R73is hydrogen. In some embodiments, R73is 5- to 12-memberedheterocycle. In some embodiments, R isP-660561 -PC

[0037] In some embodiments, the compound is selected from:H

[0038] The present disclosure provides a compound having a structure of Formula (VI):Oor pharmaceutically acceptable salt thereof or solvate thereof,wherein:R81is hydrogen, deuterium, -OH, C1-5 alkyl, or C1-5 haloalkyl;R82is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12- membered heterocycle;R83is C1-5 alkyl, C1-5 haloalkyl, -OR83a, -NO2, -CN, or -N(R83a)2,each R83ais independently selected from hydrogen, deuterium, and C1-5 alkyl;q is 0, 1, or 2; andR84is absent or selected from C1-5 alkylene, C2-5 alkenylene, and C2-5 alkynylene, each of the C1-5 alkylene, C2-5 alkenylene, and C2-5 alkynylene is optionally substituted with one or more halogen, -NO2, -CN, -OH, -SH, or -NH2.P-660561 -PC

[0039] In some embodiments, R81is -OH. In some embodiments, R81is C1-5 alkyl. In some embodiments, R81is C4 alkyl. In some embodiments, R81is -CH2CH2CH2CH3. In some embodiments, R81is -CH2CH2(CH3)CH3.

[0040] In some embodiments, R82is hydrogen. In some embodiments, R82is C5-12 carbocycle. In some embodiments, R82is phenyl.

[0041] In some embodiments, R83is C1-5 alkyl. In some embodiments, R83is -CH2CH3. In some embodiments, R83is -OR83a. In some embodiments, R83ais -CH3. In some embodiments, R83is -N(R83a)2. In some embodiments, R83ais hydrogen. In some embodiments, q is 1.

[0042] In some embodiments, R84is C1-5 alkylene. In some embodiments, R84is -CH2CH2-. In some embodiments, R84is -CH(OH)CH2CH2-. In some embodiments, R84is -CH2CH(NH2)CH2-.In some embodiments, the compound is selected from: Hacceptable salt thereof or solvate thereof.

[0043] The present disclosure provides a composition comprising a compound disclosed herein and an excipient. The present disclosure provides a composition comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

[0044] In some embodiments, the composition provided herein is a pharmaceutical composition. In some embodiments, the salt comprises a pharmaceutically acceptable salt. In some embodiments, the excipient is a pharmaceutically acceptable excipient. In some embodiments, theP-660561 -PCpharmaceutically acceptable excipient comprises a carrier for a topical application of the composition.

[0045] In some embodiments, the composition is a cosmetic composition. In some embodiments, the salt comprises a cosmetically acceptable salt. In some embodiments, the excipient is a cosmetically acceptable excipient. In some embodiments, the cosmetically acceptable excipient comprises a carrier for a topical application of the composition. In some embodiments, the composition is suitable for topical administration.

[0046] In some embodiments, an administration of the composition prevents or treats a skin condition, disorder, or disease. In some embodiments, a weight % of the compound of the composition is in the range of 0.0001 % to 20 % by weight relative to the total weight of the composition.

[0047] In some embodiments, an administration of the composition provided herein increases skin collagen production or collagen-depositing cell proliferation, skin elastin production or elastindepositing cell proliferation, skin hyaluronic acid production or hyaluronic acid-depositing cell proliferation. In some embodiments, the carrier (delivery vehicle) is suitable for a topical application of the composition. In some embodiments, the carrier comprises 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, cyclodextrins, vesicles such as liposomes or niosomes, lipid based emulsions, nanosuspensions, lipid nanoparticles, different size particles such as nanoparticles, microparticles, or macroparticles, solid powders, salts, polymer -based nanoparticles, including those made from poly(lactic-co-glycolic acid) (PLGA) and chitosan; and metallic nanoparticles, including gold, silver, copper, titanium, platinum, zinc, magnesium, iron, and alginate nanoparticles, or any combination thereof. In some embodiments, the carrier (delivery vehicle) comprises hydrogels, aerosols, foams, creams, lotions, ointments, transdermal patches, subcutaneous implants, intradermal injections, and dissolvable microneedles.

[0048] 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, a spray, an edible supplement, a direct injection, a beverage, a transdermal patch, a topical patch, a moisturizer, a face mask, aP-660561 -PCshampoo, a foam, a cleanser, a mousse, a liquid, a powder, an aerosol, a foundation, a primer, a concealer, a sunscreen, an eyeshadow, or a combination thereof.

[0049] The present disclosure provides a method for preventing or treating a skin condition, disorder, or disease. The present disclosure also provides a method for treating a skin condition, disorder, or disease. The present disclosure is related to a method for increasing skin extracellular matrix component production, cell proliferation, or extracellular matrix component-depositing cell proliferation. The method comprises administering to a subject in need thereof a compound disclosed herein or a composition disclosed herein. In some embodiments, the extracellular matrix component comprises collagen, elastin, or hyaluronic acid.

[0050] In some embodiments, the composition is topically administered to the skin of the subject. In some embodiments, the skin comprises scalp skin, face skin, elbow skin, neck skin, chest skin, butt skin, thigh skin, hand skin, penile skin, skin around a joint, or a combination thereof. In some embodiments, the composition is topically administered under or around eyes, skin around mouth, skin around nose, cheeks, forehead, or a combination thereof.

[0051] In some embodiments, administering the composition reduces appearance of wrinkles and fine lines of the skin, increases collagen production of the skin, increases elastin production of the skin, increases hyaluronic acid production of the skin, fades age spots of the skin, improves firmness of the skin, improves elasticity of the skin, reduces roughness of the skin, or a combination thereof. In some embodiments, administering the composition removes dirt, oil, bacteria, dead skin, makeup, and any impurities from the skin. In some embodiments, administering the composition brightens the skin, lightens color of the skin, improves color of the skin, improves radiance of the skin, reduces hyperpigmentation of the skin, or a combination thereof. In some embodiments, administering the composition hydrates the skin, moisturizes the skin, reinforces the skin barrier, or a combination thereof. In some embodiments, administering the composition protects the skin from ultraviolet radiation, from ultraviolet radiation-induced damage, from environmental damage, from stress-induced damage, or a combination thereof. In some embodiments, administering the composition heals a wound of the skin, promotes healing a wound of the skin, reduces inflammation, or reduces age-induced inflammation.

[0052] In some embodiments, the composition is administered one to three times a day. In some embodiments, the composition is administered two times per day. In some embodiments, theP-660561 -PCcomposition is administered three times per 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 in response to symptoms or conditions as and when required. In some embodiments, the composition is administered intermittently at a frequency of 1-2 times per week or 1-2 times per month, not necessarily on consecutive days. In some embodiments, the composition is administered for at least about 15 days, about 30 days, about 60 days, about 90 days, about 6 months, or a year.

[0053] The present disclosure provides a kit for use in performing the method disclosed 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, an aerosol bottle, a pump bottle, a tube, an applicator wand, a doe foot applicator, a sponge, a foam blender, a silicone applicator, a rollerball, a powder puff, a tottle, or a combination thereof. In some embodiments, the kit further comprises written instructions for using the kit.

[0054] 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 present 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.

[0055] 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

[0056] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained byP-660561 -PCreference 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:

[0057] FIG. 1 illustrates the percentage increase in metabolic activity in response to various example compounds disclosed herein, in accordance with one or more embodiments of the present disclosure. The compounds are shown to elevate fibroblast metabolic activity, as evidenced by the rise in cytosolic ATP, which was evaluated using CellTiter Gio, in comparison to the vehicle control, dimethyl sulfoxide (DMSO). Each data point signifies a unique fibroblast donor and encapsulates the average of at least three technical replicates. The data bars denote the average increase in metabolic activity, while the error bars display the standard deviation among a minimum of three fibroblast donors. The figure represents the result of an experiment where primary human dermal fibroblasts (hDF) were treated with the example compounds for a duration of 48 hours.

[0058] FIG. 2A- FIG. 2C depict the enhanced production of extracellular matrix components by fibroblasts as a result of exposure to example compounds disclosed herein, in accordance with one or more embodiments of the present disclosure. FIG.2A demonstrates the increase in elastin, FIG.2B shows the heightened levels of hyaluronan, and FIG. 2C presents the rise in pro-collagen I. Each of these increases is shown relative to the vehicle treatment (DMSO). Each individual data point represents a unique fibroblast donor and is based on the average of at least three technical replicates. The data bars in the figures represent the average increase in the production of each matrix component, while the error bars indicate the standard deviation among four fibroblast donors. These figures are the result of an experiment in which primary human dermal fibroblasts (hDF) were treated with the test compounds for a duration of 24 hours.

[0059] FIG. 3 shows fibroquin derivatives increase elastin production rate in adult female donor full thickness reconstructed tissue. Data was normalized as each tissue (biological replicate) to its own basal elastin production (the time point of interest was divided by the time zero production), and calculated as a percent increase relative to the global DMSO average. Each point is an individual biological replicate.P-660561 -PC

[0060] FIG. 4A and FIG. 4B provide the penetration of the example compound 17A into the epidermis and dermis layers of the skin, in accordance with one or more embodiments of the present disclosure. A 3D skin model was treated with the example compound 17A at a concentration of 0.1% w / w, formulated in two different mediums: cream (FIG. 4A) and silicone (FIG. 4B). The data show the distribution area of the compound within the epidermis and dermis, as well as its concentration in these skin layers.

[0061] FIG. 5 presents the percentage of cell viability in various human cell types after exposure to the example compound 17A, in accordance with one or more embodiments of the present disclosure. The graph indicates that the example compound 17A does not lead to a decrease in cell viability across any of the cell types tested, thereby suggesting its non-toxic nature. Cell viability was determined using a standard metabolic activity assay, specifically through the quantification of total ATP. The resulting data was then normalized to the vehicle control condition.

[0062] FIG. 6 presents the percentage of cell viability in various human cell types after exposure to the example compound 17C, in accordance with one or more embodiments of the present disclosure. The graph indicates that the example compound 17C does not lead to a decrease in cell viability across any of the cell types tested, thereby suggesting its non-toxic nature. Cell viability was determined using a standard metabolic activity assay, specifically through the quantification of total ATP. The resulting data was then normalized to the vehicle control condition.

[0063] FIG. 7 presents the percentage of cell viability in various human cell types after exposure to the example compound 17B, in accordance with one or more embodiments of the present disclosure. The graph indicates that the example compound 17B does not lead to a decrease in cell viability across any of the cell types tested, thereby suggesting its non-toxic nature. Cell viability was determined using a standard metabolic activity assay, specifically through the quantification of total ATP. The resulting data was then normalized to the vehicle control condition.

[0064] FIG. 8 presents the percentage of cell viability in various human cell types after exposure to the example compound 17E, in accordance with one or more embodiments of the present disclosure. The graph indicates that the example compound 17E does not lead to a decrease in cell viability across any of the cell types tested, thereby suggesting its non-toxic nature. Cell viability was determined using a standard metabolic activity assay, specifically through the quantification of total ATP. The resulting data was then normalized to the vehicle control condition.P-660561 -PC

[0065] FIG. 9 presents the percentage of cell viability in various human cell types after exposure to the example compound 17D, in accordance with one or more embodiments of the present disclosure. The graph indicates that the example compound 17D does not lead to a decrease in cell viability across any of the cell types tested, thereby suggesting its non-toxic nature. Cell viability was determined using a standard metabolic activity assay, specifically through the quantification of total ATP. The resulting data was then normalized to the vehicle control condition.

[0066] FIG. 10 illustrates the SOS-induction factor (SOSIF) across various example compounds disclosed herein, in accordance with one or more embodiments of the present disclosure. The measurement was achieved by expressing a reporter protein in response to DNA damage in an engineered E. coli strain. The genotoxicity of the compounds was then assessed by measuring the absorbance at 420 nm and 600 nm and subsequently calculating the SOSIF, which was normalized to the vehicle control (DMSO). An SOSIF value greater than 1.5 is indicative of genotoxicity.FIG. 10 shows that 4-nitroquinoline 1 -oxide (4NQO), a known mutagen, is genotoxic. However, all of the example compounds are non-genotoxic.

[0067] FIG. 11 shows compound sensitization. Results reflect the average of four independent experimental replications. The average Luminescent signal for gene induction or viability normalized to DMSO is shown for each dose point. Error bars represent the standard deviation. The relative luminescence is normalized to cell viability and only plotted for points where viability is above the defined threshold (0.7).DETAILED DESCRIPTION

[0068] While various embodiments of the 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 may 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.

[0069] The aging process of skin is complex and contributes to visible signs of skin aging. While current methods to counteract skin aging exist, they often struggle with accurately targeting the root causes in the skin without causing unwanted side effects. The present disclosure seeks toP-660561 -PCaddress these challenges by providing compounds, compositions, and methods designed specifically for reducing properties associated with skin aging at the cellular level. This disclosure introduces compounds that can assist in reducing the manifestations of skin aging. These compounds may form part of a composition that can be topically applied to the skin of a subject in need thereof. The present disclosure further provides compositions and methods aimed at effectively tackling the visible signs of skin aging.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons.P-660561 -PC

[0074] 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.

[0075] " Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0076] " 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., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 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.

[0077] " 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., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6 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.

[0078] " Alkylene" or "alkylene chain" refers to a straight / linear 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, / ?-butylene, and the like. The alkylene chain (linear or branched) 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., C1-C8 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, anP-660561 -PCalkylene 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., C5-C8 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).

[0079] " 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., C2-C8 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 comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene).

[0080] 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.P-660561 -PC

[0081] 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.

[0082] “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.

[0083] " 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. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2. l]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0084] The term “halo” or, alternatively, “halogen” or “halide,” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0085] 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,P-660561 -PC2,2,2-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.

[0086] 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 bicylic rings e.g., 5 to 12-membered spiro bicycles.

[0087] 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, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, and thiophenyl (i.e. thienyl).

[0088] 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 hydrogenP-660561 -PCatoms 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.

[0089] 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 tis 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-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(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); wherein each Raais independently selected from hydrogen, 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-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 tis 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 straightP-660561 -PCor branched alkylene, alkenylene, or alkynylene chain, and each Rccis a straight or branched alkylene, alkenylene or alkynylene chain.

[0090] 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)”

[0091] 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.

[0092] 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 and 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.

[0093] 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, forP-660561 -PCexample, 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.

[0094] 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 aluminum, 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, 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.

[0095] 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.

[0096] 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 artisanP-660561 -PCwill 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.

[0097] 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.

[0098] 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, and 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.

[0099] The term “zn vivo” is used to describe an event that takes place in a subject’s body.

[0100] 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.

[0101] 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.P-660561 -PC

[0102] 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.

[0103] 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 severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0104] 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.

[0105] “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.

[0106] An excipient, a pharmacologically / cosmetically inactive substance, plays a role in formulating the active compounds, enhancing their stability, bioavailability or delivery rate, or offering patient-friendly dosage forms. It can serve various functions such as binders, fillers,P-660561 -PCdisintegrants, lubricants, sweeteners or coatings, depending on the type of dosage form. In some embodiments, the excipient comprises a carrier (delivery vehicle) of the compound. The specific excipient(s) used in the compositions of the present disclosure have been carefully selected to maximize the efficacy of the active compounds and ensure optimal absorption and delivery to the skin cells, thereby aiding in the reduction of skin aging properties. The choice of excipient, while not influencing the anti-aging effects directly, significantly contributes to the overall effectiveness and usability of the composition. “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.

[0107] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.COMPOUNDS

[0108] The present disclosure provides compounds or a salt or solvate thereof, designed with the intention of reducing properties associated with aging in cells within or on a subject requiring such intervention. These compounds may have a structural Formula (I)-Formula (VI) or a salt or solvate thereof. The compounds or salts or solvates thereof disclosed herein may be utilized in the compositions and methods disclosed herein, thereby offering promising applications in the field of senolytics.

[0109] In certain aspects, disclosed herein is a compound having a structure of Formula (I):O Formula (I),or a salt or solvate thereof,wherein:Y is -O-, -S-, or -N(R11)-,R11is hydrogen, deuterium, or C1-5 alkyl;P-660561 -PCX is hydrogen, C1-5 alkyl, -C(O)R12, -C(O)OR12, C(O)N(R12)2, -(CH2)nC(O)R12, -(CH2)nC(O)OR12, -(CH2)nC(O)N(R12)2, C5-12carbocycle, or 5- to 12-membered heterocycle, the C5-12carbocycle and 5- to 12-membered heterocycle each being independently optionally substituted with one or more R15;each R12is independently hydrogen, deuterium, C1-5 alkyl, C2-6 alkenyl, or C2-6alkynyl, each C1-5 alkyl, C2-6 alkenyl, and C2-6 alkynyl being independently optionally substituted with one or more substituents selected from the group consisting of halogen, -NO2, -CN, -OH, -SH, -NH2, C3-12carbocycle, and 3- to 12-membered heterocycle;n is 1-5; andeach R15is independently hydrogen, deuterium, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, =0, -NO2, -CN, -OH, -SH, or -NH2.

[0110] In some embodiments, Y is -O-. In some embodiments, Y is -S-. In some embodiments, Y is -N(R11)-.

[0111] In some embodiments, R11is hydrogen. In some embodiments, R11is C1-5 alkyl. In some embodiments, R11is -CH3. In some embodiments, R11is -CH2CH3. In some embodiments, R11is -CH2CH2CH3. In some embodiments, R11is -CH(CH3)2. In some embodiments, R11is -CH2CH(CH3)2. In some embodiments, R11is -CH(CH3)CH2CH3. In some embodiments, R11is -C(CH3)3. In some embodiments, R11is -CH2CH2CH2CH3. In some embodiments, R11is -CH2CH2CH(CH3)CH3. In some embodiments, R11is -CH2CH(CH3)CH2CH3. In some embodiments, R11is -CH2CH2CH2CH2CH3.

[0112] In some embodiments, X is C1-5 alkyl. In some embodiments, X is -CH3. In some embodiments, X is -CH2CH3. In some embodiments, X is -CH2CH2CH3. In some embodiments, X is -CH(CH3)CH3. In some embodiments, X is -CH2CH(CH3)CH3. In some embodiments, X is -CH(CH3)CH2CH3. In some embodiments, X is -CH2CH2CH2CH3. In some embodiments, X is -CH2CH2CH(CH3)2. In some embodiments, X is -C(CH3)2CH2CH3. In some embodiments, X is -CH2CH(CH3)CH2CH3. In some embodiments, X is -CH2CH2CH2CH2CH3.

[0113] In some embodiments, X is -CH2C(O)R12. In some embodiments, X is -CH2C(O)N(R12)2.P-660561 -PC

[0114] In some embodiments, each R12is independently optionally substituted C1-5 alkyl. In some embodiments, each R12is independently optionally substituted methyl. In some embodiments, each R12is independently optionally substituted ethyl. In some embodiments, each R12is independently optionally substituted propyl. In some embodiments, each R12is independently optionally substituted -propyl. In some embodiments, each R12is independently optionally substituted -butyl. In some embodiments, each R12is independently optionally substituted secbutyl. In some embodiments, each R12is independently optionally substituted zso-butyl. In some embodiments, each R12is independently optionally substituted -pentyl. In some embodiments, each R12is independently optionally substituted tert-pentyl. In some embodiments, each R12is independently optionally substituted zso-pentyl. In some embodiments, each R12is independently optionally substituted sec-pentyl. In some embodiments, each R12is independently optionally substituted 3 -pentyl.

[0115] In some embodiments, X is optionally substituted 5- to 12-membered heterocycle. In some embodiments, X is optionally substituted 5 -membered heterocycle. In some embodiments, X is optionally substituted 6-membered heterocycle. In some embodiments, X is optionally substituted 7-membered heterocycle. In some embodiments, X is optionally substituted 8-membered heterocycle. In some embodiments, X is optionally substituted 9-membered heterocycle. In some embodiments, X is optionally substituted 10-membered heterocycle. In some embodiments, X is optionally substituted 11 -membered heterocycle. In some embodiments, X is optionally substituted 12-membered heterocycle. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has an oxygen atom. In some embodiments, the heterocycle has at least one sulfur atom. In some embodiments, the heterocycle has a sulfur atom.

[0116] In some embodiments, the 5-membered heterocycle is 5-membered heterocyclyl. In some embodiments, the 5 -membered heterocycle comprises 5 -membered heterocyclyl.P-660561 -PC

[0117] In some embodiments, the 5-membered heterocycle is 5-membered heteroaryl. In some embodiments, the 5-membered heterocycle comprises 5-membered heteroaryl.

[0118] In some embodiments, X is selected fromH, I, I, Hsome embodiments,X is I. In some embodiments,X is I. In some embodiments,some embodiments, X is' O. In some embodiments, X is' S

[0119] In some embodiments, X is -CH2C(O)R12. In some embodiments, X is -CH2C(O)N(R12)2.In some embodiments, each R12is independently optionally substituted C1-5 alkyl. In some embodiments, each R12is independently optionally substituted methyl.

[0120] In some embodiments, X is optionally substituted 5- to 12-membered heterocycle. In some embodiments, X is optionally substituted 5 -membered heterocycle. In some embodiments, the 5-membered heterocycle is or comprises 5 -membered heterocyclyl. In some embodiments, the 5-membered heterocycle is or comprises 5 -membered heteroaryl. In some embodiments, X isP-660561 -PC

[0121] In some embodiments, R15is halogen. In some embodiments, R15is -Cl. In some embodiments, R15is -F. In some embodiments, R15is -Br. In some embodiments, R15is -I.

[0122] In some embodiments, R15is =0.

[0123] In some embodiments, R15is -CH3.

[0124] In some embodiments, X is selected fromHIn some embodiments, X is H. In some embodiments, X issome embodiments,X isH. In some embodiments, X is O. In some embodiments,

[0125] In some embodiments, the compound is selected from:OP-660561 -PCembodiments, the compound is O or a salt or solvate thereof. In some embodiments, the compound is or a salt or solvate thereofO in some embodiments, the compound is embodiments, the compound isembodiments, the compoundisP-660561 -PCembodiments, the compound isHor a salt or solvate thereof. In some embodiments, the compoundis or a salt or solvate thereof. In some or a salt or solvate thereof. In someembodiments, the compound isHor a salt or solvate thereof. In some embodiments, the compound is,or a salt or solvate thereof. In some embodiments, the compound isHor a salt or solvate thereof. In someP-660561 -PC~''Nembodiments, the compoundis0or a salt or solvate thereof. In someembodiments, the compound isCl or a salt or solvate thereof.

[0126] In certain aspects, disclosed herein is a compound having a structure of Formula (II):or a salt or solvate thereof,wherein:A is -O-, -S-, or -N(Rla)-,Rlais hydrogen, deuterium, or C1-5 alkyl;R21is C5-12 carbocycle or 5- to 12-membered heterocycle, the C5-12 carbocycle and 5- to 12- membered heterocycle each being independently substituted with one or more R21a, each R21ais independently halogen, -NO2, -CN, -OR21b, -SR21b, -N(R21b)2, -C(O)R21b, - C(O)OR21b, -OC(O)N(R21b)2, -NR21bC(O)R21b, - NR21bC(O)OR21b, - NR21bC(O)N(R21b)2, or -C(O)N(R21b)2,each R21bis independently hydrogen, deuterium, or C1-5 alkyl; andR22is O or S.

[0127] In some embodiments, A is -O-. In some embodiments, A is -S-. In some embodiments, A is -N(Rla)-. In some embodiments, Rlais hydrogen. In some embodiments, Rlais deuterium. In some embodiments, Rlais C1-5 alkyl. In some embodiments, Rlais -CH3. In some embodiments, Rlais -CH2CH3. In some embodiments, Rlais -CH2CH2CH3. In some embodiments, Rlais -CH(CH3)2. In some embodiments, Rlais -CH2CH(CH3)2. In some embodiments, Rlais -CH(CH3)CH2CH3. In some embodiments, Rlais -C(CH3)3. In some embodiments, Rlais -P-660561 -PCCH2CH2CH2CH3. In some embodiments, Rlais -CH2CH2CH(CH3)CH3. In some embodiments, Rlais -CH2CH(CH3)CH2CH3. In some embodiments, Rlais -CH2CH2CH2CH2CH3.

[0128] In some embodiments, R21is C5-12 carbocycle. In some embodiments, R21is optionally substituted C5 carbocycle. In some embodiments, R21is optionally substituted C6carbocycle. In some embodiments, R21is optionally substituted phenyl. In some embodiments, R21is optionally substituted C7 carbocycle. In some embodiments, R21is optionally substituted C8carbocycle. In some embodiments, R21is optionally substituted C9 carbocycle. In some embodiments, R21is optionally substituted C10 carbocycle. In some embodiments, R21is optionally substituted C11carbocycle. In some embodiments, R21is optionally substituted C12 carbocycle. In some embodiments, the C5-12 carbocycle is optionally substituted with one or more R21a.

[0129] In some embodiments, R21is 5- to 12-membered heterocycle. In some embodiments, R21is 5 -membered heterocycle. In some embodiments, R21is 6-membered heterocycle. In some embodiments, R21is 7-membered heterocycle. In some embodiments, R21is 8-membered heterocycle. In some embodiments, R21is 9-membered heterocycle. In some embodiments, R21is 10-membered heterocycle. In some embodiments, R21is 11 -membered heterocycle. In some embodiments, R21is 12-membered heterocycle. In some embodiments, the 5- to 12-membered heterocycle each being independently substituted with one or more R21a. In some embodiments, R21is optionally substituted 6-membered heterocycle. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has an oxygen atom. In some embodiments, the heterocycle has at least one sulfur atom. In some embodiments, the heterocycle has a sulfur atom.P-660561 -PC

[0130] In some embodiments, R21is selected fromN, triazole, andN. In some embodiments, R21is. In some embodiments, R21is. In someembodiments, R21is triazole. In some embodiments,R21is N in some embodiments, R21is

[0131] In some embodiments, each R21ais independently halogen, -NO2, -CN, -OR21b, -SR21b, -N(R21b)2, -C(O)R21b, -C(O)OR21b, -OC(O)N(R21b)2, -NR21bC(O)R21b, - NR21bC(O)OR21b, -NR21bC(O)N(R21b)2, or -C(O)N(R21b)2. In some embodiments, each R21ais independently halogen. In some embodiments, each R21ais independently -NO2. In some embodiments, each R21ais independently -CN. In some embodiments, each R21ais independently -OR21b. In some embodiments, each R21ais independently -SR21b. In some embodiments, each R21ais independently -N(R21b)2. In some embodiments, each R21ais independently -C(O)R21b. In some embodiments, each R21ais independently -OC(O)N(R21b)2. In some embodiments, each R21ais independently -NR21bC(O)R21b. In some embodiments, each R21ais independently -NR21bC(O)OR21b. In some embodiments, each R21ais independently -NR21bC(O)N(R21b)2. In some embodiments, each R21ais independently -C(O)N(R21b)2.

[0132] In some embodiments, each R21bis independently hydrogen, deuterium, or C1-5 alkyl. In some embodiments, each R21bis independently hydrogen. In some embodiments, each R21bis independently deuterium. In some embodiments, each R21bis independently C1-5 alkyl. In some embodiments, R21bis -CH3. In some embodiments, R21bis -CH2CH3. In some embodiments, R21bis -CH2CH2CH3. In some embodiments, R21bis -CH(CH3)2. In some embodiments, R21bis -CH2CH(CH3)2. In some embodiments, R21bis -CH(CH3)CH2CH3. In some embodiments, R21bis -C(CH3)3. In some embodiments, R21bis -CH2CH2CH2CH3. In some embodiments, R21bis -P-660561 -PCCH2CH2CH(CH3)CH3. In some embodiments, R21bis -CH2CH(CH3)CH2CH3. In some embodiments, R21bis -CH2CH2CH2CH2CH3.

[0133] In some embodiments, R21is C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is halogen. In some embodiments, R21is C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is -F or -Cl. In some embodiments, R21is C5-12 carbocycle substituted with one or more -F. In some embodiments, R21is C5-12carbocycle substituted with one or more -Cl. In some embodiments, R21is 5- to 12-membered heterocycle substituted with one or more -F. In some embodiments, R21is 5- to 12-membered heterocycle substituted with one or more -Cl. In some embodiments, R21is C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is independently -OR21bor -N(R21b)2. In some embodiments, R21is C5-12 carbocycle substituted with one or more -OR21b. In some embodiments, R21is C5-12 carbocycle substituted with one or more -N(R21b)2. In some embodiments, R21is 5- to 12-membered heterocycle substituted with one or more -OR21b. In some embodiments, R21is 5- to 12-membered heterocycle substituted with one or more -N(R21b)2.P-660561 -PC

[0135] In some embodiments, R21is selected fromF, OCH3, N Cl, and \ N / . In some embodiments, R21is F. In some embodiments, R21is OCH3. In \N / some embodiments,R21is Cl. In some embodiments, R21is

[0136] In some embodiments, R21is optionally substituted C5-12 carbocycle. In some embodiments, R21is optionally substituted C6carbocycle. In some embodiments, R21is optionally substituted phenyl. In some embodiments, R21is optionally substituted 5- to 12-membered heterocycle. In some embodiments, R21is optionally substituted 6-memberedNheterocycle. In some embodiments, R21is selected from, and. In some embodiments, R21is C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is halogen. In some embodiments, R21is C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is -F or -Cl. In some embodiments, R21is C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is independently -OR21bor -N(R21b)2. In some embodiments, each R21bis independently C1-5 alkyl. In some embodiments, each R21bis independently -CH3 or -CH2CH3. Insome embodiments, R21is selected fromClP-660561 -PCH3CO H3CO. In some embodiments, R21is selected

[0137] In some embodiments, R22is O. In some embodiments, R22is S.P-660561 -PCCl or a salt or solvate thereof. In some embodiments, the compound is F or a salt or solvate thereof. In some embodiments, the compound isCl or a salt or solvate thereof. In some embodiments, the compound is H3CO or a salt or solvate thereof. In some embodiments, the compound is3or a salt or solvate thereof. In some embodiments, the compound isP-660561 -PC— Nor a salt or solvate thereof. In some embodiments, the compound isCl or a salt or solvate thereof. In some embodiments, the compound isor a salt or solvate thereof. In some embodiments, the compound isH3COor a salt or solvate thereof.

[0139] In certain aspects, disclosed herein is a compound having a structure of Formula (III):P-660561 -PCY1R51Formula (III),or salts or solvate thereof,wherein:Y1is O and Y2is O, Y1is O and Y2is S, or Y1is S and Y2is O;R51is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12- membered heterocycle, each of the C5-12 carbocycle, and 5- to 12-membered heterocycle bring optionally substituted with one or more R51a,each R51ais independently hydrogen, deuterium, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, =0, -NO2, -CN, -OH, -SH, or -NH2; andR52is hydrogen, deuterium, optionally substituted C1-5 alkyl, optionally substituted C1-5 haloalkyl, -(CH2)m1OR52a, -(CH2)m2O(CH2)m3OR52a, -(CH2)m4N(R52a)(R52b), (CH2)m5C(O)OR52a, (CH2)m6C(O)R52a, -C(O)N(R52a)2, or -N(R52a)C(O)R,each R52aand R52bis independently hydrogen, deuterium, or optionally substituted C1-5 alkyl; andeach ml, m2, m3, m4, m5 and m6 is independently selected at each occurrence from 1, 2, 3, 4, and 5.

[0140] In some embodiments, Y1is O and Y2is O. In some embodiments, Y1is O and Y2is S. In some embodiments, Y1is S and Y2is O.

[0141] In some embodiments, R51is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12-membered heterocycle. In some embodiments, R51is hydrogen. In some embodiments, R51is deuterium. In some embodiments, R51is C1-5 alkyl. In some embodiments, R51is -CH3. In some embodiments, R51is -CH2CH3. In some embodiments, R51is -CH2CH2CH3. In some embodiments, R51is -CH(CH3)2. In some embodiments, R51is -CH2CH(CH3)2. In some embodiments, R51is -CH(CH3)CH2CH3. In some embodiments, R51is -C(CH3)3. In some embodiments, R51is -CH2CH2CH2CH3. In some embodiments, R51is -CH2CH2CH(CH3)CH3. In some embodiments, R51is -CH2CH(CH3)CH2CH3. In some embodiments, R51is -P-660561 -PCCH2CH2CH2CH2CH3. In some embodiments, R51is C1-5 haloalkyl. In some embodiments, R51is Ci haloalkyl. In some embodiments, R51is -CH2CI. In some embodiments, R51is -CH2F. In some embodiments, R51is C2 haloalkyl. In some embodiments, R51is -CH2CH2CI. In some embodiments, R51is -CH2CH2F. In some embodiments, R51is C3 haloalkyl. In some embodiments, R51is -CH2CH2 CH2CI. In some embodiments, R51is -CH2CH2 CH2F. In some embodiments, R51is C4 haloalkyl. In some embodiments, R51is C5 haloalkyl.

[0142] In some embodiments, R51is C5-12 carbocycle. In some embodiments, R51is 5- to 12-membered heterocycle. In some embodiments, each of the C5-12 carbocycle, and 5- to 12-membered heterocycle bring optionally substituted with one or more R51a. In some embodiments, R51is optionally substituted C5 carbocycle. In some embodiments, R51is optionally substituted G> carbocycle. In some embodiments, R51is optionally substituted R51is phenyl. In some embodiments, R51is optionally substituted C7 carbocycle. In some embodiments, R51is optionally substituted C8 carbocycle. In some embodiments, R51is optionally substituted C9 carbocycle. In some embodiments, R51is optionally substituted C10 carbocycle. In some embodiments, R51is optionally substituted C11 carbocycle. In some embodiments, R51is optionally substituted C12 carbocycle. In some embodiments, R51is optionally substituted 5-membered heterocycle. In some embodiments, R51is optionally substituted 6-membered heterocycle. In some embodiments, R51is optionally substituted 7-membered heterocycle. In some embodiments, R51is optionally substituted 8-membered heterocycle. In some embodiments, R51is optionally substituted 9-membered heterocycle. In some embodiments, R51is optionally substituted 10-membered heterocycle. In some embodiments, R51is optionally substituted 11 -membered heterocycle. In some embodiments, R51is optionally substituted 12-membered heterocycle. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has an oxygen atom. In someP-660561 -PCembodiments, the heterocycle has at least one sulfur atom. In some embodiments, the heterocycle has a sulfur atom.

[0143] In some embodiments, each R51ais independently hydrogen, deuterium, C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, =0, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, each R51ais independently hydrogen. In some embodiments, each R51ais independently deuterium. In some embodiments, each R51ais independently C1-5 alkyl. In some embodiments, each R51ais independently -CH3. In some embodiments, each R51ais independently -CH2CH3. In some embodiments, each R51ais independently -CH2CH2CH3. In some embodiments, each R51ais independently -CH(CH3)2. In some embodiments, each R51ais independently -CH2CH(CH3)2. In some embodiments, each R51ais independently -CH(CH3)CH2CH3. In some embodiments, each R51ais independently -C(CH3)3. In some embodiments, each R51ais independently -CH2CH2CH2CH3. In some embodiments, each R51ais independently -CH2CH2CH(CH3)CH3. In some embodiments, each R51ais independently -CH2CH(CH3)CH2CH3. In some embodiments, each R51ais independently -CH2CH2CH2CH2CH3. In some embodiments, each R51ais independently C2-6 alkenyl. In some embodiments, each R51ais independently C2 alkenyl. In some embodiments, each R51ais independently C3 alkenyl. In some embodiments, each R51ais independently C4 alkenyl. In some embodiments, each R51ais independently C5 alkenyl. In some embodiments, each R51ais independently C6 alkenyl. In some embodiments, each R51ais independently C2-6 alkynyl. In some embodiments, each R51ais independently C2 alkynyl. In some embodiments, each R51ais independently C3 alkynyl. In some embodiments, each R51ais independently C4 alkynyl. In some embodiments, each R51ais independently C5 alkynyl. In some embodiments, each R51ais independently C6 alkynyl. In some embodiments, each R51ais independently halogen. In some embodiments, each R51ais independently =0. In some embodiments, each R51ais independently -NO2. In some embodiments, each R51ais independently -CN. In some embodiments, each R51ais independently -OH. In some embodiments, each R51ais independently -SH. In some embodiments, each R51ais independently -NH2.

[0144] In some embodiments, R51is hydrogen. In some embodiments, R51is C1-5 alkyl. In some embodiments, R51is -CH2CH3. In some embodiments, R51is C5-12 carbocycle. In some embodiments, R51is C6carbocycle. In some embodiments, R51is phenyl.P-660561 -PC

[0145] In some embodiments, R52is hydrogen, deuterium, optionally substituted C1-5 alkyl, optionally substituted C1-5 haloalkyl, -(CH2)m1OR52a, -(CH2)m2O(CH2)m3OR52a, (CH2)m4N(R52a)(R52b), (CH2)m5C(O)OR52a, -C(O)N(R52a)2, or -N(R52a)C(O)R In some embodiments, R52is hydrogen. In some embodiments, R52is deuterium. In some embodiments, R52is optionally substituted C1-5 alkyl. In some embodiments, R52is optionally substituted methyl. In some embodiments, R52is methyl optionally substituted with a heterocycle. In someembodiments, R52is[nsome embodiments, R52is optionally substituted ethyl. In some embodiments, R52is optionally substituted propyl. In some embodiments, R52is optionally substituted / .so -propyl. In some embodiments, R52is optionally substituted / ?-butyl. In some embodiments, R52is optionally substituted.scc-butyl. In some embodiments, R52is optionally substituted zso-butyl. In some embodiments, R52is optionally substituted -pentyl. In some embodiments, R52is optionally substituted tert-pentyl. In some embodiments, R52is optionally substituted zso-pentyl. In some embodiments, R52is optionally substituted.sec-pentyl. In some embodiments, R52is optionally substituted 3 -pentyl. In some embodiments, R52is optionally substituted C1-5 haloalkyl. In some embodiments, R52is optionally substituted Ci haloalkyl. In some embodiments, R52is optionally substituted C2 haloalkyl. In some embodiments, R52is optionally substituted C3 haloalkyl. In some embodiments, R52is optionally substituted C4 haloalkyl. In some embodiments, R52is optionally substituted C5 haloalkyl. In some embodiments, R52is -(CH2)miOR52a. In some embodiments, R52is -(CH2)m2O(CH2)m3OR52a. In some embodiments, R52is -(CH2)m4N(R52a)(R52b). In some embodiments, R52is (CH2)m5C(O)OR52a. In some embodiments, R52is -C(O)N(R52a)2. In some embodiments, R52is -C(O)N(R52a)2. In some embodiments, R52is -N(R52a)C(O)R In some embodiments, R52is -(CH2)m6C(O)R52a.

[0146] In some embodiments, each R52aand R52bis independently hydrogen, deuterium, or optionally substituted C1-5 alkyl. In some embodiments, each R52ais independently hydrogen, deuterium, or optionally substituted C1-5 alkyl. In some embodiments, each R52ais independently hydrogen. In some embodiments, each R52ais independently deuterium. In some embodiments, each R52ais independently optionally substituted C1-5 alkyl. In some embodiments, each R52ais independently optionally substituted methyl. In some embodiments, each R52ais independently optionally substituted ethyl. In some embodiments, each R52ais independently optionallyP-660561 -PCsubstituted propyl. In some embodiments, each R52ais propyl optionally substituted with one or more halogens. In some embodiments, each R52ais propyl optionally substituted with one or more-F. In some embodiments, R52ais. In some embodiments, each R52ais independently optionally substituted / .so -propyl. In some embodiments, each R52ais independently optionally substituted / ? -butyl. In some embodiments, each R52ais independently optionally substituted secbutyl. In some embodiments, each R52ais independently optionally substituted zso-butyl. In some embodiments, each R52ais independently optionally substituted -pentyl. In some embodiments, each R52ais independently optionally substituted tert-pentyl. In some embodiments, each R52ais independently optionally substituted zso-pentyl. In some embodiments, each R52ais independently optionally substituted sec-pentyl. In some embodiments, each R52ais independently optionally substituted 3 -pentyl.

[0147] In some embodiments, each R52bis independently hydrogen, deuterium, or optionally substituted C1-5 alkyl. In some embodiments, each R52bis independently hydrogen. In some embodiments, each R52bis independently deuterium. In some embodiments, each R52bis independently optionally substituted C1-5 alkyl. In some embodiments, each R52bis independently optionally substituted methyl. In some embodiments, each R52bis independently optionally substituted ethyl. In some embodiments, each R52bis independently optionally substituted propyl. In some embodiments, each R52bis independently optionally substituted / .so-propyl. In some embodiments, each R52bis independently optionally substituted zz-butyl. In some embodiments, each R52bis independently optionally substituted.see- butyl. In some embodiments, each R52bis independently optionally substituted zso-butyl. In some embodiments, each R52bis independently optionally substituted zz-pentyl. In some embodiments, each R52bis independently optionally substituted tert-pentyl. In some embodiments, each R52bis independently optionally substituted zso-pentyl. In some embodiments, each R52bis independently optionally substituted.sec-pentyl. In some embodiments, each R52bis independently optionally substituted 3 -pentyl.

[0148] In some embodiments, each ml, m2, m3, m4, m5 and m6 is independently selected at each occurrence from 1, 2, 3, 4, and 5. In some embodiments, each ml is independently selected at each occurrence from 1, 2, 3, 4, and 5. In some embodiments, each ml is 1. In some embodiments, eachP-660561 -PCml is 2. In some embodiments, each ml is 3. In some embodiments, each ml is 4. In some embodiments, each ml is 5. In some embodiments, each m2 is independently selected at each occurrence from 1, 2, 3, 4, and 5. In some embodiments, each m2 is 1. In some embodiments, each m2 is 2. In some embodiments, each m2 is 3. In some embodiments, each m2 is 4. In some embodiments, each m2 is 5. In some embodiments, each m3 is independently selected at each occurrence from 1, 2, 3, 4, and 5. In some embodiments, each m3 is 1. In some embodiments, each m3 is 2. In some embodiments, each m3 is 3. In some embodiments, each m3 is 4. In some embodiments, each m3 is 5. In some embodiments, each m4 is independently selected at each occurrence from 1, 2, 3, 4, and 5. In some embodiments, each m4 is 1. In some embodiments, each m4 is 2. In some embodiments, each m4 is 3. In some embodiments, each m4 is 4. In some embodiments, each m4 is 5. In some embodiments, each m5 is independently selected at each occurrence from 1, 2, 3, 4, and 5. In some embodiments, each m5 is 1. In some embodiments, each m5 is 2. In some embodiments, each m5 is 3. In some embodiments, each m5 is 4. In some embodiments, each m5 is 5. In some embodiments, each m6 is independently selected at each occurrence from 1, 2, 3, 4, and 5. In some embodiments, each m6 is 1. In some embodiments, each m6 is 2. In some embodiments, each m6 is 3. In some embodiments, each m6 is 4. In some embodiments, each m6 is 5.

[0149] In some embodiments, R52is -(CH2)3OCH2CH3. In some embodiments, R52is -(CH2)4OCH2CH3. In some embodiments, R52is -(CH2)3OCH3. In some embodiments, R52is -(CH2)m4N(R52a)(R52b). In some embodiments, R52ais -CH3. In some embodiments, R52bis -CH3. In some embodiments, m4 is 3.

[0150] In some embodiments, R52is hydrogen. In some embodiments, R52is optionally substituted -C1-5 alkyl. In some embodiments, R52is optionally substituted propyl. In someembodiments, R52is optionally substituted methyl. In some embodiments, R52is

[0151] In some embodiments, R52is -(CH2)m1OR52aIn some embodiments, R52ais optionally substituted ethyl. In some embodiments, R52ais optionally substituted methyl. In someE F >embodiments, R52ais optionally substituted propyl. In some embodiments, R52aisFP-660561 -PCIn some embodiments, ml is 2. In some embodiments, ml is 3. In some embodiments, ml is 4. In some embodiments, R52is -(CH2)3OCH2CH3. In some embodiments, R52is -(CH2)4OCH2CH3.In some embodiments, R52is -(CH2)3OCH3. In some embodiments, R52isIn some embodiments, R52is -(CH2)m4N(R52a)(R52b). In some embodiments, R52ais -CH3. In some embodiments, R52bis -CH3. In some embodiments, m4 is 3. In some embodiments, R52is - (CH2)3N(CH3)(CH3).P-660561 -PCor a salt or solvate thereof. In some embodiments, the compound isor a salt or solvate thereof. In some embodiments, the compound is 0or a salt or solvate thereof. In some embodiments, the compound is 0or a salt or solvate thereof. In some embodiments, the compound is Oor a salt or solvate thereof. In some embodiments, the compound is HO or a salt or solvate thereof. In some embodiments, the compound SisHor a salt or solvate thereof. In some embodiments, the compoundP-660561 -PCis or a salt or solvate thereof. In some embodiments, the compound isor a salt or solvate thereof. In some embodiments, the compound isor a salt or solvate thereof. In some embodiments, the compound isor a salt or solvate thereof. In some embodiments, the compound is,or a salt or solvate thereof. In some embodiments, the compound is Oor a salt or solvate thereof. In some embodiments, the compound is oor a salt or solvate thereof. In some embodiments, the compound isP-660561 -PCH or a salt or solvate thereof. In some embodiments, the compound

[0153] In certain aspects, disclosed herein is a compound having a structure of Formula (IV):R64Formula (IV),or salts or solvate thereof,wherein:Z is -O-, -S-, or -N(RZ)-,Rzis hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12- membered heterocycle, each of the C5-12 carbocycle, and 5- to 12-membered heterocycle being optionally substituted with one or more Rza,each Rzais independently selected from the group consisting of C 1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -NO2, -CN, -OH, -SH, and -NH2;R61is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12- membered heterocycle, each C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, and 5- to 12- membered heterocycle being optionally substituted with one or more R61a,each R61ais independently selected from the group consisting of -OH, -SH, -NH2, C5-12 carbocycle, and 5- to 12-membered heterocycle;each R62and R63is independently hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, -NO2, - CN, -OH, -SH, or -NH2; andR64is hydrogen, deuterium, C1-5 alkyl, or C1-5 haloalkyl.P-660561 -PC

[0154] In some embodiments, Z is -O-, -S-, or -N(RZ)-. In some embodiments, Z is -O-. In some embodiments, Z is -S-. In some embodiments, Z is -N(RZ)-.

[0155] In some embodiments, Rzis hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12-membered heterocycle. In some embodiments, Rzis hydrogen. In some embodiments, Rzis deuterium. In some embodiments, Rzis C1-5 alkyl. In some embodiments, Rzis -CH3. In some embodiments, Rzis -CH2CH3. In some embodiments, Rzis -CH2CH2CH3. In some embodiments, Rzis -CH(CH3)2. In some embodiments, Rzis -CH2CH(CH3)2. In some embodiments, Rzis -CH(CH3)CH2CH3. In some embodiments, Rzis -C(CH3)3. In some embodiments, Rzis -CH2CH2CH2CH3. In some embodiments, Rzis -CH2CH2CH(CH3)CH3. In some embodiments, Rzis -CH2CH(CH3)CH2CH3. In some embodiments, Rzis -CH2CH2CH2CH2CH3. In some embodiments, Rzis C1-5 haloalkyl. In some embodiments, Rzis C1haloalkyl. In some embodiments, Rzis -CH2Cl. In some embodiments, Rzis -CH2F. In some embodiments, Rzis C2 haloalkyl. In some embodiments, Rzis -CH2CH2Cl. In some embodiments, Rzis -CH2CH2F. In some embodiments, Rzis C3 haloalkyl. In some embodiments, Rzis -CH2CH2CH2Cl. In some embodiments, Rzis -CH2CH2CH2F. In some embodiments, Rzis C4 haloalkyl. In some embodiments, Rzis C5 haloalkyl.

[0156] In some embodiments, Rzis C5-12 carbocycle. In some embodiments, Rzis 5- to 12-membered heterocycle. In some embodiments, each of the C5-12 carbocycle, and 5- to 12-membered heterocycle being optionally substituted with one or more Rza. In some embodiments, Rzis C5-12 carbocycle optionally substituted with one or more Rza. In some embodiments, Rzis C5 carbocycle optionally substituted with one or more Rza. In some embodiments, Rzis C6carbocycle optionally substituted with one or more Rza. In some embodiments, Rzis C7carbocycle optionally substituted with one or more Rza. In some embodiments, Rzis C8carbocycle optionally substituted with one or more Rza. In some embodiments, Rzis C9carbocycle optionally substituted with one or more Rza. In some embodiments, Rzis C10 carbocycle optionally substituted with one or more Rza. In some embodiments, Rzis C11 carbocycle optionally substituted with one or more Rza. In some embodiments, Rzis C12 carbocycle optionally substituted with one or more Rza. In some embodiments, Rzis 5- to 12-membered heterocycle optionally substituted with one or more Rza. In some embodiments, Rzis 5-membered heterocycle optionally substituted with one or more Rza.P-660561 -PCIn some embodiments, RzisO. In some embodiments, Rzis 6-membered heterocycle optionally substituted with one or more Rza. In some embodiments, Rzis 7-membered heterocycle optionally substituted with one or more Rza. In some embodiments, Rzis 8-membered heterocycle optionally substituted with one or more Rza. In some embodiments, Rzis 9-membered heterocycle optionally substituted with one or more Rza. In some embodiments, Rzis 10-membered heterocycle optionally substituted with one or more Rza. In some embodiments, Rzis 11 -membered heterocycle optionally substituted with one or more Rza. In some embodiments, Rzis 12-membered heterocycle optionally substituted with one or more Rza. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has an oxygen atom. In some embodiments, the heterocycle has at least one sulfur atom. In some embodiments, the heterocycle has a sulfur atom.

[0157] In some embodiments, each Rzais independently selected from the group consisting of Ci-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -NO2, -CN, -OH, -SH, and -NH2. In some embodiments, each Rzais independently C1-5 alkyl. In some embodiments, each Rzais independently -CH3. In some embodiments, each Rzais independently -CH2CH3. In some embodiments, each Rzais independently -CH2CH2CH3. In some embodiments, each Rzais independently -CH(CH3)2. In some embodiments, each Rzais independently -CH2CH(CH3)2. In some embodiments, each Rzais independently -CH(CH3)CH2CH3. In some embodiments, each Rzais independently -C(CH3)3. In some embodiments, each Rzais independently -CH2CH2CH2CH3. In some embodiments, each Rzais independently -CH2CH2CH(CH3)CH3. In some embodiments, each Rzais independently -CH2CH(CH3)CH2CH3. In some embodiments, each Rzais independently -CH2CH2CH2CH2CH3. In some embodiments, each Rzais independently C2-6 alkenyl. In some embodiments, each Rzais independently C2 alkenyl. In some embodiments, each Rzais independently C3 alkenyl. In someP-660561 -PCembodiments, each Rzais independently C4 alkenyl. In some embodiments, each Rzais independently C5 alkenyl. In some embodiments, each Rzais independently C6alkenyl. In some embodiments, each Rzais independently C2-6 alkynyl. In some embodiments, each Rzais independently C2 alkynyl. In some embodiments, each Rzais independently C3 alkynyl. In some embodiments, each Rzais independently C4 alkynyl. In some embodiments, each Rzais independently C5 alkynyl. In some embodiments, each Rzais independently C6alkynyl. In some embodiments, each Rzais independently halogen. In some embodiments, each Rzais independently -NO2. In some embodiments, each Rzais independently -CN. In some embodiments, each Rzais independently -OH. In some embodiments, each Rzais independently -SH. In some embodiments, each Rzais independently -NH2.

[0158] In some embodiments, R61is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12-membered heterocycle. In some embodiments, R61is hydrogen. In some embodiments, R61is deuterium. In some embodiments, R61is C1-5 alkyl. In some embodiments, R61is -CH3. In some embodiments, R61is -CH2CH3. In some embodiments, R61is -CH2CH2CH3. In some embodiments, R61is -CH(CH3)2. In some embodiments, R61is -CH2CH(CH3)2. In some embodiments, R61is -CH(CH3)CH2CH3. In some embodiments, R61is -C(CH3)3. In some embodiments, R61is -CH2CH2CH2CH3. In some embodiments, R61is -CH2CH2CH(CH3)CH3. In some embodiments, R61is -CH2CH(CH3)CH2CH3. In some embodiments, R61is -CH2CH2CH2CH2CH3. In some embodiments, R61is C1-5 haloalkyl. In some embodiments, R61is C1haloalkyl. In some embodiments, R61is -CH2Cl. In some embodiments, R61is -CH2F. In some embodiments, R61is C2 haloalkyl. In some embodiments, R61is -CH2CH2Cl. In some embodiments, R61is -CH2CH2F. In some embodiments, R61is C3 haloalkyl. In some embodiments, R61is -CH2CH2CH2Cl. In some embodiments, R61is -CH2CH2CH2F. In some embodiments, R61is C4 haloalkyl. In some embodiments, R61is C5 haloalkyl. In some embodiments, each C1-5 alkyl and C1-5 haloalkyl is optionally substituted with one or more R61a. In some embodiments, C1-5 alkyl is optionally substituted with one or more R61a. In some embodiments, C1-5 haloalkyl is optionally substituted with one or more R61a.

[0159] In some embodiments, R61is C5-12 carbocycle. In some embodiments, R61is 5- to 12-membered heterocycle. In some embodiments, each of the C5-12 carbocycle, and 5- to 12-membered heterocycle is optionally substituted with one or more R61a. In some embodiments, RzP-660561 -PCis C5-12 carbocycle optionally substituted with one or more R61a. In some embodiments, R61is C5 carbocycle optionally substituted with one or more R61a. In some embodiments, R61is C6carbocycle optionally substituted with one or more R61a. In some embodiments, R61is C7carbocycle optionally substituted with one or more R61a. In some embodiments, R61is C8carbocycle optionally substituted with one or more R61a. In some embodiments, R61is C9carbocycle optionally substituted with one or more R61a. In some embodiments, R61is C10 carbocycle optionally substituted with one or more R61a. In some embodiments, R61is C11 carbocycle optionally substituted with one or more R61a. In some embodiments, R61is C12 carbocycle optionally substituted with one or more R61a. In some embodiments, R61is 5- to 12-membered heterocycle optionally substituted with one or more R61a. In some embodiments, R61is 5-membered heterocycle optionally substituted with one or more R61a. In some embodiments, R61is 6-membered heterocycle optionally substituted with one or more R61a. In some embodiments, R61is 7-membered heterocycle optionally substituted with one or more R61a. In some embodiments, R61is 8-membered heterocycle optionally substituted with one or more R61a. In some embodiments, R61is 9-membered heterocycle optionally substituted with one or more R61a. In some embodiments, R61is 10-membered heterocycle optionally substituted with one or more R61a. In some embodiments, R61is 11 -membered heterocycle optionally substituted with one or more R61a. In some embodiments, R61is 12-membered heterocycle optionally substituted with one or more R61a. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has an oxygen atom. In some embodiments, the heterocycle has at least one sulfur atom. In some embodiments, the heterocycle has a sulfur atom.

[0160] In some embodiments, each R61ais independently selected from the group consisting of -OH, -SH, -NH2, C5-12 carbocycle, and 5- to 12-membered heterocycle. In some embodiments, each R61ais independently -OH. In some embodiments, each R61ais independently -SH. In someP-660561 -PCembodiments, each R61ais independently -NH2. In some embodiments, each R61ais independently C5-12 carbocycle. In some embodiments, each R61ais independently C5 carbocycle. In some embodiments, each R61ais independently C6carbocycle. In some embodiments, each R61ais independently C7 carbocycle. In some embodiments, each R61ais independently C8carbocycle. In some embodiments, each R61ais independently C9 carbocycle. In some embodiments, each R61ais independently C10 carbocycle. In some embodiments, each R61ais independently C11 carbocycle. In some embodiments, each R61ais independently C12 carbocycle. In some embodiments, each R61ais independently 5- to 12-membered heterocycle. In some embodiments, each R61ais independently 5-membered heterocycle. In some embodiments, each R61ais independently 6-membered heterocycle. In some embodiments, each R61ais independently 7-membered heterocycle. In some embodiments, each R61ais independently 8-membered heterocycle. In some embodiments, each R61ais independently 9-membered heterocycle. In some embodiments, each R61ais independently 10-membered heterocycle. In some embodiments, each R61ais independently 11 -membered heterocycle. In some embodiments, each R61ais independently 12-membered heterocycle. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has an oxygen atom. In some embodiments, the heterocycle has at least one sulfur atom. In some embodiments, the heterocycle has a sulfur atom.

[0161] In some embodiments, R61is -CH3. In some embodiments, R61is -CH2OH. In some embodiments, R61is -CH2NH2.

[0162] In some embodiments, R61ais alkyl substituted with 5-membered heterocycle. In someembodiments, R61is' — '. In some embodiments, R61is C6carbocycle. In some embodiments, R61is phenyl.P-660561 -PC

[0163] In some embodiments, R62is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R62is hydrogen. In some embodiments, R62is deuterium. In some embodiments, R62is C1-5 alkyl. In some embodiments, R62is -CH3. In some embodiments, R62is -CH2CH3. In some embodiments, R62is -CH2CH2CH3. In some embodiments, R62is -CH(CH3)2. In some embodiments, R62is -CH2CH(CH3)2. In some embodiments, R62is -CH(CH3)CH2CH3. In some embodiments, R62is -C(CH3)3. In some embodiments, R62is -CH2CH2CH2CH3. In some embodiments, R62is -CH2CH2CH(CH3)CH3. In some embodiments, R62is -CH2CH(CH3)CH2CH3. In some embodiments, R62is -CH2CH2CH2CH2CH3. In some embodiments, R62is C1-5 haloalkyl. In some embodiments, R62is C1haloalkyl. In some embodiments, R62is C2 haloalkyl. In some embodiments, R62is C3 haloalkyl. In some embodiments, R62is C4 haloalkyl. In some embodiments, R62is C5 haloalkyl. In some embodiments, R62is -NO2. In some embodiments, R62is -CN. In some embodiments, R62is -OH. In some embodiments, R62is -SH. In some embodiments, R62is -NH2.

[0164] In some embodiments, R63is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R63is hydrogen. In some embodiments, R63is deuterium. In some embodiments, R63is C1-5 alkyl. In some embodiments, R63is -CH3. In some embodiments, R63is -CH2CH3. In some embodiments, R63is -CH2CH2CH3. In some embodiments, R63is -CH(CH3)2. In some embodiments, R63is -CH2CH(CH3)2. In some embodiments, R63is -CH(CH3)CH2CH3. In some embodiments, R63is -C(CH3)3. In some embodiments, R63is -CH2CH2CH2CH3. In some embodiments, R63is -CH2CH2CH(CH3)CH3. In some embodiments, R63is -CH2CH(CH3)CH2CH3. In some embodiments, R63is -CH2CH2CH2CH2CH3. In some embodiments, R63is C1-5 haloalkyl. In some embodiments, R63is C1haloalkyl. In some embodiments, R63is C2 haloalkyl. In some embodiments, R63is C3 haloalkyl. In some embodiments, R63is C4 haloalkyl. In some embodiments, R63is C5 haloalkyl. In some embodiments, R63is -NO2. In some embodiments, R63is -CN. In some embodiments, R63is -OH. In some embodiments, R63is -SH. In some embodiments, R63is -NH2.

[0165] In some embodiments, R64is hydrogen, deuterium, C1-5 alkyl, or C1-5 haloalkyl. In some embodiments, R64is hydrogen. In some embodiments, R64is deuterium. In some embodiments, R64is C1-5 alkyl. In some embodiments, R64is -CH3. In some embodiments, R64is -CH2CH3. In some embodiments, R64is -CH2CH2CH3. In some embodiments, R64is -CH(CH3)2. In someP-660561 -PCembodiments, R64is -CH2CH(CH3)2. In some embodiments, R64is -CH(CH3)CH2CH3. In some embodiments, R64is -C(CH3)3. In some embodiments, R64is -CH2CH2CH2CH3. In some embodiments, R64is -CH2CH2CH(CH3)CH3. In some embodiments, R64is -CH2CH(CH3)CH2CH3. In some embodiments, R64is -CH2CH2CH2CH2CH3. In some embodiments, R64is C1-5 haloalkyl. In some embodiments, R64is Ci haloalkyl. In some embodiments, R64is C2 haloalkyl. In some embodiments, R64is C3 haloalkyl. In some embodiments, R64is C4 haloalkyl. In some embodiments, R64is C5 haloalkyl.

[0166] In some embodiments, the compound is selected fromH,or a salt or solvate thereof. In someembodiments, the compoundis or a salt or solvate thereof. In someP-660561 -PCOembodiments, the compoundis or a salt or solvate thereof. In someembodiments, the compoundis or a salt or solvate thereof. In some Oembodiments, the compound is \ or a salt or solvate thereof.

[0167] In certain aspects, disclosed herein is a compound having a structure of Formula (V):Formula (V),or salts or solvate thereof,wherein:Xais -O- or -S-;R71is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, -C(R71a)2N(R71a)2, - C(R71a)(R71b)N(R71a)(R71b), -C(R71a)2C(O)N(R71a)2, -C(R71a)2C(O)N(R71b)2, - C(R71a)(R71b)C(O)N(R71a)(R71b), -CH2Ph, C5-12 carbocycle, or 5- to 12-membered heterocycle;each R71aand R71bis independently hydrogen, deuterium, C1-5 alkyl, or C1-5 haloalkyl, each R72, R74, and R75is independently hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, - NO2, -CN, -OH, -SH, or -NH2; andR73is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12- membered heterocycle, each of the C5-12 carbocycle and 5- to 12-membered heterocycle isP-660561 -PCoptionally substituted with one or more C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, - NO2, -CN, -OH, -SH, or -NH2.

[0168] In some embodiments, Xais -O-. In some embodiments, Xais -S-.

[0169] In some embodiments, R71is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, -C(R71a)2N(R71a)2, -C(R71a)(R71b)N(R71a)(R71b), -C(R71a)2C(O)N(R71a)2, -C(R71a)2C(O)N(R71b)2, -C(R71a)(R71b)C(O)N(R71a)(R71b), -CH2Ph, C5-12 carbocycle, or 5- to 12-membered heterocycle. In some embodiments, R71is hydrogen. In some embodiments, R71is deuterium. In some embodiments, R71is C1-5 alkyl. In some embodiments, R71is -CH3. In some embodiments, R71is -CH2CH3. In some embodiments, R71is -CH2CH2CH3. In some embodiments, R71is -CH(CH3)2. In some embodiments, R71is -CH2CH(CH3)2. In some embodiments, R71is -CH(CH3)CH2CH3. In some embodiments, R71is -C(CH3)3. In some embodiments, R71is -CH2CH2CH2CH3. In some embodiments, R71is -CH2CH2CH(CH3)CH3. In some embodiments, R71is -CH2CH(CH3)CH2CH3. In some embodiments, R71is -CH2CH2CH2CH2CH3. In some embodiments, R71is C1-5 haloalkyl. In some embodiments, R71is Ci haloalkyl. In some embodiments, R71is -CH2CI. In some embodiments, R71is -CH2F. In some embodiments, R71is C2 haloalkyl. In some embodiments, R71is -CH2CH2CI. In some embodiments, R71is -CH2CH2F. In some embodiments, R71is C3 haloalkyl. In some embodiments, R71is -CH2CH2 CH2CI. In some embodiments, R71is -CH2CH2 CH2F. In some embodiments, R71is C4 haloalkyl. In some embodiments, R71is C5 haloalkyl. In some embodiments, R71is -C(R71a)2N(R71a)2. In some embodiments, R71is -C(R71a)(R71b)N(R71a)(R71b). In some embodiments, R71is -CH2Ph. In some embodiments, R71is -C(R71a)2C(O)N(R71a)2. In some embodiments, R71is -C(R71a)2C(O)N(R71b)2. In some embodiments, R71is -C(R71a)(R71b)C(O)N(R71a)(R71b).

[0170] In some embodiments, R71is C5-12 carbocycle. In some embodiments, R71is C5 carbocycle. In some embodiments, R71is C6carbocycle. In some embodiments, R71is phenyl. In some embodiments, R71is C7 carbocycle. In some embodiments, R71is Cs carbocycle. In some embodiments, R71is C9 carbocycle. In some embodiments, R71is C10 carbocycle. In some embodiments, R71is Cn carbocycle. In some embodiments, R71is C12 carbocycle.

[0171] In some embodiments, R71is 5- to 12-membered heterocycle. In some embodiments, R71is 5-membered heterocycle. In some embodiments, R71is 6-membered heterocycle. In some embodiments, R71is 7-membered heterocycle. In some embodiments, R71is 8-memberedP-660561 -PCheterocycle. In some embodiments, R71is 9-membered heterocycle. In some embodiments, R71is 10-membered heterocycle. In some embodiments, R71is 11 -membered heterocycle. In some embodiments, R71is 12-membered heterocycle. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has an oxygen atom. In some embodiments, the heterocycle has at least one sulfur atom. In some embodiments, the heterocycle has a sulfur atom.

[0172] In some embodiments, each R71ais independently hydrogen, deuterium, C1-5 alkyl, or C1-5 haloalkyl. In some embodiments, each R71ais independently hydrogen. In some embodiments, each R71ais independently deuterium. In some embodiments, each R71ais independently C1-5 alkyl. In some embodiments, each R71ais independently -CH3. In some embodiments, each R71ais independently -CH2CH3. In some embodiments, each R71ais independently -CH2CH2CH3. In some embodiments, each R71ais independently -CH(CH3)2. In some embodiments, each R71ais independently -CH2CH(CH3)2. In some embodiments, each R71ais independently -CH(CH3)CH2CH3. In some embodiments, each R71ais independently -C(CH3)3. In some embodiments, each R71ais independently -CH2CH2CH2CH3. In some embodiments, each R71ais independently -CH2CH2CH(CH3)CH3. In some embodiments, each R71ais independently -CH2CH(CH3)CH2CH3. In some embodiments, each R71ais independently -CH2CH2CH2CH2CH3. In some embodiments, each R71ais independently C1-5 haloalkyl. In some embodiments, each R71ais independently Ci haloalkyl. In some embodiments, each R71ais independently -CH2CI. In some embodiments, each R71ais independently -CH2F. In some embodiments, each R71ais independently C2 haloalkyl. In some embodiments, each R71ais independently -CH2CH2CI. In some embodiments, each R71ais independently -CH2CH2F. In some embodiments, each R71ais independently C3 haloalkyl. In some embodiments, each R71ais independently -CH2CH2 CH2CI. In some embodiments, each R71ais independently -CH2CH2 CH2F. In some embodiments, each R71ais independently C4 haloalkyl. In some embodiments, each R71ais independently C5 haloalkyl.P-660561 -PC

[0173] In some embodiments, each R71bis independently hydrogen, deuterium, C1-5 alkyl, or C1-5 haloalkyl. In some embodiments, each R71bis independently hydrogen. In some embodiments, each R71bis independently deuterium. In some embodiments, each R71bis independently C1-5 alkyl. In some embodiments, each R71bis independently -CH3. In some embodiments, each R71bis independently -CH2CH3. In some embodiments, each R71bis independently -CH2CH2CH3. In some embodiments, each R71bis independently -CH(CH3)2. In some embodiments, each R71bis independently -CH2CH(CH3)2. In some embodiments, each R71bis independently -CH(CH3)CH2CH3. In some embodiments, each R71bis independently -C(CH3)3. In some embodiments, each R71bis independently -CH2CH2CH2CH3. In some embodiments, each R71bis independently -CH2CH2CH(CH3)CH3. In some embodiments, each R71bis independently -CH2CH(CH3)CH2CH3. In some embodiments, each R71bis independently -CH2CH2CH2CH2CH3. In some embodiments, each R71bis independently C1-5 haloalkyl. In some embodiments, each R71bis independently Ci haloalkyl. In some embodiments, each R71bis independently -CH2CI. In some embodiments, each R71bis independently -CH2F. In some embodiments, each R71bis independently C2 haloalkyl. In some embodiments, each R71bis independently -CH2CH2CI. In some embodiments, each R71bis independently -CH2CH2F. In some embodiments, each R71bis independently C3 haloalkyl. In some embodiments, each R71bis independently -CH2CH2 CH2CI. In some embodiments, each R71bis independently -CH2CH2 CH2F. In some embodiments, each R71bis independently C4 haloalkyl. In some embodiments, each R71bis independently C5 haloalkyl.

[0174] In some embodiments, R71is C1-5 alkyl. In some embodiments, R71is C3 alkyl. In some embodiments, R71is -CH(CH3)CH3. In some embodiments, R71is -C(R71a)2N(R71a)2. In some embodiments, R71ais hydrogen. In some embodiments, R71is -CH2NH2. In some embodiments, R71is -C(R71a)2C(O)N(R71b)2. In some embodiments, R71ais hydrogen. In some embodiments, R71bis -CH3. In some embodiments, R71is -CH2C(O)N(CH3)2. In some embodiments, R71is C5-12 carbocycle. In some embodiments, R71is C6carbocycle. In some embodiments, R71is phenyl.

[0175] In some embodiments, R72is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R72is hydrogen. In some embodiments, R72is deuterium. In some embodiments, R72is C1-5 alkyl. In some embodiments, R72is -CH3. In some embodiments, R72is -CH2CH3. In some embodiments, R72is -CH2CH2CH3. In some embodiments, R72is -CH(CH3)2. In some embodiments, R72is -CH2CH(CH3)2. In some embodiments, R72is -P-660561 -PCCH(CH3)CH2CH3. In some embodiments, R72is -C(CH3)3. In some embodiments, R72is -CH2CH2CH2CH3. In some embodiments, R72is -CH2CH2CH(CH3)CH3. In some embodiments, R72is -CH2CH(CH3)CH2CH3. In some embodiments, R72is -CH2CH2CH2CH2CH3. In some embodiments, R72is C1-5 haloalkyl. In some embodiments, R72is Ci haloalkyl. In some embodiments, R72is -CH2CI. In some embodiments, R72is -CH2F. In some embodiments, R72is C2 haloalkyl. In some embodiments, R72is -CH2CH2CI. In some embodiments, R72is -CH2CH2F. In some embodiments, R72is C3 haloalkyl. In some embodiments, R72is -CH2CH2CH2CI. In some embodiments, R72is -CH2CH2CH2F. In some embodiments, R72is C4 haloalkyl. In some embodiments, R72is C5 haloalkyl. In some embodiments, R72is -NO2. In some embodiments, R72is -CN. In some embodiments, R72is -OH. In some embodiments, R72is -SH. In some embodiments, R72is -NH2.

[0176] In some embodiments, R74is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R74is hydrogen. In some embodiments, R74is deuterium. In some embodiments, R74is C1-5 alkyl. In some embodiments, R74is -CH3. In some embodiments, R74is -CH2CH3. In some embodiments, R74is -CH2CH2CH3. In some embodiments, R74is -CH(CH3)2. In some embodiments, R74is -CH2CH(CH3)2. In some embodiments, R74is -CH(CH3)CH2CH3. In some embodiments, R74is -C(CH3)3. In some embodiments, R74is -CH2CH2CH2CH3. In some embodiments, R74is -CH2CH2CH(CH3)CH3. In some embodiments, R74is -CH2CH(CH3)CH2CH3. In some embodiments, R74is -CH2CH2CH2CH2CH3. In some embodiments, R74is C1-5 haloalkyl. In some embodiments, R74is Ci haloalkyl. In some embodiments, R74is -CH2CI. In some embodiments, R74is -CH2F. In some embodiments, R74is C2 haloalkyl. In some embodiments, R74is -CH2CH2CI. In some embodiments, R74is -CH2CH2F. In some embodiments, R74is C3 haloalkyl. In some embodiments, R74is -CH2CH2CH2CI. In some embodiments, R74is -CH2CH2CH2F. In some embodiments, R74is C4 haloalkyl. In some embodiments, R74is C5 haloalkyl. In some embodiments, R74is -NO2. In some embodiments, R74is -CN. In some embodiments, R74is -OH. In some embodiments, R74is -SH. In some embodiments, R74is -NH2.

[0177] In some embodiments, R75is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R75is hydrogen. In some embodiments, R75is deuterium. In some embodiments, R75is C1-5 alkyl. In some embodiments, R75is -CH3. In someP-660561 -PCembodiments, R75is -CH2CH3. In some embodiments, R75is -CH2CH2CH3. In some embodiments, R75is -CH(CH3)2. In some embodiments, R75is -CH2CH(CH3)2. In some embodiments, R75is -CH(CH3)CH2CH3. In some embodiments, R75is -C(CH3)3. In some embodiments, R75is -CH2CH2CH2CH3. In some embodiments, R75is -CH2CH2CH(CH3)CH3. In some embodiments, R75is -CH2CH(CH3)CH2CH3. In some embodiments, R75is -CH2CH2CH2CH2CH3. In some embodiments, R75is C1-5 haloalkyl. In some embodiments, R75is Ci haloalkyl. In some embodiments, R75is -CH2CI. In some embodiments, R75is -CH2F. In some embodiments, R75is C2 haloalkyl. In some embodiments, R75is -CH2CH2CI. In some embodiments, R75is -CH2CH2F. In some embodiments, R75is C3 haloalkyl. In some embodiments, R75is -CH2CH2CH2CI. In some embodiments, R75is -CH2CH2CH2F. In some embodiments, R75is C4 haloalkyl. In some embodiments, R75is C5 haloalkyl. In some embodiments, R75is -NO2. In some embodiments, R75is -CN. In some embodiments, R75is -OH. In some embodiments, R75is -SH. In some embodiments, R75is -NH2.

[0178] In some embodiments, R73is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12-membered heterocycle. In some embodiments, R73is hydrogen. In some embodiments, R73is deuterium. In some embodiments, R73is C1-5 alkyl. In some embodiments, R73is -CH3. In some embodiments, R73is -CH2CH3. In some embodiments, R73is -CH2CH2CH3. In some embodiments, R73is -CH(CH3)2. In some embodiments, R73is -CH2CH(CH3)2. In some embodiments, R73is -CH(CH3)CH2CH3. In some embodiments, R73is -C(CH3)3. In some embodiments, R73is -CH2CH2CH2CH3. In some embodiments, R73is -CH2CH2CH(CH3)CH3. In some embodiments, R73is -CH2CH(CH3)CH2CH3. In some embodiments, R73is -CH2CH2CH2CH2CH3. In some embodiments, R73is C1-5 haloalkyl. In some embodiments, R73is Ci haloalkyl. In some embodiments, R73is -CH2CI. In some embodiments, R73is -CH2F. In some embodiments, R73is C2 haloalkyl. In some embodiments, R73is -CH2CH2CI. In some embodiments, R73is -CH2CH2F. In some embodiments, R73is C3 haloalkyl. In some embodiments, R73is -CH2CH2CH2CI. In some embodiments, R73is -CH2CH2CH2F. In some embodiments, R73is C4 haloalkyl. In some embodiments, R73is C5 haloalkyl.

[0179] In some embodiments, R73is C5-12 carbocycle. In some embodiments, R73is C5-12 carbocycle optionally substituted with one or more C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R73is optionally substituted C5 carbocycle.P-660561 -PCIn some embodiments, R73is optionally substituted C6carbocycle. In some embodiments, R73is optionally substituted C7 carbocycle. In some embodiments, R73is optionally substituted C8carbocycle. In some embodiments, R73is optionally substituted C9 carbocycle. In some embodiments, R73is optionally substituted C10 carbocycle. In some embodiments, R73is optionally substituted C11 carbocycle. In some embodiments, R73is optionally substituted C12 carbocycle. In some embodiments, R73is C5-12 carbocycle optionally substituted with one or more C1-5 alkyl. In some embodiments, R73is C5-12 carbocycle optionally substituted with one or more C2-6 alkenyl. In some embodiments, R73is C5-12 carbocycle optionally substituted with one or more C2-6 alkynyl. In some embodiments, R73is C5-12 carbocycle optionally substituted with one or more halogen. In some embodiments, R73is C5-12 carbocycle optionally substituted with one or more -NO2. In some embodiments, R73is C5-12 carbocycle optionally substituted with one or more -CN. In some embodiments, R73is C5-12 carbocycle optionally substituted with one or more -OH. In some embodiments, R73is C5-12 carbocycle optionally substituted with one or more -SH. In some embodiments, R73is C5-12 carbocycle optionally substituted with one or more -NH2.

[0180] In some embodiments, R73is 5- to 12-membered heterocycle. In some embodiments, R73is 5- to 12-membered heterocycle optionally substituted with one or more C1-5 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R73is optionally substituted 5-membered heterocycle. In some embodiments, R73is optionally substituted 6-membered heterocycle. In some embodiments, R73is optionally substituted 7-membered heterocycle. In some embodiments, R73is optionally substituted 8-membered heterocycle. In some embodiments, R73is optionally substituted 9-membered heterocycle. In some embodiments, R73is optionally substituted 10-membered heterocycle. In some embodiments, R73is optionally substituted 11 -membered heterocycle. In some embodiments, R73is optionally substituted 12-membered heterocycle. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has an oxygenP-660561 -PCatom. In some embodiments, the heterocycle has at least one sulfur atom. In some embodiments, the heterocycle has a sulfur atom.

[0181] In some embodiments, R73is 5- to 12-membered heterocycle optionally substituted with one or more C1-5 alkyl. In some embodiments, R73is 5- to 12-membered heterocycle optionally substituted with one or more C2-6 alkenyl. In some embodiments, R73is 5- to 12-membered heterocycle optionally substituted with one or more C2-6 alkynyl. In some embodiments, R73is 5-to 12-membered heterocycle optionally substituted with one or more halogen. In some embodiments, R73is 5- to 12-membered heterocycle optionally substituted with one or more -NO2. In some embodiments, R73is 5- to 12-membered heterocycle optionally substituted with one or more -CN. In some embodiments, R73is 5- to 12-membered heterocycle optionally substituted with one or more -OH. In some embodiments, R73is 5- to 12-membered heterocycle optionally substituted with one or more -SH. In some embodiments, R73is 5- to 12-membered heterocycle optionally substituted with one or more -NH2.

[0182] In some embodiments, R73is hydrogen. In some embodiments, R73is 5- to 12-membered heterocycle. In some embodiments, R73is 6-membered heterocycle. In some embodiments, R73is NP-660561 -PCcompound is H or a salt or solvate thereof. In some embodiments,NH2the compoundis or a salt or solvate thereof. In someembodiments, the compound is,H or a salt or solvate thereof. Insome embodiments, the compoundis or a salt or solvate thereof. InNH2HOsome embodiments, the compoundis or a salt or solvate thereof.

[0184] In certain aspects, disclosed herein a compound having a structure of Formula (VI):Oor a salt or solvate thereof,wherein:R81is hydrogen, deuterium, -OH, C1-5 alkyl, or C1-5 haloalkyl;R82is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12- membered heterocycle;P-660561 -PCR83is Ci-5 alkyl, C1-5 haloalkyl, -OR83a, -NO2, -CN, or -N(R83a)2,each R83ais independently selected from hydrogen, deuterium, and C1-5 alkyl;q is 0, 1, or 2; andR84is absent or selected from C1-5 alkylene, C2-5 alkenylene, and C2-5 alkynylene, each of the C1-5 alkylene, C2-5 alkenylene, and C2-5 alkynylene is optionally substituted with one or more halogen, -NO2, -CN, -OH, -SH, or -NH2.

[0185] In some embodiments, R81is hydrogen, deuterium, -OH, C1-5 alkyl, or C1-5 haloalkyl. In some embodiments, R81is hydrogen. In some embodiments, R81is deuterium. In some embodiments, R81is -OH. In some embodiments, R81is C1-5 alkyl. In some embodiments, R81is -CH3. In some embodiments, R81is -CH2CH3. In some embodiments, R81is -CH2CH2CH3. In some embodiments, R81is -CH(CH3)2. In some embodiments, R81is -CH2CH(CH3)2. In some embodiments, R81is -CH(CH3)CH2CH3. In some embodiments, R81is -C(CH3)3. In some embodiments, R81is -CH2CH2CH2CH3. In some embodiments, R81is -CH2CH2CH(CH3)CH3. In some embodiments, R81is -CH2CH(CH3)CH2CH3. In some embodiments, R81is -CH2CH2CH2CH2CH3. In some embodiments, R81is C1-5 haloalkyl. In some embodiments, R81is Ci haloalkyl. In some embodiments, R81is -CH2CI. In some embodiments, R81is -CH2F. In some embodiments, R81is C2 haloalkyl. In some embodiments, R81is -CH2CH2CI. In some embodiments, R81is -CH2CH2F. In some embodiments, R81is C3 haloalkyl. In some embodiments, R81is -CH2CH2CH2CI. In some embodiments, R81is -CH2CH2CH2F. In some embodiments, R81is C4 haloalkyl. In some embodiments, R81is C5 haloalkyl.

[0186] In some embodiments, R81is -OH. In some embodiments, R81is C1-5 alkyl. In some embodiments, R81is C4 alkyl. In some embodiments, R81is -CH2CH2CH2CH3. In some embodiments, R81is -CH2CH2(CH3)CH3.

[0187] In some embodiments, R82is hydrogen, deuterium, C1-5 alkyl, C1-5 haloalkyl, C5-12 carbocycle, or 5- to 12-membered heterocycle. In some embodiments, R82is hydrogen. In some embodiments, R82is deuterium. In some embodiments, R82is C1-5 alkyl. In some embodiments, R82is -CH3. In some embodiments, R82is -CH2CH3. In some embodiments, R82is -CH2CH2CH3. In some embodiments, R82is -CH(CH3)2. In some embodiments, R82is -CH2CH(CH3)2. In some embodiments, R82is -CH(CH3)CH2CH3. In some embodiments, R82is -C(CH3)3. In some embodiments, R82is -CH2CH2CH2CH3. In some embodiments, R82is -CH2CH2CH(CH3)CH3. InP-660561 -PCsome embodiments, R82is -CH2CH(CH3)CH2CH3. In some embodiments, R82is -CH2CH2CH2CH2CH3. In some embodiments, R82is C1-5 haloalkyl. In some embodiments, R82is Ci haloalkyl. In some embodiments, R82is -CH2CI. In some embodiments, R82is -CH2F. In some embodiments, R82is C2 haloalkyl. In some embodiments, R82is -CH2CH2CI. In some embodiments, R82is -CH2CH2F. In some embodiments, R82is C3 haloalkyl. In some embodiments, R82is -CH2CH2CH2CI. In some embodiments, R82is -CH2CH2CH2F. In some embodiments, R82is C4 haloalkyl. In some embodiments, R82is C5 haloalkyl.

[0188] In some embodiments, R82is C5-12 carbocycle. In some embodiments, R82is C5 carbocycle. In some embodiments, R82is G> carbocycle. In some embodiments, R82is phenyl. In some embodiments, R82is C7 carbocycle. In some embodiments, R82is Cs carbocycle. In some embodiments, R82is C9 carbocycle. In some embodiments, R82is C10 carbocycle. In some embodiments, R82is Cn carbocycle. In some embodiments, R82is C12 carbocycle. In some embodiments, R82is 5- to 12-membered heterocycle. In some embodiments, R82is 5-membered heterocycle. In some embodiments, R82is 6-membered heterocycle. In some embodiments, R82is 7-membered heterocycle. In some embodiments, R82is 8-membered heterocycle. In some embodiments, R82is 9-membered heterocycle. In some embodiments, R82is 10-membered heterocycle. In some embodiments, R82is 11 -membered heterocycle. In some embodiments, R82is 12-membered heterocycle. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has an oxygen atom. In some embodiments, the heterocycle has at least one sulfur atom. In some embodiments, the heterocycle has a sulfur atom.

[0189] In some embodiments, R82is hydrogen. In some embodiments, R82is C5-12 carbocycle. In some embodiments, R82is phenyl.

[0190] In some embodiments, R83is C1-5 alkyl, C1-5 haloalkyl, -OR83a, -NO2, -CN, or -N(R83a)2. In some embodiments, R83is C1-5 alkyl. In some embodiments, R83is -CH3. In some embodiments,P-660561 -PCR83is -CH2CH3. In some embodiments, R83is -CH2CH2CH3. In some embodiments, R83is -CH(CH3)2. In some embodiments, R83is -CH2CH(CH3)2. In some embodiments, R83is -CH(CH3)CH2CH3. In some embodiments, R83is -C(CH3)3. In some embodiments, R83is -CH2CH2CH2CH3. In some embodiments, R83is -CH2CH2CH(CH3)CH3. In some embodiments, R83is -CH2CH(CH3)CH2CH3. In some embodiments, R83is -CH2CH2CH2CH2CH3. In some embodiments, R83is C1-5 haloalkyl. In some embodiments, R83is Ci haloalkyl. In some embodiments, R83is -CH2CI. In some embodiments, R83is -CH2F. In some embodiments, R83is C2 haloalkyl. In some embodiments, R83is -CH2CH2CI. In some embodiments, R83is -CH2CH2F. In some embodiments, R83is C3 haloalkyl. In some embodiments, R83is -CH2CH2CH2CI. In some embodiments, R83is -CH2CH2CH2F. In some embodiments, R83is C4 haloalkyl. In some embodiments, R83is C5 haloalkyl. In some embodiments, R83is -OR83a. In some embodiments, R83is -NO2. In some embodiments, R83is -CN. In some embodiments, R83is -N(R83a)2.

[0191] In some embodiments, each R83ais independently selected from hydrogen, deuterium, and C1-5 alkyl. In some embodiments, each R83ais independently hydrogen. In some embodiments, each R83ais independently deuterium. In some embodiments, each R83ais independently C1-5 alkyl. In some embodiments, each R83ais independently -CH3. In some embodiments, each R83ais independently -CH2CH3. In some embodiments, each R83ais independently -CH2CH2CH3. In some embodiments, each R83ais independently -CH(CH3)2. In some embodiments, each R83ais independently -CH2CH(CH3)2. In some embodiments, each R83ais independently -CH(CH3)CH2CH3. In some embodiments, each R83ais independently -C(CH3)3. In some embodiments, each R83ais independently -CH2CH2CH2CH3. In some embodiments, each R83ais independently -CH2CH2CH(CH3)CH3. In some embodiments, each R83ais independently -CH2CH(CH3)CH2CH3. In some embodiments, each R83ais independently -CH2CH2CH2CH2CH3.

[0192] In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0193] In some embodiments, R83is C1-5 alkyl. In some embodiments, R83is -CH2CH3. In some embodiments, R83is -OR83a. In some embodiments, R83ais -CH3. In some embodiments, R83is -O CH3. In some embodiments, R83is -N(R83a)2. In some embodiments, R83ais hydrogen. In some embodiments, R83is -NH2. In some embodiments, q is 1.P-660561 -PC

[0194] In some embodiments, R84is absent or selected from C1-5 alkylene, C2-5 alkenylene, and C2-5 alkynylene, each of the C1-5 alkylene, C2-5 alkenylene, and C2-5 alkynylene is optionally substituted with one or more halogen, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R84is absent. In some embodiments, R84is optionally substituted C1-5 alkylene. In some embodiments, R84is optionally substituted Ci alkylene. In some embodiments, R84is optionally substituted C2 alkylene. In some embodiments, R84is optionally substituted C3 alkylene. In some embodiments, R84is optionally substituted C4 alkylene. In some embodiments, R84is optionally substituted C5 alkylene. In some embodiments, R84is optionally substituted C2-5 alkenylene. In some embodiments, R84is optionally substituted C2 alkenylene. In some embodiments, R84is optionally substituted C3 alkenylene. In some embodiments, R84is optionally substituted C4 alkenylene. In some embodiments, R84is optionally substituted C5 alkenylene. In some embodiments, R84is optionally substituted C2-5 alkynylene. In some embodiments, R84is optionally substituted C2 alkynylene. In some embodiments, R84is optionally substituted C3 alkynylene. In some embodiments, R84is optionally substituted C4 alkynylene. In some embodiments, R84is optionally substituted C5 alkynylene. In some embodiments, R84is C1-5 alkylene optionally substituted with one or more halogen, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R84is C1-5 alkylene optionally substituted with one or more halogen. In some embodiments, R84is C1-5 alkylene optionally substituted with one or more -CN. In some embodiments, R84is C1-5 alkylene optionally substituted with one or more -OH. In some embodiments, R84is C1-5 alkylene optionally substituted with one or more -SH. In some embodiments, R84is C1-5 alkylene optionally substituted with one or more -NH2. In some embodiments, R84is C2-5 alkenylene optionally substituted with one or more halogen, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R84is C2-5 alkenylene optionally substituted with one or more halogen. In some embodiments, R84is C2-5 alkenylene optionally substituted with one or more -CN. In some embodiments, R84is C2-5 alkenylene optionally substituted with one or more -OH. In some embodiments, R84is C2-5 alkenylene optionally substituted with one or more -SH. In some embodiments, R84is C2-5 alkenylene optionally substituted with one or more -NH2. In some embodiments, R84is C2-5 alkynylene optionally substituted with one or more halogen, -NO2, -CN, -OH, -SH, or -NH2. In some embodiments, R84is C2-5 alkynylene optionally substituted with one or more halogen. In some embodiments, R84is C2-5 alkynylene optionally substituted with one or more -CN. In someP-660561 -PCembodiments, R84is C2-5 alkynylene optionally substituted with one or more -OH. In some embodiments, R84is C2-5 alkynylene optionally substituted with one or more -SH. In some embodiments, R84is C2-5 alkynylene optionally substituted with one or more -NH2.

[0195] In some embodiments, R84is C1-5 alkylene. In some embodiments, R84is -CH2CH2-. In some embodiments, R84is -CH(OH)CH2CH2-. In some embodiments, R84is -CH2CH(NH2)CH2-.

[0196] In some embodiments, the compound is selected from: Hsome embodiments, the compound isor a salt or solvate thereof.In some embodiments, the compound is or a salt or solvate thereof.In some embodiments, the compound is or a salt or solvateP-660561 -PCthereof. In some embodiments, the compoundis or a salt or solvatethereof. In some embodiments, the compoundisthereof. In some embodiments, the compoundis or a salt or solvate thereof.

[0197] In some embodiments, compounds of the present invention 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.

[0198] 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.

[0199] 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, Inc., 1981,P-660561 -PCherein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0200] 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.

[0201] In some embodiments, the compounds disclosed herein include an ester prodrug form of any compound described herein. Specifically, any compound possessing a functional group amenable to esterification such as a hydroxyl ( — OH) or carboxyl ( — COOH) group may also be provided in the form of its corresponding ester prodrug derivative, wherein the esterifying moiety is selected to improve one or more properties, including solubility, permeability, stability, or bioavailability.COMPOSITIONS

[0202] In certain aspects, the present disclosure provides a composition comprising a compound disclosed herein or a salt or solvate thereof and an excipient. In certain aspects, the present disclosure provides a composition comprising a compound disclosed herein or a salt or solvate thereof and a pharmaceutically acceptable carrier. In some embodiments, the composition comprises a compound having a structure of Formula (I)- (VI) or a salt or solvate thereof and excipient. In some embodiment, the excipient comprises a carrier for the compound. In certain aspects, the present disclosure provides a composition comprising a compound disclosed herein or a salt or solvate thereof and a carrier for the compound.

[0203] The compounds disclosed herein or a salt thereof may be carried in various carriers 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, cyclodextrins, vesicles such as liposomes or niosomes, lipid based emulsions, nanosuspensions, lipid nanoparticles, different sizeP-660561 -PCparticles such as nanoparticles, microparticles, or macroparticles, solid powders, salts, polymer-based nanoparticles, including those made from poly(lactic-co-glycolic acid) (PLGA) and chitosan; and metallic nanoparticles, including gold, silver, copper, titanium, platinum, zinc, magnesium, iron, and alginate nanoparticles, or any combination of these. Additional carriers could include hydrogels, aerosols, foams, creams, lotions, ointments, transdermal patches, subcutaneous implants, intradermal injections, and dissolvable microneedles. The present disclosure provides a carrier designed to optimize the delivery and absorption of the disclosed compounds into skin cells. This carrier is specifically engineered to enhance the bioavailability of the active compounds, ensuring they reach the target site in the skin in their most effective form. The vehicle could be a microemulsion, liposome, nanoparticle, or any other suitable carrier system that facilitates the penetration of the active compounds through the skin's barrier, while preserving their stability and potency. The carrier may not only maximize the therapeutic benefits of the compounds but also minimize any potential side effects.

[0204] The composition disclosed herein may be used for preventing or treating a skin condition, disorder, or disease of a subject in need thereof. In some embodiments, the composition disclosed herein may be used for treating a skin condition, disorder, or disease of a subject in need thereof. In some embodiments, the composition disclosed herein may be used for increasing skin extracellular matrix component production, cell proliferation, or extracellular matrix componentdepositing cell proliferation. In some embodiments, the composition disclosed herein may be used for increasing skin extracellular matrix component production. In some embodiments, the composition disclosed herein may be used for increasing cell proliferation. In some embodiments, the composition disclosed herein may be used for increasing extracellular matrix componentdepositing cell proliferation. The extracellular matrix component comprises collagen, elastin, or hyaluronic acid.

[0205] In some embodiments, an administration of the composition may increase skin collagen production or collagen-depositing cell proliferation, skin elastin production or elastin-depositing cell proliferation, skin hyaluronic acid production or hyaluronic acid-depositing cell proliferation. In some embodiments, an administration of the composition may increase skin collagen production or collagen-depositing cell proliferation. In some embodiments, an administration of the composition may increase skin elastin production or elastin-depositing cell proliferation. In someP-660561 -PCembodiments, an administration of the composition may increase skin hyaluronic acid production or hyaluronic acid-depositing cell proliferation.

[0206] In some embodiments, the composition may be a pharmaceutical composition. This composition may comprise a pharmaceutically acceptable salt and / or a pharmaceutically acceptable excipient. In some instances, the pharmaceutically acceptable excipient serves as a carrier for the topical application of the composition.

[0207] In some embodiments, the composition may be a cosmetic composition. This composition may comprise a cosmetically acceptable salt and / or a cosmetically acceptable excipient. In some instances, the cosmetically acceptable excipient serves as a carrier for the topical application of the composition.

[0208] In some embodiments, the composition may be suitable for topical administration. In some embodiments, an administration of the composition may prevent or treat a skin condition, disorder, or disease. In some embodiments, the administration of the composition may treat a skin condition, disorder, or disease. In certain embodiments, the administration of the composition has therapeutic effects on various skin conditions, disorders, or diseases. The composition disclosed herein may enhance the production of skin extracellular matrix components, stimulate cell proliferation, or boost the proliferation of cells that deposit extracellular matrix components. In some embodiments, the composition may enhance the production of skin extracellular matrix components. In some embodiments, the composition may promote cell proliferation. In some embodiments, the composition may be used to increase the proliferation of cells that deposit extracellular matrix components. These extracellular matrix components comprise collagen, elastin, or hyaluronic acid.

[0209] In some embodiments, the composition comprises a compound disclosed herein that constitutes from 0.0001% to 30% by weight of the total weight of the composition. In some embodiments, a weight % of the compound of the composition is in the range of 0.0001 % to 30 % by weight relative to the total weight of the composition. In some embodiments, a weight % of the compound of the composition is 0.0001 %, 0.0005%, 0.001%, 0.005%, 0.01%, 0.05%, 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%, 10%, 12%, 14%, 16%, 18%, 20%, 22%, 24%, 26%, 28%, or 30 % by weight relative to the total weight of the composition. In some embodiments, a weight % of the compound of the composition is about 0.0001 %, about 0.0005%, about 0.001%, about 0.005%, about 0.01%, about 0.05%, aboutP-660561 -PC0.1%, 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%, about 10%, about 12%, about 14%, about 16%, about 18%, about 20%, about 22%, about 24%, about 26%, about 28%, or about 30 % by weight relative to the total weight of the composition. In some embodiments, a weight % of the compound of the composition is at least 0.0001 %, at least 0.0005%, at least 0.001%, at least 0.005%, at least 0.01%, at least 0.05%, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least 0.7%, at least 0.8%, at least 0.9%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 24%, at least 26%, at least 28%, or at least 30 % by weight relative to the total weight of the composition. In some embodiments, a weight % of the compound of the composition is at most 0.001%, at most 0.005%, at most 0.01%, at most 0.05%, at most 0.1%, at most 0.2%, at most 0.3%, at most 0.4%, at most 0.5%, at most 0.6%, at most 0.7%, at most 0.8%, at most 0.9%, at most 1%, at most 2%, at most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most 8%, at most 9%, at most 10%, at most 12%, at most 14%, at most 16%, at most 18%, at most 20%, at most 22%, at most 24%, at most 26%, at most 28%, or at most 30 % by weight relative to the total weight of the composition. In some embodiments, a weight % of the compound of the composition is from 0.0001 % to 24%, from 0.0005% to 18%, from 0.01% to 6%, from 0.2% to 28%, from 0.5% to 5%, or from 1% to 30 %, including all values and sub ranges in between, by weight relative to the total weight of the composition.

[0210] In some embodiments, the carrier may be suitable for a topical application of the composition disclosed herein. The carrier includes but is 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, cyclodextrins, vesicles such as liposomes or niosomes, lipid based emulsions, nanosuspensions, lipid nanoparticles, different size particles such as nanoparticles, microparticles, or macroparticles, solid powders, salts, polymer-based nanoparticles, including those made from poly(lactic-co-glycolic acid) (PLGA) and chitosan; and metallic nanoparticles, including gold, silver, copper, titanium, platinum, zinc, magnesium, iron, and alginate nanoparticles, or any combination thereof. In some embodiments, the carrier comprises hydrogels, aerosols, foams,P-660561 -PCcreams, lotions, ointments, transdermal patches, subcutaneous implants, intradermal injections, and dissolvable microneedles.

[0211] In some embodiments, the composition may be formulated into various types of products. The formulated products include but are not limited to a toner, a cream, an emulsion, a lotion, an ointment, a paste, a gel, a suspension, a serum, an oil, a spray, 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 foundation, a primer, a concealer, a sunscreen, an eyeshadow, or a combination thereof.

[0212] The composition may further comprise at least one additive. The additive includes but is not limited to a carrier, an excipient, an adjuvant, and a diluent.METHODS

[0213] The compounds or compositions described herein may be useful for preventing or treating a skin condition, disorder, or disease of a subject in need. The compounds or compositions described herein may be useful for treating a skin condition, disorder, or disease of a subject in need. In certain aspects, the present disclosure provides methods for treating a skin condition, disorder, or disease of a subject in need by administering the compound or the composition. In certain aspects, the present disclosure provides methods for increasing skin extracellular matrix component production, cell proliferation, or extracellular matrix component-depositing cell proliferation by administering the compound or the composition. In some embodiments, the method may enhance the production of skin extracellular matrix components. In some embodiments, the method may promote cell proliferation. In some embodiments, the method may be used to increase the proliferation of cells that deposit extracellular matrix components. These extracellular matrix components comprise collagen, elastin, or hyaluronic acid. The method comprises administering the subject the compound or the composition disclosed herein. The compound of Formula (I)-(VI) or the composition comprising a compound of Formula (I)-(VI) has been designed to enhance the production of skin extracellular matrix components, promote cell proliferation, or increase the proliferation of cells that deposit extracellular matrix components.

[0214] In certain embodiments, the method encompasses the topical administration of the composition to the subject's skin. The subject’s skin includes various areas such as, but not limitedP-660561 -PCto, the skin of the scalp, face, elbow, neck, hands, chest, butt, thigh, penile region, or around joints, or a combination of these areas. In specific instances related to facial skin, the composition could be applied to skin beneath or surrounding eyes, skin around mouth, or skin around nose, cheeks, forehead, or a combination thereof.

[0215] The skin condition, disorder, or disease addressed in the present disclosure may involve various symptoms or manifestations related to aging or damage, including but not limited to the emergence of wrinkles and fine lines, decreased collagen production, increased appearance of age spots, damaged skin barrier, loss of skin firmness and elasticity, increased roughness, presence of impurities or makeup residues, a lack of skin brightness, hyperpigmentation, dehydration, damage induced by ultraviolet exposure, damage resulting from environmental factors, stress-induced damage, inflammation-induced damage, the presence of wounds, the presence of acne, the presence of clogged pores, the presence of excess sebum, or a combination of these conditions. A diagnosis of skin condition, disorder, or disease may or may not have been made. In some embodiments of any method described herein, the subject may have been diagnosed with skin condition, disorder, or disease. In some embodiments of any method described herein, the subject may not have been diagnosed with skin condition, disorder, or disease.

[0216] In some embodiments, the method comprises administering the subject the composition comprising a compound having a structure of Formula (I)-(VI). In some embodiments, the method comprises topically administering the composition to a skin of the subject.

[0217] 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.

[0218] In some embodiments, the composition is administered in response to symptoms or conditions as and when required. In some embodiments, the composition is administered at anyP-660561 -PCtime as needed. In some embodiments, the composition is administered not necessarily on consecutive days. For example, the composition is administered intermittently at a frequency of 1-2 times per week or 1 -2 times per month.

[0219] In some embodiments, the composition is administered for about 2 days, about 3 days, about 5 days, about 7 days, about 10 days, about 15 days, about 20 days, about 30 days, about 50 days, about 60 days, about 80 days, about 90 days, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about a year, about 2 years, or about 3 years. 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 2 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, including all values and sub ranges in between.

[0220] In some embodiments, administering the composition may reduce wrinkles and fine lines of the skin, increase collagen production of the skin, increase elastin production of the skin, increase hyaluronic acid production of the skin, fade age spots of the skin, improve firmness of the skin, improve elasticity of the skin, reduce roughness of the skin, or a combination thereof. In some embodiments, the method may reduce wrinkles and fine lines of the skin. In some embodiments, the method may increase the subject’s skin collagen production of the skin. In some embodiments, the method may increase elastin production of the skin. In some embodiments, the method may increase hyaluronic acid production of the skin. In some embodiments, the method may fade age spots of the skin. In some embodiments, the method may improve firmness of the skin. In some embodiments, the method may improve elasticity of the skin. In some embodiments, the method may reduce roughness of the skin.P-660561 -PC

[0221] In some embodiments, the method may clean dirt, oil, bacteria, dead skin, makeup, and any impurities from the skin. In some embodiments, the method may clean makeup from the subject’s skin.

[0222] In some embodiments, administering the composition may brighten the skin, lighten color of the skin, improve color of the skin, improve radiance of the skin, reduce hyperpigmentation of the skin, or a combination thereof. In some embodiments, the method may improve the subject’s skin color. In some embodiments, the method may brighten the skin. In some embodiments, the method may improve radiance of the skin. In some embodiments, the method may reduce the subject’s skin hyperpigmentation. In some embodiments, administering the composition may lighten color of the skin.

[0223] In some embodiments, the method may reduce the subject’s skin roughness. In some embodiments, the method may improve the subject’s skin firmness. In some embodiments, the method may improve elasticity of the subject’s skin. In some embodiments, the method may reduce fine skin lines on the subject. In some embodiments, the method may soften a rough skin patch on the subject. In some embodiments, the method may reduce the presence of acne on the skin of the subject. In some embodiments, the method may reduce the presence of clogged pores on the skin of the subject. In some embodiments, the method may reduce the production of sebum.

[0224] In some embodiments, administering the composition may hydrate the skin, reinforce the skin barrier, moisturize the skin, or a combination thereof. In some embodiments, the method may moisturize or hydrate the subject’s skin. In some embodiments, administering the composition may reinforce the skin barrier.

[0225] In some embodiments, the method may protect the subject’s skin from ultraviolet radiation, from ultraviolet radiation-induced damage, or a combination thereof. In some embodiments, the method may protect the subject’s skin from environmental damage, from stress-induced damage, or a combination thereof. In some embodiments, the method may protect the subject from adverse effects of aging.

[0226] In some embodiments, the method may heal a wound of the subject. In some embodiments, the method may promote healing a wound of the skin. In some embodiments, the method may reduce inflammation. In some embodiments, the method may reduce age-induced inflammation.P-660561 -PC

[0227] In some embodiments, the method may improve health of an aged organ in the subject. In some embodiments, the aged organ comprises liver, muscle, lung, kidney, brain, large intestine, small intestine, stomach, or heart.KITS

[0228] This disclosure also provides a kit comprising the composition disclosed herein.

[0229] 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, an aerosol bottle, a pump bottle, a tube, an applicator wand, a doe foot applicator, a sponge, a foam blender, a silicone applicator, a rollerball, a powder puff, a tottle, or a combination thereof. In some embodiments, the kit further comprises written instructions for the method disclosed herein.EXAMPLES

[0230] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.Example 1: Evaluation of efficacy

[0231] Assay of metabolic activity of fibroblasts

[0232] The metabolic activity enhancement capacity of the example compounds or their salts listed in Table 1 was evaluated using the Promega CellTiter-Glo® Luminescent Cell Viability Assay, in comparison to the vehicle control, DMSO. This assay measures the amount of ATP produced by cells, providing a direct indication of their metabolic activity. The human dermal fibroblasts used in the experiment were derived from healthy adult donors of Caucasian or Black ethnicity, aged between 22 and 34 years. These cells were cultivated in Fibroblast Growth Medium 2, supplemented with 1% Penicillin / Streptomycin. The example compounds or their salts wereP-660561 -PCincorporated at a final concentration of 1.25 pg / mL, and the metabolic activity was a _ O _ O_ZZ-ssessed using ^ ^ y XXX*"-the Promega CellTiter-Glo® Luminescent Cell Viability Assay after 48 hours of incubation.z

[0233] The increase in metabolic activity in the cell populations treated with a compound or its salt was calculated using the equation:(SampleLum- VehicleLum) / (VehicleLum) x 100 %.Positive values denote an increase in metabolic activity in the cells treated with a compound or its salt, compared to the vehicle control. The results of the experiment are displayed in FIG. 1. It was observed that the example compounds increased fibroblast metabolic activity, demonstrating the potential efficacy of these compounds or their salts in stimulating metabolic functions in human dermal fibroblasts.TABLE 1. Example CompoundsMolecularID Name Chemical Structure Weight17A 3-(3-ethoxypropyl)-l, 2,3,4- 248.2777 0 tetrahydroquinazoline-2, 4-dione; 3- o xz= / — ^0^(3-ethoxypropyl)quinazoline- 2,4(1H,3H)-dioneH17B 7-(3,4-difluorobenzoyl)-5- 310.2959methyloctahydro-4 / 7-pyrrolo[3,4- z —\b] [ 1,4] oxazepin-4-one(5aS,8aS)-7-(3,4-difluorobenzoyl)- 5 -methy l-octahydro-2H-pyrrolo[3,4-b][1,4]oxazepin-4-one;(5aS,8aS)-7-(3,4-difluorobenzoyl)- 5-methyloctahydro-4 / 7-pyrrolo[3,4- b] [ 1,4] oxazepin-4-one17C 3-[3-(dimethylamino)propyl]- 247.293l,2,3,4-tetrahydroquinazoline-2,4- dione; 3-(3- (dimethylamino)propyl)quinazoline-2,4(1H,3H)-dioneP-660561 -PC17D (dimethylcarbamoyl)methyl 1 - 260.2884 / methyl-lH-indole-5-carboxylate2 h 1 / > — T\ 017E l-methyl-2-oxopyrrolidin-3-yl 1- 275.3229benzothiophene-5 -carboxylate— N o

[0234] Assay of measurement of extracellular matrix components (I)

[0235] The experiment tested the ability of the example compounds or their salts to increase the production of extracellular matrix (ECM) components in fibroblasts, using enzyme-linked immunosorbent assays (ELISAs). The ECM components evaluated were elastin (assessed with Abeam Human Elastin ELISA Kit), hyaluronan (assessed with Quantikine Human, Mouse, & Rat Hyaluronan ELISA Kit), and pro-collagen I (assessed with Abeam Human Pro-Collagen I alpha 1 ELISA Kit and Quantikine Human Pro-Collagen I al Kit). The human dermal fibroblasts used in the experiment were derived from healthy adult donors of Caucasian or Black ethnicity, aged between 22 and 34 years. Human dermal fibroblasts were cultivated in Fibroblast Growth Medium 2, supplemented with 1% Penicillin / Streptomycin and 20% Fetal Bovine Serum. An example compound or its salt was added at a concentration of 1.25 pg / mL. After a 24-hour incubation period, the supernatant was harvested and analyzed for levels of elastin, hyaluronan, and procollagen I.

[0236] The increase in ECM components was calculated using the equation:(SampleA450- VehicleA450) / (VehicleA450) x 100%.Positive values indicate an increase in ECM production. The results, as depicted in FIG. 2A to FIG. 2C, demonstrate that the example compounds enhance the production of elastin, hyaluronan, and pro-collagen I, as compared to the vehicle control (DMSO), underscoring their potential role in promoting skin health and regeneration.

[0237] Assay of measurement of extracellular matrix components (II)

[0238] The capacity of a compound or salt of the present disclosure to increase the production of extracellular matrix (ECM) components in fibroblasts is tested under various conditions. The impact of serum starvation is examined by culturing fibroblasts in low-serum media (FibroblastP-660561 -PCGrowth Media with 0.5% - 2% fetal bovine serum) and supplementing with additional serum immediately prior to treatment with the compound or salt. The influence of ascorbic acid, a necessary co-factor for collagen synthesis, is also assessed by treating fibroblasts with ascorbic acid in conjunction with the compound or salt. The potential effects of different concentrations of the compound or salt on ECM production is tested, with fibroblasts treated with a compound or salt of the present disclosure at concentrations ranging from 0.3 pg / mL to 10 pg / mL. The effect of varying incubation lengths is examined by treating fibroblasts with the compound or salt and incubating for periods ranging from 24 to 72 hours. In all these conditions, the levels of elastin, collagen, and hyaluronic acid are measured using ELISA techniques as previously described, with elastin and collagen additionally quantified through immunofluorescence staining. In parallel, the ability of the compound or salt to increase the production of ECM components in a 3D in vitro skin model is tested, with collagen, elastin, and hyaluronic acid levels quantified in these samples.

[0239] Assay of gene expression profile

[0240] The experiment aimed to assess the ability of the example compounds or their salts to modify gene expression. A full-thickness 3D skin model, consisting of epidermal keratinocytes and dermal fibroblasts, was developed and treated with 0.9% saline, an example compound or its salt, or a Cu-GHK peptide, which is a common active ingredient in anti-aging products. The expression profile of genes related to skin biology was assessed using quantitative polymerase chain reaction (qPCR) and compared to samples treated with 0.9% saline. Significant changes in gene expression are reported, with a positive % change indicating gene upregulation and a negative % change indicating gene downregulation. FIG. 3 presents the data on the expression levels of genes relevant to skin biology in a 3D skin model treated with example compound 17A and a Cu-GHK peptide. In comparison to samples treated with a 0.9% saline control, example compound 17A was found to significantly increase the expression of Aquaporin-3 (AQP3) and Hyaluronan synthase 2 (HAS2), genes that play a crucial role in promoting skin hydration.

[0241] Assay of skin penetration

[0242] The experiment evaluated the ability of the example compounds or their salts to penetrate the skin. A 3D skin model was treated with an example compound or its salt, formulated at a concentration of 0.1% w / w in either cream or silicone. The distribution area and concentration of the example compound or its salt in the epidermal and dermal layers of the skin were thenP-660561 -PCmeasured. FIG. 4A and FIG. 4B show the penetration of the example compound 17A into the epidermis and dermis layers of the skin. The 3D skin model was treated with the example compound 17A, formulated at a concentration of 0.1 % w / w in two different mediums: cream (FIG.4A) and silicone (FIG. 4B). The data depict the distribution area of the compound within the epidermis and dermis, along with its concentration in these skin layers. This analysis provides valuable insights into the penetrative capacity of the example compound 17A when formulated in different mediums.

[0243] Assay of measurement of hydration properties

[0244] The ability of a compound or salt of the present disclosure to enhance skin hydration-related properties is evaluated through a series of tests. Immunofluorescence staining and imaging are performed on human dermal fibroblasts and human epidermal keratinocytes treated with the compound or salt to evaluate the expression levels of proteins such as aquaporin 3, which is responsible for water transport within the dermis, and hyaluronan synthase 2, which oversees the synthesis of hyaluronic acid. Additionally, the capability of the compound or salt to increase the production of hyaluronic acid by human dermal fibroblasts is assessed using previously described ELISA techniques. Concurrently, the potential of the compound or salt to inhibit hyaluronidase, an enzyme responsible for the breakdown of hyaluronic acid, is evaluated. This is conducted using the QuantiChrom Hyaluronidase Inhibitor Screening Assay Kit, where higher OD600values correlate with higher levels of hyaluronic acid, indicating increased inhibition. Hyaluronidase is incubated with the compound or salt, and the OD600is measured. The percent inhibition is calculated using the formula:(1 - (ODNo Enzyme- ODSample) / (ODNo Enzyme- ODNo Inhibitor)) x 100%.Example 2: Toxicology / safety

[0245] Assay of cytotoxicity against various human cell types

[0246] The experiment was conducted to assess the ability of the example compounds or their salts to maintain the viability of various healthy human cell types. This was tested using the Promega CellTiter-Glo® Luminescent Cell Viability Assay. The human cell types evaluated included fibroblasts, follicle dermal papilla cells, epidermal keratinocytes, epidermal melanocytes, hematopoietic stem cells, aortic smooth muscle cells, renal cortical epithelial cells, microvascularP-660561 -PCendothelial cells, and skeletal muscle cells. The example compound or its salt was added at varying concentrations. All cell types were cultured on tissue culture-treated plastic using predefined growth media, such as fibroblast growth media from Promocell containing basic fibroblast growth factor (FGFβ), or fully-supplemented DMEM containing 10% Fetal Bovine Serum and 1% Penicillin / Streptomycin. FIG. 5 to FIG. 9 display the cell viability (%) data for the example compounds across various cell types. The results show that cell viability remains approximately 100% for all the example compounds across all the cell types tested, indicating their non -toxic nature and potential for safe use in diverse cellular environments.

[0247] Assay of genotoxicity

[0248] The genotoxicity of the example compounds or their salts was evaluated using the SOS-Chromotest, which employs engineered Escherichia coli that express a reporter protein in response to DNA damage. The engineered E. coli were cultivated in Luria Broth and treated with an example compound or its salt. Both example compound 17A and example compound 17C were administered at a final concentration of 12.5 pg / mL, while all other compounds were dosed at a final concentration of 10 pg / mL. A substrate that reacts with the expressed reporter protein was added to the samples, and the absorbance was measured.

[0249] Genotoxicity was assessed using the equation:SOS-induction factor (SOSIF) = (SampleA600 / SampleA420) / (VehicleA600 / VehicleA420).An SOSIF value lower than 1.5 indicated that the compound or salt was non-genotoxic. FIG. 10 presents the SOSIF across various example compounds, with values obtained by expressing a reporter protein in response to DNA damage in an engineered E. coli strain. The genotoxicity was assessed by measuring the absorbance at 420 nm and 600 nm and calculating the SOSIF, which was normalized to the vehicle control (DMSO). While an SOSIF value greater than 1.5 indicates genotoxicity, FIG. 10 reveals that, aside from 4-nitroquinoline 1 -oxide (4NQO), a known mutagen, all example compounds tested were non-genotoxic.

[0250] Assay of measurement of skin sensitization potential

[0251] The potential of the example compounds or their salts to induce skin sensitization was evaluated using the HaCaT-KeratinoSens cell line. Compounds that cause skin sensitization typically induce the expression of luciferase in this cell line, which can be quantified using the Bright-Glo Luciferase Assay System. The cell line has been engineered to express luciferase uponP-660561 -PCactivation of the cellular stress Nrf2-ARE pathway. The cells were cultured in DMEM supplemented with 10% FBS and 1% Penicillin / Streptomycin. The upregulation of the luciferase gene upon treatment with the experimental compounds was quantified using the Bright-Glo™ luminescence detection kit from Promega.

[0252] The relative change in skin sensitization induction was calculated using the equation: SampleLUM / VehicleLUM.Scores higher than 1 indicate skin sensitizing potential, while scores near 1 suggest no change in skin sensitization potential. FIG. 11 presents the normalized skin sensitization of various example compounds. The data shows that these compounds do not cause skin sensitization. The HaCaT-KeratinoSens cell line was treated with both cinnamic aldehyde, a known sensitizer, and the example compounds. FIG. 11 shows the example compounds have normalized sensitization values close to 1, implying they do not cause skin sensitization, unlike cinnamic aldehyde, which has a sensitization value greater than 1.

[0253] In vitro carcinogenicity studies

[0254] The safety / toxicology profiles of a compound or salt of the present disclosure is evaluated using a series of additional in vitro genotoxicity assays. These include the TK.6 micronucleus assay, which is designed to detect chromosomal damage and forward mutations. These assessments provide insights into the genotoxic potential of the compounds, thereby contributing to a comprehensive understanding of their safety profiles.

[0255] Skin and ocular sensitization studies

[0256] The skin sensitization profiles of a compound or salt of the present disclosure is evaluated using standard repeat insult patch testing on human volunteers. This method involves repeated exposure to the compound or salt to evaluate the potential for skin sensitization and allergic reactions, providing a direct measure of its safety for human use. Additionally, ocular sensitization is assessed using the standard HET-CAM test. This test is commonly employed to evaluate the potential irritation that a compound may cause to the eyes. Together, these tests form aP-660561 -PCcomprehensive evaluation of the safety profile of the compound or salt, assessing its potential impact on both skin and eye health.Example 3: Formulation

[0257] Compositions

[0258] Formulations containing compounds disclosed herein include, but not limited to a cosmetic skin primer, a foundation, a concealer, a moisturizer, a toner, a cream, an emulsion, a lotion, an ointment, a paste, a gel, a suspension, a serum, an oil, a spray, an edible supplement, a direct injection, a beverage, a transdermal patch, a topical patch, 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 sunscreen, or a combination thereof.

[0259] Delivery

[0260] The compounds disclosed herein or a salt thereof can be carried in various delivery vehicles (carriers) 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, cyclodextrins, vesicles such as liposomes or niosomes, lipid based emulsions, nanosuspensions, lipid nanoparticles, different size particles such as nanoparticles, microparticles, or macroparticles, solid powders, salts, polymer-based nanoparticles, including those made from poly(lactic-co-glycolic acid) (PLGA) and chitosan; and metallic nanoparticles, including gold, silver, copper, titanium, platinum, zinc, magnesium, iron, and alginate nanoparticles, or any combination of these.

[0261] Additional carriers could include hydrogels, aerosols, foams, creams, lotions, ointments, transdermal patches, subcutaneous implants, intradermal injections, and dissolvable microneedles.

[0262] 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.

[0263] Stability

[0264] The stability of the compounds from the present disclosure in final formulations is determined. These tests include their inclusion in cosmetic skin primer formulations, as well as other formulations. Extended shelf-life testing is carried out on solid raw materials under variousP-660561 -PCconditions, including open air and UV-irradiated room temperature settings. These tests provide a comprehensive understanding of the compound's stability over time and under different conditions, which is essential for ensuring their efficacy and safety in the final product. For a reliable comparison, samples stored in dark, refrigerated conditions serve as a baseline. These rigorous testing procedures help ensure that the compounds maintain their stability and effectiveness in various formulations, contributing to the development of high-quality, reliable skincare products.

[0265] Topical efficacy studies

[0266] The topical efficacy profile of a compound or salt of the present disclosure is investigated in human observational studies. Selected compound(s) is formulated in a topical product with at least 50 human subjects to determine the self-perceived or externally evaluated effectiveness of a compound or salt of the present disclosure to improve the appearance of skin tightening, brightening, and other skin anti-aging features.

[0267] While preferred embodiments of the present disclosure 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. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. 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-660561 -PCCLAIMSWhat is claimed is:

1. A compound having a structure of Formula (II):R22or pharmaceutically acceptable salt thereof or solvate thereof,wherein:A is -O-, -S-, or -N(Rla)-,Rlais hydrogen, deuterium, or C1-5 alkyl;R21is C1-5 alkyl, C5-12 carbocycle or 5- to 12-membered heterocycle, the C5-12 carbocycle and 5- to 12-membered heterocycle each being independently substituted with one or more R21a,each R21ais independently halogen, -NO2, -CN, -OR21b, -SR21b, -N(R21b)2, -C(O)R21b, - C(O)OR21b, -OC(O)N(R21b)2, -NR21bC(O)R21b, - NR21bC(O)OR21b, - NR21bC(O)N(R21b)2, or -C(O)N(R21b)2,each R21bis independently hydrogen, deuterium, or C1-5 alkyl; andR22is O or S.

2. The compound of claim 1, wherein A is -O-.

3. The compound of claim 1, wherein A is -S-.

4. The compound of claim 1, wherein A is -N(Rla)-.

5. The compound of claim 1, wherein Rlais H.

6. The compound of claim 1, wherein Rlais C1-5 alkyl.

7. The compound of claim 6, wherein Rlais -CH3.

8. The compound of claim 1, wherein R21is optionally a substituted C5-12 carbocycle.

9. The c compound of claim 8, wherein R21is optionally a substituted C carbocycle.

10. The compound of claim 9, wherein R21is optionally a substituted phenyl.P-660561 -PC11. The compound of claim 1, wherein R21is optionally a substituted 5- to 12-membered heterocycle.

12. The compound of claim 11, wherein R21is optionally a substituted 6-membered heterocycle.

13. The compound of claim 12, wherein R21is selected from14. The compound of claim 1, wherein R21is a C5-12 carbocycle or a 5- to 12-membered heterocycle substituted with one or more R21athat is halogen.

15. The compound of claim 1, wherein R21is a C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is -F or -Cl.

16. The compound of claim 1, wherein R21is a C5-12 carbocycle or 5- to 12-membered heterocycle substituted with one or more R21athat is independently -OR21bor -N(R21b)2.

17. The compound of claim 16, wherein each R21bis independently C1-5 alkyl.

18. The compound of claim 17, wherein each R21bis independently -CH3 or -CH2CH3.

19. The compound of any one of claims 8-12, wherein R21is selected from, and20. The compound of claim 11 or 12, wherein R21is selected fromOCH3P-660561 -PC21. The compound of claim 1, wherein R22is O.

22. The compound of claim 1, wherein R22is S.

23. The compound of claim 1, wherein the compound is selected from24. The compound of claim 23, wherein the compound isFor a salt or solvate thereof.P-660561 -PC25. A pharmaceutical composition comprising the compound of any one of claims 1-24, or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

26. The composition of claim 25, wherein the composition is a topical composition.

27. A method for preventing or treating a skin condition, disorder, or disease, the method comprising administering to a subject in need thereof a pharmaceutical composition of claim 25.

28. A method for treating a skin condition, disorder, or disease, the method comprising administering to a subject in need thereof a pharmaceutical composition of claim 25.

29. A method for increasing skin extracellular matrix component production, cell proliferation, or extracellular matrix component-depositing cell proliferation, the method comprising administering to a subject in need thereof a pharmaceutical composition of claim 25.

30. The method of claim 29, wherein the extracellular matrix component comprises collagen, elastin, or hyaluronic acid.

31. The method any one of claims 27-30, wherein the composition is topically administered to the skin of the subject.

32. The method claim 31 wherein the skin comprises scalp skin, face skin, elbow skin, neck skin, chest skin, butt skin, thigh skin, hand skin, penile skin, skin around a joint, or a combination thereof.

33. The method claim 32, wherein the composition is topically administered under or around eyes, skin around mouth, skin around nose, cheeks, forehead, or a combination thereof.

34. The method of any one of claims 27-33, wherein the composition reduces appearance of wrinkles and fine lines of the skin, increases collagen production of the skin, increases elastin production of the skin, increases hyaluronic acid production of the skin, fades age spots of the skin, improves firmness of the skin, improves elasticity of the skin, reduces roughness of the skin, or a combination thereof.

35. The method of any one of claims 27-34, wherein administering the composition removes dirt, oil, bacteria, dead skin, makeup, and any impurities from the skin.

36. The method of any one of claims 27-35, wherein administering the composition brightens the skin, lightens color of the skin, improves color of the skin, improves radiance of the skin, reduces hyperpigmentation of the skin, or a combination thereof.P-660561 -PC37. The method of any one of claims 27-36, wherein administering the composition hydrates the skin, moisturizes the skin, reinforces the skin barrier, or a combination thereof.

38. The method of any one of claims 27-37, wherein administering the composition protects the skin from ultraviolet radiation, from ultraviolet radiation-induced damage, from environmental damage, from stress -induced damage, or a combination thereof.

39. The method of any one of claims 27-38, wherein administering the composition heals a wound of the skin, promotes healing a wound of the skin, reduces inflammation, or reduces age-induced inflammation.

40. The method of any one of claims 27-39, wherein the composition is administered one to three times a day.

41. The method of any one of claims 27-40, wherein the composition is administered for at least two consecutive days, five consecutive days or seven consecutive days.

42. The method of any one of claims 27-40, wherein the composition is administered intermittently at a frequency of 1-2 times per week or 1-2 times per month, not necessarily on consecutive days.

43. The method of any one of claims 27-40, wherein the composition is administered for at least about 15 days, about 30 days, about 60 days, about 90 days, about 6 months, or a year.

44. A kit for use in performing the method of any one of claims 27-43.

Images