Compositions and formulations for the treatment, prevention, and improvement of a sign of aging of the skin

Abstract

Provided here in are compositions and formulations for treating, preventing, or improving a sign of aging of skin. Further, provided herein is a method of treating, preventing, or reducing a sign of aging of skin, the method comprising administering to the skin a composition comprising an effective amount of a compound, or salt thereof, described herein.

Description

Attorney Docket No.: 62826-725.601 COMPOSITIONS AND FORMULATIONS FOR THE TREATMENT, PREVENTION, AND IMPROVEMENT OF A SIGN OF AGING OF THE SKIN CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 572,853 filed on April 1, 2024, which is incorporated herein by references in its entirety. BACKGROUND OF THE DISCLOSURE

[0002] Skin aging affects skin appearance and function. Reducing a sign of aging of the skin, such as wrinkles or dark spots, is desirable. Accordingly, there is a need to treat, prevent, and / or improve a sign of aging of the skin. INCORPORATION BY REFERENCE

[0003] 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. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. BRIEF SUMMARY

[0002] In one aspect, compositions and formulations described herein satisfy the need to develop treatment for a sign of aging of the skin. In various aspects, the disclosure herein relates to the topical use of a composition comprising a compound of Formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III); and the salts thereof, the solvates thereof, and / or the isomers thereof, for treating or preventing a sign of aging of the skin.

[0003] For many, reducing the signs of aging present on the skin, such as those described herein, is highly desirable. Among other contributing factors, as skin ages, it produces less collagen, and elastin, and has an overall lower rate of cell turnover. These changes are associated with aging, and, in combination with other lifestyle factors that contribute to premature aging, such as a nutrition deficiency, stress, hormonal changes, smoking, or exposure to UV rays and pollution, exacerbate the development of signs of aging, such as wrinkles. Thus,Attorney Docket No.: 62826-725.601 a method of treating existing signs of aging of the skin or preventing the development of a sign of aging of the skin, is beneficial and desirable.

[0004] As described herein, strategies for treating or preventing a sign of aging may include topically administering a composition comprising a compound of Formula (I), (I-A), (I-B), (I- AA), (I-BB), (II), or (III) as described below, and the salts thereof, the solvates thereof, and / or the isomers thereof to the skin of a subject in need thereof. Compositions that can prevent or treat a sign of aging of the skin described herein may be administered in a formulation that is not irritating to the skin. Topical administration of a composition may comprise transdermal application, cutaneous application, dermal application, intralesional application, or any combination or two or more thereof.

[0005] In one aspect, the present disclosure provides a topical pharmaceutical composition. The topical pharmaceutical composition comprises one or more compounds, or salts thereof, represented by Formula (I):wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R2is an optionally substituted C6-12 aryl or optionally substituted 3- to 12- membered heteroaryl; and n is 0 to 5.

[0006] In some embodiments, R2is an optionally substituted C6-12 aryl or optionally substituted 3- to 12- membered heteroaryl. In some embodiments, R2is an optionally substituted C6-12aryl. In some embodiments, R2is an optionally substituted C6-10aryl. In some embodiments, R2is an optionally substituted phenyl or naphthyl. In some embodiments, R2is an optionally substituted 3- to 12- membered heteroaryl. In some embodiments, R2is an optionally substituted 6- to 12- membered heteroaryl. In some embodiments, R2is an optionally substituted 8- to 10- membered heteroaryl. In some embodiments, R2is an optionally substituted 9- membered heteroaryl. In some embodiments, R2is an optionally substituted benzisoxazolyl,Attorney Docket No.: 62826-725.601 imidazolyl, indolyl, or indazolyl. In some embodiments, R2is an optionally substituted indazolyl.

[0007] The one or more compounds, or salts thereof, comprises a first compound, or salt thereof, having a first structure of Formula (I-A):a second compound, or salt thereof, having a second structure of Formula (I-B):combination thereof, wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R4is hydrogen or C1-6 alkyl; and n is 0 to 5.

[0008] In some embodiments, each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6 haloalkyl, or C1-6alkoxy. In some embodiments, each R1is independently halogen, - OH, -NH2 or -CN. In some embodiments, each R1is independently C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy. In some embodiments, each R1is independently C1-6alkyl. In some embodiments, each R1is independently methyl, ethyl, propyl, or butyl. In some embodiments, each R1is independently methyl or ethyl. In some embodiments, each R1is methyl.

[0009] In some embodiments, n is 0 to 5. In some embodiments, n is 0 to 4. In some embodiments, n is 0 to 3. In some embodiments, n is 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0010] In some embodiments, the one or more compounds, or salts thereof, comprises: a first compound, or salt thereof, having a first structure of Formula (I-AA)Attorney Docket No.: 62826-725.601a second compound, or salt thereof, having a second structure of Formula (I-BB):wherein: R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6 alkyl.

[0011] In some embodiments, the one or more compounds, or salts thereof, comprises: a first compound, or salt thereof, having a first structure of Formula (I-AA):a second compound, or salt thereof, having a second structure of Formula (I-BB):R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6alkyl.

[0012] In some embodiments, R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy. In some embodiments, R3is hydrogen or C1-6 alkyl. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-6alkyl. In some embodiments, R3is methyl, ethyl, propyl, or butyl. In some embodiments, R3is methyl or ethyl. In some embodiments, R3is methyl.Attorney Docket No.: 62826-725.601

[0013] In some embodiments, R4is hydrogen or C1-6alkyl. In some embodiments, R4is hydrogen. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is C1-4 alkyl. In some embodiments, R4is methyl, ethyl, or propyl. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is methyl.

[0014] The compound, or salt thereof, can be represented by Formula (II):wherein RAis C1-20alkyl.

[0015] In some embodiments, RAis C5-20 alkyl. In some embodiments, RAis C10-20 alkyl. In some embodiments, RAis C12-20 alkyl. In some embodiments, RAis C14-20 alkyl. In some embodiments, RAis C14-18alkyl. In some embodiments, RAis C16alkyl.

[0016] The compound, or salt thereof, can be represented by Formula (III):(III).

[0017] In some embodiments, the one or more compounds, or salts thereof, comprises: a first compound, or salt thereof, having a first structure of Compound 11H tautomer:(Compound 11H tautomer), and a second compound, or salt thereof, having a second structure of Compound 12H tautomer:

[0018] Compositions described herein may include, but are not limited to, the compound, or salt thereof, of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof. The composition may be formulated at about 0.1% or aboutAttorney Docket No.: 62826-725.601 1%, compound of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III), or a salt thereof. The composition may be formulated at about 0.1% to about 1%, compound of formula (I), (I-A), (I- B), (I-AA), (I-BB), (II), or (III), or a salt thereof. The composition may be formulated at about 0.1% or about 1%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. The composition may be formulated at about 0.1% to about 1%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0019] In one aspect, the present disclosure provides a method of treating or preventing a sign of aging of the skin in a subject in need thereof, the method comprising administering to the subject a composition, as described herein. In another aspect, the present disclosure provides a method of treating or preventing a sign of aging of skin, the method comprising topically administering to the skin a composition comprising: a compound, or salt thereof, having a structure of: Formula (I):wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R2is an optionally substituted C6-12 aryl or optionally substituted 3- to 12- membered heteroaryl; and n is 0 to 5; or Formula (I-A), Formula (I-B), or a combination thereof:Attorney Docket No.: 62826-725.601 wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R4is hydrogen or C1-6alkyl; and n is 0 to 5.

[0020] In some embodiments, R2is an optionally substituted 3- to 12- membered heteroaryl. In some embodiments, the compound, or salt thereof, has a structure of Formula (I-AA) and / or Formula (I-BB):wherein: R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; and R4is hydrogen or C1-6alkyl.

[0021] In some embodiments, X is N. In some embodiments, n is 0. In some embodiments, the compound, or salt thereof, has a structure of Formula (I-AA) and Formula (I-BB):Attorney Docket No.: 62826-725.601 wherein: R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6 alkyl.

[0022] In some embodiments, R3is C1-3alkyl. In some embodiments, R4is H. In some embodiments, the composition comprises the compound, or salt thereof, having the structure:.

[0023] In some embodiments, the compound is in a salt form. In some embodiments, the total amount of the compound or salt thereof (i) is from about 0.1% to about 2.0% by weight. In some embodiments, the total amount of the compound of salt thereof is about 1.0% by weight.

[0024] In some embodiments, the composition may be formulated at about 0.1% or about 1% of a compound having the structure of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III) or a salt thereof. The composition may be formulated at about 0.1% to about 1%, compound of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III), or a salt thereof. The composition may be formulated at about 0.1% or about 1%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. The composition may be formulated at about 0.1% to about 1%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0025] In some embodiments, the composition is in the form of a gel, ointment, lotion, foam, spray, aerosol, cream, suspension, or emollient. In some embodiments, the composition is a gel formulation.

[0026] In some embodiments, the sign of aging of the skin comprises fine lines, wrinkles, skin dullness, hyperpigmentation, skin sagging, scars, lesions, lentigos, ephelides, striae, stretch marks, uneven skin tone, uneven skin texture, dehydrated skin, or other age-related skin imperfections, or any combination of two or more thereof. In other embodiments, a sign of aging may comprise fine lines, wrinkles, deep rhytids, skin texture, skin tone, skin brightness, collagenAttorney Docket No.: 62826-725.601 production of the skin, skin volume, elastin production of the skin, skin elasticity, skin sagging, moisture content of the skin, water retention of the skin, hyperpigmentation of the skin, lentigos, ephelides, scars, striae, or stretch marks, or any combination of two or more thereof. In some embodiments, the sign of aging of the skin comprises fine lines, wrinkles, skin dullness, hyperpigmentation, photoinduced hyperpigmentation, UV induced hyperpigmentation, skin sagging, scars, lesions, lentigos, ephelides, striae, stretch marks, uneven skin tone, uneven skin texture, dehydrated skin, or other age-related skin imperfections, or any combination of two or more thereof. In some embodiments, the hyperpigmentation of the skin may be photoinduced hyperpigmentation. In some embodiments, the hyperpigmentation of the skin may be UV induced hyperpigmentation. In some instances, lentigos comprises sunspots, age spots, freckles, or ephelides, or any combination of two or more, thereof. In some embodiments, the lentigos comprises sunspots, age spots, liver spots, or freckles, or any combination of two or more thereof. In some embodiments, the scars may be a mark left by a healed wound, sore, blemish, or burn.

[0027] In some embodiments, the sign of aging of the skin is caused by UV exposure, pollution exposure, smoking, a nutrition deficiency, stress, hormonal changes, repeated and / or sustained facial movements, or any combination of two or more thereof. In some embodiments, the sign of aging is hyperpigmentation. In some instances, the hyperpigmentation is photoinduced hyperpigmentation, UV induced hyperpigmentation, or any combination of two of more thereof. In some embodiments, the hyperpigmentation is photoinduced hyperpigmentation. In some embodiments, the hyperpigmentation is UV induced hyperpigmentation.

[0028] In some embodiments, the topically administering to the skin the composition reduces or prevents the sign of the aging of the skin. In some embodiments, the treating or preventing the sign of aging of the skin comprises improving skin texture, skin tone, skin brightness, skin suppleness, skin tightness, skin wrinkling, moisture content of the skin, water retention of the skin, elastin production of the skin, skin volume, collagen production of the skin, or skin elasticity, or any combination of two or more thereof.

[0029] In some embodiments, the treating or preventing the sign of aging comprises stimulating the collagen production of the skin. In some embodiments, the stimulating the collagen production increases the volume of the skin. In some embodiments, the treating or preventing the sign of aging comprises increasing the volume of the skin. In some embodiments, the treating or preventing the sign of aging comprises stimulating the elastin production of the skin. In some embodiments, the stimulating the elastin production of the skin increases skin elasticity.Attorney Docket No.: 62826-725.601

[0030] In some embodiments, the treating or preventing the sign of aging comprises reducing skin sagging. In some embodiments, treating comprises inducing or otherwise increasing collagen production of the skin, elastin production of the skin, water retention of the skin, or lightening of the skin.

[0031] In some embodiments, the treating or preventing the sign of aging comprises reducing or preventing fine lines and wrinkles. In some embodiments, the treating or preventing the sign of aging comprises causing the texture of the skin to become more uniform. In some embodiments, the treating or preventing the sign of aging comprises causing the skin tone to become more uniform. In some embodiments, the treating or preventing the sign of aging comprises increasing skin brightness or reducing the dullness of the skin. In some embodiments, treating comprises improving the appearance of fine lines, wrinkles, deep rhytids, uneven skin texture, uneven skin tone, dull skin, skin sagging, dehydration of the skin, hyperpigmentation of the skin, lentigos, ephelides, scars, striae, or stretch marks, or any combination of two or more thereof.

[0032] In some embodiments, the treating or preventing the sign of aging comprises reducing or preventing hyperpigmentation of the skin. The hyperpigmentation of the skin may be photoinduced hyperpigmentation. The hyperpigmentation of the skin may be UV induced hyperpigmentation. The lentigos may be sunspots, age spots, liver spots, or freckles, or any combination of two or more thereof. The scars may be a mark left by a healed wound, sore, blemish, or burn. In some instances, improving comprises amelioration, reduction, reducing the progression, partial resolution, or full resolution of a sign of aging. In some embodiments, improving comprises the texture of the skin becoming more uniform.

[0033] In some embodiments, treating comprises preventing fine lines, wrinkles, deep rhytids, uneven skin texture, uneven skin tone, dull skin, skin sagging, dehydration of the skin, hyperpigmentation of the skin, lentigos, ephelides, scars, striae, or stretch marks, or any combination of two or more thereof. The hyperpigmentation of the skin may be photoinduced hyperpigmentation. The hyperpigmentation of the skin may be UV induced hyperpigmentation. The lentigos may be sunspots, age spots, liver spots, or freckles, or any combination of two or more thereof. The scars may be a mark left by a healed wound, sore, blemish, or burn.

[0034] In some embodiments, treating comprises improving skin texture, skin tone, skin brightness, skin suppleness, skin tightness, moisture content of the skin, water retention of the skin, elastin production of the skin, skin volume, collagen production of the skin, or skin elasticity, or any combination of two or more thereof. In some embodiments, the treating orAttorney Docket No.: 62826-725.601 preventing the sign of aging comprises reducing or preventing striae and stretch marks. In some embodiments, the treating or preventing the sign of aging comprises reducing or preventing deep rhytids. In some embodiments, the treating or preventing the sign of aging comprises increasing the moisture content or water retention of the skin. In some embodiments, a sign of aging is treated by causing the skin texture to become more uniform. In some embodiments a sign of aging is wrinkles or rhytids. In some embodiments, a sign of aging is treated by causing the skin tone to become more uniform. In some embodiments, a sign of aging is treated by increasing the moisture content of the skin, water retention of the skin, elastin production of the skin, skin volume, collagen production of the skin, or skin elasticity, or any combination of two or more thereof.

[0035] In some embodiments, the treating or preventing the sign of aging comprises lightening the skin. In some embodiments, the treating or preventing the sign of aging comprises lightening of the lentigos on the skin. In some embodiments, the treating or preventing the sign of aging comprises reducing or preventing scars or lesions. In some embodiments, the treating or preventing the sign of aging comprises improving skin texture, decreasing in rhytids, decreasing follicular prominence, improving skin tone, decreasing evidence of photodamage, or combination thereof.

[0036] In some embodiments, a sign of aging as described above is present on the skin of a human subject. In some embodiments, a sign of aging is present on the skin of the face, trunk, or an extremity, or a combination thereof, of the human subject. In some embodiments, a sign of aging is present on the arms, legs, hands, feet, digits, neck, decolletage, chest, neck, shoulders, scalp, eyelids, ears, or a combination thereof, of the human subject.

[0037] In one aspect, the present disclosure provides a kit comprising a topical pharmaceutical composition as described herein, in a tube, flexible aluminum tube or laminated plastic tube, with instructions for use.

[0038] In one aspect, the present disclosure provides a method of treating or preventing a sign of aging of the skin, the method comprising topically administering to the skin a composition comprising a compound having the structure of formula (I), (I-A), (I-B), (I-AA), (I- BB), (II), or (III) wherein the total amount of the compound, or salt thereof, present in the composition is about 0.1% to about 1%. In some embodiments, the compound, or salt thereof, is present in the composition at about 0.1% or about 1%. The Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof may be present in the compositionAttorney Docket No.: 62826-725.601 at about 0.1% to about 1%. The Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof may be present in the composition at about 0.1% or about 1%.

[0039] In one aspect, the present disclosure provides a method of treating or preventing a sign of aging of the skin in a subject in need thereof, the method comprising administering to the subject a composition, as described herein. The composition may be formulated at about 0.1% or about 1% of a compound having the structure of formula (I-A), (I-B), or a salt thereof. The composition may be formulated at about 0.1% to about 1%, compound of formula (I-A), (I-B), or a salt thereof. The composition may be formulated at about 0.1% or about 1%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. The composition may be formulated at about 0.1% to about 1%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0040] In some instances, the composition is present in a kit comprising the composition in a tube, with instructions for use. In one aspect, the present disclosure provides a kit comprising a topical pharmaceutical composition as described herein, in a tube, flexible aluminum tube or laminated plastic tube, with instructions for use.

[0041] In one aspect, the present disclosure provides a method of treating or preventing a sign of aging of the skin, the method comprising topically administering to the skin a composition comprising a compound having the structure of formula (I-A), (I-B) wherein the total amount of the compound, or salt thereof, present in the composition is about 0.1% to about 1%. In some embodiments, the compound, or salt thereof, present in the composition at about 0.1% or about 1%. Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof may be present in the composition at about 0.1% to about 1%. The Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof may be present in the composition at about 0.1% or about 1%.

[0042] In one aspect, the present disclosure provides a composition comprising a compound having the structure of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein the total amount of the compound present in the composition is about 0.1% to about 1%. In some embodiments, the total amount of the compound, or salt thereof, present in the composition is about 0.1% to about 1%. In some embodiments, the compound is Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0043] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is a topical composition. In some embodiments, the compositionAttorney Docket No.: 62826-725.601 is in the form of a gel, ointment, lotion, foam, spray, aerosol, cream, suspension, or emollient. In some embodiments, the composition is a component of a patch, mask, roller, bar, glove, mitten, sock, wrap, brush, paper, shower cap, hair cover, tape, film, wafer, or bandage. In some embodiments, the patch, mask, roller, bar, glove, mitten, sock, wrap, brush, paper, shower cap, hair cover, tape, film, wafer, or bandage further comprises an adhesive.

[0044] In one aspect, the present disclosure provides a method of treating or preventing a sign of aging of skin in a subject in need thereof, comprising administering to the subject the composition described herein.

[0045] In some embodiments, a sign of aging of the skin, as described above, comprises any modification of the appearance of the skin caused by aging, UV exposure, pollution exposure, smoking, a nutrition deficiency, stress, hormonal changes, repeated and / or sustained facial movements, or any combination of two or more thereof.

[0046] In some embodiments, the sign of aging is present on the head, scalp, face, ear(s), decolletage, shoulders, eyelids, digits, neck, chest, back, inframammary region(s), arm(s), leg(s), intertriginous zone(s), hand(s), foot or feet, groin, or any combination of two or more thereof, on a human subject.

[0047] In some embodiments, the topically administering to the skin the composition comprises topically administering the composition to the head, scalp, face, ear(s), decolletage, shoulders, eyelids, digits, neck, chest, back, inframammary region(s), arm(s), leg(s), intertriginous zone(s), hand(s), foot or feet, groin, or any combination of two or more thereof, on a human subject. In some embodiments, the composition is applied topically to the head, scalp, face, ear(s), neck, chest, back, inframammary region(s), arm(s), leg(s), intertriginous zone(s), hand(s), foot or feet, or groin. In some embodiments, the composition is applied topically to the skin of the face. In some embodiments, the composition is applied topically to the arms, legs, hands, feet, digits, neck, decolletage, chest, neck, shoulders, scalp, eyelids, ears, or any combination of two or more thereof, of the human subject.

[0048] In some embodiments, the composition is administered in a pulsed cycle. In some embodiments, the composition is administered under occlusion. In some embodiments, the composition is applied two times daily. In some embodiments, the composition is topically applied two times daily for at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks. In some embodiments, the composition is topically applied two times daily for at least 8 weeks. In some embodiments, the composition is topically applied two times daily for about 1 week,Attorney Docket No.: 62826-725.601 about 2 weeks, about 3 weeks, or about 4 weeks. In some embodiments, the composition is topically applied two times daily for about 8 weeks.

[0049] In some embodiments, the composition is applied for a period of at least 2 weeks to at least 8 weeks. In some embodiments, the composition is topically applied two times daily for about 2 weeks to about 8 weeks.

[0050] In one aspect, the present disclosure provides a kit comprising a topical pharmaceutical composition in a tube, flexible aluminum tube or laminated plastic tube, with instructions for use. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] FIG.1A-FIG.1B. Representative photos demonstrate the local improvement of fine lines, wrinkles, skin texture, and skin tone of the skin of a subject, further identified by arrows on FIG.1B, when treated twice daily (BID) by topical administration of a composition comprising 0.1% of compound 1 for a period of 28 days. FIG.1A shows images taken on days 1, 8, 16, 24, 28, 35, 42, 56, 70, 84, and 98. FIG.1B shows local improvement of fine lines, wrinkles, skin texture, and skin tone of the skin of a subject.

[0052] FIG.2A-FIG.2B. Representative photos demonstrate the local improvement of fine lines, wrinkles, skin texture, and skin tone of the skin of a subject, further identified by arrows and oval markings on FIG.2B, when treated twice daily (BID) by topical administration of a composition comprising 1% of compound 1 for a period of 28 days. FIG.2A shows images taken on days 1, 8, 16, 24, 28, 35, 42, 56, 70, and 84. FIG.2B shows local improvement of fine lines, wrinkles, skin texture, and skin tone of the skin of a subject.

[0053] FIG.3A-FIG.3B. Representative photos demonstrate the local improvement of deep rhytid, skin texture, and skin tone of the skin of a subject, further identified by arrows on FIG. 3B, when treated twice daily (BID) by topical administration of a composition comprising 1% of compound 1 for a period of 28 days. FIG.3A shows images taken on days 1, 8, 16, 24, 28, 35, 42, 56, 70, 84, and 98. FIG.3B shows local improvement of fine lines, wrinkles, skin texture, and skin tone of the skin of a subject.

[0054] FIG.4A-FIG.4B. Representative photos demonstrate the local improvement of fine lines, wrinkles, and skin tone of the skin of a subject, further identified by arrows and oval markings on FIG.4B, when treated twice daily (BID) by topical administration of a composition comprising 1% of compound 1 for a period of 28 days. FIG.4A shows images taken on days 1, 8, 16, 24, 28, 35, 42, 56, 70, 84, and 98. FIG.4B shows local improvement of fine lines, wrinkles, skin texture, and skin tone of the skin of a subject.Attorney Docket No.: 62826-725.601

[0055] FIG.5A-FIG.5B. Representative photos demonstrate the local improvement of lentigos, age spots, deep rhytid, skin texture, and skin tone of the skin of a subject, further identified by arrows and oval markings on FIG.5B, when treated twice daily (BID) by topical administration of a composition comprising 1% of compound 1 for a period of 28 days. FIG.5A shows images taken on days 1, 8, 16, 24, 28, 35, 42, 56, 70, 84, and 98. FIG.5B shows local improvement of fine lines, wrinkles, skin texture, and skin tone of the skin of a subject. DETAILED DESCRIPTION OF THE INVENTION GENERAL

[0056] Provided herein, in various aspects, are compositions and methods of using these compositions for the treatment or prevention of a sign of aging of the skin. The compositions may be administered topically, thereby treating or preventing a sign of aging of the skin. A sign of aging includes, but is not limited to, any one of fine lines, wrinkles, deep rhytids, uneven skin texture, uneven skin tone, dull skin, skin sagging, dehydration of the skin, hyperpigmentation of the skin, lentigos, ephelides, scars, striae, stretch marks, and any combination of two or more thereof. The hyperpigmentation of the skin may be photoinduced hyperpigmentation. the hyperpigmentation of the skin may be UV induced hyperpigmentation. The lentigos may be sunspots, age spots, liver spots, or freckles, or any combination of two or more thereof. The scars may be a mark left by a healed wound, sore, blemish, or burn.

[0057] In some aspects fine lines, wrinkles, or rhytids, comprise folds, ridges, creases, crevices, or valleys in the skin measuring less than about 0.1-4.0mm in depth. In some aspects, wrinkles comprise folds, ridges, creases, crevices, or valleys in the skin measuring about 0.1- 4.0mm or greater in depth. In some instances, the dimensions (e.g., depths, lengths, etc.) of the wrinkles can vary by the area of the skin. Certain compositions and methods of using these compositions herein may reduce the depth of fine lines, wrinkles, or rhytids (e.g., folds, ridges, creases, crevices, or valleys in the skin). In some instances, skin texture comprises the surface condition of the skin, which may comprise characteristics of the surface of the skin such as rough, smooth, irregular, course, soft, uneven. Certain compositions and methods of using these compositions herein may increase the smoothness of the skin. In some instances, skin tone comprises the amount of melanin or pigment of the skin, wherein the skin tone can show a sign of aging such as unevenness or dullness. Certain compositions and methods of using these compositions herein may reduce the amount of melanin or pigment of the skin. In some aspects, skin volume is determined by the fat, collagen, and elastin contents of the skin. Certain compositions and methods of using these compositions herein may increase the skin volume.Attorney Docket No.: 62826-725.601 Certain compositions and methods of using these compositions herein may increase the fat content of the skin. Certain compositions and methods of using these compositions herein may increase the collagen content of the skin. Certain compositions and methods of using these compositions herein may increase the elastin content of the skin. In some aspects, skin volume is correlated to the definition of facial contours such as the hollows of the cheeks, temples, under eyes, eyelids, marionette lines, nasal labial lines and folds. In some instances, skin elasticity comprises the elasticity, firmness, suppleness, plumpness, rigidity, or tonicity of the skin. DEFINITIONS

[0058] The abbreviations used herein may have their conventional meaning within the chemical and biological arts.

[0059] “Tautomer” refers to one of two or more structural isomers which exist in equilibrium, and which are readily converted from one form to another. Compound 1 can exist in 1H and / or 2H tautomer forms, as shown below:As used herein, “Compound 1” includes, but is not limited to, the 1H tautomer, the 2H tautomer, and mixtures of the 1H tautomer and 2H tautomer. Compound 1 also includes, but is not limited to, salts of 1H tautomer, the 2H tautomer, and mixtures of salts of the 1H tautomer and 2H tautomer.

[0060] “Solvate” refers to a compound provided herein or a salt thereof, that further includes, but is not limited to, a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0061] “Composition” or “formulation” as used herein is intended to encompass a product comprising the specified ingredients, as well as any product, which results, directly or indirectly, from combination of the specified ingredients. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient are compatible with the other ingredients of the composition (or formulation) and not deleterious to the recipient thereof.

[0062] “A relative purity of the compound in the topical composition” refers to the purity of the compound (e.g., Compound 1) at a certain time point (e.g., number of weeks) stored under stressed conditions (e.g., 40°C) or under normal storage conditions (e.g., room temperature orAttorney Docket No.: 62826-725.601 25℃) as compared to an initial purity of the compound at time zero (i.e., day 0). In some instances, the relative purity of the compound at time zero (i.e., day 0) is set as 100%.

[0063] “About” means a range of values including, but is not limiting to, the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In some embodiments, the term “about” means within a standard deviation using measurements generally acceptable in the art. In some embodiments, about means a range extending to + / - 10% of the specified value. In some embodiments, about means the specified value.

[0064] “Substantially free of …” may refer to a composition containing no more than 1% by weight of other excipients.

[0065] “Inhibition,” “inhibits” and “inhibitor” refer to a compound that prohibits or a method of prohibiting, a specific action or function.

[0066] “Administering” refers to providing a composition or formulation to a subject (e.g., a patient, such as a human patient) via a desired route, such as via topical administration. Topical administration may comprise, for example, application of a composition in the form of a gel, ointment, lotion, foam, spray, emollient, or as a component of a patch, mask, roller, bar, glove, mitten, sock, wrap, brush, paper, shower cap, hair cover, tape, film, wafer, or bandage to a surface of a subject, such as to the skin of the subject. The area over which the composition is applied may vary based upon, e.g., the condition of the subject as well as the characteristics of the composition (e.g., form, drug load, etc.).

[0067] “Treat”, “treating” and “treatment” in some embodiments, refer to any indicia of success in the treatment or amelioration of a condition, disease, or disorder, including, but not limiting to, any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient (e.g., by improving the appearance of the condition, disease, or disorder); slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including, but not limiting to, the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. In some embodiments, a sign of aging of the skin is a condition, disease, or disorder.

[0068] “Prevent,” “preventing” or “prevention” in some embodiments, includes, but is not limited to, reducing the likelihood or occurrence or the severity of initial clinical or aestheticalAttorney Docket No.: 62826-725.601 symptoms of a condition, disease, or disorder. In some embodiments, a sign of aging of the skin is a condition, disease, or disorder.

[0069] “Patient” or “subject” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples are humans, other mammals, bovines, rats, mice, dogs, cats, primates, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient or subject is human.

[0070] “Therapeutically effective amount” refers to an amount of a compound or of a pharmaceutical composition useful for treating, preventing, or ameliorating an identified condition, disease, or disorder, or for exhibiting a detectable therapeutic or inhibitory effect. In some embodiments, a sign of aging of the skin is a condition, disease, or disorder.

[0071] “A,” “an,” or “a(n),” when used in reference to a group of substituents or "substituent group" herein, mean at least one. For example, where a compound is substituted with "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl, wherein each alkyl and / or aryl is optionally different. In another example, where a compound is substituted with “a” substituent group, the compound is substituted with at least one substituent group, wherein each substituent group is optionally different. TOPICAL COMPOSITIONS

[0072] In certain aspects, the present disclosure provides a composition comprising one or more compounds, or salts thereof, having a structure represented by Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III). In some embodiments, the one or more compounds, or salts thereof, having a structure represented by Formula (I):wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy;Attorney Docket No.: 62826-725.601 R2is an optionally substituted C6-12aryl or optionally substituted 3- to 12- membered heteroaryl; and n is 0 to 5.

[0073] In some embodiments, R2is an optionally substituted 3- to 12- membered heteroaryl.

[0074] In some embodiments, the one or more compounds, or salts thereof, comprises more than one structures. In some embodiments, the more than one structures comprise tautomers. In some embodiments, the one or more compounds, or salts thereof, comprises: a first compound, or salt thereof, having a first structure of Formula (I-A):a second compound, or salt thereof, having a second structure of Formula (I-B):combination thereof, wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R4is hydrogen or C1-6 alkyl; and n is 0 to 5.

[0075] In some embodiments, R2is an optionally substituted 3- to 12- membered heteroaryl.

[0076] In some embodiments, the one or more compounds, or salts thereof, comprises a first compound, or salt thereof, having a first structure of Formula (I-AA):Attorney Docket No.: 62826-725.601 a second compound, or salt thereof, having a second structure of Formula (I-BB):combination thereof, wherein: R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6alkyl;

[0077] In some embodiments, X is N. In some embodiments, n is 0. In some embodiments, the one or more compounds, or salts thereof, comprises: a first compound, or salt thereof, having a first structure of Formula (I-AA):a second compound, or salt thereof, having a second structure of Formula (I-BB):R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6alkyl.

[0078] In some embodiments, R3is C1-3 alkyl. In some embodiments, R4is H.

[0079] In some embodiments, the one or more compounds, or salts thereof, comprises a compound having a structure represented by Formula (II):wherein RAis C1-20 alkyl.

[0080] In some embodiments, the one or more compounds, or salts thereof, comprises a compound having a structure represented by Formula (III):Attorney Docket No.: 62826-725.601

[0081] In some instances, the composition comprises one or more compounds, or salts thereof, having a structure of Formula (I). In some instances, the composition comprises one or more compounds, or salts thereof, having a structure of Formula (I), Formula (I-A), Formula (I- B), or a combination thereof. In some instances, the composition comprises one or more compounds, or salts thereof, having a structure of Formula (I-AA), Formula (I-BB), or a combination thereof. In some instances, the composition comprises one or more compounds, or salts thereof, having a structure of Formula (I-AA) and / or Formula (I-BB). In some instances, the composition comprises one or more compounds, or salts thereof, having a structure of Formula (I-AA) and Formula (I-BB).

[0082] In some instances, the one or more compounds, or salts thereof, comprises a first compound, or salt thereof, having a first structure of Compound 11H tautomer:(Compound 11H tautomer), a second compound, or salt thereof, having a second structure of Compound 12H tautomer:(Compound 12H tautomer), or a combination / a mixture thereof.

[0083] The composition may comprise the compound, or salt thereof, of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), or Formula (II) in a total amount of about 0.1% or about 1%. The composition may comprise the compound, or salt thereof, of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), or Formula (II) in a total amount of about 0.1% to about 1%. The compound may be (e.g.,Attorney Docket No.: 62826-725.601 Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. The composition may comprise Compound 1 in a total amount of about 0.1% or about 1%. The compound may be (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. The composition may comprise Compound 1 in a total amount of about 0.1% to about 1%.

[0084] In embodiments wherein the composition comprises a compound, or salt thereof, having the structure of Formula (I), one or more components may vary between embodiments. In some of those embodiments, R2is an optionally substituted C6-12aryl or optionally substituted 3- to 12- membered heteroaryl. In some embodiments, R2is an optionally substituted C6-12aryl. In some embodiments, R2is an optionally substituted C6-10 aryl. In some embodiments, R2is an optionally substituted phenyl or naphthyl. In some embodiments, R2is an optionally substituted 3- to 12- membered heteroaryl. In some embodiments, R2is an optionally substituted 6- to 12- membered heteroaryl. In some embodiments, R2is an optionally substituted 8- to 10- membered heteroaryl. In some embodiments, R2is an optionally substituted 9- membered heteroaryl. In some embodiments, R2is an optionally substituted benzisoxazolyl, imidazolyl, indolyl, or indazolyl. In some embodiments, R2is an optionally substituted indazolyl.

[0085] In embodiments wherein the composition comprises a compound, or salt thereof, having the structure of Formula (I-A) or Formula (I-B), one or more components may vary between embodiments. In some of those embodiments, each R1is independently halogen, -OH, - NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy. In some embodiments, each R1is independently halogen, -OH, -NH2or -CN. In some embodiments, each R1is independently C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy. In some embodiments, each R1is independently C1-6alkyl. In some embodiments, each R1is independently methyl, ethyl, propyl, or butyl. In some embodiments, each R1is independently methyl or ethyl. In some embodiments, each R1is methyl.

[0086] In embodiments wherein the composition comprises a compound, or salt thereof, having the structure of Formula (I-AA) or Formula (I-BB), one or more component may vary between embodiments. In some of those embodiments, R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy. In some embodiments, R3is hydrogen or C1-6alkyl. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-6 alkyl. In some embodiments, R3is methyl, ethyl, propyl, or butyl. In some embodiments, R3is methyl or ethyl. In some embodiments, R3is methyl. In some embodiments, R4is hydrogen or C1-6alkyl. In some embodiments, R4is hydrogen. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is C1-4 alkyl. In some embodiments, R4is methyl, ethyl, or propyl. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is methyl.Attorney Docket No.: 62826-725.601

[0087] In embodiments wherein the composition comprises a compound, or salt thereof, having the structure of Formula (II), one or more component may vary between embodiments. In some of those embodiments, RAis C5-20 alkyl. In some embodiments, RAis C10-20 alkyl. In some embodiments, RAis C12-20alkyl. In some embodiments, RAis C14-20alkyl. In some embodiments, RAis C14-18 alkyl. In some embodiments, RAis C16 alkyl.

[0088] In some embodiments, at least one of the one or more compounds, or salts thereof, is in a salt form.

[0089] In some embodiments, at least one of the one or more compounds, or salts thereof, is in a free base form. As such, provided herein are compositions comprising a free base form of the compounds herein, such as those having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III).

[0090] The composition may be formulated at about 0.1% to about 1% of one or more compounds having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a salt thereof. The composition may be formulated at about 0.1% or about 1% of one or more compounds having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a salt thereof. The composition may be formulated at about 0.1% to about 1% of Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. The composition may be formulated at about 0.1% or about 1% of Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0091] In some embodiments, the one of the one or more compounds, or salts thereof, in the compositions described herein, can be represented by Formula (I):wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1- 6alkoxy; R2is an optionally substituted C6-12 aryl or optionally substituted 3- to 12- membered heteroaryl; andAttorney Docket No.: 62826-725.601 n is 0 to 5.

[0092] In some embodiments, R2is an optionally substituted C6-12 aryl or optionally substituted 3- to 12- membered heteroaryl. In some embodiments, R2is an optionally substituted C6-12aryl. In some embodiments, R2is an optionally substituted C6-10aryl. In some embodiments, R2is an optionally substituted phenyl or naphthyl. In some embodiments, R2is an optionally substituted 3- to 12- membered heteroaryl. In some embodiments, R2is an optionally substituted 6- to 12- membered heteroaryl. In some embodiments, R2is an optionally substituted 8- to 10- membered heteroaryl. In some embodiments, R2is an optionally substituted 9- membered heteroaryl. In some embodiments, R2is an optionally substituted benzisoxazolyl, imidazolyl, indolyl, or indazolyl. In some embodiments, R2is an optionally substituted indazolyl.

[0093] In some instances, the one of the one or more compounds, or salts thereof, in the compositions described herein, comprises a first compound, or salt thereof, having a first structure of Formula (I-A);a second compound, or salt thereof, having a second structure of Formula (I-B):combination thereof, wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R4is hydrogen or C1-6 alkyl; and n is 0 to 5.

[0094] In some embodiments, each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6 haloalkyl, or C1-6alkoxy. In some embodiments, each R1is independently halogen, -Attorney Docket No.: 62826-725.601 OH, -NH2or -CN. In some embodiments, each R1is independently C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy. In some embodiments, each R1is independently C1-6 alkyl. In some embodiments, each R1is independently methyl, ethyl, propyl, or butyl. In some embodiments, each R1is independently methyl or ethyl. In some embodiments, each R1is methyl.

[0095] In some embodiments, X is CH or N. In some embodiments, X is CH. In some embodiments, X is N.

[0096] In some embodiments, n is 0 to 5. In some embodiments, n is 0 to 4. In some embodiments, n is 0 to 3. In some embodiments, n is 0 to 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0097] In some embodiments, one of the one or more compounds, or salts thereof, in the compositions described herein, comprises a first compound, or salt thereof, having a first structure of Formula (I-AA):a second compound, or salt thereof, having a second structure of Formula (I-BB):combination thereof, wherein: R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6 alkyl.

[0098] In some embodiments, R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy. In some embodiments, R3is hydrogen or C1-6alkyl. In some embodiments, R3is hydrogen. In some embodiments, R3is C1-6 alkyl. In some embodiments, R3is methyl, ethyl, propyl, or butyl. In some embodiments, R3is methyl or ethyl. In some embodiments, R3is methyl.

[0099] In some embodiments, R4is hydrogen or C1-6alkyl. In some embodiments, R4is hydrogen. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is C1-4 alkyl. In some embodiments, R4is methyl, ethyl, or propyl. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is methyl.Attorney Docket No.: 62826-725.601

[0100] In some embodiments, the composition described herein comprises one or more compounds, or salts thereof, wherein the one or more compounds, or salts thereof, comprises a first compound, or salt thereof, having a first structure of Formula (I-AA), and a second compound, or salt thereof, having a second structure of Formula (I-BB).

[0101] In some embodiments, the composition comprises one or more compounds, or salts thereof, wherein the one or more compounds, or salts thereof, comprises a first compound, or salt thereof, having a first structure of Compound 11H tautomer:(Compound 11H tautomer), and a second compound, or salt thereof, having a second structure of Compound 12H tautomer:

[0102] The compound, or salt thereof, can be represented by Formula (II):wherein RAis C1-20 alkyl.

[0103] In some embodiments, RAis C5-20 alkyl. In some embodiments, RAis C10-20 alkyl. In some embodiments, RAis C12-20alkyl. In some embodiments, RAis C14-20alkyl. In some embodiments, RAis C14-18 alkyl. In some embodiments, RAis C16 alkyl.

[0104] The compound, or salt thereof, can be represented by Formula (III):Attorney Docket No.: 62826-725.601

[0105] In some embodiments, the one or more compounds, or salts thereof, may be Compound 1 in a 1H tautomer form represented by the formula:salt thereof, and / or in a 2H tautomer form represented by the formula:salt thereof, or a mixture thereof.

[0106] One or more compounds, or salt thereof, having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a mixture thereof may be comprised in the composition.

[0107] The compound can be a pharmaceutically acceptable salt of one or more compounds having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I- BB), Formula (II), or Formula (III), or a mixture thereof.

[0108] The compound, or salt thereof, can be in a solvate or hydrate form of one or more compounds having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a mixture thereof.

[0109] In some embodiments, the one or more compounds, or salts thereof, is a compound having the structure of Formula (I).

[0110] In some embodiments, the one or more compounds, or salts thereof, is a compound having the structure of Formula (I-A). In some embodiments, the one or more compounds, or salts thereof, is a compound having the structure of Formula (I-B). In some embodiments, the one or more compounds, or salts thereof, a compound having the structure of Formula (I-AA).

[0111] In some embodiments, the one or more compounds, or salts thereof, is a compound having the structure of Formula (I-BB).

[0112] In some embodiments, the one or more compounds, or salts thereof, is a compound having the structure of Formula (II).Attorney Docket No.: 62826-725.601

[0113] In some embodiments, the one or more compounds, or salts thereof, is a compound having the structure of Formula (III).

[0114] In some embodiments, the one or more compounds, or salts thereof, is Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer).

[0115] In some embodiments, the one or more compounds, or salts thereof, is Compound 2, represented by the structure:.

[0116] In some embodiments, the one or more compounds, or salts thereof, is Compound 3, represented by the structure:.

[0117] In some embodiments, the one or more compounds, or salts thereof, is Compound 4, represented by the structure:.

[0118] In some embodiments, the one or more compounds, or salts thereof, is Compound 5, represented by the structure:.

[0119] In some embodiments, the one or more compounds, or salts thereof, is Compound 6, represented by the structure:.Attorney Docket No.: 62826-725.601

[0120] In some embodiments, the one or more compounds, or salts thereof, is Compound 7, represented by the structure:.

[0121] In some embodiments, the one or more compounds, or salts thereof, is Compound 8, represented by the structure:.

[0122] In some embodiments, the one or more compounds, or salts thereof, is Compound 9, represented by the structure:.

[0123] In some embodiments, the one or more compounds, or salts thereof, is Compound 10, represented by the structure:.

[0124] In some embodiments, the one or more compounds, or salts thereof, is Compound 11, represented by the structure:.

[0125] In some instances, “a combination thereof” refers to “a mixture thereof”. In some embodiments, the composition described herein comprises a mixture of the one or more compounds, or salts thereof, having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III). In some embodiments, the composition described herein comprises a mixture of the one or more compounds, or salts thereof, having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), or Formula (I-BB).Attorney Docket No.: 62826-725.601

[0126] In some embodiments, the composition described herein comprises a mixture of the one or more compounds, or salts thereof, and the one or more compounds, or salts thereof are tautomers. In some embodiments, the composition described herein comprises a mixture of the one or more compounds, or salts thereof, comprising a first compound, or salt thereof, having a first structure of Formula (I-A), or second compound, or salt thereof, having a second structure of Formula (I-B). In some embodiments, the composition described herein comprises a mixture of the one or more compounds, or salts thereof, comprising a first compound, or salt thereof, having a first structure of Formula (I-AA), or second compound, or salt thereof, having a second structure of Formula (I-BB). In some embodiments, the composition described herein comprises a mixture of tautomers, comprising a first compound, or salt thereof, having a first structure of Compound 11H tautomer and a and a second compound, or salt thereof, having a second structure of Compound 12H tautomer.

[0127] In some embodiments, the one or more compounds, or salts thereof, is a mixture of any two or more of compounds having the structure of Formula (I), Formula (I-A), Formula (I- B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof. In some embodiments, the one or more compounds, or salts thereof, is a mixture of any two or more of compounds having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof, wherein two or more of compounds having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), or Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof is present in the mixture in an amount of from 1% to 99%. In some embodiments, the two or more of compounds having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof are present in the mixture in an amount of from 50% to 99%, from 60% to 99%, from 70% to 99%, from 80% to 99%, or from 90% to 99%. In some embodiments, the two or more of compounds having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I- BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof is present in the mixture in an amount of from 80% to 99%. In some embodiments, the two or more of compounds having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof is present in the composition comprising the mixture in an amount of from 0.1% to about 1%. In some embodiments, the two or more of compounds having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), orAttorney Docket No.: 62826-725.601 pharmaceutically acceptable salts thereof is present in the composition comprising the mixture in an amount of about 0.1% or about 1%. In some embodiments, the two or more of the compounds, or salt thereof, comprises Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer), where Compound 1 is present in the composition in an amount of about 0.1% to about 1%. In some embodiments, the two or more of compounds comprises Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer), where Compound 1 is present in the composition in an amount of about 0.1% or about 1%.

[0128] In some embodiments, the total amount of the one or more compounds, or salts thereof, is from about 0.1% to about 5.0%, from about 0.1% to about 4.0%, from about 0.1% to about 3.0%, from about 0.1% to about 2.0%, or from about 0.1% to about 1.0% by weight. In some embodiments, the total amount of the one or more compounds, or salts thereof, is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, or about 3.0% by weight. In some embodiments, the total amount of the one or more compounds, or salts thereof, is 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 1.1%, at least 1.2%, at least 1.3%, at least 1.4%, at least 1.5%, at least 1.6%, at least 1.7%, at least 1.8%, at least 1.9%, or at least 2% by weight. In some embodiments, the total amount of the one or more compounds, or salts thereof, is 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 1.1%, at most 1.2%, at most 1.3%, at most 1.4%, at most 1.5%, at most 1.6%, at most 1.7%, at most 1.8%, at most 1.9%, at most 2%, at most 2.1%, at most 2.2%, at most 2.3%, at most 2.4%, at most 2.5%, at most 2.6%, at most 2.7%, at most 2.8%, at most 2.9%, or at most 3.0%by weight. In some embodiments, the total amount of the one or more compounds, or salts thereof, is from about 0.1% to about 2.0% by weight. In some embodiments, the total amount of the one or more compounds, or salts thereof, is about 1.0% by weight. Forms of Compositions

[0129] In some instances, topical compositions useful for delivering the compound, or salt thereof, to a subject (e.g., to the skin of a subject) include, but are not limited to, foams, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, and suspensions. In some embodiments, the topical composition used to deliver the compound, or salt thereof, is a gel, ointment, lotion, foam, spray, or emollient.Attorney Docket No.: 62826-725.601

[0130] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is a topical composition. In some embodiments, the composition is in the form of a gel, ointment, lotion, foam, spray, aerosol, cream, suspension, or emollient. In some embodiments, the composition is a component of a patch, mask, roller, bar, glove, mitten, sock, wrap, brush, paper, shower cap, hair cover, tape, film, wafer, or bandage. In some instances, the patch, mask, roller, bar, glove, mitten, sock, wrap, brush, paper, shower cap, hair cover, tape, film, wafer, or bandage further comprises an adhesive.

[0131] In some embodiments, the topical composition used to deliver the compound, or salt thereof, is a lotion or a cream.

[0132] In some embodiments, the composition is a gel formulation. In some embodiments, the topical composition used to deliver the compound, or salt thereof, is a gel, for example, a two-phase gel or a single-phase gel. In some instances, gels are semisolid systems consisting of suspensions of small inorganic particles or large organic molecules interpenetrated by a liquid. In some instances, when the gel mass comprises a network of small discrete inorganic particles, it is classified as a two-phase gel. In another instances, single-phase gels comprises organic macromolecules distributed uniformly throughout a liquid such that no apparent boundaries exist between the dispersed macromolecules and the liquid.

[0133] In some embodiments, the topical composition used to deliver the compound, or salt thereof, is an ointment. In some instances, ointments are oleaginous semisolids that contain little if any water. In some instances, the ointment is hydrocarbon based, such as a wax, petrolatum, or gelled mineral oil.

[0134] In some embodiments the topical composition used to deliver the compound, or salt thereof, is an emulsified gel. In some embodiments the topical composition used to deliver the compound, or salt thereof, is an emulsified spray.

[0135] In some instances, the topical composition may be formulated in the form of a patch, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap or hair cover, tape, film, wafer, or bandage including, but not limiting to, the topical composition as described herein. In some embodiments, the patch, tape, film, wafer, or bandage is in contact with the affected area on the skin. In some embodiments, the patch, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap or hair cover, tape, film, wafer, or bandage, when applied to a subject, is in contact with areas of the skin of the subject that are adjacent to the affected or target area.

[0136] In some instances, the topical administration may be achieved in the form of a patch, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap or hair cover, tape, film, wafer, orAttorney Docket No.: 62826-725.601 bandage including, but not limiting to, the topical composition as described herein. In some embodiments, the patch, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap or hair cover, tape, film, wafer, or bandage is in contact with the affected area on the skin. In some embodiments, the patch, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap or hair cover, tape, film, wafer, or bandage, when applied to a subject, is in contact with areas of the skin of the subject that are adjacent to the affected or target area.

[0137] In some embodiments, the patch, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap or hair cover, tape, film, wafer, or bandage includes, but is not limited to, an adhesive.

[0138] In some instances, the tape or film may be adhesive tape, waterproof adhesive tape, or a plastic film (with or without an adhesive layer). In some embodiments, the transparent film used to form an occlusion is Tegaderm.

[0139] In some embodiments, the composition is impregnated in the tape, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap or hair cover, or film. In some embodiments, the tape, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap or hair cover, or film is a foam-containing tape or film. In some instances, pores or interstitial spaces in the foam can be loaded with the composition as described herein. The foam can have an adhesive layer for adhering the foam to skin. In some instances, if the foam is porous, an outer non-porous layer can be provided on the back of the foam to enhance tape occlusion.

[0140] In some embodiments, the composition may be a form of a slow-release wafer or dot, may also be made by using a porous foam, may have a quantity of the composition placed behind the porous foam, and may have a non-porous backing layer placed behind the composition. In some instances, the non-porous backing layer can have a portion extending beyond the composition containing Compound 1 and the porous layer. In some embodiments, this portion can include, but not limit to, a quantity of adhesive for facilitating adhesion of the wafer or dot to the skin of a user peripheral to the skin being treated.

[0141] In some instances, the composition for application may be covered by a film or thermosensitive gel material. In some instances, the film or thermosensitive gel material may be impregnated with the composition.

[0142] In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition is a topical composition. In some embodiments, the composition is in the form of a gel, ointment, lotion, foam, spray, or emollient. In some embodiments, theAttorney Docket No.: 62826-725.601 composition is a component of a patch, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap, hair cover, tape, film, wafer, or bandage.

[0143] In some instances, the composition is present in a kit comprising the composition in a tube. In some embodiments, the composition is present in a kit comprising the composition in a tube, with instructions for use.

[0144] The compositions of this disclosure can be administered with other agents in a combination therapy mode for the treatment or prevention of a sign of aging of the skin as described above. METHODS

[0145] In certain aspects, the present disclosure provides a method of treating or preventing a sign of aging in the skin in a subject in need thereof, the method comprising administering to the subject a composition, as described herein.

[0146] In certain aspects, the composition described herein provides a method by which Akt activity is inhibited by modulators of Akt activity. In some embodiments the modulators target Akt or Akt regulators. The compounds, or salt thereof, represented by Formula (I), Formula (I- A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), and / or Formula (III), may be modulators of Akt activity. In some embodiments, the compound, or salt thereof, may be Compound 1 in a 1H tautomer form and / or a 2H tautomer form, a salt thereof, or a mixture thereof. In some embodiments, Compound 1 may modulate Akt activity. In some embodiments, Compound 1 may have modulator effects on AKT activity.

[0147] In some instances, a compound with the structure of Formula (III) as described herein may have modular effects on AKT activity. In some embodiments, the composition and compound, or salt thereof, described herein targets, inhibits, or modulates kinases. In some instances, the kinase is Akt.

[0148] In some embodiments, the inhibition or modulation of the target kinase or kinase pathway by the composition or compound, or salt thereof, described herein is useful for treating or preventing a sign of aging of the skin as described above.

[0149] In one aspect, the present disclosure provides a method of treating or preventing a sign of aging of the skin, the method comprising topically administering to the skin a composition comprising: a compound, or salt thereof, of Formula (I),Attorney Docket No.: 62826-725.601wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R2is an optionally substituted C6-12aryl or optionally substituted 3- to 12- membered heteroaryl; and n is 0 to 5, Formula (I-A) or (I-B),wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R4is hydrogen or C1-6alkyl; and n is 0 to 5; Formula (I-AA) or Formula (I-BB),Attorney Docket No.: 62826-725.601Formula (I-BB),Formula (II):wherein RAis C1-20alkyl, and / or Formula (III)wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is about 0.1% to about 1%.

[0150] In some embodiments, a sign of aging of the skin, as described herein, is present on the skin of a human subject. In some embodiments, a sign of aging is present on the skin of the face, trunk, or an extremity, or a combination thereof, of the human subject. In some embodiments, a sign of aging is present on the skin of the arms, legs, hands, feet, digits, neck, decolletage, chest, neck, shoulders, scalp, eyelids, ears, or any combination of two or more thereof, of the human subject. In some embodiments, In some embodiments, the sign of aging is present on the head, scalp, face, ear(s), decolletage, shoulders, eyelids, digits, neck, chest, back,Attorney Docket No.: 62826-725.601 inframammary region(s), arm(s), leg(s), intertriginous zone(s), hand(s), foot or feet, groin, or any combination of two or more thereof, on a human subject.

[0151] In some embodiments, the sign of aging of the skin comprises fine lines, wrinkles, skin dullness, hyperpigmentation, skin sagging, scars, lesions, lentigos, ephelides, striae, stretch marks, uneven skin tone, uneven skin texture, dehydrated skin, or other age-related skin imperfections, or any combination of two or more thereof. In some embodiments, the sign of aging of the skin comprises fine lines, wrinkles, skin dullness, hyperpigmentation, photoinduced hyperpigmentation, UV induced hyperpigmentation, skin sagging, scars, lesions, lentigos, ephelides, striae, stretch marks, uneven skin tone, uneven skin texture, dehydrated skin, or other age-related skin imperfections, or any combination of two or more thereof. In some embodiments, treating comprises reducing fine lines, wrinkles, deep rhytids, uneven skin texture, uneven skin tone, dull skin, skin sagging, dehydration of the skin, hyperpigmentation of the skin, lentigos, ephelides, scars, striae, or stretch marks, or any combination of two or more thereof.

[0152] In some embodiments, the sign of aging of the skin is caused by UV exposure, pollution exposure, smoking, a nutrition deficiency, stress, hormonal changes, repeated and / or sustained facial movements, or any combination of two or more thereof. In some embodiments, hyperpigmentation is photoinduced hyperpigmentation, UV induced hyperpigmentation, or any combination of two of more thereof. In some embodiments, the hyperpigmentation is photoinduced hyperpigmentation. In some embodiments, the hyperpigmentation is UV induced hyperpigmentation. In some embodiments, the hyperpigmentation of the skin may be photoinduced hyperpigmentation. In some embodiments, the hyperpigmentation of the skin may be UV induced hyperpigmentation.

[0153] In some embodiments, the lentigos comprise sunspots, age spots, liver spots, or freckles, or any combination of two or more thereof. In some embodiments, the lentigos may be sunspots, age spots, liver spots, or freckles, or any combination of two or more thereof. In some embodiments, the scars comprise a mark left by a healed wound, sore, blemish, or burn. In some embodiments, the scars may be a mark left by a healed wound, sore, blemish, or burn. In some embodiments, treating comprises causing the skin texture, skin tone, skin brightness, skin suppleness, skin tightness, skin wrinkling, or any combination of two or more thereof, to become more uniform. In some embodiments, treating comprises causing the moisture content of the skin, water retention of the skin, elastin production of the skin, skin volume, collagen production of the skin, or skin elasticity, or any combination of two or more thereof, to be increased.Attorney Docket No.: 62826-725.601

[0154] In some embodiments, topically administering the composition reduces or prevents the sign of the aging of the skin. In some embodiments, the treating or preventing the sign of aging of the skin comprises improving skin texture. In some embodiments, the skin texture comprises skin smoothness, skin suppleness, or both. In some embodiments, the treating or preventing the sign of aging of the skin comprises decreasing in rhytids. In some embodiments, the rhytids comprise fine lines, wrinkles, or both. In some embodiments, the treating or preventing the sign of aging of the skin comprises decreasing follicular prominence. In some embodiments, the treating or preventing the sign of aging of the skin comprises improving skin tone. In some embodiments, the skin tone comprises color evenness. In some embodiments, the treating or preventing the sign of aging of the skin comprises decreasing evidence of photodamage. In some embodiments, the evidence of photodamage comprises dyschromia, blotchy pigmentation, or both.

[0155] In some instances, the treating or preventing the sign of aging of the skin comprises improving skin texture (e.g., smooth, more supple), decreasing in rhytids (e.g., fine lines and wrinkles), decreasing follicular prominence, improving skin tone (e.g., color evenness), decreasing evidence of photodamage (e.g., dyschromia, blotchy pigmentation), or combination thereof. In some embodiments, the treating or preventing the sign of aging of the skin comprises decreasing evidence of photodamage (e.g., dyschromia, blotchy pigmentation).

[0156] In some embodiments, topical administration is useful for preventing a sign of aging. In some embodiments, preventing comprises reducing the number of instances in which a sign of aging, as described above, develops, and / or stopping the development of a sign of aging before they occur.

[0157] In one aspect, the present disclosure provides a method of treating or preventing a sign of aging of the skin in a subject in need thereof, comprising administering to the subject the composition described herein. In some embodiments, the treating or preventing the sign of aging of the skin comprises improving skin texture, skin tone, skin brightness, skin suppleness, skin tightness, skin wrinkling, moisture content of the skin, water retention of the skin, elastin production of the skin, skin volume, collagen production of the skin, or skin elasticity, or any combination of two or more thereof. In some embodiments, the treating or preventing the sign of aging comprises reducing or preventing fine lines and wrinkles. In some embodiments, the treating or preventing the sign of aging comprises causing the texture of the skin to become more uniform. In some embodiments, the treating or preventing the sign of aging comprises causing the skin tone to become uniform or more uniform than a reference skin tone. In some embodiments, the treating or preventing the sign of aging comprises increasing skin brightnessAttorney Docket No.: 62826-725.601 or reducing the dullness of the skin. In some embodiments, the treating or preventing the sign of aging comprises reducing or preventing hyperpigmentation of the skin. In some embodiments, the treating or preventing the sign of aging comprises reducing or preventing striae and stretch marks. In some embodiments, the treating or preventing the sign of aging comprises reducing or preventing deep rhytids.

[0158] In some embodiments, the treating or preventing the sign of aging comprises increasing the moisture content or water retention of the skin.

[0159] In some embodiments, the treating or preventing the sign of aging comprises stimulating the collagen production of the skin. In some embodiments, the stimulating the collagen production increases the volume of the skin. In some embodiments, the treating or preventing the sign of aging comprises increasing the volume of the skin. In some embodiments, the treating or preventing the sign of aging comprises stimulating the elastin production of the skin. In some embodiments, the stimulating the elastin production of the skin increases skin elasticity. In some embodiments, the treating or preventing the sign of aging comprises reducing skin sagging.

[0160] In some embodiments, the treating or preventing the sign of aging comprises lightening the skin. In some embodiments, the treating or preventing the sign of aging comprises lightening of the lentigos on the skin. In some embodiments, the treating or preventing the sign of aging comprises reducing or preventing scars or lesions.

[0161] In some embodiments, the topically administering to the skin the composition comprises topically administering the composition to the head, scalp, face, ear(s), decolletage, shoulders, eyelids, digits, neck, chest, back, inframammary region(s), arm(s), leg(s), intertriginous zone(s), hand(s), foot or feet, groin, or any combination of two or more thereof, on a human subject. In some embodiments, the composition is applied topically to the head, scalp, face, ear(s), decolletage, shoulders, eyelids, neck, chest, back, inframammary region(s), arm(s), leg(s), intertriginous zone(s), hand(s), foot or feet, or groin. In some embodiments, the composition is applied topically to the arms, legs, hands, feet, digits, neck, decolletage, eyelids, or any combination of two or more thereof.

[0162] In some embodiments, the composition is administered one time per day, two times per day, three times per day, or four times per day. In some embodiments, the composition is administered at least one time per day, at least two times per day, at least three times per day, or at least four times per day. In some embodiments, the composition is administered at most oneAttorney Docket No.: 62826-725.601 time per day, at most two times per day, at most three times per day, or at most four times per day. In some embodiments, the composition is administered twice daily.

[0163] In some embodiments, the composition is topically applied for about or at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In some embodiments, the composition is administered for about 1 week to about 10 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 7 weeks, about 2 weeks to about 6 weeks, about 2 weeks to about 5 weeks, or about 2 weeks to about 4 weeks. In some embodiments, the composition is administered for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks.

[0164] In some embodiments, the composition is topically applied two times daily for about or at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In some embodiments, the composition is topically applied two times daily for about 1 week to about 10 weeks, about 2 weeks to about 8 weeks, about 2 weeks to about 7 weeks, about 2 weeks to about 6 weeks, about 2 weeks to about 5 weeks, or about 2 weeks to about 4 weeks. the composition is topically applied two times daily for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks.

[0165] In some embodiments, the composition is administered in a pulsed cycle. In some embodiments, the composition is administered under occlusion.

[0166] In some embodiments, the composition described herein is administered to a face of the subject. In some embodiments, the composition described herein is administered to the body of the subject. In some embodiments, the composition described herein is administered topically to the head, scalp, face, ears, decolletage, shoulders, or eyelids, neck, chest, back, inframammary regions, arms, legs, groin intertriginous regions, hands, and / or feet. In some embodiments, the composition covers (e.g., occludes) the skin associated with a sign of aging.

[0167] In some embodiments, the composition described herein is administered to a face of the subject, thereby treating, or preventing a sign of aging of the skin. In some embodiments, the composition described herein is administered to the body of the subject, thereby treating, or preventing a sign of aging of the skin. In some embodiments, the composition described herein is administered topically to one or more areas selected from head, scalp, face, ears, decolletage,Attorney Docket No.: 62826-725.601 shoulders, eyelids, neck, chest, back, inframammary regions, arms, legs, groin, intertriginous regions, hands, and / or feet thereby treating a sign of aging of the skin in any one of these areas.

[0168] In some embodiments, a sign of aging to be reduced, ameliorated, treated, or prevented is fine lines, wrinkles, deep rhytids, uneven skin texture, uneven skin tone, dull skin, skin sagging, dehydration of the skin, hyperpigmentation of the skin, lentigos, ephelides, scars, striae, or stretch marks, or any combination of two or more thereof. In some instances, the hyperpigmentation of the skin may be photoinduced hyperpigmentation. In some instances, the hyperpigmentation of the skin may be UV induced hyperpigmentation. In some instances, the lentigos may be sunspots, age spots, liver spots, or freckles, or any combination of two or more thereof. In some instances, the scars may be a mark left by a healed wound, sore, blemish, or burn.

[0169] In some embodiments, a sign of aging is treated by causing the skin texture, skin tone, skin brightness, skin suppleness, skin tightness, skin wrinkling, or any combination of two or more thereof, to become more uniform. In some embodiments, treating a sign of aging comprises increasing the moisture content of the skin, water retention of the skin, elastin production of the skin, skin volume, collagen production of the skin, or skin elasticity, or any combination of two or more thereof.

[0170] In some embodiments, the composition administered is in the form of a gel, ointment, lotion, foam, spray, aerosol, cream, suspension, or emollient.

[0171] In some embodiments, the composition administered is a component of a patch, tape, film, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap, hair cover, wafer, or bandage. In some embodiments, the patch, tape, film, mask, roller, bar, glove, mitten, sock, wrap, paper, shower cap, hair cover, wafer, or bandage further comprises an adhesive.

[0172] In some embodiments, the subject in need thereof is a human. In some instances, after the administration of the composition described herein, the subject has following outcomes comprising improved skin texture (e.g., smooth, more supple), decrease in rhytids (e.g., fine lines and wrinkles), decrease follicular prominence, improved skin tone (e.g., color evenness), decrease evidence of photodamage (e.g., dyschromia, blotchy pigmentation), or combinations thereof. KITS

[0173] Also provided are kits for use in methods of treatment or prevention of a sign of aging of the skin where the subject is in need thereof with the composition as described herein inAttorney Docket No.: 62826-725.601 a tube, e.g., a flexible aluminum tube or laminated plastic tube. IN some instances, the composition is present in a kit comprising the composition in a tube, with instructions for use. In some embodiments, the kits can include, but not limit to, a topical composition comprising the compound, or salt thereof, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating or preventing a sign of aging of the skin. In some instances, instructions may be provided in printed form or in the form of an electronic or digital medium such as a floppy disc, CD, or DVD, data storage device, flash drive, or in the form of a website address where such instructions may be obtained. In some instances, a unit dose of a compound, or salt thereof, or a topical composition provided herein, or a second agent or composition, can include, but not limit to, a dosage such that when administered to a subject, a therapeutically or prophylactically effective level of the compound, or salt thereof, or the topical composition can be maintained at the site of treatment in the subject for at least 1 day.

[0174] In another aspect, the present disclosure provides a kit comprising a topical pharmaceutical composition in a tube, e.g., flexible aluminum tube or laminated plastic tube, with instructions for use.

[0175] In some embodiments, suitable packaging is provided. As used herein, “packaging” includes, but is not limited to, a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound, or salt thereof, provided herein and / or a second agent suitable for administration to a subject. Such materials include, but are not limited to, glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents. EXAMPLES

[0176] These examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein. Example 1: Preparation of Compositions

[0177] Example topical compositions of the present disclosure comprise Compound 1, represented by the formula:Attorney Docket No.: 62826-725.601Composition Ex.1 – Compound 1, at a concentration of about 0.1% or about 1% by weight. Example 2: Potency Of Compound 1 On Modulation Of Akt Activity

[0178] In this example, assessment on modulation on Akt activity of Compound 1 was performed using an AssayQuant PhosphoSens assay.

[0179] Table 1 shows Compound 1’s increased potency in inhibiting AKT1 at a concentration of 1 mM in an AssayQuant PhosphoSens assay. Table 1. Potency of Compound 1.No time dependence was observed. Compound-dependent lag was observed, and preincubation progress curves had increased lags.

[0180] Additionally, in this example, assessment on modulation of Akt activity of a compound with the structure of Formula (III) was performed.

[0181] Table 2 shows a compound with the structure of Formula (III)’s moderate potency in inhibiting AKT1 at a concentration of 1 mM in an AssayQuant PhosphoSens assay.Attorney Docket No.: 62826-725.601 Table 2. Potency of Compound with structure of Formula (III).

[0182] No time dependence was observed, and preincubation progress curves had increased lags. Example 3: Demonstration of Topical Applications for Treatment of A Sign of Aging of The Skin In Human

[0183] A first human subject having a sign of aging of the skin was treated with Composition Ex.1 – Compound 1, at 0.1% which was topically applied BID (twice a day) daily for 28 days. The human subject was followed for 98 days. Photographs of the area receiving treatment depicting the improvement of a sign of aging were taken on days 1, 8, 16, 24, 28, 35, 42, 56, 70, 84, and 98, and are shown in FIG.1A. The representative photographs demonstrate the local improvement of fine lines, wrinkles, skin texture, and skin tone of the skin of the human subject, and the areas of improvement of a sign of aging are further identified by arrows on FIG.1B. Example 4: Demonstration of Topical Applications for Treatment of A Sign of Aging of The Skin In Human

[0184] A second human subject having a sign of aging of the skin was treated with Composition Ex.1 – Compound 1, at 1% which was topically applied BID (twice a day) daily for 28 days. The human subject was followed for 84 days. Photographs of the area receiving treatment depicting the improvement of a sign of aging were taken on days 1, 8, 16, 24, 28, 35, 42, 56, 70, and 84, and are shown in FIG.2A. The representative photographs demonstrate the local improvement of fine lines, wrinkles, skin texture, and skin tone of the skin of the human subject, and the areas of improvement of a sign of aging are further identified by arrows and oval markings on FIG.2B. Example 5: Demonstration of Topical Applications for Treatment of A sign of Aging of The Skin In HumanAttorney Docket No.: 62826-725.601

[0185] A third human subject having a sign of aging of the skin was treated with Composition Ex.1 – Compound 1, at 1% which was topically applied BID (twice a day) daily for 28 days. The human subject was followed for 98 days. Photographs of the area receiving treatment depicting the improvement of a sign of aging were taken on days 1, 8, 16, 24, 28, 35, 42, 56, 70, 84, and 98 and are shown in FIG.3A. The representative photographs demonstrate the local improvement of deep rhytid, skin texture, and skin tone of the skin of the human subject, and the areas of improvement of a sign of aging are further identified by arrows and oval markings on FIG.3B. Example 6: Demonstration of Topical Applications for Treatment of A sign of Aging of The Skin In Human

[0186] A fourth human subject having a sign of aging of the skin was treated with Composition Ex.1 – Compound 1, at 1% which was topically applied BID (twice a day) daily for 28 days. The human subject was followed for 98 days. Photographs of the area receiving treatment depicting the improvement of a sign of aging were taken on days 1, 8, 16, 24, 28, 35, 42, 56, 70, 84, and 98 and are shown in FIG.4A. The representative photographs demonstrate the local improvement of fine lines, wrinkles, and skin tone of the skin of the human subject, and the areas of improvement of a sign of aging are further identified by arrows and oval markings on FIG.4B. Example 7: Demonstration of Topical Applications for Treatment of A Sign of Aging of The Skin In Human

[0187] A fifth human subject having a sign of aging of the skin was treated with Composition Ex.1 – Compound 1, at 1% which was topically applied BID (twice a day) daily for 28 days. The human subject was followed for 98 days. Photographs of the area receiving treatment depicting the improvement of a sign of aging were taken on days 1, 8, 16, 24, 28, 35, 42, 56, 70, 84, and 98 and are shown in FIG.5A. The representative photographs demonstrate the local improvement of lentigos, age spots, deep rhytid, skin texture, and skin tone of the skin of the human subject, and the areas of improvement of a sign of aging are further identified by arrows and oval markings on FIG.5B. Example 8: Assessment of Cellular Stress, Formation of Reactive Oxygen Species and DNA Damage Summary

[0188] Cellular responses to oxidative stress, DNA damage, Ultraviolet (UV) light or reactive oxygen species (ROS) can be measured in vitro. The assays described below areAttorney Docket No.: 62826-725.601 performed in vitro using skin cell lines primary human epidermal keratinocytes, primary dermal fibroblasts, or normal human melanocytes. These assays test the ability of a kinase inhibitor to reduce the impact of UV exposure or oxidative stress that contributes to a sign of aging. DCFH-DA (2',7'-Dichlorofluorescin Diacetate) Assay

[0189] Principle: DCFH-DA is a non-fluorescent dye that permeates into cells, undergoing cleavage by cellular esterases to form DCFH. In the presence of reactive oxygen species (ROS), DCFH is oxidized, yielding the fluorescent compound DCF. The resulting fluorescence intensity is directly proportional to intracellular ROS levels and can be measured by a fluorescent plate reader.

[0190] Application: This assay is employed to measure oxidative stress in human epidermal keratinocytes and dermal fibroblasts. Cells treated with and without the claimed composition comprising Compound 1 can be exposed to UV radiation, and the subsequent increase in ROS levels can be quantified by assessing the fluorescence intensity of the oxidized DCF.

[0191] Positive Control: Hydrogen peroxide (H2O2). Comet Assay (Single Cell Gel Electrophoresis)

[0192] Principle: Cells embedded in agarose on a microscope slide are subjected to electrophoresis, causing DNA fragments with broken ends to migrate away from the nucleus, forming a comet-like tail. The length and intensity of the tail correlate with the extent of DNA damage, providing a visual and quantitative assessment.

[0193] Application: This assay is utilized to evaluate DNA damage in human epidermal keratinocytes and dermal fibroblasts. Cells treated with and without the claimed composition comprising Compound 1 can be exposed to UV radiation, and the resulting DNA damage is visualized and quantified through comet tail analysis.

[0194] Positive Control: Exposure to a known DNA-damaging agent, such as hydrogen peroxide or ionizing radiation. Glutathione Assay

[0195] Principle: Glutathione (GSH), a tripeptide antioxidant, reacts with a thiol-reactive compound to produce a colored product. The color intensity is proportional to the amount of intracellular GSH, providing a measure of cellular oxidative stress.

[0196] Application: This assay is applied to assess changes in cellular oxidative stress in human epidermal keratinocytes and dermal fibroblasts. Cells treated with and without theAttorney Docket No.: 62826-725.601 claimed composition comprising Compound 1 can be exposed to UV radiation, and alterations in glutathione levels are quantified by measuring the change in color intensity using the optical density on a plate reader.

[0197] Positive Control: Depletion of glutathione levels using a thiol-reactive compound, such as buthionine sulfoximine (BSO). Superoxide Dismutase (SOD) Activity Assay

[0198] Principle: Superoxide dismutase catalyzes the dismutation of superoxide radicals (O2-) to hydrogen peroxide (H2O2) and oxygen. The assay involves inhibiting a tetrazolium salt reduction by superoxide, and the degree of inhibition reflects SOD activity. Absorbance or fluorescence is then measured.

[0199] Application: This assay is utilized to evaluate SOD activity in human epidermal keratinocytes and dermal fibroblasts. Cells treated with and without the claimed composition comprising Compound 1 can be exposed to UV radiation, and the impact on SOD enzymatic activity is then quantified on a plate reader.

[0200] Positive Control: Addition of a known SOD inhibitor, such as diethyldithiocarbamate (DDC). Cytokine / Inflammatory Marker Analysis

[0201] Principle: UV radiation induces an inflammatory response, leading to the release of cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Enzyme-linked immunosorbent assays (ELISA) or other immunoassay methods are used to quantify the levels of these cytokines, providing insight into the inflammatory status of the cells. Increase in mRNA expression levels of IL-6 and TNF-α can also be measured using quantitative PCR.

[0202] Application: This assay is employed to assess the inflammatory response in human epidermal keratinocytes and dermal fibroblasts. Cells treated with and without the claimed composition comprising Compound 1 can be exposed to UV radiation, and the resulting cytokine release is quantified through immunoassay techniques.

[0203] Positive Control: Stimulation of cells with a pro-inflammatory agent like lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-α) serves as a positive control increasing TNF-α expression. p53 Activation AssayAttorney Docket No.: 62826-725.601

[0204] Principle: p53 is a tumor suppressor protein that plays a crucial role in responding to DNA damage and cellular stress. In response to such stress, p53 undergoes post-translational modifications, leading to its activation. Activated p53 acts as a transcription factor, regulating the expression of genes involved in cell cycle arrest, DNA repair, and apoptosis. Therefore, the activation of p53 can be indicative of cellular stress, including damage induced by UV radiation.

[0205] Application: The activation of p53 in skin cells treated with and without the claimed composition comprising Compound 1 (or a kinase inhibitor of interest) and exposed to UV radiation can be assessed using immunofluorescence or Western blotting. Immunofluorescence allows visualization of the cellular localization and intensity of activated p53, while Western blotting provides quantitative information about the levels of activated p53.

[0206] Positive Control: Exposure of cells to a known DNA-damaging agent, such as UV radiation or a genotoxic compound, or treatment with a well-established p53 activator, like doxorubicin or etoposide. Example 9: Assessment of Collagen Production

[0207] Compositions provided herein, such as a composition comprising compound 1, can be assessed for ability to stimulate collagen production by culturing primary normal human dermal fibroblasts in vitro with and without specific growth factors and with and without the compositions provided herein, such as a composition comprising compound 1. The collagen produced in the cells, the cell culture supernatant, and the lysates can be quantified using the methods described herein. Sircol Collagen Assay

[0208] The Sircol Collagen Assay is a colorimetric assay that is based on the specific binding of the dye Sirius Red to the triple helical structure of collagen. The absorbance of Sirius Red dye that is bound to collagen can be measured at a specific wavelength. Enzyme-Linked Immunosorbent Assay (ELISA) for Procollagen Peptides

[0209] Commercial ELISA kits are available for procollagen types (e.g., type I procollagen) using specific antibodies to detect and quantify procollagen peptides from fibroblast cell lysates. Western Blotting for collagen proteins

[0210] Proteins that are both (i) extracted from cells and (ii) collected from cell culture supernatants, are separated by gel electrophoresis, transferred to a membrane, and probed with antibodies specific to collagen proteins.Attorney Docket No.: 62826-725.601 Real-Time Polymerase Chain Reaction (RT-PCR) for Collagen mRNA

[0211] RNA is extracted from cells, converted to cDNA, and then amplified using primers specific to collagen genes. Real-time PCR allows for quantification of gene expression levels. Immunofluorescence Staining for Collagen

[0212] Cells are cultured on treated histology slides and are then fixed and permeabilized. Specific antibodies against collagen proteins, including procollagen, are then be applied. Fluorescently labeled secondary antibodies are used for visualization. Example 10: Full Thickness Skin Wrinkle Assay

[0213] Wrinkles represent a characteristic symptom of skin aging, and a 3D tissue engineering assay has been developed to mimic full thickness wrinkles. Wrinkle reduction can be measured using 2D and 3D Swept Source-Optical Coherence Tomography (SS-OCT) imaging.

[0214] Materials and methods: Full-thickness (FT) skin wrinkle mimics with various widths and depths are fabricated using a collagen stamping method. These are analyzed and compared using 2D and 3D Swept Source-Optical Coherence Tomography (SS-OCT) imaging. Human neonatal dermal fibroblasts (HDFn) and human neonatal epidermal keratinocytes (HEKn) are used in this assay. First a dermis is cultured on a collagen mold followed by the seeding and growing of an epidermis on the dermis. The mold, or stamp, is then removed leaving wrinkle mimics. The wrinkle mimics are then treated with Composition Ex.1 – Compound 1, at 1% BID daily for 28 days and other treatment regimens.

[0215] Results: Superficial and cross-sectional images of the wrinkle mimics are taken, and the size of the wrinkles are measured using SS-OCT imaging. The skin wrinkles are measured for depth and width after treatment with Composition Ex.1 – Compound 1 at 1%. Example 11: Assessment of Skin Color, Melanin Production, Melanocyte and Tissue Morphology Tissue Test Procedure

[0216] The effects of compounds on skin color, melanin production, melanocyte morphology and tissue morphology and viability are assessed using MelanoDerm tissue (MEL- 300-B) by MatTek Corporation (MatTek), Ashland, MA. MelanoDerm tissue is an epidermal equivalent system that consists of normal, human-derived epidermal keratinocytes (NHEK) and melanocytes (NHM) which have been cultured to form a multilayered, highly differentiated model of the human epidermis. The NHM within co-cultures undergo spontaneousAttorney Docket No.: 62826-725.601 melanogenesis leading to tissue pigmentation. The MEL-300-B system contains melanocytes derived from a black donor.

[0217] On Day zero of the study, prior to exposure to any composition provided herein, such as a composition comprising compound 1, MelanoDerm tissue samples are placed into wells on plates containing maintenance medium that is pre-warmed to about 370C (Long life maintenance medium, EPI-100- LLMM). All medium, reagents and MEL-300-B tissues are supplied by MatTek. The MelanoDerm tissue samples are then incubated for about an hour in a humidified incubator maintained at a temperature of about 370C in an atmosphere of about 5% CO2. Following incubation, the maintenance medium is removed by aspiration. A cell culture stand is placed in each well on the plate containing a MelanoDerm tissue sample. About 5 mL of fresh maintenance medium pre-warmed to about 370C is added to each well having a MelanoDerm tissue sample. Then a cell culture insert is placed on top of each cell culture stand.25 μL portions of each of composition provided herein, negative control (DI H2O), and positive control (2% kojic acid, KA) are applied by pipette to six separate MelanoDerm tissue samples for each composition provided herein, such as a composition comprising compound 1, being tested (e.g., a composition comprising compound 1, is applied topically to six tissue samples in six different wells).25 μL portions of each of the compositions provided herein, such as a composition comprising compound 1, and controls are also applied to the same MelanoDerm tissue samples on Days, 0, 5, 9, and 14 of the study for each sample remaining (some samples will be used for testing). Throughout the study, the maintenance medium is changed every two days to maintain the MelanoDerm tissue samples.

[0218] On each of Days 0, 5, 9, and 14, one tissue sample for each composition provided herein, such as a composition comprising compound 1, and control is fixed with formalin, photographed to document macroscopic darkening, microscopically observed to examine melanocyte morphology, and is processed for histology and macroscopic analysis. On Days 0, 9 and 14, two tissue samples for each composition provided herein, such as a composition comprising compound 1, and control are frozen and later assayed for melanin content.

[0219] As part of standard quality control (QC) procedures, random tissues from the study tissue lot are used to determine tissue viability and confirm tissue pigmentation. To determine viability, n=3 tissues are treated with 100 uL of 1.0% Triton X-100. An exposure time of 5.0 hours is used. N=3 tissues treated with water for 5 hours are used as negative control. Tissue are assessed for viability using alarmarBlue. Results from the Triton X-100 and water treated controls are used to determine whether the produced tissue lot is valid to perform the intended study. To ensure progressive pigmentation while in culture, n=1 tissue is cultured in EPI-100-Attorney Docket No.: 62826-725.601 NMM-113 media for -1, 5, 9 and 14 days. On day -1, 5, 9 and 14 tissues are harvested and macroscopically photographed. Melanin Assay

[0220] To assay the tissues for melanin content, the frozen tissues are thawed and placed in Dulbecco's phosphate buffered saline (D-PBS) to remove excess phenol red from the maintenance medium. The tissues are removed from the D-PBS and each tissue is blotted dry and placed in a separate 1.7 ml microfuge tube. To each microfuge tube 250 μl of a tissue and gel solubilizer are added (Solvable™, 0.5 M— Packard BioScience Co. Catalogue No.6NE9 100 (NEF910)). Dilutions for creating a standard curve are also prepared containing from 0 - 250 μg of melanin (Sigma cat. M 8631) in a total of 250 μl Solvable™. The tissues are incubated in their tubes overnight at 60 °C along with the dilutions. The tissue samples are vortexed. Then the tissue samples are centrifuged at 13,000 rpm for 5 minutes to pellet. The supernatant from the tissue samples are collected.250 μl of the supernatant from each tissue sample as well as the dilutions are added to separate wells of a 96-microwell plate. The plate is read on a plate reader at 490 nM. The optical densities of the dilutions are used to prepare a standard curve against which the optical densities of the tissue sample supernatants are compared to determine the melanin content of the tissue samples. Melanin assay results at Days 0, 9 and 14 are assessed and plotted compared to negative and positive control. Skin Lightening Assessment

[0221] The fixed tissues from Days 0, 5, 9, and 14 are observed macroscopically. Comparing the tissues over time shows that the tissues darken progressively with increased time in culture. At Days 5, 9, and 10 the positive control (2% Kojac Acid) treated tissues are evaluated via chroma metric analysis to verify that they are lighter than the negative control (water). The compositions provided herein, such as a composition comprising compound 1, are also evaluated for a lightening effect compared with the negative control at all time points. Macroscopic and microscopic digital photographs are taken for assessment. Example 12. Study of the safety and efficacy on subjects with Seborrheic Keratosis Target Lesion

[0222] Seborrheic Keratosis (SKs) are benign skin tumors that develop as individuals age. They are non-cancerous tumors but can be a nuisance or cosmetically undesirable. In this example, safety and efficacy of Composition Ex.1 – Compound 1 are determined.

[0223] Briefly, human subjects with a lesion suspected of being a Seborrheic Keratosis (eligible Seborrheic Keratosis Target Lesion or “SKTL”) are treated with Composition Ex.1 –Attorney Docket No.: 62826-725.601 Compound 1, at 1.0% which is topically applied BID (twice a day) daily for 28 days. A control group (vehicle group) is treated with a similar composition that does not contain Compound 1. Composition Ex.1 – Compound 1 and the similar composition are formulated as a gel. Subjects are followed for another 12-weeks after final application. The efficacy endpoints are used to compare the twice daily application of Composition Ex.1 – Compound 1, 1.0% gel to a vehicle gel (e.g., the similar composition).

[0224] Physician’s Lesion Assessment (PLA), which indicates the lesion severity of an SK based on the presence of the SK and the thickness of the SK lesion, is used to evaluate the SKTL of the human subjects. The PLA are determined for each SKTL at each clinic study visit of the human subjects. Table 3 below shows the PLA scale used to evaluate the SKTL. Table 3. Physician’s Lesion Assessment Scale:

[0225] Subjects also perform self-reported assessments of SK lesion severity based on (1) the presence of an SK lesion, and (2) the thickness and coloration of the SK lesion using a Subject's Self-Assessment (SSA) Scale, as depicted in Table 4. Table 4. Subject's Self-Assessment (SSA) Scale.

[0226] For safety evaluation, Application Site Reactions (ASRs) are evaluated through assessment of the severity of the signs and symptoms including pain, burning, stinging, pruritus, erythema, edema, exudation, erosion / ulceration, hyperpigmentation, and hypopigmentation at each SKTL treatment site since the human subject’s last visit, and adverse events (AEs) are additionally reviewed. In addition, the following safety evaluations are performed with respectAttorney Docket No.: 62826-725.601 to the following aspects of the human subjects: vital signs, complete blood count (CBC), comprehensive chemistry panel (Chem panel), and urine pregnancy test for female subjects of childbearing potential.

[0227] In addition to investigation of safety and efficacy on SKTL, efficacy of Composition Ex.1 – Compound 1 on treating or preventing a sign of aging of skin is also determined on the lesion and nearby area. Changes on skin texture (e.g., smoothness, elasticity), rhytids (e.g., lines, wrinkles), follicular prominence, skin tone (e.g., color evenness), and / or evidence of photodamage (e.g., dyschromia, blotchy pigmentation) are evaluated before, during, and after the application. Example 13. Study Of Safety And Efficacy On Inframammary Cohort

[0228] In this example, safety and efficacy of Composition Ex.1 – Compound 1 are determined for human subjects of an inframammary cohort.

[0229] Briefly, human subjects with inframammary SKTLs are treated with Composition Ex.1 – Compound 1, at 1.0% which is topically applied BID (twice a day) daily for 28 days. A control group (vehicle group) is treated with a similar composition that does not contain Compound 1. Composition Ex.1 and the similar composition are formulated as a gel. The human subjects are then followed for another 12-weeks after final application.

[0230] Similar procedures as described in Example 12 are performed. Additionally, efficacy of Composition Ex.1 – Compound 1 on treating or preventing a sign of aging of skin on the human subjects of the inframammary cohort is determined. Changes in skin texture (e.g., smoothness, elasticity), rhytids (e.g., lines, wrinkles), follicular prominence, skin tone (e.g., color evenness), and / or evidence of photodamage (e.g., dyschromia, blotchy pigmentation) are evaluated before, during, and after the application.

[0231] While preferred aspects of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the aspects of the disclosure described herein may be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

Attorney Docket No.: 62826-725.601 CLAIMS What is claimed is:

1. A method of treating or preventing a sign of aging of skin, the method comprising topically administering to the skin a composition comprising: one or more compounds, or salts thereof, having a structure of:wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R2is an optionally substituted C6-12 aryl or optionally substituted 3- to 12- membered heteroaryl; and n is 0 to 5.

2. The method of claim 1, wherein the one or more compounds, or salts thereof, comprises: a first compound, or salt thereof, having a first structure of Formula (I-A),a second compound, or salt thereof, having a second structure of Formula (I-B):wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy;Attorney Docket No.: 62826-725.601 R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R4is hydrogen or C1-6 alkyl; and n is 0 to 5.

3. The method of any one of claim 1 or claim 2, wherein R2is an optionally substituted 3- to 12- membered heteroaryl.

4. The method of any one of claims 1 to 3, wherein the one or more compounds, or salts thereof, comprises: a first compound, or salt thereof, having a first structure of Formula (I-AA):a second compound, or salt thereof, having a second structure of Formula (I-BB):thereof wherein: R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; and R4is hydrogen or C1-6 alkyl.

5. The method of any one of claims 1 to 4, wherein X is N.

6. The method of any one of claims 1 to 5, wherein n is 0.

7. The method of any one of claims 1 to 6, wherein the one or more compounds, or salts thereof, comprises: a first compound, or salt thereof, having a first structure of Formula (I-AA):a second compound, or salt thereof, having a second structure of Formula (I-BB):Attorney Docket No.: 62826-725.601 wherein: R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6 alkyl.

8. The method of any one of claims 1 to 7, wherein R3is C1-3alkyl.

9. The method of any one of claims 1 to 8, wherein R4is H.

10. The method of any one of claims 1 to 9, wherein the one or more compounds, or salts thereof, comprises: a first compound, or salt thereof, having a first structure of Compound 11H tautomer:(Compound 11H tautomer), and a second compound, or salt thereof, having a second structure of Compound 12H tautomer:(Compound 12H tautomer).

11. The method of any one of claims 1 to 10, wherein at least one of the one or more compounds, or salts thereof, is in a salt form.

12. The method of any one of the preceding claims, wherein the total amount of the one or more compounds or salts thereof is from about 0.1% to about 2.0% by weight.

13. The method of any one of the preceding claims, wherein the total amount of the one or more compounds or salt thereof is about 1.0% by weight.

14. The method of any one of the preceding claims, wherein the composition is in the form of a gel, ointment, lotion, foam, spray, aerosol, cream, suspension, or emollient.

15. The method of any one of the preceding claims, wherein the composition is a gel formulation.

16. The method of any one of the preceding claims, wherein the composition is a component of a patch, mask, roller, bar, glove, mitten, sock, wrap, brush, paper, shower cap, hair cover, tape, film, wafer, or bandage.Attorney Docket No.: 62826-725.601 17. The method of claim 16, wherein the patch, mask, roller, bar, glove, mitten, sock, wrap, brush, paper, shower cap, hair cover, tape, film, wafer, or bandage further comprises an adhesive.

18. The method of any one of the preceding claims, wherein the composition is present in a kit comprising the composition in a tube, with instructions for use.

19. The method of any one of claims 1-18, wherein the sign of aging of the skin comprises fine lines, wrinkles, skin dullness, hyperpigmentation, skin sagging, scars, lesions, lentigos, ephelides, striae, stretch marks, uneven skin tone, uneven skin texture, dehydrated skin, or other age-related skin imperfections, or any combination of two or more thereof.

20. The method of any one of claims 1-19, wherein the sign of aging of the skin is caused by ultraviolet (UV) exposure, pollution exposure, smoking, a nutrition deficiency, stress, hormonal changes, repeated and / or sustained facial movements, or any combination of two or more thereof.

21. The method of any one of claims 19-20, wherein the hyperpigmentation is photoinduced hyperpigmentation.

22. The method of any one of claims 19- 21, wherein the hyperpigmentation is UV induced hyperpigmentation.

23. The method of claim 19, wherein the lentigos comprise sunspots, age spots, liver spots, or freckles, or any combination of two or more thereof.

24. The method of claim 19, wherein the scars comprise a mark left by a healed wound, sore, blemish, or burn.

25. The method of any one of claims 1-24, wherein topically administering the composition to the skin reduces or prevents the sign of the aging of the skin.

26. The method of any one of claims 1-25, wherein the treating or preventing the sign of aging of the skin comprises improving skin texture, skin tone, skin brightness, skin suppleness, skin tightness, skin wrinkling, moisture content of the skin, water retention of the skin, elastin production of the skin, skin volume, collagen production of the skin, or skin elasticity, or any combination of two or more thereof.

27. The method of any one of claims 1-26, wherein the treating or preventing the sign of aging comprises reducing or preventing fine lines and wrinkles.

28. The method of any one of claims 1-27, wherein the treating or preventing the sign of aging comprises causing the texture of the skin to become more uniform.

29. The method of any one of claims 1-28, wherein the treating or preventing the sign of aging comprises causing the skin tone to become uniform or more uniform relative to a reference skin tone.Attorney Docket No.: 62826-725.601 30. The method of any one of claims 1-29, wherein the treating or preventing the sign of aging comprises increasing skin brightness or reducing the dullness of the skin.

31. The method of any one of claims 1-30, wherein the treating or preventing the sign of aging comprises reducing or preventing hyperpigmentation of the skin.

32. The method of any one of claims 1-31, wherein the treating or preventing the sign of aging comprises reducing or preventing striae and stretch marks.

33. The method of any one of claims 1-32, wherein the treating or preventing the sign of aging comprises reducing or preventing deep rhytids.

34. The method of any one of claims 1-33, wherein the treating or preventing the sign of aging comprises increasing the moisture content or water retention of the skin.

35. The method of any one of claims 1-34, wherein the treating or preventing the sign of aging comprises stimulating the collagen production of the skin.

36. The method of claim 35, wherein the stimulating the collagen production increases the volume of the skin.

37. The method of any one of claims 1-36, wherein the treating or preventing the sign of aging comprises increasing the volume of the skin.

38. The method of any one of claims 1-37, wherein the treating or preventing the sign of aging comprises stimulating the elastin production of the skin.

39. The method of claim 38, wherein the stimulating the elastin production of the skin increases skin elasticity.

40. The method of any one of claims 1-39, wherein the treating or preventing the sign of aging comprises reducing skin sagging.

41. The method of any one of claims 1-40, wherein the treating or preventing the sign of aging comprises lightening the skin.

42. The method of any one of claims 19-41, wherein the treating or preventing the sign of aging comprises lightening of the lentigos on the skin.

43. The method of any one of claims 1-42, wherein the treating or preventing the sign of aging comprises reducing or preventing scars or lesions.

44. The method of any one of claims 1-43, wherein the treating or preventing the sign of aging comprises improving skin texture, decreasing in rhytids, decreasing follicular prominence, improving skin tone, decreasing evidence of photodamage, or combination thereof.

45. The method of any one of claims 1-44, wherein the sign of aging is present on the head, scalp, face, ear(s), decolletage, shoulders, eyelids, digits, neck, chest, back, inframammary region(s), arm(s), leg(s), intertriginous zone(s), hand(s), foot or feet, groin, or any combination of two or more thereof, on a human subject.Attorney Docket No.: 62826-725.601 46. The method of any one of claims 1-45, wherein the topically administering to the skin the composition comprises topically administering the composition to the head, scalp, face, ear(s), decolletage, shoulders, eyelids, digits, neck, chest, back, inframammary region(s), arm(s), leg(s), intertriginous zone(s), hand(s), foot or feet, groin, or any combination of two or more thereof, on a human subject.

47. The method of any one of claims 1-46, wherein the composition is topically applied two times daily for at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks.

48. The method of any one of claims 1-46, wherein the composition is topically applied two times daily for at least 8 weeks.

49. The method of any one of claims 1-46, wherein the composition is topically applied two times daily for about 2 weeks to about 8 weeks.

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