Compositions and formulations for the prevention, treatment, and improvement of skin diseases, conditions, and disorders

Abstract

Provided here in is a method of treating, preventing, or reducing the progression of a skin cancer, the method comprising administering to the skin cancer a composition comprising an effective amount of a compound herein.

Description

Attorney Docket No.62826-719.601 COMPOSITIONS AND FORMULATIONS FOR THE PREVENTION, TREATMENT, AND IMPROVEMENT OF SKIN DISEASES, CONDITIONS, AND DISORDERS CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 480,940 filed on January 20, 2023, which is hereby incorporated by reference in its entirety. BACKGROUND

[0002] Non melanoma skin cancers, such as basal cell carcinoma and squamous cell carcinomas are the most common forms of skin cancer. Squamous cell carcinomas (SCC) are a form of skin cancer that occur with uncontrolled proliferation or growth of squamous skin cells. Basal cell carcinomas (BCC) are a form of skin cancer that occur when there is uncontrolled proliferation or growth of basal skin cells. BCCs have been estimated to impact 3.6 million people each year in the US. BCCs occur as a result of mutations, often from UV exposure, in the epidermis. BRIEF SUMMARY

[0003] As described herein, strategies for treating melanoma, SCCs, and BCCs include targeting pathways that regulate tumor growth and proliferation, such as inhibiting AKT and / or other pathways regulating tumor development in melanoma, SCCs, and BCCs. Compounds that can inhibit AKT and / or tumor growth and proliferation pathways described herein may be administered in a formulation that is not irritating to the skin.

[0004] In one aspect, the present disclosure provides a topical pharmaceutical composition. The topical pharmaceutical composition comprises a compound represented by Formula (I):wherein:Attorney Docket No.62826-719.601 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.

[0005] 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.

[0006] In some embodiments, the compound can be represented by Formula (I-A) or Formula (I-B):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 C1-6alkoxy;Attorney Docket No.62826-719.601 R4is hydrogen or C1-6 alkyl; and n is 0 to 5.

[0007] 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 C1-6 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.

[0008] 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.

[0009] In some embodiments, the compound can be represented by Formula (I-AA) or Formula (I-BB):wherein: R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6alkyl.

[0010] 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 C1-6 alkyl. In some embodiments, R3is methyl, ethyl, propyl, or butyl. In some embodiments, R3is methyl or ethyl. In some embodiments, R3is methyl.

[0011] In some embodiments, R4is hydrogen or C1-6 alkyl. In some embodiments, R4is hydrogen. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is C1-4 alkyl. InAttorney Docket No.62826-719.601 some embodiments, R4is methyl, ethyl, or propyl. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is methyl.

[0012] In any of the compositions as described herein, the compound can be represented by Formula (II):wherein RAis C1-20alkyl.

[0013] 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 C14-18 alkyl. In some embodiments, RAis C16 alkyl.

[0014] In any of the compositions as described herein, the compound can be represented by Formula (III):

[0015] In some embodiments, the composition comprises the structure:.

[0016] In some embodiments, compositions described herein may include the compound of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, and one or more excipients selected from (a)-(g): a) C2-6alcohol;Attorney Docket No.62826-719.601 b) an organic solvent and / or a penetration enhancer; c) an antioxidant; d) a preservative; e) water; f) a pH adjuster; and g) a gelling agent, wherein C2-6 alcohol, the organic solvent and / or a penetration enhancer, the antioxidant, the preservative, water, the pH adjuster, and the gelling agent are defined and described herein. In some embodiments, the composition may be formulated at about 0.01% to about 10%, compound of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III), or a salt thereof. In some embodiments, the composition may be formulated at about 0.01% to about 1.5%, compound of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III), or a salt thereof. In some embodiments, the composition may be formulated at about 0.01% to about 10%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. In some embodiments, the composition may be formulated at about 0.1% to about 1.5%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0017] In one aspect, the present disclosure provides a topical pharmaceutical composition, the 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 or tautomer thereof, and five or more excipients comprising ethanol, propylene glycol, 2-(2- ethoxyethoxy)ethanol, water, hydroxypropyl cellulose, optionally an antioxidant, and optionally a preservative, wherein the antioxidant and preservative are defined and described herein. In some embodiments, the composition may be formulated at about 0.01% to about 10% a compound having the structure of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III) or a salt thereof. In some embodiments, the composition may be formulated at about 0.01% to about 1.5%, compound of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III), or a salt thereof. In some embodiments, the composition may be formulated at about 0.01% to about 10%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. In some embodiments, the composition may be formulated at about 0.1% to about 1.5%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.Attorney Docket No.62826-719.601

[0018] In one aspect, the present disclosure provides a method of treating or preventing a skin disease, condition or disorder in a subject in need thereof, the method comprising administering to the subject a composition, as described herein. In some embodiments, the composition may be formulated at about 0.01% to about 10% of a compound having the structure of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III) or a salt thereof. In some embodiments, the composition may be formulated at about 0.01% to about 1.5%, compound of formula (I), (I-A), (I-B), (I-AA), (I-BB), (II), or (III), or a salt thereof. In some embodiments, the composition may be formulated at about 0.01% to about 10%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. In some embodiments, the composition may be formulated at about 0.1% to about 1.5%, Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. In some embodiments, the skin disease may comprise a cutaneous lesion. In some embodiments, the cutaneous lesion may be skin cancer. In some embodiments, the skin cancer may be a melanoma. In some embodiments, the skin cancer may be a basal cell carcinoma (BCC) or a squamous cell carcinoma (SCC). In some embodiments, the SCC may be an invasive SCC or an SCC in situ. In some embodiments, the SCC in situ may be Bowen’s disease.

[0019] 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. In one aspect, the present disclosure provides a method of treating or preventing a cutaneous lesion, the method comprising topically administering to the cutaneous lesion 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 present in the composition is 0.01% to 10%. In some embodiments, the compound present in the composition at about 0.01% to about 1.5%. In some embodiments, 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 0.01% to about 10%. In some embodiments, 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% to about 1.5%.

[0020] In some embodiments, the cutaneous lesion is a carcinoma. In some embodiments, the carcinoma is a basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). In someAttorney Docket No.62826-719.601 embodiments, the lesion is a melanoma. In some embodiments, the SCC may be an invasive SCC or an SCC in situ. In some embodiments, the SCC in situ may be Bowen’s disease.

[0021] In some embodiments, the skin condition treated or prevented is a melanoma.

[0022] In some embodiments, the method further comprises occluding the cutaneous lesion.

[0023] In some embodiments, the cutaneous lesion is present on a human subject. In some embodiments, the cutaneous lesion is present on the face, trunk, or an extremity, or a combination thereof, of the human subject.

[0024] In some embodiments, treating comprises reducing the thickness of the cutaneous lesion to less than 1 mm. In some embodiments, the thickness of the cutaneous lesion prior administering is greater than or equal to 1 mm. In some embodiments, the length of the cutaneous lesion prior to administering is from 1 mm to 15 mm, and the width of the cutaneous lesion prior to administering is from 1 mm to 15 mm.

[0025] In some embodiments, treating comprises inducing apoptosis of a keratinocyte or melanocyte in the cutaneous lesion.

[0026] In some embodiments, treating comprises amelioration, reduction, reducing the progression, partial resolution, full resolution of the cutaneous lesion.

[0027] In some embodiments, treating comprises prevention of a cutaneous lesion. In some embodiments, treating comprises prevention of a basal cell carcinoma, squamous cell carcinoma, and / or melanoma. In some embodiments, treating comprises reducing the progression of a basal cell carcinoma, squamous cell carcinoma, and / or melanoma.

[0028] In some embodiments, apoptosis is measured by TUNEL assay.

[0029] In some embodiments, the composition is a gel formulation. In some embodiments, the composition comprises an alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof.

[0030] 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 0.01% to 10%. In some embodiments, the total amount of the compound present in the composition is about 0.01% to about 1.5%. In some embodiments,Attorney Docket No.62826-719.601 the compound is Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0031] In some embodiments, the composition is a gel formulation. In some embodiments, the composition comprises an alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof. In some embodiments, the composition further comprises a preservative. In some embodiments, the composition further comprises a gelling agent.

[0032] 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 salt thereof; and one or more excipients selected from (a)-(e): a) alcohol; b) an organic solvent and / or a penetration enhancer; c) an antioxidant; d) a preservative; and e) a gelling agent. In some embodiments, the compound is Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0033] In any of the foregoing and forthcoming aspects and embodiments, the composition may comprise an alcohol, organic solvent and / or penetration enhancer, an antioxidant, a preservative, or a gelling agent, or a combination of two or more thereof. The composition may be administered in the methods described herein.

[0034] In some embodiments, the composition comprises the alcohol. In some embodiments, the alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2- butanol, or tert-butanol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, or a combination or two or more thereof. In some embodiments, the alcohol comprises a C2-6 alcohol. In some embodiments, the C2-6alcohol comprises ethanol, propanol, isopropanol, n- butanol, isobutanol, 2-butanol, or tert-butanol, or a combination or two or more thereof. In some embodiments, the C2-6 alcohol comprises ethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the C2-6 alcohol is present in an amountAttorney Docket No.62826-719.601 of 1% to 30%, from 5% to 30%, from 10% to 30%, from 5% to 20%, from 10% to 20%, or about 15% by weight of the composition. In some embodiments, where the composition is for use in treating or preventing BCC, the total amount of alcohol present in the composition is about 1% to about 80% by weight of the composition.

[0035] In some embodiments, the alcohol comprises an organic solvent and / or penetration enhancer.

[0036] In some embodiments, the composition comprises the organic solvent and / or penetration enhancer. In some embodiments, the organic solvent and / or penetration enhancer comprises a C2-6alkylene glycol, C1-3alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof. In some embodiments, the C2-6alkylene glycol is propylene glycol; the C1-3alkyl- (OCH2CH2)1-5-OH is 2-(2-ethoxyethoxy)ethanol; and the polyethylene glycol is PEG200, PEG400, or a combination thereof. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is present in an amount of from 50% to 99%, from 50% to 80%, from 50% to 70%, or about 60% by weight of the composition.

[0037] In some embodiments, the composition comprises the antioxidant. In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. In some embodiments, the antioxidant comprises butylated hydroxytoluene. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is present in an amount of from 0.01% to 5%, from 0.01% to 0.2%, from 0.01% to 0.1%, or about 0.05% by weight of the composition.

[0038] In some embodiments, the composition comprises the preservative. In some embodiments, the preservative comprises phenoxyethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the preservative is present in an amount of from 0.5% to 5.0%, from 0.5% to 2%, or about 1% by weight of the composition. In some embodiments, where the composition is for use in treating or preventing BCC, the composition further comprises water in an amount of from 0% to 25%, from 5% to 25%, from 10% to 25%, from 15% to 25%, or about 20% by weight of the composition.Attorney Docket No.62826-719.601

[0039] In some embodiments, the composition comprises the gelling agent. In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of from 700,000 Da to 1,150,000 Da. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agent is present in an amount of from 0.5% to 5%, or about 2% by weight of the composition.

[0040] In some embodiments, the composition comprises ethanol, propylene glycol, 2-(2- ethoxyethoxy)ethanol, and hydroxypropyl cellulose. In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight; propylene glycol is present in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight; 2-(2- ethoxyethoxy)ethanol is present in an amount of from 30% to 70%, from 40% to 60%, or about 47% by weight; and hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 1% to 3% or about 2% by weight of the composition. In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of about 15% by weight; propylene glycol is present in an amount of about 15% by weight; 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight; and hydroxypropyl cellulose having an average molecular weight of about 850,000 Da is present in an amount of about 2% by weight of the composition.

[0041] In some embodiments, the composition further comprises an antioxidant and / or a preservative. In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, or propyl gallate, or a combination of two or more thereof; and the preservative comprises phenoxyethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant comprises butylated hydroxytoluene in an amount of from 0.01% to 0.1% or about 0.05% by weight; and the preservative comprises phenoxyethanol in an amount of from 0.5% to 2%, or about 1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant comprises butylated hydroxytoluene in an amount of about 0.05% by weight; and the preservative comprises phenoxyethanol in an amount of about 1% by weight of the composition.Attorney Docket No.62826-719.601

[0042] In some embodiments, the composition comprises a pH adjuster, optionally an acid, and further optionally a citric acid, acetic acid, acetate buffer, lactic acid, or ascorbic acid.

[0043] In some embodiments, propylene glycol is a super refined propylene glycol.

[0044] In some embodiments, 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of > 99.90%.

[0045] 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 salt thereof; and ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, hydroxypropyl cellulose, and optionally an antioxidant, and optionally a preservative. In some embodiments, the compound is Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer).

[0046] In some embodiments, the antioxidant, when present, comprises butylated hydroxytoluene; and the preservative, when present, comprises phenoxyethanol.

[0047] In some embodiments, the composition has a viscosity of about 10000 cp to about 30000 cp.

[0048] 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 or emollient. In some embodiments, the composition is a component of a patch, tape, film, wafer, or bandage.

[0049] In one aspect, the present disclosure provides a method of treating or preventing a skin disease, condition or disorder in a subject in need thereof, comprising administering to the subject the composition described herein.

[0050] In some embodiments, the skin disease, condition or disorder is basal cell carcinoma (BCC), squamous cell carcinoma (SCC), seborrheic keratosis, actinic keratosis, benign tumor, malignant tumor, melanoma, non-melanoma skin cancer, parasite, virus of the skin, immune disease or disorder, or a bacterial, fungal or microbial infection. In some embodiments, the skin disease, condition or disorder is basal cell carcinoma, squamous cell carcinoma, or melanoma. In some embodiments, the SCC may be an invasive SCC or an SCC in situ. In some embodiments, the SCC in situ may be Bowen’s disease.Attorney Docket No.62826-719.601

[0051] In some embodiments, the skin disease, condition or disorder is the benign tumor, wherein the benign tumor is a benign vascular tumor, benign fibrotic tumor, benign adipocyte tumor, benign sebaceous tumor, benign epidermal tumor, benign melanocytic lesion, or benign neural tumor; the skin disease, condition or disorder is the malignant tumor, wherein the malignant tumor is a malignant melanocytic tumor, malignant epidermal tumor, malignant vascular tumor, malignant metastatic tumor, malignant adipocyte tumor, malignant sebaceous tumor, or malignant fibrotic tumor, basal cell carcinoma, non-melanoma skin cancer, squamous cell carcinoma, melanoma; the skin disease, condition or disorder is the parasite, wherein the parasite is of the genus Trypanasoma or Lieshmania; the skin disease, condition or disorder is the virus, wherein the virus is molluscum contagiosum virus or human papilloma virus; or the skin disease, condition or disorder is the bacterial, fungal or microbial infection, wherein the bacterial, fungal or microbial infection is otitis media, Staphylococcus aureus infection, Mycobacterium infection, Porphyromonas infection, Salmonella infection, Chlamydia infection, tuberculosis, gingivitis or periodontal disease.

[0052] 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.

[0053] In some embodiments, the composition is administered in a pulsed cycle. In some embodiments, the composition is administered under occlusion.

[0054] In some embodiments, the skin disease, condition or disorder is skin pigmentation disorder. In some embodiments, the skin pigmentation disorder is Acanthosis nigricans.

[0055] 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

[0056] FIG.1A-FIG.1D show local skin tolerability of four (4) compositions of Example 2 including a compound having the structure of formula (I), (I-A), (I-B), (I-AA), (I- BB), Formula (II), or Formula (III), or a salt thereof and the respective placebos following once daily or every other day dermal administration for 14 days to Göttingen Minipigs, measured by scores of Erythema and Edema.Attorney Docket No.62826-719.601

[0057] FIG.2 shows explant TUNEL assay images. TUNEL (brown) demonstrates increased apoptosis in the keratinocytes of human seborrheic keratosis treated with the composition of Example 5 including 1% a compound having the structure of formula (I), (I- A), (I-B), (I-AA), (I-BB), Formula (II), or Formula (III), or a salt thereof as compared with untreated and vehicle treated explants. Top row: 4X magnification, Bottom row 10X magnification.

[0058] FIG.3A. Time-to-event KM plot of when lesions have 1 point drop in PLA scores, during the first 8 weeks post treatment, stratified by cohorts. For cohort 1, median response time of 1 point PLA drop is 42 days (28 to 42 days, 95% CI). For cohort 2 and 3, median response time of 1point PLA drop is 21 days (cohort 295% CI: 21 to 35 days; cohort 395% CI: 21 to 56 days). Censoring time is set to be the last visit.

[0059] FIG.3B. Time-to-event KM plot of when lesions have 1 point drop in PLA scores, during the first 8 weeks post treatment, in all cohorts. For all cohorts combined, median response time of 1 point PLA drop is 21 days (21 to 35 days, 95% CI).

[0060] FIG.3C. Time-to-event KM plot of when lesions have 1 point drop in PLA scores, during the first 8 weeks post treatment. For lesions at PLA baseline = 2, median response time of 1 point PLA drop is 28 days (21 to 42 days, 95% CI). For lesions at PLA baseline = 3, median response time of 1point PLA drop is 21 days (7 to 42 days, 95% CI).

[0061] FIG.4A. Time-to-event KM plot of when lesions have 2 points drop in PLA scores, during the first 8 weeks post treatment, stratified by cohorts. For cohort 1, median response time of 2 points PLA drop is 84 days (84 to 84 days, 95% CI). For cohort 2, median response time of 2 points PLA drop is 63 days (42 to 98 days, 95% CI). For cohort 3, median response time of 2 points PLA drop is 98 days (56 to 98 days, 95% CI). Censoring time is set to be the last visit.

[0062] FIG.4B. Time-to-event KM plot of when lesions have 2 points drop in PLA scores, during the first 8 weeks post treatment, in all cohorts. For all cohorts combined, median response time of 2 points PLA drop is 84 days (56 to 98 days, 95% CI).

[0063] FIG.4C. Time-to-event KM plot of when lesions have 2 points drop in PLA scores, during the first 8 weeks post treatment. For lesions at PLA baseline = 2, median response time of 2 points PLA drop is 84 days (70 to 98 days, 95% CI). For lesions at PLA baseline = 3, median response time of 2 points PLA drop is 56 days (28 to 56 days, 95% CI).Attorney Docket No.62826-719.601

[0064] FIG.5A. Time-to-event KM plot of when lesions have PLA scores drop to 0, during the 8 weeks post treatment, stratified by cohorts. For cohort 1, median response time is ≥ 84 days. For cohort 2, median response time is 70 days (56 to 98 days, 95% CI). For cohort 3, median response time is ≥ 98 days. Censoring time is set to be the last visit.

[0065] FIG.5B. Time-to-event KM plot of when lesions have PLA scores drop to 0. In all cohorts, the overall median response time is ≥ 84 days.

[0066] FIG.5C. Time-to-event KM plot of when lesions have PLA scores drop to 0, for lesions at PLA baseline = 2, median response time is 84 days (70 to 98 days, 95% CI); for lesions at PLA baseline = 3, median response time is 84 days (56 to 98 days, 95% CI).

[0067] FIG.6. Representative photos demonstrate the response of Composition Ex.5 – Compound 1 to an SK in Cohort 1 (BID for 14 days) and an SK in a background lentigo in Cohort 2 (BID for 28 days) respectively.

[0068] FIG.7. Time-to-event KM plot of when patients have a 1 point drop in PLA scores, during the first 28 days of treatment, stratified by cohorts (0.1% facial application, 1% facial application, and 1% truncal three times a week application).

[0069] FIG.8. Representative photos demonstrate the response of a Basal Cell Carcinoma to Composition Ex.5 – Compound 1 – 1% when treated twice a day (BID) for 28 days. Images taken weekly up to 96 days. DETAILED DESCRIPTION OF THE INVENTION GENERAL

[0070] Provided herein, in various aspects, are compositions including Compound 1 (as a compound that can inhibit Akt or inhibit other kinases) or salts thereof, and methods of using these compositions for the treatment or prevention of skin diseases, conditions, or disorders. The compositions may be administered topically, orally, systemically, intralesionally, intradermally, subdermally, thereby treating or preventing the skin diseases, conditions, or disorders. The skin diseases, conditions or disorders include any one of carcinomas, basal cell carcinomas, squamous cell carcinoma, benign tumors, malignant tumors, melanoma, parasites, viruses of the skin, immune diseases or disorders, and a bacterial, fungal or microbial infection. In particular, the topical compositions are useful for treating or preventing basal cell carcinomas. Specifically, mutations in Akt 1 or mutations that affect theAttorney Docket No.62826-719.601 regulation of Akt, have been shown to be involved in tumor growth in BCCs and SCCs. Melanomas are one of the most deadly form of skin cancer due to uncontrolled proliferation or growth of melanocytes. Multiple pathways are involved in melanoma proliferation including dysregulation of the Akt pathway. Accordingly, compositions that inhibit those mutations may result in prevention or treatment of BCCs, SCCs, and / or melanomas. DEFINITIONS

[0071] The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0072] “Alcohol” refers to an alkyl group (e.g., C2-6 alkyl), as defined within, having a hydroxy group attached to a carbon of the chain. For example, alcohols useful in the present invention include, but are not limited to, ethanol, benzyl alcohol, propanol, isopropanol, butanol, isobutanol, tertbutanol, pentanol and hexanol, among others. Alcohols useful in the present invention are fully saturated. In some embodiments, the alcohol is C2-6 alcohol.

[0073] “Alkylene glycol” refers to a compound having the formula of H-[O-alkylene]- OH, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the alkylene glycol is a C2-6alkylene glycol. In some embodiments, the C2-6alkylene glycol is propylene glycol (1.2- propanediol). In some embodiments the glycol is butylene glycol and hexylene glycol.

[0074] “Di-alkylene glycol” refers to a compound having the formula of HO-(alkylene- O)2-H, wherein the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, the di-alkylene glycol is a di-(C2-6 alkylene) glycol. In some embodiments, the di-(C2-6 alkylene) glycol is dipropylene glycol. Dipropylene glycol can include one or more isomers, for example 4-oxa-2,6-heptandiol, 2-(2-hydroxy-propoxy)-propan-1-ol, 2-(2- hydroxy-1-methyl-ethoxy)-propan-1-ol, and 3,3'-oxybis(propan-1-ol).

[0075] “Polyethylene glycol” refers to a polymer having the formula of HO- (CH2CH2O)n-OH with variations in subscript “n”. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule, or may have one or more hydroxyl groups etherified with a lower alkyl, e.g., a methyl group. Also suitable are derivatives of polyethylene glycols having esterifiable carboxy groups. Polyethylene glycols useful in the present invention can be polymers of any chain length or molecular weight, and can include branching. In some embodiments the PEG is methoxy PEG (macrogol monomethyl ether orAttorney Docket No.62826-719.601 polyethylene glycol monomethyl ether). In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 9000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 5000. In some embodiments, the average molecular weight of the polyethylene glycol is from about 200 to about 900. In some embodiments, the average molecular weight of the polyethylene glycol is about 400. Suitable polyethylene glycols include, but are not limited to PEG200, PEG300, PEG400, PEG600, and PEG900. The number following the “PEG” in the name refers to the average molecular weight of the polymer.

[0076] “USP Grade” excipients refers to excipients (e.g., alcohol, propylene glycol, polyethylene glycol, such as PEG200 and PEG400, and the like) meet or exceed requirements of the United States Pharmacopeia (USP).

[0077] “Super refined” excipients refer to excipients that are stripped of their impurities. Super refining removes polar impurities (including primary and secondary oxidation products) from an excipient without altering its chemical composition. The removal of these impurities helps to reduce excipient-Active Pharmaceutical Ingredient (API) interaction and subsequent API degradation, thereby maintaining both the stability of the drug and the final composition or formulation. In addition, the removal of these impurities can minimize cellular irritation, ideal for various drug administration routes. Super Refined excipients of the present invention include a super refined propylene glycol.

[0078] “Super refined propylene glycol” or “S.R. propylene glycol” refers to a highly purified propylene glycol that can enhance drug activity and composition (or formulation) stability. In some embodiments, S.R. propylene glycol has a purity of no less than about 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, S.R. propylene glycol has a purity of no less than about 99.8% or 99.9%.

[0079] “Transcutol” is represented by the formula: CH3CH2OCH2CH2OCH2CH2OH, which has a preferred IUPAC name of 2-(2-ethoxyethoxy)ethanol. Other names for 2-(2- Ethoxyethoxy)ethanol includes diethylene glycol monoethyl ether (abbreviated as DGME or DEGEE), diethylene glycol ethyl ether (abbreviated as DEGEE), ethyldiglycol, dioxitol, 3,6- dioxa-1-octanol, Carbitol, Carbitol Cellosolve, Polysolv DE, or Dowanal DE. Transcutol includes “Transcutol P”, “Transcutol CG”, and “Transcutol HP”.Attorney Docket No.62826-719.601

[0080] “Transcutol P” refers to a high purity grade of 2-(2-ethoxyethoxy)ethanol. “Transcutol CG” refers to a specific grade of 2-(2-ethoxyethoxy)ethanol, which is a powerful solubilizer and efficacy booster that has been used in the cosmetic and pharmaceutical industries. “Transcutol HP” refers to a highly purified grade of 2-(2-ethoxyethoxy)ethanol that can enhance drug activity and composition (or formulation) stability. In some embodiments, Transcutol P, CG, or HP has a purity of no less than about 99.5%, 99.6%, 99.7%, 99.8%, or 99.9%. In some embodiments, Transcutol P or HP has a purity of no less than 99.8% or 99.9%. In some embodiments, Transcutol HP has a purity of about 99.90%.

[0081] “Fatty alcohol” refers to a primary alcohol with a long aliphatic chain, which is either saturated or unsaturated. The fatty alcohol can also range from as few as 4–6 carbons to as many as 22–26 carbons. The fatty alcohol includes, but is not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol (unsaturated), heptadecyl alcohol, stearyl alcohol, oleyl alcohol (unsaturated), nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol (unsaturated), and lignoceryl alcohol.

[0082] “Fatty ester” or “fatty acid ester” refers to a type of ester that results from the combination of a fatty acid with an alcohol. When the alcohol is a polyethylene glycol, the fatty ester refers to a polyoxyethylene fatty ester or a polyoxyethylene fatty acid ester.

[0083] “Fatty ether” refers to a type of ether that results from the combination of a fatty alcohol with a second alcohol. When the second alcohol is a polyethylene glycol, the fatty ether refers to a polyoxyethylene fatty ether.

[0084] “Polysorbate” refers a type of fatty ester that results from an ethoxylated sorbitan (a polyethylene glycol derivative of sorbitol) with a fatty acid. Examples of polysorbates include Polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate). Suitable polysorbates include, but are not limited to the TweenTMseries (available from Uniqema), which includes Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethylene (20) sorbitan monopalmitate), Tween 60 (polyoxyethylene (20) sorbitan monostearate), and Tween 80 (polyoxyethylene (20) sorbitan monooleate). Other suitable polysorbates include the ones listed in R. C. Rowe and P. J. Shesky, Handbook ofAttorney Docket No.62826-719.601 pharmaceutical excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety.

[0085] “Glyceride” refers to a fatty ester when the alcohol component is glycerol. The glyceryl fatty esters (or glycerides) produced can be monoglycerides, diglycerides, or triglycerides. “Monoglyceride” is glyceride consisting of one fatty acid chain covalently bonded to a glycerol molecule through an ester linkage. “Diglyceride” is glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. “Triglyceride” is glyceride consisting of three fatty acid chains covalently bonded to a glycerol molecule through ester linkages.

[0086] “Salt” refers to acid or base salts of the compounds of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0087] “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 the 1H tautomer, the 2H tautomer, and mixtures of the 1H tautomer and 2H tautomer. Compound 1 also includes salts of 1H tautomer, the 2H tautomer, and mixtures of salts of the 1H tautomer and 2H tautomer.

[0088] “Solvate” refers to a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.Attorney Docket No.62826-719.601

[0089] “Hydrate” refers to a compound that is complexed to water molecule. The compounds of the present invention can be complexed with ½ water molecule or from 1 to 10 water molecules.

[0090] “Composition” or “formulation” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any prod uct, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the composition (or formulation) and not deleterious to the recipient thereof.

[0091] For any one of topical compositions as described herein, the content of water refers to a total amount by weight including the portion from a pH adjusting solution (when present) (e.g., 0.1 M, 0.5 M, or 1 M solution of citric acid in water), ethanol (if ethanol is not absolute ethanol), and the final Q.S.100 (Q.S stands for quantum satis).

[0092] “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 or 25℃) as compared to an initial purity of the compound at time zero (i.e., day 0). As always, the relative purity of the compound at time zero (i.e., day 0) is set as 100%.

[0093] “About” means a range of values including 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.

[0094] “Substantially free of …” refers to a composition containing no more than 1% by weight of other excipients, such as a di-(C2-6 alkylene) glycol, glycerol, a fatty alcohol, a fatty ester (e.g., Polysorbate), a fatty ether, or combinations thereof, each of which is defined and described herein. Polyethylene glycol (e.g., PEG200 and / or PEG400) and / or C1-3alkyl- (OCH2CH2)1-5-OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol HP) contain impurities including ethylene glycol and / or diethylene glycol. When the polyethylene glycol (e.g., PEG200 and / or PEG400) and / or C1-3 alkyl-(OCH2CH2)1-5-OH (e.g., 2-(2- ethoxyethoxy)ethanol or Transcutol HP) are present in a composition, the compositionAttorney Docket No.62826-719.601 contains no more than 0.5% by weight of ethylene glycol and / or diethylene glycol as impurities. In some embodiments, when the polyethylene glycol (e.g., PEG200 and / or PEG400) and / or C1-3alkyl-(OCH2CH2)1-5-OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol HP) are present in a composition, the composition contains no more than 0.25% by weight of ethylene glycol and / or diethylene glycol as impurities.

[0095] “Inhibition”, “inhibits” and “inhibitor” refer to a compound that prohibits or a method of prohibiting, a specific action or function.

[0096] “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, emollient, or as a component of a patch, 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.).

[0097] “Treat”, “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; 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 the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation.

[0098] “Prevent”, “preventing” or “prevention” includes completely or substantially reducing the likelihood or occurrence or the severity of initial clinical or aesthetical symptoms of a condition, disease, or disorder.

[0099] “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 include 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.Attorney Docket No.62826-719.601

[0100] “Therapeutically effective amount” refers to an amount of a compound or of a pharmaceutical composition useful for treating, preventing, or ameliorating an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques.

[0101] “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

[0102] As will be appreciated, some excipients of the topical compositions described herein can possess multiple functions. For example, a given substance may act as both a solvent and an enhancer, both an antioxidant and a stabilizer, both an emulsifier and a surfactant, both an emulsifier and a thickening agent, and so on. In some such cases, the function of a given substance can be considered singular, even though its properties may allow multiple functionality.

[0103] In certain aspects, the present disclosure provides a composition comprising a compound 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.62826-719.601 R2is an optionally substituted C6-12 aryl or optionally substituted 3- to 12- membered heteroaryl; and n is 0 to 5, a compound having a structure represented by Formula (I-A) or (I-B):wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R4is hydrogen or C1-6 alkyl; and n is 0 to 5; a compound having a structure represented by Formula (I-AA) or Formula (I-BB):wherein:Attorney Docket No.62826-719.601 R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6 alkyl; a compound having a structure represented by Formula (II):wherein RAis C1-20alkyl; or a compound having a structure represented by Formula (III):(III). In some embodiments, the composition may comprise the compound of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), or Formula (II) in a total amount of 0.01% to 10%. In some embodiments, the composition may comprise the compound of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), or Formula (II) in a total amount of 0.1% to 1.5%. In some embodiments, the compound may be (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. In some embodiments, the composition may comprise Compound 1 in a total amount of 0.01% to 10%. In some embodiments, the compound may be (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. In some embodiments, the composition may comprise Compound 1 in a total amount of 0.1% to 1.5%.

[0104] In embodiments wherein the composition comprises a compound having the structure of Formula (I), one or more component 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 optionallyAttorney Docket No.62826-719.601 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.

[0105] In embodiments wherein the composition comprises a compound having the structure of Formula (I-A) or Formula (I-B), one or more component 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.

[0106] In embodiments wherein the composition comprises a compound 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, C1-6 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 C1-6 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 C1-6alkyl. In some embodiments, R4is C1-4alkyl. In some embodiments, R4is methyl, ethyl, or propyl. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is methyl.

[0107] In embodiments wherein the composition comprises a compound 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 C14-18alkyl. In some embodiments, RAis C16alkyl.

[0108] In some embodiments, the composition is a gel formulation. In some embodiments, the composition comprises an alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof. In some embodiments, the composition furtherAttorney Docket No.62826-719.601 comprises a preservative. In some embodiments, the composition further comprises a gelling agent.

[0109] In certain aspects, the present disclosure provides a composition comprising 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, and one or more excipients selected from (a)-(e): a) alcohol; b) an organic solvent and / or a penetration enhancer; c) an antioxidant; d) a preservative; and e) a gelling agent. In some embodiments, the one or more compounds comprises Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0110] In some embodiments, the composition comprises the alcohol. In some embodiments, the alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2- butanol, or tert-butanol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, or a combination or two or more thereof. In some embodiments, the alcohol comprises a C2-6 alcohol. In some embodiments, the C2-6 alcohol comprises ethanol, propanol, isopropanol, n- butanol, isobutanol, 2-butanol, or tert-butanol, or a combination or two or more thereof. In some embodiments, the C2-6alcohol comprises ethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the C2-6 alcohol is present in an amount of 1% to 30%, from 5% to 30%, from 10% to 30%, from 5% to 20%, from 10% to 20%, or about 15% by weight of the composition.

[0111] In some embodiments, where the composition is for use in treating or preventing BCC, the total amount of alcohol present in the composition is about 1% to about 80% by weight of the composition.

[0112] In some embodiments, the alcohol comprises an organic solvent and / or penetration enhancer.

[0113] In some embodiments, the composition further comprises the organic solvent and / or penetration enhancer. In some embodiments, the organic solvent and / or penetrationAttorney Docket No.62826-719.601 enhancer comprises a C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof. In some embodiments, the C2-6alkylene glycol is propylene glycol; the C1-3alkyl- (OCH2CH2)1-5-OH is 2-(2-ethoxyethoxy)ethanol; and the polyethylene glycol is PEG200, PEG400, or a combination thereof.

[0114] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is present in an amount of from 50% to 99%, from 50% to 80%, from 50% to 70%, or about 60% by weight of the composition.

[0115] In some embodiments, the composition further comprises the antioxidant. In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. In some embodiments, the antioxidant comprises butylated hydroxytoluene. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is present in an amount of from 0.01% to 5%, from 0.01% to 0.2%, from 0.01% to 0.1%, or about 0.05% by weight of the composition.

[0116] In some embodiments, comprising the preservative. In some embodiments, the preservative comprises phenoxyethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the preservative is present in an amount of from 0.5% to 5.0%, from 0.5% to 2%, or about 1% by weight of the composition. In some embodiments, where the composition is for use in treating or preventing BCC, the composition further comprises water in an amount of from 0% to 25%, from 5% to 25%, from 10% to 25%, from 15% to 25%, or about 20% by weight of the composition.

[0117] In some embodiments, the composition comprises the gelling agent. In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of from 700,000 Da to 1,150,000 Da. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agent is present in an amount of from 0.5% to 5%, or about 2% by weight of the composition.Attorney Docket No.62826-719.601

[0118] In some embodiments, the composition comprises ethanol, propylene glycol, 2-(2- ethoxyethoxy)ethanol, and hydroxypropyl cellulose

[0119] In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight; propylene glycol is present in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight; 2-(2-ethoxyethoxy)ethanol is present in an amount of from 30% to 70%, from 40% to 60%, or about 47% by weight; and hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 1% to 3% or about 2% by weight.

[0120] In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of about 15% by weight; propylene glycol is present in an amount of about 15% by weight; 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight; and hydroxypropyl cellulose having an average molecular weight of about 850,000 Da is present in an amount of about 2% by weight.

[0121] In some embodiments, the composition further comprises an antioxidant and / or a preservative. In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, or propyl gallate, or a combination of two or more thereof; and the preservative comprises phenoxyethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant comprises butylated hydroxytoluene in an amount of from 0.01% to 0.1% or about 0.05% by weight; and the preservative comprises phenoxyethanol in an amount of from 0.5% to 2%, or about 1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant comprises butylated hydroxytoluene in an amount of about 0.05% by weight; and the preservative comprises phenoxyethanol in an amount of about 1% by weight.

[0122] In some embodiments, the composition comprises a pH adjuster, optionally an acid, and further optionally a citric acid, acetic acid, acetate buffer, lactic acid, or ascorbic acid.

[0123] In some embodiments, propylene glycol is a super refined propylene glycol.

[0124] In some embodiments, 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of > 99.90%.Attorney Docket No.62826-719.601

[0125] In certain aspects, the present disclosure provides a composition comprising 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, and ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, hydroxypropyl cellulose, and optionally an antioxidant, and optionally a preservative. In some embodiments, the one or more compounds comprises Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0126] In some embodiments, the antioxidant, when present, comprises butylated hydroxytoluene; and the preservative, when present, comprises phenoxyethanol.

[0127] In some embodiments, the composition has a viscosity of about 10000 cp to about 30000 cp.

[0128] 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 or emollient. In some embodiments, the composition is a component of a patch, tape, film, wafer, or bandage.

[0129] In certain aspects, the present disclosure provides a topical pharmaceutical composition. The topical pharmaceutical composition comprises 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 pharmaceutically acceptable salt or tautomer thereof, and one or more excipients selected from (a)-(g): a) C2-6alcohol; b) an organic solvent and / or a penetration enhancer; c) an antioxidant; d) a preservative; e) water; f) a pH adjuster; and g) a gelling agent. In some embodiments, the one or more compounds comprises Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.Attorney Docket No.62826-719.601

[0130] In some embodiments, the composition may be formulated at about 0.01% to about 10% 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. In some embodiments, the composition may be formulated at about 0.1% to about 1.5% 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. In some embodiments, the composition may be formulated at about 0.01% to about 10% of Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof. In some embodiments, the composition may be formulated at about 0.1% to about 1.5% of Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer) or a salt thereof.

[0131] In some embodiments, the composition comprises ethanol, propylene glycol, 2-(2- ethoxyethoxy)ethanol, and hydroxypropyl cellulose.

[0132] In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight; propylene glycol is present in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight; 2-(2-ethoxyethoxy)ethanol is present in an amount of from 30% to 70%, from 40% to 60%, or about 47% by weight; and hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 1% to 3% or about 2% by weight.

[0133] In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of about 15% by weight; propylene glycol is present in an amount of about 15% by weight; 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight; and hydroxypropyl cellulose having an average molecular weight of about 850,000 Da is present in an amount of about 2% by weight. Excipients A. Alcohol

[0134] In some embodiments, a composition herein comprises an alcohol. In some embodiments, the alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2- butanol, or tert-butanol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, or a combination or two or more thereof. In some embodiments, the alcohol comprises a C2-6Attorney Docket No.62826-719.601 alcohol. In some embodiments, the C2-6 alcohol comprises ethanol, propanol, isopropanol, n- butanol, isobutanol, 2-butanol, or tert-butanol, or a combination or two or more thereof. In some embodiments, the C2-6alcohol comprises ethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the C2-6 alcohol is present in an amount of 1% to 30%, from 5% to 30%, from 10% to 30%, from 5% to 20%, from 10% to 20%, or about 15% by weight of the composition.

[0135] In some embodiments, where the composition is for use in treating or preventing BCC, the total amount of alcohol present in the composition is about 1% to about 80% by weight of the composition.

[0136] In some embodiments, the alcohol comprises an organic solvent and / or penetration enhancer.

[0137] In some embodiments, the alcohol comprises ethanol. In some embodiments, the alcohol comprises propylene glycol. In some embodiments, the alcohol comprises a transcutol. In some embodiments, the alcohol comprises phenoxyethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the total amount of alcohol present in the composition is about 1% to about 80% by weight of the composition, or about 30-80%, 40-80%, 50-80%, 60-80%, 70-80%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80%. C2-6alcohol

[0138] In some embodiments, the composition comprises C2-6alcohol. In some embodiments, the C2-6alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, benzyl alcohol, hexanol, pentanol, or tert-butanol, or combinations thereof. In some embodiments, the C2-6 alcohol is ethanol or isopropanol. In some embodiments, the C2-6 alcohol is ethanol. In some embodiments, the composition comprises ethanol.

[0139] In some embodiments, the composition does not include C2-6 alcohol. In some embodiments, the composition does not include ethanol.

[0140] In some embodiments, where the composition is for use in treating or preventing BCC, the composition comprises C2-6 alcohol in an amount of from 0.0% to 90%, from 5% to 40%, from 10% to 30%, from 5% to 20%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, C2-6Attorney Docket No.62826-719.601 alcohol is present in the composition in an amount of from 0.0% to 20%, from 5% to 20%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, C2-6alcohol is present in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, C2-6 alcohol is present in an amount of from 10% to 20% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, C2-6 alcohol is present in an amount of about 15% by weight.

[0141] In some embodiments, where the composition is for use in treating or preventing BCC, the composition comprises ethanol in an amount of from 0.0% to 90%, from 5% to 40%, from 10% to 30%, from 5% to 20%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in the composition in an amount of from 0.0% to 20%, from 5% to 20%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of from 10% to 20% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of about 15% by weight. B. Organic solvent and / or Penetration Enhancer

[0142] In some embodiments, the composition comprises an organic solvent and / or penetration enhancer. Suitable solvents and / or penetration enhancers can include a C2-6 alkylene glycol (e.g., propylene glycol), a di-(C2-6 alkylene) glycol (e.g., dipropylene glycol), C1-3alkyl-(OCH2CH2)1-5-OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol P), a polyethylene glycol (e.g., PEG200 and / or PEG400), glycerol, a fatty alcohol (e.g., octyldodecanol), diether of an anhydrosugar alcohol (e.g. dimethyl isosorbide), a fatty ester (e.g., diisopropyl adipate, isopropyl myristate, medium-chain triglycerides, sorbitan monooleate, or the like), or a fatty ether (e.g., Laureth-4), or combinations thereof. In some embodiments, the organic solvent and / or penetration enhancer is a C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or combinations thereof.

[0143] In some embodiments, the organic solvent and / or penetration enhancer is an alcohol.Attorney Docket No.62826-719.601

[0144] In some embodiments, the organic solvent and / or penetration enhancer comprises a C2-6alkylene glycol, C1-3alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof. In some embodiments, the C2-6 alkylene glycol is propylene glycol; the C1-3 alkyl-(OCH2CH2)1-5-OH is 2-(2-ethoxyethoxy)ethanol; and the polyethylene glycol is PEG200, PEG400, or a combination thereof.

[0145] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is present in an amount of from 50% to 99%, from 50% to 80%, from 50% to 70%, or about 60% by weight of the composition.

[0146] In some embodiments, propylene glycol is a super refined propylene glycol.

[0147] In some embodiments, 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of > 99.90%.

[0148] In some embodiments, the organic solvent and / or penetration enhancer is a C2-6 alkylene glycol and / or C1-3 alkyl-(OCH2CH2)1-5-OH. In some embodiments, the organic solvent and / or penetration enhancer comprises a C2-6 alkylene glycol. In some embodiments, the organic solvent and / or penetration enhancer comprises C1-3 alkyl-(OCH2CH2)1-5-OH. In some embodiments, the organic solvent and / or penetration enhancer comprises a C2-6alkylene glycol and C1-3alkyl-(OCH2CH2)1-5-OH. In some embodiments, the organic solvent and / or penetration enhancer is a mixture of a C2-6alkylene glycol and C1-3alkyl-(OCH2CH2)1-5-OH. In some embodiments, the composition comprises a C2-6 alkylene glycol and C1-3 alkyl-(OCH2CH2)1-5-OH.

[0149] In some embodiments, C1-3 alkyl-(OCH2CH2)1-5-OH is 2-(2-ethoxyethoxy)ethanol (i.e., Transcutol P). In some embodiments, the C2-6 alkylene glycol is propylene glycol.

[0150] In some embodiments, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or penetration comprises propylene glycol. In some embodiments, the organic solvent and / or penetration enhancer comprises 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the organic solvent and / orAttorney Docket No.62826-719.601 penetration enhancer is a mixture of propylene glycol and 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition comprises propylene glycol and 2-(2- ethoxyethoxy)ethanol.

[0151] In some embodiments, the organic solvent and / or penetration enhancer comprises a polyethylene glycol. In some embodiments, the polyethylene glycol is PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800, or PEG900, or a combination thereof. In some embodiments the organic solvent and / or penetration enhancer is methoxy PEG (macrogol monomethyl ether or polyethylene glycol monomethyl ether).In some embodiments, the polyethylene glycol is PEG-200, or PEG-400, or a combination thereof. In some embodiments, the polyethylene glycol comprises PEG200. In some embodiments, the polyethylene glycol comprises PEG400. In some embodiments, the polyethylene glycol comprises a mixture of PEG200 and PEG400. In some embodiments, the polyethylene glycol is PEG-200 and / or PEG-400. In some embodiments, the organic solvent and / or penetration enhancer comprises PEG200. In some embodiments, the organic solvent and / or penetration enhancer comprises PEG400. In some embodiments, the organic solvent and / or penetration enhancer comprises a mixture of PEG200 and PEG400. In some embodiments, the composition comprises PEG200. In some embodiments, the composition comprises PEG400. In some embodiments, the composition comprises a mixture of PEG200 and PEG400.

[0152] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty alcohol. As used herein, the term “fatty alcohol” refers to an aliphatic alcohol that is saturated or unsaturated. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has between about 12-20, 14-20, 12- 18, 14-18, or 16-18 carbons on average. Suitable fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, lignoceryl alcohol, octyldodecanol, or mixtures thereof. In some embodiments, the organic solvent and / or penetration enhancer comprises one or more fatty alcohols selected from capric alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, palmitoleyl alcohol, stearyl alcohol, oleyl alcohol, arachidyl alcohol, heneicosyl alcohol, behenyl alcohol, erucyl alcohol, and lignoceryl alcohol. In some embodiments, the organicAttorney Docket No.62826-719.601 solvent and / or penetration enhancer comprises octyldodecanol. In some embodiments, the composition comprises octyldodecanol.

[0153] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty ester. In some embodiments, the fatty ester is a glyceryl fatty ester, ethylene glycol monoester and diester of a fatty acid, propylene glycol monoester and diester of a fatty acid, a sorbitan ester, a C1-6 alkyl ester of a fatty acid, di-(C1-6 alkyl) ester of adipic acid, or combinations thereof.

[0154] In some embodiments, the fatty ester is a glyceride. In some embodiments, the glyceride is monoglycerides, diglycerides, or triglycerides. The glycerides may be optionally substituted with sulfonic acid groups, or pharmaceutically acceptable salts thereof. Suitable fatty acids for deriving glycerides of fatty acids include, but are not limited to, those described herein. In some embodiments, the glyceride is a mono-glyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the glyceride is a diglyceride of a fatty acid having 12 to 18 carbon atoms. In some embodiments, the glyceride is a triglyceride of a fatty acid having 12 to 18 carbon atoms (e.g., also referred herein as a medium-chain triglyceride). In some embodiments, the organic solvent and / or penetration enhancer comprises a triglyceride of a fatty acid having 12 to 18 carbon atoms (e.g., also referred herein as a medium-chain triglyceride). In some embodiments, the composition comprises a triglyceride of a fatty acid having 12 to 18 carbon atoms (e.g., also referred herein as a medium-chain triglyceride).

[0155] In some embodiments, the fatty ester is an ethylene glycol monoester of a fatty acid, a propylene glycol monoester of a fatty acid, or a C1-6 alkyl ester of a fatty acid. In some embodiments, the fatty ester is an ethylene glycol monoester, a propylene glycol monoester, or a C1-4 alkyl ester of a fatty acid. Suitable fatty acids for deriving any one of the ethylene glycol monoester, propylene glycol monoester, and the C1-4 alkyl ester of fatty acids include, but are not limited to, those described herein. In some embodiments, the fatty ester is an ethylene glycol monoester, a propylene glycol monoester, or a C1-4alkyl ester of a fatty acid having 12 to 18 carbon atoms. Non-limiting examples of esters of a fatty acid include a laurate, a myristate, a palmitate, a stearate, or an oleate. In some embodiments, the fatty ester is isopropyl myristate. In some embodiments, the organic solvent and / or penetration enhancer comprises isopropyl myristate. In some embodiments, the composition comprises isopropyl myristate.Attorney Docket No.62826-719.601

[0156] In some embodiments, the fatty ester is a sorbitan ester. Suitable fatty acids for deriving the sorbitan esters include, but are not limited to, those described herein. Suitable sorbitan esters include, but are not limited to, the SpanTM series (available from Uniqema), which includes Span 20 (Sorbitan monolaurate), 40 (Sorbitan monopalmitate), 60 (sorbitan monostearate), 65 (sorbitan tristearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate). In some embodiments, the fatty ester is sorbitan monooleate. In some embodiments, the organic solvent and / or penetration enhancer comprises sorbitan monooleate. In some embodiments, the composition comprises sorbitan monooleate. In some embodiments the composition comprises polyoxyethylene sorbitol esters (e.g. Tween).

[0157] In some embodiments, the fatty ester is a di-(C1-4alkyl) ester of adipic acid (i.e., an adipate) or di-(C1-4alkyl) ester of sebacic acid (i.e., a sebacate). In some embodiments, the fatty ester is diisopropyl adipate. In some embodiments, the organic solvent and / or penetration enhancer comprises diisopropyl adipate. In some embodiments, the composition comprises diisopropyl adipate.

[0158] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty ether. In some embodiments, the organic solvent and / or penetration enhancer comprises a polyoxyethylene fatty ether. In some embodiments, the organic solvent and / or penetration enhancer comprises Laureth-4. In some embodiments, the composition comprises Laureth-4.

[0159] In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is present in the composition in an amount of from 30% to 99%, from 40% to 99%, from 50% to 99%, from 50% to 80%, from 50% to 70%, or about 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is present in the composition in an amount of from 50% to 99%, from 50% to 80%, from 50% to 70%, or about 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is present in the composition in an amount of from 50% to 80%, from 50% to 70%, or about 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is present in the composition in an amount of from 50% to 70% or about 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer isAttorney Docket No.62826-719.601 present in the composition in an amount of from 50% to 70% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is present in the composition in an amount of about 60% by weight.

[0160] In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2- ethoxyethoxy)ethanol; and a total amount of which is present in the composition in an amount of from 50% to 80%, from 50% to 70%, or about 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol; and a total amount of which is present in the composition in an amount of from 50% to 80%, from 50% to 70%, or about 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol; and a total amount of which is present in the composition in an amount of from 50% to 70% or about 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol; and a total amount of which is present in the composition in an amount of from 50% to 70% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2- ethoxyethoxy)ethanol; and a total amount of which is present in the composition in an amount of about 60% by weight.

[0161] In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2- (2-ethoxyethoxy)ethanol; and a total amount of which is present in the composition in an amount of from 50% to 80%, from 50% to 70%, or about 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2-(2- ethoxyethoxy)ethanol; and a total amount of which is present in the composition in an amount of from 50% to 80%, from 50% to 70%, or about 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2-(2-Attorney Docket No.62826-719.601 ethoxyethoxy)ethanol; and a total amount of which is present in the composition in an amount of from 50% to 70% or about 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2-(2-ethoxyethoxy)ethanol; and a total amount of which is present in the composition in an amount of from 50% to 70% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the organic solvent and / or penetration enhancer is a mixture of propylene glycol and 2-(2- ethoxyethoxy)ethanol; and a total amount of which is present in the composition in an amount of about 60% by weight.

[0162] In some embodiments, where the composition is for use in treating or preventing BCC, propylene glycol is present in the composition in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, propylene glycol is present in the composition in an amount of from 10% to 20% or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, propylene glycol is present in the composition in an amount of from 10% to 20% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, propylene glycol is present in the composition in an amount of about 15% by weight.

[0163] In some embodiments, where the composition is for use in treating or preventing BCC, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of from 30% to 70%, from 40% to 60%, or about 47% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of from 40% to 60% or about 47% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, 2-(2- ethoxyethoxy)ethanol is present in the composition in an amount of from 40% to 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 47% by weight.

[0164] In some embodiments, where the composition is for use in treating or preventing BCC, the composition comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol; propylene glycol is present in an amount of from 10% to 20% by weight; and 2-(2- ethoxyethoxy)ethanol is present in an amount of from 40% to 60% by weight. In someAttorney Docket No.62826-719.601 embodiments, where the composition is for use in treating or preventing BCC, the composition comprises propylene glycol and 2-(2-ethoxyethoxy)ethanol; propylene glycol is present in an amount of about 15% by weight; and 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight.

[0165] In some embodiments, propylene glycol is a super refined propylene glycol.

[0166] In some embodiments, 2-(2-ethoxyethoxy)ethanol is Transcutol HP. In some embodiments, 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of > 99.90%. C. Antioxidant

[0167] In some embodiments, the composition comprises an antioxidant. In some embodiments, the composition does not include an antioxidant.

[0168] In some embodiments, the antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, alpha tocopherol, ascorbyl palmitate, ascorbic acid, citric acid or salts thereof, sodium meta / bisulfite, or combinations thereof. In some embodiments, the antioxidant is butylated hydroxytoluene. In some embodiments, the antioxidant is butylated hydroxyanisole. In some embodiments, the antioxidant is propyl gallate. In some embodiments, the antioxidant is a mixture of butylated hydroxytoluene and butylated hydroxyanisole.

[0169] In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is present in the composition in an amount of from 0.001% to 5% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is present in an amount of from 0.01% to 0.5%, from 0.01% to 0.2%, from 0.01% to 0.1%, or about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is present in an amount of from 0.01% to 0.5% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is present in an amount of from 0.01% to 0.2% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is present in an amount of from 0.01% to 0.1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is present in an amount of about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is present in an amount of about 0.1% by weight. In some embodiments, where the composition is for use in treatingAttorney Docket No.62826-719.601 or preventing BCC, the antioxidant is butylated hydroxytoluene in an amount of from 0.01% to 0.1% or about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is butylated hydroxytoluene in an amount of from 0.01% to 0.1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is butylated hydroxytoluene in an amount of about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is butylated hydroxyanisole in an amount of from 0.01% to 0.1% or about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is butylated hydroxyanisole in an amount of from 0.01% to 0.1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is butylated hydroxyanisole in an amount of about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is propyl gallate in an amount of from 0.01% to 0.1% or about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is propyl gallate in an amount of from 0.01% to 0.1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is propyl gallate in an amount of about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each of which is present in an amount of from 0.01% to 0.1% or about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each of which is present in an amount of from 0.01% to 0.1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each of which is present in an amount of about 0.05% by weight.

[0170] In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. In some embodiments, the antioxidant comprises butylated hydroxytoluene. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant is present in an amount of from 0.01% to 5%, from 0.01% to 0.2%, from 0.01% to 0.1%, or about 0.05% by weight of the composition.Attorney Docket No.62826-719.601

[0171] In some embodiments, the antioxidant, when present, comprises butylated hydroxytoluene; and the preservative, when present, comprises phenoxyethanol. D. Preservative

[0172] In some embodiments, the composition comprises a preservative. In some embodiments, the composition does not include a preservative.

[0173] In some embodiments, the composition comprises a preservative; and the preservative is benzyl alcohol, phenoxyethanol, methyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, sodium benzoate, imidurea, chlorocresol, chloroxylenol, benzoic acid, sodium sulfite, sodium metabisulfite, boric acid, calcium acetate, or a combination thereof. In some embodiments, the preservative, when present, is benzyl alcohol. In some embodiments, the preservative, when present, is phenoxyethanol. In some embodiments, the preservative, when present, is a mixture of benzyl alcohol and phenoxyethanol.

[0174] In some embodiments, where the composition is for use in treating or preventing BCC, the preservative is present in the composition in an amount of from 0.01% to 5% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the preservative is present in an amount of from 0.5% to 5.0%, from 0.5% to 2%, or about 1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the preservative is present in an amount of from 0.5% to 2% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the preservative is present in an amount of about 1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the preservative is phenoxyethanol in an amount of from 0.5% to 5%, from 0.5% to 4%, from 0.5% to 3%, or from 0.5% to 2% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the preservative is phenoxyethanol in an amount of from 0.5% to 2% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the preservative is phenoxyethanol in an amount of about 1% by weight.

[0175] In some embodiments, the preservative comprises phenoxyethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the preservative is present in an amount of from 0.5% to 5.0%, from 0.5% to 2%, or about 1% by weight of the composition.Attorney Docket No.62826-719.601

[0176] In some embodiments, the composition further comprises an antioxidant and / or a preservative. In some embodiments, the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, or propyl gallate, or a combination of two or more thereof; and the preservative comprises phenoxyethanol. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant comprises butylated hydroxytoluene in an amount of from 0.01% to 0.1% or about 0.05% by weight; and the preservative comprises phenoxyethanol in an amount of from 0.5% to 2%, or about 1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant comprises butylated hydroxytoluene in an amount of about 0.05% by weight; and the preservative comprises phenoxyethanol in an amount of about 1% by weight.

[0177] In some embodiments, the antioxidant, when present, comprises butylated hydroxytoluene; and the preservative, when present, comprises phenoxyethanol. E. Water

[0178] In some embodiments, the composition comprises water. In some embodiments, the composition does not include water. F. pH Adjuster

[0179] In some embodiments, the composition comprises a pH adjuster. In some embodiments, the composition does not include a pH adjuster.

[0180] In some embodiments, the composition comprises a pH adjuster; and the pH adjuster is an acid. In some embodiments, the acid is an organic acid. Suitable organic acids include, but are not limited to, citric acid, acetate buffer, ascorbic acid, formic acid, lactic acid, benzoic acid, oxalic acid, acetic acid, and propionic acid. In some embodiments, the acid is an organic acid, such as citric acid, formic acid, lactic acid, benzoic acid, oxalic acid, acetic acid, or propionic acid. In some embodiments, the acid is an organic acid such as citric acid, formic acid, lactic acid, benzoic acid, acetic acid, or propionic acid. In some embodiments, the acid is an organic acid such as citric acid, formic acid, lactic acid, or acetic acid. In some embodiments, the acid is an organic acid such as citric acid or acetic acid. In some embodiments, the acid is an inorganic acid such as hydrochloric acid (HCl), boric acid (H3BO3), sulfuric acid (H2SO4), carbonic acid (H2CO3), or phosphoric acid (H3PO4). In some embodiments, the acid is an inorganic acid such as hydrochloric acid (HCl), boric acid (H3BO3), or phosphoric acid (H3PO4). In some embodiments, the acid is an inorganic acidAttorney Docket No.62826-719.601 such as hydrochloric acid (HCl) or phosphoric acid (H3PO4). In some embodiments, the acid is citric acid, acetic acid, or a combination thereof. In some embodiments, the acid is citric acid. In some embodiments, the acid is acetic acid. In some embodiments, the acid is lactic acid. In some embodiments, the acid is ascorbic acid.

[0181] The pH adjuster can be in an aqueous solution of an acid as described herein. In some embodiments, the pH adjuster is an aqueous solution of citric acid. In some embodiments, the pH adjuster is an aqueous solution of citric acid in a concentration of 0.1 M, 0.5 M, or 1 M. G. Gelling Agent

[0182] In some embodiments, the composition comprises a gelling agent (e.g., a polymer thickener). Gelling agents include, for example, hydrophilic and hydroalcoholic gelling agents frequently used in the cosmetic and pharmaceutical industries. In some embodiments, the gelling agent is a Carbopol (also referred to as a carbomer), carboxymethyl cellulose, ethylcellulose, gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose, magnesium aluminum silicate (Veegum), methylcellulose, a poloxamer (Pluronics), polyvinyl alcohol, sodium alginate, dermacryl, acrylates, octylacrylamide copolymer, HPMC (hydroxypropyl methylcellulose), PVP (Polyvinylpyrrolidone), bentonite clay, tragacanth, xanthan gum, Sepineo P600, a polyethylene glycol having an average molecular weight of at least about 2500 Da, or a combination thereof. In some embodiments, the gelling agent comprises Sepineo P600. In some embodiments, the gelling agent is Sepineo P600. In some embodiments, the gelling agent comprises a polyethylene glycol having an average molecular weight of from about 2500 to 3500 Da (e.g., PEG3350). In some embodiments, the gelling agent is a polyethylene glycol having an average molecular weight of from about 2500 to 3500 Da (e.g., PEG3350). In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the gelling agent is hydroxypropyl cellulose.

[0183] In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 40,000 Dalton (Da), about 80,000 Da, about 100,000 Da, about 140,000 Da, about 180,000 Da, about 280,000 Da, about 370,000 Da, about 700,000 Da, about 850,000 Da, about 1,000,000 Da, about 1,150,000 Da, or about 2,500,000 Da. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 140,000 Da, about 180,000 Da, about 280,000 Da, about 370,000 Da, about 700,000 Da, about 850,000 Da, about 1,000,000 Da, or about 1,150,000 Da. In some embodiments, the hydroxypropylAttorney Docket No.62826-719.601 cellulose has an average molecular weight of about 700,000 Da, about 850,000 Da, about 1,000,000 Da, or about 1,150,000 Da. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of from about 700,000 Da to about 1,150,000 Da.

[0184] Hydroxypropyl cellulose (HPC) includes, for example Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, Nisso VH, Klucel ELF, Klucel EF, Klucel LF, Klucel JF, Klucel GF, Klucel MF, and Klucel HF.

[0185] Nisso SSL has an average molecular weight of about 40,000 Da; Nisso SL has an average molecular weight of about 100,000 Da; Nisso L has an average molecular weight of about 140,000 Da; Nisso LM has an average molecular weight of about 180,000 Da; Nisso LMM has an average molecular weight of about 280,000 Da; Nisso M has an average molecular weight of about 700,000 Da; Nisso H has an average molecular weight of about 1,000,000 Da; and Nisso VH has an average molecular weight of about 2,500,000 Da. Suitable particle sizes of Nisso HPC (i.e., Nisso SSL, Nisso SL, Nisso L, Nisso LM, Nisso LMM, Nisso M, Nisso H, and Nisso VH) in the composition include regular powder (40 mesh), fine powder (100 mesh), and super fine powder (300 mesh). See Technical date sheets of Nisso HPCs, the entirety of which is incorporated herein by reference.

[0186] In some embodiments, the hydroxypropyl cellulose is Nisso L, Nisso LM, Nisso LMM, Nisso M, or Nisso H. In some embodiments, the hydroxypropyl cellulose is Nisso LM, Nisso LMM, Nisso M, or Nisso H. In some embodiments, the hydroxypropyl cellulose is Nisso LMM, Nisso M, or Nisso H. In some embodiments, the hydroxypropyl cellulose is Nisso M or Nisso H. In some embodiments, the hydroxypropyl cellulose is Nisso M. In some embodiments, the hydroxypropyl cellulose is Nisso H.

[0187] Klucel ELF has an average molecular weight of about 40,000 Da; Klucel EF has an average molecular weight of about 80,000 Da; Klucel LF has an average molecular weight of about 95,000 Da; Klucel JF has an average molecular weight of about 140,000 Da; Klucel GF has an average molecular weight of about 370,000 Da; Klucel MF has an average molecular weight of about 850,000 Da; and Klucel HF has an average molecular weight of about 1,150,000 Da. Suitable particle sizes of Klucel HPC in the composition include regular grade and fine grade. See Technical date sheets of Klucel HPC products, the entirety of which is incorporated herein by reference.Attorney Docket No.62826-719.601

[0188] In some embodiments, the hydroxypropyl cellulose is Klucel JF, Klucel GF, Klucel MF, or Klucel HF. In some embodiments, the hydroxypropyl cellulose is Klucel GF, Klucel MF, or Klucel HF. In some embodiments, the hydroxypropyl cellulose is Klucel GF. In some embodiments, the hydroxypropyl cellulose is Klucel MF. In some embodiments, the hydroxypropyl cellulose is Klucel HF.

[0189] When the gelling agent is present in the composition, in some embodiments, the composition has a viscosity of from 5,000 cP to 100,000 cP. When the gelling agent is present, in some embodiments, the composition has a viscosity of from 5,000 cP to 50,000 cP. When the gelling agent is present, in some embodiments, the composition has a viscosity of from 5,000 cP to 40,000 cP. When the gelling agent is present, in some embodiments, the composition has a viscosity of from 5,000 cP to 30,000 cP. When the gelling agent is present, in some embodiments, the composition has a viscosity of from 10,000 cP to 30,000 cP. When the gelling agent is present, in some embodiments, the composition has a viscosity of from 15,000 cP to 30,000 cP. When the gelling agent is present, in some embodiments, the composition has a viscosity of from 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10000 cp to about 30000 cp.

[0190] When the hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of from 5,000 cP to 100,000 cP. When the hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of from 5,000 cP to 50,000 cP. When the hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of from 5,000 cP to 40,000 cP. When the hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of from 5,000 cP to 30,000 cP. When the hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of from 10,000 cP to 30,000 cP. When the hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of from 15,000 cP to 30,000 cP. When the hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of from 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10000 cp to about 30000 cp.

[0191] In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agent is present in the composition in an amount of from 0.5% to 30% by weight, while the composition has a viscosity of from 5,000 cP to 100,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the gellingAttorney Docket No.62826-719.601 agent is present in an amount of from 0.5% to 30% by weight, while the composition has a viscosity of from 5,000 cP to 50,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agent is present in an amount of from 0.5% to 30% by weight, while the composition has a viscosity of from 5,000 cP to 40,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agents are present in an amount of from 0.5% to 30% by weight, while the composition has a viscosity of from 5,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agents are present in an amount of from 0.5% to 30% by weight, while the composition has a viscosity of from 10,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agents are present in an amount of from 0.5% to 30% by weight, while the composition has a viscosity of from 15,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agents are present in an amount of from 0.5% to 30% by weight, while the composition has a viscosity of from 20,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the composition has a viscosity of about 10000 cp to about 30000 cp.

[0192] In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose is present in an amount of from 0.5% to 5%, from 5% to 10%, from 10% to 20%, or from 20% to 30% by weight, while the composition has a viscosity of from 5,000 cP to 100,000 cP. When a hydroxypropyl cellulose having an average molecular weight of less than about 700,000 Da is used, in some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose is present in an amount of 5% to 30% by weight, while the composition has a viscosity of from 5,000 cP to 100,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose is present in an amount of from 0.5% to 5%, from 0.5% to 4%, from 0.5% to about 3%, from 0.5% to 2%, from 1% to 5%, from 1% to 4%, from 1% to 3%, from 1% to 2%, or from 2% to 5% by weight while the composition has a viscosity of from 5,000 cP to 50,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose is present in an amount of from 0.5% to 5%, from 0.5% to 4%, from 0.5% to about 3%, from 0.5% to 2%, from 1% to 5%, from 1% to 4%, from 1% to 3%, from 1% to 2%, or from 2% to 5% by weight while the composition has a viscosity of from 5,000 cP to 40,000 cP. In someAttorney Docket No.62826-719.601 embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose is present in an amount of from 0.5% to 5%, from 0.5% to 4%, from 0.5% to about 3%, from 0.5% to 2%, from 1% to 5%, from 1% to 4%, from 1% to 3%, from 1% to 2%, or from 2% to 5% by weight while the composition has a viscosity of from 5,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose is present in an amount of from 0.5% to 4%, from 0.5% to 3%, from 0.5% to 2%, from 1% to 5%, from 1% to 4%, from 1% to 3%, from 1% to 2%, or from 2% to 5% by weight, while the composition has a viscosity of from 10,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose is present in an amount of from 0.5% to 4%, from 0.5% to 3%, from 0.5% to 2%, from 1% to 5%, from 1% to 4%, from 1% to 3%, from 1% to 2%, or from 2% to 5% by weight, while the composition has a viscosity of from 15,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose is present in an amount of from 0.5% to 4%, from 0.5% to 3%, from 0.5% to 2%, from 1% to 5%, from 1% to 4%, from 1% to 3%, from 1% to 2%, or from 2% to 5% by weight, while the composition has a viscosity of from 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10000 cp to about 30000 cp.

[0193] In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 0.5% to about 2% by weight of the composition. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 0.5% to 2% by weight, while the composition has a viscosity of from about 5,000 cP to about 50,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 0.5% to 2% by weight, while the composition has a viscosity of from about 5,000 cP to about 40,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 0.5% to 2% by weight, while the composition has a viscosity of from about 5,000 cP to about 30,000 cP. In some embodiments, where the composition is for use in treating orAttorney Docket No.62826-719.601 preventing BCC, the hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 0.5% to 2% by weight, while the composition has a viscosity of from 10,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 0.5% to 2% by weight, while the composition has a viscosity of from 15,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 0.5% to 2% by weight, while the composition has a viscosity of from 20,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the composition has a viscosity of about 10000 cp to about 30000 cp.

[0194] In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of about 1% by weight of the composition. In some embodiments, where the composition is for use in treating or preventing BCC, the hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of about 2% by weight of the composition.

[0195] In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of from 700,000 Da to 1,150,000 Da. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agent is present in an amount of from 0.5% to 5%, or about 2% by weight of the composition. Apparent pH Value

[0196] When the composition is a non-aqueous formulation, the pH value of the composition is an apparent pH value. When the composition includes water, the composition includes substantial amounts of other excipients (e.g., C2-6alcohol, organic solvents and / or penetration enhancers, a gelling agent). Therefore, the pH value of a partially aqueous solutions can be regarded only as an apparent pH value. The apparent pH value of a non- aqueous or a partially aqueous solution is anticipated for variability, and may be up to approximately 1 pH unit.Attorney Docket No.62826-719.601

[0197] In some embodiments, when a pH adjuster is absent from a composition, the composition has an apparent pH value of from about 7.5 to about 9.5. In some embodiments, when a pH adjuster is absent from a composition, the composition has an apparent pH value of from about 7.5 to about 8.5. In some embodiments, when a pH adjuster is absent from a composition, the composition has an apparent pH value of from about 8.5 to about 9.5. In some embodiments, when a pH adjuster is absent from a composition, the composition has an apparent pH value of about 8. In some embodiments, when a pH adjuster is absent from a composition, the composition has an apparent pH value of about 9.

[0198] In some embodiments, when a pH adjuster is present in a composition, the composition has an apparent pH value of no more than about 7. In some embodiments, when a pH adjuster is present in a composition, the composition has an apparent pH value of from about 5 to about 7 or from about 6 to about 7. In some embodiments, when a pH adjuster is present in a composition, the composition has an apparent pH value of from about 6 to about 7. In some embodiments when a pH adjuster is present in a composition the composition has an apparent pH of about 6 to about 9.5. In some embodiments when a pH adjuster is present in a composition the composition has an apparent pH of about 7 to about 8. In some embodiments when a pH adjuster is present in a composition the composition has an apparent pH of about 7. Compound

[0199] In any of the compositions as described herein, the compound 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;Attorney Docket No.62826-719.601 R2is an optionally substituted C6-12 aryl or optionally substituted 3- to 12- membered heteroaryl; and n is 0 to 5.

[0200] 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 C6-12 aryl. 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.

[0201] In some embodiments, the compound can be represented by Formula (I-A) or Formula (I-B):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 C1-6alkoxy; R4is hydrogen or C1-6 alkyl; and n is 0 to 5.Attorney Docket No.62826-719.601

[0202] In some embodiments, each R1is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6haloalkyl, 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 C1-6 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.

[0203] 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.

[0204] In some embodiments, the compound can be represented by Formula (I-AA) or Formula (I-BB):wherein: R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6alkyl.

[0205] 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.

[0206] In some embodiments, R4is hydrogen or C1-6 alkyl. 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.62826-719.601

[0207] In any of the compositions as described herein, the compound can be represented by Formula (II):wherein RAis C1-20alkyl.

[0208] In some embodiments, RAis C5-20alkyl. In some embodiments, RAis C10-20alkyl. 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.

[0209] In any of the compositions as described herein, the compound can be represented by Formula (III):

[0210] In any one of the compositions as described herein, the compound 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:a mixture thereof.

[0211] In any one of the compositions described herein, 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 may be comprised in the composition.Attorney Docket No.62826-719.601

[0212] In any one of the compositions as described herein, 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. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, and quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.

[0213] In any one of the compositions as described herein, the compound 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.

[0214] In some embodiments, the compound is a compound having the structure of Formula (I).

[0215] In some embodiments, the compound is a compound having the structure of Formula (I-A). In some embodiments, the compound is a compound having the structure of Formula (I-B). In some embodiments, the compound is a compound having the structure of Formula (I-AA).

[0216] In some embodiments, the compound is a compound having the structure of Formula (I-BB).

[0217] In some embodiments, the compound is a compound having the structure of Formula (II).

[0218] In some embodiments, the compound is a compound having the structure of Formula (III).

[0219] In some embodiments, the compound is Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer).

[0220] In some embodiments, the compound is Compound 2, represented by the structure:.Attorney Docket No.62826-719.601

[0221] In some embodiments, the compound is Compound 3, represented by the structure:.

[0222] In some embodiments, the compound is Compound 4, represented by the structure:.

[0223] In some embodiments, the compound is Compound 5, represented by the structure:.

[0224] In some embodiments, the compound is Compound 6, represented by the structure:.

[0225] In some embodiments, the compound is Compound 7, represented by the structure:.

[0226] In some embodiments, the compound is Compound 8, represented by the structure:Attorney Docket No.62826-719.601.

[0227] In some embodiments, the compound is Compound 9, represented by the structure:.

[0228] In some embodiments, the compound is Compound 10, represented by the structure:.

[0229] In some embodiments, the compound is Compound 11, represented by the structure:.

[0230] In some embodiments, the compound 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 a pharmaceutically acceptable salts thereof. In some embodiments, the compound 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 is 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%. InAttorney Docket No.62826-719.601 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 mixture in an amount of from 0.01% to 10%. 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 0.1% to 1.5%. 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 mixture in an amount of from 0.01% to 10%. 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 mixture in an amount of from 0.1% to 1.5%. Embodiments

[0231] In some embodiments, the composition comprises three or more excipients from (a)-(g): a) C2-6 alcohol; b) a C2-6 alkylene glycol and C1-3 alkyl-(OCH2CH2)1-5-OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjuster; and g) a gelling agent. In some embodiments, the composition comprises four or more excipients from (a)-(g): a) C2-6 alcohol; b) a C2-6 alkylene glycol and C1-3 alkyl-(OCH2CH2)1-5-OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjuster; and g) a gelling agent. In some embodiments, the composition comprises five or more excipients from (a)-(g): a) C2-6alcohol; b) a C2-6alkylene glycol and C1-3alkyl-(OCH2CH2)1-5-OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjuster; and g) a gelling agent. In some embodiments, the composition comprises six or more excipients from (a)-(g): a) C2-6 alcohol; b) a C2-6 alkylene glycol and C1-3 alkyl- (OCH2CH2)1-5-OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjuster; and g) a gelling agent. The composition may be formulated at about 0.01% to 10% compound 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 1.5% compound 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. TheAttorney Docket No.62826-719.601 composition may be formulated at about 0.01% to 10% 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 1.5% Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer), or a salt thereof.

[0232] In some embodiments, the composition comprises a) C2-6 alcohol; b) a C2-6 alkylene glycol and C1-3 alkyl-(OCH2CH2)1-5-OH; e) water; and g) a gelling agent. In some embodiments, the composition comprises a) C2-6 alcohol; b) a C2-6 alkylene glycol and C1-3 alkyl-(OCH2CH2)1-5-OH; c) an antioxidant; d) a preservative; e) water; and g) a gelling agent. In some embodiments, the composition comprises a) C2-6alcohol; b) a C2-6alkylene glycol and C1-3alkyl-(OCH2CH2)1-5-OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjuster; and g) a gelling agent. The composition may be formulated at about 0.01% to 10% compound 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 1.5% compound 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 0.01% to 10% 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 1.5% Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer), or a salt thereof.

[0233] In some embodiments, the present disclosure provides a topical pharmaceutical composition (A) comprising a compound having the structure of Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III): wherein the compound, the C2-6 alcohol, C1-3 alkyl-(OCH2CH2)1-5-OH, the antioxidant, the preservative, water, the pH adjuster, and the gelling agent are as described herein. The composition may be formulated at about 0.01% to 10% compound 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 1.5% compound 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 0.01% to 10% 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 1.5% Compound 1 (e.g., Compound 11H tautomer and / or Compound 12HAttorney Docket No.62826-719.601 tautomer), or a salt thereof.In some embodiments of composition (A), the antioxidant is absent in the composition. In some embodiments of composition (A), the preservative is absent in the composition. In some embodiments of composition (A), the pH adjuster is absent in the composition. In some embodiments of composition (A), all of the antioxidant, the preservative, and the pH adjuster are absent in the composition.

[0234] In some embodiments of composition (A), one or more of the antioxidant, the preservative, and the pH adjuster are present in the composition. In some embodiments of composition (A), both the antioxidant and the preservative are present in the composition; and the pH adjuster is absent in the composition.

[0235] In some embodiments, the present disclosure provides a topical pharmaceutical composition (B) comprising a compound 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, wherein the compound, the C2-6 alcohol, C1-3 alkyl-(OCH2CH2)1-5-OH, water, and the gelling agent are as described herein. The composition may be formulated at about 0.01% to 10% compound 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 1.5% compound 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 0.01% to 10% 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 1.5% Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer), or a salt thereof.

[0236] In some embodiments, the present disclosure provides a topical pharmaceutical composition (C) comprising a compound 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 pharmaceutically acceptable salt or tautomer thereof, and excipients a) to e) and g): a) C2-6 alcohol; b) a C2-6 alkylene glycol and C1-3 alkyl-(OCH2CH2)1-5-OH;Attorney Docket No.62826-719.601 c) an antioxidant; d) a preservative; e) water; and g) a gelling agent, wherein the compound, the C2-6 alcohol, C1-3 alkyl-(OCH2CH2)1-5-OH, the antioxidant, the preservative, water, and the gelling agent are as described herein. The composition may be formulated at about 0.01% to 10% compound 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 1.5% compound 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 0.01% to 10% 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 1.5% Compound 1 (e.g., Compound 11H tautomer and / or Compound 12H tautomer), or a salt thereof.

[0237] In some embodiments of any one of compositions (A), (B) and (C), where the composition is for use in treating or preventing BCC, the C2-6alcohol is present in the composition in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the C2-6 alcohol is present in an amount of from 10% to 30%. In some embodiments, where the composition is for use in treating or preventing BCC, the C2-6 alcohol is present in an amount of from 10% to 20%. In some embodiments, where the composition is for use in treating or preventing BCC, the C2-6alcohol is present in an amount of about 15% by weight.

[0238] In some embodiments of any one of compositions (A), (B) and (C), where the composition is for use in treating or preventing BCC, the C2-6alkylene glycol is present in the composition in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the C2-6 alkylene glycol is present in an amount of from 10% to 30%. In some embodiments, where the composition is for use in treating or preventing BCC, the C2-6 alkylene glycol is present in an amount of from 10% to 20%. In some embodiments, where the composition isAttorney Docket No.62826-719.601 for use in treating or preventing BCC, the C2-6 alkylene glycol is present in an amount of about 15% by weight.

[0239] In some embodiments of any one of compositions (A), (B) and (C), where the composition is for use in treating or preventing BCC, C1-3 alkyl-(OCH2CH2)1-5-OH is present in an amount of from 30% to 70%, from 40% to 60%, or about 47% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, C1-3 alkyl- (OCH2CH2)1-5-OH is present in an amount of from 30% to 70% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, C1-3 alkyl- (OCH2CH2)1-5-OH is present in an amount of from 40% to 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, C1-3alkyl- (OCH2CH2)1-5-OH is present in an amount of about 47% by weight.

[0240] In some embodiments of any one of compositions (A), (B) and (C), where the composition is for use in treating or preventing BCC, water is present in an amount of from 10% to 30%, from 15% to 25%, or about 20% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, water is present in an amount of from 10% to 30% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, water is present in an amount of from 15% to 25% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, water is present in an amount of about 20% by weight.

[0241] In some embodiments of any one of compositions (A), (B) and (C), where the composition is for use in treating or preventing BCC, the gelling agent is present in an amount of from 1% to 3% or about 2% by weight, while the composition has a viscosity of from 5,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agent is present in an amount of from 1% to 3% or about 2% by weight, while the composition has a viscosity of from 10,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agent is present in an amount of from 1% to 3% or about 2% by weight, while the composition has a viscosity of from 15,000 cP to 30,000 cP. In some embodiments, where the composition is for use in treating or preventing BCC, the gelling agent is present in an amount of from 1% to 3% or about 2% by weight, while the composition has a viscosity of from 20,000 cP to 30,000 cP.Attorney Docket No.62826-719.601

[0242] In some embodiments of any one of compositions (A), (B) and (C), the C2-6 alcohol is ethanol, the C2-6alkylene glycol is propylene glycol; C1-3alkyl-(OCH2CH2)1-5-OH is 2-(2-ethoxyethoxy)ethanol; and the gelling agent is hydroxypropyl cellulose.

[0243] In some embodiments, the composition (A1) comprises the compound and four or more excipients from (a)-(g): a) ethanol; b) propylene glycol and 2-(2-ethoxyethoxy)ethanol; c) optionally an antioxidant; d) optionally a preservative; e) water; f) optionally a pH adjuster; and g) hydroxypropyl cellulose. wherein the compound, the antioxidant, the preservative, and the pH adjuster are as described herein.

[0244] In some embodiments, the composition (B1) comprises the compound and excipients a), b), e), and g): a) ethanol; b) propylene glycol and 2-(2-ethoxyethoxy)ethanol; e) water; and g) hydroxypropyl cellulose, wherein the compound is as described herein.

[0245] In some embodiments, the composition (C1) comprises the compound and excipients a) to e) and g): a) ethanol; b) propylene glycol and 2-(2-ethoxyethoxy)ethanol; c) an antioxidant; d) a preservative;Attorney Docket No.62826-719.601 e) water; and g) hydroxypropyl cellulose, wherein the compound, the antioxidant and the preservative are as described herein.

[0246] In some embodiments of composition (A) or (A1), the pH adjuster, when present, is an acid. In some embodiment, the pH adjuster, when present, is citric acid. In some embodiments of composition (A) or (A1), the pH adjuster, when present, is an acid. In some embodiment, the pH adjuster, when present, is lactic acid or ascorbic acid.

[0247] In some embodiments of any one of compositions (A), (C), (A1), and (C1), the antioxidant, when present, is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or combinations thereof. In some embodiments, the antioxidant, when present, is butylated hydroxytoluene.

[0248] In some embodiments of any one of compositions (A), (C), (A1), and (C1), the preservative, when present, is phenoxyethanol.

[0249] In some embodiments of any one of compositions (A), (C), (A1), and (C1), the antioxidant, when present, is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or combinations thereof; and the preservative, when present, is phenoxyethanol. In some embodiments, the antioxidant, when present, is butylated hydroxytoluene; and the preservative, when present, is phenoxyethanol.

[0250] In some embodiments of any one of compositions (A), (C), (A1), and (C1), where the composition is for use in treating or preventing BCC, the antioxidant, when present, is present in an amount of from 0.01% to 0.1% or about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the antioxidant, when present, is present in an amount of from 0.01% to 0.1% by weight. In some embodiments, the antioxidant, when present, is present in an amount of about 0.05% by weight.

[0251] In some embodiments of any one of compositions (A), (C), (A1), and (C1), where the composition is for use in treating or preventing BCC, the preservative, when present, is present in an amount of from 0.5% to 2% or about 1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, the preservative, when present, is present in an amount of from 0.5% to 2% by weight. In some embodiments,Attorney Docket No.62826-719.601 where the composition is for use in treating or preventing BCC, the preservative, when present, is present in an amount of about 1% by weight.

[0252] In some embodiments, the composition (C1a) comprises the compound and excipients a) to e) and g): a) ethanol; b) propylene glycol and 2-(2-ethoxyethoxy)ethanol; c) butylated hydroxytoluene; d) phenoxyethanol; e) water; and g) hydroxypropyl cellulose, wherein the compound is as described herein.

[0253] In some embodiments of any one of compositions (A1), (B1), (C1), and (C1a), where the composition is for use in treating or preventing BCC, ethanol is present in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of from 10% to 30% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of from 10% to 20% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, ethanol is present in an amount of about 15% by weight.

[0254] In some embodiments of any one of compositions (A1), (B1), (C1), and (C1a), where the composition is for use in treating or preventing BCC, propylene glycol is present in an amount of from 10% to 30%, from 10% to 20%, or about 15% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, propylene glycol is present in an amount of from 10% to 30% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, propylene glycol is present in an amount of from 10% to 20% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, propylene glycol is present in an amount of about 15% by weight.

[0255] In some embodiments of any one of compositions (A1), (B1), (C1), and (C1a), where the composition is for use in treating or preventing BCC, 2-(2-ethoxyethoxy)ethanol isAttorney Docket No.62826-719.601 present in an amount of from 30% to 70%, from 40% to 60%, or about 47% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, 2-(2- ethoxyethoxy)ethanol is present in an amount of from 30% to 70% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, 2-(2- ethoxyethoxy)ethanol is present in an amount of from 40% to 60% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, 2-(2- ethoxyethoxy)ethanol is present in an amount of about 47% by weight.

[0256] In some embodiments of any one of compositions (A1), (B1), (C1), and (C1a), where the composition is for use in treating or preventing BCC, water is present in an amount of from 10% to 30%, from 15% to 25%, or about 20% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, water is present in an amount of from 10% to 30% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, water is present in an amount of from 15% to 25% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, water is present in an amount of about 20% by weight.

[0257] In some embodiments of any one of compositions (A1), (B1), (C1), (C1a), where the composition is for use in treating or preventing BCC, hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 1% to 3% or about 2% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of from 1% to 3% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of about 1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, hydroxypropyl cellulose having an average molecular weight of from 700,000 Da to 1,150,000 Da is present in an amount of about 2% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, hydroxypropyl cellulose is Klucel MF in an amount of about 2% by weight.

[0258] In some embodiments of composition (C1a), where the composition is for use in treating or preventing BCC, butylated hydroxytoluene is present in the composition in an amount of from 0.01% to 0.1% or about 0.05% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, butylated hydroxytoluene is present inAttorney Docket No.62826-719.601 an amount of from 0.01% to 0.1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, butylated hydroxytoluene is present in an amount of about 0.5% by weight.

[0259] In some embodiments of composition (C1a), where the composition is for use in treating or preventing BCC, phenoxyethanol is present in the composition in an amount of from 0.5% to 2% or about 1% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, phenoxyethanol is present in an amount of from 0.5% to 2% by weight. In some embodiments, where the composition is for use in treating or preventing BCC, phenoxyethanol is present in an amount of about 1% by weight.

[0260] In some embodiments of composition (C1a), where the composition is for use in treating or preventing BCC, butylated hydroxytoluene is present in an amount of about 0.5% by weight; and phenoxyethanol is present in an amount of about 1% by weight.

[0261] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), propylene glycol is a super refined propylene glycol.

[0262] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of > 99.90%.

[0263] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), the compound is present in the composition in an amount of from 0.01% to 10%. Forms of Compositions

[0264] Topical compositions useful for delivering the compound 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 is a gel, ointment, lotion, foam or emollient.

[0265] In some embodiments, the topical composition used to deliver the compound is a lotion or a cream.

[0266] In some embodiments, the topical composition used to deliver the compound is a gel, for example, a two-phase gel or a single-phase gel. Gels are semisolid systems consisting of suspensions of small inorganic particles or large organic molecules interpenetrated by a liquid. When the gel mass comprises a network of small discrete inorganic particles, it is classified as a two-phase gel. Single-phase gels consist of organicAttorney Docket No.62826-719.601 macromolecules distributed uniformly throughout a liquid such that no apparent boundaries exist between the dispersed macromolecules and the liquid.

[0267] In some embodiments, the topical composition used to deliver the compound is an ointment. 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.

[0268] In some embodiments the topical composition used to deliver the compound is an emulsified gel. In some embodiments the topical composition used to deliver the compound is an emulsified spray.

[0269] In some embodiments, the topical composition may be achieved in the form of a patch, tape, film, wafer, or bandage including 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, 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.

[0270] In some embodiments, the topical administration may be achieved in the form of a patch, tape, film, wafer, or bandage including 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, 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.

[0271] In some embodiments, the patch, tape, film, wafer, or bandage includes an adhesive.

[0272] In some embodiments, the topical composition may be delivered to a basal cell carcinoma, squamous cell carcinoma, or melanoma using a tape or film which provides an occluding environment for the tumor. In some embodiments, the squamous cell carcinoma may be an invasive squamous cell carcinoma or a squamous cell carcinoma in situ. In some embodiments, the squamous cell carcinoma in situ may be Bowen’s disease.

[0273] 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.Attorney Docket No.62826-719.601

[0274] In some embodiments, the composition is impregnated in the tape or film. In some embodiments, the tape or film is a foam-containing tape or film. 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. If the foam is porous, an outer non- porous layer can be provided on the back of the foam to enhance tape occlusion.

[0275] 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. The non-porous backing layer can have a portion extending beyond the composition containing Compound 1 and the porous layer. This portion can include a quantity of adhesive for facilitating adhesion of the wafer or dot to the skin of a user peripheral to the carcinoma or melanoma being treated.

[0276] In some embodiments the composition for application may be covered by a film or thermosensitive gel material including but not limited to poly(ethylene glycol) / poly(propylene glycol) block copolymers (poloxamers), poly(ethylene glycol) / poly(butylenes glycol) block copolymers, poloxamer-g-poly(acrylic acid) and copolymers of Nisopropylacrylamide that exhibit a sol-to-gel transition in aqueous solutions. In some embodiments the film or thermosensitive gel material may be impregnated with the composition. In some embodiments the film or thermosensitive gel material impregnated with the composition may include but is not limited to poly(ethylene glycol) / poly(propylene glycol) block copolymers (poloxamers), poly(ethylene glycol) / poly(butylenes glycol) block copolymers, poloxamer-g-poly(acrylic acid) and copolymers of Nisopropylacrylamide that exhibit a sol-to-gel transition in aqueous solutions.

[0277] 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 or emollient. In some embodiments, the composition is a component of a patch, tape, film, wafer, or bandage.

[0278] In some embodiments, the compositions of this disclosure can be administered with other agents in a combination therapy mode for the treatment or prevention of skin diseases, disorders, or conditions. In some instances the skin disease is Basal cell carcinoma, Squamous cell carcinoma or melanoma. In some embodiments, the squamous cell carcinoma may be an invasive squamous cell carcinoma or a squamous cell carcinoma in situ. In someAttorney Docket No.62826-719.601 embodiments, the squamous cell carcinoma in situ may be Bowen’s disease. In some embodiments the other agent can include one or more of the following but is not limited to: anti-inflammatory drugs, NSAIDs, antimicrobials, antibiotics, steroids, anti-viral agents, chemotherapy agents, alkylating agents, antimetabolites, or antimicrotubular agents, Vitamin D Derivatives, Oxidative compounds, Acids, Retinoid derivatives, Keratolytics, Corticosteroids, immunoregulators, immune modulators, sunscreens, UV blockers, zinc compounds, retinoids, dyschromia treatments, hyperpigmentation treatments, moisturizers, anti-aging treatments. Administration can be sequential, over a period of hours or days, or simultaneously.

[0279] In some embodiments, the compositions of this disclosure can be administered with other agents in a combination therapy mode for the treatment or prevention of skin diseases, disorders, or conditions. In some instances the skin disease is a non-melanoma skin cancer such as a Basal Cell Carcinoma or Squamous cell carcinoma, or melanoma. In some embodiments the other agent is preventative, and can include but is not limited to: anti- inflammatory drugs, NSAIDs, antimicrobials, antibiotics, steroids, anti-viral agents, chemotherapy agents, alkylating agents, antimetabolites, or antimicrotubular agents, Vitamin D Derivatives, Oxidative compounds, Acids, Retinoid derivatives, Keratolytics, Corticosteroids, immunoregulators, immune modulators, sunscreens, UV blockers, zinc compounds, retinoids, dyschromia treatments, hyperpigmentation treatments, moisturizers, anti-aging treatments. Administration can be sequential, over a period of hours or days, or simultaneously.

[0280] In some embodiments, anti-viral agents can include Abacavir, Acyclovir, Adefovir, Amprenavir, Atazanavir, Cidofovir, Darunavir, Delavirdine, Didanosine, Docosanol, Efavirenz, Elvitegravir, Emtricitabine, Enfuvirtide, Etravirine, Famciclovir, Foscarnet, Fomivirsen, Ganciclovir, Indinavir, Idoxuridine, Lamivudine, Lopinavir Maraviroc, MK-2048, Nelfinavir, Nevirapine, Penciclovir, Raltegravir, Rilpivirine, Ritonavir, Saquinavir, Stavudine, Tenofovir Trifluridine, Valaciclovir, Valganciclovir, Vidarabine, Ibacitabine, Amantadine, Oseltamivir, Rimantidine, Tipranavir, Zalcitabine, Zanamivir and Zidovudine.

[0281] In one embodiment, the compositions are included in combination therapy with one or more corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressive drugs, cyclosporin A, mercaptopurine, azathiopurine, prednisone,Attorney Docket No.62826-719.601 methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotrienes, anti-cholinergic drugs for rhinitis, anti- cholinergic decongestants, mast- cell stabilizers, monoclonal anti-IgE antibodies, vaccines, and combinations thereof. METHODS

[0282] In certain aspects, the present disclosure provides a method of treating or preventing a skin disease, condition or disorder in a subject in need thereof, the method comprising administering to the subject a composition, as described herein.

[0283] 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. In some embodiments, compounds 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, Compound 1 may modulate Akt activity. In some embodiments the modulators may include but are not limited to PTEN – PIP2—PIP3, PI3K, PDK1, PP2A, EGFR, IGFR, or other receptor tyrosine kinases.

[0284] Compound 1 may have modulator effects on AKT activity. Table 34 shows Compound 1’s increased potency in inhibiting AK1 at a concentration of 1 mM in an AssayQuant PhosphoSens assay. Table 34No time dependence was observed. Compound-dependent lag was observed, and preincubation progress curves had increased lags.Attorney Docket No.62826-719.601

[0285] Additionally, a compound with the structure of Formula (III) as described herein may have modular effects on AKT activity. Table 35 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. Table 35No time dependence was observed, and preincubation progress curves had increased lags.

[0286] In some embodiments the composition described herein provides a method by which Akt inhibition suppresses AKT signaling to downstream targets that regulate multimodal cellular functions including but not limited to cell survival, apoptosis, cell proliferation, cellular metabolism, proteasomal degradation, protein translation, and lipid synthesis. In some embodiments, compositions comprising a compound described herein (e.g., a compound having a structure represented by Formula (I), Formula (I-A), Formula (I- B), Formula (I-AA), Formula (I-BB), Formula (II), and / or Formula (III)) may induce apoptosis. In some embodiments, a compound having a structure represented by Formula (I), Formula (I-A), Formula (I-B), Formula (I-AA), Formula (I-BB), or Formula (II) may be a more potent inhibitor of AKT than a compound having a structure represented by Formula (III).

[0287] In some embodiments the composition described herein provides a method by which a compound that can inhibit Akt can modulate other targets and pathways. In some embodiments these targets include but are not limited to ASK1, AS160, GLUT1, GLUT4, TXNIP, HK2, PFKFB2, TKT, SIRT1, PTP1B, PRAS40, MDM2, BAD, BH3 family members, ACLY, NFkappaB, MDM2 – p53, IKKalpha, P21CIP1, P27KIP1, Casp9, TBC1D4, PDE3B, WNK1, eNOS, FOXO, FOXO1, FOXO3 / 3A, FOXO4, TSC2, TSC- mTORC1, GSK3alpha / beta, FAF1, PRAS40, Chk1, PDK1, EGFR, EGFR / ADCK, Akt1,Attorney Docket No.62826-719.601 AKT1 (allosteric), P13KA, PI3Kd, p110a, Pi3K / Mtor / DNA-PK, DNA-PK, FGFR, VEGFR1, VEGFR2, PDGFR, KIT, and FLT3.

[0288] In some embodiments, the method may comprise using the composition described herein to regulates cellular functions through Akt by modulating the GSK3Beta pathway. In some embodiments, Akt inhibition will impact the function and regulation of GSK3beta and one or more of the non-limiting list of following targets: PGC1alpha, bTrCP, PDE3B, TBC1D4, SREBP, Myc, HIF1alpha, NRF2, C / EBP, eIF2B, Gli, Gli2, Gli3, FBXW7, and / or ERRalpha. In some embodiments the compound that can inhibit Akt will modulate transcription factors. In some embodiments the transcription factors include but are not limited to Myc, HIF1, SREBP, ATF4, NRF2, Forkhead box family of transcription factors, FOXO, FOXO3 FoxO1, FOXO4 and FOXO6, and or DAF-16. In some embodiments the Akt inhibition influences transcription factors that regulate genes that regulate apoptosis, cell cycle, cell growth and proliferation. These genes may include but are not limited to: BAD, FASL, TRAIL, BIM, PUMA, CDKN1a (p21 / CIP1), CDKN1b (P27 / KIP1), RBL2, GADD45a

[0289] In some embodiments, methods may comprise using the composition described herein to inhibit Akt which may have a profound effect on the function of the TSC-mTORC1 complex / pathway including but not limited to: TSC2, Rheb, mTORC1, 4E-BP, S6K, S6, 4EBP1. S6K may act downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth, and cell cycle progression. S6K may additionally regulate protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K and promote cell survival by repressing the pro-apoptotic function of BAD.

[0290] In some embodiments, methods may comprise using the composition comprising the compound that can inhibit Akt to regulate intrinsic apoptosis. In some embodiments, the compound that inhibit can Akt targets and impacts BH3 proteins, Bad, BIM, BCL-2, BCLxL, other BH3 proteins, other mitochondrial membrane proteins, NFKappaB, and / or MDM2-p53.

[0291] In some embodiments the composition and compound described herein targets, inhibits, or modulates kinases. In some instances the kinase is Akt. In some instances the kinase is not Akt.

[0292] In some embodiments the composition and compound described herein can inhibit, and / or modulate a target kinase or kinase pathway. The inhibition of targets describedAttorney Docket No.62826-719.601 herein may lead to the prevention or treatment of certain skin cancers (e.g., BCCs, SCCs, or melanoma). For example, CLK2 is expressed in BCC, SCC, and cross talks with the HH / WNT pathway, DYRK1B is expressed in SCC and interacts with the HH pathway, CLK1 is expressed in BCC and cross talks with the HH / WNT pathway, ICK / CILK1 is expressed in BCC and SCC and interacts with the mTOR and HH pathway, CLK4 is expressed in BCC and SCC and cross talks with the HH / WNT pathway, DYRK1A is expressed in SCC, some BCC, and interacts with the HH pathway, and P70S6KA is a major AKT and mTOR effector kinase. As described further herein, each of CLK2, DYRK1B, CLK1, ICK / CILK1, CLK4, DYRK1A, and P70S6KA are all inhibited at greater than 70% when one or more compounds (e.g., compounds having a structure represented by Formula (I), Formula (I-A), Formula (I- B), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III)) is administered.

[0293] In some embodiments the target is ABL1 E255K, ABL1 F317I, ABL1 F317L, ABL1 G250E, ABL1 T315I, ABL1 Y253F, ABL1, ABL2 (Arg), ACVR1B (ALK4), ADRBK1 (GRK2), ADRBK2 (GRK3), AKT1 (PKB alpha), AKT2 (PKB beta), AKT3 (PKB gamma), ALK, AMPK (A1 / B2 / G2), AMPK (A1 / B2 / G3), AMPK (A2 / B1 / G2), AMPK (A2 / B1 / G3), AMPK (A2 / B2 / G3), AMPK A1 / B1 / G1, AMPK A2 / B1 / G1, AURKA (Aurora A), AURKB (Aurora B), AURKC (Aurora C), AXL, BLK, BMX, BRAF V599E, BRAF, BRSK1 (SAD1), BTK, CAMK1D (CaMKI delta), CAMK1G (CAMKI gamma), CAMK2A (CaMKII alpha), CAMK2B (CaMKII beta), CAMK2D (CaMKII delta), CAMK4 (CaMKIV), CDC42 BPA (MRCKA), CDC42 BPB (MRCKB), CDC42 BPG (MRCKG), CDK1 / cyclin B, CDK17 / cyclin Y, CDK18 / cyclin Y, CDK2 / cyclin A, CDK5 / p25, CDK5 / p35, CDKL5, CHEK1 (CHK1), CHEK2 (CHK2), CLK1, CLK2, CLK3, CSF1R (FMS), CSK, CSNK1A1 (CK1 alpha 1), CSNK1A1L, CSNK1D (CK1 delta), CSNK1E (CK1 epsilon) R178C, CSNK1E (CK1 epsilon), CSNK1G1 (CK1 gamma 1), CSNK1G2 (CK1 gamma 2), CSNK1G3 (CK1 gamma 3), CSNK2A1 (CK2 alpha 1), CSNK2A2 (CK2 alpha 2), DAPK3 (ZIPK), DCAMKL1 (DCLK1), DCAMKL2 (DCK2), DNA-PK, DYRK1A, DYRK1B, DYRK3, DYRK4, EEF2K, EGFR (ErbB1) C797S, EGFR (ErbB1) G719C, EGFR (ErbB1) G719S, EGFR (ErbB1) L858R, EGFR (ErbB1) L861Q, EGFR (ErbB1) T790M C797S L858R, EGFR (ErbB1) T790M L858R, EGFR (ErbB1) T790M, EGFR (ErbB1), EPHA1, EPHA2, EPHA4, EPHA5, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, ERBB2 (HER2), ERBB4 (HER4), FER, FES (FPS), FGFR1, FGFR2 N549H, FGFR2, FGFR3 K650E, FGFR3 V555M, FGFR3, FGFR4, FGR, FLT1 (VEGFR1), FLT3 D835Y, FLT3, FLT4 (VEGFR3), FRAP1 (mTOR), FRK (PTK5), FYN, GRK4, GRK5, GRK6, GRK7, GSK3A (GSK3 alpha),Attorney Docket No.62826-719.601 GSK3B (GSK3 beta), HCK, HIPK1 (Myak), HIPK2, HIPK3 (YAK1), HIPK4, IGF1R, IKBKB (IKK beta), IKBKE (IKK epsilon), INSR, INSRR (IRR), IRAK4, ITK, JAK1, JAK2 JH1 JH2 V617F, JAK2 JH1 JH2, JAK2, JAK3, KDR (VEGFR2), KIT T670I, KIT V559D V654A, KIT V559D, KIT V560G, KIT, KSR2, LCK, LTK (TYK1), LYN A, LYN B, MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K6 (MKK6), MAP3K19 (YSK4), MAP3K8 (COT), MAP3K9 (MLK1), MAP4K2 (GCK), MAP4K4 (HGK), MAP4K5 (KHS1), MAPK1 (ERK2), MAPK10 (JNK3), MAPK11 (p38 beta), MAPK12 (p38 gamma), MAPK13 (p38 delta), MAPK14 (p38 alpha) Direct, MAPK14 (p38 alpha), MAPK3 (ERK1), MAPK7 (ERK5), MAPK8 (JNK1), MAPK9 (JNK2), MAPKAPK2, MAPKAPK3, MAPKAPK5 (PRAK), MARK1 (MARK), MARK2, MARK3, MARK4, MATK (HYL), MELK, MERTK (cMER), MET (cMet) Y1235D, MET (cMet), MET M1250T, MINK1, MKNK1 (MNK1), MST1R (RON), MST4, MUSK, MYLK2 (skMLCK), NEK1, NEK2, NEK4, NEK6, NEK9, NIM1K, NTRK1 (TRKA), NTRK2 (TRKB), NTRK3 (TRKC), PAK1, PAK2 (PAK65), PAK3, PAK4, PAK6, PAK7 (KIAA1264), PASK, PDGFRA (PDGFR alpha), PDGFRA D842V, PDGFRA T674I, PDGFRA V561D, PDGFRB (PDGFR beta), PDK1 Direct, PDK1, PEAK1, PHKG1, PHKG2, PIM1, PIM2, PIM3, PKN1 (PRK1), PLK1, PLK2, PLK3, PRKACA (PKA), PRKCA (PKC alpha), PRKCB1 (PKC beta I), PRKCB2 (PKC beta II), PRKCD (PKC delta), PRKCE (PKC epsilon), PRKCG (PKC gamma), PRKCH (PKC eta), PRKCI (PKC iota), PRKCN (PKD3), PRKCQ (PKC theta), PRKCZ (PKC zeta), PRKD1 (PKC mu), PRKD2 (PKD2), PRKG1, PRKG2 (PKG2), PRKX, PTK2 (FAK), PTK2B (FAK2), PTK6 (Brk), RAF1 (cRAF) Y340D Y341D, RET A883F, RET S891A, RET V804E, RET V804L, RET Y791F, RET, ROCK1, ROCK2, ROS1, RPS6KA1 (RSK1), RPS6KA2 (RSK3), RPS6KA3 (RSK2), RPS6KA4 (MSK2), RPS6KA5 (MSK1), RPS6KA6 (RSK4), RPS6KB1 (p70S6K), RPS6KB2 (p70S6Kb), SBK1, SGK (SGK1), SGK2, SGKL (SGK3), SNF1LK2, SRC N1, SRC, SRMS (Srm), SRPK1, SRPK2, STK22B (TSSK2), STK22D (TSSK1), STK23 (MSSK1), STK24 (MST3), STK25 (YSK1), STK3 (MST2), STK4 (MST1), SYK, TAOK2 (TAO1), TBK1, TEK (TIE2) Y897S, TEK (Tie2), TNK1, TXK, TYK2, TYRO3 (RSE), YES1, ZAP70, CAMK1 (CaMK1), CDK4 / cyclin D1, CDK4 / cyclin D3, CDK6 / cyclin D1, CDK7 / cyclin H / MNAT1, CDK9 / cyclin T1, CHUK (IKK alpha), DAPK1, GSG2 (Haspin), IRAK1, LRRK2 FL, LRRK2 G2019S FL, LRRK2 G2019S, LRRK2 I2020T, LRRK2 R1441C, LRRK2, NUAK1 (ARK5), PI4K2A (PI4K2 alpha), PI4K2B (PI4K2 beta), PI4KA (PI4K alpha), PI4KB (PI4K beta), PIK3C2A (PI3K-C2 alpha), PIK3C2B (PI3K-C2 beta), PIK3C2G (PI3K-C2 gamma), PIK3C3 (hVPS34), PIK3CAAttorney Docket No.62826-719.601 E542K / PIK3R1 (p110 alpha E542K / p85 alpha), PIK3CA E545K / PIK3R1 (p110 alpha E545K / p85 alpha), PIK3CA / PIK3R1 (p110 alpha / p85 alpha), PIK3CA / PIK3R3 (p110 alpha / p55 gamma), PIK3CB / PIK3R1 (p110 beta / p85 alpha), PIK3CB / PIK3R2 (p110 beta / p85 beta), PIK3CD / PIK3R1 (p110 delta / p85 alpha), PIK3CG (p110 gamma), PIP4K2A, PIP5K1A, PIP5K1B, PIP5K1C, SPHK1, SPHK2, AAK1, ABL1 H396P, ABL1 M351T, ABL1 Q252H, ACVR1 (ALK2) R206H, ACVR1 (ALK2), ACVR2A, ACVR2B, ACVRL1 (ALK1), ADCK3, ALK C1156Y, ALK F1174L, ALK L1196M, ALK R1275Q, ALK T1151_L1152insT, AMPK (A1 / B1 / G2), AMPK (A1 / B1 / G3), AMPK (A1 / B2 / G1), AMPK (A2 / B2 / G1), AMPK (A2 / B2 / G2), ANKK1, AXL R499C, BMPR1A (ALK3), BMPR1B (ALK6), BMPR2, BRAF V599E, BRAF, BRSK2, CAMK2G (CaMKII gamma), CAMKK1 (CAMKKA), CAMKK2 (CaMKK beta), CASK, CDC7 / DBF4, CDK11 (Inactive), CDK11 / cyclin C, CDK13 / cyclin K, CDK14 (PFTK1) / cyclin Y, CDK16 (PCTK1) / cyclin Y, CDK2 / cyclin A1, CDK2 / cyclin E1, CDK2 / cyclin O, CDK3 / cyclin E1, CDK5 (Inactive), CDK8 / cyclin C, CDK9 (Inactive), CDK9 / cyclin K, CLK4, DAPK2, DDR1, DDR2 N456S, DDR2 T654M, DDR2, DMPK, DYRK2, EGFR (ErbB1) d746-750, EGFR (ErbB1) d747-749 A750P, EIF2AK2 (PKR), EPHA3, EPHA6, EPHA7, ERN1, ERN2, FGFR1 V561M, FGFR3 G697C, FGFR3 K650M, FLT3 ITD, FYN A, GAK, GRK1, HUNK, ICK, IRAK3, KIT A829P, KIT D816H, KIT D816V, KIT D820E, KIT N822K, KIT T670E, KIT V559D T670I, KIT V654A, KIT Y823D, LATS2, LIMK1, LIMK2, MAP2K1 (MEK1) S218D S222D, MAP2K1 (MEK1), MAP2K2 (MEK2), MAP2K4 (MEK4), MAP2K5 (MEK5), MAP2K6 (MKK6) S207E T211E, MAP2K6 (MKK6), MAP3K10 (MLK2), MAP3K11 (MLK3), MAP3K14 (NIK), MAP3K2 (MEKK2), MAP3K3 (MEKK3), MAP3K5 (ASK1), MAP3K7 / MAP3K7IP1 (TAK1-TAB1), MAP4K1 (HPK1), MAP4K3 (GLK), MAPK10 (JNK3), MAPK15 (ERK7), MAPK8 (JNK1), MAPK9 (JNK2), MASTL, MERTK (cMER) A708S, MET D1228H, MKNK2 (MNK2), MLCK (MLCK2), MLK4, MYLK (MLCK), MYLK4, MYO3A (MYO3 alpha), MYO3B (MYO3 beta), NEK8, NLK, NUAK2, PKMYT1, PKN2 (PRK2), PLK4, PRKACB (PRKAC beta), PRKACG (PRKAC gamma), RAF1 (cRAF) Y340D Y341D, RET G691S, RET M918T, RET V804M, RIPK2, RIPK3, SIK1, SIK3, SLK, STK16 (PKL12), STK17A (DRAK1), STK17B (DRAK2), STK32B (YANK2), STK32C (YANK3), STK33, STK38 (NDR), STK38L (NDR2), STK39 (STLK3), TAOK1, TAOK3 (JIK), TEC, TEK (TIE2) R849W, TEK (TIE2) Y1108F, TESK1, TESK2, TGFBR1 (ALK5), TGFBR2, TLK1, TLK2, TNIK, TNK2 (ACK), TTK, ULK1, ULK2, ULK3, VRK2, WEE1, WNK1, WNK2, WNK3, ZAK. In some embodiments, the target may be AKT2Attorney Docket No.62826-719.601 (PKBb), AKT1 (PKB), AKT3 (PKBg), PRKCH (PKCη [eta]), PRKG2 (PKG2, PGK2, CGK2), PKN3, LATS2, PRKX, IKKE (IKKe), STK38 (NDR1), LATS1, FLT1, STK38L (NDR2), PKN1, TSSK3, RPS6KB2, (p70S6KB), FLT4, PRKAA2-B2-G2 (AMPKα2β2γ2), EPHA3, PAK4, TBK1, PRKCQ (PKC^ [theta]), PAK5 (PAK7), RIPK3, PDGFRA (PDGFRα), CAMK2B (CAMK2β), DDR1 [SRC treated], CAMK2G (CAMK2γ), TAOK3 (TAO3), CDK4 / CycD3, SGK3 , PRKAA1-B1-G3 (AMPKα1β1γ3), DDR2, PRKAA2-B1- G2 (AMPKα2β1γ2), FGFR3, PRKACB (PKACB, PKACβ), STK4 (MST1), SRPK2, DSTYK (RIPK5, SGK496), KDR (VEGFR2), MAPK9 (JNK2), CDK1 (CDC2) / CycA1 , ERN1 (IRE1), TNK1, STK3 (CLIK1, MST2), STK24 (MST3), GRK5 (GPRK5), ERN2 (IRE2), CDK17 (PCTAIRE2, PCTK2) / p35NCK, MAP4K4 (HGK, ZC1), PTK2 (FAK), PRKAA2-B1-G1 (AMPKα2β1γ1), PRKAA1-B1-G2 (AMPKα1β1γ2), PRKAA1-B2-G2 (AMPKα1β2γ2), DCLK1 (DCAMKL1), MAP2K1 (MEK1), SIK2 (QIK), MAP4K5 (KHS1), CDC42BPG (DMPK2), IGF1R, MAP3K19 (YSK4), ROCK1, MAPK11 (p38b), EPHA7, CDK2 / CycE2, HUNK, PRKDC (DNA-PK), NEK2, RPS6KB1 (p70S6K), PRKACA (PKACA, PKACα), TYRO3, ROS1 (ROS), MARK2, EPHA6, PRKG1 (PKG1, PGK), EGFR (ERBB1), GRK3 (ADRBK2, BARK2), PRKCE (PKCe [epsilon]), FAM20C, PKN2, MAP3K3 (MEKK3), MARK3, PRKAA1-B2-G3 (AMPKα1β2γ3), FGR, PTK2B (PYK2), MYLK (smMLCK), CDK19 (CDK11) / CycC, HIPK4, FGFR4, CDK13 (CHED) / CycK, PDGFRB (PDGFRβ), PRKD2 (PKD2), PRKD1 (PKD1), MST1R (RON), EPHA8, CSNK1E (CK1E, CK1ε), CAMK2A (CAMK2α), WEE1, EPHB4, RET, NIM1 (NIM1K), FGFR2, STK11 (LKB1, AMPKK), PRKAA2-B1-G3 (AMPKα2β1γ3), EIF2AK1 (HRI), PIM2, JAK2 [JH1], CDK1 (CDC2) / CycB1 , SLK, GRK2 (ADRBK1, BARK1), BLK, HIPK1, CSNK1G1 (CK1G1, CK1γ1), MAPK8 (JNK1), MAP3K14 (NIK), SRC, PRKAA1-B1-G1 (AMPKα1β1γ1), RPS6KA5 (MSK1), STK33, RIPK2, INSRR (IRR), FER, PAK6, TESK2, FES, PRKD3 (PKD3), BMP2K (BIKE), PTK6 (BRK), HIPK2, CSNK1A1L (CK1A1L, CK1a2), MAP3K8 (COT, Tpl2), PHKG2, PIM3, FYNa (FYN), CDK2 / CycA1, ICK, SYK, MERTK (MER), PHKG1, SBK1 (SBK), CSNK2A2 (CK2A2, CK2α2), GRK4 (GPRK4), FYNb (FYN), TEK (TIE2), AXL, CDK1 (CDC2) / CycE1 , TSSK2, CDK7 / CycH1, JAK1 [JH1-JH2], TRPM7 (CHAK1), CAMKK1, FLT3, PASK, CDK6 / CycD1, LIMK2, ZAP70, TXK, MAP4K3 (GLK, KHS2), TNIK (ZC2), TSSK1B (TSSK1), MAPK10 (JNK3), EPHA1, BMX, PRKAA1-B2-G1 (AMPKα1β2γ1), RPS6KA4 (MSK2), GRK6 (GPRK6), CSNK2A1 (CK2A1, CK2α1), TSSK6 (SSTK), JAK2 [JH1-JH2], PLK1, HIPK3, MARK1, NUAK1 (ARK5), PRKCB1 (PKCβ1 [beta1]), MAST3, DYRK4, CDK3 / CycE2, EIF2AK3Attorney Docket No.62826-719.601 (PERK / PEK), PAK3, EIF2AK2 (PKR), FGFR1, IKKB (IKKβ), TAOK2 (TAO2), CHUK (IKKA, IKKa), DMPK (DMPK1), SNRK, PLK3, TAOK1 (TAO1), MARK4, PRKAA2-B2- G1 (AMPKα2β2γ1), YES1 (YES), EPHA2, PRKAA2-B2-G3 (AMPKα2β2γ3), TNK2 (ACK), MAP4K2 (GCK), TTBK1, SGK2, FRK, MATK (CTK), PRKACG (PKACG, PKACg), ERBB2 (HER2), PBK (TOPK), NUAK2 (SNARK), MAP3K9 (MLK1), ULK1, STK17A (DRAK1), BUB1, CSNK1G3 (CK1G3, CK1γ3), IRAK1, STK25 (YSK1), NEK5, CDK6 / CycD3, BRSK1, ERBB4 (HER4), GAK, EPHA5, ABL2 (ARG), CDK9 (TAK) / CycK, SRMS (SRM), DAPK3 (ZIPK), CDK15 (PFTAIRE2, PFTK2) / CycB1, CDK2 / CycO, MYLK3 (caMLCK), EEF2K (eEF2K), DAPK2 (DRP-1), LIMK1, TTBK2, MAPK12 (p38γ) , PRKCA (PKCα [alpha]), MAK, JAK1 [JH1], BUB1B (BUBR1), SIK1 (SIK), EPHA4, TEC, PDK4 (PDHK4), CAMK1 (CAMK1a), EPHB1, NLK (LAK1), CDK5 / p35NCK, CLK3, MAP3K7 (TAK1), PDK3 (PDHK3), GRK7 (GPRK7), CDK14 (PFTAIRE1, PFTK1) / CycY, TYK2 [JH1], MYLK4 (SgK085), SGK1 (SGK), INSR (IR), CDK9 (TAK) / CycT1, MELK, CSF1R (FMS), PDK2 (PDHK2), RIPK1, CDK2 / CycA2, EIF2AK4 (GCN2), HASPIN, MAP4K1 (HPK1), HCK, BRAF, b-[V600E], CAMK1G (CAMK1γ), ABL1, CDK6 / CycD2, DCLK2 (DCAMKL2), PAK2, NEK6, MAPK14 (p38a), SRPK1, DYRK1B, CSNK1A1 (CK1A1, CK1α), MYLK2 (skMLCK), AURKA (AURA), CDK3 / CycE1, CDK2 / CycE1, MINK1 (MAP4K6, MINK, ZC3), MLK4 (MAP3K21), RAF1 [Y340E / Y341E], or CSK. In some embodiments, the target may be CLK2, DYRK1B, AKT1, CLK1, ICK, AKT3, CLK4, DYRK1A, P70S6KA, PKCH, STK33, PGK2, AKT2, PKCQ, CDK17 / P35, LATS2, FLT3, HASPIN, MSK1, PKN1, GCK, P70S6KB, CDK7 / H1, LIMK2, ROCK1, CDK3 / E2, PIM1, PKD3, PRKX, LATS1, MST3, HGK, CDK1 / E1, CDK3 / E1, MAK, MST1R, CAMK2G,PIM3, CDK2 / E2, CLK3, ERK7, PGK, HIPK1, PAK6, CDK2 / A1, CDK1 / A1, WEE1, GRK5, NDR2, MINK, CAMK2B, ERN1, MAP3K14, PKCA, PKACA, CAMKK1, FER, DDR2, PDHK3, SRPK2, PKACB, GRK7, GLK / KHS2, CDK11 / C, MST1, GRK3, PAK4, CDK15 / B1, RSK2, SGK3, PKD2, CDK9 / T2, PDGFRA, CDK5 / P35, DDR1, GAK, TNIK, SGK2, EPHA6, SIK2, CDK9 / T1, JAK2(JH1), LRRK2, CDK1 / B1, KHS1, CRIK, NUAK1, CDK4 / D3, PEK, CDK7, BTK, MERTK, PKCE, JNK1, CK1G1, FLT1, EGFR, TESK2, CK1D, AMPK222, GRK2, MAST3, CDK1 / A2, EPHA2, P38B, MK5, MYO3A, CK2A2, KDR, FGFR3, TAOK3, FYNA, MST2, ERN2, HPK1, CDK2 / O, AMPK223, CDK2 / A2, LKB1, CDK14, TAOK2, MAP3K9, NEK2, ROCK2, RSK1, PAK3, IGF1R, MEK1, AXL, MAP3K10, FLT4, TNK2, PKCG, RIPK5, RET, MST4, PKCB1, ZAP70, TNK1, FGFR4, INSRR, PKCD, DYRK3, EPHA3, AMPK112, MSK2, PAK2,Attorney Docket No.62826-719.601 HUNK, PDHK4, NEK9, YSK4, FGR, AMPK213, NEK6, JAK1(JH1JH2), MRCKB, EPHB4, PKN2, PKACG, JNK3, EPHA8, CK1A1, PKN3, LIMK1, GRK6, PKD1, YSK1, NIM1, AMPK122, PASK, SLK, PHKG1, CDK18, LOK, HIPK3, DNA-PK, RSK3, AMPK123, CDK5 / P25, CDK12 / K, TAOK1, EPHA5, HIPK4, AMPK212, CHK1, BRSK1, DMPK2, CDK6 / D3, MAP3K11, MEK2, ROS, TYRO3, EPHA1, FGFR2, TBK1, MAP3K3, PAK1, HER4, HRI, HCK, JAK2(JH1JH2), CDK6 / D2, CHK2, ERK2, AMPK121, LYNA, GRK4, CK1A1L, PDHK2, PTK2, YES, DYRK2, FES, MARK2, RIPK3, MARK4, TTBK2, CDK13 / K, ERK1, MARK3, TSSK1, FRK, EPHA7, MRCKA, PHKG2, CK2A1, MAP3K12, MLCK, CDK2 / E1, TYK2(JH1), JAK1(JH1), DRAK1, P38A, CK1G3, MAP3K1, AURA, PLK3, DYRK4, FYNB, PTK2B, AMPK211, BUBR1, ABL2, LYNB, PLK2, RIPK2, PLK4, AMPK221, P38G, MET, CAMK1B, FGFR1, CK1E, SYK, CTK, CDK9 / K, AMPK113, TTBK1, SRC N1, AMPK111, GCN2, KIT, LTK, HIPK2, GSK3B, CAMK1G, PDGFRB, NDR1, CDK4 / D2, CDK16, MLK4, IKKE, CDK6 / D1, PDK1, SGK, DRAK2, MARK1, INSR, ZAK, BLK, JNK2, CAMK1A, NEK5, BUB1, MAP3K5, BCR RET, NEK4, FMS / CSF1R, DCAML1, LCK, SRC, SIK1, CDC7, PKR, TXK, or IKKA. In some embodiments, a target may be included in a group. In some embodiments, the group may be CMGC Kinases (CDK (Cyclin-Dependent Kinases), MAPK (Mitogen-Activated Protein Kinases), GSK (Glycogen Synthase Kinase), and CLK (CDC-Like Kinases) - Kinases involved in the regulation of cell cycle progression, transcription, and various signaling pathways), AGC Kinases (PKA (Protein Kinase A), PKG (Protein Kinase G), and PKC (Protein Kinase C) - AGC kinases play critical roles in cellular signaling, metabolism, growth, and other physiological processes), CAMK Kinases ((Calcium / Calmodulin- Dependent Protein Kinases) - involved in calcium-mediated signaling pathways, such as CaMKI, CaMKII, and CaMKIV, which regulate various cellular processes upon activation by calcium-calmodulin complexes), Tyrosine Kinases (phosphorylate tyrosine residues, which are subdivided into receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases - involved in cell signaling, growth, differentiation, and other cellular processes), Other Kinases, STE Kinases (involved in various signaling cascades, including mitogen-activated protein kinase (MAPK) cascades, and are named after three yeast kinases: STE20, STE11, and STE7), TKL Kinases (Tyrosine Kinase-Like Kinases, which are structurally similarities to tyrosine kinases phosphorylate serine and threonine residues instead of tyrosine residues, like RAF and MLK (Mixed Lineage Kinases), Atypical Kinases (which have unique structural features or functions that distinguish them from the other groups), or CK1 KinasesAttorney Docket No.62826-719.601 (Casein Kinase 1, which are a family of serine / threonine kinases involved in various cellular processes, including cell division, DNA repair, and signal transduction).

[0294] In some embodiments, the compound described herein targets, inhibits, or modulates genes, gene pathways, or signaling pathways. In some embodiments, the genes, gene pathways, or signaling pathways include the hedgehog signal transduction pathway. In some embodiments the genes, gene pathways, or signaling pathways include but are not limited to SOFU, PTCH1, PTCH1 wt, PTCH1 mutated, Shh, SMO, GLI genes, GLI1, GLI2, GLI3, GLI transcription factors, PKA, AMPK, MEKK1, Hck, GSK3beta, CK1, S6K, AKT, HDAC, KRT1, KRT10, IVL, LOR, CCND, CCNE, E2F, CDK1, CCNA, CCNB, BCL2, SNAIL1. In some embodiments target gene, gene pathway or signally pathway is GLI1 and genes modulated by GLI1.

[0295] In some embodiments, the inhibition or modulation of the target kinase or kinase pathway by the composition or compound described herein can treat or prevent carcinomas, malignant tumors, cancers, benign tumors, or growths.

[0296] In some embodiments, the inhibition or modulation of the target kinase or kinase pathway by the composition or compound described herein can treat or prevent basal cell carcinomas, squamous cell carcinomas, or seborrheic keratoses. In some embodiments, the squamous cell carcinoma may be an invasive squamous cell carcinoma or a squamous cell carcinoma in situ. In some embodiments, the squamous cell carcinoma in situ may be Bowen’s disease.

[0297] In one aspect, the present disclosure provides a method of treating or preventing a cutaneous lesion, the method comprising topically administering to the cutaneous lesion a composition comprising: a compound of Formula (I),wherein: X is CH or N;Attorney Docket No.62826-719.601 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, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; R4is hydrogen or C1-6 alkyl; and n is 0 to 5; Formula (I-AA) or Formula (I-BB),Formula (I-BB),Attorney Docket No.62826-719.601wherein RAis C1-20alkyl, and / or Formula (III)wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10%.

[0298] In some embodiments, the cutaneous lesion is a keratosis. In some embodiments, the keratosis is a seborrheic keratosis. In some embodiments the cutaneous lesion is a carcinoma. In some embodiments the carcinoma is a basal cell carcinoma, or squamous cell carcinoma. In some embodiments, the squamous cell carcinoma may be an invasive squamous cell carcinoma or a squamous cell carcinoma in situ. In some embodiments, the squamous cell carcinoma in situ may be Bowen’s disease. In some embodiments the cutaneous lesion is a melanoma.

[0299] In some embodiments, the method further comprises occlusion of the cutaneous lesion.

[0300] In some embodiments, the cutaneous lesion is present on a human subject. In some embodiments, the cutaneous lesion is present on the face, trunk, or an extremity, or a combination thereof, of the human subject.

[0301] In some embodiments, treating comprises reducing the thickness of the cutaneous lesion to less than 1 mm. In some embodiments, the thickness of the cutaneous lesion prior administering is greater than or equal to 1 mm. In some embodiments, the length of theAttorney Docket No.62826-719.601 cutaneous lesion prior to administering is from 1 mm to 15 mm, and the width of the cutaneous lesion prior to administering is from 1 mm to 15 mm.

[0302] In some embodiments, administration leads to prevention of a cutaneous lesion such as a non-melanoma skin cancer such as Basal cell carcinoma or Squamous cell carcinoma, or administration leads to prevention of a melanoma.

[0303] In some embodiments, treating comprises inducing apoptosis of a keratinocyte or melanocyte in the cutaneous lesion.

[0304] Terminal deoxynucleotidyl transferase dUTP nick end labeling assay or TUNEL assay is a method for detecting or quantifying cellular apoptosis by labeling the 3’-hydroxyl termini in the double-strand DNA breaks of DNA fragmentation generated during apoptosis. The TUNEL assay utilizes the terminal deoxynucleotidyl transferase (TdT), which is an enzyme that catalyzes attachment of deoxynucleotides, tagged with a fluorochrome or another marker, to 3'-hydroxyl termini of DNA double strand breaks. In some embodiments, apoptosis is measured by TUNEL assay.

[0305] In some embodiments, the composition is a gel formulation. In some embodiments, the composition comprises an alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof.

[0306] In one aspect, the present disclosure provides a method of treating or preventing a skin disease, condition or disorder in a subject in need thereof, comprising administering to the subject the composition described herein.

[0307] In some embodiments, the skin disease, condition or disorder is seborrheic keratosis, Basal cell carcinoma, Squamous cell carcinoma, melanoma, benign tumor, malignant tumor, parasite, virus of the skin, immune disease or disorder, or a bacterial, fungal or microbial infection. In some embodiments, the squamous cell carcinoma may be an invasive squamous cell carcinoma or a squamous cell carcinoma in situ. In some embodiments, the squamous cell carcinoma in situ may be Bowen’s disease. In some embodiments, the skin disease, condition or disorder is seborrheic keratosis. In some embodiments, the skin disease, condition or disorder is the benign tumor, wherein the benign tumor is a benign vascular tumor, benign fibrotic tumor, benign adipocyte tumor, benign sebaceous tumor, benign epidermal tumor, benign melanocytic lesion, or benign neural tumor; the skin disease, condition or disorder is the malignant tumor, wherein the malignantAttorney Docket No.62826-719.601 tumor is a malignant melanocytic tumor, malignant epidermal tumor, malignant vascular tumor, malignant metastatic tumor, malignant adipocyte tumor, malignant sebaceous tumor, or malignant fibrotic tumor; the skin disease, condition or disorder is the parasite, wherein the parasite is of the genus Trypanasoma or Lieshmania; the skin disease, condition or disorder is the virus, wherein the virus is molluscum contagiosum virus or human papilloma virus; or the skin disease, condition or disorder is the bacterial, fungal or microbial infection, wherein the bacterial, fungal or microbial infection is otitis media, Staphylococcus aureus infection, Mycobacterium infection, Porphyromonas infection, Salmonella infection, Chlamydia infection, tuberculosis, gingivitis or periodontal disease.

[0308] 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 administered twice daily. In some embodiments, the composition is administered for about 2 weeks to about 8 weeks. In some embodiments, the composition is administered for about 4 weeks.

[0309] In some embodiments the composition is delivered orally, systemically, intradermally, subdermally, intralesionally.

[0310] In some embodiments, the composition is administered in a pulsed cycle. In some embodiments, the composition is administered under occlusion.

[0311] In some embodiments, the skin disease, condition or disorder is skin pigmentation disorder. In some embodiments, the skin pigmentation disorder is Acanthosis nigricans.

[0312] In some embodiments, the skin disease, condition or disorder is seborrheic keratosis, benign tumors or skin conditions, malignant tumors, parasites, viruses of the skin, immune diseases or disorders, and a bacterial, fungal or microbial infection.

[0313] In some embodiments, the skin disease, condition or disorder is seborrheic keratosis.

[0314] In some embodiments, the compositions described herein are useful for treating or preventing benign tumors or skin conditions. In some embodiments, the benign tumors are benign vascular tumors, benign fibrotic tumors, benign adipocyte tumors, benign sebaceous tumors, benign epidermal tumors, benign melanocytic lesions, or benign neural tumors. Benign tumors or skin conditions include, but are not limited to, nodules, benign skin tumors, angiomas, hemangiomas, pyogenic granuloma, angiofibroma, tuberous sclerosis complex,Attorney Docket No.62826-719.601 angiomyofibroma, angiolipoma, dermatofibroma, fibroma, neurofibromas, scars, scar tissue, keloids, lipomas, acrochordons, melanoacanthoma, acanthoma, clear cell acanthoma, acanthosis nigricans, epidermoid cysts, pilar cysts, dermoid cyst, melanocytic nevi, epidermal nevi, verrucous epidermal nevi, lentigos, café au lait macules, neuroma, schwannoma, and neurolemmoma. In some embodiments, benign tumors are nodules, benign skin tumors, angiomas, hemangiomas, pyogenic granuloma, angiofibroma, tuberous sclerosis complex, angiomyofibroma, angiolipoma, dermatofibroma, fibroma, neurofibromas, scars, scar tissue, keloids, lipomas, acrochordons, melanoacanthoma, acanthoma, clear cell acanthoma, acanthosis nigricans, epidermoid cysts, pilar cysts, dermoid cyst, melanocytic nevi, epidermal nevi, verrucous epidermal nevi, lentigos, café au lait macules, neuroma, schwannoma, or neurolemmoma.

[0315] In some embodiments, the skin disease, condition or disorder is a carcinoma. In some embodiments, the skin disease, condition or disorder is basal cell carcinoma or squamous cell carcinoma. In some embodiments, the squamous cell carcinoma may be an invasive squamous cell carcinoma or a squamous cell carcinoma in situ. In some embodiments, the squamous cell carcinoma in situ may be Bowen’s disease. In some embodiments, the skin disease or condition is melanoma.

[0316] In some embodiments, the skin disease, condition or disorder is Gorlin syndrome

[0317] In some embodiments, the skin disease, condition or disorder is basal cell nevus syndrome.

[0318] In some embodiments the skin disease, condition or disorder is a melanoma or a non-melanoma skin cancer.

[0319] In some embodiments, the compositions described herein are useful for treating or preventing malignant tumors. In some embodiments, the malignant tumors are malignant melanocytic tumors, malignant epidermal tumors, malignant vascular tumors, malignant metastatic tumors, malignant adipocyte tumors, malignant sebaceous tumors, or malignant fibrotic tumors. Malignant tumors include, but are not limited to, melanomas, squamous cell carcinoma, keratoacanthoma, actinic keratoses, basal cell carcinomas, angiosarcoma, Kaposi sarcoma, cutaneious breast cancer, Merkel cell cancer, liposarcoma, sebaceoma, sebaceous carcinoma, dermatofibroma sarcoma protuberens, and fibrosarcoma. In some embodiments, malignant tumors are melanomas, squamous cell carcinoma, keratoacanthoma, actinicAttorney Docket No.62826-719.601 keratoses, basal cell carcinomas, angiosarcoma, Kaposi sarcoma, cutaneious breast cancer, Merkel cell cancer, liposarcoma, sebaceoma, sebaceous carcinoma, dermatofibroma sarcoma protuberens, or fibrosarcoma.

[0320] In some embodiments, the compositions described herein are useful for treating or preventing the skin disease, condition or disorder caused by a parasite. In some embodiments, the parasites are parasites of the genus Trypanasoma or Lieshmania. In some embodiments, the parasites are parasites of the genus Leishmania, Endotrypanum, Novymonas, Porcisia, or Zelonia. In some embodiments, the parasite is L. major, L. tropica, L. aethiopica, L. Mexicana, or L. braziliensis. In some embodiments, the disease or condition caused by or associated with the parasite is cutaneous or mucosal or mucocutaneous. In some embodiments, the parasite is Leishmania aethiopica, Leishmania amazonensis, Leishmania arabica, Leishmania aristidesi, Leishmania donovani, Leishmania forattinii, Leishmania gerbilli, Leishmania infantum, Leishmania killicki, Leishmania major, Leishmania Mexicana, Leishmania pifanoi, Leishmania tropica, Leishmania turanica, Leishmania venezeulensis, Leishmania waltoni, Leishmania enriettii, Leishmania macropodum, Leishmania martiniquensis, Leishmania orientalis, Leishmania adleri, Leishmania agamae, Leishmania ceramodactyli, Leishmania gulikae, Leishmania gymnodactyli, Leishmania helioscopi, Leishmania hemidactyli, Leishmania hoogstraali, Leishmania nicollei, Leishmania platycephala, Leishmania phrynocephali, Leishmania senegalensis, Leishmania sofieffi, Leishmania tarentolae, Leishmania zmeevi, Leishmania zuckermani, Leishmania braziliensis, Leishmania guyanensis, Leishmania lainsoni, Leishmania lindenbergi, Leishmania naiffi, Leishmania panamensis, Leishmania peruviana, Leishmania shawi, Leishmania utingensis, Endotrypanum colombiensis, Endotrypanum equatorensis, Endotrypanum herreri, Endotrypanum monterogeii, Endotrypanum schaudinni, Novymonas esmeraldas, Porcisia deanei, Porcisia hertigi, Zelonia australiensis, or Zelonia costaricensis.

[0321] In some embodiments, the compositions described herein are useful for treating or preventing a skin disease, condition or disorder caused by a virus. Viral pathogens include, but are not limited to, adenoviruses, influenza, human herpes virus, Avibirnavirus, HIV, and coronaviruses. In some embodiments, the viruses are poxviruses that cause molluscum contagiosum or human papilloma viruses that cause warts.Attorney Docket No.62826-719.601

[0322] In some embodiments, the compositions described herein are useful for treating or preventing a skin disease, condition or disorder associated with bacterial, fungal or microbial infection. In some embodiments, the bacterial, fungal or microbial infection is otitis media, Staphylococcus aureus infection, Mycobacterium infection, salmonellosis, Chlamydia infection, tuberculosis, Porphyromonas infection, gingivitis or periodontal disease.

[0323] 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, 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 the disease, condition or disorder. As a non- limiting example, the composition covers a basal cell carcinoma, squamous cell carcinoma, and / or melanoma. In some embodiments, the squamous cell carcinoma may be an invasive squamous cell carcinoma or a squamous cell carcinoma in situ. In some embodiments, the squamous cell carcinoma in situ may be Bowen’s disease.

[0324] In some embodiments, the composition described herein is administered to a face of the subject, thereby treating or preventing basal cell carcinomas, squamous cell carcinomas, or melanomas on the face. In some embodiments, the composition described herein is administered to the body of the subject, thereby treating or preventing seborrheic keratosis. In some embodiments, the composition described herein is administered topically to one or more areas selected from head, scalp, face, ears, neck, chest, back, inframammary regions, arms, legs, groin, intertriginous regions, hands, and / or feet thereby treating seborrheic keratosis in any one of these areas.

[0325] In some embodiments, the skin disease, condition or disorder to be reduced, ameliorated, treated, or prevented is non melanoma skin cancer such as Basal cell carcinoma or Squamous cell carcinoma, or melanoma. In some embodiments, the composition described herein is administered in a therapeutically effective amount to achieve partial or complete resolution, involution, or removal of at least one Basal cell carcinoma, Squamous cell carcinoma, or melanoma in a subject. In some embodiments, the composition described herein is administered in a therapeutically effective amount to achieve a partial resolution of at least one Basal cell carcinoma, Squamous cell carcinoma, or melanoma in a subject. In some embodiments, the composition described herein is administered in a therapeuticallyAttorney Docket No.62826-719.601 effective amount to achieve a complete resolution of at least one Basal cell carcinoma, Squamous cell carcinoma, or melanoma in a subject. In some embodiments, the composition described herein is administered in a therapeutically effective amount to achieve an involution of at least one Basal cell carcinoma, Squamous cell carcinoma, or melanoma in a subject. In some embodiments, the composition described herein is administered in a therapeutically effective amount to achieve removal of at least one Basal cell carcinoma, Squamous cell carcinoma, or melanoma in a subject.

[0326] In some embodiments, the composition described herein is administered to the 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, neck, chest, back, inframammary regions, arms, legs, groin, intertriginous regions, hands, feet, mouth, lips, gums, nose, nostrils, anus, genitals, eyes and / or eyelids. In some embodiments, the composition covers (e.g. occludes) the skin associated with the disease, condition or disorder. As a non-limiting example, the composition covers a basal cell carcinoma. In some embodiments the composition is delivered intralesionally, orally, systemically, intradermally, and / or subdermally.

[0327] In some embodiments, the composition described herein is administered to a face of the subject, thereby treating or preventing basal cell carcinoma, squamous cell carcinoma, or melanoma on the face. In some embodiments, the composition described herein is administered to the body of the subject, thereby treating or preventing Basal cell carcinoma, Squamous cell carcinoma, or melanoma. In some embodiments, the composition described herein is administered topically to one or more areas selected from head, scalp, face, ears, neck, chest, back, inframammary regions, arms, legs, feet, groin, intertriginous regions, hands, mouth, lips, gums, nose, nostrils, anus, genitals, eyes and / or eyelids, thereby treating ore preventing basal cell carcinoma, SCC or melanoma in any one of these areas. In some embodiments, the composition described herein is administered topically to one or more areas selected from head, scalp, face, ears, neck, chest, back, inframammary regions, arms, legs, feet, groin, intertriginous regions, hands, mouth, lips, gums, nose, nostrils, anus, genitals, eyes and / or eyelids, thereby preventing basal cell carcinoma, SCC or melanoma in any one of these areas.

[0328] In some embodiments, the skin disease, condition or disorder to be reduced, ameliorated, treated, or prevented is Basal cell carcinoma, SCCs, or melanomas. In someAttorney Docket No.62826-719.601 embodiments, the composition described herein is administered in a therapeutically effective amount to achieve partial or complete resolution, involution, or removal of at least one Basal cell carcinoma, SCC, or melanoma in a subject. In some embodiments, the composition described herein is administered in a therapeutically effective amount to reduce the progression of at least one Basal cell carcinoma, SCC or melanoma in a subject. In some embodiments, the composition described herein is administered in a therapeutically effective amount to achieve a partial resolution of at least one basal cell carcinoma, SCC, or melanoma in a subject. In some embodiments, the composition described herein is administered in a therapeutically effective amount to achieve a complete resolution of at least one basal cell carcinoma, SCC or melanoma in a subject. In some embodiments, the composition described herein is administered in a therapeutically effective amount to achieve an involution of at least one basal cell carcinoma, SCC or melanoma, in a subject. In some embodiments, the composition described herein is administered in a therapeutically effective amount to achieve removal of at least one basal cell carcinoma in a subject. In some embodiments, the composition described herein is administered in a therapeutically effective amount to prevent at least one Basal cell carcinoma, SCC or melanoma in a subject.

[0329] In some embodiments the composition is administered topically. In some embodiments the composition is administered orally. In some embodiments the composition is administered systemically or intravenously. In some embodiments the composition is administered by lesion. In some embodiments the composition is administered subcutaneously or subdermally. In some embodiments, the composition is administered intralesionally. In some embodiments, the composition is administered subdermally. In some embodiments, the composition is administered intradermally. In some embodiments the composition is administered intralesionally, orally, systemically, intradermally, and / or subdermally. In some embodiments the composition is administered by application over large areas of the skin or body. In some embodiments the composition is administered as a preventative for basal cell carcinomas, squamous cell carcinomas, melanomas, or seborrheic keratoses.

[0330] In some embodiments, the composition administered is in the form of a gel, ointment, lotion, foam or emollient.

[0331] In some embodiments, the composition administered is a component of a patch, tape, film, wafer, or bandage.Attorney Docket No.62826-719.601

[0332] In some embodiments, the subject in need thereof is a human. KITS

[0333] Also provided are kits for use in methods of treatment or prevention of a skin disease, condition or disorder where the subject is in need thereof with the composition as described herein in a tube, flexible aluminum tube or laminated plastic tube. The kits can include a topical composition comprising the compound, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating or preventing a skin disease, condition or disorder. 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. A unit dose of a compound or a topical composition provided herein, or a second agent or composition, can include a dosage such that when administered to a subject, a therapeutically or prophylactically effective level of the compound or the topical composition can be maintained at the site of treatment in the subject for at least 1 day.

[0334] In another 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.

[0335] In some embodiments, suitable packaging is provided. As used herein, “packaging” includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and / or a second agent suitable for administration to a subject. Such materials include 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. EXEMPLARY EMBODIMENTS

[0336] Methods and compositions described herein may be in one or more exemplary embodiments, as described below: 1. A method of preventing or treating a cutaneous lesion, the method comprising topically administering to the cutaneous lesion a composition comprising: (i) a compound having the structure of Formula (I):Attorney Docket No.62826-719.601wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, 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; (ii) a compound having the structure of Formula (I-A) or Formula (I-B):wherein: X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R4 is hydrogen or C1-6 alkyl; and n is 0 to 5; (iii) a compound having the structure of Formula (I-AA) or Formula (I-BB):Attorney Docket No.62826-719.601wherein: R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6 alkyl; and / or (iv) a compound having the structure of Formula (II):wherein RAis C1-20 alkyl (v) a compound having the structure of Formula (III):wherein the total amount of (i), (ii), (iii), (iv), (v), or any combination of two or more thereofpresent in the composition is 0.01% to 10% by weight. 2. The method of embodiment 1, wherein the cutaneous lesion is a skin cancer, optionally wherein: the skin cancer is melanoma, or the skin cancer is not melanoma, further optionally wherein if the skin cancer is non-melanoma skin cancer, the non-melanoma skin cancer is basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). 3. The method of embodiment 2, wherein the skin cancer is the not melanoma, optionally wherein the skin cancer is basal cell carcinoma (BCC) or squamous cell carcinoma (SCC).Attorney Docket No.62826-719.601 4. The method of any one of embodiments 1-3, comprising occluding the cutaneous lesion. 5. The method of any one of embodiments 1-4, wherein the cutaneous lesion is present on a human subject. 6. The method of embodiment 5, wherein the cutaneous lesion is present on the face, trunk, an extremity, or any combination of two or more thereof, of the human subject. 7. The method of any one of embodiments 1-6, wherein treating comprises an improvement of one grade or more in Physician’s Lesion Assessment (PLA) score as compared to before administering the composition. 8. The method of any one of embodiments 1-7, wherein the thickness of the cutaneous lesion prior to administering is greater than or equal to 1 mm. 9. The method of any one of embodiments 1-8, wherein the length of the cutaneous lesion prior to administering is from 1 mm to 15 mm, and the width of the cutaneous lesion prior to administering is from 1 mm to 15 mm. 10. The method of any one of embodiments 1-9, wherein treating comprises inducing apoptosis of a keratinocyte or melanocyte in the cutaneous lesion. 11. The method of embodiment 10, wherein the apoptosis is measured by TUNEL assay. 12. The method of any one of embodiments 1-11, wherein the composition is a gel formulation. 13. The method of any one of embodiments 1-12, wherein the composition comprises an alcohol, a gelling agent, an antioxidant, or a combination of two or more thereof. 14. A composition comprising: a. a compound having the structure of Formula (I):wherein: X is CH or N;Attorney Docket No.62826-719.601 each R1is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6haloalkyl, or C1-6alkoxy; R2is an optionally substituted C6-12aryl or optionally substituted 3- to 12- membered heteroaryl; and n is 0 to 5; b. a compound having the structure of Formula (I-A) or Formula (I-B):X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R4 is hydrogen or C1-6 alkyl; and n is 0 to 5; c. a compound having the structure of Formula (I-AA) or Formula (I-BB):Attorney Docket No.62826-719.601 R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6alkyl; and / or d. a compound having the structure of Formula (II):wherein RAis C1-20alkyl, wherein the total amount of (i), (ii), (iii), (iv) or any combination of two or more thereof is present in the composition is 0.01% to 10%, by weight. 15. The composition of embodiment 14, wherein the composition is a gel formulation. 16. The composition of embodiment 14 or embodiment 15, wherein the composition comprises an alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof. 17. A composition comprising: a. a compound having the structure of 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; and n is 0 to 5; b. a compound having the structure of Formula (I-A) or Formula (I-B):Attorney Docket No.62826-719.601X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R4 is hydrogen or C1-6 alkyl; and n is 0 to 5; c. a compound having the structure of Formula (I-AA) or Formula (I-BB):wherein: R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6 alkyl; and / or d. a compound having the structure of Formula (II):wherein RAis C1-20 alkyl,Attorney Docket No.62826-719.601 and one or more excipients selected from (a)-(e): a) alcohol; b) an organic solvent and / or a penetration enhancer; c) an antioxidant; d) a preservative; and e) a gelling agent. 18. The composition of embodiment 17, comprising the alcohol. 19. The composition of embodiment 18, wherein the alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, propylene glycol, (2-(2- ethoxyethoxy)ethanol), phenoxyethanol, or a combination or two or more thereof. 20. The composition of embodiment 18, wherein the alcohol comprises a C2-6alcohol. 21. The composition of embodiment 20, wherein the C2-6 alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, or a combination or two or more thereof. 22. The composition of embodiment 21, wherein the C2-6 alcohol comprises ethanol. 23. The composition of any one of embodiments 18-22, wherein the alcohol comprises an organic solvent and / or penetration enhancer. 24. The composition of any one of embodiments 17-23, comprising the organic solvent and / or penetration enhancer. 25. The composition of embodiment 23 or embodiment 24, wherein the organic solvent and / or penetration enhancer comprises a C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5- OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, a fatty ether, or a combination of two or more thereof. 26. The composition of embodiment 25, wherein: the C2-6 alkylene glycol is propylene glycol; the C1-3 alkyl-(OCH2CH2)1-5-OH is 2-(2-ethoxyethoxy)ethanol; and the polyethylene glycol is PEG200, PEG400, or a combination thereof.Attorney Docket No.62826-719.601 27. The composition of embodiment 23 or embodiment 24, wherein the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2- ethoxyethoxy)ethanol. 28. The composition of any one of embodiments 17-27, comprising the antioxidant. 29. The composition of embodiment 28, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. 30. The composition of embodiment 29, wherein the antioxidant comprises butylated hydroxytoluene. 31. The composition of any one of embodiments 14-16, comprising a preservative. 32. The composition of any one of embodiments 17-30, comprising the preservative. 33. The composition of embodiment 31 or embodiment 32, wherein the preservative comprises phenoxyethanol. 34. The composition of any one of embodiments 14-16, comprising a gelling agent. 35. The composition of any one of embodiments 17-33, comprising the gelling agent. 36. The composition of embodiment 34 or embodiment 35, wherein the gelling agent comprises hydroxypropyl cellulose. 37. The composition of embodiment 36, wherein the hydroxypropyl cellulose has an average molecular weight of from 700,000 Da to 1,150,000 Da. 38. The composition of embodiment any one of embodiments 14-37, comprising ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and hydroxypropyl cellulose. 39. The composition of any one of embodiments 14-38, comprising an antioxidant and / or a preservative. 40. The composition of embodiment 39, comprising the antioxidant, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, or propyl gallate, or a combination of two or more thereof; and the preservative comprises phenoxyethanol. 41. The composition of any one of embodiments 14-40, comprising a pH adjuster, optionally an acid, and further optionally a citric acid.Attorney Docket No.62826-719.601 42. A composition comprising: (i) a compound having the structure:tautomer) or a salt thereof, and / or (ii) a compound having the structure:43. ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, hydroxypropyl cellulose, and optionally an antioxidant, and optionally a preservative. 44. The composition of embodiment 43, wherein: the antioxidant, when present, comprises butylated hydroxytoluene; and the preservative, when present, comprises phenoxyethanol. 45. The composition of any one of embodiments 15-44, wherein the composition has a viscosity of about 10000 cp to about 30000 cp. 46. The composition of any one of embodiments 15-45, wherein the composition is a pharmaceutical composition. 47. The composition of any one of embodiments 15-46, wherein the composition is a topical composition, or a composition for oral, systemic, intralesional, subcutaneous, or intradermal administration or application. 48. The composition of any one of embodiments 15-47, or the method of any one of embodiments 1-14, wherein the composition is in the form of a gel, ointment, lotion, foam or emollient. 49. The composition of any one of embodiments 15-48, or the method of any one of embodiments 1-14, wherein the composition is a component of a patch, tape, film, wafer, or bandage.Attorney Docket No.62826-719.601 50. A method of treating a skin disease, condition or disorder in a subject in need thereof, comprising administering to the subject a composition of any one of embodiments 15-50. 51. The method of embodiment 50, wherein the skin disease, condition or disorder is skin cancer. 52. The method of embodiment 51, wherein the skin cancer is melanoma. 53. The method of embodiment 51, wherein the skin cancer is not melanoma. 54. The method of embodiment 53, wherein the skin cancer is basal cell carcinoma (BCC). 55. method of embodiment 53, wherein the skin cancer is squamous cell carcinoma (SCC)), 56. The method of any one of embodiments 50-55, wherein 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. 57. A kit comprising a topical pharmaceutical composition of any one of embodiments 15-49, in a tube, flexible aluminum tube or laminated plastic tube, with instructions for use. 58. A method of treating, preventing, or reducing the progression of a cutaneous lesion, the method comprising administering to the cutaneous lesion a composition comprising an effective amount of a compound having Akt inhibitory activity and inhibitory or modulatory activity in another kinase pathway. 59. The method of embodiment 58, wherein the cutaneous lesion is a carcinoma. 60. The method of embodiment 58, wherein the cutaneous lesion is a basal cell carcinoma, squamous cell carcinoma, or melanoma. 61. The method of embodiment 58-60, wherein the mode of administration is oral, systemic, topical, intradermal, intralesional and / or subcutaneous. 62. A method of treating, preventing, or reducing the progression of a cutaneous lesion, the method comprising administering to the cutaneous lesion a composition comprising: (i) a compound having the structure of Formula (I):Attorney Docket No.62826-719.601 wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6alkyl, C1-6 haloalkyl, or C1-6alkoxy; R2is an optionally substituted C6-12 aryl or optionally substituted 3- to 12- membered heteroaryl; and n is 0 to 5; (ii) a compound having the structure of Formula (I-A) or Formula (I-B):X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R4 is hydrogen or C1-6 alkyl; and n is 0 to 5; (iii) a compound having the structure of Formula (I-AA) or Formula (I-BB):Attorney Docket No.62826-719.601R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6 alkyl; and / or (iv) a compound having the structure of Formula (II):wherein RAis C1-20 alkyl wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10%. The method of embodiment 67, wherein the cutaneous lesion is a skin cancer. 63. The method of embodiment 62, wherein the cutaneous lesion is a basal cell carcinoma, squamous cell carcinoma, or melanoma. 64. The method of embodiment 62-63, where the mode of administration is topical, oral, systemic, intradermal, intralesional, or subcutaneous. 65. The method of any one of embodiments 62-64, comprising occluding the cutaneous lesion. 66. The method of any one of embodiments 62-65, wherein the cutaneous lesion is present on a human subject. 67. The method of embodiment 66, wherein the cutaneous lesion is present on the face, trunk, an extremity, or a combination thereof, of the human subject. 68. The method of any one of embodiments 62-67, wherein treating comprises reducing the thickness of the cutaneous lesion to less than 1 mm. 69. The method of any one of embodiments 62-68, wherein the thickness of the cutaneous lesion prior administering is greater than or equal to 1 mm.Attorney Docket No.62826-719.601 70. The method of any one of embodiments 62-69, wherein the length of the cutaneous lesion prior to administering is from 1 mm to 15 mm, and the width of the cutaneous lesion prior to administering is from 1 mm to 15 mm. 71. The method of any one of embodiments 62-70, wherein treating comprises inducing apoptosis of a keratinocyte or melanocyte in the cutaneous lesion. 72. The method of embodiment 71, wherein apoptosis is measured by TUNEL assay. 73. The method of any one of embodiments 62-72, wherein the composition is a gel formulation. 74. The method of any one of embodiments 62-73, wherein the composition comprises an alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof. 75. A composition comprising: a. a compound having the structure of Formula (I):wherein: X is CH or N; each R1is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6haloalkyl, or C1-6alkoxy; R2is an optionally substituted C6-12aryl or optionally substituted 3- to 12- membered heteroaryl; and n is 0 to 5; b. a compound having the structure of Formula (I-A) or Formula (I-B):Attorney Docket No.62826-719.601wherein: X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R4 is hydrogen or C1-6 alkyl; and n is 0 to 5; c. a compound having the structure of Formula (I-AA) or Formula (I-BB):R3is hydrogen, C1-6alkyl, C1-6haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6 alkyl; and / or d. a compound having the structure of Formula (II):wherein RAis C1-20 alkyl, wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10%, by weight. 76. The composition of embodiment 75, wherein the composition is a gel formulation.Attorney Docket No.62826-719.601 77. The composition of embodiment 75 or embodiment 76, wherein the composition comprises an alcohol, a gelling agent, an antioxidant, or a combination of two or more thereof. 78. A composition comprising: (i) a compound having the structure:tautomer) or a salt thereof, and / or (ii) a compound having the structure:and one or more excipients selected from (a)-(e): a) alcohol; b) an organic solvent and / or a penetration enhancer; c) an antioxidant; d) a preservative; and e) a gelling agent. 79. The composition of embodiment 78, comprising the alcohol. 80. The composition of embodiment 79, wherein the alcohol comprises a C2-6 alcohol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, or a combination or two or more thereof. 81. The composition of embodiment 80, wherein the alcohol comprises the C2-6alcohol. 82. The composition of embodiment 81, wherein the C2-6alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, or a combination or two or more thereof.Attorney Docket No.62826-719.601 83. The composition of embodiment 82, wherein the C2-6 alcohol comprises ethanol. 84. The composition of any one of embodiments 79-83, wherein the alcohol comprises an organic solvent and / or penetration enhancer. 85. The composition of any one of embodiments 78-83, comprising an organic solvent and / or penetration enhancer. 86. The composition of embodiment 84 or embodiment 85, wherein the organic solvent and / or penetration enhancer comprises a C2-6 alkylene glycol, C1-3 alkyl-(OCH2CH2)1-5- OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof. 87. The composition of embodiment 86, wherein: the C2-6alkylene glycol is propylene glycol; the C1-3 alkyl-(OCH2CH2)1-5-OH is 2-(2-ethoxyethoxy)ethanol; and the polyethylene glycol is PEG200, PEG400, or a combination thereof. 88. The composition of embodiment 86 or embodiment 87, wherein the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2- ethoxyethoxy)ethanol. 89. The composition of any one of embodiments 78-88, comprising the antioxidant. 90. The composition of embodiment 89, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. 91. The composition of embodiment 90, wherein the antioxidant comprises butylated hydroxytoluene. 92. The composition of any one of embodiments 78-91, comprising a preservative. 93. The composition of embodiment 92, wherein the preservative comprises phenoxyethanol. 94. The composition of any one of embodiments 78-93, comprising the gelling agent. 95. The composition of embodiment 94, wherein the gelling agent comprises hydroxypropyl cellulose.Attorney Docket No.62826-719.601 96. The composition of embodiment 95, wherein the hydroxypropyl cellulose has an average molecular weight of from 700,000 Da to 1,150,000 Da. 97. The composition of embodiment 78, comprising ethanol, propylene glycol, 2-(2- ethoxyethoxy)ethanol, and hydroxypropyl cellulose. 98. The composition of embodiment 78, further comprising an antioxidant and / or a preservative. 99. The composition of embodiment 98, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, or propyl gallate, or a combination of two or more thereof; and the preservative comprises phenoxyethanol. 100. The composition of any one of embodiments 78-99, comprising a pH adjuster, optionally an acid, and further optionally a citric acid. 101. The composition of embodiment 80, 88, or 97, wherein propylene glycol is a super refined propylene glycol. 102. The composition of embodiment 86 or 97, wherein 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of > 99.90%. 103. The composition of embodiment 98, wherein the antioxidant, when present, comprises butylated hydroxytoluene; and the preservative, when present, comprises phenoxyethanol. 104. The composition of any one of embodiments 78-103, wherein the composition has a viscosity of about 10000 cp to about 30000 cp. 105. The composition of any one of embodiments 78-104, wherein the composition is a pharmaceutical composition. 106. The composition of any one of embodiments 78-105, wherein the composition is a topical, oral, systemic, intralesional, subdermal, or intradermal composition. 107. The composition of any one of embodiments 78-106, wherein the composition is in the form of a gel, ointment, lotion, foam or emollient. 108. The composition of any one of embodiments 78-107, or the method of any one of embodiments 58-80, wherein the composition is a component of a patch, tape, film, wafer, or bandage.Attorney Docket No.62826-719.601 109. A method of treating or preventing or reducing the progression of a skin disease, condition or disorder in a subject in need thereof, comprising administering in an effective amount to the subject a pharmaceutical composition of any one of embodiments 81-118. 110. The method of embodiment 109, wherein the skin disease, condition or disorder is basal cell carcinoma, squamous cell carcinoma, melanoma, non-melanoma skin cancer, Gorlin syndrome, basal cell nevus syndrome, a benign tumor, a malignant tumor, parasite, virus of the skin, immune disease or disorder, or a bacterial, fungal or microbial infection. 111. The method of embodiment 109, wherein the skin disease, condition, or disorder is basal cell carcinoma, squamous cell carcinoma, or melanoma. 112. The method of embodiment 109, wherein: the skin disease, condition or disorder is the benign tumor, wherein the benign tumor is a benign vascular tumor, benign fibrotic tumor, benign adipocyte tumor, benign sebaceous tumor, benign epidermal tumor, benign melanocytic lesion, or benign neural tumor; the skin disease, condition or disorder is the malignant tumor, wherein the malignant tumor is a malignant melanocytic tumor, a basal cell carcinoma, squamous cell carcinoma, melanoma, malignant epidermal tumor, malignant vascular tumor, malignant metastatic tumor, malignant adipocyte tumor, malignant sebaceous tumor, or malignant fibrotic tumor; the skin disease, condition or disorder is the parasite, wherein the parasite is of the genus Trypanasoma or Lieshmania; the skin disease, condition or disorder is the virus, wherein the virus is molluscum contagiosum virus or human papilloma virus; or the skin disease, condition or disorder is the bacterial, fungal or microbial infection, wherein the bacterial, fungal or microbial infection is otitis media, Staphylococcus aureus infection, Mycobacterium infection, Porphyromonas infection, Salmonella infection, Chlamydia infection, tuberculosis, gingivitis or periodontal disease. 113. The method of any one of embodiments 109-112, wherein 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.Attorney Docket No.62826-719.601 114. The method of any one of embodiments 109-113, wherein the composition is administered in a pulsed cycle. 115. The method of any one of embodiments 109-114, wherein the composition is administered under occlusion. 116. The method of any one of embodiments 109-115, comprising administering the composition orally, systematically, subdermally, intralesionally, or intradermally. 117. The method of any one of embodiments 109-116, wherein the composition is combined or used in combination with one or more of the following: anti-inflammatory drugs, NSAIDs, antimicrobials, antibiotics, steroids, anti-viral agents, chemotherapy agents, alkylating agents, antimetabolites, or antimicrotubular agents, Vitamin D Derivatives, Oxidative compounds, Acids, Retinoid derivatives, Keratolytics, Corticosteroids, immunoregulators, immune modulators, sunscreens, UV blockers, zinc compounds, retinoids, dyschromia treatments, hyperpigmentation treatments, moisturizers, and / or anti-aging treatments. 118. The method of embodiment 109, wherein the skin disease, condition or disorder is skin pigmentation disorder. 119. The method of embodiment 109, where in the skin pigmentation disorder is Acanthosis nigricans. 120. A kit comprising a topical pharmaceutical composition of any one of embodiments 78-119, in a tube, flexible aluminum tube or laminated plastic tube, with instructions for use. EXAMPLES Example 1: Preparation of Compositions

[0337] Example topical compositions of the present disclosure, where the composition is for use in treating or preventing BCC, can be prepared according to the procedure provided below. Reaction conditions, steps and reactants not provided in the procedure below would be apparent to, and known by, those skilled in the art.

[0338] Excipients (i.e., C2-6alcohol, an organic solvent and / or a penetration enhancer, an antioxidant, a preservative, and / or water) were aliquoted or weighted into individual vessels to form a mixture. Compound 1, represented by the formula:Attorney Docket No.62826-719.601was added to the mixture to achieve a desired concentration. Then the gelling agent (e.g., HPC) were added accordingly. In some of the compositions where a pH adjuster (e.g., citric acid) was used, pH of the formed mixture was adjusted with an aqueous citric acid solution (e.g., 0.1 M, 0.5 M, or 1 M solution) to a desired apparent pH (e.g., about 5.5 to 6.5). In some of compositions, a second addition of water (if present) was finally used to titrate the composition to 100% by weight. The final mixture was then mixed well to form the composition. Example 2: Various Compositions with / without Compound 1

[0339] The following compositions for use in treating or preventing BCC, were prepared according to the general procedure using excipients of Table 1 to Table 7. Table 1: Various Compositions in HPC GelsTable 2: Various Compositions in Sepineo GelsAttorney Docket No.62826-719.601Table 3: Various Compositions in Anhydrous Sepineo GelsTable 4: Various Compositions Containing High Transcutol in HPC GelsAttorney Docket No.62826-719.601 Table 5: Various Compositions Containing Low Transcutol in HPC GelsTable 6: Various Compositions Containing in PEG OintmentsAttorney Docket No.62826-719.601 Table 7: Various Compositions Containing PEG / Transcutol in HPC GelsExample 3: A 14-Day Dermal Tolerability Study in Gottingen Minipigs SUMMARY

[0340] The objective of this study was to determine the local skin tolerability of four (4) compositions of Compound 1 for use in treating or preventing BCC, and the respective placebos (Sepineo Gels of Table 2, Anhydrous Sepineo Gels of Table 3, High Transcutol Gels of Table 4, or Low Transcutol Gels of Table 5) following once daily or every other day dermal administration for 14 days to Göttingen Minipigs. MATERIALS & METHODS

[0341] The test articles and placebos (Sepineo Gels of Table 2, Anhydrous Sepineo Gels of Table 3, High Transcutol Gels of Table 4, or Low Transcutol Gels of Table 5) were administered on the left side of each animal once daily for 14 days during the study via dermal application. The test articles and placebos were administered on the right side of each animal once every other day, beginning on Day 2 (Days 2, 4, 6, 8, 10, 12, and 14) via dermal application. The dose concentrations of Compound 1 were 0.01% and 0.1% (the first animal / sex) or 0.1% and 1% (the second animal / sex) and were administered at a dose volume of 0.5 mL / site. On the day prior to the first dose administration, the hair was clipped from the back of the animal. Repeated clipping was done as necessary. Care was taken to avoid abrading the skin. Each exposure site was marked at the corners with an indelible marker. The test articles and placebos were distributed to individual sites (6 / side), measuring 1.4 x 1.4-inch each, on the dorsal surface by gentle inunction with a glass stirring rod orAttorney Docket No.62826-719.601 appropriate instrument (e.g., stainless steel spatula). The test articles and placebos were applied evenly with a thin, uniform film of the appropriate dosing material over the test sites. The area was not occluded.

[0342] The sites were observed for gross signs of irritation (i.e., erythema and edema, lesion) and any other signs of local or systemic effect and ranked on a scale from 0 – 5 where 0 corresponded to ‘no effect’. Clinical observations unrelated to application site observations were recorded as unscheduled observations if necessary.

[0343] Following the Day 14 dose (2 to 4 hours postdose), all animals were euthanized for skin biopsy sample collection. Prior to the collection, the dosing site(s) were gently washed with a 10% soap solution (e.g., Dawn dish soap) followed by a tepid water rinse using a Wypall®, or equivalent. A hose was utilized to facilitate the rinse using a low- pressure stream of tepid tap water; followed by tape stripping to remove any residual composition prior to performing the punch biopsy. Full thickness samples were collected from each dose site (including placebo sites) and a single naïve site per animal via a 5 mm circular or elliptical punch biopsy instrument or by dissection with a surgical blade. RESULTS, INTERPRETATIONS AND CONCLUSIONS

[0344] All compositions and placebos were generally well-tolerated following once daily or once every other day dermal administration for 14 days. All test articles and placebos were generally well-tolerated. The only finding of irritation occurred in male 1002. With daily dosing, very slight erythema was present on site 3 (Ex.2D-1% of Table 4) on Days 12 to 14 and on site 6 (Ex.2E-1% of Table 5) on Days 4 and 7 to 14. No edema was present at any time point in any animal.

[0345] FIG.1A-FIG.1D show local skin tolerability of four (4) compositions including Compound 1 and the respective placebos following once daily or every other day dermal administration for 14 days to Göttingen Minipigs, measured by scores of Erythema and Edema. The four (4) compositions correspond to compositions of Table 2 to Table 5 as follows:Attorney Docket No.62826-719.601Example 4: Further Optimization of Compositions Containing High Transcutol

[0346] The compositions of Table 4 that contain about 47-48% of Transcutol P ((2-(2- ethoxyethoxy)ethanol) was further studied with additions of antioxidants (e.g., butylated hydroxytoluene (BHT) and / or butylated hydroxyanisole (BHA), or propyl gallate), preservatives (e.g., phenoxyethanol), and / or a pH adjuster (e.g., aq. citric acid solution). Accordingly, the compositions are shown in Table 8 and Table 9.Attorney Docket No.62826-719.601 Table 8: Compositions including Compound 1Attorney Docket No.62826-719.601Table 9: Compositions without Compound 1 (Placebo)Attorney Docket No.62826-719.601Example 5: Induction of Apoptosis in Seborrheic Keratosis SUMMARY

[0347] A non-clinical ex-vivo human SK explant model was used to test a composition including 1% Compound 1 to induce apoptosis in SK samples. The aim of this study was to investigate the ability of a topically applied Compound to suppress cell viability in SK. The use of human explants allowed for the assay of compositions and the effect of drug product on topical penetration to be assessed in an environment closely mimicking the clinical setting. Shave biopsies of SK were taken from patients undergoing excision of SK for clinical purposes. Pieces of the biopsies, 3- 4 mm2in size, were embedded in media and agar for experimentation. Protruding sample surfaces were treated with 2.5 microliter ( ^l) of a composition including 1% Compound 1 (e.g., Ex.4-6a or Ex.5-1%), with vehicle only, or left untreated. The explants were then incubated for 72 hours (hr) and fixed for staining and histological assessment. The 72 hr timeframe was used as an efficacy end point and relative apoptosis was assessed by TUNEL staining at the end of the experiment. The resulting images were assessed qualitatively by visual inspection and showed observably moreAttorney Docket No.62826-719.601 apoptosis in the explants treated with Compound 1 as compared to those treated with vehicle or left untreated. This non-clinical explant study was designed to build confidence in the use of 1% compound 1 for treatment for SK and, indeed, induced an observable increase in apoptosis when applied to SK explants. MATERIALS & METHODS

[0348] Materials required for tissue culture included RPMI 1640 (Thermo Fisher,11875093), Human serum (GeminiBio #100-110), Amphotericin B (Thermo Fisher, Cat# 15290018), and Penicillin Streptomycin (5,000 U / mL, Thermo Fisher, Cat# 15140-122), Agarose (Sigma ,CAS 9012-36-6) DMSO Sigma Aldrich (#D8418), Transwell Permeable Supports, 12 well plate (Corning 12 mm Transwell® with 3.0 µm PorePolycarbonate Membrane Insert, Sterile Cat# 3402).

[0349] The composition including Compound 1 and the corresponding vehicle, as shown in Table 10, were used in the study. Table 10: Compositions

[0350] The ex vivo study was conducted to determine whether Compound 1 in a composition containing a high level of Transcutol (e.g., Ex.4-6a of Example 4 or Ex.5-1%) would penetrate a human cutaneous lesion leading to increased apoptosis as measured by TUNEL assay. Biopsies of human seborrheic keratoses were collected and immediately prepared for drug treatment as described in the Experimental Model section.Attorney Docket No.62826-719.601

[0351] A total of five (5) seborrheic keratoses were collected from patients under an IRB approved protocol with informed consent. Each SK collected was divided into pieces to be used in different treatment groups. Two separate experiments were performed at different time points. In the first experiment, two keratoses were collected and each was divided in to two pieces. A section of each sample was treated 1% Compound 1 and a section of each was treated with vehicle. The treatment groups were: 1) 1% Compound 1 (N=2); and 2) Vehicle (N=2).

[0352] In the second study, three seborrheic keratoses were collected and divided into 3 pieces, each of which were treated with either 1% Compound 1, vehicle only, or were left untreated. The treatment groups were: 1) 1% Compound 1 (N=3); 2) Vehicle (N=3); and 3) Untreated (N=3). In both experiments, either 1% Compound 1 in the composition (Ex.5-1%) or Vehicle was applied topically to partially submerged tissue samples that were approximately 3.5 mm2. Specifically, 2.5 microliter ( ^l) of the composition of Ex.5-1% (including 1% Compound 1) was added to the samples, as described above, or 2.5 ^l of vehicle was added to the samples as a control. In the second experiment, and additional three pieces of the SKs were left untreated for comparison. Drug product or vehicle was added to each sample topically by pipetting onto the exposed surface area immediately after plating. After a 72 hour incubation at 37°C and 5% CO2, the specimen was fixed for 24 hours in 10% formalin and then transferred to 70% ethanol for TUNEL staining. RESULTS, INTERPRETATIONS, AND CONCLUSIONS

[0353] All seborrheic keratosis (n=5) treated with the composition of Ex.5-1% (including 1% Compound 1) demonstrated a relative increase in apoptosis as measured by TUNEL staining as compared with vehicle (n=5) and untreated samples (n=3). One vehicle treated sample also demonstrated increased apoptosis as compared with untreated but the remaining 4 vehicle treated samples had similar apoptosis levels as compared with untreated controls. FIG.2 shows explant TUNEL assay images.

[0354] It can be concluded that one ex-vivo topical application of the composition (e.g., Ex.5-1%) can lead to increased apoptosis of the keratinocytes in the seborrheic keratosis 72 hours after application.Attorney Docket No.62826-719.601 Example 6: Short-Term Stability of Compositions of Example 4

[0355] The compositions of Table 8 and Table 9 for use in treating or preventing BCC, were subjected to short-term physicochemical stability study following storage up to 8 weeks at 25℃ and 40℃. Parameters evaluated were content and purity of the compound (i.e., Compound 1), apparent pH, macroscopic observations, and microscopic observations. Content and Purity of Compound

[0356] The content and purity of Compound 1 in compositions following storage up to 8 weeks are detailed in Table 11 and Table 12, respectively (note: only Ex.4-1a and Ex.4-6a were further extended to t=8 weeks).

[0357] Percentage recovery (%) compares the response of drug peak to a standard of known concentration whereas percentage peak purity (% area) compares the area of the drug peak to the sum of the areas of all peaks in the chromatogram. The change in purity (%) of Compound 1 in the compositions following up to 8 weeks of stability testing from t=0 is detailed in Table 13. Table 11: Content of Compound 1 at t = 0 and under Stability StudyAttorney Docket No.62826-719.601Table 12: Purity of Compound 1 at t = 0 and under Stability StudyAttorney Docket No.62826-719.601Attorney Docket No.62826-719.601 Table 13: Change in Purity of Compound 1 under Stability Study from t = 0Attorney Docket No.62826-719.601

[0358] The content of Compound 1 in all seven aqueous gels was within a value of 95- 105% from t=0 to 2 weeks. However, following 4 weeks of storage, there was a decrease in drug recovery up to 5% in Ex.4-4a (94.25% at t=4 weeks, 2 – 8°C) and Ex.4-6a (95.91% at t=4 weeks, 40°C). At t=0, the purity of Compound 1 in all seven aqueous gels were > 97 area%. Following 4 weeks of storage, the drug purity of the compositions decreased by approximately 0.36 – 2.64 area% at 25°C and 0.88 – 4.13 area% area at 40°C. The decrease in drug purity was lower (0.18 – 0.38 area%) in the compositions stored at 2 – 8°C. Relative purity of Compound 1 in all seven aqueous gels was maintained in > 95% for up to 4 weeks at both 25℃ and 40℃. Ex.4-4a (without a preservative, an antioxidant, and a pH adjuster) and Ex.4-6a (based on Ex.4-4a with BHT) were stable for up to 8 weeks at both 25℃ (< 1 area% decrease of purity) and 40℃ (< 1.5 area% decrease of purity). The addition of antioxidant and preservative (without adjusting a pH) appeared to further stabilize the composition (see Ex.4-6a). Apparent pH

[0359] The apparent pH of compositions with or without Compound 1 at t=0 and 4 weeks (2 – 8℃, 25℃, and 40℃) is presented in Table 14. Table 14: Apparent pH of Compositions under Stability StudyAttorney Docket No.62826-719.601

[0360] At t=0, the apparent pH of the compositions with pH adjuster ranged from 5.94 - 7.67 with no notable (± >1 pH unit) difference in pH between the placebo and corresponding active compositions. Following 4 weeks of storage, the pH values ranged from 5.52 – 6.86 (2 – 8°C), 5.54 – 8.06 (25°C) and 5.48 – 7.67 (40°C), in line with the pH values are t=0. The pH of gel compositions which were not adjusted for pH remained at about pH 9: Ex.4-1a (active) (9.13 at t=0, 9.21 at t=4 weeks, 2 – 8°C, 9.15 at t=4 weeks, 25°C, and 9.11 at t=4 weeks, 40 °C); and Ex.4-6a (active) (9.42 at t=0, 8.94 at t=4 weeks, 2 – 8°C, 8.82 at t=4 weeks, 25°C, and 8.79 at t= 4 weeks, 40°C). Macroscopic observations

[0361] The macroscopic appearance and macroscopic images against light and dark backgrounds were accessed for all seven compositions including Compound 1 and corresponding vehicles.

[0362] At t=0, all compositions (both active and vehicles) were clear, had medium viscosity and smooth application. The placebo compositions appeared colorless whereas theAttorney Docket No.62826-719.601 active compositions had a light beige coloration. There were no obvious changes to the compositions when stored for t=4 weeks at 2 – 8℃, 25℃, and 40℃ except slight discoloration observed in Ex.4-4b (vehicle) at t=4 weeks (40℃), where propyl gallate was present in the composition. Microscopic observations

[0363] The microscopic appearance and microscopic images (non-polarised and polarised light) were accessed for all seven compositions including Compound 1 and corresponding vehicles.

[0364] There was no evidence of drug particulates in all compositions (both active and vehicles) over the experimental duration (t=0 to 4 weeks, 2-8°C, 25℃, and 40℃). Though most of the studied compositions were free of excipients particulates, at t=0 and 2 weeks, excipient particulates were observed in three placebo compositions (Ex.4-4b, Ex.4-7b, and Ex.4-8b) and Ex.4-8a (active). At t=4 weeks, excipient particulates were observed in Ex.4- 1a (active) (40℃), Ex.4-1b (vehicle) (25°C), Ex.4-2a (active) and Ex.4-2b (vehicle) (2- 8°C), Ex.4-4a (active) (40°C), and Ex.4-7a (active) (t=2 weeks and 4 weeks, 25 and 40°C). It should be noted that the morphology of the particulates was not consistent across the time points and could potentially be un-hydrated gelling agent (HPC), indicating that longer hydration time would be required for the gelling agent, which would be further optimized during process development.

[0365] Compositions Ex.4-6a (active) and Ex.4-6b (vehicle) were observed to be free of both drug and excipients particulates over the experimental duration (t=0 to 4 weeks, 2-8°C, 25℃, and 40℃). Viscosity

[0366] Viscosity of Ex.4-4a (1.00 wt / wt% Compound 1) (as Ex.6-4a-1%), the same composition (0.10 wt / wt% Compound 1) (as Ex.6-4a-0.1%), and Ex.4-4b (vehicle) (as Ex. 6-4b) was monitored for a period of 3 months, as shown in Table 15.Attorney Docket No.62826-719.601 Table 15: Viscosity of Compositions under Stability StudyExample 7: In Human Demonstration of topical applications for treatment of Seborrheic Keratosis SUMMARY

[0367] Promising in vitro and explant studies prompted further investigation to the benefits of Composition Ex.5 – Compound 1 in human clinical studies for the treatment of SKs. This study is a first-in-human open label adaptive design trial to explore the safety and efficacy of Composition Ex.5 – Compound 1 at a concentration of 1.0% or 0.1% with excipient topical gel in patients with Seborrheic Keratosis (SK). METHODS

[0368] The study enrolled up to 35 subjects with 4 SK Target Lesions (SKTSs) each, across six cohorts with different treatment regimens. The duration of subject participation was approximately 12-16 weeks.

[0369] The 3 completed cohorts all had truncal SKs that were treated with Composition Ex.5 – Compound 1: Cohort 1 was treated with 1.0% twice daily (BID) dosing for 14 days; Cohort 2 was treated with 1.0 % BID for 28 days; and Cohort 3 was treated with 1.0% pulsed-BID 4 days on / 4 days off over 28 days. All subjects were followed for a minimum of 4 weeks after the last dose at which time all four SKTL lesions were scored using the PLAAttorney Docket No.62826-719.601 scale. Forty three lesions were included for primary and secondary analysis. As defined in the protocol, 17 lesions were excluded; 3 were biopsied as non-responsive SKs without 4 weeks of post-treatment follow up, and 14 were histologically confirmed as not being SKs (6 nevi, 4 verrucous keratoses, and 4 lentigos).

[0370] Primary and secondary efficacy endpoints were based on PLA scoring, a 4 point scale with a 3 indicating a > 1mm thickness SK, a 2 with < 1mm thickness SK, a 1 with nearly clear but residual surface changes suggestive of an SK and 0 with no visible surface changes remaining. RESULTS, INTERPRETATIONS, AND CONCLUSIONS

[0371] All three cohorts combined showed 81% of lesions had at least 1 point improvement in Physician Lesion Assessment (PLA) score, 74% of SK lesions were clear (PLA of 0) or nearly clear (PLA of 1), and 44% lesion were completely clear (PLA of 0). The study showed early dose response efficacy, whereby the 28 day treatment regimens, Cohorts 2 and 3, showed the highest percentage of improvements in SKTLs: 100% SKTLs with at least one PLA improvement for both cohorts, 79% and 100% clear or nearly clear, and 57% and 46% completely clear, respectively. The treatment was well tolerated with no serious adverse events or adverse events and only mild (16.7%) or moderate (3.3%) irritation in a small percentage of lesions. Table 16. Results from first three cohorts treated with Composition Ex.5 – Compound 1 Cohort 1 Cohort 2 Cohort 3 All Cohorts (4 at pulsed 4 (5 pts. at BID (5 pts. at BID on / 4 off over (n=14) 14 day) 28 day) 28 day) PLA 0: SK lesions 31% (5 / 16) 57% (8 / 14) 46% (6 / 13) 44% (19 / 43) clear PI 14-56% PI 32-79% PI 23-71% PI 30-59% SK lesions clear or 31% (5 / 16) 57% (8 / 14) 54% (7 / 13) 47% (20 / 43) nearly clear AND atAttorney Docket No.62826-719.601 Cohort 1 Cohort 2 Cohort 3 All Cohorts least 2 grades improvement PLA PLA 0 or 1: SK lesions 50% (8 / 16) 79% (11 / 14) 100% (13 / 13) 74% (32 / 43) clear or nearly clear Primary Endpoint: SK lesions with at least 1 50% (8 / 16) 100% (14 / 14) 100% (13 / 13) 81% (35 / 43) point improvement PLA Note: PI = probability index Table 17a. The number and percentage of lesions with at least 1 unit improvement in PLA scores from baseline to 4 weeks post treatment.Attorney Docket No.62826-719.601 Table 17b. The number and percentage of lesions with at least 1 unit improvement in PLA scores by last visit.Table 17c. The number and percentage of lesions with at least 1 unit improvement in PLA scores by end of study.Attorney Docket No.62826-719.601Table 18a. The number and percentage of lesions that are clear (0) or nearly clear (1) at 4 weeks post treatment.Attorney Docket No.62826-719.601 Table 18b. The number and percentage of lesions that are clear (0) or nearly clear (1) 4 weeks post treatment; and have at least 2 grades of improvement from baseline.Table 18c. The number and percentage of lesions that are clear (0) at 4 weeks post treatment.Attorney Docket No.62826-719.601 Table 18d. The number and percentage of lesions that are clear (0) or nearly clear (1) by last visit.Table 18e. The number and percentage of lesions that are clear (0) or nearly clear (1) by last visit; and have at least 2 grades of improvement from baseline.Attorney Docket No.62826-719.601 Table 18f. The number and percentage of lesions that are clear (0) by last visit.Table 18g. The number and percentage of lesions that are clear (0) or nearly clear (1) by end of study.Attorney Docket No.62826-719.601 Table 18h. The number and percentage of lesions that are clear (0) or nearly clear (1); and have at least 2 grades of improvement from baseline, by end of study.Table 18i. The number and percentage of lesions that are clear (0) by end of study.Attorney Docket No.62826-719.601 Table 19a. The number and percentage of subjects that are clear (0) in all 4 lesions or in at least 3 lesions at 4 weeks post treatment.Table 19b. The number and percentage of subjects that are clear (0) in all 4 lesions or in at least 3 lesions by last visit.Table 19c. The number and percentage of subjects that are clear (0) in all 4 lesions or in at least 3 lesions by end of study.Attorney Docket No.62826-719.601Table 20. Between the lesions with baseline PLA score 2 and baseline PLA score 3, the lesions with PLA scores of ≤ 1 and at least two grades of improvements at 4 weeks post treatment.Attorney Docket No.62826-719.601 Table 21a. PLA scores of Cohorts 1, 2, 3 lesions at various time points between the baseline and Day 56.Table 21b. PLA scores of Cohorts 2 & 3 lesions at various time points between the baseline and Day 56.Attorney Docket No.62826-719.601

[0372] FIGS.3A-5C provide time-to-event KM plots, as described in the Brief Description of the Drawings. Representative photos demonstrating the response of Composition Ex.5 – Compound 1 to an SK in Cohort 1 (BID for 14 days) and an SK in a background lentigo in Cohort 2 (BID for 28 days), respectively, are shown in FIG.6. Table 22. In the first three cohorts of the study, there were no SAEs or AEs. Pain, pruritus, erythema, edema and scabbing were rated as none (0), mild (1), moderate (2) or severe (3). Visit (Day) Mild (1) Moderate (2) Severe (3) Baseline 0 (0.0%) 0 (0.0%) 0 (0.0%) 7 6 (10.0%) 0 (0.0%) 0 (0.0%) 14 10 (16.7%) 2 (3.3%) 0 (0.0%) 21 0 (0.0%) 0 (0.0%) 0 (0.0%) 28 0 (0.0%) 0 (0.0%) 0 (0.0%) 35 0 (0.0%) 0 (0.0%) 0 (0.0%) 42 0 (0.0%) 0 (0.0%) 0 (0.0%) 56 0 (0.0%) 0 (0.0%) 0 (0.0%) 70 0 (0.0%) 0 (0.0%) 0 (0.0%) 84 0 (0.0%) 0 (0.0%) 0 (0.0%) 98 0 (0.0%) 0 (0.0%) 0 (0.0%)

[0373] These data demonstrate that Composition Ex.5 – Compound 1 is an effective, selective and safe treatment for SKs, improving on current treatment methods. Example 8: In Human Demonstration of topical applications for treatment of facial and occluded Seborrheic Keratosis SUMMARY

[0374] Promising in vitro and explant studies prompted further investigation to the benefits of Composition Ex.5 – Compound 1 in human clinical studies for the treatment of SKs. This study is a first-in-human open label adaptive design trial to explore the safety and efficacy of Composition Ex.5 – Compound 1 at a concentration of 1.0% or 0.1% with excipient topical gel in patients with Seborrheic Keratosis (SK). A cohort will have a two-Attorney Docket No.62826-719.601 week treatment period of twice daily applications followed by a four-week follow-up period. Based on the results at any time from the first and subsequent cohorts, additional cohorts will explore different dosing regimens. METHODS

[0375] The study enrolls up to 35 subjects with 4 SK Target Lesions (SKTLs) each, across seven cohorts with different treatment regimens. The duration of subject participation was approximately 12-16 weeks. Cohorts 4, 5, 6, and 7 were enrolled or planned to be enrolled in the second part of this adaptive design study (results from Cohorts 1, 2, and 3 are described in Example 7). All cohorts had SKs that were treated with Composition Ex.5 – Compound 1.

[0376] Cohort 4 (n = 5 subjects) each subject receives Composition Ex.5 – 1.0% compound 1 application to four Seborrheic Keratosis target lesions (SKTLs) on the face BID (twice a day). Twice daily Composition Ex.5 – 1.0% compound 1 is applied to the facial SKTLs for 28 days.

[0377] Cohort 5 (n = 5 subjects) each subject receives Composition Ex.5 – 1.0% compound 1 application to four Seborrheic Keratosis target lesions (SKTLs) on the trunk and extremities under (Tegaderm) occlusion QD (once daily) / TIW (three times a week). The Composition Ex.5 – 1.0% compound 1 is applied and kept under occlusion once a day, three times a week.

[0378] Cohort 6 (n = 5 subjects) each subject receives Composition Ex.5 – 1.0% compound 1 application to four Seborrheic Keratosis target lesions (SKTLs) on the Trunk (including intertriginous) or Extremity BID. The Composition Ex.5 – 1.0% compound 1 is applied twice daily for 28 days.

[0379] Cohort 7 (n = 5 subjects) each subject receives Composition Ex.5 – 0.1% compound 1 application to four Seborrheic Keratosis target lesions (SKTLs) on the face BID. The Composition Ex.5 – 0.1% compound 1 is applied twice daily for 28 days.

[0380] All subjects were followed for a minimum of 4 weeks after the last dose. All four SKTL lesions were scored using the PLA scale at each visit.

[0381] Primary and secondary efficacy endpoints were based on PLA scoring, a 4 point scale with a 3 indicating a > 1mm thickness SK, a 2 with < 1mm thickness SK, a 1 withAttorney Docket No.62826-719.601 nearly clear but residual surface changes suggestive of an SK and 0 with no visible surface changes remaining.

[0382] In particular, the primary outcome measure is 1. Proportion of treated SKs with at least a 1 grade improvement in PLA score, change from state of the treatment period through 4 weeks safety follow up [Time Frame: 4 weeks after last dose]

[0383] Secondary primary outcome measures include: 2. Proportion of treated SKs with a Physician's Lesion Assessment (PLA) of 0 or 1, Change from start of the treatment period through 4 weeks safety follow-up [Time Frame: 4 weeks after last dose] 3. Proportion of treated SKs with a PLA of 0, Change from start of the treatment period through 4 weeks safety follow-up [Time Frame: 4 weeks after last dose] 4. Proportion of treated SKs with a PLA of 0 or 1, Change from start of the treatment period to week 12 [Time Frame: At week 12] 5. Proportion of treated SKs with a PLA of 0, Change from start of the treatment period to week 12 [Time Frame: At week 12] 6. Proportion of treated SKs with a Subject Self Assessment (SSA) of 0 or 1, Change from start of the treatment period through 4 weeks safety follow-up [Time Frame: 4 weeks after last dose] 7. Proportion of treated SKs with a SSA of 0, Change from start of the treatment period through 4 weeks safety follow-up [Time Frame: 4 weeks after last dose] 8. Proportion of treated SKs with a SSA of 0 or 1, Change from start of the treatment period to week 12 [Time Frame: At week 12] 9. Proportion of treated SKs with a SSA of 0, Change from start of the treatment period to week 12 [Time Frame: At week 12] 10. Time to treated SKs achieving a PLA of 0 or 1, Duration of time from Baseline / Day 1 (PLA 3 or 2) to PLA of 0 or 1 [Time Frame: At study exit. In this adaptive design trial, study exit will be 4 to 10 weeks after completion of the treatment period.]Attorney Docket No.62826-719.601 11. Time to treated SKs achieving a PLA of 0, Duration of time from Baseline / Day 1 (PLA 3 or 2) to PLA of 0 [Time Frame: At study exit. In this adaptive design trial, study exit will be 4 to 10 weeks after completion of the treatment period.]

[0384] Inclusion criteria for all cohorts include: 1. At least 18 years of age. 2. Have four eligible SKs on the face, trunk, or extremities. An eligible SK must: a. Have a clinically typical appearance, b. Have a Physician’s Lesion Assessment (PLA) of ≥2, c. Have a length that is ≥1mm and ≤15mm, d. Have a width that is ≥1mm and ≤15mm, e. Have a thickness that is ≤2mm, f. Be a discrete lesion, g. Not be covered with hair which, in the Investigator’s opinion, would interfere with the study medication treatment or the study evaluations, h. Not be pedunculated 3. Must be in good general health and free of any known disease state or physical condition which, in the Investigator’s opinion, might impair evaluation of any target SK lesion or which exposes the subject to an unacceptable risk by study participation. 4. Must be willing and able to follow all study instructions and to attend all study visits. 5. As applicable, technical ability and willingness to apply Investigational Product (IP). 6. Must be able to comprehend and willing to sign an informed consent form (ICF).

[0385] Exclusion criteria include: 1. Positive urine pregnancy test, pregnant, lactating, or female of childbearing potential who does not agree to use an active method of birth control for the duration of the study. 2. Have SK lesions that are clinically atypical and / or rapidly growing in size. 3. Presence of multiple eruptive SK lesions (sign of Leser-Trelat) 4. Current systemic malignancy.Attorney Docket No.62826-719.601 5. Any use of the following systemic therapies within the specified period prior to the Screening visit: a. Retinoids; 180 days, b. Glucocorticosteroids; 28 days, c. Anti-metabolites (e.g., methotrexate); 28 days 6. Any use of the following topical therapies within the specified period prior to the Screening visit on, or in a proximity to any target SK lesion, that in the Investigator’s opinion could interfere with the study medication treatment or the study assessments: a. Laser, light or other energy-based therapy [e.g., intense pulsed, light (IPL), photo- dynamic therapy (PDT)]; 180 days, b. Liquid nitrogen, electrodesiccation, curettage, imiquimod, 5-flurouracil, or ingenol mebutate; 60 days, c. Microdermabrasion or superficial chemical peels; 14 days, d. Glucocorticosteroids or antibiotics; 14 days 7. Occurrence or presence of any of the following within the specified period prior to the Screening visit on or in the proximity of any target SK lesion that, in the Investigator’s opinion, could interfere with the study medication treatment or the study assessments: a. Cutaneous malignancy; 180 days, b. Sunburn; currently, c. Excessive suntan; currently, d. A pre-malignancy (e.g., actinic keratosis); currently, e. Body art (e.g., tattoos, piercing, etc.); currently 8. History of sensitivity to any of the ingredients in the study medications. 9. Any current skin disease (e.g., psoriasis, atopic dermatitis, eczema, sun damage, etc.), or condition (e.g., sunburn, excessive hair, open wounds) that, in the opinion of the Investigator, might put the subject at undue risk by study participation or interfere with the study conduct or evaluations. 10. Participation in an investigational drug trial in which administration of an investigational study medication occurred within 30 days prior to the Screening visit.Attorney Docket No.62826-719.601 Table 23. Composition Ex.5 with 1.0% and 0.1% of compound 1.Results

[0386] The clinical trial is ongoing, and the results reported here are interim results. Cohort 7 is fully enrolled and participants have completed up to the day 28 visit, Cohort 4 is fully enrolled and visits completed to day 14 and some participants up to day 21, Cohort 5 has 4 out 5 potential participants enrolled and participants have completed up to the screening visit and some participants up to day 7, Cohort 6 has not yet been enrolled .Attorney Docket No.62826-719.601

[0387] The column in tables 24-29 entitled “Missing” indicates whether there are any participants or lesions of enrolled participants that have not yet completed the visit and have not been assessed on the designated day. The percentage of all anticipated lesions that or individuals who have not yet been scored is also given.

[0388] The treatments are well tolerated and an analysis of all SK lesions across all treatments show only mild local tolerability reactions, if any, and no moderate or severe reactions. The highest number of mild tolerability reactions by lesion was 8 or 15.4% of the lesions on day 7 (Table 24) and all other lesions had no reactions. The local tolerability was also assessed on a patient level where each patient had multiple lesions treated. The majority of patients across all treatment groups had no local tolerability reactions and the highest number of mild tolerability reactions was on day 7 when 3 patients or 27.3% of the patients had mild tolerability reactions. There were no moderate or severe reactions (Table 25).

[0389] In Cohorts 4 (1% facial) and 7 (0.1% facial), the majority (approximately 70%) of patients saw at least a 1 point decrease in PLA score after 28 days or 21 days, respectively, of treatment (Fig.7; Table 27 and Table 29). In cohort 5 (1% TIW), at least one patient out of three who had completed the day 7 screening, saw a 1 point decrease in PLA score (Table 28). Table 24. Local Tolerability score for all lesions treated.Attorney Docket No.62826-719.601 Table 25. Local tolerability score per patient.Table 26. PLA scores for all patientsAttorney Docket No.62826-719.601 Table 27. PLA scores for Cohort 4 (1% facial)Table 28. PLA scores for Cohort 5 (1% TIW)Attorney Docket No.62826-719.601 Table 29. PLA Cohort 7 (0.1% facial)Example 9: Stability of Composition Ex.5 - 0.1% and 1.0% Compound 1

[0390] The content and purity of Compound 1 in Composition Ex.5-0.1% and Ex.5-1.0% for use in treating or preventing BCC, following storage up to 6 months are detailed in Table 30.

[0391] Percentage recovery (%) compares the response of drug peak to a standard of known concentration in a chromatogram using standard HPLC methods. The change in content (%) of Compound 1 in the compositions following up to 6 months of stability testing was measured starting from t=0 and three technical replicates were performed at each stability time point for each storage condition and each content of Compound 1. There were no deviations from the expected range of content of Compound 1 in Composition Ex.5- 0.1% and 1.0% over time. The acceptable range of Compound 1 content was 90.0% - 110.0% Apparent pH

[0392] The apparent pH of Composition Ex.5-0.1% Compound 1 and Composition Ex.5- 1.0% Compound 1 following storage up to 6 months at 25℃ and 40℃ is presented in Table 24. Apparent pH was measured using standard equipment and methods in the field.

[0393] Apparent pH remained consistent from 0 to 6 months at 25℃ and at 40℃ for Ex.5-0.1% Compound 1 and Ex.5-1.0% Compound 1. The pH of Ex.5-1.0% Compound 1 at both temperatures ranged from 8.49 to 8.62. The pH of Ex.5-0.1% Compound 1 at both temperatures ranged from 7.78 to 8.18.Attorney Docket No.62826-719.601 Macroscopic observations

[0394] The macroscopic appearance and macroscopic images against light and dark backgrounds were assessed for Compositions Ex.5-0.1% Compound 1 and Ex.5-1.0% Compound 1 following storage up to 6 months at 25℃ and 40℃ (Table 30).

[0395] At t=0, all compositions were yellow or slightly yellow, slightly turbid, had medium viscosity and smooth application. The color, viscosity and feel remained consistent over time and temperature. The color in Composition Ex.5-1.0% Compound 1 was scored as stronger than Composition Ex.5-0.1% Compound 1. Microscopic observations

[0396] The microscopic appearance and microscopic images (non-polarized and polarized light) were assessed using standard microscopy methods for all compositions at the designated time points and storage temperatures.

[0397] There was no evidence of drug particulates or crystals in any of the compositions (Table 30). Viscosity

[0398] The viscosity was assessed for Compositions Ex.5-0.1% Compound 1 and Ex.5- 1.0% Compound 1 following storage up to 6 months at 25℃ and 40℃ (Table 24). Viscosity was measured using standard methods. The viscosity of Ex.5-1.0% Compound 1 ranged from 22440cp to 29600cp. The viscosity of Composition Ex.5-0.1% Compound 1 ranged from 12800cp to 28400cp.

[0399] Table 30. Macroscopic, microscopic, apparent pH and average content of Composition Ex.5 with 1.0% and 0.1% of compound 1. RH = Relative humidity, cP = centipoise.Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Example 10: In Human Demonstration of topical applications for treatment of Basal Cell Carcinoma SUMMARY

[0400] Further investigation was done into the benefits of Composition Ex.5 – Compound 1 -1% in humans for the treatment of Basal Cell Carcinomas. Composition Ex.5 – Compound 1- 1%, containing 1.0% API in an excipient topical gel was found to improve Basal Cell Carcinomas. METHODS

[0401] The Basal Cell Carcinoma (BCC) was treated with Composition Ex.5 – Compound 1-1.0% that contains a 1.0% API concentration in an excipient gel. The lesion was treated with twice daily (BID) dosing for 28 days and was confirmed to be a BCC by histological analysis. The lesion was followed for 6 weeks after last dose and was scored at each visit using the Physician’s Lesion Assessment (PLA) scale, a 4 point scale with a 3 indicating a > 1mm thickness, a 2 with < 1mm thickness, a 1 with nearly clear but residualAttorney Docket No.62826-719.601 surface changes and 0 with no visible surface changes remaining. Safety and Tolerability were evaluated through assessment of signs and symptoms of local tolerability as Local Tolerability Reactions (LTR). The signs and symptoms assessed were pain, pruritus, erythema, edema, and scabbing using 4 point scales (0= None; 1= Mild; 2= Moderate; 3= Severe). LTRs were scored for all lesions and adverse events were assessed for all subjects. The BCC was located on the face of the subject. RESULTS, INTERPRETATIONS, AND CONCLUSIONS

[0402] The BCC lesion visibly decreased in size and thickness from Day 21 to Day 42 (2 weeks after last administration of treatment). From Day 56 to day 96 the lesion appeared to grow back to a fraction of the original size (Figure 8). The PLA scores of the BCC lesion corroborated the results. At baseline the PLA score was 2, at day 7 the PLA score was 2, day 14 the PLA score was 2, day 21 the PLA score was 2, day 26 the PLA score was 1, day 35 the PLA score was 0, day 42 the PLA score was 0, day 56 the PLA score was 1, day 70 the PLA score was 2, day 84 the PLA score was 2, and Day 98 the PLA score was 2 (Table 31).

[0403] There were no adverse events related to the treatment of the BCC and only mild local tolerability reactions were experienced. Mild pruritis, erythema and scabbing were recorded at the day 14 visit; mild pain, pruritis, erythema, and scabbing were recorded at the day 21 visit; and mild scabbing was recorded at the day 28 visit. No other LTRs were recorded, and edema was never experienced.

[0404] The BCC clearly responded to treatment by visual inspection and as measured by PLA score. Only mild LTRs occurred during the treatment of the BCC and no serious adverse events occurred. Table 31.Attorney Docket No.62826-719.601Example 11: In Human topical applications for treatment of Seborheic Keratoses, Basal Cell Carcinomas, and Squamous cell carcinoma in situ SUMMARY

[0405] Further investigation was done into the benefits of Composition Ex.5 – Compound 1 -1.0% in humans for the treatment of Basal Cell Carcinomas and Squamous cell carcinomas in situ. METHODS

[0406] An open-label trial was done to explore the safety and efficacy of gel containing 1.0% API in subjects with seborrheic keratoses (SK) and non-melanoma skin cancer (basal cell carcinoma (BCC) and squamous cell carcinoma in situ (SCCIS)). Subjects were enrolled into 1 of 5 cohorts: Cohort 1: gel containing 1.0% API, BID for 28 days to superficial BCCs Cohort 2: gel containing 1.0% API, BID for 28 days to nodular BCCs Cohort 3: gel containing 1.0% API, BID for 28 days to infiltrating BCCs Cohort 4: gel containing 1.0% API, BID for 28 days to SCCISs Cohort 5: gel containing 1.0% API, BID for 28 days to SKs

[0407] Each cohort enrolled 5-10 subjects with at least 1 eligible lesion treated. A maximum of 5 lesions were enrolled per subject. Multiple or different tumor types were enrolled in each cohort, but the subject had primary analysis performed for their assigned cohort tumor subtype and secondary analysis for any alternate tumor subtypes.Attorney Docket No.62826-719.601

[0408] Eligible subjects must have had at least 1 and up to 5 eligible lesions at screening that were histologically confirmed seborrheic keratoses or non-melanoma skin cancers, ranging from 1.0-2.0 cm in greatest diameter. All potentially eligible lesions screened had a biopsy at screening (either a 2.0 mm punch or shave biopsy), removing no more than 25% of the tumor, for histological confirmation and eligibility, as well as biomarker assessment. All lesions were primary previously untreated lesions meaning that they were not recurrent lesions. All SK lesions were a PLA of 2.

[0409] All NMSC only subjects and subjects with SKs and NMSC were followed through post-op suture removal 7-14 days post-excision of NMSCs, for a total of up to approximately 12-weeks of required participation in the study (4-weeks screening, 4-weeks on treatment, 2-weeks of follow up with excision, and up to 2 weeks for post-op follow up and suture removal).

[0410] All subjects with seborrheic keratoses only completed the study at their 2 week follow up visit after their shave excision, for a total of up to approximately 10 weeks of required participation in the study (4-weeks screening, 4-weeks on treatment, 2-weeks of follow up with tangential shave excision).

[0411] Application Site Reactions (ASRs) were evaluated through assessment of the severity of the signs and symptoms of pain, burning, stinging, pruritus, erythema, edema, exudation, erosion / ulceration, hyperpigmentation, and hypopigmentation, at each TL treatment site since last visit, and review of adverse events (AEs). Study Endpoints

[0412] All subjects who were dispensed study IP (API gel 1.0%) and who received at least one (1) confirmed dose of study IP will be included in the safety analysis. All subjects who were consented were included in the Intent-to-treat (ITT) analysis.

[0413] A Per Protocol (PP) population was used for primary efficacy analysis: The per protocol population was defined by subjects that had completed their final week 6 visit assessments. Efficacy assessments were summarized descriptively by treatment group and visits.Attorney Docket No.62826-719.601 Primary efficacy endpoint: Percentage of lesions that achieve a 50% reduction in greatest diameter of cohort-assigned TL(s) at week 6 compared to baseline. Secondary efficacy endpoints: a. Percentage of lesions that achieve a 50% reduction in greatest diameter of all TL(s) at week 6 compared to baseline b. Percentage of subjects that achieve a 50% reduction in greatest diameter of all TL(s) at week 6 compared to baseline c. Percentage of subjects that achieve a 50% reduction in greatest diameter of cohort-assigned TL(s) at week 6 compared to baseline d. Percentage of lesions that achieve histologic cure (complete cure) of cohort- assigned TLs at week 6 e. Percentage of subjects that achieve histologic cure (complete cure) of cohort- assigned TLs at week 6 f. Percentage of lesions that achieve histologic cure (complete cure) of all TLs at week 6 g. Percentage of subjects that achieve histologic cure (complete cure) of all TLs at week 6 h. Percentage of all lesions, nodular BCCs, superficial BCCs, Infiltrating BCCs, SCCISs and SKs achieving a 50% reduction in greatest diameter at week 6 compared to baseline. i. Histologic subtypes of non-melanoma skin cancers and SKs most commonly associated with reduction in greatest tumor diameter at week 6 j. Histologic subtypes of non-melanoma skin cancers and SKs most commonly associated with histologic cure (complete cure) at week 6 k. Association of tumor greatest diameter at baseline to change in greatest diameter at week 6 l. Association of tumor greatest diameter at baseline to histologic cure (complete clearance) at week 6Attorney Docket No.62826-719.601 Exploratory Efficacy Endpoints: a. Evaluated the association between reduction in greatest tumor diameter and biomarkers such as AKT-pathway activity or mutational profiling. b. Evaluated the association between histologic cure and biomarkers such as AKT- pathway activity or mutational profiling. c. Comparison of reduction in greatest tumor diameter at week 4 to frequency and severity of ASRs e. Comparison of histologic cure at week 4 to frequency and severity of ASRs Primary safety endpoints:

[0414] Safety and Tolerability was evaluated through assessment of the severity of the signs and symptoms of Application Site Reactions (ASRs): pain, burning, stinging, pruritus, erythema, edema, exudation, erosion / ulceration, hyperpigmentation, hypopigmentation, and review of adverse events. Example 12: Profiling of Target Kinases in Response to Compounds for Prevention and / or Treatment of Skin Cancers

[0415] A study for testing compounds as described herein with regard to inhibiting target kinases was carried out as described below.

[0416] Compounds were tested on 397 kinases using KinSight™ Quantitative Kinome Profile screen from AssayQuant Technologies, Inc. Marlboro, MA. In brief, the AKT1 IC50 of Compound 1 and GSK690693 were determined. Ten-times the IC50 determination was used as the compound concentration in each kinase inhibition assay along with 1 mM ATP and the appropriate proprietary PhosphoSens® substrate in a continuous kinase inhibition assay. The Sox-based substrate allows for direct quantification of the enzyme activity of the kinase and reports substrate phosphorylation during the entire reaction. The continuous assay format yielded a reaction rate for each kinase determined from dozens of data t ime points, and a progress curve was generated for every reaction well. Percent inhibition and notable observations were calculated for each compound-kinase pair, providing compound mechanism of action and potency insights.

[0417] Percent inhibition of target kinases when Compound 1 was administered is shown in Table 32.Attorney Docket No.62826-719.601 Table 32:Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601 ULK2 - Other

[0418] Percent inhibition of target kinases when GSK690693 was administered is shown in Table 33. Table 33:Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601Attorney Docket No.62826-719.601

Claims

Attorney Docket No.62826-719.601 CLAIMS What is claimed is:

1. A method of preventing or treating skin cancer, the method comprising topically administering to the skin cancer a composition comprising: (i) a compound having the structure of 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; and n is 0 to 5; (ii) a compound having the structure of Formula (I-A) or Formula (I-B):wherein: X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy;Attorney Docket No.62826-719.601 R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; R4 is hydrogen or C1-6 alkyl; and n is 0 to 5; (iii) a compound having the structure of Formula (I-AA) or Formula (I-BB):R3is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6alkoxy; and R4is hydrogen or C1-6 alkyl; (iv) a compound having the structure of Formula (II):wherein RAis C1-20 alkyl; and / or (v) a compound having the structure of Formula (III):wherein the total amount of (i), (ii), (iii), (iv), (v), or any combination of two or more thereof present in the composition is about 0.1% to about 1.5% by weight.

2. The method of claim 1, wherein the skin cancer comprises a basal cell carcinoma (BCC).

3. The method of claim 1 or 2, wherein the skin cancer comprises a squamous cell carcinoma (SCC).

4. The method of claim 3, wherein the SCC is an invasive SCC or an SCC in situ.Attorney Docket No.62826-719.601 5. The method of claim 4, wherein the SCC is from Bowen’s disease.

6. The method of any one of claims 1 to 5, wherein the skin cancer comprises a melanoma.

7. The method of any one of claims 1 to 6, further comprising occluding the skin cancer.

8. The method of any one of claims 1 to 7, comprising inducing apoptosis of a keratinocyte or melanocyte in the skin cancer.

9. The method of any one of claims 1 to 8, wherein the skin cancer is malignant.

10. The method of any one of claims 1 to 8, wherein the skin cancer is benign.

11. The method of any one of claims 1 to 10, wherein the skin cancer is present on the face, trunk, an extremity, or any combination of two or more thereof, of a human subject.

12. The method of any one of claims 1 to 11, wherein a thickness of the skin cancer prior to administering the composition is greater than or equal to 1 mm.

13. The method of any one of claims 1 to 12, wherein a length of the skin cancer prior to administering is from 1 mm to 15 mm, and the width of the cancer prior to administering is from 1 mm to 15 mm.

14. The method of any one of claims 1 to 13, wherein the composition is a gel formulation.

15. The method of any one of claims 1 to 14, wherein the composition comprises an alcohol, a gelling agent, an antioxidant, or a combination of two or more thereof .

16. The method of claim 15, wherein the composition comprises the alcohol, wherein the alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, or a combination or two or more thereof.

17. The method of claim 15 or 16, wherein the composition comprises the alcohol, wherein the alcohol comprises ethanol.

18. The method of any one of claims 1 to 17, wherein the composition comprises an organic solvent and / or penetration enhancer.

19. The method of claim 18, comprising the organic solvent and / or penetration enhance, wherein the organic solvent and / or penetration enhancer comprises a C2-6 alkyleneAttorney Docket No.62826-719.601 glycol, C1-3 alkyl-(OCH2CH2)1-5-OH, a polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof.

20. The method of claim 19, wherein: the C2-6alkylene glycol is propylene glycol; the C1-3alkyl-(OCH2CH2)1-5-OH is 2-(2-ethoxyethoxy)ethanol; and / or the polyethylene glycol is PEG200, PEG400, or a combination thereof.

21. The method of any one of claims 15 to 20, wherein the composition comprises the antioxidant, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof.

22. The method of any one of claims 15 to 21, wherein the composition comprises the antioxidant, wherein the antioxidant comprises butylated hydroxytoluene.

23. The method of any one of claims 1 to 22, wherein the composition comprises a preservative.

24. The method of claim 23, wherein the preservative is phenoxyethanol.

25. The method of any one of claims 15 to 24, wherein the composition comprises the gelling agent, wherein the gelling agent comprises hydroxypropyl cellulose.

26. The method of any one of claims 1 to 25, wherein the composition comprises a pH adjustor.

27. The method of claim 26, wherein the pH adjustor comprises an acid.

28. The method of claim 27, wherein the acid comprises citric acid, acetic acid, acetate buffer, lactic acid, or ascorbic acid.

29. The method of any one of claims 1 to 28, wherein the composition has a pH of about 7 to about 9.

30. The method of any one of claims 1 to 29, wherein the composition is in the form of a gel, ointment, lotion, foam or emollient.

31. The method of any one of claims 1 to 30, wherein the composition is a component of a patch, tape, film, wafer, or bandage.

32. The method of any one of claims 1 to 31, wherein topically administering the composition comprises topically administering the composition 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.Attorney Docket No.62826-719.601 33. The method of any one of claims 1 to 32, wherein the composition comprises the compound having the structure:.

34. The method of any one of claims 1 to 33, wherein the composition comprises the compound having the structure of Formula (III).

35. The method of any one of claims 1 to 34, wherein the composition comprises the compound having the structure:.

36. The method of any one of claims 1 to 35, wherein the composition comprises the compound having the structure:.

37. The method of any one of claims 1 to 36, wherein the composition comprises the compound having the structure:.

38. The method of any one of claims 1 to 37, wherein the composition comprises the compound having the structure:Attorney Docket No.62826-719.

601.

39. The method of any one of claims 1 to 38, wherein the composition comprises the compound having the structure:.

40. The method of any one of claims 1 to 39, wherein the composition comprises the compound having the structure:.

41. The method of any one of claims 1 to 40, wherein the composition comprises the compound having the structure:.

42. The method of any one of claims 1 to 41, wherein the composition comprises the compound having the structure:.

43. The method of any one of claims 1 to 42, wherein the composition comprises the compound having the structure:.Attorney Docket No.62826-719.601 44. The method of any one of claims 1 to 43, wherein the composition comprises the compound having the structure:.

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