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

Abstract

Provided herein are methods for treating, preventing, or reducing the progression of skin cancer, the methods comprising administering to the skin cancer a composition comprising an effective amount of a compound herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 480,940, filed January 20, 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Non-melanoma skin cancers, such as basal cell carcinoma and squamous cell carcinoma, are the most common forms of skin cancer. Squamous cell carcinoma (SCC) is a form of skin cancer that develops due to the uncontrolled proliferation or growth of squamous epithelial cells. Basal cell carcinoma (BCC) is a form of skin cancer that develops when there is uncontrolled proliferation or growth of basal skin cells. BCC is estimated to affect 3.6 million people in the United States each year. BCC develops as a result of mutations in the epidermis, often from UV exposure. Summary of the Invention

[0003] As described herein, strategies for treating melanoma, SCC, and BCC include targeting pathways that regulate tumor growth and proliferation, such as inhibiting the AKT pathway and / or other pathways that regulate tumor growth in melanoma, SCC, and BCC. Compounds that can inhibit the AKT and / or tumor growth and proliferation pathways described herein can be administered in formulations that do not irritate the skin.

[0004] In one aspect, the present disclosure provides a topical pharmaceutical composition, the topical pharmaceutical composition comprising a compound of formula (I):

[0005] [ka] and a compound represented by During the ceremony, X is CH or N; R 1are each independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 2 is an optionally substituted C 6-12 aryl or optionally substituted 3- to 12-membered heteroaryl; n is 0 to 5.

[0006] In some embodiments, R 2 is an optionally substituted C 6-12 aryl or optionally substituted 3-12 membered heteroaryl. In some embodiments, R 2 is an optionally substituted C 6-12 In some embodiments, R 2 is an optionally substituted C 6-10 In some embodiments, R 2 is optionally substituted phenyl or naphthyl. In some embodiments, R 2 is an optionally substituted 3-12 membered heteroaryl. In some embodiments, R 2 is an optionally substituted 6-12 membered heteroaryl. In some embodiments, R 2 is an optionally substituted 8-10 membered heteroaryl. In some embodiments, R 2 is an optionally substituted 9-membered heteroaryl. In some embodiments, R 2 is an optionally substituted benzisoxazolyl, imidazolyl, indolyl, or indazolyl. In some embodiments, R 2 is an optionally substituted indazolyl.

[0007] In some embodiments, the compound has formula (IA) or formula (IB):

[0008] [ka] can be expressed by During the ceremony, X is CH or N; R 1 are each independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 4 is hydrogen or C 1-6 is alkyl, n is 0 to 5.

[0009] In some embodiments, R 1 are each independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R 1 are each independently a halogen, —OH, —NH, or —CN. In some embodiments, R 1 are each independently, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R 1 are each independently, C 1-6 In some embodiments, R 1 are each independently methyl, ethyl, propyl, or butyl. In some embodiments, R 1 are each independently methyl or ethyl. In some embodiments, R 1 are each methyl.

[0010] 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.

[0011] In some embodiments, the compound has formula (I-AA) or formula (I-BB):

[0012] [ka] can be expressed by During the ceremony, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is alkoxy, and R 4 is hydrogen or C 1-6 It is alkyl.

[0013] In some embodiments, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R 3 is hydrogen or C 1-6 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1-6 In some embodiments, R 3 is methyl, ethyl, propyl, or butyl. In some embodiments, R 3 is methyl or ethyl. In some embodiments, R 3 is methyl.

[0014] In some embodiments, R 4 is hydrogen or C 1-6 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1-6 In some embodiments, R 4 is C 1-4 In some embodiments, R 4 is methyl, ethyl, or propyl. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R 4 is methyl.

[0015] In any of the compositions described herein, the compound has the formula (II):

[0016] [ka] can be expressed by In the formula, R A is C 1-20 It is alkyl.

[0017] In some embodiments, R A is C 5-20 In some embodiments, R A is C 10-20 In some embodiments, R A is C 12-20 In some embodiments, R A is C 14-20 In some embodiments, R A is C 14-18 In some embodiments, R A is C 16 It is alkyl.

[0018] In any of the compositions described herein, the compound has the formula (III):

[0019] [ka] It can be expressed as:

[0020] In some embodiments, the composition has the following structure:

[0021] [ka] Includes:

[0022] In some embodiments, the compositions described herein include a compound of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, and one of the following (a) through (g): a)C 2-6 alcohol, b) organic solvents and / or penetration enhancers; c) antioxidants, d) preservatives, e) water; f) pH adjusters, and g) Gelling Agent and one or more excipients selected from 2-6Alcohols, organic solvents and / or penetration enhancers, antioxidants, preservatives, water, pH adjusters, and gelling agents are defined and described herein. In some embodiments, the composition may be formulated with about 0.01% to about 10% of a compound of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III) or a salt thereof. In some embodiments, the composition may be formulated with about 0.01% to about 1.5% of a compound of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III) or a salt thereof. In some embodiments, the composition may be formulated with about 0.01% to about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some embodiments, the compositions may be formulated with about 0.1% to about 1.5% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof.

[0023] In one aspect, the present disclosure provides a topical pharmaceutical composition comprising a compound having the structure of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III), or a pharmaceutically acceptable salt or tautomer thereof, and five or more excipients including 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 with about 0.01% to about 10% of a compound having the structure of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III), or a salt thereof. In some embodiments, the compositions may be formulated with about 0.01% to about 1.5% of a compound of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III) or a salt thereof. In some embodiments, the compositions may be formulated with about 0.01% to about 10% of Compound 1 (e.g., the Compound 1 1H tautomer and / or the Compound 1 2H tautomer) or a salt thereof. In some embodiments, the compositions may be formulated with about 0.1% to about 1.5% of Compound 1 (e.g., the Compound 1 1H tautomer and / or the Compound 1 2H tautomer) or a salt thereof.

[0024] 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 with about 0.01% to about 10% of a compound having a structure of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III) or a salt thereof. In some embodiments, the composition may be formulated with about 0.01% to about 1.5% of a compound of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III) or a salt thereof. In some embodiments, the composition may be formulated with about 0.01% to about 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some embodiments, the composition may be formulated with about 0.1% to about 1.5% Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some embodiments, the skin condition may include a skin lesion. In some embodiments, the skin lesion may be skin cancer. In some embodiments, the skin cancer may be melanoma. In some embodiments, the skin cancer may be basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). In some embodiments, the SCC is invasive SCC or intradermal SCC. In some embodiments, the intradermal SCC may be Bowen's disease.

[0025] In one aspect, the present disclosure provides a kit comprising a topical pharmaceutical composition described herein in a tube, such as a flexible aluminum tube or laminated plastic tube, along with instructions for use. In one aspect, the present disclosure provides a method for treating or preventing a skin lesion, the method comprising topically administering to the skin lesion a composition comprising a compound having the structure of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III), wherein the total amount of compound present in the composition is 0.01% to 10%. In some embodiments, the compound is present in the composition at about 0.01% to about 1.5%. In some embodiments, Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof may be present in the composition at about 0.01% to about 10%. In some embodiments, Compound 1 (eg, Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof may be present in the composition at about 0.1% to about 1.5%.

[0026] In some embodiments, the skin lesion is a carcinoma. In some embodiments, the carcinoma is a basal cell carcinoma (BCC) or a squamous cell carcinoma (SCC). In some embodiments, the lesion is a melanoma. In some embodiments, the SCC is an invasive SCC or an intradermal SCC. In some embodiments, the intradermal SCC can be Bowen's disease.

[0027] In some embodiments, the skin disease being treated or prevented is melanoma.

[0028] In some embodiments, the method further comprises sealing the skin lesion.

[0029] In some embodiments, the skin lesion is present on a human subject. In some embodiments, the skin lesion is present on the face, torso, or extremities, or a combination thereof, of the human subject.

[0030] In some embodiments, the treating step comprises reducing the thickness of the skin lesion to less than 1 mm. In some embodiments, the thickness of the skin lesion before administration is 1 mm or greater. In some embodiments, the length of the skin lesion before administration is 1 mm to 15 mm, and the width of the skin lesion before administration is 1 mm to 15 mm.

[0031] In some embodiments, the treating step comprises inducing apoptosis of keratinocytes or melanocytes in the skin lesion.

[0032] In some embodiments, treating includes improving, reducing, reducing the progression of, partially resolving, or completely resolving skin lesions.

[0033] In some embodiments, the treating step comprises preventing skin lesions. In some embodiments, the treating step comprises preventing basal cell carcinoma, squamous cell carcinoma, and / or melanoma. In some embodiments, the treating step comprises reducing the progression of basal cell carcinoma, squamous cell carcinoma, and / or melanoma.

[0034] In some embodiments, apoptosis is measured by a TUNEL assay.

[0035] 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.

[0036] In one aspect, the disclosure provides a composition comprising a compound having the structure of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein the total amount of compound present in the composition is 0.01% to 10%. In some embodiments, the total amount of compound present in the composition is about 0.01% to about 1.5%. In some embodiments, the compound is Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof.

[0037] 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.

[0038] In one aspect, the disclosure provides a compound having the structure of formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III), or a salt thereof, (a) to (e) below: a) alcohol, b) organic solvents and / or penetration enhancers; c) antioxidants, d) preservatives, and e) Gelling agent and one or more excipients selected from: In some embodiments, the compound is Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof.

[0039] In any of the foregoing and following aspects and embodiments, the composition may include an alcohol, an organic solvent and / or a penetration enhancer, an antioxidant, a preservative, or a gelling agent, or a combination of two or more thereof. The composition may be administered in a manner described herein.

[0040] In some embodiments, the composition 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 of two or more thereof. In some embodiments, the alcohol is C 2-6 In some embodiments, C 2-6The alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, or a combination of two or more thereof. 2-6 The alcohol comprises ethanol. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alcohol is present in an amount of 1% to 30%, 5% to 30%, 10% to 30%, 5% to 20%, 10% to 20%, or about 15% by weight of the composition. In some embodiments, the composition is for use in treating or preventing BCC, and the total amount of alcohol present in the composition is about 1% to about 80% by weight of the composition.

[0041] In some embodiments, the alcohol comprises an organic solvent and / or a penetration enhancer.

[0042] In some embodiments, the composition comprises an organic solvent and / or a penetration enhancer. In some embodiments, the organic solvent and / or penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester, or fatty ether, or a combination of two or more thereof. 2-6 The alkylene glycol is propylene glycol, C 1-3 Alkyl-(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, the composition is for use in treating or preventing BCC, and the organic solvent and / or penetration enhancer is present in an amount of 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight of the composition.

[0043] In some embodiments, the composition comprises an 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, the composition is for use in treating or preventing BCC, and the antioxidant is present in an amount of 0.01% to 5%, 0.01% to 0.2%, 0.01% to 0.1%, or about 0.05% by weight of the composition.

[0044] In some embodiments, the composition comprises a preservative. In some embodiments, the preservative comprises phenoxyethanol. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the preservative is present in an amount of 0.5% to 5.0%, 0.5% to 2%, or about 1% by weight of the composition. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the composition further comprises water in an amount of 0% to 25%, 5% to 25%, 10% to 25%, 15% to 25%, or about 20% by weight of the composition.

[0045] In some embodiments, the composition comprises a gelling agent. In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of 700,000 Da to 1,150,000 Da. In some embodiments, the composition is for use in treating or preventing BCC, and the gelling agent is present in an amount of 0.5% to 5%, or about 2% by weight of the composition.

[0046] In some embodiments, the composition comprises ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and hydroxypropyl cellulose. In some embodiments, the composition is for use in treating or preventing BCC, wherein the ethanol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight of the composition, the propylene glycol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight of the composition, the 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70%, 40% to 60%, or about 47% by weight of the composition, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3%, or about 2% by weight of the composition. In some embodiments, the composition is for use in treating or preventing BCC, wherein the ethanol is present in an amount of about 15% by weight of the composition, the propylene glycol is present in an amount of about 15% by weight of the composition, the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight of the composition, and the 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.

[0047] 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, the composition is for use in the treatment or prevention of BCC, wherein the antioxidant comprises butylated hydroxytoluene in an amount of 0.01% to 0.1%, or about 0.05% by weight, and the preservative comprises phenoxyethanol in an amount of 0.5% to 2%, or about 1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the antioxidant comprises butylated hydroxytoluene in an amount of about 0.05% by weight of the composition, and the preservative comprises phenoxyethanol in an amount of about 1% by weight of the composition.

[0048] In some embodiments, the composition comprises a pH adjuster, optionally an acid, further optionally citric acid, acetic acid, acetate buffer, lactic acid, or ascorbic acid.

[0049] In some embodiments, the propylene glycol is ultra-refined propylene glycol.

[0050] In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of greater than 99.90%.

[0051] In one aspect, the disclosure provides a composition comprising a compound having a structure of Formula (I), (IA), (IB), (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 1 1H tautomer and / or Compound 1 2H tautomer).

[0052] In some embodiments, the antioxidant, if present, comprises butylated hydroxytoluene and the preservative, if present, comprises phenoxyethanol.

[0053] In some embodiments, the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0054] 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.

[0055] In one aspect, the present disclosure provides a method of treating or preventing a disease, illness, or disorder of the skin in a subject in need thereof, the method comprising administering to the subject a composition described herein.

[0056] 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, cutaneous virus, immune disease or disorder, or 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 is invasive SCC or intradermal SCC. In some embodiments, the intradermal SCC can be Bowen's disease.

[0057] In some embodiments, the skin disease, condition, or disorder is a benign tumor, which is a benign hemangioma, a benign fibrous tumor, a benign adipocyte tumor, a benign sebaceous adenoma, a benign epidermal tumor, a benign melanocytic lesion, or a benign neurological tumor; the skin disease, condition, or disorder is a malignant tumor, which is a malignant melanocytic tumor, a malignant epidermal tumor, a malignant hemangioma, a malignant metastatic tumor, a malignant adipocyte tumor, a malignant sebaceous adenoma, or a malignant fibrous tumor, a basal cell carcinoma, a non-melanoma skin cancer, a squamous cell carcinoma, or a melanoma; the skin disease, condition, or disorder is a benign tumor, which is a malignant melanocytic tumor, a malignant epidermal tumor, a malignant hemangioma, a malignant metastatic tumor, a malignant adipocyte tumor, a malignant sebaceous adenoma, or a malignant fibrous tumor, a basal cell carcinoma, a non-melanoma skin cancer, a squamous cell carcinoma, or a melanoma. is a parasite, wherein the parasite is of the genus Trypanasoma or Leishmania; the skin disease, disease, or disorder is a virus, wherein the virus is molluscum contagiosum virus or human papillomavirus; the skin disease, disease, or disorder is a 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.

[0058] In some embodiments, the composition is applied topically to the head, scalp, face, ears, neck, chest, back, inframammary area, arms, legs, intertriginous areas, hands, feet, or groin.

[0059] In some embodiments, the composition is administered in a pulsatile cycle. In some embodiments, the composition is administered under occlusion.

[0060] In some embodiments, the skin disease, condition, or disorder is a skin pigmentation disorder. In some embodiments, the skin pigmentation disorder is acanthosis nigricans.

[0061] In one aspect, the present disclosure provides a kit comprising a topical pharmaceutical composition in a tube, such as a flexible aluminum tube or laminated plastic tube, along with instructions for use. [Brief explanation of the drawings]

[0062] [Figure 1A]FIG. 1 shows the topical skin tolerability of the four compositions of Example 2 containing a compound having the structure of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III) or a salt thereof and a placebo, respectively, after 14 days of cutaneous administration to Göttingen minipigs once daily or every other day, as measured by erythema and edema scores. [Figure 1B] FIG. 1 shows the topical skin tolerability of the four compositions of Example 2 containing a compound having the structure of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III) or a salt thereof and a placebo, respectively, after 14 days of cutaneous administration to Göttingen minipigs once daily or every other day, as measured by erythema and edema scores. [Figure 1C] FIG. 1 shows the topical skin tolerability of the four compositions of Example 2 containing a compound having the structure of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III) or a salt thereof and a placebo, respectively, after 14 days of cutaneous administration to Göttingen minipigs once daily or every other day, as measured by erythema and edema scores. [Figure 1D] FIG. 1 shows the topical skin tolerability of the four compositions of Example 2 containing a compound having the structure of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III) or a salt thereof and a placebo, respectively, after 14 days of cutaneous administration to Göttingen minipigs once daily or every other day, as measured by erythema and edema scores. [Figure 2] 1 shows images of an explant TUNEL assay. TUNEL (brown) demonstrates increased apoptosis in keratinocytes of human seborrheic keratosis treated with the composition of Example 5 containing 1% of a compound having the structure of Formula (I), (IA), (IB), (I-AA), (I-BB), (II), or (III), or a salt thereof, compared to untreated and vehicle-treated explants. Top: 4X magnification, bottom: 10X magnification. [Figure 3A]Time-to-event KM plots for a 1-point PLA score reduction for lesions stratified by cohort for the first 8 weeks after treatment. For cohort 1, the median duration of response to a 1-point PLA reduction was 42 days (28-42 days, 95% CI). For cohorts 2 and 3, the median duration of response to a 1-point PLA reduction was 21 days (cohort 2 95% CI: 21-35 days, cohort 3 95% CI: 21-56 days). Censoring time was set to the last visit. [Figure 3B] Time-to-event KM plots for lesions achieving a 1-point PLA score reduction across all cohorts during the first 8 weeks after treatment. For all cohorts combined, the median duration of response to a 1-point PLA reduction was 21 days (21-35 days, 95% CI). [Figure 3C] Time-to-event KM plot for lesions achieving a 1-point PLA score reduction during the first 8 weeks after treatment. For lesions with a PLA baseline of 2, the median duration of response to a 1-point PLA reduction is 28 days (21-42 days, 95% CI). For lesions with a PLA baseline of 3, the median duration of response to a 1-point PLA reduction is 21 days (7-42 days, 95% CI). [Figure 4A] Time-to-event KM plots for a 2-point reduction in lesion PLA score, stratified by cohort, for the first 8 weeks after treatment. For cohort 1, the median duration of response to a 2-point reduction in PLA is 84 days (84-84 days, 95% CI). For cohort 2, the median duration of response to a 2-point reduction in PLA is 63 days (42-98 days, 95% CI). For cohort 3, the median duration of response to a 2-point reduction in PLA is 98 days (56-98 days, 95% CI). Censoring time is set to the last visit. [Figure 4B] Time-to-event KM plots for a 2-point reduction in lesion PLA score across all cohorts during the first 8 weeks after treatment. For all cohorts combined, the median duration of response to a 2-point reduction in PLA was 84 days (56-98 days, 95% CI). [Figure 4C] Time-to-event KM plots for lesions achieving a 2-point PLA score reduction during the first 8 weeks after treatment. For lesions with a PLA baseline of 2, the median duration of response to a 2-point PLA reduction is 84 days (70-98 days, 95% CI). For lesions with a PLA baseline of 3, the median duration of response to a 2-point PLA reduction is 56 days (28-56 days, 95% CI). [Figure 5A] Time-to-event KM plots for lesion PLA score reduction to 0 8 weeks after treatment, stratified by cohort. For cohort 1, the median response duration is ≥84 days. For cohort 2, the median response duration is 70 days (56-98 days, 95% CI). For cohort 3, the median response duration is ≥98 days. Censoring time is set to the last visit. [Figure 5B] Time-to-event KM plot for lesion PLA score reduction to 0. The median overall response duration was 84 days or more in all cohorts. [Figure 5C] Time-to-event KM plot for lesions whose PLA score decreases to 0. For lesions with a PLA baseline of 2, the median duration of response is 84 days (70-98 days, 95% CI); for lesions with a PLA baseline of 3, the median duration of response is 84 days (56-98 days, 95% CI). [Figure 6] Representative photographs show the response of Composition Ex.5-Compound 1 to SK (14 days BID) in Cohort 1 and SK (28 days BID) in background lentigo in Cohort 2, respectively. [Figure 7] Time-to-event KM plot for patients achieving a 1-point decrease in PLA score during the first 28 days of treatment, stratified by cohort (0.1% face, 1% face, and 1% trunk, three times per week). [Figure 8]Representative photographs show the response of basal cell carcinoma to Composition Ex.5-Compound 1-1% when treated twice daily (BID) for 28 days. Images were taken weekly up to day 96. DETAILED DESCRIPTION OF THE INVENTION

[0063] overview In various embodiments, provided herein are compositions comprising Compound 1 or a salt thereof (as a compound capable of inhibiting Akt or inhibiting other kinases) and methods of using these compositions to treat or prevent skin diseases, conditions, or disorders. The compositions may be administered topically, orally, systemically, intralesionally, intradermally, or subcutaneously to treat or prevent skin diseases, conditions, or disorders. Skin diseases, conditions, or disorders include any one of carcinoma, basal cell carcinoma, squamous cell carcinoma, benign tumors, malignant tumors, melanoma, parasites, skin viruses, immune diseases or disorders, and bacterial, fungal, or microbial infections. In particular, topical compositions are useful for treating or preventing basal cell carcinoma. Specifically, mutations in Akt1 or mutations affecting the regulation of Akt have been shown to be involved in tumor growth in BCC and SCC. Melanoma is one of the most deadly forms of skin cancer, caused by uncontrolled proliferation or growth of melanocytes. Multiple pathways, including dysregulation of the Akt pathway, are involved in melanoma growth. Therefore, compositions that inhibit these mutations may result in the prevention or treatment of BCC, SCC, and / or melanoma.

[0064] definition The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0065] An "alcohol" is an alkyl group, as defined herein, having a hydroxy group attached to a carbon atom in the chain (e.g., C 2-6Alcohols useful in the present invention include, but are not limited to, ethanol, benzyl alcohol, propanol, isopropanol, butanol, isobutanol, tert-butanol, pentanol, and hexanol, among others. Alcohols useful in the present invention are fully saturated. In some embodiments, the alcohol is C 2-6 It's alcohol.

[0066] "Alkylene glycol" refers to a compound having the formula H-[O-alkylene]-OH, where the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, alkylene glycol is C 2-6 In some embodiments, C is an alkylene glycol. 2-6 The alkylene glycol is propylene glycol (1,2-propanediol). In some embodiments, the glycols are butylene glycol and hexylene glycol.

[0067] "Di-alkylene glycol" refers to a compound having the formula HO-(alkylene-O)-H, where the alkylene group has 2 to 6, 2 to 4, or 2 to 3 carbon atoms. In some embodiments, di-alkylene glycol is di-(C 2-6 In some embodiments, di-(C alkylene) glycol. 2-6 The alkylene glycol is dipropylene glycol. Dipropylene glycol can include one or more isomers, such as 4-oxa-2,6-heptanediol, 2-(2-hydroxy-propoxy)-propan-1-ol, 2-(2-hydroxy-1-methyl-ethoxy)-propan-1-ol, and 3,3'-oxybis(propan-1-ol).

[0068] "Polyethylene glycol" is a compound that varies with the subscript "n": HO-(CH2CH2O) n"PEG" refers to a polymer having the formula -OH. Suitable polyethylene glycols may have a free hydroxyl group at each end of the polymer molecule or one or more hydroxyl groups etherified with a lower alkyl, e.g., methyl, group. Also suitable are polyethylene glycol derivatives having esterifiable carboxy groups. Polyethylene glycols useful in the present invention may be polymers of any chain length or molecular weight and may contain branching. In some embodiments, the PEG is methoxy PEG (macrogol monomethyl ether or polyethylene glycol monomethyl ether). In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 9,000. In some embodiments, the average molecular weight of the polyethylene glycol is about 200 to about 5,000. In some embodiments, the average molecular weight of the polyethylene glycol is 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, PEG 200, PEG 300, PEG 400, PEG 600, and PEG 900. The number following "PEG" in the name refers to the average molecular weight of the polymer.

[0069] "USP grade" excipients refer to excipients that meet or exceed the requirements of the United States Pharmacopeia (USP) (e.g., alcohols, propylene glycol, polyethylene glycols such as PEG200 and PEG400).

[0070] "Super refined" excipients refer to excipients from which their impurities have been removed. Super refining removes polar impurities (including primary and secondary oxidation products) from excipients without altering their chemical composition. Removal of these impurities helps reduce excipient-active pharmaceutical ingredient (API) interactions and subsequent API degradation, thereby maintaining the stability of both the drug and the final composition or formulation. Furthermore, removal of these impurities can minimize cell irritation, making them ideal for various drug administration routes. The ultra-refined excipients of the present invention include ultra-refined propylene glycol.

[0071] "Ultra-purified propylene glycol" or "SR propylene glycol" refers to highly refined propylene glycol, which can enhance drug activity and composition (or formulation) stability. In some embodiments, the SR propylene glycol has a purity of about 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or greater. In some embodiments, the SR propylene glycol has a purity of about 99.8% or 99.9% or greater.

[0072] "Transcutol" has the formula CH3CH2OCH2CH2OCH2CH2OH and has the preferred IUPAC name 2-(2-ethoxyethoxy)ethanol. Other names for 2-(2-ethoxyethoxy)ethanol include diethylene glycol monoethyl ether (abbreviated DGME or DEGEE), diethylene glycol ethyl ether (abbreviated DEGEE), ethyl diglycol, dioxytol, 3,6-dioxa-1-octanol, Carbitol, Carbitol Cellosolve, Polysolv DE, or Dowanal DE. Transcutol includes "Transcutol P," "Transcutol CG," and "Transcutol HP."

[0073] "Transcutol P" refers to a highly purified grade of 2-(2-ethoxyethoxy)ethanol. "Transcutol CG" refers to a specific grade of 2-(2-ethoxyethoxy)ethanol, which is a potent solubilizer and efficacy booster used in the cosmetics and pharmaceutical industries. "Transcutol HP" refers to a highly purified grade of 2-(2-ethoxyethoxy)ethanol, which can enhance drug activity and composition (or formulation) stability. In some embodiments, Transcutol P, CG, or HP has a purity of about 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% or greater. In some embodiments, Transcutol P or HP has a purity of 99.8% or 99.9% or greater. In some embodiments, Transcutol HP has a purity of about 99.90%.

[0074] "Fatty alcohol" refers to a primary alcohol with a long aliphatic chain, either saturated or unsaturated. Fatty alcohols can range from as few as 4-6 carbons to as many as 22-26 carbons. Fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleic alcohol (unsaturated), heptadecyl alcohol, stearyl alcohol, oleyl alcohol (unsaturated), nonadecyl alcohol, arachidyl alcohol, henicosyl alcohol, behenyl alcohol, erucyl alcohol (unsaturated), and lignoceryl alcohol.

[0075] "Fatty ester" or "fatty acid ester" refers to a type of ester resulting from the combination of a fatty acid and an alcohol. When the alcohol is polyethylene glycol, the fatty ester refers to a polyoxyethylene fatty ester or a polyoxyethylene fatty acid ester.

[0076] "Fatty ether" refers to a type of ether resulting from the combination of a fatty alcohol with a second alcohol. When the second alcohol is polyethylene glycol, the fatty ether refers to a polyoxyethylene fatty ether.

[0077] "Polysorbate" refers to a type of fatty ester derived from ethoxylated sorbitan (a polyethylene glycol derivative of sorbitol) with fatty acids. 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 Tween™ series (available from Uniqema), including 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 those listed in R.C. Rowe and P.J. Shesky, Handbook of Pharmaceutical Excipients, (2006), 5th ed., which is incorporated herein by reference in its entirety.

[0078] "Glyceride" refers to a fatty ester where the alcohol component is glycerol. The resulting glyceryl fatty ester (or glyceride) can be a monoglyceride, diglyceride, or triglyceride. A "monoglyceride" is a glyceride consisting of one fatty acid chain covalently attached to a glycerol molecule by an ester bond. A "diglyceride" is a glyceride consisting of two fatty acid chains covalently attached to a glycerol molecule by ester bonds. A "triglyceride" is a glyceride consisting of three fatty acid chains covalently attached to a glycerol molecule by ester bonds.

[0079] "Salt" refers to the acid or base salt of the compound of the present invention. Examples of pharmaceutically acceptable salts include inorganic acid salts (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information about 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.

[0080] "Tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one form to another. Compound 1 is shown below.

[0081] [ka] Compound 1 can exist in the 1H and / or 2H tautomeric forms, as shown in Figure 1. As used herein, "Compound 1" includes the 1H tautomer, the 2H tautomer, and a mixture of the 1H and 2H tautomers. Compound 1 also includes salts of the 1H tautomer, salts of the 2H tautomer, and a mixture of salts of the 1H and 2H tautomers.

[0082] "Solvate" refers to a compound provided herein or a salt thereof that further comprises a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0083] "Hydrate" refers to a compound complexed with water molecules. The compounds of the invention can be complexed with 1 / 2 water molecules or 1 to 10 water molecules.

[0084] As used herein, a "composition" or "formulation" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent, or excipient must be compatible with the other ingredients of the composition (or formulation) and not deleterious to the recipient thereof.

[0085] For any one of the topical compositions described herein, the water content refers to the total weight including the pH adjusting solution (if present) (e.g., a solution of 0.1 M, 0.5 M, or 1 M citric acid in water), ethanol (if the ethanol is not absolute ethanol), and the portion from the final QS100 (QS stands for quantum satis).

[0086] "Relative purity of a compound in a topical composition" refers to the purity of a compound (e.g., Compound 1) at a particular time point (e.g., number of weeks) compared to the initial purity of the compound at time zero (i.e., day 0) when stored under stress conditions (e.g., 40°C) or under normal storage conditions (e.g., room temperature or 25°C). As usual, the relative purity of a compound at time zero (i.e., day 0) is set as 100%.

[0087] "About" refers to a range of values ​​that includes the specified value, which one of ordinary skill in the art would consider to be reasonably similar to the specified value. In some embodiments, the term "about" refers to within a standard deviation using measurements generally accepted in the art. In some embodiments, about refers to a range that extends to + / - 10% of the specified value. In some embodiments, about refers to the specified value.

[0088] "Substantially free of..." means 2-6 "Compositions containing 1% by weight or less of other excipients, such as polyethylene glycol (e.g., PEG 200 and / or PEG 400), polyethylene glycol (e.g., PEG 200 and / or PEG 400), glycerol, fatty alcohol, fatty ester (e.g., polysorbate), fatty ether, or combinations thereof, each of which is defined and described herein. 1-3 Alkyl-(OCH2CH2) 1-5 -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol HP) contains impurities including ethylene glycol and / or diethylene glycol. Polyethylene glycol (e.g., PEG 200 and / or PEG 400) and / or C 1-3 Alkyl-(OCH2CH2) 1-5 When -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol HP) is present in the composition, the composition contains 0.5% by weight or less of ethylene glycol and / or diethylene glycol as an impurity. In some embodiments, polyethylene glycol (e.g., PEG 200 and / or PEG 400) and / or C 1-3 Alkyl-(OCH2CH2) 1-5 When -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol HP) is present in the composition, the composition contains no more than 0.25% by weight of ethylene glycol and / or diethylene glycol as impurities.

[0089] "Inhibition," "inhibit," and "inhibitor" refer to a compound or method that prevents a particular action or function.

[0090] "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 topical administration. Topical administration can include applying the composition to a surface of a subject, such as the subject's skin, for example, in the form of a gel, ointment, lotion, foam, emollient, or as a component of a patch, tape, film, wafer, or bandage. The area to which the composition is applied can vary based, for example, on the condition of the subject and the characteristics of the composition (e.g., form, drug loading, etc.).

[0091] "Treate," "treating," and "treatment" refer to any indicator of success in treating or ameliorating an injury, pathology, or disease, including any objective or subjective parameter, such as palliation, remission, reduction of symptoms, or making the injury, pathology, or disease more tolerable to the patient, slowing the rate of degeneration or decline, reducing decline in the final stages of degeneration, improving the patient's physical or mental well-being, etc. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0092] "Prevent," "preventing," or "prevention" includes completely or substantially reducing the likelihood, occurrence, or severity of early clinical or cosmetic symptoms of a disease, condition, or disorder.

[0093] "Patient" or "subject" refers to an organism suffering from or prone to a disease or disorder that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, cats, primates, goats, sheep, cattle, deer, and other non-mammals. In some embodiments, the patient or subject is a human.

[0094] A "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition useful for treating, preventing, or ameliorating an identified disease or disorder, or for exhibiting a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques.

[0095] "One (a, an, or a(n)," when used herein with respect to a substituted group or "substituent," means at least one. For example, a compound is substituted with "one" alkyl or aryl, where the compound is optionally substituted with at least one alkyl and / or at least one aryl, and each alkyl and / or aryl is optionally different. In another example, a compound is substituted with "one (a)" substituent, where the compound is substituted with at least one substituent, and each substituent is optionally different.

[0096] Topical Compositions As will be understood, some excipients of the topical compositions described herein may have 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 thickener, etc. In some such cases, the function of a given substance may be considered singular, even though its properties may allow for multiple functionalities.

[0097] In certain aspects, the present disclosure provides a compound of formula (I):

[0098] [ka] A compound having a structure represented by During the ceremony, X is CH or N; R 1 are each independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R2 is an optionally substituted C 6-12 aryl or optionally substituted 3- to 12-membered heteroaryl; n is 0 to 5; Formula (IA) or (IB):

[0099] [ka] A compound having a structure represented by During the ceremony, X is CH or N; R 1 are each independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 4 is hydrogen or C 1-6 is alkyl, n is 0 to 5; Formula (I-AA) or Formula (I-BB):

[0100] [ka] A compound having a structure represented by During the ceremony, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is alkoxy, and R 4 is hydrogen or C 1-6 a compound, Formula (II):

[0101] [ka] A compound having a structure represented by In the formula, R A C 1-20 a compound which is alkyl, or Formula (III):

[0102] [ka] The present invention provides a composition comprising a compound having a structure represented by: In some embodiments, the composition may include a compound of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), or Formula (II) in a total amount of 0.01% to 10%. In some embodiments, the composition may include a compound of Formula (I), Formula (IA), Formula (IB), 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 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some embodiments, the composition may include Compound 1 in a total amount of 0.01% to 10%. In some embodiments, the compound may be (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some embodiments, the composition may include Compound 1 in a total amount of 0.1% to 1.5%.

[0103] In embodiments in which the composition comprises a compound having the structure of Formula (I), one or more components may vary between embodiments. In some of these embodiments, R 2 is an optionally substituted C 6-12 aryl or optionally substituted 3-12 membered heteroaryl. In some embodiments, R 2 is an optionally substituted C 6-12 In some embodiments, R 2 is an optionally substituted C 6-10 In some embodiments, R 2is optionally substituted phenyl or naphthyl. In some embodiments, R 2 is an optionally substituted 3-12 membered heteroaryl. In some embodiments, R 2 is an optionally substituted 6-12 membered heteroaryl. In some embodiments, R 2 is an optionally substituted 8-10 membered heteroaryl. In some embodiments, R 2 is an optionally substituted 9-membered heteroaryl. In some embodiments, R 2 is an optionally substituted benzisoxazolyl, imidazolyl, indolyl, or indazolyl. In some embodiments, R 2 is an optionally substituted indazolyl.

[0104] In embodiments in which the composition comprises a compound having the structure of Formula (IA) or Formula (IB), one or more components may vary between embodiments. In some of these embodiments, R 1 are each independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R 1 are each independently a halogen, —OH, —NH, or —CN. In some embodiments, R 1 are each independently, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R 1 are each independently, C 1-6 In some embodiments, R 1 are each independently methyl, ethyl, propyl, or butyl. In some embodiments, R 1 are each independently methyl or ethyl. In some embodiments, R 1 are each methyl.

[0105] In embodiments in which the composition includes a compound having the structure of Formula (I-AA) or Formula (I-BB), one or more components may vary between embodiments. In some of these embodiments, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R 3 is hydrogen or C 1-6 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1-6 In some embodiments, R 3 is methyl, ethyl, propyl, or butyl. In some embodiments, R 3 is methyl or ethyl. In some embodiments, R 3 is methyl. In some embodiments, R 4 is hydrogen or C 1-6 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1-6 In some embodiments, R 4 is C 1-4 In some embodiments, R 4 is methyl, ethyl, or propyl. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R 4 is methyl.

[0106] In embodiments in which the composition includes a compound having the structure of Formula (II), one or more components may vary between embodiments. In some of these embodiments, R A is C 5-20 In some embodiments, R A is C 10-20 In some embodiments, R A is C 12-20 In some embodiments, RA is C 14-20 In some embodiments, R A is C 14-18 In some embodiments, R A is C 16 It is alkyl.

[0107] 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.

[0108] In certain embodiments, the present disclosure provides a method for treating a patient with a compound having a structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a salt thereof, in combination with one or more compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a salt thereof, in combination with one or more of the following: a) alcohol, b) organic solvents and / or penetration enhancers; c) antioxidants, d) preservatives, and e) Gelling agent and one or more excipients selected from: In some embodiments, the one or more compounds is Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof.

[0109] In some embodiments, the composition 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 of two or more thereof. In some embodiments, the alcohol is C 2-6 In some embodiments, C 2-6The alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, or a combination of two or more thereof. 2-6 The alcohol comprises ethanol. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alcohol is present in an amount of 1% to 30%, 5% to 30%, 10% to 30%, 5% to 20%, 10% to 20%, or about 15% by weight of the composition.

[0110] In some embodiments, the composition is for use in treating or preventing BCC, and the total amount of alcohol present in the composition is from about 1% to about 80% by weight of the composition.

[0111] In some embodiments, the alcohol comprises an organic solvent and / or a penetration enhancer.

[0112] In some embodiments, the composition further comprises an organic solvent and / or a penetration enhancer. In some embodiments, the organic solvent and / or penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester, or fatty ether, or a combination of two or more thereof. 2-6 The alkylene glycol is propylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol, and the polyethylene glycol is PEG200, PEG400, or a combination thereof.

[0113] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition is for use in treating or preventing BCC, and the organic solvent and / or penetration enhancer is present in an amount of 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight of the composition.

[0114] In some embodiments, the composition further comprises an 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, the composition is for use in treating or preventing BCC, and the antioxidant is present in an amount of 0.01% to 5%, 0.01% to 0.2%, 0.01% to 0.1%, or about 0.05% by weight of the composition.

[0115] In some embodiments, the composition includes a preservative. In some embodiments, the preservative includes phenoxyethanol. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the preservative is present in an amount of 0.5% to 5.0%, 0.5% to 2%, or about 1% by weight of the composition. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the composition further includes water in an amount of 0% to 25%, 5% to 25%, 10% to 25%, 15% to 25%, or about 20% by weight of the composition.

[0116] In some embodiments, the composition comprises a gelling agent. In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of 700,000 Da to 1,150,000 Da. In some embodiments, the composition is for use in treating or preventing BCC, and the gelling agent is present in an amount of 0.5% to 5%, or about 2% by weight of the composition.

[0117] In some embodiments, the composition comprises ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and hydroxypropyl cellulose.

[0118] In some embodiments, the composition is for use in treating or preventing BCC, wherein the ethanol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight, the propylene glycol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight, the 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70%, 40% to 60%, or about 47% by weight, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3%, or about 2% by weight.

[0119] In some embodiments, the composition is for use in treating or preventing BCC, wherein the ethanol is present in an amount of about 15% by weight, the propylene glycol is present in an amount of about 15% by weight, the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight, and the hydroxypropyl cellulose having an average molecular weight of about 850,000 Da is present in an amount of about 2% by weight.

[0120] 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, the composition is for use in the treatment or prevention of BCC, wherein the antioxidant comprises butylated hydroxytoluene in an amount of 0.01% to 0.1% by weight, or about 0.05% by weight, and the preservative comprises phenoxyethanol in an amount of 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein 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.

[0121] In some embodiments, the composition comprises a pH adjuster, optionally an acid, further optionally citric acid, acetic acid, acetate buffer, lactic acid, or ascorbic acid.

[0122] In some embodiments, the propylene glycol is ultra-refined propylene glycol.

[0123] In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of greater than 99.90%.

[0124] In certain aspects, the disclosure provides compositions comprising one or more compounds having the structure of Formula (I), Formula (IA), Formula (IB), 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 comprise Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof.

[0125] In some embodiments, the antioxidant, if present, comprises butylated hydroxytoluene and the preservative, if present, comprises phenoxyethanol.

[0126] In some embodiments, the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0127] 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.

[0128] In certain aspects, the present disclosure provides topical pharmaceutical compositions, which contain one or more compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a pharmaceutically acceptable salt or tautomer thereof, and one or more of the following (a) to (g): a)C 2-6 alcohol, b) organic solvents and / or penetration enhancers; c) antioxidants, d) preservatives, e) water; f) pH adjusters, and g) Gelling Agent and one or more excipients selected from: In some embodiments, the one or more compounds include Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof.

[0129] In some embodiments, the compositions may be formulated with about 0.01% to about 10% of one or more compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a salt thereof. In some embodiments, the compositions may be formulated with about 0.1% to about 1.5% of one or more compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a salt thereof. In some embodiments, the compositions may be formulated with about 0.01% to about 10% of Compound 1 (e.g., the Compound 1 1H tautomer and / or the Compound 1 2H tautomer) or a salt thereof. In some embodiments, the compositions may be formulated with about 0.1% to about 1.5% of Compound 1 (e.g., the Compound 1 1H tautomer and / or the Compound 1 2H tautomer) or a salt thereof.

[0130] In some embodiments, the composition comprises ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and hydroxypropyl cellulose.

[0131] In some embodiments, the composition is for use in treating or preventing BCC, wherein the ethanol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight, the propylene glycol is present in an amount of 10% to 30%, 10% to 20%, or about 15% by weight, the 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70%, 40% to 60%, or about 47% by weight, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3%, or about 2% by weight.

[0132] In some embodiments, the composition is for use in treating or preventing BCC, wherein the ethanol is present in an amount of about 15% by weight, the propylene glycol is present in an amount of about 15% by weight, the 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight, and the hydroxypropyl cellulose having an average molecular weight of about 850,000 Da is present in an amount of about 2% by weight.

[0133] excipients A. Alcohol In some embodiments, the compositions herein include an alcohol. In some embodiments, the alcohol includes ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, or a combination of two or more thereof. In some embodiments, the alcohol is C 2-6 In some embodiments, C 2-6 The alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, or tert-butanol, or a combination of two or more thereof. 2-6 The alcohol comprises ethanol. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alcohol is present in an amount of 1% to 30%, 5% to 30%, 10% to 30%, 5% to 20%, 10% to 20%, or about 15% by weight of the composition.

[0134] In some embodiments, the composition is for use in treating or preventing BCC, and the total amount of alcohol present in the composition is from about 1% to about 80% by weight of the composition.

[0135] In some embodiments, the alcohol comprises an organic solvent and / or a penetration enhancer.

[0136] In some embodiments, the alcohol comprises ethanol. In some embodiments, the alcohol comprises propylene glycol. In some embodiments, the alcohol comprises Transcutol. In some embodiments, the alcohol comprises phenoxyethanol. In some embodiments, the composition is for use in treating or preventing BCC, and 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%.

[0137] C 2-6 alcohol In some embodiments, the composition comprises C 2-6 In some embodiments, C 2-6 The alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, benzyl alcohol, hexanol, pentanol, or tert-butanol, or a combination thereof. 2-6 The alcohol is ethanol or isopropanol. 2-6 The alcohol is ethanol. In some embodiments, the composition comprises ethanol.

[0138] In some embodiments, the composition comprises C 2-6 Alcohol-free: In some embodiments, the composition is ethanol-free.

[0139] In some embodiments, the composition is for use in treating or preventing BCC, and the composition comprises C. 2-6 The alcohol is present in an amount of 0.0% to 90% by weight, 5% to 40% by weight, 10% to 30% by weight, 5% to 20% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and 2-6The alcohol is present in the composition in an amount of 0.0% to 20% by weight, 5% to 20% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alcohol is present in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alcohol is present in an amount of 10% to 20% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alcohol is present in an amount of about 15% by weight.

[0140] In some embodiments, the composition is for use in the treatment or prevention of BCC, and the composition comprises ethanol in an amount of 0.0% to 90% by weight, 5% to 40% by weight, 10% to 30% by weight, 5% to 20% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the ethanol is present in the composition in an amount of 0.0% to 20% by weight, 5% to 20% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the ethanol is present in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the ethanol is present in an amount of 10% to 20% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the ethanol is present in an amount of about 15% by weight.

[0141] B. Organic Solvents and / or Penetration Enhancers In some embodiments, the composition comprises an organic solvent and / or a penetration enhancer. Suitable solvents and / or penetration enhancers include C 2-6 Alkylene glycols (e.g., propylene glycol), di-(C 2-6alkylene) glycols (e.g., dipropylene glycol), C 1-3 Alkyl-(OCH2CH2) 1-5 -OH (e.g., 2-(2-ethoxyethoxy)ethanol or Transcutol P), polyethylene glycol (e.g., PEG 200 and / or PEG 400), glycerol, fatty alcohols (e.g., octyldodecanol), diethers of anhydrosugar alcohols (e.g., dimethyl isosorbide), fatty esters (e.g., diisopropyl adipate, isopropyl myristate, medium chain triglycerides, sorbitan monooleate, etc.), or fatty ethers (e.g., laureth-4), or combinations thereof. In some embodiments, the organic solvent and / or penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination thereof.

[0142] In some embodiments, the organic solvent and / or penetration enhancer is an alcohol.

[0143] In some embodiments, the organic solvent and / or penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, polyethylene glycol, glycerol, fatty alcohol, fatty ester, or fatty ether, or a combination of two or more thereof. 2-6 The alkylene glycol is propylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol, and the polyethylene glycol is PEG200, PEG400, or a combination thereof.

[0144] In some embodiments, the organic solvent and / or penetration enhancer comprises propylene glycol and / or 2-(2-ethoxyethoxy)ethanol. In some embodiments, the composition is for use in treating or preventing BCC, and the organic solvent and / or penetration enhancer is present in an amount of 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight of the composition.

[0145] In some embodiments, the propylene glycol is ultra-refined propylene glycol.

[0146] In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of greater than 99.90%.

[0147] In some embodiments, the organic solvent and / or penetration enhancer is C 2-6 Alkylene glycol and / or C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the organic solvent and / or penetration enhancer is C 2-6 In some embodiments, the organic solvent and / or penetration enhancer comprises C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the organic solvent and / or penetration enhancer comprises C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition is a mixture of C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 Contains -OH.

[0148] In some embodiments, C 1-3 Alkyl-(OCH2CH2) 1-5 -OH is 2-(2-ethoxyethoxy)ethanol (i.e., Transcutol P). In some embodiments, C 2-6 The alkylene glycol is propylene glycol.

[0149] 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 enhancer 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 / or 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.

[0150] In some embodiments, the organic solvent and / or penetration enhancer comprises 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 PEG 200. In some embodiments, the composition comprises PEG 400. In some embodiments, the composition comprises a mixture of PEG 200 and PEG 400.

[0151] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty alcohol. As used herein, the term "fatty alcohol" refers to a saturated or unsaturated fatty alcohol. In some embodiments, the fatty alcohol is in a mixture of different fatty alcohols. In some embodiments, the fatty alcohol has an average of about 12-20, 14-20, 12-18, 14-18, or 16-18 carbon atoms. Suitable fatty alcohols include, but are not limited to, capric alcohol, undecyl alcohol, lauryl alcohol, tridecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmitoleic alcohol, heptadecyl alcohol, stearyl alcohol, oleyl alcohol, nonadecyl alcohol, arachidyl alcohol, henicosyl 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, palmitoleic alcohol, stearyl alcohol, oleyl alcohol, arachidyl alcohol, henicosyl alcohol, behenyl alcohol, erucyl alcohol, and lignoceryl alcohol. In some embodiments, the organic solvent and / or penetration enhancer comprises octyldodecanol. In some embodiments, the composition comprises octyldodecanol.

[0152] In some embodiments, the organic solvent and / or penetration enhancer comprises a fatty ester. In some embodiments, the fatty ester includes glyceryl fatty esters, ethylene glycol monoesters and diesters of fatty acids, propylene glycol monoesters and diesters of fatty acids, sorbitan esters, C6 fatty acids, and the like. 1-6 Alkyl esters of adipic acid, di-(C 1-6 alkyl) esters, or combinations thereof.

[0153] In some embodiments, the fatty acid ester is a glyceride. In some embodiments, the glyceride is a monoglyceride, diglyceride, or triglyceride. The glyceride may be optionally substituted with a sulfonic acid group or a pharmaceutically acceptable salt thereof. Suitable fatty acids for delivering glycerides of fatty acids include, but are not limited to, those described herein. In some embodiments, the glyceride is a monoglyceride 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 to 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 to herein as a medium-chain triglyceride). In some embodiments, the composition comprises triglycerides of fatty acids having 12 to 18 carbon atoms (eg, also referred to herein as medium chain triglycerides).

[0154] 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 C 1-6 In some embodiments, the fatty ester is an ethylene glycol monoester, a propylene glycol monoester, or a C alkyl ester of a fatty acid. 1-4 Alkyl esters. Ethylene glycol monoesters, propylene glycol monoesters, and C 1-4 Suitable fatty acids for delivering any one of the alkyl esters 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 C alkyl ester of a fatty acid having 12 to 18 carbon atoms. 1-4The fatty acid ester is an alkyl ester. Non-limiting examples of esters of fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, or oleic acid. In some embodiments, the fatty acid 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.

[0155] In some embodiments, the fatty acid ester is a sorbitan ester. Suitable fatty acids for delivering sorbitan esters include, but are not limited to, those described herein. Suitable sorbitan esters include, but are not limited to, the Span™ series (available from Uniqema), including Span 20 (sorbitan monolaurate), 40 (sorbitan monopalmitate), 60 (sorbitan monostearate), 80 (sorbitan monooleate), and 85 (sorbitan trioleate). In some embodiments, the fatty acid 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 a polyoxyethylene sorbitol ester (e.g., Tween).

[0156] In some embodiments, the fatty ester is a di-(C 1-4 alkyl) esters (i.e., adipates) or di-(C 1-4 In some embodiments, the fatty acid 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.

[0157] 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.

[0158] In some embodiments, the composition is for use in the treatment or prevention of BCC, and the organic solvent and / or penetration enhancer are present in the composition in an amount of 30% to 99%, 40% to 99%, 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the organic solvent and / or penetration enhancer are present in the composition in an amount of 50% to 99%, 50% to 80%, 50% to 70%, or about 60% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the organic solvent and / or penetration enhancer are present in the composition in an amount of 50% to 80%, 50% to 70%, or about 60% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the organic solvent and / or penetration enhancer are present in the composition in an amount of 50% to 70%, or about 60% by weight. In some embodiments, the composition is for use in treating or preventing BCC, and the organic solvent and / or penetration enhancer is present in the composition in an amount of 50% to 70% by weight, hi some embodiments, the composition is for use in treating or preventing BCC, and the organic solvent and / or penetration enhancer is present in the composition in an amount of about 60% by weight.

[0159] In some embodiments, the composition is for use in the treatment or prevention of BCC, and the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and is present in the composition in a total amount of 50% to 80% by weight, 50% to 70% by weight, or about 60% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and is present in the composition in a total amount of 50% to 80% by weight, 50% to 70% by weight, or about 60% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and is present in the composition in a total amount of 50% to 70% by weight, or about 60% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and the total amount thereof is present in the composition in an amount of 50% to 70% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the organic solvent and / or penetration enhancer is propylene glycol and / or 2-(2-ethoxyethoxy)ethanol, and the total amount thereof is present in the composition in an amount of about 60% by weight.

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

[0161] In some embodiments, the composition is for use in the treatment or prevention of BCC, and propylene glycol is present in the composition in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and propylene glycol is present in the composition in an amount of 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and propylene glycol is present in the composition in an amount of 10% to 20% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and propylene glycol is present in the composition in an amount of about 15% by weight.

[0162] In some embodiments, the composition is for use in the treatment or prevention of BCC, and 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of 30% to 70% by weight, 40% to 60% by weight, or about 47% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of 40% to 60% by weight, or about 47% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of 40% to 60% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and 2-(2-ethoxyethoxy)ethanol is present in the composition in an amount of about 47% by weight.

[0163] In some embodiments, the composition is for use in treating or preventing BCC, the composition comprises glycol and 2-(2-ethoxyethoxy)ethanol, wherein propylene glycol is present in an amount of 10% to 20% by weight and 2-(2-ethoxyethoxy)ethanol is present in an amount of 40% to 60% by weight. In some embodiments, the composition is for use in treating or preventing BCC, the composition comprises glycol and 2-(2-ethoxyethoxy)ethanol, wherein 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.

[0164] In some embodiments, the propylene glycol is ultra-refined propylene glycol.

[0165] In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP. In some embodiments, the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of greater than 99.90%.

[0166] C. Antioxidants In some embodiments, the composition comprises an antioxidant. In some embodiments, the composition does not comprise an antioxidant.

[0167] In some embodiments, the antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, α-tocopherol, ascorbyl palmitate, citric acid or a salt thereof, sodium metabisulfite, or a combination 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.

[0168] In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is present in the composition in an amount of 0.001% to 5% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is present in an amount of 0.01% to 0.5% by weight, 0.01% to 0.2% by weight, 0.01% to 0.1% by weight, or about 0.05% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is present in an amount of 0.01% to 0.5% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is present in an amount of 0.01% to 0.2% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is present in an amount of 0.01% to 0.1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is present in an amount of about 0.05% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is present in an amount of about 0.1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is butylated hydroxytoluene in an amount of 0.01% to 0.1% by weight, or about 0.05% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is butylated hydroxytoluene in an amount of 0.01% to 0.1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is butylated hydroxytoluene in an amount of about 0.05% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is butylated hydroxyanisole in an amount of 0.01% to 0.1% by weight, or about 0.05% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is butylated hydroxyanisole in an amount of 0.01% to 0.1% by weight.In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is butylated hydroxyanisole in an amount of about 0.05% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is propyl gallate in an amount of 0.01% to 0.1% by weight, or about 0.05% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is propyl gallate in an amount of 0.01% to 0.1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is propyl gallate in an amount of about 0.05% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the antioxidant is a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each of which is present in an amount of 0.01% to 0.1% by weight, or about 0.05% by weight. In some embodiments, the composition is for use in treating or preventing BCC, and the antioxidant is a mixture of butylated hydroxytoluene and butylated hydroxyanisole, each of which is present in an amount of 0.01% to 0.1% by weight. In some embodiments, the composition is for use in treating or preventing BCC, and 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.

[0169] 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, the composition is for use in treating or preventing BCC, and the antioxidant is present in an amount of 0.01% to 5%, 0.01% to 0.2%, 0.01% to 0.1%, or about 0.05% by weight of the composition.

[0170] In some embodiments, the antioxidant, if present, comprises butylated hydroxytoluene and the preservative, if present, comprises phenoxyethanol.

[0171] D. Preservatives In some embodiments, the composition comprises a preservative. In some embodiments, the composition does not comprise a preservative.

[0172] In some embodiments, the composition comprises a preservative, and the preservative is benzyl alcohol, phenoxyethanol, methylparaben, propylparaben, butylparaben, 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.

[0173] In some embodiments, the composition is for use in the treatment or prevention of BCC, and the preservative is present in the composition in an amount of 0.01% to 5% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the preservative is present in an amount of 0.5% to 5.0% by weight, 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the preservative is present in an amount of 0.5% to 2% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the preservative is phenoxyethanol in an amount of 0.5% to 5% by weight, 0.5% to 4% by weight, 0.5% to 3% by weight, or 0.5% to 2% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the preservative is phenoxyethanol in an amount of 0.5% to 2% by weight. In some embodiments, the composition is for use in treating or preventing BCC and the preservative is phenoxyethanol in an amount of about 1% by weight.

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

[0175] 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, the composition is for use in the treatment or prevention of BCC, wherein the antioxidant comprises butylated hydroxytoluene in an amount of 0.01% to 0.1% by weight, or about 0.05% by weight, and the preservative comprises phenoxyethanol in an amount of 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein 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.

[0176] In some embodiments, the antioxidant, if present, comprises butylated hydroxytoluene and the preservative, if present, comprises phenoxyethanol.

[0177] E.Water In some embodiments, the composition comprises water. In some embodiments, the composition does not comprise water.

[0178] F. pH adjuster In some embodiments, the composition comprises a pH adjuster. In some embodiments, the composition does not comprise a pH adjuster.

[0179] 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 acid 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.

[0180] 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 at a concentration of 0.1M, 0.5M, or 1M.

[0181] G. Gelling Agent In some embodiments, the composition includes a gelling agent (e.g., a polymeric thickener). Gelling agents include, for example, hydrophilic and hydroalcoholic gelling agents frequently used in the cosmetics and pharmaceutical industries. In some embodiments, the gelling agent is Carbopol (also known as carbomer), carboxymethylcellulose, ethylcellulose, gelatin, hydroxyethylcellulose, hydroxypropylcellulose, magnesium aluminum silicate (Veegum), methylcellulose, poloxamer (Pluronics), polyvinyl alcohol, sodium alginate, Dermacryl, acrylate, octylacrylamide copolymer, HPMC (hydroxypropylmethylcellulose), PVP (polyvinylpyrrolidone), bentonite clay, tragacanth, xanthan gum, Sepineo P600, polyethylene glycol having an average molecular weight of at least about 2500 Da, or a combination thereof. In some embodiments, the gelling agent includes Sepineo P600. In some embodiments, the gelling agent is Sepineo P600. In some embodiments, the gelling agent comprises polyethylene glycol (e.g., PEG 3350) having an average molecular weight of about 2500-3500 Da. In some embodiments, the gelling agent is polyethylene glycol (e.g., PEG 3350) having an average molecular weight of about 2500-3500 Da. In some embodiments, the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the gelling agent is hydroxypropyl cellulose.

[0182] In some embodiments, the hydroxypropyl cellulose has an average molecular weight of about 40,000 daltons (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 hydroxypropyl 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 about 700,000 Da to about 1,150,000 Da.

[0183] Hydroxypropyl celluloses (HDL) include, 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.

[0184] 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 for 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 standard powder (40 mesh), fine powder (100 mesh), and extra fine powder (300 mesh). See Nisso HPC Technical Data Sheet, which is incorporated herein by reference in its entirety.

[0185] 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.

[0186] 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 standard grade and fine grade. Please refer to the Klucel HPC product technical data sheet, which is incorporated herein by reference in its entirety.

[0187] 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.

[0188] When a gelling agent is present in the composition, in some embodiments, the composition has a viscosity of 5,000 cP to 100,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 5,000 cP to 50,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 5,000 cP to 40,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 5,000 cP to 30,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 10,000 cP to 30,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 15,000 cP to 30,000 cP. When a gelling agent is present, in some embodiments, the composition has a viscosity of 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0189] When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 5,000 cP to 100,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 5,000 cP to 50,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 5,000 cP to 40,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 5,000 cP to 30,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 10,000 cP to 30,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 15,000 cP to 30,000 cP. When hydroxypropyl cellulose is present, in some embodiments, the composition has a viscosity of 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10,000 cP to about 30,000 cP.

[0190] In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in the composition in an amount of 0.5% to 30% by weight, while the composition has a viscosity of 5,000 cP to 100,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in an amount of 0.5% to 30% by weight, while the composition has a viscosity of 5,000 cP to 50,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in an amount of 0.5% to 30% by weight, while the composition has a viscosity of 5,000 cP to 40,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in an amount of 0.5% to 30% by weight, while the composition has a viscosity of 5,000 cP to 30,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in an amount of 0.5% to 30% by weight, and the composition has a viscosity of 10,000 cP to 30,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in an amount of 0.5% to 30% by weight, and the composition has a viscosity of 15,000 cP to 30,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in an amount of 0.5% to 30% by weight, and the composition has a viscosity of 20,000 cP to 30,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the composition has a viscosity of about 10,000 cP to about 30,000 cP.

[0191] In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose is present in an amount of 0.5% to 5%, 5% to 10%, 10% to 20%, or 20% to 30% by weight, while the composition has a viscosity of 5,000 cP to 100,000 cP. In some embodiments, when hydroxypropyl cellulose having an average molecular weight of less than about 700,000 Da is used, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose is present in an amount of 5% to 30% by weight, while the composition has a viscosity of 5,000 cP to 100,000 cP. In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose is present in an amount of 0.5% to 5%, 0.5% to 4%, 0.5% to about 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight, while the composition has a viscosity of 5,000 cP to 50,000 cP. In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose is present in an amount of 0.5% to 5%, 0.5% to 4%, 0.5% to about 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight, while the composition has a viscosity of 5,000 cP to 40,000 cP. In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose is present in an amount of 0.5% to 5%, 0.5% to 4%, 0.5% to about 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight, while the composition has a viscosity of 5,000 cP to 30,000 cP.In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose is present in an amount of 0.5% to 4%, 0.5% to 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight, while the composition has a viscosity of 10,000 cP to 30,000 cP. In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose is present in an amount of 0.5% to 4%, 0.5% to 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight, while the composition has a viscosity of 15,000 cP to 30,000 cP. In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose is present in an amount of 0.5% to 4%, 0.5% to 3%, 0.5% to 2%, 1% to 5%, 1% to 4%, 1% to 3%, 1% to 2%, or 2% to 5% by weight, while the composition has a viscosity of 20,000 cP to 30,000 cP. In some embodiments, the composition has a viscosity of about 10,000 cP to about 30,000 cP.

[0192] In some embodiments, the composition is for use in the treatment or prevention of BCC, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to about 2% by weight of the composition. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, while the composition has a viscosity of about 5,000 cP to about 50,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, while the composition has a viscosity of about 5,000 cP to about 40,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, and the composition has a viscosity of about 5,000 cP to about 30,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, and the composition has a viscosity of 10,000 cP to 30,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, and the composition has a viscosity of 15,000 cP to 30,000 cP. In some embodiments, the composition is for use in treating or preventing BCC, wherein the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 0.5% to 2% by weight, while the composition has a viscosity of 20,000 cP to 30,000 cP.In some embodiments, the composition is for use in treating or preventing BCC, and the composition has a viscosity of about 10,000 cp to about 30,000 cp.

[0193] In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of about 1% by weight of the composition. In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of about 2% by weight of the composition.

[0194] In some embodiments, the composition is for use in treating or preventing BCC, and the gelling agent comprises hydroxypropyl cellulose. In some embodiments, the hydroxypropyl cellulose has an average molecular weight of 700,000 Da to 1,150,000 Da. In some embodiments, the composition is for use in treating or preventing BCC, and the gelling agent is present in an amount of 0.5% to 5%, or about 2% by weight of the composition.

[0195] Apparent pH value When the composition is a non-aqueous formulation, the pH value of the composition is the apparent pH value. When the composition contains water, the composition may contain a significant amount of other excipients (e.g., C 2-6 The pH value of a partially aqueous solution can therefore only be considered as an apparent pH value. The apparent pH value of a non-aqueous or partially aqueous solution is to be expected due to variability and can be up to approximately 1 pH unit.

[0196] In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 7.5 to about 9.5. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 7.5 to about 8.5. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 8.5 to about 9.5. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 8. In some embodiments, when a pH adjuster is not present in the composition, the composition has an apparent pH value of about 9.

[0197] In some embodiments, when a pH adjusting agent is present in the composition, the composition has an apparent pH of about 7 or less. In some embodiments, when a pH adjusting agent is present in the composition, the composition has an apparent pH of about 5 to about 7 or about 6 to about 7. In some embodiments, when a pH adjusting agent is present in the composition, the composition has an apparent pH of about 6 to about 7. In some embodiments, when a pH adjusting agent is present in the composition, the composition has an apparent pH of about 6 to about 9.5. In some embodiments, when a pH adjusting agent is present in the composition, the composition has an apparent pH of about 7 to about 8. In some embodiments, when a pH adjusting agent is present in the composition, the composition has an apparent pH of about 7.

[0198] compound In any of the compounds described herein, the compound has the formula (I):

[0199] [ka] can be expressed by During the ceremony, X is CH or N; R 1 are each independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 2 is an optionally substituted C 6-12 aryl or optionally substituted 3- to 12-membered heteroaryl; n is 0 to 5.

[0200] In some embodiments, R 2 is an optionally substituted C 6-12 aryl or optionally substituted 3-12 membered heteroaryl. In some embodiments, R 2 is an optionally substituted C 6-12 In some embodiments, R 2 is an optionally substituted C 6-10 In some embodiments, R 2 is optionally substituted phenyl or naphthyl. In some embodiments, R 2 is an optionally substituted 3-12 membered heteroaryl. In some embodiments, R 2 is an optionally substituted 6-12 membered heteroaryl. In some embodiments, R 2 is an optionally substituted 8-10 membered heteroaryl. In some embodiments, R 2 is an optionally substituted 9-membered heteroaryl. In some embodiments, R 2 is an optionally substituted benzisoxazolyl, imidazolyl, indolyl, or indazolyl. In some embodiments, R 2 is an optionally substituted indazolyl.

[0201] In some embodiments, the compound has formula (IA) or formula (IB):

[0202] [ka] can be expressed by During the ceremony, X is CH or N; R1 are each independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 4 is hydrogen or C 1-6 is alkyl, n is 0 to 5.

[0203] In some embodiments, R 1 are each independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R 1 are each independently a halogen, —OH, —NH, or —CN. In some embodiments, R 1 are each independently, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R 1 are each independently, C 1-6 In some embodiments, R 1 are each independently methyl, ethyl, propyl, or butyl. In some embodiments, R 1 are each independently methyl or ethyl. In some embodiments, R 1 are each methyl.

[0204] 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.

[0205] In some embodiments, the compound has formula (I-AA) or formula (I-BB):

[0206] [ka] can be expressed by During the ceremony, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is alkoxy, and R 4 is hydrogen or C 1-6 It is alkyl.

[0207] In some embodiments, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 In some embodiments, R 3 is hydrogen or C 1-6 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C 1-6 In some embodiments, R 3 is methyl, ethyl, propyl, or butyl. In some embodiments, R 3 is methyl or ethyl. In some embodiments, R 3 is methyl.

[0208] In some embodiments, R 4 is hydrogen or C 1-6 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1-6 In some embodiments, R 4 is C 1-4 In some embodiments, R 4 is methyl, ethyl, or propyl. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R 4 is methyl.

[0209] In any of the compositions described herein, the compound has the formula (II):

[0210] [ka] can be expressed by In the formula, R A is C 1-20 It is alkyl.

[0211] In some embodiments, R A is C 5-20 In some embodiments, R A is C 10-20 In some embodiments, R A is C 12-20 In some embodiments, R A is C 14-20 In some embodiments, R A is C 14-18 In some embodiments, R A is C 16 It is alkyl.

[0212] In any of the compositions described herein, the compound has the formula (III):

[0213] [ka] It can be expressed as:

[0214] In any of the compositions described herein, the compound has the following formula:

[0215] [ka] or a salt thereof, and / or a compound of the formula:

[0216] [ka] or a salt thereof, or a mixture thereof.

[0217] In any of the compositions described herein, one or more compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or mixtures thereof, may be included in the composition.

[0218] In any of the compositions described herein, the compound may be a pharmaceutically acceptable salt of one or more compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or mixtures thereof. Illustrative examples of pharmaceutically acceptable salts are inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid) salts, organic acid (such as acetic acid, propionic acid, glutamic acid, citric acid) salts, and quaternary ammonium (such as methyl iodide, ethyl iodide) salts.

[0219] In any of the compositions described herein, the compound may be in the form of a solvate or hydrate of one or more compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or mixtures thereof.

[0220] In some embodiments, the compound is a compound having the structure of Formula (I):

[0221] In some embodiments, the compound is a compound having the structure of Formula (IA). In some embodiments, the compound is a compound having the structure of Formula (IB). In some embodiments, the compound is a compound having the structure of Formula (I-AA).

[0222] In some embodiments, the compound is a compound having the structure of formula (I-BB):

[0223] In some embodiments, the compound is a compound having the structure of Formula (II):

[0224] In some embodiments, the compound is a compound having the structure of Formula (III):

[0225] In some embodiments, the compound is Compound 1 (eg, Compound 1 1H tautomer and / or Compound 1 2H tautomer).

[0226] In some embodiments, the compound has the following structure:

[0227] [ka] Compound 2 is represented by the formula:

[0228] In some embodiments, the compound has the following structure:

[0229] [ka] Compound 3 is represented by the formula:

[0230] In some embodiments, the compound has the following structure:

[0231] [ka] Compound 4 is represented by the formula:

[0232] In some embodiments, the compound has the following structure:

[0233] [ka] Compound 5 is represented by the formula:

[0234] In some embodiments, the compound has the following structure:

[0235] [ka] Compound 6 is represented by the formula:

[0236] In some embodiments, the compound has the following structure:

[0237] [ka] Compound 7 is represented by the formula:

[0238] In some embodiments, the compound has the following structure:

[0239] [ka] Compound 8 is represented by the formula:

[0240] In some embodiments, the compound has the following structure:

[0241] [ka] Compound 9 is represented by the formula:

[0242] In some embodiments, the compound has the following structure:

[0243] [ka] Compound 10 is represented by the formula:

[0244] In some embodiments, the compound has the following structure:

[0245] [ka] Compound 11 is represented by the formula:

[0246] In some embodiments, the compound is a mixture of any two or more compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof. In some embodiments, the compound is a mixture of any two or more compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof, wherein two or more of the compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof, are present in the mixture in an amount of 1% to 99%. In some embodiments, two or more of the compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof, are present in the mixture in an amount of 50% to 99%, 60% to 99%, 70% to 99%, 80% to 99%, or 90% to 99%. In some embodiments, two or more of the compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof, are present in the mixture in an amount of 80% to 99%. In some embodiments, two or more of the compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof, are present in the mixture in an amount of 0.01% to 10%. In some embodiments, two or more of the compounds having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or pharmaceutically acceptable salts thereof, are present in the mixture in an amount of 0.1% to 1.5%. In some embodiments, two or more of the compounds include Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), and Compound 1 is present in the mixture in an amount of 0.01% to 10%.In some embodiments, two or more of the compounds include Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer), and Compound 1 is present in the mixture in an amount of 0.1% to 1.5%.

[0247] Embodiment In some embodiments, the composition comprises one of the following (a) to (g): a) C 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises three or more excipients selected from the group consisting of: a) C—OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjuster; and g) a gelling agent. 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises four or more excipients selected from the group consisting of: a) C—OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjuster; and g) a gelling agent. 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises five or more excipients selected from the group consisting of: a) C—OH; c) an antioxidant; d) a preservative; e) water; f) a pH adjuster; and g) a gelling agent. 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5The composition comprises six or more excipients selected from the group consisting of: a) an -OH, b) an antioxidant, c) a preservative, d) an antiseptic, e) water, f) a pH adjuster, and g) a gelling agent. The composition may be formulated with about 0.01% to 10% of a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III) or a salt thereof. The composition may be formulated with about 0.1% to 1.5% of a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III) or a salt thereof. The composition may be formulated with about 0.01% to 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. The compositions can be formulated with about 0.1% to 1.5% of Compound 1 (eg, Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof.

[0248] In some embodiments, the composition comprises: a) C 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises a) C 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition comprises a) C—OH, c) an antioxidant, d) a preservative, e) water, and g) a gelling agent. 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5-OH, c) antioxidant, d) preservative, e) water, f) pH adjuster, and g) gelling agent. The composition may be formulated with about 0.01% to 10% of a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III) or a salt thereof. The composition may be formulated with about 0.1% to 1.5% of a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III) or a salt thereof. The composition may be formulated with about 0.01% to 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. The compositions can be formulated with about 0.1% to 1.5% of Compound 1 (eg, Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof.

[0249] In some embodiments, the present disclosure provides a topical pharmaceutical composition (A) comprising a compound having a structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), wherein compound C 2-6 Alcohol, C 1-3 Alkyl-(OCH2CH2) 1-5The -OH, antioxidant, preservative, water, pH adjuster, and gelling agent are as described herein. The composition may be formulated with about 0.01% to 10% of a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III) or a salt thereof. The composition may be formulated with about 0.1% to 1.5% of a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III) or a salt thereof. The composition may be formulated with about 0.01% to 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. The composition may be formulated with about 0.1% to 1.5% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. In some embodiments of Composition (A), an antioxidant is not present in the composition. In some embodiments of Composition (A), a preservative is not present in the composition. In some embodiments of Composition (A), a pH adjuster is not present in the composition. In some embodiments of Composition (A), all of an antioxidant, a preservative, and a pH adjuster are not present in the composition.

[0250] In some embodiments of composition (A), one or more of an antioxidant, a preservative, and a pH adjuster are present in the composition. In some embodiments of composition (A), both an antioxidant and a preservative are present in the composition, and a pH adjuster is not present in the composition.

[0251] In some embodiments, the present disclosure provides a topical pharmaceutical composition (B) comprising a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a salt thereof, wherein the compound, C 2-6 Alcohol, C 1-3 Alkyl-(OCH2CH2) 1-5The -OH, water, and gelling agent are as described herein. The composition may be formulated with about 0.01% to 10% of a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III) or a salt thereof. The composition may be formulated with about 0.1% to 1.5% of a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III) or a salt thereof. The composition may be formulated with about 0.01% to 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. The composition may be formulated with about 0.1% to 1.5% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof.

[0252] In some embodiments, the present disclosure provides a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III), or a pharmaceutically acceptable salt or tautomer thereof, in combination with one of the following: a)C 2-6 alcohol, b) C 2-6 Alkylene glycol and C 1-3 Alkyl-(OCH2CH2) 1-5 -OH, c) antioxidants, d) preservatives, e) water, and g) Gelling Agent and a topical pharmaceutical composition (C) comprising the compound C. 2-6 Alcohol, C 1-3 Alkyl-(OCH2CH2) 1-5The -OH, antioxidant, preservative, water, and gelling agent are as described herein. The composition may be formulated with about 0.01% to 10% of a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III) or a salt thereof. The composition may be formulated with about 0.1% to 1.5% of a compound having the structure of Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III) or a salt thereof. The composition may be formulated with about 0.01% to 10% of Compound 1 (e.g., Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof. The compositions can be formulated with about 0.1% to 1.5% of Compound 1 (eg, Compound 1 1H tautomer and / or Compound 1 2H tautomer) or a salt thereof.

[0253] In some embodiments of any one of compositions (A), (B), and (C), the composition is for use in treating or preventing BCC, and 2-6 The alcohol is present in the composition in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alcohol is present in an amount of 10% to 30%. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alcohol is present in an amount of 10% to 20%. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alcohol is present in an amount of about 15% by weight.

[0254] In some embodiments of any one of compositions (A), (B), and (C), the composition is for use in treating or preventing BCC, and 2-6 The alkylene glycol is present in the composition in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6The alkylene glycol is present in an amount of 10% to 30%. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alkylene glycol is present in an amount of 10% to 20%. In some embodiments, the composition is for use in the treatment or prevention of BCC, 2-6 The alkylene glycol is present in an amount of about 15% by weight.

[0255] In some embodiments of any one of compositions (A), (B), and (C), the composition is for use in treating or preventing BCC, and 1-3 Alkyl-(OCH2CH2) 1-5 -OH is present in an amount of 30% to 70% by weight, 40% to 60% by weight, or about 47% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition is for use in the treatment or prevention of BCC, and the -OH is present in an amount of 30% to 70% by weight. 1-3 Alkyl-(OCH2CH2) 1-5 In some embodiments, the composition is for use in treating or preventing BCC, and the -OH is present in an amount of 40% to 60% by weight. 1-3 Alkyl-(OCH2CH2) 1-5 The -OH is present in an amount of about 47% by weight.

[0256] In some embodiments of any one of compositions (A), (B), and (C), the composition is for use in the treatment or prevention of BCC, and water is present in an amount of 10% to 30% by weight, 15% to 25% by weight, or about 20% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and water is present in an amount of 10% to 30% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and water is present in an amount of 15% to 25% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and water is present in an amount of about 20% by weight.

[0257] In some embodiments of any one of compositions (A), (B), and (C), the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in an amount of 1% to 3% by weight or about 2% by weight, while the composition has a viscosity of 5,000 cP to 30,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in an amount of 1% to 3% by weight or about 2% by weight, while the composition has a viscosity of 10,000 cP to 30,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in an amount of 1% to 3% by weight or about 2% by weight, while the composition has a viscosity of 15,000 cP to 30,000 cP. In some embodiments, the composition is for use in the treatment or prevention of BCC, wherein the gelling agent is present in an amount of 1% to 3% by weight or about 2% by weight, while the composition has a viscosity of 20,000 cP to 30,000 cP.

[0258] In some embodiments of any one of compositions (A), (B), and (C), C 2-6 The alcohol is ethanol, C 2-6 The alkylene glycol is propylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5-OH is 2-(2-ethoxyethoxy)ethanol and the gelling agent is hydroxypropyl cellulose.

[0259] In some embodiments, composition (A1) comprises a compound and one of the following (a) to (g): a) ethanol, b) propylene glycol and 2-(2-ethoxyethoxy)ethanol; c) optionally antioxidants; d) optionally a preservative; e) water; f) optionally a pH adjuster, and g) Hydroxypropyl cellulose and four or more excipients, wherein the compound, antioxidant, preservative, and pH adjuster are as described herein.

[0260] In some embodiments, composition (B1) comprises the compound and one of the following 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.

[0261] In some embodiments, composition (C1) comprises a compound and one of the following excipients a) to e) and g): a) ethanol, b) propylene glycol and 2-(2-ethoxyethoxy)ethanol; c) antioxidants, d) preservatives, e) water, and g) Hydroxypropyl cellulose wherein the compound, antioxidant, and preservative are as described herein.

[0262] In some embodiments of Composition (A) or (A1), the pH adjuster, if present, is an acid. In some embodiments, the pH adjuster, if present, is citric acid. In some embodiments of Composition (A) or (A1), the pH adjuster, if present, is an acid. In some embodiments, the pH adjuster, if present, is lactic acid or ascorbic acid.

[0263] 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 a combination thereof. In some embodiments, the antioxidant, when present, is butylated hydroxytoluene.

[0264] In some embodiments of any one of compositions (A), (C), (A1), and (C1), the preservative, if present, is phenoxyethanol.

[0265] In some embodiments of any one of compositions (A), (C), (A1), and (C1), the antioxidant, if present, is butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination thereof, and the preservative, if present, is phenoxyethanol. In some embodiments, the antioxidant, if present, is butylated hydroxytoluene, and the preservative, if present, is phenoxyethanol.

[0266] In some embodiments of any one of compositions (A), (C), (A1), and (C1), the composition is for use in treating or preventing BCC, and the antioxidant, if present, is present in an amount of 0.01% to 0.1% by weight or about 0.05% by weight. In some embodiments, the composition is for use in treating or preventing BCC, and the antioxidant, if present, is present in an amount of 0.01% to 0.1% by weight. In some embodiments, the antioxidant, if present, is present in an amount of about 0.05% by weight.

[0267] In some embodiments of any one of compositions (A), (C), (A1), and (C1), the composition is for use in the treatment or prevention of BCC, and the preservative, if present, is present in an amount of 0.5% to 2% by weight or about 1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the preservative, if present, is present in an amount of 0.5% to 2% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the preservative, if present, is present in an amount of about 1% by weight.

[0268] In some embodiments, composition (C1a) comprises a compound and one of the following 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.

[0269] In some embodiments of any one of compositions (A1), (B1), (C1), and (C1a), the composition is for use in the treatment or prevention of BCC, and the ethanol is present in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the ethanol is present in an amount of 10% to 30% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the ethanol is present in an amount of 10% to 20% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the ethanol is present in an amount of about 15% by weight.

[0270] In some embodiments of any one of compositions (A1), (B1), (C1), and (C1a), the composition is for use in the treatment or prevention of BCC, and propylene glycol is present in an amount of 10% to 30% by weight, 10% to 20% by weight, or about 15% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and propylene glycol is present in an amount of 10% to 30% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and propylene glycol is present in an amount of 10% to 20% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and propylene glycol is present in an amount of about 15% by weight.

[0271] In some embodiments of any one of compositions (A1), (B1), (C1), and (C1a), the composition is for use in treating or preventing BCC, and 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70% by weight, 40% to 60% by weight, or about 47% by weight. In some embodiments, the composition is for use in treating or preventing BCC, and 2-(2-ethoxyethoxy)ethanol is present in an amount of 30% to 70% by weight. In some embodiments, the composition is for use in treating or preventing BCC, and 2-(2-ethoxyethoxy)ethanol is present in an amount of 40% to 60% by weight. In some embodiments, the composition is for use in treating or preventing BCC, and 2-(2-ethoxyethoxy)ethanol is present in an amount of about 47% by weight.

[0272] In some embodiments of any one of compositions (A1), (B1), (C1), and (C1a), the composition is for use in the treatment or prevention of BCC, and water is present in an amount of 10% to 30% by weight, 15% to 25% by weight, or about 20% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and water is present in an amount of 10% to 30% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and water is present in an amount of 15% to 25% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and water is present in an amount of about 20% by weight.

[0273] In some embodiments of any one of compositions (A1), (B1), (C1), and (C1a), the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3% by weight or about 2% by weight. In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of 1% to 3% by weight. In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of about 1% by weight. In some embodiments, the composition is for use in treating or preventing BCC, and the hydroxypropyl cellulose having an average molecular weight of 700,000 Da to 1,150,000 Da is present in an amount of about 2% by weight. In some embodiments, the composition is for use in treating or preventing BCC and the hydroxypropyl cellulose is Klucel MF in an amount of about 2% by weight.

[0274] In some embodiments of composition (C1a), the composition is for use in the treatment or prevention of BCC, and the butylated hydroxytoluene is present in the composition in an amount of 0.01% to 0.1% by weight, or about 0.05% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the butylated hydroxytoluene is present in an amount of 0.01% to 0.1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the butylated hydroxytoluene is present in an amount of about 0.5% by weight.

[0275] In some embodiments of composition (C1a), the composition is for use in the treatment or prevention of BCC, and the phenoxyethanol is present in the composition in an amount of 0.5% to 2% by weight, or about 1% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the phenoxyethanol is present in an amount of 0.5% to 2% by weight. In some embodiments, the composition is for use in the treatment or prevention of BCC, and the phenoxyethanol is present in an amount of about 1% by weight.

[0276] In some embodiments of composition (C1a), the composition is for use in treating or preventing BCC, and the butylated hydroxytoluene is present in an amount of about 0.5% by weight and the phenoxyethanol is present in an amount of about 1% by weight.

[0277] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), the propylene glycol is ultra-refined propylene glycol.

[0278] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of greater than 99.90%.

[0279] In some embodiments of compositions (A), (B), (C), (A1), (B1), (C1), and (C1a), the compound is present in the composition in an amount of 0.01% to 10%.

[0280] Form of composition Topical compositions useful for delivering a 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 a compound is a gel, ointment, lotion, foam, or emollient.

[0281] In some embodiments, the topical composition used to deliver the compound is a lotion or cream.

[0282] 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 semi-solid systems consisting of a suspension of small inorganic particles or large organic molecules interpenetrated by liquid.If the gel mass contains a network of small, discrete inorganic particles, it is classified as a two-phase gel.Single-phase gels consist of organic polymers that are uniformly distributed throughout the liquid, with no clear boundary between the dispersed polymers and the liquid.

[0283] In some embodiments, the topical composition used to deliver the compound is an ointment. An ointment is an oily semi-solid that contains little, if any, water. In some instances, the ointment is hydrocarbon-based, such as wax, petrolatum, or gelled mineral oil.

[0284] 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.

[0285] In some embodiments, the topical composition can be in the form of a patch, tape, film, wafer, or bandage containing the topical composition 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, when applied to a subject, the patch, tape, film, wafer, or bandage is in contact with the area of ​​the subject's skin adjacent to the affected or target area.

[0286] In some embodiments, topical administration can be achieved in the form of a patch, tape, film, wafer, or bandage containing the topical composition 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 an area of ​​the subject's skin adjacent to the affected or target area.

[0287] In some embodiments, the patch, tape, film, wafer, or bandage comprises an adhesive.

[0288] In some embodiments, the topical composition can be delivered to basal cell carcinoma, squamous cell carcinoma, or melanoma using a tape or film that provides an occlusive environment for the tumor. In some embodiments, the squamous cell carcinoma can be invasive squamous cell carcinoma or squamous intraepithelial carcinoma. In some embodiments, the squamous intraepithelial carcinoma can be Bowen's disease.

[0289] The tape or film can be adhesive tape, waterproof adhesive tape, or plastic film (with or without an adhesive layer). In some embodiments, the transparent film used to form the occlusion is Tagaderm.

[0290] In some embodiments, the composition is impregnated into a tape or film. In some embodiments, the tape or film is a foam-containing tape or film. The pores or interstitial spaces in the foam can be filled with the composition described herein. The foam can have an adhesive layer for adhering the foam to the skin. If the foam is porous, an outer non-porous layer can be provided on the back of the foam to strengthen the closure of the tape.

[0291] In some embodiments, the composition may be in the form of a sustained-release wafer or dot, may be made using a porous foam, may have a quantity of the composition disposed behind the porous foam, and may have a non-porous backing layer disposed behind the composition. The non-porous backing layer may have a portion extending beyond the composition containing Compound 1 and the porous layer. This portion may include a quantity of adhesive that facilitates adhesion of the wafer or dot to the user's skin around the carcinoma or melanoma to be treated.

[0292] In some embodiments, the composition for application may be covered with a film or thermosensitive gel material that exhibits a sol-gel transition in aqueous solution, including, but not limited to, poly(ethylene glycol) / poly(propylene glycol) block copolymers (poloxamers), poly(ethylene glycol) / poly(butylene glycol) block copolymers, poly(ethylene glycol) / poly(butylene glycol) block copolymers, poloxamer-g-poly(acrylic acid), and copolymers of dimethyl acrylate. 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(butylene glycol) block copolymers, poloxamer-g-poly(acrylic acid), and copolymers of dimethyl acrylate.

[0293] 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.

[0294] In some embodiments, the compositions of the present disclosure may be administered with other agents in a combination therapy mode for the treatment or prevention of a skin disease, disorder, or condition. In some examples, the skin disease is basal cell carcinoma, squamous cell carcinoma, or melanoma. In some embodiments, the squamous cell carcinoma can be invasive squamous cell carcinoma or squamous intraepithelial carcinoma. In some embodiments, the squamous intraepithelial carcinoma can be Bowen's disease. In some embodiments, the other agents can include, but are not limited to, one or more of the following: anti-inflammatory drugs, NSAIDs, antibacterial agents, antibiotics, steroids, antiviral agents, chemotherapeutic agents, alkylating agents, antimetabolites, or antimicrotubule agents, vitamin D derivatives, oxidizing compounds, acids, retinoid derivatives, keratolytic agents, corticosteroids, immunomodulators, immunomodulators, sunscreens, UV blockers, zinc compounds, retinoids, pigmentation disorder treatments, pigmentation treatments, moisturizers, and anti-aging treatments. Administration can be sequential, over a period of hours or days, or simultaneously.

[0295] In some embodiments, the compositions of the present disclosure may be administered with other agents in a combination therapy mode for the treatment or prevention of a skin disease, disorder, or condition. In some examples, the skin disease is non-melanoma skin cancer, such as basal cell carcinoma or squamous cell carcinoma, or melanoma. In some embodiments, the other agents are prophylactic and may include, but are not limited to, anti-inflammatory drugs, NSAIDs, antibacterial agents, antibiotics, steroids, antiviral agents, chemotherapeutic agents, alkylating agents, antimetabolites, or anti-microtubule agents, vitamin D derivatives, oxidizing compounds, acids, retinoid derivatives, keratolytic agents, corticosteroids, immunomodulators, immunomodulators, sunscreens, UV blockers, zinc compounds, retinoids, pigmentation disorder treatments, hyperpigmentation treatments, moisturizers, and anti-aging treatments. Administration may be sequential, over a period of hours or days, or simultaneously.

[0296] In some embodiments, the antiviral agent includes Abacavir, Acyclovir, Adefovir, Amprenavir, Atazanavir, Cidofovir, Darunavir, Delavirdine, Didanosine, Docosanol, Efavirenz, Elvitegra, Elvitegravir, Emtricitabine, Enfuvirtide, Etravirine, Famciclovir, Foscarnet, Fomivirsen, Ganciclovir, Indinavir, Idoxuridine, Lamivudine, Lopinavir Lopinavir, Maraviroc, MK-2048, Nelfinavir, Nevirapine, Penciclovir, Raltegravir, Rilpivirine, Ritonavir, Saquinavir, Stavudine, Tenofovir, Trifluridine, May include Valacyclovir, Valganciclovir, Vidarabine, Ibacitabine, Amantadine, Oseltamivir, Rimantidine, Tipranavir, Zalcitabine, Zanamivir, and Zidovudine.

[0297] In one embodiment, the composition is included in combination therapy with one or more corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressants, cyclosporine A, mercaptopurine, azathioprine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotrienes, anticholinergics for rhinitis, anticholinergic decongestants, mast cell stabilizers, monoclonal anti-IgE antibodies, vaccines, and combinations thereof.

[0298] method 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 described herein.

[0299] In certain aspects, the compositions described herein provide methods in which Akt activity is inhibited by a modulator of Akt activity. In some embodiments, the modulator targets Akt or an Akt regulator. In some embodiments, a compound represented by Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), and / or Formula (III) can be a modulator of Akt activity. In some embodiments, Compound 1 can modulate Akt activity. In some embodiments, the modulator can include, but is not limited to, PTEN-PIP2-PIP3, PI3K, PDK1, PP2A, EGFR, IGFR, or other receptor tyrosine kinases.

[0300] Compound 1 may have a modulatory effect on AKT activity. Table 34 shows that at 1 mM concentration, Compound 1 had improved potency to inhibit AK1 in the AssayQuant PhosphoSens assay.

[0301] [Table 1] No time dependence was observed. A compound-dependent delay was observed, with preincubation progression increasing the delay.

[0302] Furthermore, compounds having the structure of formula (III) described herein may have a modular effect on AKT activity. Table 35 shows compounds having the structure of formula (III) that exhibit moderate activity in inhibiting AKT1 at a concentration of 1 mM in the AssayQuant PhosphoSens assay.

[0303] [Table 2] No time dependence was observed, with the preincubation progress curve increasing with lag.

[0304] In some embodiments, the compositions described herein provide methods for suppressing AKT signaling to downstream targets where Akt inhibition regulates multiple 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 (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), and / or Formula (III)) can induce apoptosis. In some embodiments, a compound having a structure represented by Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), or Formula (II) can be a more potent inhibitor of AKT than a compound having a structure represented by Formula (III).

[0305] In some embodiments, the compositions described herein provide methods by which compounds capable of inhibiting Akt can modulate other targets and pathways. In some embodiments, these targets include ASK1, AS160, GLUT1, GLUT4, TXNIP, HK2, PFKFB2, TKT, SIRT1, PTP1B, PRAS40, MDM2, BAD, BH3 family members, ACLY, NFκB, MDM2-p53, IKKα, P21CIP1, P27KIP1, Casp9, TBC1D4, PDE3B, WNK1, eNOS, FOXO, FOXO1, FO These include, but are not limited to, XO3 / 3A, FOXO4, TSC2, TSC-mTORC1, GSK3α / β, FAF1, PRAS40, Chk1, PDK1, EGFR, EGFR / ADCK, Akt1, AKT1 (allosteric), P13KA, PI3Kd, p110a, Pi3K / Mtor / DNA-PK, DNA-PK, FGFR, VEGFR1, VEGFR2, PDGFR, KIT, and FLT3.

[0306] In some embodiments, a method may include using a composition described herein to regulate cellular function via Akt by modulating the GSK3β pathway. In some embodiments, Akt inhibition will affect the function and regulation of GSK3β and one or more of the following targets (non-limiting list): PGC1α, bTrCP, PDE3B, TBC1D4, SREBP, Myc, HIF1α, NRF2, C / EBP, eIF2B, Gli, Gli2, Gli3, FBXW7, and / or ERRα. In some embodiments, a compound capable of inhibiting Akt will modulate a transcription factor. In some embodiments, transcription factors include, but are not limited to, Myc, HIF1, SREBP, ATF4, NRF2, the forkhead box family of transcription factors, FOXO, FOXO3, FOXO1, FOXO4, and FOXO6, and / or DAF-16. In some embodiments, Akt inhibition affects transcription factors that regulate genes that control apoptosis, the cell cycle, cell growth and proliferation, which may include, but are not limited to, BAD, FASL, TRAIL, BIM, PUMA, CDKN1a (p21 / CIP1), CDKN1b (P27 / KIP1), RBL2, and GADD45a.

[0307] In some embodiments, methods may include using the compositions described herein to inhibit Akt, which may have a significant effect on the function of the TSC-mTORC1 complex / pathway, including but not limited to TSC2, Rheb, mTORC1, 4E-BP, S6K, S6, and 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 also regulate protein synthesis through phosphorylation of EIF4B, RPS6, and EEF2K, and may promote cell survival by suppressing the pro-apoptotic function of BAD.

[0308] In some embodiments, the method may include using a composition comprising a compound capable of inhibiting Akt to regulate intrinsic apoptosis. In some embodiments, the inhibitory compound may target and affect BH3 proteins, Bad, BIM, BCL-2, BCLxL, other BH3 proteins, other mitochondrial membrane proteins, NFKappaB, and / or MDM2-p53.

[0309] In some embodiments, the compositions and compounds described herein target, inhibit, or modulate a kinase. In some examples, the kinase is Akt. In some examples, the kinase is not Akt.

[0310] In some embodiments, the compositions and compounds described herein can inhibit and / or modulate target kinases or kinase pathways. Inhibition of the targets described herein can lead to the prevention or treatment of certain skin cancers (e.g., BCC, SCC, or melanoma). For example, CLK2 is expressed in BCC and SCC and crosstalks with the HH / WNT pathway; DYRK1B is expressed in SCC and interacts with the HH pathway; CLK1 is expressed in BCC and crosstalks with the HH / WNT pathway; ICK / CILK1 is expressed in BCC and SCC and interacts with mTOR and the HH pathway; CLK4 is expressed in BCC and SCC and crosstalks with the HH / WNT pathway; DYRK1A is expressed in SCC and some BCCs and interacts with the HH pathway; and P70S6KA is a major AKT and mTOR effector kinase. As further described herein, when one or more compounds (e.g., compounds having a structure represented by Formula (I), Formula (IA), Formula (IB), Formula (I-AA), Formula (I-BB), Formula (II), or Formula (III)) are administered, each of CLK2, DYRK1B, CLK1, ICK / CILK1, CLK4, DYRK1A, and P70S6KA are all inhibited by greater than 70%.

[0311] 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), AURK (Aurora C), AURK (Aurora D), AURK (Aurora E), AURK (Aurora F), AURK (Aurora G), AURK (Aurora H ... B), AURKC (Aurora C), AXL, BLK, BMX, BRAF V599E, BRAF, BRSK1 (SAD1), BTK, CAMK1D (CaMKII 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 B 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), 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), MAPK15(p38 Direct), MAPK16(p38Alpha), 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 eta z), PRKD1 (PKC Mu), PRKD2 (PKD2), PRKG1, PRKG2 (PKG2), PRKX, PTK2 (FAK), PTK2B (FAK2), PTK6 (Brk), RAF1 (cRAF) Y340D Y341D, R Eta 883F, RET S891A, RET V804E, RET V804L, RETY791F, RET, ROCK1, ROCK2, ROS1, RPS6KA1(RSK1), RPS6KA2(RSK3), RPS6KA3(RSK2), RPS6KA4(MSK2), RPS6KA5(MS K1), 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), PIK3CA 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 / p85alpha), 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) S218DS222D, 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 / MA P3K7IP1 (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 (PRKA C 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, and ZAK. In some embodiments, the targets are AKT2 (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 θ[シタ]), PAK5(PAK7), RIPK3, PDGFRA(PDGFRα), CAMK2B(CAMK2β), DDR1[SRC activator], CAMK2G(CAMK2γ), TAOK3(TAO3), CDK4 / CycD3、SGK3 PRKAA1-B1-G3(AMPKα1β1γ3), DDR2, PRKAA2-B1-G2(AMPKα2β1γ2), FGFR3, PRKACB(PKACB, PKAC β), 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); 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), BA RK2, PRKCE(PKCe[イプシロン]), 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)、PTK 6(BRK)、HIPK2、CSNK1A1L(CK1A1L、CK1a2)、MAP3K8(COT、Tpl2)、PHKG2、PIM3、FYNa(FYN)、CDK2 / CycA1、ICK、SYK、MER TK(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, HIPK 3、MARK1、NUAK1(ARK5)、PRKCB1(PKCβ1[ベータ1])、MAST3、DYRK4、CDK3 / CycE2、EI F2AK3(PERK / PEK)、PAK3、EIF2AK2(PKR)、FGFR1、IKKB(IKKβ)、TAOK2(TAO2)、CH UK(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, STK17 A(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, TTB K2, 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), SGK 1(SGK), INSR(IR), CDK9(TAK) / CycT1, MELK, CSF1R(FMS), PDK2(PDHK2), RIPK1, CDK2 / CycA2, EIF2AK4(GCN2), HASPIN, MAP4K1(HPK1), HCK, B In some embodiments, the target may be RAF, 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 is CLK2, DYRK1B, AKT1, CLK1, ICK, AKT3, CLK4, DYRK1A, P70S6KA, PKCH,STK33, PGK2, AKT2, PKCQ, CDK17 / P35, LATS2, FLT3, HASPIN, MSK1, PKN1, GKK, 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, MA P3K14、PKCA、PKACA、CAMKK1、FER、DDR2、PDHK3、SRPK2、PKACB、GRK7、GLK / KH S2、CDK11 / C、MST1、GRK3、PAK4、CDK15 / B1、RSK2、SGK3、PKD2、CDK9 / T2、PDGFR A、CDK5 / P35、DDR1、GAK、TNIK、SGK2、EPHA6、SIK2、CDK9 / T1、JAK2(JH1)、LRR K2、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、I GF1R、MEK1、AXL、MAP3K10、FLT4、TNK2、PKCG、RIPK5、RET、MST4、PKCB1、ZAP70 、TNK1、FGFR4、INSRR、PKCD、DYRK3、EPHA3、AMPK112、MSK2、PAK2、HUNK、PDHK 4、NEK9、YSK4、FGR、AMPK213、NEK6、JAK1(JH1JH2)、MRCKB、EPHB4、PKN2、PKAC G、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、JA K2(JH1JH2), CDK6 / D2, CHK2, ERK2, AMPK121, LYNA, GRK4, CK1A1L, PDHK2, PTK2, YES, DYRK2, FES, MARK2, RIPK3, MARK4, TTBK2, CDK13 / K, ERK1, MA RK3、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、NDR、 In some embodiments, the target may be comprised in a group. In some embodiments, the group includes CMGC kinases (CDKs (cyclin-dependent kinases), MAPKs (mitogen-activated protein kinases), GSKs (glycogen synthase kinases), and CLKs (CDC-like kinases) - kinases involved in regulating cell cycle progression, transcription, and various signaling pathways), AGC kinases (PKAs (protein kinase A), PKGs (protein kinase G), and PKCs (protein kinase C) - AGC kinases play important roles in cell signaling, metabolism, growth, and other physiological processes), CAMK kinases ((calcium / calmodulin-dependent protein kinases) - involved in calcium-mediated signaling pathways such as CaMK1, CaMKII, and CaMKIV, which regulate various cellular processes upon activation by calcium-calmodulin complexes), tyrosine kinases (receptor tyrosine kinases (RT They may be other kinases, STE kinases (which are involved in various signaling cascades, including the mitogen-activated protein kinase (MAPK) cascade, and are named after three yeast kinases: STE20, STE11, and STE7), TKL kinases (tyrosine kinase-like kinases that are structurally similar to tyrosine kinases, such as RAF and MLK (mixed lineage kinases), which phosphorylate serine and threonine residues instead of tyrosine residues), atypical kinases (which have unique structural features or functions that distinguish them from other groups), or CK1 kinases (casein kinase 1, a family of serine / threonine kinases involved in various cellular processes, including cell division, DNA repair, and signal transduction).

[0312] In some embodiments, the compounds described herein target, inhibit, or modulate a gene, gene pathway, or signaling pathway. In some embodiments, the gene, gene pathway, or signaling pathway includes the Hedgehog signaling pathway. In some embodiments, the gene, gene pathway, or signaling pathway includes, but is not limited to, SOFU, PTCH1, PTCH1wt, PTCH1 mutant, Shh, SMO, GLI genes, GLI1, GLI2, GLI3, GLI transcription factors, PKA, AMPK, MEKK1, Hck, GSK3β, CK1, S6K, AKT, HDAC, KRT1, KRT10, IVL, LOR, CCND, CCNE, E2F, CDK1, CCNA, CCNB, BCL2, and SNAIL1. In some embodiments, the target gene, gene pathway, or signaling pathway is GLI1 and genes modulated by GLI1.

[0313] In some embodiments, inhibition or modulation of a target kinase or kinase pathway by a composition or compound described herein can treat or prevent carcinoma, malignant tumor, cancer, benign tumor, or growth.

[0314] In some embodiments, inhibition or modulation of a target kinase pathway by a composition or compound described herein can treat or prevent basal cell carcinoma, squamous cell carcinoma, or seborrheic keratosis. In some embodiments, the squamous cell carcinoma can be invasive squamous cell carcinoma or squamous intraepithelial carcinoma. In some embodiments, the squamous intraepithelial carcinoma can be Bowen's disease.

[0315] In one aspect, the disclosure provides a method of treating or preventing a skin lesion, the method comprising topically administering to the skin lesion a composition comprising a compound represented by formula (I):

[0316] [ka] A compound of the formula: During the ceremony, X is CH or N; Each R 1 are independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 2 is an optionally substituted C 6-12 aryl, or optionally substituted 3- to 12-membered heteroaryl; Compounds of formula (I), wherein n is 0 to 5; Formula (IA) or (IB):

[0317] [ka] A compound of the formula: During the ceremony, X is CH or N; Each R 1 are independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 4 is hydrogen or C 1-6 is alkyl, n is 0 to 5; Formula (I-AA) or Formula (I-BB):

[0318] [ka] The compound Formula (I-BB):

[0319] [ka] The compound Formula (II):

[0320] [ka] A compound of the formula: In the formula, R A is C 1-20 alkyl, and / or Compounds of formula (III):

[0321] [ka] Including, wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10%.

[0322] In some embodiments, the skin lesion is a keratosis. In some embodiments, the keratosis is seborrheic keratosis. In some embodiments, the skin lesion is a carcinoma. In some embodiments, the cancer is a basal cell carcinoma or a squamous cell carcinoma. In some embodiments, the squamous cell carcinoma can be an invasive squamous cell carcinoma or a carcinoma in situ. In some embodiments, the carcinoma in situ can be Bowen's disease. In some embodiments, the skin lesion is a melanoma.

[0323] In some embodiments, the method further comprises occlusion of the skin lesion.

[0324] In some embodiments, the skin lesion is present on a human subject. In some embodiments, the skin lesion is present on the face, trunk, or extremities, or a combination thereof, of the human subject.

[0325] In some embodiments, treatment comprises reducing the thickness of the skin lesion to at least 1 mm. In some embodiments, the thickness of the skin lesion before administration is 1 mm or greater. In some embodiments, the length of the skin lesion before administration is 1 mm to 15 mm, and the width of the skin lesion before administration is 1 mm to 15 mm.

[0326] In some embodiments, the administration leads to the prevention of a skin lesion, such as a non-melanoma skin cancer, such as a basal cell carcinoma or squamous cell carcinoma, or the administration leads to the prevention of melanoma.

[0327] In some embodiments, the treatment comprises inducing apoptosis of keratinocytes or melanocytes in the skin lesion.

[0328] The terminal deoxynucleotidyl transferase dUTP nick end labeling assay, or TUNEL assay, is a method for detecting or quantifying cell apoptosis by labeling the 3'-hydroxyl ends of double-stranded DNA breaks in DNA fragmentation generated during apoptosis. The TUNEL assay utilizes terminal deoxynucleotidyl transferase (TdT), an enzyme that catalyzes the attachment of deoxynucleotides tagged with fluorescent dyes or other markers to the 3'-hydroxyl ends of DNA double-stranded breaks. In some embodiments, cell death is measured by the TUNEL assay.

[0329] 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.

[0330] In one aspect, the present disclosure provides a method of treating or preventing a skin disease, condition, or disorder in a subject in need of such treatment, comprising administering to the subject a composition described herein.

[0331] In some embodiments, the skin disease, condition, or disorder is seborrheic keratosis, basal cell carcinoma, squamous cell carcinoma, melanoma, benign tumor, malignant tumor, parasite, cutaneous virus, immune disease or disorder, or bacterial, fungal, or microbial infection. In some embodiments, the squamous cell carcinoma can be invasive squamous cell carcinoma or squamous intraepithelial carcinoma. In some embodiments, the squamous intraepithelial carcinoma can be Bowen's disease. In some embodiments, the skin disease, condition, or disorder is seborrheic keratosis. In some embodiments, the skin disease, disease, or disorder is a benign tumor, wherein the benign tumor is a benign vascular tumor, a benign fibrous tumor, a benign adipocyte tumor, a benign sebaceous tumor, a benign epidermal tumor, a benign melanocytic lesion, or a benign neural tumor; the skin disease, disease, or disorder is a malignant tumor, wherein the malignant tumor is a malignant melanocyte tumor, a malignant epidermal tumor, a malignant vascular tumor, a malignant metastatic tumor, a malignant adipocyte tumor, a malignant sebaceous tumor, or a malignant fibrous tumor; the skin disease, disease, or disorder is a parasitic tumor. the skin disease, illness, or disorder is a virus, and the virus is molluscum contagiosum or human papillomavirus; or the skin disease, illness, or disorder is a bacterial, fungal, or microbial infection, and the bacterial, fungal, or microbial infection is otitis media, a Staphylococcus aureus infection, a Mycobacterium infection, a Porphyromonas infection, a Salmonella infection, a Chlamydia infection, tuberculosis, gingivitis, or periodontal disease.

[0332] In some embodiments, the composition is applied topically to the head, scalp, face, ears, neck, chest, back, submammary area, arms, legs, intertriginous areas, hands, feet or legs, 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.

[0333] In some embodiments, the composition is delivered orally, systemically, intradermally, subcutaneously, or intradermally.

[0334] In some embodiments, the composition is administered in a pulsatile cycle. In some embodiments, the composition is administered under occlusion.

[0335] In some embodiments, the skin disease, condition, or disorder is a skin pigmentation disorder, hi some embodiments, the skin pigmentation disorder is acanthosis nigricans.

[0336] In some embodiments, the skin disease, illness, or disorder is seborrheic keratosis, a benign tumor or skin condition, a malignant tumor, a parasite, a skin virus, an immune disease or disorder, and a bacterial, fungal, or microbial infection.

[0337] In some embodiments, the skin disease, condition, or disorder is seborrheic keratosis.

[0338] In some embodiments, the compositions described herein are useful for treating or preventing a benign tumor or skin condition, hi some embodiments, the benign tumor is a benign vascular tumor, a benign fibrous tumor, a benign adipocyte tumor, a benign sebaceous tumor, a benign epidermal tumor, a benign melanocytic lesion, or a benign neural tumor. Benign tumors or diseases of the skin include, but are not limited to, nodules, benign skin tumors, hemangiomas, hemangiomas, pyogenic granulomas, angiofibromas, tuberous sclerosis complex, angiomyofibromas, angiolipomas, dermatofibromas, fibromas, neurofibromas, scars, scar tissue, keloids, lipomas, acrochodons, melanoacanthomas, acanthomas, clear cell acanthomas, acanthoma nigricans, epidermoid cysts, pilar cysts, dermoid cysts, melanocytic nevus, epidermal nevus, verrucous epidermal nevus, lentigines, cafe au lait macules, neuromas, schwannomas, and neurinomas. In some embodiments, the benign tumor is a nodule, benign skin tumor, hemangioma, hemangioma, pyogenic granuloma, angiofibroma, tuberous sclerosis complex, angiomyofibroma, angiolipoma, dermatofibroma, fibroma, neurofibroma, scar, scar tissue, keloid, lipoma, acrochodon, melanoacanthoma, acanthoma, clear cell acanthoma, acanthoma nigricans, epidermoid cyst, pilar cyst, dermoid cyst, melanocytic nevus, epidermal nevus, verrucous epidermal nevus, lentigo, cafe au lait spot, neuroma, schwannoma, or neuroma.

[0339] In some embodiments, the skin disease, condition, or disorder is 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 can be invasive squamous cell carcinoma or squamous intraepithelial carcinoma. In some embodiments, the squamous intraepithelial carcinoma can be Bowen's disease. In some embodiments, the skin disease or condition is melanoma.

[0340] In some embodiments, the skin disease, condition, or disorder is Gorlin's syndrome.

[0341] In some embodiments, the skin disease, condition, or disorder is basal cell nevus syndrome.

[0342] In some embodiments, the skin disease, condition, or disorder is melanoma or non-melanoma skin cancer.

[0343] In some embodiments, the compositions described herein are useful for treating or preventing malignant tumors. In some embodiments, the malignant tumor is a malignant melanocytic tumor, a malignant epidermal tumor, a malignant vascular tumor, a malignant metastatic tumor, a malignant adipocyte tumor, a malignant sebaceous tumor, or a malignant fibrous tumor. Malignant tumors include, but are not limited to, melanoma, squamous cell carcinoma, keratosis keratosis, basal cell carcinoma, angiosarcoma, Kaposi's sarcoma, skin cancer of the breast, Merkel cell carcinoma, liposarcoma, seboma, dermatofibroma, dermatosarcoma adenoidoma, and fibrosarcoma. In some embodiments, the malignant tumor is a melanoma, squamous cell carcinoma, keratosis keratosis, basal cell carcinoma, angiosarcoma, Kaposi's sarcoma, skin cancer of the breast, Merkel cell carcinoma, liposarcoma, seboma, dermatofibroma, dermatosarcoma adenoidoma, or fibrosarcoma.

[0344] In some embodiments, the compositions described herein are useful for treating or preventing a skin disease, illness, or disorder caused by a parasite. In some embodiments, the parasite is a parasite of the genus Trypanasoma or Lieshmania. In some embodiments, the parasite is a parasite 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 illness caused by or associated with a 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 tropica), Leishmania turanica, Leishmania venezeulensis, Leishmania waltoni, Leishmania enriettiienriettii, Leishmania macropodum, Leishmania martiniquensis, Leishmania orientalis, Leishmania adleri, Leishmania agamae, Leishmania ceramodactyli, Leishmania gulikae, Leishmania gymnodactyli, Leishmania helioscopi, Leishmania hemidactyli, Leishmania hoogstraali, Leishmania nicolei 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 naifi naiffi), Leishmania panamensis, Leishmania peruvianaperuviana, Leishmania shawi, Leishmania utingensis, Endotrypanum colombiensis, Endotrypanum equatorensis, Endotrypanum herreri, Endotrypanum monterogeii, Endotrypanum schaudinni, Novymonas esmeraldas, Porcisia deanei, Porcisia hertigi, Zelonia australiensis, or Zelonia costariensis costaricensis).

[0345] In some embodiments, the compositions described herein are useful for treating or preventing skin diseases, illnesses, or disorders caused by viruses. Viral pathogens include, but are not limited to, adenovirus, influenza, human herpesvirus, avian virus, HIV, and coronavirus. In some embodiments, the virus is a poxvirus that causes molluscum contagiosum or a human papillomavirus that causes warts.

[0346] In some embodiments, the compositions described herein are useful for treating or preventing a skin disease, illness, or disorder associated with a bacterial, fungal, or microbial infection, hi 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.

[0347] In some embodiments, the compositions described herein are administered to the face of a subject. In some embodiments, the compositions described herein are administered to the body of a subject. In some embodiments, the compositions described herein are administered topically to the head, scalp, face, ears, neck, chest, back, submammary area, arms, legs, groin, hands, and / or feet. In some embodiments, the compositions cover (e.g., occlude) skin associated with a disease, condition, or disorder. By way of non-limiting example, the compositions cover basal cell carcinoma, squamous cell carcinoma, and / or melanoma. In some embodiments, the squamous cell carcinoma can be invasive squamous cell carcinoma or squamous intraepithelial carcinoma. In some embodiments, the squamous intraepithelial carcinoma can be Bowen's disease.

[0348] In some embodiments, the compositions described herein are administered to a subject's face to treat or prevent facial basal cell carcinoma, squamous cell carcinoma, or melanoma. In some embodiments, the compositions described herein are administered to a subject's body to treat or prevent seborrheic keratosis. In some embodiments, the compositions described herein are administered topically to one or more areas selected from the head, scalp, face, ears, neck, chest, back, submammary area, arms, legs, groin, intertriginous areas, hands, and / or feet to treat seborrheic keratosis in any one of these areas.

[0349] In some embodiments, the skin disease, condition, or disorder to be alleviated, ameliorated, treated, or prevented is not a non-melanoma skin cancer, such as a basal cell carcinoma or squamous cell carcinoma, or a melanoma. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve partial or complete resolution, regression, or elimination of at least one basal cell carcinoma, squamous cell carcinoma, or melanoma in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve partial resolution of at least one basal cell carcinoma, squamous cell carcinoma, or melanoma in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve complete resolution of at least one basal cell carcinoma, squamous cell carcinoma, or melanoma in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve regression of at least one basal cell carcinoma, squamous cell carcinoma, or melanoma in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve elimination of at least one basal cell carcinoma, squamous cell carcinoma, or melanoma in a subject.

[0350] In some embodiments, the compositions described herein are administered to the face of a subject. In some embodiments, the compositions described herein are administered to the body of a subject. In some embodiments, the compositions described herein are administered topically to the head, scalp, face, ears, neck, chest, back, submammary area, arms, legs, groin, interbody areas, hands, feet, mouth, lips, gums, nose, nostrils, anus, genitals, eyes, and / or eyelids. In some embodiments, the composition covers (e.g., occludes) skin associated with a disease, condition, or disorder. As a non-limiting example, the composition covers basal cell carcinoma. In some embodiments, the composition is delivered intradermally, orally, systemically, intradermally, and / or subcutaneously.

[0351] In some embodiments, the compositions described herein are administered to the face of a subject to treat or prevent facial basal cell carcinoma, squamous cell carcinoma, or melanoma. In some embodiments, the compositions described herein are administered to the body of a subject to treat or prevent basal cell carcinoma, squamous cell carcinoma, or melanoma. In some embodiments, the compositions described herein are administered topically to one or more areas selected from the head, scalp, face, ears, neck, chest, back, submammary area, arms, legs, feet, groin, intertriginous areas, hands, mouth, lips, gums, nose, nostrils, anus, genitals, eyes, and / or eyelids to treat or prevent basal cell carcinoma, SCC, or melanoma in any one of these areas. In some embodiments, the compositions described herein are administered topically to one or more areas selected from the head, scalp, face, ears, neck, chest, back, submammary area, arms, legs, feet, groin, interlingual area, 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.

[0352] In some embodiments, the skin disease, condition, or disorder to be alleviated, ameliorated, treated, or prevented is basal cell carcinoma, SCC, or melanoma. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve partial or complete resolution, regression, or elimination of at least one basal cell carcinoma, SCC, or melanoma in a subject. In some embodiments, the compositions described herein are 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 compositions described herein are administered in a therapeutically effective amount to achieve partial resolution of at least one basal cell carcinoma, SCC, or melanoma in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve complete resolution of at least one basal cell carcinoma, SCC, or melanoma in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve regression of at least one basal cell carcinoma, SCC, or melanoma in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to achieve elimination of at least one basal cell carcinoma, SCC, or melanoma in a subject. In some embodiments, the compositions described herein are administered in a therapeutically effective amount to prevent at least one basal cell carcinoma, SCC, or melanoma in a subject.

[0353] 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 intralesionally. 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 subcutaneously. In some embodiments, the composition is administered intradermally. In some embodiments, the composition is administered intralesionally, orally, systemically, intradermally, and / or subcutaneously. In some embodiments, the composition is administered by application to a large area of ​​the skin or body. In some embodiments, the composition is administered as a preventative agent for basal cell carcinoma, squamous cell carcinoma, melanoma, or seborrheic keratosis.

[0354] In some embodiments, the composition administered is in the form of a gel, ointment, lotion, foam, or emollient.

[0355] In some embodiments, the composition to be administered is a component of a patch, tape, film, wafer, or bandage.

[0356] In some embodiments, the subject in need is a human.

[0357] kit Also provided are kits for use in methods for treating or preventing skin diseases, conditions, or disorders in a subject in need thereof, packaged in tubes, flexible aluminum tubes, or laminated plastic tubes, along with the compositions described herein. The kits may include a topical composition containing the compound, second agent, or composition, and instructions providing a healthcare provider with information regarding use to treat or prevent skin diseases, conditions, or disorders. The instructions may be provided in printed form, or in the form of an electronic or digital medium such as a floppy disk, CD, or DVD, a data storage device, a flash drive, or a website address where such instructions can be obtained. A unit dose of the compound or topical composition, or second agent or composition provided herein, may comprise a dose such that, when administered to a subject, a therapeutically or prophylactically effective level of the compound or topical composition can be maintained at the treatment site in the subject for at least one day.

[0358] In another aspect, the disclosure provides a kit including a topical pharmaceutical composition in a tube, a flexible aluminum tube, or a laminated plastic tube, and instructions for use.

[0359] In some embodiments, suitable packaging is provided. As used herein, "packaging" refers to a solid matrix or material that is conventionally used in systems and can hold the compounds provided herein and / or second agents suitable for administration to a subject within fixed limits. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes, etc. When electron beam sterilization technology is employed, the packaging should have a sufficiently low density to allow sterilization of the contents.

[0360] Illustrative Embodiments The methods and compositions described herein can be in one or more exemplary embodiments, as described below. Embodiment 1. A method of preventing or treating a skin lesion, the method comprising topically administering to said skin lesion a composition comprising: (i) Formula (I):

[0361] [ka] A compound having the structure During the ceremony, X is CH or N; Each R 1 are independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 2 is an optionally substituted C 6-12 aryl, or optionally substituted 3- to 12-membered heteroaryl; n is 0 to 5; (ii) Formula (IA) or Formula (IB):

[0362] [ka] A compound having the structure During the ceremony, X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R4 is hydrogen or C1-6 alkyl; n is 0 to 5; (iii) Formula (I-AA) or Formula (I-BB):

[0363] [ka] A compound having the structure During the ceremony, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is alkoxy, and R 4 is hydrogen or C 1-6 a compound having the structure of formula (I-AA) or formula (I-BB), wherein: (iv) Structure of Formula (II):

[0364] [ka] A compound having the formula: During the ceremony, R A is C 1-20 a compound, (v) Formula (III):

[0365] [ka] and a compound having the structure wherein the total amount of (i), (ii), (iii), (iv), (v), or any combination of two or more thereof present in the composition is 0.01% to 10% by weight. Embodiment 2. The skin lesion is skin cancer, and optionally: The skin cancer is melanoma, or 2. The method of embodiment 1, wherein the skin cancer is not melanoma, and optionally, if the skin cancer is non-melanoma skin cancer, the non-melanoma skin cancer is basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). Embodiment 3. The method of embodiment 2, wherein said skin cancer is not melanoma, and optionally, said skin cancer is basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). Embodiment 4. The method of any one of embodiments 1 to 3, comprising occluding said skin lesion. Embodiment 5. The method of any one of embodiments 1 to 4, wherein the skin lesion is present in a human subject. Embodiment 6 The method of embodiment 5, wherein the skin lesion is present on the face, trunk, extremities, or any combination of two or more thereof of the human subject. Embodiment 7. The method of any one of embodiments 1-6, wherein the treatment comprises an improvement of 1 or more grades in Physician Lesion Assessment (PLA) score compared to before administering the composition. Embodiment 8. The method of any one of embodiments 1 to 7, wherein the thickness of said skin lesion before administration is 1 mm or greater. Embodiment 9. The method of any one of embodiments 1 to 8, wherein the length of the skin lesion before administration is 1 mm to 15 mm and the width of the skin lesion before administration is 1 mm to 15 mm. Embodiment 10. The method of any one of embodiments 1 to 9, wherein treating comprises inducing apoptosis of keratinocytes or melanocytes in said skin lesion. Embodiment 11. The method of embodiment 10, wherein said apoptosis is measured by a TUNEL assay. Embodiment 12. The method of any one of embodiments 1 to 11, wherein the composition is a gel formulation. Embodiment 13. The method of any one of embodiments 1 to 12, wherein the composition comprises an alcohol, a gelling agent, an antioxidant, or a combination of two or more thereof. Embodiment 14. A composition comprising: a. Formula (I):

[0366] [ka] A compound having the structure During the ceremony, X is CH or N; Each R 1 are independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C1-6 Haloalkyl, or C 1-6 is an alkoxy; R 2 is an optionally substituted C 6-12 aryl, or optionally substituted 3- to 12-membered heteroaryl; n is 0 to 5; b. Formula (IA) or Formula (IB):

[0367] [ka] A compound having the structure During the ceremony, X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R4 is hydrogen or C1-6 alkyl; n is 0 to 5; c. Formula (I-AA) or Formula (I-BB):

[0368] [ka] A compound having the structure During the ceremony, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is alkoxy, and R 4 is hydrogen or C 1-6 alkyl, and / or d.Formula (II):

[0369] [ka] A compound having the structure During the ceremony, R A is C 1-20 alkyl, wherein the total amount of (i), (ii), (iii), (iv), or any combination of two or more thereof present in the composition is 0.01% to 10% by weight. Embodiment 15. The composition of embodiment 14, wherein the composition is a gel formulation. Embodiment 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. Embodiment 17. A composition comprising: a. Formula (I):

[0370] [ka] A compound having the structure During the ceremony, X is CH or N; Each R 1 are independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 2 is an optionally substituted C 6-12 aryl, or optionally substituted 3- to 12-membered heteroaryl; n is 0 to 5; b. Formula (IA) or Formula (IB):

[0371] [ka] A compound having the structure During the ceremony, X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R4 is hydrogen or C1-6 alkyl; n is 0 to 5; c. Formula (I-AA) or Formula (I-BB):

[0372] [ka] A compound having the structure During the ceremony, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is alkoxy, and R 4 is hydrogen or C 1-6 alkyl, and / or d.Formula (II):

[0373] [ka] A compound having the structure During the ceremony, R A is C 1-20 a compound, (a) to (e) below: a) alcohol, b) organic solvents and / or penetration enhancers; c) antioxidants; d) preservatives, and e) Gelling Agent and one or more excipients selected from: Embodiment 18. The composition of embodiment 17, comprising the alcohol. Embodiment 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 thereof, or two or more thereof. Embodiment 20. The alcohol is C 2-6 The composition of embodiment 18, comprising an alcohol. Embodiment 21. Above C 2-6 21. The composition of embodiment 20, wherein the alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, or a combination thereof, or two or more thereof. Embodiment 22. Above C 2-6 22. The composition of embodiment 21, wherein the alcohol comprises ethanol. Embodiment 23. The composition of any one of embodiments 18 to 22, wherein the alcohol comprises an organic solvent and / or a penetration enhancer. Embodiment 24. The composition of any one of embodiments 17 to 23, comprising the organic solvent and / or penetration enhancer. Embodiment 25. The organic solvent and / or penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2)CH2) 1-5 The composition of embodiment 23 or embodiment 24, comprising: —OH, polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, a fatty ether, or a combination of two or more thereof. Embodiment 26. Above C 2-6 The alkylene glycol is propylene glycol, 1-3 Alkyl-(OCH2CH2) 1-5 The composition of embodiment 25, wherein —OH is 2-(2-ethoxyethoxy)ethanol and the polyethylene glycol is PEG200, PEG400, or a combination thereof. Embodiment 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. Embodiment 28. The composition of any one of embodiments 17 to 27, comprising the antioxidant. Embodiment 29. The composition of embodiment 28, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. Embodiment 30. The composition of embodiment 29, wherein the antioxidant comprises butylated hydroxytoluene. Embodiment 31. The composition of any one of embodiments 14 to 16, comprising a preservative. Embodiment 32. The composition of any one of embodiments 17 to 30, comprising a preservative. Embodiment 33. The composition of embodiment 31 or embodiment 32, wherein the preservative comprises phenoxyethanol. Embodiment 34. The composition of any one of embodiments 14 to 16, comprising a gelling agent. Embodiment 35. The composition of any one of embodiments 17 to 33, comprising a gelling agent. Embodiment 36. The composition of embodiment 34 or embodiment 35, wherein the gelling agent comprises hydroxypropyl cellulose. Embodiment 37. The composition of embodiment 36, wherein the hydroxypropyl cellulose has an average molecular weight of 700,000 Da to 1,150,000 Da. Embodiment 38. The composition of any one of embodiments 14 to 37, comprising ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and hydroxypropyl cellulose. Embodiment 39. The composition of any one of embodiments 14 to 38, comprising an antioxidant and / or a preservative. Embodiment 40. The composition of embodiment 39, wherein the composition comprises an 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. Embodiment 41. The composition of any one of embodiments 14 to 40, comprising a pH adjuster, optionally an acid, and further optionally citric acid. Embodiment 42. A composition comprising: (i) Structure:

[0374] [ka] or a salt thereof, and / or (ii) Structure:

[0375] [ka] A composition comprising a compound having the formula: Embodiment 43. Ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, hydroxypropyl cellulose, and optionally an antioxidant, and optionally a preservative. Embodiment 44. The antioxidant, when present, comprises butylated hydroxytoluene; The composition of embodiment 43, wherein the preservative, if present, comprises phenoxyethanol. Embodiment 45. The composition of any one of embodiments 15 to 44, wherein the composition has a viscosity of about 10,000 cp to about 30,000 cp. Embodiment 46. The composition of any one of embodiments 15 to 45, wherein the composition is a pharmaceutical composition. Embodiment 47. The composition of any one of embodiments 15 to 46, wherein the composition is a topical composition or a composition for oral, systemic, intralesional, subcutaneous, or intradermal administration or application. Embodiment 48. The composition of any one of embodiments 15 to 47 or the method of any one of embodiments 1 to 14, wherein the composition is in the form of a gel, ointment, lotion, foam, or emollient. Embodiment 49. The composition of any one of embodiments 15 to 48 or the method of any one of embodiments 1 to 14, wherein the composition is a component of a patch, tape, film, wafer, or bandage. Embodiment 50. A method of treating a skin disease, condition, or disorder in a subject in need thereof, the method comprising administering to the subject a composition of any one of embodiments 15 to 50. Embodiment 51. The method of embodiment 50, wherein the skin disease, illness, or disorder is skin cancer. Embodiment 52. The method of embodiment 51, wherein the skin cancer is melanoma. Embodiment 53 The method of embodiment 51, wherein the skin cancer is not melanoma. Embodiment 54. The method of embodiment 53, wherein the skin cancer is basal cell carcinoma (BCC). Embodiment 55. The method of embodiment 53, wherein the skin cancer is squamous cell carcinoma (SCC). Embodiment 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, submammary area(s), arm(s), leg(s), intertriginous area(s), hand(s), foot(s), or groin. Embodiment 57. A kit comprising the topical pharmaceutical composition of any one of embodiments 15 to 49 in a tube, flexible aluminum tube, or laminated plastic tube, and instructions for use. Embodiment 58. A method for treating, preventing, or reducing the progression of a skin lesion, the method comprising administering to the skin lesion a composition comprising an effective amount of a compound having Akt inhibitory activity and inhibitory or modulating activity in another kinase pathway. Embodiment 59. The method of embodiment 58, wherein the skin lesion is a carcinoma. Embodiment 60. The method of embodiment 58, wherein the skin lesion is basal cell carcinoma, squamous cell carcinoma, or melanoma. Embodiment 61. The method of embodiments 58-60, wherein the mode of administration is oral, systemic, topical, intradermal, intralesional and / or subcutaneous. Embodiment 62. A method of treating, preventing, or reducing the progression of a skin lesion, the method comprising administering to said skin lesion a composition comprising: (i) Formula (I):

[0376] [ka] A compound having the structure During the ceremony, X is CH or N; Each R 1 are independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 2 is an optionally substituted C 6-12 aryl, or optionally substituted 3- to 12-membered heteroaryl; n is 0 to 5; (ii) Formula (IA) or Formula (IB):

[0377] [ka] A compound having the structure During the ceremony, X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R4 is hydrogen or C1-6 alkyl; n is 0 to 5; (iii) Formula (I-AA) or Formula (I-BB):

[0378] [ka] A compound having the structure During the ceremony, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is alkoxy, and R 4 is hydrogen or C 1-6 alkyl, and / or (iv) Formula (II):

[0379] [ka] A compound having the structure During the ceremony, R A is C 1-20 alkyl, 68. The method of embodiment 67, wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% to 10%. 69. The method of embodiment 67, wherein the skin lesion is skin cancer. Embodiment 63. The method of embodiment 62, wherein the skin lesion is basal cell carcinoma, squamous cell carcinoma, or melanoma. Embodiment 64. The method of any one of embodiments 62-63, wherein the mode of administration is topical, oral, systemic, intradermal, intralesional, or subcutaneous. Embodiment 65. The method of any one of embodiments 62 to 64, comprising occluding the skin lesion. Embodiment 66. The method of any one of embodiments 62 to 65, wherein the skin lesion is present in a human subject. Embodiment 67. The method of embodiment 66, wherein the skin lesion is present on the face, trunk, limbs, or a combination thereof of the human subject. Embodiment 68. The method of any one of embodiments 62 to 67, wherein treatment comprises reducing the thickness of said skin lesion to at least 1 mm. Embodiment 69. The method of any one of embodiments 62 to 68, wherein the thickness of the skin lesion before administration is 1 mm or greater. Embodiment 70. The method of any one of embodiments 62 to 69, wherein the length of the skin lesion before administration is 1 mm to 15 mm and the width of the skin lesion before administration is 1 mm to 15 mm. Embodiment 71. The method of any one of embodiments 62 to 70, wherein the treatment comprises inducing apoptosis of keratinocytes or melanocytes in said skin lesion. Embodiment 72. The method of embodiment 71, wherein said apoptosis is measured by a TUNEL assay. Embodiment 73. The method of any one of embodiments 62 to 72, wherein the composition is a gel formulation. Embodiment 74. The method of any one of embodiments 62 to 73, wherein the composition comprises an alcohol, a gelling agent, or an antioxidant, or a combination of two or more thereof. Embodiment 75. A composition comprising: a. Formula (I):

[0380] [ka] A compound having the structure During the ceremony, X is CH or N; Each R 1 are independently halogen, -OH, -NH2, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is an alkoxy; R 2 is an optionally substituted C 6-12aryl, or optionally substituted 3- to 12-membered heteroaryl; n is 0 to 5; b. Formula (IA) or Formula (IB):

[0381] [ka] A compound having the structure During the ceremony, X is CH or N; each R1 is independently halogen, -OH, -NH2, -CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R4 is hydrogen or C1-6 alkyl; n is 0 to 5; c. Formula (I-AA) or Formula (I-BB):

[0382] [ka] A compound having the structure During the ceremony, R 3 is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is alkoxy, and R 4 is hydrogen or C 1-6 alkyl, and / or d.Formula (II):

[0383] [ka] A compound having the structure During the ceremony, R A is C 1-20 alkyl, wherein the total amount of (i), (ii), or (i) and (ii) present in the composition is 0.01% by weight to 10% by weight. Embodiment 76. The composition of embodiment 75, wherein the composition is a gel formulation. Embodiment 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. Embodiment 78. A composition comprising: (i) Structure:

[0384] [ka] or a salt thereof, and / or (ii) Structure:

[0385] [ka] or a salt thereof; (a) to (e) below: a) alcohol, b) organic solvents and / or penetration enhancers; c) antioxidants; d) preservatives, and e) one or more excipients selected from gelling agents. Embodiment 79. The composition of embodiment 78, comprising the alcohol. Embodiment 80. The alcohol is C 2-6 The composition of embodiment 79, comprising alcohol, propylene glycol, (2-(2-ethoxyethoxy)ethanol), phenoxyethanol, or a combination thereof, or two or more thereof. Embodiment 81. The alcohol is C 2-6 The composition of embodiment 80, comprising an alcohol. Embodiment 82. Above C 2-6The composition of embodiment 81, wherein the alcohol comprises ethanol, propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol, or a combination thereof, or two or more thereof. Embodiment 83. Above C 2-6 The composition of embodiment 82, wherein the alcohol comprises ethanol. Embodiment 84. The composition of any one of embodiments 79 to 83, wherein the alcohol comprises an organic solvent and / or a penetration enhancer. Embodiment 85. The composition of any one of embodiments 78 to 83, comprising an organic solvent and / or a penetration enhancer. Embodiment 86. The organic solvent and / or penetration enhancer is C 2-6 Alkylene glycol, C 1-3 Alkyl-(OCH2CH2) 1-5 The composition of embodiment 84 or embodiment 85, comprising -OH, polyethylene glycol, glycerol, a fatty alcohol, a fatty ester, or a fatty ether, or a combination of two or more thereof. Embodiment 87. Above C 2-6 The alkylene glycol is propylene glycol, 1-3 Alkyl-(OCH2CH2) 1-5 The composition of embodiment 86, wherein —OH is 2-(2-ethoxyethoxy)ethanol and the polyethylene glycol is PEG200, PEG400, or a combination thereof. Embodiment 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. Embodiment 89. The composition of any one of embodiments 78 to 88, comprising an antioxidant. Embodiment 90. The composition of embodiment 89, wherein the antioxidant comprises butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, or a combination of two or more thereof. Embodiment 91. The composition of embodiment 90, wherein the antioxidant comprises butylated hydroxytoluene. Embodiment 92. The composition of any one of embodiments 78 to 91, comprising a preservative. Embodiment 93. The composition of embodiment 92, wherein the preservative comprises phenoxyethanol. Embodiment 94. A composition according to any one of embodiments 78 to 93, comprising the gelling agent. Embodiment 95. The composition of embodiment 94, wherein the gelling agent comprises hydroxypropyl cellulose. Embodiment 96. The composition of embodiment 95, wherein the hydroxypropyl cellulose has an average molecular weight of 700,000 Da to 1,150,000 Da. Embodiment 97. The composition of embodiment 78, comprising ethanol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, and hydroxypropyl cellulose. Embodiment 98. The composition of embodiment 78, further comprising an antioxidant and / or a preservative. Embodiment 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. Embodiment 100. The composition of any one of embodiments 78 to 99, comprising a pH adjuster, optionally an acid, and further optionally citric acid. Embodiment 101. The composition of embodiment 80, 88, or 97, wherein the propylene glycol is ultra-refined propylene glycol. Embodiment 102. The composition of embodiment 86 or 97, wherein the 2-(2-ethoxyethoxy)ethanol is Transcutol HP having a purity of greater than 99.90%. Embodiment 103. The composition of embodiment 98, wherein the antioxidant, if present, comprises butylated hydroxytoluene, and the preservative, if present, comprises phenoxyethanol. Embodiment 104. The composition of any one of embodiments 78 to 103, wherein the composition has a viscosity of about 10,000 cp to about 30,000 cp. Embodiment 105. The composition of any one of embodiments 78 to 104, wherein the composition is a pharmaceutical composition. Embodiment 106. The composition of any one of embodiments 78 to 105, wherein the composition is a topical, oral, systemic, intralesional, subcutaneous, or intradermal composition. Embodiment 107. The composition of any one of embodiments 78 to 106, wherein the composition is in the form of a gel, ointment, lotion, foam, or emollient. Embodiment 108. The composition of any one of embodiments 78 to 107 or the method of any one of embodiments 58 to 80, wherein the composition is a component of a patch, tape, film, wafer, or bandage. Embodiment 109. A method for treating or preventing, or attenuating the progression of, a skin disease, condition, or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition described in any one of embodiments 81 to 118. Embodiment 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, benign tumor, malignant tumor, parasite, skin virus, immune disease or disorder, or bacterial, fungal, or microbial infection. Embodiment 111. The method of embodiment 109, wherein the skin disease, condition, or disorder is basal cell carcinoma, squamous cell carcinoma, or melanoma. Embodiment 112. The skin disease, condition, or disorder is a benign tumor, wherein the benign tumor is a benign vascular tumor, a benign fibrous tumor, a benign adipocyte tumor, a benign sebaceous tumor, a benign epidermal tumor, a benign melanocytic lesion, or a benign neural tumor; the skin disease, condition, or disorder is a malignant tumor, wherein the malignant tumor is a malignant melanocytic tumor, a basal cell carcinoma, a squamous cell carcinoma, a melanoma, a malignant epidermal tumor, a malignant vascular tumor, a malignant metastatic tumor, a malignant adipocyte tumor, a malignant sebaceous tumor, or a malignant fibrous tumor; the skin disease, condition, or disorder is a parasite, wherein 110. The method of embodiment 109, wherein the parasite is of the genus Trypanosoma or Leishmania; the skin disease, illness, or disorder is a virus, wherein the virus is molluscum contagiosum virus or human papillomavirus; or the skin disease, illness, or disorder is a bacterial, fungal, or microbial infection, wherein the bacterial, fungal, or microbial infection is otitis media, a Staphylococcus aureus infection, a Mycobacterium infection, a Porphyromonas infection, a Salmonella infection, a Chlamydia infection, tuberculosis, gingivitis, or periodontal disease. Embodiment 113. The method of any one of embodiments 109 to 112, wherein the composition is applied topically to the head, scalp, face, ear(s), neck, chest, back, submammary area(s), arm(s), leg(s), intertriginous area(s), hand(s), foot(s), or groin. Embodiment 114. The method of any one of embodiments 109 to 113, wherein the composition is administered in pulsed cycles. Embodiment 115. The method of any one of embodiments 109 to 114, wherein the composition is administered under occlusion. Embodiment 116. The method of any one of embodiments 109-115, comprising administering the composition orally, systemically, subcutaneously, intralesionally, or intradermally. Embodiment 117. The method of any one of embodiments 109 to 116, wherein the composition is combined or used in combination with one or more of the following: anti-inflammatory agents, NSAIDs, antibacterial agents, antibiotics, steroids, antivirals, chemotherapeutic agents, alkylating agents, antimetabolites, or anti-microtubule agents, vitamin D derivatives, oxidizing compounds, acids, retinoid derivatives, keratolytic agents, corticosteroids, immunomodulators, immunomodulators, sunscreens, UV blockers, zinc compounds, retinoids, dyschromia treatments, hyperpigmentation treatments, moisturizers, and / or anti-aging treatments. Embodiment 118. The method of embodiment 109, wherein the skin disease, condition, or disorder is a skin pigmentation disorder. Embodiment 119. The method of embodiment 109, wherein the skin pigmentation disorder is acanthosis nigricans. Embodiment 120. A kit comprising the topical pharmaceutical composition of any one of embodiments 78 to 119 in a tube, a flexible aluminum tube, or a laminated plastic tube, and instructions for use. [Example]

[0386] Example 1: Preparation of the composition Exemplary topical compositions of the present disclosure can be prepared according to the procedures provided below, where the compositions are for use in treating or preventing BCC. Reaction conditions, steps, and reactants not provided in the procedures below will be apparent and known to those skilled in the art.

[0387] Excipients (i.e., C 2-6 Alcohol, organic solvent and / or penetration enhancer, antioxidant, preservative, and / or water) were dispensed or weighed into individual containers to form a mixture.

[0388] [ka] Compound 1, represented by the formula: was added to the mixture to achieve the desired concentration. A gelling agent (e.g., HPC) was then added accordingly. In some compositions using a pH adjuster (e.g., citric acid), the pH of the formed mixture was adjusted to the desired apparent pH (e.g., about 5.5-6.5) with an aqueous citric acid solution (e.g., a 0.1 M, 0.5 M, or 1 M solution). In some compositions, a second addition of water (if present) was finally used to titrate the composition to 100% by weight. The final mixture was then thoroughly mixed to form the composition.

[0389] Example 2: Various compositions with / without Compound 1 The following compositions for use in the treatment or prevention of BCC were prepared according to the general procedure using the excipients in Tables 1 to 7.

[0390] [Table 3]

[0391] [Table 4]

[0392] [Table 5]

[0393] [Table 6]

[0394] [Table 7]

[0395] [Table 8]

[0396] [Table 9]

[0397] Example 3: 14-day skin tolerance study in Göttingen minipigs overview The objective of this study was to determine the topical dermal tolerability of four (4) compositions of Compound 1, and their respective placebos (Sepineo in Table 2, Anhydrous Sepineo in Table 3, High Transcutol Gel in Table 4, or Low Transcutol Gel in Table 5) for use in the treatment or prevention of BCC, after 14 days of cutaneous administration once daily or every other day to Göttingen minipigs.

[0398] material and method The test article and placebo (Sepineo in Table 2, Anhydrous Sepineo in Table 3, High Transcutol Gel in Table 4, or Low Transcutol Gel in Table 5) were administered via dermal application to the left side of each animal once daily for 14 days during the study. Starting on day 2 (days 2, 4, 6, 8, 10, 12, and 14), the test article and placebo were administered via dermal application to the right side of each animal once every other day. Compound 1 dose concentrations were 0.01% and 0.1% (first animal / sex) or 0.1% and 1% (second animal / sex) and administered in a dose volume of 0.5 mL / site. The day before the first dose administration, hair was clipped from the back of the animals. Repeated clippings were performed as necessary. Care was taken to avoid abrading the skin. Each exposure site was marked at the corner with an indelible marker. The test article and placebo were distributed to individual sites (6 / side), each 1.4 x 1.4 inches, on the dorsal surface by gentle injunction with a glass stirring rod or suitable instrument (e.g., a stainless steel spatula). The test article and placebo were applied evenly to the test sites with a thin, uniform film of the appropriate dosing material. The sites were not occluded.

[0399] Sites were observed for gross signs of irritation (i.e., erythema and edema, lesions) and other signs of local or systemic effects and ranked on a scale of 0 to 5, with 0 corresponding to "no effect." Clinical observations unrelated to application site observations were recorded as unscheduled observations, as needed.

[0400] On Day 14, after dosing (2-4 hours post-dose), all animals were euthanized for skin biopsy sample collection. Prior to collection, the dosing site was gently cleaned with a 10% soap solution (e.g., Dawn dish soap) followed by rinsing with lukewarm water using Wypall® or equivalent. A low-pressure stream of lukewarm tap water was used with a hose to facilitate rinsing, followed by tape stripping to remove residual composition and punch biopsy. Full-thickness samples were collected from each dosing site (including placebo sites) and a single naive site per animal via a 5 mm circular or oval punch biopsy device or by incision with a surgical blade.

[0401] Results, interpretation, and conclusions All compositions and placebo were generally well tolerated after 14 days of cutaneous application once daily or once every other day. All test substances and placebo were generally well tolerated. Signs of irritation were observed only in male 1002. Following daily administration, very slight erythema was present at Site 3 on Days 12-14 (Ex. 2D-1% in Table 4) and at Site 6 on Days 4 and 7-14 (Ex. 2E-1% in Table 5). Edema was not present in any animal at any time point.

[0402] Figures 1A-1D show the local skin tolerability of four compositions containing Compound 1 and their respective placebos after cutaneous administration once daily or once every other day to Göttingen minipigs for 14 days, as measured by erythema and edema scores. The four (4) compositions correspond to the compositions in Tables 2-5, as follows:

[0403] [Table 10]

[0404] Example 4: Further optimization of compositions containing high Transcutol The compositions of Table 4, containing approximately 47-48% Transcutol P (2-(2-ethoxyethoxy)ethanol), were further tested with the addition of antioxidants (e.g., butylated hydroxytoluene (BHT) and / or butylated hydroxyanisole (BHA), or propyl gallate), preservatives (e.g., phenoxyethanol), and / or pH adjusters (e.g., aqueous citric acid). The compositions are therefore shown in Tables 8 and 9.

[0405] [Table 11-1]

[0406] [Table 11-2]

[0407] [Table 12-1]

[0408] [Table 12-2]

[0409] Example 5: Induction of apoptosis in seborrheic keratosis overview Using a non-clinical ex-vivo human SK explant model, a composition containing 1% Compound 1 was tested to induce apoptosis in SK specimens. The purpose of this study was to investigate the ability of topically applied compounds to suppress cell viability in SK. The use of human explants allowed the assay of compositions and the effect of pharmaceutical agents on local penetration to be evaluated in an environment that closely mimicked the clinical setting. Shaved biopsies of SK were taken from patients undergoing SK resection for clinical purposes. 3-4 mm 2 Biopsy specimens measuring 100 μg were embedded in culture medium and agar for the experiment. The protruding sample surface was treated with 2.5 microliters (ml) of a composition containing 1% Compound 1 (e.g., Ex. 4-6a or Ex. 5-1%), vehicle alone, or left untreated. The explants were then incubated for 72 hours (hr) and fixed for staining and histological evaluation. The 72-hr time frame was used as the efficacy endpoint, and at the end of the experiment, relative apoptosis was assessed by TUNEL staining. The resulting images were qualitatively evaluated by visual inspection and showed more observable apoptosis in explants treated with Compound 1 compared with 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 the treatment of SKs, and indeed, when applied to SK explants, it induced an observable increase in apoptosis.

[0410] material and method Materials required for tissue culture included RPMI 1640 (Thermo Fisher, 11875093), human serum (GeminiBio #100-110), amphotericin B (Thermo Fisher, Cat. No. 15290018), and penicillin-streptomycin (5,000 U / mL, Thermo Fisher, Cat. No. 15140-122), agarose (Sigma, CAS 9012-36-6) DMSO Sigma Aldrich (#D8418), Transwell Permeable Supports, and 12-well plates (Corning 12 mm Transwell®, 3.0 μm PorePolycarbonate Membrane Insert, Sterile Cat. #3402).

[0411] Compositions containing Compound 1 and the corresponding vehicle were used in the study, as shown in Table 10.

[0412] [Table 13]

[0413] Ex vivo studies were performed to determine whether Compound 1 in compositions containing high levels of Transcutol (e.g., Ex. 4-6a or Ex. 5-1% in Example 4) could penetrate human skin lesions and result in increased apoptosis as measured by the TUNEL assay. Human seborrheic keratosis biopsies were collected and immediately prepared for drug treatment as described in the experimental model section.

[0414] A total of five seborrheic keratoses were collected from patients who provided informed consent under an IRB-approved protocol. Each collected SK was divided into pieces for use in different treatment groups. Two separate experiments were performed at different time points. In the first experiment, two keratoses were collected and each divided into two pieces. A section of each sample was treated with 1% Compound 1, and another section was treated with vehicle. The treatment groups were 1) 1% Compound 1 (N=2), and 2) vehicle (N=2).

[0415] In the second study, three seborrheic keratoses were collected and divided into three sections, each of which was treated with 1% Compound 1, vehicle only, or left untreated. 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 (Ex. 5-1%) or vehicle in the composition reduced the area by approximately 3.5 mm. 2 The drug was applied topically to partially immersed tissue samples. Specifically, 2.5 microliters (μl) of the Ex.5-1% composition (containing 1% Compound 1) was added to the sample, as described above, or 2.5 μl of vehicle was added to the sample as a control. In a second experiment, three additional SKs were left untreated for comparison. The drug or vehicle was added topically to each sample by pipetting onto the exposed surface area immediately after plating. After 72 hours of incubation at 37°C and 5% CO2, the samples were fixed in 10% formalin for 24 hours and then transferred to 70% ethanol for TUNEL staining.

[0416] Results, interpretation, and conclusions All seborrheic keratoses (n=5) treated with the Ex. 5-1% (containing 1% Compound 1) composition showed a relative increase in apoptosis as measured by TUNEL staining compared to vehicle (n=5) and untreated samples (n=3). One vehicle-treated sample also showed increased apoptosis compared to untreated, while the remaining four vehicle-treated samples had similar apoptosis levels compared to untreated controls. Figure 2 shows the explant TUNEL assay images.

[0417] It can be concluded that a single ex-vivo topical application of the composition (e.g., Ex. 5-1%) can result in increased keratinocyte apoptosis in seborrheic keratosis 72 hours after application.

[0418] Example 6: Short-term stability of the composition of Example 4 The compositions in Tables 8 and 9 for use in the treatment or prevention of BCC were subjected to short-term physicochemical stability testing after storage for up to 8 weeks at 25° C. and 40° C. Parameters evaluated were compound (i.e., Compound 1) content and purity, apparent pH, macroscopic observations, and microscopic observations.

[0419] Compound content and purity The content and purity of Compound 1 in the compositions after storage for 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).

[0420] Percentage recovery (%) compares the response of the drug peak to a standard of known concentration, while 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 from t=0 to 8 weeks after the stability study is detailed in Table 13.

[0421] [Table 14-1]

[0422] [Table 14-2]

[0423] [Table 15-1]

[0424] [Table 15-2]

[0425] [Table 16-1]

[0426] [Table 16-2]

[0427] The content of Compound 1 in all seven aqueous gels was within the range of 95-105% at t = 0 to 2 weeks. However, after 4 weeks of storage, there was a maximum 5% decrease in drug recovery 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 was greater than 97 area%. After 4 weeks of storage, the drug purity of the compositions decreased by approximately 0.36-2.64 area% at 25°C and approximately 0.88-4.13 area% at 40°C. The decrease in drug purity was lower in compositions stored at 2-8°C (0.18-0.38 area%). The relative purity of Compound 1 in all seven aqueous gels remained greater than 95% for up to 4 weeks at both 25°C and 40°C. Ex. 4-4a (without preservatives, antioxidants, and pH adjusters) and Ex. 4-6a (based on Ex. 4-4a with BHT) were stable for up to 8 weeks at both 25° C. (less than 1 area % loss in purity) and 40° C. (less than 1.5 area % loss in purity). The addition of antioxidants and preservatives (without adjusting the pH) appeared to further stabilize the compositions (see Ex. 4-6a).

[0428] Apparent pH The apparent pH at t=0 and 4 weeks (2-8° C., 25° C., and 40° C.) for compositions with and without Compound 1 are shown in Table 14.

[0429] [Table 17]

[0430] At t=0, the apparent pH of the compositions containing the pH adjuster ranged from 5.94 to 7.67, with no significant differences (±>1 pH unit) in pH between the placebo and the corresponding active compositions. After 4 weeks of storage, pH values ​​ranged from 5.52 to 6.86 (2-8°C), 5.54 to 8.06 (25°C), and 5.48 to 7.67 (40°C), which were consistent with the pH values ​​at t=0. The pH of the gel compositions that 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).

[0431] Macroscopic Observation Macroscopic appearance and macroscopic images against light and dark backgrounds were evaluated for all seven compositions, including Compound 1 and the corresponding vehicle.

[0432] At t=0, all compositions (both active and vehicle) were clear, with medium viscosity and smooth application. The placebo compositions appeared colorless, while the active compositions had a light beige coloration. There were no obvious changes in the compositions when stored at 2-8°C, 25°C, and 40°C for t=4 weeks, except for a slight discoloration observed in Ex. 4-4b (vehicle) at t=4 weeks (40°C), indicating the presence of propyl gallate in the compositions.

[0433] microscopic observation Microscopic appearance and microscopic images (unpolarized and polarized) were evaluated for all seven compositions, including Compound 1 and the corresponding vehicle.

[0434] There was no evidence of drug particulates in all compositions (both active and vehicle) throughout the experimental period (t = 0-4 weeks, 2-8°C, 25°C, and 40°C). Most of the compositions tested were free of excipient particulates, but 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 = 0 and 2 weeks. At t = 4 weeks, excipient particulates were observed in Ex. 4-1a (active) (40°C), 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 and 4 weeks, 25 and 40°C). It should be noted that the microparticle morphology was not consistent across time points, potentially indicating non-hydrating gelling agent (HPC), and that the gelling agent required a longer hydration time, which will be further optimized during process development.

[0435] Compositions Ex.4-6a (active) and Ex.4-6b (vehicle) were observed to be free of particulates of both drug and excipients over the experimental period (t = 0 to 4 weeks, 2 to 8°C, 25°C, and 40°C).

[0436] viscosity The viscosities 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) were monitored for three months, as shown in Table 15.

[0437] [Table 18]

[0438] Example 7: Human demonstration of topical application for the treatment of seborrheic keratosis overview Promising in vitro and explant studies prompted further investigation of the benefits of Composition Ex.5-Compound 1 in human clinical trials for the treatment of SK. This study is a first-in-human, open-label, adaptive design study to explore the safety and efficacy of Composition Ex.5-Compound 1 at concentrations of 1.0% or 0.1% using a vehicle topical gel in patients with seborrheic keratosis (SK).

[0439] method The study enrolled up to 35 subjects, each with four SK target lesions (SKTS), across six cohorts with different treatment regimens. Subjects participated for approximately 12 to 16 weeks.

[0440] All three completed cohorts had truncal SK treated with Composition Ex 5 - Compound 1: Cohort 1 was treated with 1.0% twice daily (BID) for 14 days, Cohort 2 was treated with 1.0% BID for 28 days, and Cohort 3 was treated with 1.0% pulse BID, 4 days on / 4 days off, for 28 days. All subjects were followed for a minimum of 4 weeks after their last dose, at which point all four SKTL lesions were scored using the PLA scale. The primary and secondary analyses included 43 lesions. As defined by the protocol, 17 lesions were excluded, 3 lesions were biopsied as non-responsive SK without 4 weeks of follow-up after treatment, and 14 lesions were histologically confirmed as not SK (6 nevi, 4 verrucous keratoses, and 4 lentigos).

[0441] The primary and secondary efficacy endpoints were based on PLA scoring, which had a 4-point scale, with 3 indicating SK greater than 1 mm thick, 2 indicating SK less than 1 mm thick, 1 indicating mostly clear but residual surface changes suggestive of SK, and 0 indicating no visible surface changes remaining.

[0442] Results, interpretation, and conclusions Across all three combined cohorts, 81% of lesions had at least a 1-point improvement in Physician Lesion Assessment (PLA) scores, with 74% of SK lesions clear (PLA0) or almost clear (PLA1), and 44% completely clear (PLA0). This study demonstrated early dose-response efficacy, with the highest SKTL improvement rates in cohorts 2 and 3, the 28-day treatment regimen. For both cohorts, the SKTL improvement rate with at least one PLA improvement was 100%, the clear or almost clear improvement rate was 79% and 100%, respectively, and the completely clear improvement rate was 57% and 46%, 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 proportion of lesions.

[0443] [Table 19]

[0444] [Table 20]

[0445] [Table 21]

[0446] Table 22

[0447] Table 23

[0448] Table 24

[0449] Table 25

[0450] Table 26

[0451] Table 27

[0452] Table 28

[0453] Table 29

[0454] Table 30

[0455] Table 31

[0456] Table 32

[0457] [Table 33]

[0458] [Table 34]

[0459] [Table 35]

[0460] [Table 36]

[0461] [Table 37]

[0462] Figures 3A-5C provide time-to-event KM plots, as described in the figure briefs. Figure 6 shows representative photographs illustrating the response of Composition Ex.5-Compound 1 to SK in Cohort 1 (14 days, twice daily administration) and background lentigo in Cohort 2 (28 days, twice daily administration), respectively. Table 22. There were no SAEs or AEs in the first three cohorts of the study. Pain, pruritus, erythema, edema, and scabbing were rated as none (0), mild (1), moderate (2), or severe (3).

[0463] [Table 38]

[0464] These data demonstrate that Composition Ex.5 - Compound 1 is an effective, selective, and safe treatment for SK, improving upon current treatment methods.

[0465] Example 8: Human demonstration of topical application for the treatment of facial and obliterative seborrheic keratoses overview Promising in vitro and explant studies prompted further investigation of the benefits of Composition Ex.5-Compound 1 in human clinical trials for the treatment of SK. This study is a first-in-human, open-label, adaptive design study to explore the safety and efficacy of Composition Ex.5-Compound 1 at 1.0% or 0.1% concentrations using a vehicle topical gel in patients with seborrheic keratosis (SK). Cohorts will have a two-week treatment period with twice-daily applications, followed by a four-week follow-up period. Based on results from the initial cohort and subsequent cohorts at any time point, additional cohorts will explore different dosing regimens.

[0466] method This study will enroll up to 35 subjects across seven cohorts with different treatment regimens, each with four SK target lesions (SKTLs). Subject participation lasted approximately 12 to 16 weeks. Cohorts 4, 5, 6, and 7 were enrolled or planned to be enrolled in Part 2 of this adaptive design study (results from Cohorts 1, 2, and 3 are described in Example 7). All cohorts had SKs treated with Composition Ex.5 - Compound 1.

[0467] Each subject in Cohort 4 (n=5 subjects) will receive Composition Ex. 5-1.0% Compound 1 applied twice daily (BID) to four facial seborrheic keratosis lesions (SKTLs). Composition Ex. 5-1.0% Compound will be applied twice daily to the facial SKTLs for 28 days.

[0468] Each subject in Cohort 5 (n=5 subjects) will receive Composition Ex.5-1.0% Compound 1 QD (once daily) / TIW (three times weekly) under Tegaderm occlusion on four seborrheic keratosis lesions (SKTLs) on the trunk and extremities. Composition Ex.5-1.0% Compound 1 will be applied once daily, three times weekly, and maintained under occlusion.

[0469] Each subject in Cohort 6 (n=5 subjects) will receive a 28-day application of Composition Ex.5-1.0% Mixture 1 to four seborrheic keratosis target lesions (SKTLs) on the trunk (including intertriginous areas) or extremities. Composition Ex.5-1.0% Compound 1 will be applied twice daily for 28 days.

[0470] Each subject in Cohort 7 (n=5 subjects) will have four seborrheic keratosis lesions (SKTLs) on their face treated with Composition Ex.5-0.1% Compound 1 applied twice daily for 28 days.

[0471] 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.

[0472] The primary and secondary efficacy endpoints were based on PLA scoring, with a 4-point scale, where 3 indicated SK greater than 1 mm thick, 2 indicated SK less than 1 mm thick, 1 indicated near-absence but residual surface changes suggestive of SK, and 0 indicated no visible surface changes remaining.

[0473] In particular, the primary outcome measures are: 1. Percentage of treated SKs with at least one grade improvement in PLA score, change from treatment period status to 4-week safety follow-up [time frame: 4 weeks after last dose]

[0474] Secondary primary outcome measures included: 2. Percentage of treated SKs with a Physician's Lesion Assessment (PLA) of 0 or 1, change from the start of the treatment period to the 4-week safety follow-up [time frame: 4 weeks after last dose] 3. Percentage of treated SKs with a PLA of 0, change from the start of the treatment period to the 4-week safety follow-up [time frame: 4 weeks after last dose] 4. Percentage of treated SKs with a PLA of 0 or 1, change from the start of the treatment period to week 12 [Time frame: week 12] 5. Percentage of treated SKs with a PLA of 0, change from the start of the treatment period to week 12 [Time frame: week 12] 6. Percentage of treated SKs with subject self-assessment (SSA) of 0 or 1, change from start of treatment period to 4-week safety follow-up [time frame: 4 weeks after last dose] 7. Percentage of treated SKs with an SSA of 0, change from the start of the treatment period to the 4-week safety follow-up [time frame: 4 weeks after last dose] 8. Percentage of treated SKs with SSA 0 or 1, change from start of treatment period to week 12 [Time frame: week 12] 9. Percentage of treated SKs with SSA 0, change from start of treatment period to week 12 [Time frame: week 12] 10. Time to treated SK achieving PLA 0 or 1, duration from baseline / day 1 (PLA 3 or 2) to PLA 0 or 1 [Time Frame: End of Study. In this adaptive design study, end of study will be 4-10 weeks after completion of the treatment period.] 11. Time to treated SK achieving PLA0, duration from baseline / Day 1 (PLA3 or 2) to PLA0 [Time Frame: End of Study. In this adaptive design study, end of study will be 4-10 weeks after completion of the treatment period.]

[0475] Inclusion criteria for all cohorts included the following: 1. At least 18 years old. 2. Have four eligible SKs in the face, trunk, or extremities. Eligible SKs must: a. have a clinically typical appearance, b. have a Physician's Lesion Assessment (PLA) of 2 or more, c. have a length of 1 mm or more and 15 mm or less, d. have a width of 1 mm or more and 15 mm or less, e. have a thickness of 2 mm or less, f. be discrete lesions, g. not be covered with hair that, in the opinion of the investigator, would interfere with study medication treatment or study evaluation, h. not be pedunculated. 3. Good general health and free from any known disease state or physical illness that, in the opinion of the investigator, could impair the evaluation of any target SK lesion or that would place the subject at unacceptable risk by participating in the study; 4. You must be willing and able to follow all study instructions and attend all study visits. 5. Have the technical ability and willingness to apply investigational new drugs (IP), if applicable; 6. Must be able to understand and willing to sign the Informed Consent Form (ICF).

[0476] Exclusion criteria included: 1. A positive urine pregnancy test, pregnant, lactating, or a woman of childbearing potential who does not agree to use active contraception during the study period, 2. Having SK lesions that are clinically atypical and / or rapidly growing in size, 3. Presence of multiple eruptive SK lesions (Leser-Trelat sign, 4. Current systemic malignancy, 5. Use of any of the following systemic therapies within the specified period prior to the screening visit: a. Retinoids, 180 days; b. Glucocorticosteroids, 28 days; c. Antimetabolites (e.g., methotrexate), 28 days 6. Use of any of the following local therapies within the specified time period prior to the screening visit for or in the vicinity of the target SK lesion that, in the opinion of the investigator, may interfere with study medication treatment or study assessments: a. Laser, light, or other energy-based therapy [e.g., intense pulsed light (IPL), photodynamic therapy (PDT)], 180 days; b. Liquid nitrogen, electrodesiccation, curettage, imiquimod, 5-flurouracil, or ingenol mebutate, 60 days; c. Microdermabrasion or superficial chemical peel, 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 for or in the vicinity of the target SK lesion that, in the opinion of the investigator, may interfere with study medication treatment or study evaluation: a. Skin malignancy, 180 days; b. Sunburn, current; c. Excessive sunburn, current; d. Pre-malignant tumor (e.g., actinic keratosis), current; e. Body art (tattoos, piercings, etc.), current; 8. History of sensitivity to any of the components of the study drug. 9. Any current skin condition (e.g., psoriasis, atopic dermatitis, eczema, sun damage, etc.) or disease (e.g., sunburn, excessive body hair, open wounds) where, in the opinion of the investigator, participation in the study may expose the subject to undue risk or interfere with the conduct or evaluation of the study. 10. Participation in an investigational drug trial involving administration of an investigational drug within 30 days prior to the screening visit.

[0477] [Table 39]

[0478] result The clinical trial is currently ongoing, and the results reported here are interim: Cohort 7 is fully enrolled, with participants completing visits up to Day 28; Cohort 4 is fully enrolled, with participants completing visits up to Day 14, with some participants completing visits up to Day 21; Cohort 5 has enrolled four of five potential participants, with participants completing the screening visit, with some participants completing visits up to Day 7; and Cohort 6 has not yet enrolled.

[0479] The columns in Tables 24-29 entitled "Missing" indicate whether there are any lesions for any participant or enrolled participant who has not yet completed the visit and has not been assessed on the specified date. The percentage of all predicted lesions or individuals that have not yet been scored is also shown.

[0480] Treatment was well tolerated, and analysis of all SK lesions across all treatments showed only mild local tolerance reactions, if any, and no moderate or severe reactions. The highest number of mild tolerance reactions by lesion was 8, or 15.4%, of lesions on Day 7 (Table 24); all other lesions were unresponsive. Local tolerance was also assessed at the patient level, with each patient having multiple lesions treated. The majority of patients in all treatment groups had no local tolerance reactions, and the highest number of mild tolerance reactions was on Day 7, when 3 patients, or 27.3% of patients, had mild tolerance reactions. There were no moderate or severe reactions (Table 25).

[0481] In Cohorts 4 (1% face) and 7 (0.1% face), the majority of patients (approximately 70%) showed at least a 1-point decrease in PLA score at 28 or 21 days after treatment, respectively (Figure 7, Table 27, and Table 29). In Cohort 5 (1% TIW), at least one of three patients who completed the day 7 screening showed a 1-point decrease in PLA score (Table 28).

[0482] [Table 40]

[0483] [Table 41]

[0484] [Table 42]

[0485] [Table 43]

[0486] [Table 44]

[0487] [Table 45]

[0488] Example 9: Composition Ex.5 - Stability of Mixture 1 at 0.1% and 1.0% The content and purity of Compound 1 in compositions Ex.5-0.1% and Ex.5-1.0% for use in the treatment or prevention of BCC after up to 6 months of storage are detailed in Table 30.

[0489] Percent recovery was determined by comparing the response of the drug peak to a standard of known concentration in the chromatogram using standard HPLC methods. Percent change in Compound 1 content in the compositions after stability testing for up to 6 months was measured starting at t=0. Three technical replicates were performed at each stability time point for each storage condition and each Compound 1 content. The Compound 1 content in compositions Ex. 5-0.1% and 1.0% did not deviate from the expected range over time. The acceptable range for Compound 1 content was 90.0% to 110.0%.

[0490] Apparent pH The apparent pH of Composition Ex.5-0.1% Compound 1 and Composition Ex.5-1.0% Compound after storage at 25° C. and 40° C. for up to 6 months is shown in Table 24. The apparent pH was measured using standard equipment and methods in the field.

[0491] The apparent pH remained consistent for 0-6 months at 25°C and 40°C for Ex. 5-0.1% Compound 1 and Ex. 5-1.0% Compound 1. The pH of Ex. 5-1.0% Compound 1 ranged from 8.49 to 8.62 at both temperatures. The pH of Ex. 5-0.1% Compound 1 ranged from 7.78 to 8.18 at both temperatures.

[0492] Macroscopic Observation After storage at 25°C and 40°C for up to 6 months, the macroscopic appearance and macroscopic images against light and dark backgrounds were evaluated for compositions Ex.5-0.1% Compound 1 and Ex.5-1.0% Compound 1 (Table 30).

[0493] At t=0, all compositions were yellow or slightly yellow, slightly hazy, had medium viscosity, and were smooth to the touch. Color, viscosity, and texture remained consistent over time and temperature. The color in Composition Ex.5-1.0% Compound 1 was scored as more intense than that in Composition Ex.5-0.1% Compound 1.

[0494] microscopic observation Microscopic appearance and microscopic images (unpolarized and polarized) were evaluated using standard microscopic methods for all compositions at the specified time points and storage temperatures.

[0495] There was no evidence of drug particles or crystals in any of the compositions (Table 30).

[0496] viscosity After storage at 25°C and 40°C for up to 6 months, the viscosities of compositions Ex.5-0.1% Compound 1 and Ex.5-0.1% Compound were evaluated (Table 24). Viscosity was measured using standard methods. The viscosities of Ex.5-1.0% Compound ranged from 22,440 cp to 29,600 cp. The viscosities of composition Ex.5-0.1% Compound 1 ranged from 12,800 cp to 28,400 cp.

[0497] Table 30. Macroscopic, microscopic, apparent pH, and average content of Composition Ex.5 containing 1.0% and 0.1% Compound 1. RH = relative humidity. cP = centipoise.

[0498] [Table 46-1]

[0499] [Table 46-2]

[0500] [Table 46-3]

[0501] [Table 46-4]

[0502] Example 10: Human demonstration of topical application for the treatment of basal cell carcinoma overview Further investigation was conducted into the benefits of Composition Ex.5 - Compound 1-1% in humans for the treatment of basal cell carcinoma. Composition Example Ex.5 Compound 1-1%, containing 1.0% API in a vehicle topical gel, was found to improve basal cell carcinoma.

[0503] method Basal cell carcinoma (BCC) was treated with Composition Ex.5-Compound 1-1.0%, containing a 1.0% API concentration in a vehicle gel. Lesions were treated twice daily (BID) for 28 days and confirmed as BCC by histological analysis. Lesions were followed for 6 weeks after the last dose and scored at each visit using a 4-point Physician's Lesion Assessment (PLA) scale, with 3 indicating greater than 1 mm in thickness, 2 indicating less than 1 mm in thickness, 1 indicating almost clear but with residual surface changes, and 0 indicating no visible surface changes remaining. Safety and tolerability were assessed by evaluation of signs and symptoms of local tolerance as Local Tolerability Reactions (LTR). Signs and symptoms assessed included pain, pruritus, erythema, edema, and crusting, using a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). LTR was scored for all lesions and adverse events were assessed for all subjects. BCCs were located on the face of the subjects.

[0504] Results, interpretation, and conclusions BCC lesions visibly decreased in size and thickness from days 21 to 42 (2 weeks after the last dose of treatment). From days 56 to 96, the lesions appeared to grow back to a percentage of their original size (Figure 8). PLA scores of BCC lesions confirmed the results. At baseline, the PLA score was 2, at day 7, the PLA score was 2, at day 14, the PLA score was 2, at day 21, the PLA score was 2, at day 26, the PLA score was 1, at day 35, the PLA score was 0, at day 42, the PLA score was 0, at day 56, the PLA score was 1, at day 70, the PLA score was 2, at day 84, the PLA score was 2, and at day 98, the PLA score was 2 (Table 31).

[0505] There were no adverse events related to BCC treatment, and only mild local tolerability reactions were experienced. Mild pruritus, erythema, and crusting were noted at visit 14, mild pain, pruritus, erythema, and crusting were noted at visit 21, and mild crusting was noted at visit 28. No other LTRs were noted, and edema was never experienced.

[0506] BCCs responded clearly to treatment as measured by visual inspection and PLA scores. Only mild LTR occurred during treatment of BCCs, and no serious adverse events occurred.

[0507] [Table 47]

[0508] Example 11: Human topical application for the treatment of seborrheic keratosis, basal cell carcinoma, and squamous intraepithelial carcinoma overview Further investigations were conducted into the usefulness of composition example Ex.5-Compound 1-1.0% in humans for the treatment of basal cell carcinoma and squamous intraepithelial carcinoma.

[0509] method An open-label trial was conducted to investigate the safety and efficacy of a gel containing 1.0% API in subjects with seborrheic keratosis (SK) and non-melanoma skin cancers (basal cell carcinoma (BCC) and squamous carcinoma in situ (SCCIS)). Subjects were enrolled in one of five cohorts: Cohort 1: 1.0% API gel, BID for 28 days for superficial BCC Cohort 2: 1.0% API gel, BID for 28 days for nodular BCC Cohort 3: 1.0% API gel, BID for 28 days for invasive BCC Cohort 4: 1.0% API gel, SCCIS, BID for 28 days Cohort 5: 1.0% API gel, SK, BID for 28 days

[0510] Each cohort enrolled 5-10 subjects, with at least one eligible lesion treated. A maximum of five lesions per subject was enrolled. Although multiple or different tumor types were enrolled in each cohort, subjects were analyzed primarily for their assigned cohort tumor subtype, with secondary analyses for any alternative tumor subtypes.

[0511] Eligible subjects must have at least one and up to five qualifying lesions at screening that were histologically confirmed as seborrheic keratosis or non-melanoma skin cancer, ranging in size from 1.0 to 2.0 cm in maximum diameter. All potentially eligible lesions screened underwent biopsy (either a 2.0 mm punch or shave biopsy) at screening, removing no more than 25% of the tumor for histological confirmation and eligibility, as well as biomarker evaluation. All lesions were previously untreated primary lesions, meaning they were not recurrent lesions. All SK lesions had a PLA of 2.

[0512] All NMSC-only subjects and subjects with SK and NMSC were followed 7–14 days after excision of the NMSC until post-surgical suture removal, requiring a total of up to approximately 12 weeks of study participation (4 weeks of screening, 4 weeks of treatment, 2 weeks of follow-up due to excision, and up to 2 weeks for post-surgical follow-up and suture removal).

[0513] All subjects with seborrheic keratosis only completed the study at the 2-week follow-up visit after shave excision, requiring a total of approximately 10 weeks of study participation (4 weeks of screening, 4 weeks of treatment, and 2 weeks of follow-up with tangential shave excision).

[0514] Application site reactions (ASR) were assessed through assessment of the severity of signs and symptoms of pain, burning, stinging, pruritus, erythema, edema, exudation, erosion / ulceration, hyperpigmentation, and hypopigmentation at each TL treatment site since the last visit, as well as review of adverse events (AEs).

[0515] Study endpoints All subjects dispensed with study IP (API gel 1.0%) and who received at least one (1) confirmatory dose of study IP will be included in the safety analysis. All consented subjects will be included in the intent-to-treat (ITT) analysis.

[0516] The Per Protocol (PP) population was used for the primary efficacy analysis and was defined by subjects who completed the final 6-week visit assessment. Efficacy assessments were summarized descriptively by treatment group and visit. Primary efficacy endpoint: Percentage of lesions achieving a 50% reduction in maximal diameter of cohort-assigned TL(s) at week 6 compared to baseline. Secondary Efficacy Endpoints: a. Percentage of lesions achieving a 50% reduction in maximum diameter of all TL(s) at week 6 compared to baseline. b. Percentage of subjects achieving a 50% reduction in the maximal diameter of all TL(s) at week 6 compared to baseline. c. Percentage of subjects achieving a 50% reduction in the maximum diameter of their cohort-assigned TL(s) at Week 6 compared to baseline d. Percentage of lesions achieving histologic healing (complete healing) in cohort-assigned TLs at week 6 e. Percentage of subjects achieving histologic healing (complete cure) of their cohort-assigned TL at Week 6 f. Percentage of lesions achieving histological healing (complete healing) of all TLs at 6 weeks g. Percentage of subjects achieving histologic healing (complete healing) of all TLs at week 6 h. Percentage of all lesions, nodular BCC, superficial BCC, invasive BCC, SCCIS, and SK that achieved a 50% reduction in maximum diameter at week 6 compared to baseline. i. Histologic subtypes of non-melanoma skin cancer and SK most commonly associated with a decrease in maximum tumor diameter at week 6 j. Non-melanoma skin cancer and SK histologic subtypes most commonly associated with histologic healing (complete cure) at 6 weeks k. Relationship between maximum tumor diameter at baseline and change in maximum diameter at 6 weeks l. The relationship between the maximum tumor diameter at baseline and histological cure (complete clearance) at 6 weeks Exploratory efficacy endpoints: a. The association between reduction in maximum tumor diameter and biomarkers such as AKT pathway activity or mutational profiling was assessed. b. The association between histological healing and biomarkers such as AKT pathway activity or mutational profiling was evaluated. c. Comparison of the reduction in maximum tumor diameter at 4 weeks with the frequency and severity of ASR e. Comparison of histological healing at 4 weeks with the frequency and severity of ASR

[0517] Primary Safety Endpoint: Safety and tolerability were assessed through assessment of application site reactions (ASR): pain, burning, stinging, pruritus, erythema, edema, exudation, erosion / ulcer, signs of pigmentation, hypopigmentation, and severity of symptoms, as well as review of adverse events. Example 12: Profiling of target kinases in response to compounds for the prevention and / or treatment of skin cancer

[0518] Studies to validate the compounds described herein for inhibition of target kinases were carried out as described below.

[0519] Compounds were tested against 397 kinases using the KinSight™ Quantitative Kinome Profile screen from AssayQuant Technologies, Inc., Marlboro, MA. Briefly, the AKT1 IC50s of compound 1 and GSK690693 were determined. Compound concentrations in each kinase inhibition assay were ten times the IC50 determination, along with 1 mM ATP and the appropriate proprietary PhosphoSens® substrate in a continuous kinase inhibition assay. The Sox-based substrate allows direct quantification of the kinase's enzymatic activity and detects substrate phosphorylation throughout the reaction. The continuous assay format resulted in reaction rates for each kinase determined from dozens of data points, and progress curves were generated for each reaction well. Percent inhibition and significant observations were calculated for each compound-kinase pair, providing insight into the compound's mechanism of action and potency.

[0520] The inhibition rates of target kinases when Compound 1 was administered are shown in Table 32.

[0521] [Table 48-1]

[0522] [Table 48-2]

[0523] [Table 48-3]

[0524] [Table 48-4]

[0525] [Table 48-5]

[0526] [Table 48-6]

[0527] [Table 48-7]

[0528] [Table 48-8]

[0529] [Table 48-9]

[0530] [Table 48-10]

[0531] [Table 48-11]

[0532] The inhibition rates of target kinases when GSK690693 was administered are shown in Table 33.

[0533] [Table 49-1]

[0534] [Table 49-2]

[0535] [Table 49-3]

[0536] Table 49-4

[0537] Table 49-5

[0538] Table 49-6

[0539] Table 49-7

[0540] Table 49-8

[0541] Table 49-9

[0542] Table 49-10

[0543] Table 49-11

Claims

1. 1. A method for preventing or treating skin cancer, comprising: (i) Formula (I): 【Chemistry 1】 A compound having the structure During the ceremony, X is CH or N; R １ are each independently a halogen, —OH, or —NH ２ , -CN,C １－６ Alkyl, C １－６ haloalkyl, or C １－６ is an alkoxy; R ２ is an optionally substituted C ６－１２ aryl or optionally substituted 3-12 membered heteroaryl; n is 0 to 5; (ii) Formula (IA) or Formula (IB): 【Chemistry 2】 A compound having the structure During the ceremony, X is CH or N; each R1 is independently halogen, —OH, —NH2, —CN, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R3 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, or C1-6 alkoxy; R4 is hydrogen or C1-6 alkyl; n is 0 to 5; (iii) Formula (I-AA) or Formula (I-BB): 【Transformation 3】 A compound having the structure During the ceremony, R ３ is hydrogen, C １－６ Alkyl, C １－６ haloalkyl, or C １－６ is alkoxy, and R ４ is hydrogen or C １－６ a compound, (iv) Formula (II): 【Chemistry 4】 A compound having the structure In the formula, R Ａ is C １－２０ alkyl, and / or (v) Formula (III): 【Transformation 5】 A compound having the structure to the skin cancer, wherein the total amount of (i), (ii), (iii), (iv), (v), or any combination of two or more thereof present in the composition is from about 0.1% to about 1.5% by weight.

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

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

4. The method of claim 3 , wherein the SCC is invasive or in situ SCC.

5. 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 melanoma.

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

8. The method of any one of claims 1 to 7, comprising inducing apoptosis of keratinocytes or melanocytes 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. 11. The method of any one of claims 1 to 10, wherein the skin cancer is present on the face, trunk, extremities, or any combination of two or more thereof of a human subject.

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

13. 13. The method of any one of claims 1 to 12, wherein the length of the skin cancer before administration is between 1 mm and 15 mm, and the width of the skin cancer before administration is between 1 mm and 15 mm.

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

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

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

19. 20. The method of claim 18, wherein the organic solvent and / or penetration enhancer comprises a C2-6 alkylene glycol, a 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. Said C ２－６ the alkylene glycol is propylene glycol, Said C １－３ Alkyl-(OCH ２ CH ２ ) １－５ -OH is 2-(2-ethoxyethoxy)ethanol, and / or 20. The method of claim 19, wherein the polyethylene glycol is PEG200, PEG400, or a combination thereof.

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

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

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

24. 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, and the gelling agent comprises hydroxypropyl cellulose.

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

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

28. 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 from about 7 to about 9.

30. 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. 32. The method of any one of claims 1-31, wherein the step of topically administering the composition comprises topically administering the composition to the head, scalp, face, ears, neck, chest, back, submammary area, arms, legs, intertriginous areas, hands, feet, or groin.

33. The composition comprises: 【Transformation 6】 33. The method of any one of claims 1 to 32, comprising a compound having the structure:

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

35. The composition comprises: 【Transformation 7】 35. The method of any one of claims 1 to 34, comprising a compound having the structure:

36. The composition comprises: 【Transformation 8】 36. The method of any one of claims 1 to 35, comprising a compound having the structure:

37. The composition comprises: 【Chemistry 9】 37. The method of any one of claims 1 to 36, comprising a compound having the structure:

38. The composition comprises: 【Chemistry 10】 38. The method of any one of claims 1 to 37, comprising a compound having the structure:

39. The composition comprises: 【Chemistry 11】 39. The method of any one of claims 1 to 38, comprising a compound having the structure:

40. The composition comprises: 【Chemistry 12】 40. The method of any one of claims 1 to 39, comprising a compound having the structure:

41. The composition comprises: 【Chemistry 13】 41. The method of any one of claims 1 to 40, comprising a compound having the structure:

42. The composition comprises: 【Chemistry 14】 42. The method of any one of claims 1 to 41, comprising a compound having the structure:

43. The composition comprises: 【Chemistry 15】 43. The method of any one of claims 1 to 42, comprising a compound having the structure:

44. The composition comprises: 【Chemistry 16】 44. The method of any one of claims 1 to 43, comprising a compound having the structure:

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