Compositions and methods for treating graying and hair loss associated with aging

Abstract

The present application provides compounds, pharmaceutical compositions, and / or dosage forms, and uses thereof. Such uses include, but are not limited to, treating and / or preventing hair loss or hair discoloration.

Description

[0001] Government funding statement This invention was developed with grant number CA166593 granted by the National Institutes of Health in the United States. The U.S. government holds certain rights to this invention. Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 625,853, filed January 26, 2024, entitled “Composition and Method for Treating Age-Related Hair Changes and Hair Loss,” the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application generally relates to compounds and their uses in hair loss and hair fading. Summary of the Invention

[0004] One aspect of this disclosure covers compounds of formula (I), formula (II), formula (II'), formula (III) or formula (IV), or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates or prodrugs thereof.

[0005] , , , ,or .

[0006] In formula (I), R1 is a substituted or unsubstituted cycloalkyl group, R2 is an alkyl group, and R3 is a substituted or unsubstituted aryl group. In formula (II), R4 is a substituted or unsubstituted heterocycloalkyl group, and R5 is a substituted or unsubstituted aryl group. In formula (II'), R4 ’ R5 is a substituted or unsubstituted heterocyclic alkyl group. ’ R6 is a substituted or unsubstituted aryl group. In formula (III), R6 is a substituted or unsubstituted nitrogen-containing heterocyclic alkyl group. In formula (IV), R7 is -NH(C=O)-R 17 or -O(C=O)-R 17 , where R 17The alkyl, alkenyl, or aryl group is substituted or unsubstituted, and R8 is hydrogen or hydroxyl. In one aspect, the compound is a compound of formula (I). In another aspect, the compound of formula (I) is a compound in which R1 is cyclohexane, R2 is methyl, and / or R3 is a phenyl group substituted with at least one alkoxy group and / or at least one halogen. In one aspect, the compound is a compound of formula II. In yet another aspect, the compound of formula (II) is a compound in which R4 is a substituted pyrrolidine (including, but not limited to, pyrrolidines substituted with alkyl or carbonyl groups). In another aspect, in the compound of formula (II), R5 is a phenyl group substituted with a carboxylic acid or ester, including, but not limited to, substituted or unsubstituted azepine or substituted or unsubstituted piperidine. In yet another aspect, the compound of formula (II') is a compound in which R4 is a phenyl group substituted with at least one alkoxy group and / or at least one halogen. ’ Compounds of substituted pyrrolidines (including, but not limited to, pyrrolidines substituted with alkyl or carbonyl groups). In another aspect, in compounds of formula (II'), R5 ’ The compound is a phenyl group substituted with a carboxylic acid or ester, including but not limited to substituted or unsubstituted azaheptatrienes or substituted or unsubstituted piperidines. In one aspect, the compound is a compound of formula III. In another aspect, a compound of formula (III) is a compound in which R6 is an unsubstituted azaheptatriene or an alkyl-substituted piperidine. In one aspect, the compound is a compound of formula IV. In yet another aspect, a compound of formula (IV) is a compound in which R7 is -NH(C=O)-R 17 R8 is hydrogen or alkyl, and R 17 The compound is an aryl-substituted alkenyl compound. In another embodiment, the compound of formula (IV) is a compound in which R7 is -O(C=O)-Ar and R8 is a hydroxyl group.

[0007] Another aspect of this disclosure covers the following compounds, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof: (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB).

[0008] Another aspect of this disclosure covers a pharmaceutical composition comprising compounds of formula (I), formula (II), formula (II'), formula (III) and / or formula (IV) (including, but not limited to, compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB)), pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof; and pharmaceutically acceptable carriers or excipients. In one aspect, the composition is intended for systemic or local delivery.

[0009] Another aspect of this disclosure covers a pharmaceutical dosage form comprising compounds of formula (I), formula (II), formula (II'), formula (III) and / or formula (IV) (including, but not limited to, compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB); pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof; and pharmaceutically acceptable carriers or excipients. In one aspect, the dosage form includes an oral dosage form, a topical dosage form, or a follicular dosage form.

[0010] Another aspect of this disclosure covers compounds having any of the following compound structures disclosed herein: cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd373, cpd680, cpd715, cpd680, cpd693, cpd64 ... d717, cpd733, cpd755, cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152, and their pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs. In another aspect, the compound has the structures cpd34, cpd37, cpd65, cpd257, cpd557, cpd1107, and cpd1840, or their pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs. In another aspect, the compound has the structures cpd571, cpd621, cpd644, cpd715, cpd758, and cpd2152, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof. In yet another aspect, the compound has the structures cpd256, cpd755, cpd795, and cpd2062, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof.

[0011] Another aspect of this disclosure covers a pharmaceutical composition comprising compounds of formula (I), formula (II), formula (II'), formula (III) and / or formula (IV) (including, but not limited to, compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA) and (IVB)), or having cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd53 as disclosed herein. 3. A compound with the structure of any one of the compounds selected from CPD557, CPD571, CPD621, CPD644, CPD680, CPD715, CPD717, CPD733, CPD755, CPD758, CPD795, CPD900, CPD935, CPD983, CPD1107, CPD1255, CPD1744, CPD1840, CPD1886, CPD2052, CPD2056, CPD2062, CPD2078, CPD2125, and CPD2152, wherein the compound is a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, prodrug, or any combination thereof. In one aspect, the composition is intended for systemic or local delivery.

[0012] Another aspect of this disclosure covers a pharmaceutical dosage form comprising compounds of formula (I), formula (II), formula (II'), formula (III) and / or formula (IV) (including, but not limited to, compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA) and (IVB)), or having cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd53 as disclosed herein. 3. A compound with the structure of any one of the compounds selected from CPD557, CPD571, CPD621, CPD644, CPD680, CPD715, CPD717, CPD733, CPD755, CPD758, CPD795, CPD900, CPD935, CPD983, CPD1107, CPD1255, CPD1744, CPD1840, CPD1886, CPD2052, CPD2056, CPD2062, CPD2078, CPD2125, and CPD2152, wherein the compound is a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, prodrug, or any combination thereof. In one aspect, the dosage form includes an oral dosage form, a topical dosage form, or a follicular dosage form.

[0013] Another aspect of this disclosure covers a method for treating hair loss and / or hair discoloration in a subject, the method comprising administering to the subject a compound, pharmaceutical composition, or pharmaceutical dosage form disclosed herein. In one aspect, the hair loss and / or hair discoloration is associated with aging. In another aspect, the subject is human. In yet another aspect, the subject is an elderly person.

[0014] Another aspect of this disclosure covers a method for activating a stem cell factor (SCF) promoter in cells, the method comprising contacting cells with a compound of formula (I), formula (II), formula (II'), formula (III) and / or formula (IV) (including, but not limited to, compounds of formulas (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB)), a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, prodrug, or any combination thereof. In one aspect, the method enhances SCF expression in cells. In another aspect, the cells are keratinocytes.

[0015] Another aspect of this disclosure covers a method for activating stem cell factor (SCF) promoters in cells, the method comprising reacting cells with promoters having the cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, and cpd373 disclosed herein. A compound with the structure of any one of the compounds selected from d717, cpd733, cpd755, cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152, its pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, prodrug, or any combination thereof. In one aspect, this method can enhance the expression of SCF in cells. In another aspect, the cells are keratinocytes.

[0016] Another aspect of this disclosure covers one or more compounds of formulas (I), (II), (II'), (III), (IV), or one or more having the cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, cpd373, cpd717, cpd733, cpd755, cpd373, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, cpd373, cpd64 ... The use of compounds with the structure of any one of the compounds selected from d758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152, in pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, prodrugs, or any combination thereof, in a method of treating a subject for hair loss and / or hair discoloration, the method comprising administering one or more of said compounds to a subject requiring such treatment. In another aspect, the disclosed pharmaceutical compositions and / or dosage forms also cover such uses.

[0017] Explanation of color illustrations This application contains at least one color photograph or color illustration. A published copy of the patent application with a color photograph or illustration will be provided by the Patent Office upon request and payment of the necessary fees. Attached Figure Description

[0018] Figure 1 The strategy and workflow for screening small molecules that can activate stem cell factor (SCF) promoters using green fluorescent protein (GFP) as a readout are described.

[0019] Figure 2 A flowchart of the High Throughput Screening (HTS) step is provided.

[0020] Figure 3 Flowcharts for Cherry-Pick high-throughput screening imaging and TaqMan PCR are provided respectively.

[0021] Figure 4 The steps for HTS Cherry-Pick image filtering are provided.

[0022] Figure 5 The heatmaps of 109 compounds at a concentration of 0.21 µM are shown.

[0023] Figure 6 The heatmaps of 126 compounds at a concentration of 0.83 µM are shown.

[0024] Figure 7 The heatmaps of 195 compounds at a concentration of 2.5 µM are shown.

[0025] Figure 8 A heatmap of 51 compounds overlapping at all three concentrations is shown.

[0026] Figure 9 A heatmap showing the superimposed values ​​of 51 compounds at a concentration of 0.21 µM is displayed.

[0027] Figure 10 Thermographs of 51 compounds at a concentration of 0.83 µM are shown.

[0028] Figure 11 A heatmap showing the superimposed values ​​of 51 compounds at a concentration of 2.5 µM is displayed.

[0029] Figure 12 This demonstrates the overlap in compound selection between HTS and TaqMan RT-PCR.

[0030] Figure 13 The diagram shows the compounds selected from the overlap between the 126 compounds (0.83 µM) selected by HTS and the 298 compounds selected by TaqMan RT-PCR.

[0031] Figure 14 The diagram shows 34 compounds selected from the overlap between the 161 compounds (at a concentration of 2.5 µM) selected by HTS and the 298 compounds selected by TaqMan RT-PCR.

[0032] Figure 15 The image shows 14 compounds selected from the overlap between the 51 compounds selected by HTS (at three concentrations of 2.5 µM, 0.83 µM, and 0.27 µM) and the 298 compounds selected by TaqMan RT-PCR.

[0033] Figure 16A , 16B 16C and 16C depict the cluster analysis of compounds (cpds).

[0034] Figure 17 The results show the tests performed on the screened compounds and the results of in vitro experiments involving vinculin in the human cell line K562.

[0035] Figure 18 The results of another in vivo experiment, in which the selected compound was applied topically to the skin of the mouse tail, are shown.

[0036] Figure 19 In in vivo experiments, certain compounds showed that they increased the expression of SCF protein.

[0037] Figure 20A , 20B The results of IHC staining of SCF with DMSO, CPD755 and CPD 256 are shown in Figures 20 and 20C, respectively.

[0038] Figure 21 The steps of SILA (stable isotope labeling of amino acids in cell culture) are shown.

[0039] Figure 22 The steps for identifying protein targets using photoaffinity chromatography are shown. Detailed Implementation

[0040] This disclosure is based in part on the screening and identification of compounds capable of activating stem cell factor (SCF) promoters in cells such as keratinocytes. Another aspect of this disclosure is based on the finding that compounds of formula (I), (II), (II'), (III), or (IV) can be used to treat or prevent hair loss, thinning hair, hair discoloration, or graying hair.

[0041] , , , ,or .

[0042] In one respect, the compound is selected from: (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB), Or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, or prodrug.

[0043] Another aspect of this disclosure is based on the following findings: having the cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, cpd758, cpd795, cpd900, cpd935, cpd983, and cpd1107 disclosed herein. One or more compounds having the structure of any one of the compounds in cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125 and cpd2152 may be used to treat or prevent hair loss, thinning hair, hair discoloration or graying hair.

[0044] compound , , , ,or .

[0045] This disclosure covers compounds of formulas (I), (II), (II'), (III), and (IV), or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof. In formula (I), R1 is a substituted or unsubstituted cycloalkyl group, R2 is an alkyl group, and R3 is a substituted or unsubstituted aryl group. In formula (II), R4 is a substituted or unsubstituted heterocycloalkyl group, and R5 is a substituted or unsubstituted aryl group. In formula (II'), R4... ’ R5 is a substituted or unsubstituted heterocyclic alkyl group. ’ The aryl group is substituted or unsubstituted. In formula (III), R6 is a substituted or unsubstituted nitrogen-containing heterocyclic alkyl group. In one aspect, the compound is a compound of formula (I). In another aspect, a compound of formula (I) is a compound in which R1 is cyclohexane, R2 is methyl, and / or R3 is a phenyl group substituted with at least one alkoxy group and / or at least one halogen group. In one aspect, the compound is a compound of formula (II). In yet another aspect, a compound of formula (II) is a compound in which R4 is a substituted pyrrolidine (including but not limited to pyrrolidines substituted with alkyl or carbonyl groups). In another aspect, in a compound of formula (II), R5 is a phenyl group substituted with a carboxylic acid or ester, including but not limited to substituted or unsubstituted azaheptatriene or substituted or unsubstituted piperidine. In one aspect, the compound is a compound of formula (II'). In yet another aspect, a compound of formula (II') is a compound in which R4 is a substituted pyrrolidine (including but not limited to substituted or unsubstituted azaheptatriene or substituted or unsubstituted piperidine). ’ Compounds of substituted pyrrolidines (including, but not limited to, pyrrolidines substituted with alkyl or carbonyl groups). In another aspect, in compounds of formula (II'), R5 ’ The phenyl group is substituted with a carboxylic acid or an ester, including but not limited to substituted or unsubstituted azaheptatrienes or substituted or unsubstituted piperidines. In one aspect, the compound is a compound of formula III. In another aspect, the compound of formula (III) is a compound in which R6 is an unsubstituted azaheptatriene or an alkyl-substituted piperidine. In one aspect, the compound is a compound of formula IV. In yet another aspect, the compound of formula (IV) is a compound in which R7 is -NH(C=O)-R 17 R8 is hydrogen, and R 17 Compounds of aryl-substituted alkenyl groups. In another aspect, compounds of formula (IV) are compounds in which R7 is -O(C=O)-Ar and R8 is a hydroxyl group.

[0046] Another aspect of this disclosure covers the following compounds, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof: (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), or (IVB)

[0047] In one aspect, the compound activates the stem cell factor (SCF) promoter in cells, such as keratinocytes. Another aspect of this disclosure is based on the discovery that compounds of formulas (I), (II), (II'), (III), and / or (IV) (including, but not limited to, compounds of formulas (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB), their pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs, can be used to treat or prevent hair loss, thinning hair, hair discoloration, or graying hair.

[0048] Another aspect of this disclosure is based on the following findings: having the cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, and cpd758 disclosed herein. A compound having the structure of any one of the compounds selected from cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152, or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, or prodrug thereof, for the treatment or prevention of hair loss, thinning hair, hair discoloration, or graying hair. In one aspect, the compound has the structure of cpd34, cpd37, cpd65, cpd257, cpd557, cpd1107, or cpd1840, or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, or prodrug thereof. In another aspect, the compound has the structures cpd571, cpd621, cpd644, cpd715, cpd758, and cpd2152, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof. In yet another aspect, the compound has the structures cpd256, cpd755, cpd795, and cpd2062, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof. The structures of these compounds are shown in Table A below.

[0049] Table A

[0050] How to use In one aspect, a compound of formula (I), (II), (II'), (III) and / or (IV), or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, prodrug, or any combination thereof, is used to activate a stem cell factor (SCF) promoter in cells (e.g., keratinocytes). In one embodiment, the compound is selected from compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB), or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, or prodrug thereof. In another aspect, the cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, cpd758, cpd795, and cpd373 disclosed herein are also present. One or more compounds, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof, of any of the following compounds: d900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152, for the purpose of activating the stem cell factor (SCF) promoter in cells, such as keratinocytes. The SCF promoter is a specific DNA sequence located upstream of the SCF gene that controls the initiation of transcription, essentially acting as a switch to turn the gene on or off, thereby regulating the production of the stem cell factor protein itself. This protein plays a crucial role in the survival, proliferation, and differentiation of hematopoietic stem cells by binding to the c-Kit receptor on the surface of hematopoietic stem cells. Multiple transcription factors bind to specific sites on the SCF promoter, thereby finely regulating SCF expression based on cellular signals and environmental cues. Different cell types may express different levels of SCF due to variations in promoter activity (which depends on specific regulatory elements present). The SCF promoter is crucial for research on hematopoietic-related diseases such as leukemia, as well as for potential therapeutic applications involving the manipulation of stem cell populations. Furthermore, SCF binds to c-Kit receptors on hair follicle stem cells, playing a key role in hair growth by regulating the activity of hair follicle stem cells, stimulating their proliferation and differentiation. This is essential for hair growth during the anagen phase of the hair cycle (active growth phase), and impaired SCF function can lead to hair loss.Low levels of SCF produced by the promoter can lead to reduced hair follicle proliferation, ultimately resulting in thinning hair. When the SCF promoter malfunctions, it reduces SCF production, thus hindering hair follicle activity and causing thinning hair. Specifically in androgenetic alopecia, studies have shown that androgens such as dihydrotestosterone (DHT) may negatively affect SCF production in the dermal papilla cells of hair follicles, leading to hair loss similar to male pattern baldness.

[0051] In another respect, compounds of formula (I), (II), (II'), (III) and / or (IV), or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates or prodrugs thereof, such as compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA) and (IVB), or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates or prodrugs thereof, are used to prevent or treat hair loss or hair discoloration via the SCF pathway or other mechanisms. In another aspect, it possesses cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, cpd758, and cpd79 as disclosed herein. 5. One or more compounds with the structure of any one of the following compounds: CPD900, CPD935, CPD983, CPD1107, CPD1255, CPD1744, CPD1840, CPD1886, CPD2052, CPD2056, CPD2062, CPD2078, CPD2125, and CPD2152, or their pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs, for the prevention or treatment of hair loss or hair discoloration via the SCF pathway or other mechanisms. There are many different types of hair loss, the most common being alopecia areata, which manifests as hair loss starting at the temples and crown in men. Although this type of hair loss primarily occurs in men and is therefore commonly known as "male pattern baldness," it can also occur in women. Furthermore, hair is classified into several types, including terminal hair, vellus hair, and variant terminal hair (such as that seen in eyelashes and eyebrows). Terminal hairs are coarse, pigmented, long hairs with follicles located deep in the dermis. Vellus hairs, on the other hand, are fine, thin, soft, unpigmented, and shorter hairs with follicles located superficially in the dermis. As hair loss progresses, a transformation occurs in the areas approaching baldness: the hair itself changes from terminal hair to vellus hair. Another factor contributing to hair loss or thinning is the change in the hair growth cycle. All hair, whether human or animal, undergoes a three-phase life cycle: the anagen (growth) phase, the catagen (transitional) phase, and the telogen (resting) phase. The anagen phase is the period of active hair growth; for scalp hair, this phase typically lasts 3 to 5 years. The catagen phase is the brief transition between the anagen and telogen phases; for scalp hair, it lasts only 1 to 2 weeks. The final phase is the telogen phase, which, practically speaking, can be called the resting phase, during which all growth activity ceases, the hair eventually falls out, and the follicle begins to grow new hair.Hair follicles in the resting phase have a relatively short lifespan, typically falling out after 3-4 months, and new hair begins to grow. Under normal hair growth conditions, approximately 88% of hair follicles are in the anagen (growth) phase, only 1% are in the catagen (transitional) phase, and the remainder are in the telogen (resting) phase. With the development of male pattern baldness, the proportion of hair follicles in the telogen phase gradually increases, while the proportion of hair follicles in the anagen (growth) phase decreases accordingly.

[0052] Hair loss is associated with a severe reduction in the number of hair follicles. A bald human subject has an average of only about 306 hair follicles per square centimeter of scalp, compared to an average of 460 follicles per square centimeter for the same age group without hair loss. This represents a reduction of one-third in the number of hair follicles; coupled with an increase in the proportion of vellus hair follicles and an increase in the number of telogen follicles, this change is both significant and noticeable. It takes approximately 50% hair loss to result in visible thinning of scalp hair. Therefore, it is the combined effect of these factors—the transition of hair from terminal to vellus hair, the increase in the number of telogen follicles (some of which have already fallen out), and the reduction and loss of hair follicles—that ultimately leads to baldness.

[0053] Compositions and dosage forms One aspect of this disclosure covers a pharmaceutical composition or dosage form for delivering compounds of formula (I), (II), (II'), (III) and / or (IV) (including, but not limited to, compounds of formula (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (IIC), (IIIC), (IVA), and (IVB), or their pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs.

[0054] Another aspect of this disclosure covers the delivery of devices having the CPD34, CPD37, CPD65, CPD256, CPD257, CPD279, CPD280, CPD300, CPD373, CPD396, CPD492, CPD511, CPD530, CPD533, CPD557, CPD571, CPD621, CPD644, CPD680, CPD715, CPD717, CPD733, and CPD755 disclosed herein. A pharmaceutical composition or dosage form of one or more compounds having the structure of any one of the compounds selected from cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125 and cpd2152, or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate or prodrug thereof.

[0055] A pharmaceutical composition or dosage form may comprise an effective amount of a compound of formula (I), (II), (II'), (III) and / or (IV) (including, but not limited to, compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA) and (IVB)), a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, prodrug, or combination thereof.

[0056] A pharmaceutical composition or dosage form may comprise an effective amount of the following cPDs disclosed herein: 34, 37, 65, 256, 257, 279, 280, 300, 373, 396, 492, 511, 530, 533, 557, 571, 621, 644, 680, 715, 717, 733, 644, 757, 759 ... One or more compounds having the structure of any one of the compounds selected from 755, cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, prodrugs, or combinations thereof.

[0057] Pharmaceutically acceptable salts may include, but are not limited to: acetates, aspartates, benzoates, tartrates, citrates, formates, gluconates, glucurons, glutamates, fumarates, hydrochlorides, hydrobromides, hydroiodates, hypophosphites, isobutyrates, isocitrates, lactates, malates, maleates, meconates, methyl bromides, methanesulfonates, monohydrates, mucilages, nitrates, oxalates, phenylpropionates, phosphates, phthalates, propionates, pyruvates, salicylates, stearates, succinates, sulfates, tannins, tartrates, terephthalates, valerates, etc.

[0058] The amount of compounds of formula (I), (II), (II'), (III) and / or (IV) (including but not limited to compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA) and (IVB)) in the composition may be a therapeutically effective amount.

[0059] It contains the cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, and cpd733 disclosed herein. The amount of any compound with the structure of any of the following compounds in the composition may be a therapeutically effective amount.

[0060] As used herein, "therapeutic effective amount" or "therapeutic effective dose" refers to an amount capable of effectively achieving the desired therapeutic effect. In some embodiments, the desired therapeutic effect includes SCF activation and / or prevention / treatment of hair loss, thinning hair, and / or hair discoloration. For example, a therapeutic effective amount can be an amount capable of increasing SCF activity by at least 10%, preferably 20% or more, preferably 25% or more, preferably 30% or more, preferably 35% or more, preferably 40% or more, preferably 45% or more, preferably 50% or more, preferably 60% or more, preferably 70% or more, preferably 80% or more, preferably 90% or more. A therapeutic effective amount can be an amount capable of promoting hair growth by at least about 2%, 5%, 8%, 10%, preferably 20% or more, preferably 25% or more, preferably 30% or more, preferably 35% or more, preferably 40% or more, preferably 45% or more, preferably 50% or more, preferably 60% or more, preferably 70% or more, preferably 80% or more, preferably 90% or more.

[0061] In certain circumstances, the amount of compounds of formula (I), (II), (II'), (III) and / or (IV) (including, but not limited to, compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA) and (IVB)), or their pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates or prodrugs, in the composition is greater than about 1 μg. For example, the composition may contain compounds of formula (I), (II), (II'), (III) and / or (IV) in amounts of about 2 μg or more, about 5 μg or more, about 10 μg or more, about 100 μg or more, about 500 μg or more, about 1000 μg or more, about 1500 μg or more, about 2000 μg or more, about 2500 μg or more, about 3000 μg or more, about 3500 μg or more, about 4000 μg or more, about 4500 μg or more, about 5000 μg or more, about 5500 μg or more, about 6000 μg or more, about 6500 μg or more, about 7000 μg or more, about 7500 μg or more, about 8000 μg or more, about 8500 μg or more. More, about 9000 μg or more, about 9500 μg or more, about 10 mg or more, about 20 mg or more, about 30 mg or more, about 40 mg or more, about 50 mg or more, about 60 mg or more, about 70 mg or more, about 80 mg or more, about 90 mg or more, about 100 mg or more, about 150 mg or more, about 200 mg or more, about 250 mg or more, about 300 mg or more, about 350 mg or more, about 400 mg or more, about 450 mg or more, about 500 mg or more, about 550 mg or more, about 600 mg or more, about 650 mg or more, about 700 mg or more, about 800 mg or more, about 900 mg or more, or about 1 g or more.

[0062] In some cases, the following cpd parameters are used: cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, and cpd758. One or more compounds having the structure of any one of the compounds selected from cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof, are present in the composition in an amount greater than about 1 μg.For example, the composition may contain cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, cpd758, cpd795, cpd900, cpd935, and cpd9... as disclosed herein. 83. One or more compounds with the structure of any of the compounds selected from CPD1107, CPD1255, CPD1744, CPD1840, CPD1886, CPD2052, CPD2056, CPD2062, CPD2078, CPD2125, and CPD2152, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof, in amounts of about 2 μg or more, about 5 μg or more, about 10 μg or more, about 100 μg or more, about 500 μg or more, about 1000 μg or more, or about 1500 μg or more. Approximately 2000 μg or more, approximately 2500 μg or more, approximately 3000 μg or more, approximately 3500 μg or more, approximately 4000 μg or more, approximately 4500 μg or more, approximately 5000 μg or more, approximately 5500 μg or more, approximately 6000 μg or more, approximately 6500 μg or more, approximately 7000 μg or more, approximately 7500 μg or more, approximately 8000 μg or more, approximately 8500 μg or more, approximately 9000 μg or more, approximately 9500 μg or more, approximately 10 mg or more, approximately 20 mg or more, approximately 30 mg or more, approximately 40 mg g or more, about 50 mg or more, about 60 mg or more, about 70 mg or more, about 80 mg or more, about 90 mg or more, about 100 mg or more, about 150 mg or more, about 200 mg or more, about 250 mg or more, about 300 mg or more, about 350 mg or more, about 400 mg or more, about 450 mg or more, about 500 mg or more, about 550 mg or more, about 600 mg or more, about 650 mg or more, about 700 mg or more, about 800 mg or more, about 900 mg or more, or about 1 g or more.

[0063] Alternatively or additionally, the amount of compounds of formula (I), (II), (III) and / or (IV) in the composition (including, but not limited to, compounds of formula (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), (IIIC), (IVA) and (IVB)) may be from about 0.01 wt% to about 95 wt%, from about 0.1 wt% to about 95 wt%, from about 1 wt% to about 95 wt%, from about 5 wt% to about 95 wt%, from about 10 wt% to about 95 wt%, from about 15 wt% to about 95 wt%, from about 20 wt% to about 95 wt%, from about 30 wt% to about 95 wt%, from about 40 wt% to about 95 wt%, from about 50 wt% to about 95 wt%. About 60 wt% to about 95 wt%, about 70 wt% to about 95 wt%, about 80 wt% to about 95 wt%; about 0.01 wt% to about 85 wt%, about 0.1 wt% to about 85 wt%, about 1 wt% to about 85 wt%, about 5 wt% to about 85 wt%, about 10 wt% to about 85 wt%, about 15 wt% to about 85 wt%, about 20 wt% to about 85 wt%, about 30 wt% to about 85 wt%, about 40 wt% to about 85 wt%, about 50 wt% to about 85 wt%, about 60 wt% to about 85 wt%, about 70 wt% to about 85 wt%; about 0.01 wt% to about 75 wt%, about 0.1 wt% to about 75 wt%, about 1 wt% to about 7 5% by weight, about 5% by weight to about 75% by weight, about 10% by weight to about 75% by weight, about 15% by weight to about 75% by weight, about 20% by weight to about 75% by weight, about 30% by weight to about 75% by weight, about 40% by weight to about 75% by weight, about 50% by weight to about 75% by weight, about 60% by weight to about 75% by weight; about 0.01% by weight to about 65% by weight, about 0.1% by weight to about 65% by weight, about 1% by weight to about 65% by weight, about 5% by weight to about 65% by weight, about 10% by weight to about 65% by weight, about 15% by weight to about 65% by weight, about 20% by weight to about 65% by weight, about 30% by weight to about 65% by weight, about 40% by weight to about 65% by weight, about 50% by weight to About 65 wt%; about 0.01 wt% to about 55 wt%, about 0.1 wt% to about 55 wt%, about 1 wt% to about 55 wt%, about 5 wt% to about 55 wt%, about 10 wt% to about 55 wt%, about 15 wt% to about 55 wt%, about 20 wt% to about 55 wt%, about 30 wt% to about 55 wt%, about 40 wt% to about 55 wt%; about 0.01 wt% to about 45 wt%, about 0.1 wt% to about 45 wt%, about 1 wt% to about 45 wt%, about 5 wt% to about 45 wt%, about 10 wt% to about 45 wt%, about 15 wt% to about 45 wt%, about 20 wt% to about 45 wt%, about 30 wt% to about 45 wt%; about 0.0.01 wt% to about 35 wt%, about 0.1 wt% to about 35 wt%, about 1 wt% to about 35 wt%, about 5 wt% to about 35 wt%, about 10 wt% to about 35 wt%, about 15 wt% to about 35 wt%, about 20 wt% to about 35 wt%; about 0.01 wt% to about 25 wt%, about 0.1 wt% to about 25 wt%, about 1 wt% to about 25 wt%, about 5 wt% to about 25 wt%, about 10 wt% to about 25 wt%; about 0.1 wt% to about 15 wt%, about 1 wt% to about 15 wt%, about 5 wt% to about 15 wt%, about 10 wt% to about 15 wt%; about 0.01 wt% to about 25 wt%, about 0.1 wt% to about 10 wt%, about 1 wt% to about 10 wt%, or about 5 wt% to about 10 wt%, including its scope and subscopes, based on the total weight of the composition.

[0064] Alternatively or concurrently, the composition contains the cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, and cpd184 disclosed herein. The amount of one or more compounds with any of the following structures can be from about 0.01 wt% to about 95 wt%, from about 0.1 wt% to about 95 wt%, from about 1 wt% to about 95 wt%, from about 5 wt% to about 95 wt%, from about 10 wt% to about 95 wt%, from about 15 wt% to about 95 wt%, from about 20 wt% to about 95 wt%, from about 30 wt% to about 95 wt%, from about 40 wt% to about 95 wt%, from about 50 wt% to about 95 wt%, from about 60 wt% to about 95 wt%, from about 70 wt% to about 95 wt%. Approximately % to 95% by weight, approximately 80% by weight to 95% by weight; approximately 0.01% by weight to 85% by weight, approximately 0.1% by weight to 85% by weight, approximately 1% by weight to 85% by weight, approximately 5% by weight to 85% by weight, approximately 10% by weight to 85% by weight, approximately 15% by weight to 85% by weight, approximately 20% by weight to 85% by weight, approximately 30% by weight to 85% by weight, approximately 40% by weight to 85% by weight, approximately 50% by weight to 85% by weight, approximately 60% by weight to 85% by weight, approximately 70% by weight to 85% by weight; approximately 0.01% by weight to 75%, approximately 0.1% by weight to 75%, approximately 1% by weight to 75%, approximately 5% by weight to 75%, approximately 10% by weight to 75% by weight. %, about 15% to about 75%, about 20% to about 75% by weight, about 30% to about 75% by weight, about 40% to about 75% by weight, about 50% to about 75% by weight, about 60% to about 75% by weight; about 0.01% to about 65% by weight, about 0.1% to about 65% by weight, about 1% to about 65% by weight, about 5% to about 65% by weight, about 10% to about 65% by weight, about 15% to about 65% by weight, about 20% to about 65% by weight, about 30% to about 65% by weight, about 40% to about 65% by weight, about 50% to about 65% by weight; about 0.01% to about 55% by weight, about 0.1 wt% to about 55 wt%, about 1 wt% to about 55 wt%, about 5 wt% to about 55 wt%, about 10 wt% to about 55 wt%, about 15 wt% to about 55 wt%, about 20 wt% to about 55 wt%, about 30 wt% to about 55 wt%, about 40 wt% to about 55 wt%; about 0.01 wt% to about 45 wt%, about 0.1 wt% to about 45 wt%, about 1 wt% to about 45 wt%, about 5 wt% to about 45 wt%, about 10 wt% to about 45 wt%, about 15 wt% to about 45 wt%, about 20 wt% to about 45 wt%, about 30 wt% to about 45 wt%; about 0.01 wt% to about 35 wt%, about 0.1 wt% to about 35 wt%, about 1 wt% to about 35 wt% %, about 5% to about 35% by weight, about 10% to about 35% by weight, about 15% to about 35% by weight, about 20% to about 35% by weight; about 0.01% to about 25% by weight, about 0.1% to about 25% by weight, about 1% to about 25% by weight, about 5% to about 25% by weight, about 10% to about 25% by weight; about 0.1% to about 15% by weight, about 1% to about 15% by weight, about 5% to about 15% by weight, about 10% to about 15% by weight; about 0.01% to about 25% by weight, about 0.1% to about 10% by weight, about 1% to about 10% by weight, or about 5% to about 10% by weight, including the scope and subscopes thereof, based on the total weight of the composition.

[0065] Alternatively or concurrently, the composition may also contain other hair growth activators, or any combination thereof, in amounts of about 0.01 wt% to about 95 wt%, about 0.1 wt% to about 95 wt%, about 1 wt% to about 95 wt%, about 5 wt% to about 95 wt%, about 10 wt% to about 95 wt%, about 15 wt% to about 95 wt%, about 20 wt% to about 95 wt%, about 30 wt% to about 95 wt%, about 40 wt% to about 95 wt%, about 50 wt% to about 95 wt%, about 60 wt% to about 95 wt%, about 70 wt% to about 95 wt%, about 80 wt% to about 95 wt%; about 0.01 wt% to about 85 wt%. About 0.1 wt% to about 85 wt%, about 1 wt% to about 85 wt%, about 5 wt% to about 85 wt%, about 10 wt% to about 85 wt%, about 15 wt% to about 85 wt%, about 20 wt% to about 85 wt%, about 30 wt% to about 85 wt%, about 40 wt% to about 85 wt%, about 50 wt% to about 85 wt%, about 60 wt% to about 85 wt%, about 70 wt% to about 85 wt%; about 0.01 wt% to about 75 wt%, about 0.1 wt% to about 75 wt%, about 1 wt% to about 75 wt%, about 5 wt% to about 75 wt%, about 10 wt% to about 75 wt%, about 15 wt% to about 75 wt% %, about 20% by weight to about 75% by weight, about 30% by weight to about 75% by weight, about 40% by weight to about 75% by weight, about 50% by weight to about 75% by weight, about 60% by weight to about 75% by weight; about 0.01% by weight to about 65% by weight, about 0.1% by weight to about 65% by weight, about 1% by weight to about 65% by weight, about 5% by weight to about 65% by weight, about 10% by weight to about 65% by weight, about 15% by weight to about 65% by weight, about 20% by weight to about 65% by weight, about 30% by weight to about 65% by weight, about 40% by weight to about 65% by weight, about 50% by weight to about 65% by weight; about 0.01% by weight to about 55% by weight, about 0.1% by weight From about 55 wt%, about 1 wt% to about 55 wt%, about 5 wt% to about 55 wt%, about 10 wt% to about 55 wt%, about 15 wt% to about 55 wt%, about 20 wt% to about 55 wt%, about 30 wt% to about 55 wt%, about 40 wt% to about 55 wt%; from about 0.01 wt% to about 45 wt%, about 0.1 wt% to about 45 wt%, about 1 wt% to about 45 wt%, about 5 wt% to about 45 wt%, about 10 wt% to about 45 wt%, about 15 wt% to about 45 wt%, about 20 wt% to about 45 wt%, about 30 wt% to about 45 wt%; from about 0.01 wt% to about 35 wt%, about 0.1 wt% to about 35 wt%, about 1 wt% to about 35 wt%, about 5 wt% to about 35 wt%, about 10 wt% to about 35 wt%, about 15 wt% to about 35 wt%, about 20 wt% to about 35 wt%; about 0.01 wt% to about 25 wt%, about 0.1 wt% to about 25 wt%, about 1 wt% to about 25 wt%, about 5 wt% to about 25 wt%, about 10 wt% to about 25 wt%; about 0.01 wt% to about 15 wt%, about 0.1 wt% to about 15 wt%, about 1 wt% to about 15 wt%, about 5 wt% to about 15 wt%, about 10 wt% to about 15 wt%; about 0.01 wt% to about 10 wt%, about 0.1 wt% to about 10 wt%, about 1 wt% to about 10 wt%, or about 5 wt% to about 10 wt%, including its scope and subscopes, based on the total weight of the composition.

[0066] Alternatively or additionally, the composition may comprise a mixture of compounds of formula (I), (II), (II'), (III) and / or (IV) (including, but not limited to, compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA) and (IVB), and / or another active agent in combination. The weight ratio of different active ingredients in the formulation may be 1:100 to 100:1, 1:50 to 50:1, 1:20 to 20:1, 1:10 to 10:1, 1:9 to 10:1, 1:8 to 10:1, 1:7 to 10:1, 1:6 to 10:1, 1:5 to 10:1, 1:4 to 10:1, 1:3 to 10:1, 1:2 to 10:1, 1:1 to 10:1, 1:10 to 9:1, 1:10 to 8:1, 1:10 to 7:1, 1:10 to 6:1, 1:10 to 5:1, 1:10 to 4:1, 1:10 to 3:1, 1:10 to 2:1, or 1:10 to 1:1, including the range and sub-ranges. In one embodiment, the compound of formula (I), formula (II) or formula (III) is used in a weight ratio of about 1:10 to 10:1, 1:9 to 10:1, 1:8 to 10:1, 1:7 to 10:1, 1:6 to 10:1, 1:5 to 10:1, 1:4 to 10:1, 1:3 to 10:1, 1:2 to 10:1, 1:1 to 10:1, 1:10 to 9:1, 1:10 to 8:1, 1:10 to 7:1, 1:10 to 6:1, 1:10 to 5:1, 1:10 to 4:1, 1:10 to 3:1, 1:10 to 2:1, or 1:10 to 1:1, including the range and subranges thereof.

[0067] Alternatively or concurrently, the composition may comprise cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, and cpd7 33. A mixture of one or more compounds with the structure of any of the following compounds: cpd755, cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152, and / or another active agent in combination. The weight ratio of different active agents in the formulation may range from 1:100 to 100:1, 1:50 to 50:1, 1:20 to 20:1, 1:10 to 10:1, 1:9 to 10:1, 1:8 to 10:1, 1:7 to 10:1, 1:6 to 10:1, 1:5 to 10:1, 1:4 to 10:1, 1:3 to 10:1, 1:2 to 10:1, 1:1 to 10:1, 1:10 to 9:1, 1:10 to 8:1, 1:10 to 7:1, 1:10 to 6:1, 1:10 to 5:1, 1:10 to 4:1, 1:10 to 3:1, 1:10 to 2:1, or 1:10 to 1:1, including the range and sub-ranges. In one embodiment, the compound of formula (I), formula (II) or formula (III) is used in a weight ratio of about 1:10 to 10:1, 1:9 to 10:1, 1:8 to 10:1, 1:7 to 10:1, 1:6 to 10:1, 1:5 to 10:1, 1:4 to 10:1, 1:3 to 10:1, 1:2 to 10:1, 1:1 to 10:1, 1:10 to 9:1, 1:10 to 8:1, 1:10 to 7:1, 1:10 to 6:1, 1:10 to 5:1, 1:10 to 4:1, 1:10 to 3:1, 1:10 to 2:1, or 1:10 to 1:1, including the range and subranges thereof.

[0068] The pharmaceutical composition or dosage form can be formulated and administered to a subject through a variety of different routes and methods. For example, the composition can be administered or delivered systemically or locally. Local delivery includes, but is not limited to, topical application, percutaneous, epidermal, scalp, or follicular delivery. The pharmaceutical composition or dosage form may, as needed, contain conventional, non-toxic, and pharmaceutically acceptable adjuvants, carriers, excipients, and solvents. In one aspect, the therapeutically effective amount of the compound may be about 0.5 mcg to about 200 mg, about 1 mcg to about 180 mg, about 5 mcg to about 150 mg, or about 10 mcg to about 120 mg. The therapeutically effective amount may be about 0.5 mcg / day to about 100 mg / day, about 1 mcg to about 60 mg / day, about 20 mcg to about 50 mg / day, about 20 mcg to about 30 mg / day, or about 15 mcg to about 25 mg / day. Administration of this composition or dosage form may result in blood concentrations of approximately 1 ng / ml, approximately 2 ng / ml, approximately 4 ng / ml, approximately 5 ng / ml, approximately 6 ng / ml, approximately 8 ng / ml, approximately 10 ng / ml, approximately 12 ng / ml, approximately 15 ng / ml, approximately 20 ng / ml, approximately 22 ng / ml, approximately 24 ng / ml, approximately 26 ng / ml, approximately 28 ng / ml, approximately 30 ng / ml, approximately 32 ng / ml, approximately 34 ng / ml, approximately 36 ng / ml, approximately 38 ng / ml, approximately 40 ng / ml, approximately 42 ng / ml, approximately 44 ng / ml, approximately 46 ng / ml, approximately 48 ng / ml, or approximately 50 ng / ml.

[0069] In another aspect, the pharmaceutical composition or dosage form may be administered to the subject daily or multiple times daily. For example, the composition may be administered once, twice, or three times daily. The duration of each administration may be as short as a few seconds. Furthermore, the composition or dosage form may be administered every 2, 3, 4, 5, 6, 7, 14, or 30 days. Such treatment regimens may be modified and adjusted according to the individual needs and responsiveness of the subject. The pharmaceutical composition may be administered for approximately 1 day to approximately 1 year, approximately 1 day to approximately 1 week, approximately 3 days to approximately 1 month, approximately 2 weeks to approximately 6 months, or approximately 2 months to approximately 4 months. The pharmaceutical composition may also be administered for approximately 1 day, approximately 7 days, approximately 30 days, approximately 60 days, approximately 120 days, or approximately 180 days and beyond. In some aspects, the composition may be administered long-term, such as approximately 24 weeks, approximately 48 weeks, approximately 60 weeks, approximately 148 weeks, approximately 208 weeks, indefinitely, or until the treated condition resolves.

[0070] A pharmaceutical formulation comprises one or more pharmaceutically acceptable excipients. Non-limiting examples of excipients include chemical enhancers, humectants, pressure-sensitive binders, antioxidants, solubilizers, thickeners, plasticizers, adjuvants, carriers, excipients, solvents, coating agents, and any combinations thereof. One or more excipients may be selected for oral, dermal, parenteral, intraperitoneal, intravascular, subcutaneous, inhalation spray, rectal, or intrapulmonary administration.

[0071] Sustained-release formulations can be used to deliver drugs substantially continuously at a preselected rate. For example, compounds of formulas (I), (II), (II'), (III) and / or (IV) (including, but not limited to, compounds of formulas (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB)) can be delivered at rates of about 1 mg to about 100 mg / day, about 40 to about 60 mg / day, or about 10 to about 30 mg / day. Another example has the cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, and cpd75 disclosed herein. 8. A compound with the structure of any of the compounds selected from CPD795, CPD900, CPD935, CPD983, CPD1107, CPD1255, CPD1744, CPD1840, CPD1886, CPD2052, CPD2056, CPD2062, CPD2078, CPD2125, and CPD2152, with a delivery rate of about 1 mg to about 100 mg / day, about 40 mg to about 60 mg / day, or about 10 mg to about 30 mg / day. Those skilled in the art can readily determine the appropriate dosage of this composition based on various factors, such as the expected duration of administration of the active ingredient in the sustained-release formulation, the delivery mechanism, the specific formulation, and the relative potency of the drug.

[0072] adhesives Non-limiting examples of binders suitable for formulations in various applications include starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethyl cellulose, ethylcellulose, polyacrylamide, polyvinyloxazolidinone, polyvinyl alcohol, C12-C18 fatty alcohols, polyethylene glycol, polyols, sugars, oligosaccharides, polypeptides, oligopeptides, and combinations thereof. The polypeptides may be any amino acid sequence with a molecular weight ranging from about 100 to about 300,000 Daltons.

[0073] The binder may be added to the mixture to be granulated in solid form (including, but not limited to, crystals, particles, powders, or any other finely dispersed solid form known in the art). Alternatively, the binder may be dissolved or suspended in a solvent and sprayed as a binder fluid onto the mixture in the granulation apparatus during the granulation process.

[0074] diluent Non-limiting examples of diluents (also known as “fillers” or “enrichers”) include carbohydrates, inorganic compounds, and biocompatible polymers such as polyvinylpyrrolidone (PVP). Other non-limiting examples of diluents include calcium sulfate dihydrate, calcium sulfate trihydrate, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starch, sugars (such as sucrose, glucose, lactose, microcrystalline cellulose, fructose, xylitol, and sorbitol), polyols; starch; pre-prepared direct compression diluents; and mixtures of any of the above substances.

[0075] Disintegrant Disintegrants can be effervescent or non-effervescent. Non-limiting examples of non-effervescent disintegrants include starches (such as corn starch, potato starch, pregelatinized starch, and modified starches), sweeteners, clays (such as bentonite), microcrystalline cellulose, alginates, sodium carboxymethyl starch, and gums (such as agar, guar gum, locust bean gum, karaya gum, pectin, and tragacanth). Suitable effervescent disintegrants include, but are not limited to, combinations of sodium bicarbonate and citric acid, and combinations of sodium bicarbonate and tartaric acid.

[0076] preservative Non-limiting examples of preservatives include, but are not limited to: ascorbic acid and its salts, ascorbyl palmitate, ascorbyl stearate, anoxomer, N-acetylcysteine, benzyl isothiocyanate, m-aminobenzoic acid, anthranilic acid, para-aminobenzoic acid (PABA), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), caffeic acid, canthaxanthin, α-carotene, β-carotene. Apocarboxylic acid, caryophyllene, carvacrol, catechins, hexadecyl gallate, chlorogenic acid, citric acid and its salts, clove extract, coffee bean extract, p-coumaric acid, 3,4-dihydroxybenzoic acid, N,N'-diphenyl-p-phenylenediamine (DPPD), dilaurate thiodipropionate, distearate thiodipropionate, 2,6-di-tert-butylphenol, dodecyl gallate, edetate, ellagic acid, isoascorbic acid, sodium ascorbate, aescin, aescin, 6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline, ethyl gallate, ethyl maltol, ethylenediaminetetraacetic acid (EDTA), eucalyptus extract, eugenol, ferulic acid, flavonoids (e.g., catechins) Epigallocatechin, Epigallocatechin Gallate, Epigallocatechin (EGC), Epigallocatechin Gallate (EGCG), Polyphenols Epigallocatechin-3-Gallate, Flavonoids (e.g., apigenin, apigenin, luteolin), Flavonols (e.g., acornitin, myricetin, daemfero), Flavanones, Fraxinus, Fumaric acid, Gallic acid, Gentian extract, Gluconic acid, Glycine, Guaiacin, Hesperidin, α-hydroxybenzylphosphonic acid, Hydroxycinnamic acid, Hydroxyglutaric acid, Hydroquinone, N-hydroxysuccinic acid, Hydroxytyrosol, Hydroxyurea, Rice bran extract, Lactic acid and its salts, Lecithin, Lecithin citrate; R-α-lipoic acid, lutein, lycopene, malic acid, maltol, 5-methoxytryptamine, methyl gallate, monoglyceride citrate; monoisopropyl citrate;Mulberry pigment, β-naphthylflavonoid, nordihydroguaiac acid (NDGA), octyl gallate, oxalic acid, palmitate citrate, phenothiazine, phosphatidylcholine, phosphoric acid, phosphate, phytic acid, phytylubichromel, allspice extract, propyl gallate, polyphosphate, quercetin, trans-resveratrol, rosemary extract, rosmarinic acid, sage extract, sesamol, silymarin, sinapic acid, succinic acid, stearate citrate, eugenol, tartaric acid, thymol, tocopherols (i.e., α-, β-, γ-, and δ-tocopherols), tocotrienols (i.e., α-, β-, γ-, and δ-tocotrienols), tyrosol, vanillic acid, 2,6-di-tert-butyl-4-hydroxymethylphenol (i.e., Ionox) 100), 2,4-(tri-3',5'-di-tert-butyl-4'-hydroxybenzyl)-trimethylbenzene (i.e., Ionox 330), 2,4,5-trihydroxybutyrophenone, ubiquinone, tert-butylhydroquinone (TBHQ), thiodipropionic acid, trihydroxybutyrophenone, tryptophan, tyramine, uric acid, vitamin K and its derivatives, vitamin Q10, wheat germ oil, zeaxanthin, or combinations thereof.

[0077] Flavor modifiers Suitable flavor modifiers include spices, masking agents, sweeteners, etc. Spices include, but are not limited to, synthetic flavor oils and flavoring spices and / or natural oils, plant, leaf, flower, and fruit extracts, and combinations thereof. Other non-limiting examples of flavor agents include cinnamon oil, wintergreen oil, peppermint oil, clover oil, hay oil, fennel oil, eucalyptus oil, vanilla oil, citrus oils (such as lemon oil, orange oil, grape oil, and grapefruit oil), and fruit flavorings (including apple, peach, pear, strawberry, raspberry, cherry, plum, pineapple, and apricot).

[0078] Flavor masking agents include, but are not limited to, hydroxypropyl cellulose ethers (HPC), such as Klucel®, Nisswo HPC, and PrimaFlo HP22; low-substituted hydroxypropyl cellulose ethers (L-HPC); hydroxypropyl methylcellulose ethers (HPMC), such as Seppifilm-LC, Pharmacoat®, Metalose SR, Opadry YS, PrimaFlo, MP3295A, Benecel MP824, and Benecel MP843; methylcellulose polymers, such as Methocel® and Metalose®; ethyl cellulose (EC) and mixtures thereof, such as E461, Ethocel®, Aqualon®-EC, and Surelease; polyvinyl alcohol (PVA), such as Opadry AMB; hydroxyethyl cellulose, such as Natrosol®; carboxymethyl cellulose and salts of carboxymethyl cellulose (CMC), such as Aualon®-CMC; and copolymers of polyvinyl alcohol and polyethylene glycol, such as Kollicoat. IR®; monoglycerides (Myverol), triglycerides (KLX), polyethylene glycol, modified food starch, acrylic polymers, and mixtures of acrylic polymers with cellulose ethers, such as Eudragit® EPO, Eudragit® RD100, and Eudragit® E100; cellulose acetate phthalate; Sepifilm (e.g., a mixture of HPMC and stearic acid), cyclodextrin, and mixtures of these materials. In other respects, other flavor masking agents considered include those described in U.S. Patents 4,851,226, 5,075,114, and 5,876,759, the entire contents of which are incorporated herein by reference.

[0079] Non-limiting examples of sweeteners include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts (such as sodium salts); dipeptide sweeteners (such as aspartame); dihydrochalcone compounds, glycyrrhizin; stevia (steviosides); chlorinated derivatives of sucrose, such as sucralose; sugar alcohols, such as sorbitol, mannitol, xylitol, hydrogenated starch hydrolysate; and synthetic sweetener 3,6-dihydro-6-methyl-1,2,3-oxathiazin-4-one-2,2-dioxide, particularly its potassium salt (acesulfame K) and its sodium and calcium salts.

[0080] Lubricants and flow aids Lubricant compositions can be used to lubricate components forming a pharmaceutical composition. As a flow aid, the lubricant helps remove solid dosage forms during manufacturing. Non-limiting examples of lubricants and flow aids include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, Sterotex, polyoxyethylene monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oils. Pharmaceutical compositions typically contain about 0.01% to about 10% (by weight) of lubricant. In some embodiments, the pharmaceutical composition contains about 0.1% by weight to about 5% by weight of lubricant. In another embodiment, the pharmaceutical composition may contain about 0.5% by weight to about 2% by weight of lubricant.

[0081] dispersant Dispersants may include, but are not limited to, starch, alginate, polyvinylpyrrolidone, guar gum, kaolin, bentonite, purified lignocellulose, sodium carboxymethyl starch, isoamorphous silicate, and microcrystalline cellulose as a high hydrophilic-lipophilic balance (HLB) emulsifying surfactant.

[0082] Colorant Coloring agents may be required depending on various aspects of this disclosure. Suitable coloring additives include, but are not limited to, food, pharmaceutical and cosmetic pigments (FD&C), pharmaceutical and cosmetic pigments (D&C), or topical pharmaceutical and cosmetic pigments (Ext. D&C). These pigments or dyes, and their corresponding lakes, as well as certain natural and derived colorants, may be used in various aspects of this disclosure.

[0083] pH adjuster Non-limiting examples of pH adjusters include citric acid, acetic acid, tartaric acid, malic acid, fumaric acid, lactic acid, phosphoric acid, sorbic acid, benzoic acid, sodium carbonate, and sodium bicarbonate.

[0084] Chelating agents Chelating agents can be added as excipients to immobilize oxidizing groups (including but not limited to metal ions), thereby inhibiting the oxidative degradation of morphine by these oxidizing groups. Non-limiting examples of chelating agents include lysine, methionine, glycine, gluconate, polysaccharides, glutamic acid, aspartic acid, and disodium ethylenediaminetetraacetate (Na2EDTA).

[0085] antimicrobial agents Antimicrobial agents may be added as excipients to minimize degradation of the compounds disclosed herein by microorganisms (including, but not limited to, bacteria and fungi). Non-limiting examples of antimicrobial agents include parabens, chlorobutanol, phenol, calcium propionate, sodium nitrate, sodium nitrite, Na2EDTA, and sulfites (including, but not limited to, sulfur dioxide, sodium bisulfite, and potassium bisulfite).

[0086] Controlled-release polymers Controlled-release polymers can be added to various aspects of solid dosage form pharmaceutical compositions comprising compounds of this disclosure. In one aspect, the controlled-release polymer can be used as a tablet coating. In other aspects, including but not limited to bilayer tablets, the controlled-release polymer can be mixed with granules and other excipients prior to tablet formation by known processes, including but not limited to compression in a tableting mold. Suitable controlled-release polymers include, but are not limited to, hydrophilic and hydrophobic polymers.

[0087] Suitable hydrophilic controlled-release polymers include, but are not limited to: cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose ethers, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, nitrocellulose, cross-linked starch, agar, casein, chitosan, collagen, gelatin, maltose, mannitol, maltodextrin, pectin, pullulan, sorbitol, xylitol, polysaccharides, ammonium alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carrageenan, fucoidan, red algae gum, gum arabic, carrageenan, gum indica, guar gum, kalachaline gum, and tamarind gum. Okra gum, tragacanth gum, stearin gum, xanthan gum, kelp polysaccharide, acrylic polymers, acrylate polymers, carboxyvinyl polymers, maleic anhydride-styrene copolymers, maleic anhydride-ethylene copolymers, maleic anhydride-propylene copolymers or maleic anhydride-isobutylene copolymers, crosslinked polyvinyl alcohol and poly-N-vinyl-2-pyrrolidone, polydextrose diester, polyacrylamide, polyacrylic acid, polyamide, polyethylene glycol, polyethylene oxide, poly(hydroxyalkyl methacrylate), polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polystyrene, polyvinylpyrrolidone, anionic and cationic hydrogels, and combinations thereof.

[0088] Coating Solid dosage forms containing compounds of this disclosure may include a coating that controls the release of the compound, acts as a moisture barrier, or buffers or regulates pH. As used herein, “controlled-release coating” or “release-controlled coating” is defined as a functional coating that may, for example, contain at least one pH-independent polymer, a pH-dependent polymer (e.g., enteric or anti-enteric polymer), a soluble polymer, an insoluble polymer, a lipid, a lipid material, or a combination thereof. When the coating is applied to a dosage form, it may slow (e.g., when applied to a conventional release matrix dosage form), further slow (e.g., when applied to a controlled-release matrix dosage form), or regulate the release rate of the compound of this disclosure compared to an uncoated dosage form. For example, a controlled-release coating may be designed such that, when applied to a dosage form, the dosage form, in combination with the controlled-release coating, exhibits the release characteristics of the compound of this disclosure, such as “modified release,” “controlled release,” “sustained release,” “extended release,” “delayed release,” “persistent release,” or a combination thereof. The “controlled-release coating” may optionally include additional materials that may alter its function.

[0089] As used herein, the term "moisture barrier" refers to a layer that prevents or delays the absorption of moisture. The compounds according to this disclosure may be hygroscopic and therefore may readily decompose over time under high humidity conditions. The component ratios of the moisture barrier and the amount optionally applied to the controlled-release coating or tablet core are typically set such that the moisture barrier does not fall under the definition and requirements of the USP for enteric coatings. Suitablely, the moisture barrier may contain enteric and / or acrylic polymers (suitably acrylic polymers), optional plasticizers, and penetration enhancers. Penetration enhancers are hydrophilic substances that allow moisture to penetrate without disrupting the physical structure of the coating. The moisture barrier may also contain other conventional inert excipients that improve the processability of the sustained-release formulation.

[0090] The coating and matrix materials that can be used according to this disclosure are materials known in the art for controlled-release formulations, such as polyvinyl-based synthetic polymers, such as polyvinyl chloride, polyvinyl acetate and its copolymers, polyvinyl alcohol and polyvinylpyrrolidone; polyethylene-based synthetic polymers, such as polyethylene and polystyrene; acrylic polymers; biopolymers or modified biopolymers, such as cellulose polymers, shellac and gelatin; fats, oils, higher fatty acids and higher alcohols (i.e. acids and alcohols containing alkyl chains of at least 10 carbon atoms), such as aluminum monostearate, cetyl alcohol, hydrogenated tallow, hydrogenated castor oil, 12-hydroxystearyl alcohol, glyceryl mono- or dipalmitate; glyceryl mono, di, or tristearate; myristyl alcohol, stearic acid, stearyl alcohol and polyethylene glycol; waxes; sugars and sugar alcohols.

[0091] The pH buffering properties of the coating can be enhanced by introducing compounds selected from those commonly used in antacids, such as magnesium oxide, magnesium hydroxide or magnesium carbonate, aluminum hydroxide or calcium hydroxide, aluminum carbonate or aluminum silicate; complex aluminum / magnesium compounds, such as Al₂O₃·6MgO·CO₂·12H₂O, (Mg₆Al₂(OH)₂) 16 (CO3·4H2O), MgO·Al2O3·2SiO2·nH2O, aluminum bicarbonate coprecipitates or similar compounds; or other pharmaceutically acceptable pH buffering compounds, such as sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; or suitable organic bases, including basic amino acids; and their salts or combinations thereof.

[0092] pH-dependent coatings are used to release drugs in desired areas of the gastrointestinal tract (GI), such as the stomach or small intestine. When pH-independent coatings are required, the coating is designed to achieve optimal release regardless of changes in the pH of the surrounding fluid, such as the gastrointestinal tract. When a coating is formulated to release the compounds disclosed herein in the intestine, particularly the upper small intestine, it is often referred to as an "enteric coating." pH-dependent coatings may include, but are not limited to, acrylic polymers and copolymers, such as polymers formed from acrylic acid, methacrylic acid, methyl acrylate, aminomethyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate (e.g., Eudragit™); cellulose polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate (CAP), cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose succinate, and sodium carboxymethyl cellulose; shellac (refined shellac); vinyl polymers and copolymers, such as polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate (PVAP), vinyl acetate-crotonic acid copolymer, and ethylene-vinyl acetate copolymer; zein; and salts and compositions thereof.

[0093] Nanoparticles The composition or dosage form may comprise nanoparticles, each nanoparticle comprising a carrier entity and at least one active agent distributed on the outer surface of the nanoparticle, and the nanoparticle being capable of binding to a predetermined epitope in vivo. In another aspect, the present invention provides a nanoparticle composition comprising nanoparticles, wherein each nanoparticle comprises at least one active agent distributed on the surface of the nanoparticle such that binding to a subject's receptor or cell is oriented outward from the surface, and the nanoparticle is capable of binding to a predetermined epitope in vivo. In other embodiments, the nanoparticles may polymerize, for example, dimerize. Polymerization may manifest as a multiple of unit molecular weight or size; for example, a 160 nm particle may polymerize to about 320 nm, 480 nm, 640 nm, etc. In some embodiments, less than 20% of the population is polymeric. In some embodiments, more than 80% of the population is polymeric.

[0094] Liposomes In an alternative embodiment, liposomes can be used as delivery carriers. Depending on their structure and chemical properties, liposomes can be used to deliver compounds of formulas (I), (II), and (III) (including, but not limited to, compounds of formulas (IA), (IB), (IIA), (IIB), (IIIA), (IIIB), and (IIIC)), their pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs. Typically, liposomes are spherical vesicles with a phospholipid bilayer membrane. The lipid bilayer of a liposome can fuse with other bilayers (e.g., cell membranes) to deliver the contents of the liposome into the cell.

[0095] Liposomes can be composed of various types of phospholipids with different hydrocarbon chain lengths. Phospholipids typically consist of two fatty acids linked by glycerophosphate to one of several polar groups. Suitable phospholipids include phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylcholine (PC), and phosphatidylethanolamine (PE). The fatty acid chain length of phospholipids can range from about 6 to about 26 carbon atoms, and the lipid chain can be saturated or unsaturated. Suitable fatty acid chains include (common names in parentheses): dodecanoate (laurate), tetradecanoate (myristate), hexadecanoate (palmitate), octadecanoate (stearate), eicosanoate (arachidate), dodecanoate (behenate), docosanoate (creosote), cis-9-hexadecenoate (palmitoleate), cis-9-octadecanoate (oleate), cis,cis-9,12-octadecadienoate (linoleate), all-cis-9,12,15-octadecanetrienoate (linolenic acid), and all-cis-5,8,11,14-eicosatetraenoate (arachidonic acid). The two fatty acid chains of phospholipids can be the same or different. Acceptable phospholipids include dioleoyl PS, dioleoyl PC, distearyl PS, distearyl PC, dimyristic PS, dimyristic PC, dipalmitoyl PG, stearoyl-oleoyl PS, palmitoyl-linoleoyl PS, etc.

[0096] Phospholipids can be derived from any natural source, and therefore mixtures of phospholipids can be included. For example, egg yolks are rich in PC, PG, and PE; soybeans contain PC, PE, PI, and PA; and animal brains or spinal cords are rich in PS. Phospholipids can also be derived from synthetic sources. Mixtures of phospholipids with different proportions of individual phospholipids can be used. Mixtures of different phospholipids can be used to prepare liposome compositions with excellent activity or activity stability properties. The above-mentioned phospholipids can be mixed with cationic lipids in optimal proportions, such as N-(1-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride, 1,1'-bis(octadecyl-3,3,3',3'-tetramethylindole carbocyanine perchlorate, 3,3'-diheptyloxacarbocyanine iodide, 1,1'-bis(dodecyl-3,3,3',3'-tetramethylindole carbocyanine perchlorate, 1,1'-dioleoyl-3,3,3',3'-tetramethylindole carbocyanine methanesulfonate, N-4-(dilinoleoylaminostyryl)-N-methylpyridine iodide, or 1,1'-dilinoleoyl-3,3,3',3'-tetramethylindole carbocyanine perchlorate.

[0097] Liposomes may optionally contain sphingolipids, wherein sphingosine is the structural counterpart of glycerol and also the counterpart of a fatty acid in phosphatidylglycerol; or cholesterol (i.e., a major component of animal cell membranes). Liposomes may optionally contain PEGylated lipids, i.e., lipids covalently bonded to polyethylene glycol (PEG). The molecular weight of PEG ranges from approximately 500 to 10,000 Daltons.

[0098] Liposomes may also contain a suitable solvent. This solvent may be an organic or inorganic solvent. Suitable solvents include, but are not limited to, dimethyl sulfoxide (DMSO), methylpyrrolidone, N-methylpyrrolidone, acetonitrile, alcohols, dimethylformamide, tetrahydrofuran, or combinations thereof.

[0099] lotion The pharmaceutical composition and dosage form can be formulated as part of a microemulsion. A microemulsion is typically a clear and thermodynamically stable solution comprising an aqueous solution, a surfactant, and an "oil." Here, the "oil" is a supercritical fluid phase. The surfactant is located at the oil-water interface. A variety of surfactants are suitable for microemulsion formulations, including those described herein or others known in the art. The aqueous microdomains suitable for use according to this disclosure typically have a characteristic structural size of about 5 nm to about 100 nm. Aggregates of this size have poor scattering ability for visible light, thus these solutions are optically clear. Those skilled in the art will understand that microemulsions can and will have a variety of different microstructures, including spherical, rod-shaped, or disc-shaped aggregates. In one embodiment, the structure can be micelles, the simplest microemulsion structure, typically spherical or cylindrical. Micelles are analogous to oil droplets in water, while anti-micelles are analogous to water droplets in oil. In another embodiment, the microemulsion structure is a layered structure comprising continuous layers of water and oil separated by layers of surfactant. The "oil" in the microemulsion preferably comprises phospholipids.

[0100] Any phospholipids detailed above for liposomes are applicable to embodiments involving microemulsions. Compositions comprising at least one antitumor therapeutic derivative may be encapsulated in microemulsions using methods known in the art.

[0101] In another embodiment, a composition comprising a compound of formula (I), formula (II), formula (II'), formula (III) and / or formula (IV) (including, but not limited to, compounds of formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA) and (IVB)), or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate or prodrug thereof, may be delivered in a dendritic macromolecule or dendritic polymer. In another embodiment, it includes cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, cpd758, c as disclosed herein. One or more compounds, or compositions of any of the compounds in the order Pd795, CPD900, CPD935, CPD983, CPD1107, CPD1255, CPD1744, CPD1840, CPD1886, CPD2052, CPD2056, CPD2062, CPD2078, CPD2125, and CPD2152, or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs, may be delivered in dendritic macromolecules or dendritic polymers. Typically, a dendritic polymer is a branching, tree-like molecule in which each branch is an interconnected chain of molecules that splits into two new branches (molecules) after reaching a certain length. This branching continues until the branches (molecules) become so dense that the canopy forms a sphere. Typically, the properties of dendritic polymers are determined by the functional groups on their surface. For example, hydrophilic end groups (such as carboxyl groups) often form water-soluble dendritic polymers. Alternatively, phospholipids can be introduced onto the surface of the dendritic polymer to facilitate transdermal absorption. Any phospholipids described above for use in the liposome embodiments are applicable to the dendritic polymer embodiments. Dendritic polymers can be prepared and encapsulated with compositions disclosed herein using any method known in the art. For example, dendritic polymers can be prepared via a series of iterative reaction steps, where each iteration yields a higher-order dendritic polymer. Therefore, they have a regular, highly branched 3D structure and are nearly uniform in size and shape. Furthermore, the final size of the dendritic polymer is typically controlled by the number of iterative steps used in the synthesis process. According to this disclosure, dendritic polymers of various sizes are suitable for use. Typically, the size range of dendritic polymers is from about 1 nm to about 100 nm.

[0102] Dosage form One aspect of this disclosure covers compounds comprising formula (I), formula (II), formula (II'), and formula (III) (including, but not limited to, compounds comprising formula (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), and (IIIC)), or pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof.

[0103] Another aspect of this disclosure covers the inclusion of cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, and cpd7... 55. One or more compounds with the structure of any one of the following compounds: cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152, or dosage forms of pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs thereof.

[0104] The dosage form may contain about 1 microgram to about 50 grams, about 1 mcg to about 5,000 mg, about 1 mcg to about 1,000 mg, about 1 mcg to about 500 mg, about 50 mcg to about 400 mg, about 75 mcg to about 150 mg, about 150 mcg to about 200 mg, about 40 mcg to about 150 mg, about 80 mcg to about 120 mg, or about 180 mcg to about 100 mg of a compound. For example, the dosage form may contain 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, or 300 mcg or more of a compound. In some respects, the dosage form may contain about 1 mcg to about 500 mg, about 1 mcg to about 400 mg, about 1 mcg to about 300 mg, about 1 mcg to about 250 mg, about 1 mcg to about 200 mg, about 1 mcg to about 150 mg, or about 1 mcg to about 100 mg of the compound.

[0105] Dosage forms include those formulated for prolonged or slow release, and those formulated for immediate release. For example, immediate-release dosage forms may contain crystalline or polymorphic forms of the compound. For example, oral instant dissolvers may contain, for example, hydrochloride salts.

[0106] Dosage forms also include those formulated for topical administration. In one aspect, such topical administration is intended to deliver a drug to the scalp, skin, and / or hair fibers or follicles. For example, the dosage form may be formulated as one or more of the following forms: gel, ointment, emulsion, microemulsion, lipid, liposome, nanocapsule, solution, suspension, paste, gel, foam, spray, lotion, or cream. In one aspect, the topical administration dosage form is a transdermal patch. When the dosage form is formulated as a transdermal patch, the transdermal patch may contain about 40 micrograms to about 60 milligrams, about 80 micrograms to about 50 milligrams, or about 180 micrograms to about 40 milligrams of a compound in crystalline form.

[0107] In addition, the dosage form can also be formulated for oral administration. Dosage forms formulated for oral administration can be tablets, capsules and chewable capsules, powders, granules, teas, drops, or liquid medications and syrups that can be swallowed, chewed, dissolved in water, or placed under the tongue. In some respects, the dosage form is an enteric-coated oral preparation.

[0108] When the dosage form is an enteric-coated oral formulation, the formulation may contain about 0.1 mcg to about 60 mg of the compound. Enteric-coated oral formulations may also contain the compound in crystalline form or a salt thereof. The salt may be a fumarate, sulfate, methanesulfonate, dihydrophosphate, ethanedisulfonate, benzoate, hydrochloride, or oxalate.

[0109] Dosage forms also include those formulated for subcutaneous and / or intramuscular injection. For example, an intramuscular injection dosage form may comprise a compound in crystalline form dissolved in an oily matrix for intramuscular injection, or separately prepared as a suspension for intramuscular injection. Dosage forms for subcutaneous or intramuscular injection may comprise the compound in salt or crystalline form as disclosed herein, and prepared into microspheres using methods known in the art. Alternatively, the compound or its salt form may be coated, for example using atomic layer deposition (ALD) techniques, with a thin coating such as zinc oxide coating, and used in subcutaneous or intramuscular injection formulations. Alternatively, the compound may be dissolved in a biodegradable polymer matrix and subsequently implanted subcutaneously (or used in transdermal patches, as described in detail below).

[0110] Reagent test kit Another aspect of this disclosure provides a kit comprising a compound, a composition thereof, or a dosage form thereof for use in the methods of this disclosure. The kit may comprise a container for containing a compound comprising formula (I), formula (II), formula (II'), formula (III), or formula (IV) (including, but not limited to, compounds of formulas (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), and (IVB)), or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, or prodrug thereof, and instructions for use. This kit may include containers for containing cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, and cpd755, as disclosed herein. The kit contains one or more compounds with the structure of any one of the compounds listed in this disclosure, including CPD758, CPD795, CPD900, CPD935, CPD983, CPD1107, CPD1255, CPD1744, CPD1840, CPD1886, CPD2052, CPD2056, CPD2062, CPD2078, CPD2125, and CPD2152, or compositions of their pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs, along with instructions for use. The kit typically includes instructions for use in performing the methods described in detail in this disclosure. These instructions may be attached to packaging material or included as a package insert. While instructions are typically written or printed, they are not limited to this. This disclosure covers any medium capable of storing and communicating such instructions to the end user. Such media include, but are not limited to, electronic storage media (e.g., disks, magnetic tapes, tape cartridges, chips), optical disc media (e.g., CD-ROMs), etc. As used herein, the term “instruction manual” may include the address of the internet website where the instruction manual is provided.

[0111] definition Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which this disclosure pertains. The following references provide general definitions for many terms used herein: Singleton et al., *Dictionary of Microbiology and Molecular Biology* (2nd edition, 1994); *Cambridge Dictionary of Science and Technology* (Walker, ed., 1988); *Glossary of Genetics* (5th edition, R. Rieger et al., eds., Springer Verlag, 1991); and Hale & Marham, *HarperCollins Dictionary of Biology* (1991). As used herein, unless otherwise stated, the following terms have the meanings assigned to them.

[0112] In describing elements of this disclosure or its preferred aspects, the indefinite and definite articles and the word "described" indicate the presence of one or more of such elements. The terms "comprising," "including," and "having" are inclusive, meaning that other elements may exist in addition to those listed.

[0113] The term "comprising" means "including but not limited to"; it specifically indicates an open-ended inclusion or attribution relationship to the described combination, group, series, etc. As used herein, "comprising" and "including" are inclusive and / or open-ended, and do not exclude additional elements or method steps not listed. The term "consistently made up of" is more restrictive than "including," but not as restrictive as "consisting of." Specifically, the term "consistently made up of" limits members to specified materials or steps, and those materials or steps that do not materially affect the essential features of the claimed invention.

[0114] As used herein, the term "alkyl" preferably describes a lower alkyl group having a main chain containing 1 to 8 carbon atoms and a total number of carbon atoms not exceeding 20. These can be straight-chain, branched, or cyclic structures, including methyl, ethyl, propyl, isopropyl, butyl, hexyl, etc.

[0115] As used herein, the term "alkenyl" preferably describes a lower alkenyl group whose main chain contains 2 to 8 carbon atoms and whose total number of carbon atoms does not exceed 20. They can be straight-chain, branched, or cyclic structures, including vinyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, etc.

[0116] As used herein, the term "alkynyl" preferably describes a lower alkynyl group whose main chain contains 2 to 8 carbon atoms and whose total number of carbon atoms does not exceed 20. They can be straight-chain or branched structures, including ethynyl, propynyl, butynyl, isobutynyl, hexynyl, etc.

[0117] As used herein, the term "aromatic group," whether used alone or as part of another group, refers to a homocyclic or heterocyclic conjugated planar ring or ring system that may be optionally substituted and contains delocalized electrons. These aromatic groups are preferably monocyclic (e.g., furan or benzene), bicyclic, or tricyclic groups with a ring moiety containing 5 to 14 atoms. The term "aromatic" encompasses the "aryl" group as defined below.

[0118] As used herein, the term "aryl" or "Ar," whether used alone or as part of another group, refers to a homocyclic aromatic group that is optionally substituted, preferably a monocyclic or bicyclic group containing 6 to 10 carbon atoms, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.

[0119] As used herein, the terms "carbocyclic" or "carbocyclic group," whether used alone or as part of another group, refer to an optionally substituted, aromatic or non-aromatic allotropic ring or ring system, wherein all atoms in the ring are carbon, and each ring preferably contains 5 or 6 carbon atoms. Exemplary substituents include one or more of the following groups: hydrocarbon group, substituted hydrocarbon group, alkyl group, alkoxy group, acyl group, acyloxy group, alkenyl group, alkenyloxy group, aryl group, aryloxy group, amino group, amide group, acetal group, carbamoyl group, carbocyclic group, cyano group, ester group, ether group, halogen group, heterocyclic group, hydroxyl group, ketol group, ketal group, phosphoryl group, nitro group, and mercapto group.

[0120] As used herein, the terms “halogen” or “halogenated”, whether used alone or as part of another group, refer to chlorine, bromine, fluorine, and iodine.

[0121] As used herein, the term "heteroatom" refers to an atom other than carbon and hydrogen. As used herein, the term "heteroaryl," whether used alone or as part of another group, refers to an optionally substituted aromatic group containing at least one heteroatom in at least one ring, preferably 5 or 6 atoms in each ring. The heteroaryl group may contain 1 to 4 oxygen, nitrogen, silicon, and / or sulfur atoms (e.g., 1 or 2 oxygen atoms and / or 1 to 4 nitrogen atoms) within the ring and be attached to the rest of the molecule via carbon atoms. Exemplary groups include furanyl, benzofuranyl, oxazolyl, isoxazolyl, oxadiazolyl, benzooxazolyl, benzooxadiazolyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indoleyl, isoindoleyl, indoleazinyl, benzimidazolyl, inzolyl, benzotriazolyl, tetrazolpyridazinyl, carbazoleyl, purineyl, quinolinyl, isoquinolinyl, imidazolepyridyl, etc. Exemplary substituents include one or more of the following groups: hydrocarbon, substituted hydrocarbon, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenyloxy, aryl, aryloxy, amino, amide, acetal, carbamoyl, carbocyclic, cyano, ester, ether, halogen, heterocyclic, hydroxyl, ketone, ketal, phosphoryl, nitro, and mercapto.

[0122] As used herein, the term "heterocyclic" or "heterocyclic group," whether used alone or as part of another group, refers to an optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic group, having at least one heteroatom in at least one ring, preferably containing 5 or 6 atoms in each ring. The heterocyclic group may contain 1 or 2 oxygen atoms and / or 1 to 4 nitrogen atoms in its ring, and be attached to the remainder of the molecule via carbon atoms or heteroatoms. Exemplary heterocyclic groups include the heteroaryl groups described above. Exemplary substituents include one or more of the following groups: hydrocarbon group, substituted hydrocarbon group, alkyl group, alkoxy group, acyl group, acyloxy group, alkenyl group, alkenyloxy group, aryl group, aryloxy group, amino group, amide group, acetal group, carbamoyl group, carbocyclic group, cyano group, ester group, ether group, halogen group, heterocyclic group, hydroxyl group, ketol group, ketal group, phosphoryl group, nitro group, and mercapto group.

[0123] As used herein, the terms "hydrocarbon" and "hydrocarbon group" refer to organic compounds or groups consisting of only carbon and hydrogen elements. These groups include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkylaryl, alkenylaryl, and alkynylaryl. Unless otherwise stated, these moieties preferably contain 1 to 20 carbon atoms.

[0124] The compounds described herein may have asymmetric centers. Compounds containing asymmetric substituted atoms in this disclosure can be isolated into optically active or racemic forms. Unless a specific stereochemical or isomer is specifically specified, this disclosure covers all chiral, isomer, racemic, and geometrical isomer forms of a given structure.

[0125] As used herein, the terms “disease,” “symptom,” or “medical condition” are used interchangeably. Each includes, but is not limited to, any condition or disease presenting with one or more physical and / or psychological symptoms that require treatment, and includes both previously known and newly discovered diseases and other conditions.

[0126] The term “treatment” is intended to include the relief or elimination of a medical condition, or one or more symptoms associated with that medical condition; or the relief or eradication of the cause of the medical condition itself.

[0127] The term "management" encompasses preventing a patient with a particular disease, condition, or medical condition from relapsing into that disease, condition, or medical condition, and / or prolonging the duration of remission in a patient with that disease, condition, or medical condition. The term also encompasses modulating the thresholds, progression, and / or duration of the disease, condition, or medical condition, or altering how a patient responds to the disease, condition, or medical condition.

[0128] The term “prevention” is intended to include methods for delaying and / or preventing the onset of a disease, illness, or medical condition and its accompanying symptoms; preventing a subject from contracting a disease, illness, or medical condition; or reducing the risk of a subject contracting a disease, illness, or medical condition.

[0129] As used herein, the term "effective dose" refers to a dose of a drug (e.g., an RNA mixture) capable of producing the expected biological, therapeutic, preventive, and / or protective outcome. This outcome may be a reduction, improvement, mitigation, alleviation, delay, prevention, and / or relief of one or more signs, symptoms, or causes of a disease (e.g., advanced solid tumor cancer). In some embodiments, an effective dose refers to an amount sufficient to stop or reduce hair loss. In some embodiments, an effective dose refers to an amount sufficient to reduce hair fading or graying. In some embodiments, an effective dose refers to an amount sufficient to delay graying. In some embodiments, an effective dose refers to an amount sufficient to prevent graying or delay the onset of graying.

[0130] As used herein, the term “co-administration” or similar expression means the administration of two or more agents as part of a single formulation, or as multiple formulations administered via the same or different routes, in parallel, simultaneously, or substantially simultaneously. As used herein, “substantially simultaneously” means within approximately 1 minute, 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, or 6 hours of interval between them.

[0131] As used herein, the term "polypeptide" refers to any polypeptide consisting of two or more amino acids linked together by peptide bonds or modified peptide bonds (i.e., peptide isosteres). Polypeptides can refer to both short chains commonly called peptides, glycopeptides, or oligomers, and long chains commonly called proteins. Polypeptides may contain amino acids other than the 20 genetically encoded amino acids. Polypeptides include amino acid sequences modified by natural processes (such as post-translational processing) or by chemical modification techniques known in the art. Such modifications are described in detail in basic textbooks, more detailed monographs, and a large body of research literature.

[0132] As used herein, the term "antibody" or "intact antibody" generally refers to a Y-shaped tetrameric protein composed of two heavy chains (H) and two light chains (L), which are linked together by covalent disulfide bonds and non-covalent interactions. Each light chain consists of a variable domain (VL) and a constant domain (CL). Each heavy chain contains a variable domain (VH) and a constant domain; for IgG, IgA, and IgD antibodies, the constant domain contains three domains called CH1, CH2, and CH3 (IgM and IgE have a fourth domain, CH4). In the IgG, IgA, and IgD classes, the CH1 and CH2 domains are separated by a flexible hinge region rich in proline and cysteine, which is of variable length (approximately 10 to 60 amino acids in different IgG subclasses). The variable domains in both the light and heavy chains are linked to the constant domains via "J" regions of approximately 12 or more amino acids, and the heavy chain also has a "D" region of approximately 10 additional amino acids. Each type of antibody also contains inter-chain and intra-chain disulfide bonds formed by paired cysteine ​​residues.

[0133] As used herein, the term "antibody" includes polyclonal antibodies, multiclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies and primate-derived antibodies, CDR transplantation antibodies, humanized antibodies, recombinant antibodies, intracellular antibodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti-idiotype antibodies, synthetic antibodies (including their mutant proteins and variants), immune-specific antibody fragments (such as Fd, Fab, F(ab′)2, F(ab′) fragments), single-chain fragments (such as ScFv and ScFvFc); and their derivatives (including Fc fusions and other modifications), as well as any other immunoreactive molecule that exhibits preferential binding or interaction with the determinant. Furthermore, unless the context otherwise requires, the term also includes all classes of antibodies (i.e., IgA, IgD, IgE, IgG, and IgM) and all subclasses (i.e., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). The constant domains of heavy chains corresponding to different antibody classes are usually represented by the corresponding lowercase Greek letters α, δ, ε, γ, and μ. The antibody light chains of any vertebrate species can be classified into one of two distinct types based on the amino acid sequence of their constant domains: κ (kappa) and λ (lambda).

[0134] As used in this article, the term "subject" preferably refers to a mammal, such as a human, but can also be an animal, such as a domesticated animal (e.g., a dog, cat), a farm animal (e.g., a cow, sheep, pig, horse), or a laboratory animal (e.g., a cynomolgus monkey, rat, mouse, guinea pig). For human subjects, those 65 years of age and older are referred to as "elderly."

[0135] As used herein, administration of a drug or agent to a subject or patient includes self-administration and administration by another person. It should also be understood that the various modes of treatment or prevention for the medical condition are intended to mean “substantial,” which includes both complete and incomplete treatment or prevention, in which certain biological or medically relevant outcomes are achieved.

[0136] Example The aforementioned documents are used only to illustrate their disclosure prior to the filing date of this application. Nothing herein should be construed as an admission that the present invention is not entitled to claim prior invention rights over such disclosures.

[0137] The following embodiments are intended to illustrate the content of this disclosure. Those skilled in the art should understand that the techniques disclosed in the following embodiments are techniques discovered by the inventors and capable of functioning well when implementing this disclosure. However, those skilled in the art should understand that many modifications can be made to this disclosure without departing from its spirit and scope, and the same or similar results can still be obtained. Therefore, all content described should be interpreted as illustrative rather than restrictive.

[0138] Example 1: Study Design This study aims to screen small molecule compounds that can activate the stem cell factor (SCF) promoter using green fluorescent protein (GFP) as the readout. Figure 1 The experimental procedure is illustrated. Candidate compounds include those that yielded positive results in both primary screening (such as high-throughput screening) and secondary screening in mouse and human cells. Figure 2 and Figure 3 Flowcharts for the high-throughput screening (HTS) steps, as well as the fine screening HTS and TaqMan PCR steps, are presented. Furthermore, the candidate compounds also showed positive results in in vitro validation assays, including a GFP signal in the SCF-GFP keratinocyte assay, while no signal (i.e., no autofluorescence) was observed in wild-type control keratinocytes. To avoid excessive SCF upregulation, the candidate compounds only showed appropriate GFP / SCF expression in the validation assays. These candidate compounds showed positive results in PCR experiments with upregulated SCF, and this assay was significantly more sensitive than the GFP assay. In addition, these candidate compounds were positive in in vivo validation assays and also positive in preclinical in vivo assays for reversing hair graying.

[0139] Example 2: Screening Results This study constructed a small molecule compound library containing approximately 300,000 compounds distributed across 987 plates (384-well plates). All compounds were screened, totaling approximately 562.8 million cells. Initial screening yielded 35,186 positive compounds (approximately 11.7% of the compound library). The two-point correction ratio (GFP signal) for these compounds ranged from 6.0% to 152.1%, and the single-point correction ratio (CNSPC) for cell number ranged from approximately -99.3% to 52.1%. A maximum of approximately 1,920 compounds were allowed for retesting, and retesting of all compounds was completed. Through testing, a series of compounds (cpds) were identified, including cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, and cpd Compounds 715, cpd717, cpd733, cpd755, cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152, with structures shown above, were compared with those screened by HTS image analysis and by RT-PCT (refined screening from rounds 1 to 52). The comparison and screening results are as follows. Figure 4 As shown. Figure 5-7 The heatmaps of 109 compounds at a concentration of 0.21 µM, 126 compounds at a concentration of 0.83 µM, and 195 compounds at a concentration of 2.5 µM are shown respectively. Figure 8-11 Heatmaps of 51 compounds at all three concentrations (0.21 µM, 0.83 µM, and 2.5 µM) are shown. The RT-PCT-based compound screening criteria included upregulating SCF or GFP mRNA expression by more than 1.5-fold in mouse or human keratinocyte cell lines. A total of 298 compounds were screened from 1,920 compounds. Figure 12 The study showed overlap between 109 compounds (0.27 µM) selected by HTS and 298 compounds selected by TaqMan RT-PCR, resulting in the selection of 22 compounds. Similarly, Figure 13 The results showed overlap between 126 compounds (0.83 µM) selected by HTS and 298 compounds selected by TaqMan RT-PCR, resulting in the selection of 26 compounds. Figure 14The study showed overlap between 161 compounds (2.5 µM) selected by HTS and 298 compounds selected by TaqMan RT-PCR, resulting in the identification of 34 compounds. Figure 15 The results showed overlap between 51 compounds selected by HTS (at three concentrations of 2.5 µM, 0.83 µM, and 0.27 µM) and 298 compounds selected by TaqMan RT-PCR, resulting in the selection of 14 compounds. Figure 16A , 16B The 16C sequence was used to characterize the cluster analysis of the compounds.

[0140] Example 3: Biological Test Results The screened compounds were tested using an in vitro assay involving adhesion plaque proteins and in the human cell line K562. The results are as follows: Figure 17 As shown. The screened compounds were also tested in another in vivo test by topical application of the compounds to the skin of mouse tails, as shown. Figure 18 As shown. The test procedure included: preparing the compound at a concentration of 1 µM in DMSO, and applying 15 µl topically to the tail once daily for one week. At the end of the week, skin samples were collected and lysates were prepared for Western blotting and immunohistochemical analysis. Figure 19 The results showed that, in the in vivo assays described above, some of the compounds increased the expression of SCF protein. Figure 20A , 20B The results of immunohistochemical staining of SCF by DMSO, CPD755 and CPD256 are shown in Figures 20 and 20C, respectively.

[0141] Example 4. Summary In summary, as shown in Table 1 below, a variety of compounds were tested. These compounds were tested through target identification, including Western blotting and RT-PCR analysis on various human and mouse cell lines, such as keratinocyte, fibroblast, and leukemia cell lines. Some compounds were also tested in vivo (animal) using SCF-BFP / WT mice.

[0142] Table 1: Summary of tested compounds

[0143] Ultimately, this study aims to identify the proteins targeted by small molecule drugs (which may or may not directly target SCF). For this purpose, a combination of quantitative proteomics and affinity chromatography can be employed. This method includes SILA (stable isotope labeling of amino acids in cell culture, such as...) Figure 21As shown in the figure, affinity chromatography is used to bind the target small molecule to the affinity matrix. The small molecule is then allowed to bind to the affinity matrix and separated from unbound molecules. Subsequently, the protein bound to the small molecule is identified by mass spectrometry. Alternatively or otherwise, as... Figure 22 As shown, target identification can be performed using photoaffinity chromatography. In this method, small molecules are modified with benzophenone and a terminal alkynyl group. The benzophenone group is photoreactive; under ultraviolet light irradiation, it generates a diradical, which covalently modifies nearby amino acids. Proteins binding to the SM-probe are labeled via a "click" reaction (a chemical process that couples the alkynyl group to an azide group), and the bound proteins are observed by SDS-PAGE and in-gel fluorescence scanning.

Claims

1. Compounds selected from Formula I, Formula II, Formula II', Formula III, and Formula IV. 、 、 、 , or Its pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, or prodrugs, wherein: R1 is a substituted or unsubstituted cycloalkyl group; R2 is an alkyl group; R3 is a substituted or unsubstituted aryl group. R4 is a substituted or unsubstituted heterocyclic alkyl group. R4 ’ For substituted or unsubstituted heterocyclic alkyl groups, R5 is a substituted or unsubstituted aryl group. R5 ’ For substituted or unsubstituted aryl groups, R6 is a substituted or unsubstituted nitrogen-containing heterocyclic alkyl group. R7 is -NH(C=O)-R 17 or -O(C=O)-R 17 , where R 17 For substituted or unsubstituted alkyl, alkenyl or aryl groups; and R8 is hydrogen, hydroxyl, or alkyl.

2. The compound according to claim 1, wherein the compound is a compound of formula I.

3. The compound according to claim 2, wherein R1 is cyclohexane.

4. The compound according to claim 2 or 3, wherein R2 is methyl.

5. The compound according to any one of claims 2 to 4, wherein R3 is a phenyl substituted with at least one alkoxy group and / or at least one halogen.

6. The compound according to claim 1, wherein the compound is a compound of formula II.

7. The compound according to claim 6, wherein R4 or R4 ’ Each is an independently substituted pyrrolidine.

8. The compound according to claim 7, wherein R4 or R4 ’ Each is an alkyl or carbonyl-substituted pyrrolidine.

9. The compound according to any one of claims 6 to 8, wherein R5 or R5 ’ Each is a phenyl group that has been substituted with a carboxylic acid or an ester.

10. The compound according to claim 1, wherein the compound is a compound of formula III.

11. The compound according to claim 10, wherein R6 is a substituted or unsubstituted azacycloheptatriene, or a substituted or unsubstituted piperidine.

12. The compound according to claim 11, wherein R6 is an unsubstituted azaheptatriene.

13. The compound according to claim 11, wherein R6 is an alkyl-substituted piperidine.

14. The compound according to claim 1, wherein the compound is a compound of formula IV.

15. The compound according to claim 14, wherein R7 is -NH(C=O)-R 17 R8 is hydrogen, and R 17 It is an aryl-substituted alkenyl group.

16. The compound according to claim 14, wherein R7 is -O(C=O)-Ar and R8 is a hydroxyl group.

17. The compound according to claims 1 to 16, wherein the compound is selected from: (IA), (IB), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC) (IVA) and (IVB), Or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, or prodrug.

18. A compound, or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate, or prodrug thereof, said compound having the cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, cpd733, cpd755, cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107 disclosed herein. The structure of any one of the compounds cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125 and cpd2152.

19. The compound of claim 18 or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate or prodrug thereof, wherein the compound has the structure of cpd34, cpd37, cpd65, cpd257, cpd557, cpd1107, or cpd1840.

20. The compound of claim 18 or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate or prodrug thereof, wherein the compound has the structures cpd571, cpd621, cpd644, cpd715, cpd758, cpd2152.

21. The compound of claim 18 or a pharmaceutically acceptable salt, polymorph, stereoisomer, solvate or prodrug thereof, wherein the compound has the structures cpd256, cpd755, cpd795, or cpd2062.

22. A pharmaceutical composition comprising any combination of the compounds of any one of claims 1 to 21, and one or more pharmaceutically suitable carriers or excipients.

23. The pharmaceutical composition of claim 22, wherein the composition is for systemic or local delivery.

24. A pharmaceutical dosage form comprising any compound or any combination thereof as claimed in any one of claims 1 to 21, and one or more pharmaceutically suitable carriers or excipients.

25. The drug dosage form according to claim 24, wherein the dosage form includes an oral dosage form, a topical dosage form, or a follicular dosage form.

26. A method for treating a subject with hair loss and / or hair discoloration, the method comprising administering to the subject the pharmaceutical composition of claim 22 or 23, or the dosage form of claim 24 or 25.

27. The method of claim 26, wherein the hair loss and / or hair discoloration is related to aging.

28. The method of claim 26 or 27, wherein the subject is a human being.

29. The method according to any one of claims 23 to 25, wherein the subject is an elderly person.

30. A method for activating a stem cell factor (SCF) promoter in a cell, the method comprising contacting the cell with a compound or any combination thereof as described in any one of claims 1 to 21.

31. The method of claim 27, further comprising increasing the expression of SCF in the cells.

32. The method of claim 28, wherein the cell is a keratinocyte.

33. Use of the compound of any one of claims 1 to 21, the pharmaceutical composition of claim 22 or 23, or the dosage form of claim 24 or 25, in a method of treating a subject for hair loss and / or hair discoloration, said method comprising administering said compound to a subject in need of treatment.

34. Use of one or more compounds, their pharmaceutically acceptable salts, polymorphs, stereoisomers, solvates, prodrugs, or any combination thereof, in a method for treating a subject for hair loss and / or hair discoloration; said method comprising administering said compound to a subject in need of treatment, wherein said one or more compounds have the cpd34, cpd37, cpd65, cpd256, cpd257, cpd279, cpd280, cpd300, cpd373, cpd396, cpd492, cpd511, cpd530, cpd533, cpd557, cpd571, cpd621, cpd644, cpd680, cpd715, cpd717, etc. disclosed herein. The structure of any one of the compounds selected from cpd733, cpd755, cpd758, cpd795, cpd900, cpd935, cpd983, cpd1107, cpd1255, cpd1744, cpd1840, cpd1886, cpd2052, cpd2056, cpd2062, cpd2078, cpd2125, and cpd2152.

Images